Any extracts used in the following article are for non-commercial research and educational purposes only and may be subject to copyright from their respective owners.
Glucocorticoids have been used in an attempt to treat practically every malady that afflicts man or animal, but there are three broad uses and dosage ranges for use of these agents.
1) Replacement of glucocorticoid activity in patients with adrenal insufficiency, 2) as an antiinflammatory agent, and
3) as an immunosuppressive.
Plumb’s Veterinary Drug Handbook, 7th ed.
One of the reasons for writing this Substack is to raise awareness of the potential drawbacks of being administered these for anything other than for short durations. I will also reference the mechanisms and risk of p53 related pro-cancer sequalae, which is very rarely discussed in the literature.
Inflammatory and autoimmune disorders are an escalating class of side effects due to the mass exposure of the population to spike protein from both viral and synthetic sources. Cases of new onset rheumatoid arthritis, back pain, lupus and exacerbation of previously managed conditions are all examples of known adverse events.
I reviewed the literature extensively last July and “steroids” are an easy quick fix for a medical profession under profound pressure without perhaps having time or resources to conclude a proper diagnosis, address the underlying cause or user safer alternatives:
If this Substack leaves you as a patient better informed or adds something to your knowledge as a practicing physician or researcher then it is meeting its objectives.
Background
Corticosteroids are a class of steroid hormone. In vertebrates they are produced in the adrenal cortex. Examples include cortisol, corticosterone, cortisone and aldosterone.
First developed in 1935 by German chemist Adolf Butenandt to treat hypogonadism, synthetic analogues include the almost pure glucocorticoid Dexamethasone, Prednisone, Hydrocortisone (cortisol) and Fludrocortisone.
Its big business - global sales have surpassed $5 billion1:
Acting as hormones, the two main classes of corticosteroid, glucocorticoids and mineralocorticoids are involved in a wide range of physiological processes. They can affect the stress response, immune response, regulate inflammation, carbohydrate metabolism, protein catabolism, blood electrolyte levels and behaviour2. As a consequence many medical conditions are treated with synthetic analogues.
Allergies and autoimmune disorders form many of the conditions being treated3:
asthma
allergic rhinitis and hay fever
urticaria (hives)
atopic eczema
chronic obstructive pulmonary disease (COPD)
painful and inflamed joints, muscles and tendons
lupus
inflammatory bowel disease (IBD) – including Crohn's disease and ulcerative colitis
giant cell arteritis and polymyalgia rheumatica
multiple sclerosis (MS)
Corticosteroids can also be used to replace certain hormones that aren't naturally produced by the body. This is the case in people with Addison's disease.
They may be administered as tablets (oral steroids), injections (into blood vessels, joints or muscles), via inhalers and topically using lotions, gels or creams.
As part of the FLCCC COVID-19 treatment protocols corticosteroid therapy have saved thousands of lives.
They would have saved many more too if they had been adopted more widely and earlier:
Corticosteroid therapy is one of the most effective interventions in COVID-19 and MATH+. From early March 2020, when the FLCCC team of physicians first came together to study and create treatment protocols for fighting the novel disease, the team, guided by Dr. G. Umberto Meduri’s expertise in corticosteroid use, placed methylprednisolone at the head — as the “M” — in its MATH+ hospital treatment formula. As a result, the two hospitals using the MATH+ formula had mortality rates of no higher than 6%, when most hospitals lost as many as 80% of their seriously ill COVID patients. This was months before the landmark RECOVERY trial convinced world authorities to allow and advocate for the use of steroids in treating the inflammatory stage of the disease. https://covid19criticalcare.com/studies/
Corticosteroid adverse effects and mechanisms of action
This would deserve a Substack of its own to get into all the pathways and DNA interactions, but Kragballe’s abstract from 1989 provides a great summary4:
After passage through the cell membrane corticosteroids react with receptor proteins in the cytoplasm to form a steroid-receptor complex. This complex moves into the nucleus, where it binds to DNA. The binding process then changes the transcription of messenger RNA (mRNA). Because mRNA acts as template for protein synthesis, corticosteroids can either stimulate or inhibit the synthesis of specific proteins. Thus corticosteroids are known to stimulate the production of a glycoprotein called lipocortin. The formed lipocortin inhibits the activity of phospholipase A2, which releases arachidonic acid, the precursor of prostanoids and leukotrienes, from phospholipids. In contrast, corticosteroids inhibit mRNA responsible for interleukin-1 formation. These actions of corticosteroids on arachidonic acid metabolism and interleukin-1 formation produce anti-inflammatory, immunosuppressive and anti-mitogenic effects.
Ramamoorthy and Cidlowski (2017) go into even greater detail. Abridged version5:
Glucocorticoids have become a clinical mainstay for the treatment of numerous inflammatory and autoimmune diseases, such as asthma, allergy, septic shock rheumatoid arthritis, inflammatory bowel disease, and multiple sclerosis. Unfortunately, the therapeutic benefits of glucocorticoids are limited by the adverse side effects that are associated with high dose (used in the treatment of systemic vasculitis and SLE) and long-term use. These side effects include osteoporosis, skin atrophy, diabetes, abdominal obesity, glaucoma, cataracts, avascular necrosis and infection, growth retardation, and hypertension3.
Furthermore, patients on long-term glucocorticoid therapy also develop tissue-specific glucocorticoid resistance4. Understanding the molecular mechanisms underlying the physiological and pharmacological actions of glucocorticoids is of great importance as it may aid in developing synthetic glucocorticoids with increased tissue selectivity, which can thereby minimize the side effects by dissociating the desired anti-inflammatory functions from undesirable adverse outcomes. Here, we summarize the recent advances and molecular processes involved in glucocorticoid action and function and discuss in detail the potential role of the glucocorticoid receptor (GR) in determining cellular responsiveness to glucocorticoids.
The importance of the HPA axis:
The circadian profile of glucocorticoid release from the adrenal glands is regulated by the hypothalamic-pituitary-adrenal (HPA) axis. Inputs from the suprachiasmatic nucleus (SCN) stimulate the para-ventricular nucleus (PVN) of the hypothalamus to release corticotrophin-releasing hormone (CRH) and arginine vasopressin (AVP). These hormones act on the anterior pituitary where they activate corticotroph cells to secrete adrenocorticotrophin hormone (ACTH) into the general circulation. Subsequently, ACTH acts on the adrenal cortex to stimulate the synthesis and release of glucocorticoids (Fig 1A)6.
FIG 1. A. Regulation of glucocorticoid secretion by the hypothalamic-pituitary-adrenal (HPA) axis. Stress induces the release of CRF from the hypothalamus, which is transported to the anterior pituitary, where it triggers the release of ACTH into the blood stream. ACTH stimulates the adrenal cortex to synthesize and release the glucocorticoids (cortisol in humans or corticosterone in rodents). Subsequently, the glucocorticoids act on the hypothalamus and pituitary to dampen excess activation of the HPA axis (“negative feedback system”). CRH, Corticotrophin-releasing hormone, ACTH, Adrenocorticotropic hormone. B. Domain structure of hGR-α. GR contains three major functional regions, the N-terminal transactivation domain (NTD), the central DBD and the C-terminal LBD. The region located between the DBD and LBD is known as the hinge region (H). Regions involved in transcriptional activation (AF1 and AF2), dimerization, nuclear localization and chaperone hsp90 binding are indicated.
Genomic action via glucocorticoid receptor (GR) interactions. Target genes can also be repressed instead of expressed:
Once inside the nucleus, GR binds directly to GREs and stimulates target gene expression. The consensus GRE is a palindromic sequence comprised of 2 half sites (GGAACAnnnTGTTCT) separated by a 3-nucleotide spacer16. GR binds GRE as a dimer and each half site is occupied by one receptor and thus the 3-nucleotide spacer between the 2 half sites is strictly required for GR:DNA interaction (Fig.2)17. Binding of GR to GRE induces conformational changes in GR leading to coordinated recruitment of coregulator and chromatin-remodeling complexes that influence the activity of RNA polymerase II and activates gene transcription and repression. A recent study has identified a negative glucocorticoid-responsive element (nGRE) that mediates glucocorticoid-dependent repression of target genes by recruiting corepressors (NCoR1 and SMRT) and histone deacetlyases (HDACs) (Fig.2)18.
FIG 2. Genomic action of GR. Upon binding glucocorticoids, cytoplasmic GR undergoes a conformation change (activation), becomes hyper-phosphorylated (P), dissociates from multi-protein complex, and translocates into the nucleus, where it regulates gene expression. GR activates or represses transcription of target genes by direct GRE binding, by tethering itself to other transcription factors apart from DNA binding, or in a composite manner by both direct GRE binding and interactions with transcription factors bound to neighboring sites. NPC = Nuclear pore complex; BTM = basal transcription machinery; TBP = TATA-binding protein; nGRE = negative GRE; RE = response element.
Only certain tissues and cells have accessible GR’s:
Glucocorticoid-induced gene expression is frequently cell type-specific and only a small proportion of genes are commonly activated between different tissues29. Tissue-specific target gene activation by glucocorticoids has been shown to be dependent on accessibility of the GR-binding site which in turn is determined by DNA methylation and higher order chromatin structures like long-range chromatin loops. Thus, tissue-specific target gene activation may be determined by the tissue-specific chromatin landscape, which influences binding of GR to the cognate DNA elements20, 30.
Non-genomic actions can also occur via physiochemical interactions with GR’s in the cytoplasm or bound to membranes. Activation can be much faster as protein synthesis is not involved.
MAPK’s regulate cellular proliferation, gene expression, differentiation, mitosis, survival and apoptosis via signalling cascades. Dysregulation can lead to insulin resistance, autoimmune disorders and cancer6:
Rapid, non-genomic glucocorticoid actions are mediated through physiochemical interactions with cytosolic GR or membrane-bound GR. Unlike genomic effects, non-genomic effects of glucocorticoids do not require protein synthesis, and occur within seconds to minutes of GR activation36. A growing body of evidence suggests that the rapid non-genomic functions of GR utilize the activity of various kinases, like phosphoinositide 3-kinase, AKT, and mitogen-activated protein kinases (MAPKs)37. Binding of glucocorticoids to GR not only activates the receptor, but also liberates accessory proteins that participate in secondary signaling cascades. For example, when released from the inactive GR protein complex, c-Src activates signaling cascades that inhibit phospholipase A2 activity, phosphorylate annexin 1, and impair the release of arachidonic acid38, 39. In thymocytes, activated GR translocates to mitochondria and regulates apoptosis40. GR has also been reported to localize in caveolae and glucocorticoid mediated activation of this membrane-associated GR regulates gap junction intercellular communication and neural progenitor cell proliferation41, 42. Thus, rapid non-genomic GR signaling adds greater complexity and diversity to glucocorticoid dependent biological actions.
GR sensitivity varies much more from tissue to tissue and person to person due to the existence of translational isoforms and polymorphisms. Understanding this could help to minimise harmful side effects that currently limit their use:
Considerable effort has been dedicated over the last several decades to enhance glucocorticoid potency while minimizing adverse side effects by modifying the chemical structure of the natural glucocorticoids87. The discovery that multiple GR isoforms with unique expression, gene-regulatory, and functional profiles are generated by alternative splicing, alternative translation initiation of the mature mRNA, and posttranslational modifications have advanced our understanding of molecular basis for the diversity in glucocorticoid sensitivity (hyposensitivity or hypersensitivity). Genome wide GR recruitment studies have shown that tissue specific chromatin landscape also exhibits profound differences in glucocorticoid sensitivity.
An important challenge in the clinical application of glucocorticoids is the heterogeneity in glucocorticoid responsiveness among individuals, with a significant portion of the population (up to 30%) exhibiting some degree of glucocorticoid resistance.
…Dissecting the molecular mechanisms of resistance permits not only the prediction of patient responsiveness to glucocorticoids but also the design of novel therapeutic strategies for combating glucocorticoid insensitivity.
In summary:
1. An important challenge in the clinical application of glucocorticoids is the heterogeneity in glucocorticoid responsiveness among individuals with a significant portion of the population exhibiting some degree of glucocorticoid resistance.
2. Glucocorticoid sensitivity and specificity is influenced by GR isoform expression profile. Inflammatory and pathological processes modulate cellular GR isoform profiles.
3. Assessing glucocorticoid sensitivity in individual patients is important for an optimal glucocorticoid treatment plan in the clinic.
4. Understanding the heterogeneity of GR signaling in both health and disease will aid in the development of safer and more effective glucocorticoid therapies with improved benefit/risk ratios for patients.
From the StatPearls site, Yasir et al provide an excellent resource for practitioners that is updated regularly. From 20227:
Endogenous cortisone was first isolated in 1935 and synthesized in 1944. In 1948, Dr. Philip S Hench published administered cortisone (called Compound E at that time) to a 29-year-old woman who was bed-ridden secondary to active rheumatoid arthritis. The patient was able to walk after three days of treatment. This case was published in 1949, and in 1950, Philip S. Hench, Edward C. Kendall, and Tadeusz Reichstein were awarded the Nobel Prize in Physiology or Medicine "for their discoveries relating to the hormones of the adrenal cortex, their structure, and biological effects."[1]
Mechanism of Action
Anti-Inflammatory and Immunosuppressive Effects
The anti-inflammatory and immunosuppressive effects of glucocorticoids are dose-dependent, with immunosuppressive effects seen mostly at higher doses. The pharmacological anti-inflammatory and immunosuppressive effects of glucocorticoids are extensive and can occur via genomic or non-genomic mechanisms. Most effects of glucocorticoids are via the genomic mechanisms, which takes time, while immediate effects via the non-genomic mechanisms can occur with high doses of glucocorticoids (such as pulse therapy). Clinically, it is not possible to separate these effects.
Genomic Mechanisms
Being small, lipophilic substances, glucocorticoids readily pass the cell membrane by diffusion and enter the cytoplasm of the target cells, where most of their action is mediated by binding to the intra-cytoplasmic glucocorticoid receptors. Glucocorticoid receptors have two isoforms, α, and β. Glucocorticoids bind to the α-isoform only. Glucocorticoid resistance in some patients has been partly attributed to higher levels of the β-isoform in these patients.[2] The binding of the glucocorticoid to the glucocorticoid receptor results in the shedding of heat-shock proteins, which are otherwise bound to the glucocorticoid receptor, which results in the formation of the activated glucocorticoid receptor-glucocorticoid complex, which easily translocates to the nucleus. In the nucleus of the target cells, this complex reversibly binds to several specific DNA sites resulting in stimulation (transactivation) and suppression (transrepression) of a large variety of gene transcription. Tranpression of transcription factors such as nuclear factor-κB [NF-κB], activator protein-1, and interferon regulatory factor-3 results in suppression of synthesis of pro-inflammatory cytokines such as IL-1, IL-2, IL-6, IL-8, TNF, IFN-gamma, Cox-2, VEGF, and prostaglandins.Transactivation of transcription factors, including glucocorticoid response elements (GREs), leads to activation of the synthesis of anti-inflammatory cytokines such as IL-10, NF-κB inhibitor, and lipocortin-1.
Non-Genomic Mechanisms
The immediate effects of high dose-glucocorticoids are mediated via non-genomic mechanisms. At high doses, glucocorticoids bind the membrane-associated glucocorticoid receptors on target cells such as T-lymphocytes, resulting in impairment of receptor signaling and immune response of the T lymphocytes. High-dose glucocorticoids also interact with the cycling of calcium and sodium across the cell membrane resulting in a rapid decrease in inflammation.
By altering the cytokine production via the genomic and non-genomic mechanisms, glucocorticoids lead to suppression of the immune system and decreased inflammation. They target a wide variety of cells, including T-lymphocytes, macrophages, fibroblasts, neutrophils, eosinophils, and basophils. Notably, glucocorticoids have almost no effect on B-cell function and immunoglobulin production. The downstream effects of glucocorticoids are summarized below:
Inhibition of neutrophil adhesion to endothelial cells and demargination of neutrophils from the marginal pool of blood vessels causing neutrophilic leukocytosis
A decrease in the number of lymphocytes, macrophages, monocytes, eosinophils, and basophils (decreased myelopoiesis and release from bone marrow, and increased apoptosis)
Decreased proliferation of fibroblasts
Decreased MHC-Class II and Fc receptor expression on macrophages and monocytes
Decreased phagocytosis and antigen presentation by macrophages
Decreased cytokine production by macrophages and lymphocytes
Decreased proliferation of fibroblasts.
Reduction in the formation of arachidonic acid derivatives by the promotion of synthesis of lipocortin-A that inhibits phospholipase A2
Inhibition of metalloproteinases collagenase and stromelysin, which are otherwise responsible for cartilage degradation
Effects on the Hypothalamic-Pituitary-Adrenal (HPA) Axis
Glucocorticoids exert negative feedback effects on the HPA axis. They directly suppress adrenocorticotropic hormone (ACTH) and corticotropin-releasing hormone (CRH) secretion. Additionally, by suppressing the release of pro-inflammatory cytokines that stimulate ACTH and CRP secretion, glucocorticoids further suppress ACTH and CRH secretion indirectly in inflammatory diseases. Chronic HPA axis suppression by glucocorticoids leads to functional adrenal atrophy (sparing the mineralocorticoid producing outer adrenal cortex that is functionally independent of ACTH). The risk of this functional adrenal atrophy and insufficiency is challenging to predict and varies from patient to patient but is largely dependant on the dose and duration of glucocorticoid therapy. The adrenal function generally recovers by slow tapering of glucocorticoids.
Mineralcorticoid Effects
Glucocorticoids bind to mineralocorticoid receptors (MRs) and produce their mineralocorticoid effect (i.e., increasing sodium and decreasing potassium), but only when used at the high dose and for an extended period.
Administration
Several preparations of glucocorticoids are available, each with varying efficacy. Dexamethasone and betamethasone are long-acting with the highest glucocorticoid efficacy with a biological half-life of 36 to 54 hours. Cortisone and cortisol are short-acting with a biological half-life of under 12 hours and are not frequently used. Prednisone, prednisolone, methylprednisolone, and triamcinolone are intermediate-acting with a biological half-life of 18 to 36 hours. The glucocorticoid and mineralocorticoid effects of each available preparation vary, with cortisol and cortisone having almost 1 to 1 glucocorticoid and mineralocorticoid effects while all others with almost no mineralocorticoid effects. Equivalent glucocorticoid doses can be calculated for these various preparations. 5 mg of prednisone is equivalent in its glucocorticoid effects to 5 mg of prednisolone, 4 mg of methylprednisolone, 4 mg of triamcinolone, 0.75 mg of dexamethasone, 0.60 mg of betamethasone, 20 mg of cortisol, and 25 mg of cortisone.
Intravenous Administration
Parenteral intravenous administration of high doses of glucocorticoids may be warranted in emergencies, such as septic shock, COPD exacerbation, and severe acute asthma. Pulse therapy of glucocorticoids (1000 mg intravenous methylprednisolone divided over 3 to 4 daily doses) for several days has been studied in several rheumatological conditions. This approach is recommended only for organ-threatening or life-threatening situations, including lupus nephritis (Class III or IV), giant cell arteritis with vision loss, ANCA-associated vasculitis, etc. Americal College of Rheumatology also recommends using intravenous glucocorticoids in patients with acute gout who are unable to take medications orally.
Oral Administration
Oral preparations are usually useful in both acute and chronic indications. For acute exacerbations of underlying chronic illness (such as asthma, COPD, gout, pseudogout, rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), etc.), short duration of moderate to high doses of oral corticosteroids is usually efficacious in treating the flare. Tapering dose packs starting at high doses and tapering daily over 7 to 9 days are commercially available and can be used in these situations as well. Long-term oral corticosteroid therapy may be necessary for chronic illnesses such as polymyalgia rheumatica, SLE, RA, vasculitis, myositis, IgG4-related disease, chronic myelogenous leukemia (CML), lymphoma, leukemia, multiple sclerosis, organ transplantation, etc. Clinicians must make every effort to use the glucocorticoids at the lowest possible dose and for the shortest possible duration in these cases. A slow taper shall be attempted in patients with prolonged exposure to glucocorticoids to prevent adrenal crisis.
Local Administration
Glucocorticoid administration can be via several non-systemic routes, including intra-articular joint injections for joint inflammation, inhalational for asthma, topical for dermatological problems, ocular drops for eye conditions, and intra-nasal for seasonal rhinitis. Clinicians generally avoid intramuscular (IM) glucocorticoids due to the risk of local muscle atrophy due to depot effect, and the only indications for intramuscular glucocorticoids are for IM triamcinolone acetonide for specific inflammatory disorders and IM injection of betamethasone to a pregnant mother less than 37 weeks of gestation to stimulate fetal lung maturity.When appropriate, a non-systemic route is preferable to the systemic route of administration to minimize systemic adverse effects.
Adverse Effects
Factors Influencing the Adverse Effects of Glucocorticoids
Given the diversity in the mechanism of action of glucocorticoids, they can cause a wide array of adverse effects ranging from mild to severe, some of which are unavoidable. Of all the factors influencing the adverse effects of glucocorticoids, dose and duration of therapy are the most important independent and well-documented risk factors. It is usually at “supra-physiologic” doses of corticosteroid administration where multiple and especially severe adverse effects of glucocorticoids occur, ranging from mild suppression of hypothalamic-pituitary axis to severe, life-threatening infections.[3]However, long-term use of low to moderate doses of glucocorticoids can also lead to several serious adverse effects.[4][5] Adverse effects of corticosteroids are both dose and time-dependent.[6] Some adverse effects follow a linear dose-response pattern where the incidence increases with an increase in the dose (ecchymosis, cushingoid features, parchment-like skin, leg edema, and sleep disturbance). Other adverse effects may follow a threshold dose-response pattern with an elevated frequency of events beyond a specific threshold value (weight gain and epistaxis at prednisone dose greater than 5 mg daily, glaucoma, depression, hypertension at prednisone dose greater than 7.5 mg daily, etc.).
Several other factors may influence the adverse effects of glucocorticoids. Older age, comorbid conditions (such as diabetes mellitus), concomitant use of other immunosuppressive agents, severity and nature of the underlying disease, and poor nutritional status can all influence the occurrence and magnitude of side effects.
Under corticosteroid treatment, RANKL, which is released by osteoblasts, links with the RANK specific osteoclast receptor and stimulates osteoclastogenesis. This reaction can be blocked by osteoprotegerin, which is a competitive inhibitor to the same receptor site. A decreased osteoblast activity stimulates bone loss. The reduced level of osteocalcin, which is regarded as a marker for bone formation, and a simultaneously elevated RANK level reveal the promotion of osteoclast proliferation in patients treated with corticosteroids.
…Glucocorticoids, widely used to treat many skin conditions, including pemphigus, are also one of the most common causes of secondary osteoporosis, or chronic, progressive disorders of outstanding low bone mass and microarchitectural degradation of bone tissue. This leads to weakening of bone strength and consequently to an increased risk of fractures [14, 15]. According to the American Society of Rheumatology, chronic corticosteroid treatment is defined as taking a prednisone dose equal to or greater than 5 mg/day for a period longer than 3 months [16]. Data from the literature indicate that the limit below which no clinically significant risk of bone loss occurs corresponds to 7.5 mg of prednisolone a day for a period of not more than 6 months [17, 18]. Some authors, however, underline that lower doses of corticosteroids may significantly reduce bone density [8]8.
Trabecular bone, also called cancellous bone, is porous bone composed of trabeculated bone tissue. It can be found at the ends of long bones like the femur, where the bone is actually not solid but is full of holes connected by thin rods and plates of bone tissue. The holes (the volume not directly occupied by bone trabecula) is the intertrabecular space, and is occupied by red bone marrow, where all the blood cells are made, as well as fibrous tissue. Even though trabecular bone contains a lot of intertrabecular space, its spatial complexity contributes the maximal strength with minimum mass. It is noted that the form and structure of trabecular bone are organized to optimally resist loads imposed by functional activities, like jumping, running and squatting. And according to Wolff's law, proposed in 1892, the external shape and internal architecture of bone are determined by external stresses acting on it. The internal structure of the trabecular bone firstly undergoes adaptive changes along stress direction and then the external shape of cortical bone undergoes secondary changes. Finally bone structure becomes thicker and denser to resist external loading.
…Studies have shown that once a human reaches adulthood, bone density steadily decreases with age, to which loss of trabecular bone mass is a partial contributor. Loss of bone mass is defined by the World Health Organization as osteopenia if bone mineral density (BMD) is one standard deviation below mean BMD in young adults, and is defined as osteoporosis if it is more than 2.5 standard deviations below the mean. A low bone density greatly increases risk for stress fracture, which can occur without warning. The resulting low-impact fractures from osteoporosis most commonly occur in the upper femur, which consists of 25-50% trabecular bone depending on the region, in the vertebrae, which are about 90% trabecular, or in the wrist9.
Musculoskeletal Adverse Effects
Glucocorticoids induced Osteoporosis is one of the well-known and devastating adverse effects of long-term use of glucocorticoids. Up to 40% of patients on long-term glucocorticoids develop bone loss leading to fractures.[7] Several mechanisms play a role, including osteoclast activation by promoting RANK-ligand as well as a decrease in function and number of osteoblasts and osteocytes. The trabecular bone is initially affected, with cortical bone loss seen with longer-term use. The loss of trabecular bone can occur within the first 6 to 12 months of therapy.
Steroid-induced myopathy, which is a reversible painless myopathy and is a direct result of muscle breakdown, can occur in both the upper and lower extremities, usually with high-dose long-term use of glucocorticoids. Muscle enzymes (CK and Aldolase) are typically normal, and findings on electromyography are non-specific. Muscle biopsy reveals Type-II fiber atrophy without inflammation. Withdrawal of glucocorticoids and exercises usually results in the resolution of myopathy. “Critical illness myopathy” may also develop in patients admitted in the intensive care unit (ICU) requiring large doses of IV glucocorticoids and neuromuscular blocking agents. It characteristically presents with a severe, diffuse, proximal, and distal weakness that develops over several days. Although it is usually reversible, critical illness myopathy can lead to prolonged ICU admissions, increased length of hospital stays, severe necrotizing myopathy, and increased mortality.
Osteonecrosis can be seen especially with long-term use of prednisone more than 20 mg daily. Patients with SLE and children are at higher risk. Hips and knees are the most commonly involved joints with less common involvement of shoulders and ankles. Pain is the initial feature, which may eventually become severe and debilitating. Magnetic resonance imaging is the most sensitive test, especially for early detection. Plain radiographs may be negative initially but can be useful for follow-up. Treatment is by decreased weight-bearing and immobilization initially, but surgery and/or joint replacement may be necessary if severe.
Metabolic and Endocrine Adverse Effects
Systemic glucocorticoids cause a dose-dependent increase in fasting glucose levels and a more significant increase in postprandial values in patients without preexisting diabetes mellitus, but the development of de novo diabetes in a patient with initially normal glucose tolerance is uncommon. Risk factors for new-onset hyperglycemia during glucocorticoid therapy appear to be the same as those for other patients. However, patients with diabetes mellitus or glucose intolerance exhibit higher blood glucose levels while taking glucocorticoids, leading to increased difficulty with glycemic control.[8]
The development of cushingoid features (redistribution of body fat with truncal obesity, buffalo hump, and moon face) and weight gain are dose and duration-dependent and can develop early. Cushingoid features showed a linear increase in frequency with dosing. Glucocorticoid therapy is the most common cause of Cushing syndrome. The clinical presentation in the pediatric population is similar to that in adults and includes truncal obesity, skin changes, and hypertension. In children, growth deceleration is also a feature.
Administration of glucocorticoids can suppress the hypothalamic-pituitary-adrenal (HPA) axis decreasing corticotropin-releasing hormone (CRH) from the hypothalamus, adrenocorticotropic hormone (ACTH) from the anterior pituitary gland, and endogenous cortisol. Prolonged ACTH suppression cause atrophy of adrenal glands, and abrupt cessation or rapid withdrawal of Glucocorticoids in such patients may cause symptoms of adrenal insufficiency. The clinical presentation of adrenal suppression is variable. Many of the signs and symptoms are non-specific and can be mistaken for symptoms of intercurrent illness or the underlying condition that is receiving treatment (weakness/fatigue, malaise, nausea, vomiting, diarrhea, abdominal pain, headache usually in the morning, fever, anorexia/weight loss, myalgia, arthralgia, psychiatric symptoms, poor growth and weight gain in children). Adrenal suppression is the most common cause of adrenal insufficiency in children and is associated with higher mortality in the pediatric population. In adults, the symptoms of adrenal suppression are non-specific; therefore, the condition may go unrecognized until exposure to physiological stress (illness, surgery, or injury), resulting in an adrenal crisis. Children with adrenal crisis secondary to adrenal suppression may present with hypotension, shock, decreased consciousness, lethargy, unexplained hypoglycemia, seizures, and even death.
The impairment of growth in young children and delay in puberty commonly presents in children receiving glucocorticoids for chronic illnesses like nephrotic syndrome and asthma. The effect is most pronounced with daily therapy and less marked with an alternate-day regimen and can also occur with inhaled glucocorticoids. Although growth impairment can be an independent adverse effect of corticosteroid therapy, it can also be a sign of adrenal suppression.
Infections
Moderate to high dose use of glucocorticoids poses a significant risk of infections, including common mild infections as well as serious life-threatening infections. There is a linear increase in the risk with dose and duration of therapy, especially with common bacterial, viral, and fungal pathogens. Concomitant use of other immunosuppressive agents and the elderly age further increases the risk of infections.[9][10] Prednisone dose of less than 10 mg daily pose minimal to no risk of infection. Patients taking glucocorticoids may not manifest common signs and symptoms of infection as clearly, due to the inhibition of cytokine release and the associated reduction in inflammatory and febrile responses leading to a failure in early recognition of infection.
Cardiovascular Adverse Effects
Mineralocorticoid effects, especially as seen with cortisol and cortisone, can lead to fluid retention, edema, weight gain, hypertension, and arrhythmias by increasing renal excretion of potassium, calcium, and phosphate. Hypertension usually occurs with higher doses only.[11]Long-term use of medium-high dose glucocorticoids has implications in premature atherosclerosis in a dose-dependent pattern.[12]
Dermatologic Adverse Effects
Several cutaneous adverse effects can occur even at a low dose use of glucocorticoids, although the risk increases linearly with the increasing dose and duration of glucocorticoid therapy. Although cutaneous adverse effects appear to be clinically significant by physicians, they are usually of most concern to the patients.[13] These adverse effects include ecchymosis, skin thinning and atrophy, acne, mild hirsutism, facial erythema, stria, impaired wound healing, thinning of hair, and perioral dermatitis.
Ophthalmologic Adverse Effects
The risk of cataracts is significantly high in patients taking prednisone more than 10 mg daily for more than one year, with a dose-dependence in a linear fashion. However, an increased risk of cataracts has been reported even with low-dose glucocorticoids.[14] Cataracts are usually bilateral and slowly progressing.[15] Increased intraocular pressure, especially in patients with a family history of open-angle glaucoma, is seen in patients receiving intraocular glucocorticoids and high dose systemic glucocorticoids.[16] Glaucoma is often painless and can lead to visual field loss, optic disc cupping, and optic nerve atrophy. After discontinuing systemic therapy, the elevation in intraocular pressure usually resolves within a few weeks, but the damage to the optic nerve is often permanent. A rare adverse effect of systemic or even topical use of glucocorticoids is central serous chorioretinopathy; this leads to the formation of subretinal fluid in the macular region, which leads to separation of the retina from its underlying photoreceptors. This condition manifests as central visual blur and reduced visual acuity.[17][18]
Gastrointestinal (GI) Adverse Effects
Glucocorticoids increase the risk of adverse GI effects, such as gastritis, gastric ulcer formation, and GI bleeding.[19]The use of NSAIDs and glucocorticoids is associated with a 4-fold increased risk of a GI adverse effect compared with the use of either drug alone. Other complications associated with glucocorticoid use include pancreatitis, visceral perforation, and hepatic steatosis (fatty liver) that can rarely lead to systemic fat embolism or cirrhosis.
Neuropsychiatric Adverse Effects
Patients receiving glucocorticoids often experience an improved sense of well-being within several days of starting the medications; mild euphoria or anxiety may also occur. Hypomanic reactions and activated states are more common early in the therapy than depression, but the prevalence of depression is greater in patients on more longstanding therapy. Psychosis can occur but does so almost exclusively at doses of prednisone above 20 mg per day given for a prolonged period. Disturbances in sleep are reported, especially with split doses that may interfere with the normal pattern of diurnal cortisol production. Akathisia (motor restlessness) is a common glucocorticoid side effect. The risk of developing a given neuropsychiatric disorder following glucocorticoid therapy may increase among patients with a history of the condition. Rare cases of pseudotumor cerebri have also correlated with glucocorticoid use.[20]
There is specific documentation of neuropsychiatric adverse effects with glucocorticoid therapy in children with acute lymphoblastic leukemia (ALL) receiving dexamethasone or prednisone for the induction and maintenance of treatment.[21] The risk is higher in preschool-age children, and the symptoms typically present during the first week of glucocorticoid therapy.[22][23] Glucocorticoid-induced acute neuropsychiatric impairment may present with a wide variety of behavioral symptoms, including euphoria, aggression, insomnia, mood fluctuations, depression, manic behavior, and even frank psychosis.[24]Although these psychiatric disturbances tend to wear off with time on cessation of glucocorticoid therapy, a small minority of the patients may experience persistent symptoms even after discontinuing the drug.[25]
Contraindications
General contraindications include hypersensitivity.
Systemic
Systemic fungal infections
Intrathecal administration
Cerebral malaria
Concomitant live or live attenuated virus vaccination (if using glucocorticoids in immunosuppressive doses)
Use in premature infants (formulations containing benzyl alcohol)
Topical
Dermatological: Bacterial, viral, or fungal infection of the mouth or throat (triamcinolone)
Ophthalmic: Acute untreated purulent ocular infections, fungal or mycobacterial ocular infections, viral conjunctivitis, or keratitis
Clinicians can administer live virus vaccines to patients who are on:
Prednisone or its equivalent in doses of less than 20 mg per day for 14 days or less
Glucocorticoids used for long-term physiologic replacement
Glucocorticoids administered topically, by aerosol, or by intra-articular or bursal injection, provided that there is no clinical or laboratory evidence of immunosuppression
Enhancing Healthcare Team Outcomes
Glucocorticoids are widely used to manage many acute and chronic inflammatory disorders. The adverse effects of glucocorticoids are extensive and can involve many organ systems. While short-term use of corticosteroids is associated with mild side effects, long-term use can result in several severe adverse effects, some of which are irreversible. This is why an interprofessional team approach to corticosteroid therapy and subsequent monitoring is necessary.
Clinicians shall consider adverse effects and patients' underlying comorbidities before prescribing glucocorticoids and use glucocorticoids judiciously. The clinician should use the lowest possible dose for the shortest possible. Patient education is vital in recognizing the adverse effects early. Children are particularly vulnerable to the side effects of corticosteroids, and parents need to understand the benefits and adverse effects of glucocorticoids. Pharmacists shall alert physicians about possible drug interactions, check dosing and duration, and answer patient questions. The nursing team can play a crucial role in communication with the patient, early detection of adverse effects, and regular monitoring.
Close communication with other health professionals is necessary to ensure that the patient is not left unmonitored.[34] This kind of interprofessional team methodology to corticosteroid therapy will yield improved patient results while mitigating the numerous and potentially serious adverse effects of such therapy, especially when these agents are used long term.
One consequence of repeat boosting with mRNA technology coupled with breakthrough viral infections is immunosuppression due to multiple pathologies not limited to: progressive depletion of CD4+1011 & CD8+ T cells12 , impaired toll like receptor (TLR) mediated responses and class switching to IgG4:
If the sequalae of the boosters and/or re-infection indicate steroid treatment then adverse clinical outcomes may result if they are already immunosuppressed.
Outcomes could be worse rather than improved by treatments, thus corticosteroids maybe contraindicated at some point.
This already happens with some HIV patients and those with inflammatory bowel diseases (IBDs), for example.
Our results indicate that the patients who will need to use corticosteroids the most in the immunosuppressed situation (EC B2-B3) will also be the ones less responsive in the long-term and require early biological treatment or rescue surgery.
…More than half of our patients who were in established IMM treatment required treatment with systemic or low-bioavailability corticosteroids throughout their subsequent follow-up. The patients' B2-B3 CD pattern and previous use of biological drugs were the only associated risk factors.
This drug strategy was clearly effective only in 35% (1/3) of the patients treated with corticosteroids; the remaining patients needed further courses of corticosteroids, biological drugs, or surgery.
Tolerance and deterioration of pre-existing conditions
In case report from 2006 by Sheth et al they discuss how an asthma patient’s condition worsened substantially instead of improving after the administration of methylprednisolone sodium succinate by IV14:
Abstract
Despite widespread use for treatment of asthma and allergies, glucocorticoids may cause allergic reactions, even anaphylaxis. The incidence of adverse reactions to systemic glucocorticoids is 0.3%. The most commonly reported corticosteroids causing anaphylaxis like reactions are hydrocortisone, prednisone, and methylprednisolone. Most authors agree that allergic reactions to systemic corticosteroids are possibly immunoglobulin E mediated. We report a patient with asthma, aspirin allergy, and nasal polyps who developed bronchospasm following the administration of intravenous methylprednisolone sodium succinate during an acute asthmatic attack. We discuss the differential diagnosis of worsening asthma despite adequate treatment, and suggest corticosteroid-induced bronchospasm in our patient. Corticosteroid-induced bronchospasm should be considered when asthmatics fail to improve, or frankly deteriorate with systemic corticosteroid therapy, particularly when a history of aspirin allergy is present.
Teaching Point:
Know the differential diagnosis for worsening of asthma despite adequate treatment.
Consider corticosteroid-induced bronchospasm when asthmatics fail to improve, or frankly deteriorate with systemic corticosteroid therapy.
Corticosteroid-induced bronchospasm is more commonly seen in asthmatics with a history of aspirin allergy.
Lim et al (2022) explored the pathology behind the induction of IgE by glucocorticoids. This relates to steroid induced allergic reactions, as above and is an explanation for why the immune response can be overstimulated, paradoxically.
They conducted investigations using ex vivo cultures and also with cKO mice (lacking GRs) and wild type mice as controls15. You may have noted earlier that B cells are not suppressed by steroids:
Abstract
IgE mediates allergic responses by coating mast cell or basophil surfaces and inducing degranulation upon binding a specific allergen. IgE can also be spontaneously produced in the absence of foreign allergens; yet the origin, regulation, and functions of such "natural" IgE still remain largely unknown. Here, we find that glucocorticoids enhance the production of IgE in B cells both in vivo and ex vivo without antigenic challenge. Such IgE production is promoted by B cell-intrinsic glucocorticoid receptor signaling that reinforces CD40 signaling and synergizes with the IL-4/STAT6 pathway. In addition, we found that rare B cells in the mesenteric lymph nodes are responsible for the production of glucocorticoid-inducible IgE. Furthermore, locally produced glucocorticoids in the gut may induce natural IgE during perturbations of gut homeostasis, such as dysbiosis. Notably, mice preemptively treated with glucocorticoids were protected from subsequent pathogenic anaphylaxis. Together, our results suggest that glucocorticoids, classically considered to be broadly immunosuppressive, have a selective immunostimulatory role in B cells.
For the patient they may be in the worst of all worlds?
From their concluding remarks:
While our findings seem to oppose long-standing perspectives on the classically immunosuppressive effects of glucocorticoids, recent studies have similarly found that glucocorticoids have dose-dependent effects on B and T cells that can be immunoenhancing at particular ranges (Cain et al., 2020; Hong et al., 2020; Shimba et al., 2018). Further, consistent with our findings, induction of NF-κB signaling by glucocorticoids has also been identified by others. For example,low-dose Cort increases NF-κB translocation and downstream proinflammatory gene transcription in microglia-like immune cells (Liu et al., 2018). Indeed, we observed that in addition to promoting IgE switching by activating NF-κB to reinforce CD40L/CD40 signaling,glucocorticoids predispose ex vivo B cells to become plasmablast-like cells with distinct transcriptomes enriched for genes like Prdm1 and Xbp1, as revealed by RNA-seq. Thus, our data further bolster the immunoenhancing role of glucocorticoids in B cells by activating NF-κB, promoting a plasmablast-like fate, and inducing downstream IgE production.
However,we also observed that despite IgE induction, the immune system was otherwise systemically suppressed by DEX treatment as we used a supraphysiological dose in our experiments (Materials and methods). In addition to our present findings on glucocorticoid induction of IgE synthesis in B cells, prior literature has reported higher IgE levels in patients receiving multiple high-dose corticosteroid treatments for asthma, despite reduced IFN-γ–producing T cells and natural killer cells as proxies for immunosuppression (Zieg et al., 1994). Thus, given that the valence of glucocorticoid regulation of immune cells is cell type specific, dose dependent, and sensitive to cues from the surrounding tissue milieu,it is probable that glucocorticoids can exhibit immunoenhancing effects on particular immune cell populations, despite a net state of immunosuppression in the whole organism. It would be particularly interesting to investigate in which physiological contexts glucocorticoids can positively regulate immune responses, and whether GR-mediated changes are accompanied by epigenetic modifications depending on the specific cell type.
In all, our study collectively suggests that glucocorticoids act as promoting factors for natural IgE production and provides important mechanistic insights into the induction and protective physiological functions of glucocorticoid-induced IgE. Moreover, our results suggest that chronic glucocorticoid treatment may potentially increase IgE levels in humans, which has indeed been previously reported for the aforementioned patients who received long-term prednisone treatment (Zieg et al., 1994).
And from 2012, Kerzerho et al used mice to investigate whether local administration of corticosteroids could be more efficacious at inducing or maintaining desired tolerance to antigens for asthmatics vs systemic dosing16.
Abstract
Respiratory exposure to allergen induces T cell tolerance and protection against the development of airway hyperactivity in animal models of asthma. Whereas systemic administration of dexamethasone during the delivery of respiratory Ag has been suggested to prevent the development of mucosal tolerance, the effects of local administration of corticosteroids, first-line treatment for patients with bronchial asthma, on mucosal tolerance remain unknown. To analyze the effects of systemic versus local administration of different types of corticosteroids on the development of mucosal tolerance, mice were exposed to respiratory allergen to induce mucosal tolerance with or without systemic or intranasal application of different doses of dexamethasone or prednisolone. After the induction of mucosal tolerance, proliferation of T cells was inhibited in tolerized mice, whereas systemic applications of corticosteroids restored T cell proliferation and secretion of Th2 cytokines. In contrast, inhaled corticosteroids showed no effect on both T cell proliferation and cytokine secretion. In addition, mice systemically treated with corticosteroids showed an increased airway hyperactivity with a significant lung inflammation, but also an increased T effector cells/regulatory T cells ratio in the second lymphoid organs when compared with mice that receive corticosteroids by inhalation. These results demonstrate that local administration of corticosteroids has no effect on the development of immune tolerance in contrast to systemically applied corticosteroids. Furthermore, although different concentrations of corticosteroids are administered to patients, our results demonstrated that the route of administration rather than the doses affects the effect of corticosteroids on respiratory tolerance induction.Considering the broad application of corticosteroids in patients with allergic disease and asthma, the route of administration of steroid substances seems crucial in terms of treatment and potential side effects. These findings may help elucidate the apparently contradicting results of corticosteroid treatment in allergic diseases.
Local administration is better for the induction of respiratory tolerance to allergens.
CS: Corticosteroids.
OVA: Ovalbumin, and antigen widely used to induce IgE-mediated allergic reactions.
AHR: Airway hyperreactivity.
In parallel to the CS therapy which relieves the symptoms of asthma, respiratory allergen tolerance induction is used in the long term asthma management. We have previously shown that respiratory allergen tolerance is highly effective in preventing the development of airway inflammation and hyperreactivity through the development of Ag-specific adaptive regulatory T cells (Treg) that express high levels of FOXp3 [8, 9]. However, we have shown that systemic treatment with CS prevents the protective effects of mucosal tolerance on the development of airway hyperresponsiveness by inhibiting the development of Treg cells [4, 5, 10]. Thus, while CS have been shown to rapidly inhibit the function of effector Th2 cells, their potential to block the development of Treg cells might in the long term exacerbate Th2 inflammatory immune responses.
Whereas CS can reduce acute inflammation in allergy [2], CS may at the same time hinder the development of mucosal tolerance, which is an immune response that downregulates Th2-driven allergic pulmonary inflammation [10]. CS have been shown to be highly effective in the treatment of inflammatory diseases by reducing cytokine production and the function of critical effector cells. In asthma, CS inhibit acute allergic inflammation and improve airway hyperresponsiveness in both mice and humans [3], by limiting cytokine production in T cells and epithelial cells, and by impairing the recruitment and growth of eosinophils and other inflammatory cells [18]. By all measures, CS, delivered either systemically or locally in the respiratory tract, is the pharmaceutical of choice for both acute and chronic asthma [19, 20]. In this report, we show that the route of application of CS significantly alters their effect. We found that systemic treatment with Dexa. or Pred. prevented the development of respiratory tolerance, resulting in Ag-specific proliferation and increased OVA-specific IgE production and Th2 cytokine production, allowing AHR to develop.
IL-10: Interleukin-10, an anti-inflammatory cytokine.
DCs: Dendritic cells.
Tregs: Regulatory T-cells that can suppress inflammatory or autoimmune responses.
Teffs: Effector T-cells that can promote inflammation.
NB. This doesn't just apply to asthma:
Previously, we found that systemic application of Dexa. blocks the development of T cell tolerance as a result of the elimination of IL-10– secreting tolerogenic DCs [10]. In this study, we found that systemic administration of CS therapy might inhibit the development of respiratory tolerance by decreasing the allergen-specific Foxp3+ Treg development, but not the allergen-specific Teff development, resulting in a shift of the Teff:Treg balance toward the T cell activation. This shift of the Teff:Treg balance induced by the systemic administration of CS occurs in the second lymphoid organs where the immune cells responsible for the tolerance induction develop. Therefore, our results suggest that Foxp3+ Treg development is more sensitive to systemic CS therapy than Th2 cell development [35], resulting in enhanced Th2 cell, but reduced Foxp3+ Treg development following systemic CS treatment.
In contrast, we found that local administration of prednisolone or dexamethasone has no effect on respiratory tolerance induction. Inhaled CS were unable to inhibit T cell tolerance and had no effect on total or OVA-specific IgE production, cytokine secretion and AHR development. However, we found that inhaled CS decrease the allergen-specific Teff : Treg ratios mainly through the increase of the Treg development. This correlates with one report describing an increased Treg activity in asthmatic patients treated with inhaled glucocorticoids, and significantly increased FOXP3 mRNA expression was found in unstimulated peripheral blood CD4+ T cells after steroid treatment [37].
Our results show that inhaled CS do not drive the allergen specific Teff : Treg ratio toward T cell activation.We therefore suggest that local administration of CS has no unwanted long-term effects and allows to limit the enhancement of the severity of subsequent immune responses that occur on re-exposure to allergen, maybe contrary to systemic administration of CS.
However, inhaled CS treatment is by no means curative, as the symptoms of asthma reappear when therapy is stopped. The development of pathogenetically aimed treatment strategies remains necessary.
Taken together, the information from our experiments could shed some light into the highly contradictory field of CS effects in allergic diseases.
From 2011, Roncoroni et al conducted a review into the efficacy of systemic steroids for treating sciatica. They found that tolerance and side effects indicated against their use to treat this condition17:
Abstract
Objectives: The efficacy of pharmacological interventions in sciatica is limited and the use of systemic steroids is still controversial. We aimed at evaluating the efficacy and tolerance of systemic steroids in sciatica.
Methods: A systematic literature search was performed in the Medline, Embase and Cochrane databases until February 2010. Randomized placebo-controlled trials evaluating the efficacy and the tolerance of systemic steroids in sciatica were included. Efficacy and tolerance were assessed using the relative risk (RR) and 95% CI with the inverse variance method (RR > 1 means that the event is more likely to occur in the steroid group). We explored the heterogeneity between the studies using subgroup analysis.
Results: Seven studies (383 patients) were included. The difference in the rate of responders between both groups was not statistically significant (RR = 1.22, 95% CI 0.96, 1.56). The rate of adverse events was 13.3% for the patients in the steroid group and 6.6% for the placebo group (RR = 2.01, 95% CI 1.06, 3.80). The number needed to harm was 20 (95% CI 10, ∞). Twenty (15.3%) patients in the steroid group and seven (5.7%) patients in the placebo group underwent surgery. A trend towards a higher requirement for spinal surgery was observed in the steroid group (RR = 1.14, 95% CI 0.74, 1.75). The methodological quality slightly influenced the results. We did not find any publication bias.
Conclusion: Steroid efficacy is not superior to the placebo in sciatica, but it has more side effects. The tolerance : efficacy ratio indicates against the use of systemic steroids in sciatica.
And there are dose dependant risks from repeated applications of topical steroids.
Skin atrophy is the most common adverse effect and occurs due to the anti-mitotic effect of topical corticosteroids.[6] Topical steroid causes the skin to undergo 3 phases: preatrophy, atrophy, and tachyphylaxis. Atrophy occurs when there is a persistent use in the same region. This leads to epidermal thinning and increased resorption within the dermis ground substance. The loss of connective tissue leads to erythema, teleangiectasias, and purpura. Atrophy presents as a burning sensation; the vasoconstrictive effect of the topical corticosteroid relieves the burn.[4] Areas most at risk for atrophy are intertriginous due to thinner skin and increased occlusion. Atrophy is reversible with cessation of steroid use; however, it may take months for the skin to appear normal again.[6]
Tachyphylaxis is the result of the skin developing tolerance to the topical corticosteroid, which ultimately is a loss of vasoconstriction at the level of the capillaries. It has been demonstrated that the capillaries regain the ability to vasoconstrict after 4 days. For this reason, pulse therapy is recommended and the topical corticosteroid should be discontinued for 4 days if it has lost its effectiveness.[13]
Corticosteroid use to manage rheumatoid arthritis
Even at the time of this review from 2021 corticosteroid prescribing in RA patients remained substantial. Crossfield et al reported their findings19:
Abstract
Objectives
To assess whether modern management of RA has reduced the prescription of oral corticosteroids and NSAIDs and to evaluate use of pharmacological prophylaxis strategies.
Methods
Using the Clinical Practice Research Datalink, we explored long-term (≥3/12 months; ≥6/12 in sub-analyses) DMARD, corticosteroid and NSAID prescribing (annually, in the year post-diagnosis and across the patient’s life course to 15 years post-diagnosis), annual proportion with co-prescribing for prophylaxis of associated bone (corticosteroids, women only) and gastrointestinal (NSAIDs) comorbidity.
Results
Reported incidence of RA was 5.98 (0.37) per 10 000 person-years and prevalence was 0.91% (0.014) in 2017. In 71 411 RA patients, long-term DMARD prescribing initially rose post-diagnosis from 41.6% in 1998 to 67.9% in 2009. Corticosteroid prescribing changed little, overall [22.2% in 1998, 19.1% in 2016; incident risk ratio (IRR) 0.92, 95% CI: 0.82, 1.03] and across the life course from the first to fifteenth year (22.2% to 16.9%). NSAID prescribing declined from 57.7% in 1998, and significantly so from 2008, to 27.1% in 2016 (IRR 0.50, 95% CI: 0.44, 0.56). This continued across the life course (41.2% to 28.4%). Bone prophylaxis increased to 68.1% in 2008 before declining to 56.4% in 2017; gastrointestinal prophylaxis increased from 11.5% in 1998 to 62.6% in 2017. Sub-analyses showed consistent patterns.
Conclusion
Despite modern treatment strategies, corticosteroid prescribing in RA patients remains substantial and persists beyond 6 months once initiated. Rheumatologists need to determine causes and develop strategies to reduce corticosteroid use to minimize adverse event occurrence.
Despite modern RA treatment strategies, long-term prescribing of corticosteroids remains substantial.
The proportion of RA patients receiving corticosteroids persists across the life course, with suboptimal bone prophylactic therapy.
Long-term corticosteroid use has implications for RA comorbidities and infection susceptibility (including COVID-19).
The authors do not offer an explanation for the peak in 2013-14:
FIG 1. Annual incidence and prevalence. (A) Annual incidence rate (N = 8 022 645); (B) annual percentage prevalence (N = 7 532 147); in 1998–2017 using three definitions of RA: ≥1 RA diagnostic code; ≥2 RA diagnostic codes at least 6 months apart; ≥1 RA diagnostic code plus a subsequent DMARD prescription.
FIG 2. The annual proportion with long-term prescribing. The annual percentage (1998–2017) of patients with ≥90 days annual prescribing: all RA patients (N = 68 939) and in the first year post-diagnosis (N = 29 918).
Trends in corticosteroid prescribing
During follow-up, 45.1% of RA patients had prescribed corticosteroids and 32.2% received long-term prescribing for at least 1 year. The mean count of prescriptions per person-year was 2.04 in 1998 and 1.89 in 2017. Among patients prescribed corticosteroids in a given year, the mean prescription count was 8.03 in 1998 and 8.02 in 2017 (Supplementary Fig. S12, available at Rheumatology online).
In 1998, 21.0% of RA patients had long-term prescribing, declining (mean APC -1.54) to 15.5% in 2017. Findings from sub-analyses were consistent. The decline was significant between 2013 (IRR 0.87, 95% CI: 0.81, 0.94) and 2017 (IRR 0.75, 95% CI: 0.70, 0.80) (Table 1). Women were slightly less likely to receive long-term corticosteroids than men (IRR 0.96, 95% CI: 0.94, 0.97). Compared with age 18–29 years, prescribing significantly increased with age from 50 (e.g. age 50–59: IRR 1.27, 95% CI: 1.16, 1.39; age 90–99: IRR 1.60, 95% CI: 1.44, 1.78) (Supplementary Fig. S13, available at Rheumatology online). Socioeconomic deprivation had no significant effect (data not shown). In the non-RA cohort, 3.8% had long-term corticosteroid prescribing during follow-up, rising from 0.9% in 1998 to 2.0% in 2017 (Supplementary Fig. S14, available at Rheumatology online).
Discussion
This study demonstrated little change in corticosteroid prescribing in RA patients in the UK by GPs, and no change in the year post-diagnosis despite modern treatment strategies. Although the decline in corticosteroid prescription was significant across the first 3 years post-diagnosis, prescribing remained substantial 3 years post-diagnosis (17.9%) and persisted for the duration of the study, particularly in older age groups. NSAID prescribing halved among RA patients, predominantly driven by changing practice for newly diagnosed patients, though remained substantial (34.3% at 3 years post-diagnosis). Additionally, the increased DMARD prescribing in the year post-diagnosis plateaued from 2009. Improvements in prophylaxis co-prescribing remain suboptimal. In elderly and comorbid populations treated with DMARD immune suppressants, persistent corticosteroid exposure with attendant immune suppression is particularly concerning and pertinent in the context of infectious diseases including COVID-19 and tuberculosis [26].
…Despite modern treatment strategies and increased DMARD prescription, long-term corticosteroid prescribing in RA patients remains substantial, especially among elderly patients, and persists once initiated. Long-term corticosteroid prescribing has clear implications for RA comorbidities and susceptibility to infection (of particular relevance during the COVID-19 pandemic). Rheumatologists need to understand the causes of persistent prescribing and develop alternative strategies of pain management.
Comfortably numb
Some of us are lucky enough to be able to take them longer term without serious complications, due to our genetics and epigenetics. But a fairly well known example of what can happen when we aren’t so lucky is the Genesis frontman and soloist Phil Collins.
Phil’s suffered from various injuries and nerve damage over the years - the rock and roll lifestyle and all that. But one of the reasons that he cannot play now was the cortisone injections he had to reduce the inflammation of his vocal cords20:
Today, Collins walks with a stick, thanks to several foot injuries from a number of falls, his spine is weak due to years of drumming and vocal cord-easing cortisone injections that can lead to brittle bones, and a misplaced nerve in his elbow has required several operations.
Cortisone and hydrocortisone:
Cortisone is a pregnene (21-carbon) steroid hormone. It is a naturally-occurring corticosteroid metabolite that is also used as a pharmaceutical prodrug; it is not synthesized in the adrenal glands. Cortisol is converted by the action of the enzyme corticosteroid 11-beta-dehydrogenase isozyme 2 into the inactive metabolite cortisone, particularly in the kidneys. Cortisone is converted back to the active steroid cortisol by the action of the enzyme 11β-Hydroxysteroid dehydrogenase type 1, particularly in the liver.
The term "cortisone" is frequently misused to mean either any corticosteroid or hydrocortisone, which is actually another name for cortisol. Many who speak of receiving a "cortisone shot" or taking "cortisone" are actually receiving hydrocortisone or one of many other, much more potent synthetic corticosteroids; it is unlikely that the drug administered is actually cortisone21.
Hydrocortisone is the name for the hormone cortisol when supplied as a medication. Uses include conditions such as adrenocortical insufficiency, adrenogenital syndrome, high blood calcium, thyroiditis, rheumatoid arthritis, dermatitis, asthma, and COPD. It is the treatment of choice for adrenocortical insufficiency. It can be given by mouth, topically, or by injection. Stopping treatment after long-term use should be done slowly.
Side effects may include mood changes, increased risk of infection, and edema (swelling). With long-term use common side effects include osteoporosis, upset stomach, physical weakness, easy bruising, and candidiasis (yeast infections). It is unclear if it is safe for use during pregnancy. Hydrocortisone is a glucocorticoid and works as an anti-inflammatory and by immune suppression22.
Risk of inducing diabetes
A longitudinal analysis of health records extracted from a sample size of 100,722 from 1998-2017 found that the cumulative risk of type 2 diabetes increased from 0.9% with non-use to 5.0% after 1 year when the daily prednisolone-equivalent dose was ≥25.0 mg.
Factoring in for lower doses of <5.0 mg corticosteroids, these still induced a multi-fold increased risk of T2DM, depending on the condition being treated23.
Abstract
Introduction In immune-mediated inflammatory diseases, there is a lack of -estimates of glucocorticoid dose–response diabetes risk that consider changes in prescribed dose over time and disease activity.
Research design and methods Population-based longitudinal analysis of electronic health records from the UK Clinical Practice Research Datalink, linked to hospital admissions and the mortality registry (1998–2017). We included 100 722 adult patients without diabetes history, diagnosed with giant cell arteritis or polymyalgia rheumatica (n=32 593), inflammatory bowel disease (n=29 272), rheumatoid arthritis (n=28 365), vasculitis (n=6082), or systemic lupus erythematosus (n=4410). We estimated risks and HRs of type 2 diabetes associated with time-variant daily and total cumulative prednisolone-equivalent glucocorticoid dose using Cox regression methods.
Results Average patient age was 58.6 years, 65 469 (65.0%) were women and 8858 (22.6%) had a body mass index (BMI) ≥30 kg/m2. Overall, 8137 (8.1%) people developed type 2 diabetes after a median follow-up of 4.9 years. At 1 year, the cumulative risk of diabetes increased from 0.9% during periods of non-use to 5.0% when the daily prednisolone-equivalent dose was ≥25.0 mg. We found strong dose-dependent associations for all immune-mediated diseases, BMI levels and underlying disease duration, even after controlling for periods of active systemic inflammation. Adjusted HR for a <5.0 mg daily dose versus non-use was 1.90, 95% CI 1.44 to 2.50; range 1.70 for rheumatoid arthritis to 2.93 for inflammatory bowel disease.
Conclusions We report dose-dependent risks of type 2 diabetes associated with glucocorticoid use for six common immune-mediated inflammatory diseases. These results underline the need for regular diabetic risk assessment and testing during glucocorticoid therapy in these patients.
This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See: https://creativecommons.org/licenses/by/4.0/.
Even topically applied steroids can put you at a 15-34% increased risk, according to one meta-analysis. Cumulative dose received and duration is more important than the potency of the formulation applied.
Background: Topical steroids have been previously associated with potential for hyperglycemia and glucosuria, and thought to have a relatively safe side effect profile. In prolonged use, there is the potential for steroids to be absorbed through the skin and eventually reach systemic circulation. We aimed to investigate the potential association between topical corticosteroid use and development of diabetes, we performed a systematic review and meta-analysis of available case-control data in the literature.
Methods: Electronic database searches was performed to identify studies comparing the proportion of patients with diabetes in cases using topical corticosteroids compared to those without. The odds ratio (OR) was used as a summary statistic.
Results: Four case-control studies were pooled for meta-analysis. Overall, we found a significant association between topical corticosteroid use and development of type 2 diabetes mellitus, even after adjustment for confounding factors (OR 1.24, 95% CI 1.15-1.34, I2 = 91%, p < .00001). There was no potency-dependent effect noted, with no significant difference noted between the subgroups.
Conclusions: We demonstrate a potential association between topical corticosteroid use and risk of developing diabetes mellitus. This risk does not appear to be dependent on potency of the topical medication, but rather the cumulative dose and cumulative duration of use.
There is no “safe dose”. Even low doses of steroids significantly increase the risk of cardiovascular disease in people with inflammatory diseases.
As with diabetes, even taking low doses of prednisolone (<5mg) can double your risk of contracting cardiovascular disease in as little as a year, and higher doses (>25mg) can increase the one year risk 6 fold.
From an analysis published in 2020 by Pujades-Rodriguez et al25. None of the cohorts had diagnosed cardiovascular disease prior to starting the course of steroids:
Abstract
Background
Glucocorticoids are widely used to reduce disease activity and inflammation in patients with a range of immune-mediated inflammatory diseases. It is uncertain whether or not low to moderate glucocorticoid dose increases cardiovascular risk. We aimed to quantify glucocorticoid dose-dependent cardiovascular risk in people with 6 immune-mediated inflammatory diseases.
Methods and findings
We conducted a population-based cohort analysis of medical records from 389 primary care practices contributing data to the United Kingdom Clinical Practice Research Datalink (CPRD), linked to hospital admissions and deaths in 1998–2017. We estimated time-variant daily and cumulative glucocorticoid prednisolone-equivalent dose-related risks and hazard ratios (HRs) of first all-cause and type-specific cardiovascular diseases (CVDs). There were 87,794 patients withgiant cell arteritis and/or polymyalgia rheumatica (n = 25,581), inflammatory bowel disease (n = 27,739), rheumatoid arthritis (n = 25,324), systemic lupus erythematosus (n = 3,951), and/or vasculitis (n = 5,199), and no prior CVD. Mean age was 56 years and 34.1% were men. The median follow-up time was 5.0 years, and the proportions of person–years spent at each level of glucocorticoid daily exposure were 80% for non-use, 6.0% for <5 mg, 11.2% for 5.0–14.9 mg, 1.6% for 15.0–24.9 mg, and 1.2% for ≥25.0 mg.
Incident CVD occurred in 13,426 (15.3%) people, including 6,013 atrial fibrillation, 7,727 heart failure, and 2,809 acute myocardial infarction events.One-year cumulative risks of all-cause CVD increased from 1.4% in periods of non-use to 8.9% for a daily prednisolone-equivalent dose of ≥25.0 mg. Five-year cumulative risks increased from 7.1% to 28.0%, respectively. Compared to periods of non-glucocorticoid use, those with <5.0 mg daily prednisolone-equivalent dose had increased all-cause CVD risk (HR = 1.74; 95% confidence interval [CI] 1.64–1.84; range 1.52 for polymyalgia rheumatica and/or giant cell arteritis to 2.82 for systemic lupus erythematosus). Increased dose-dependent risk ratios were found regardless of disease activity level and for all type-specific CVDs. HRs for type-specific CVDs and <5.0-mg daily dose use were: 1.69 (95% CI 1.54–1.85) for atrial fibrillation, 1.75 (95% CI 1.56–1.97) for heart failure, 1.76 (95% CI 1.51–2.05) for acute myocardial infarction, 1.78 (95% CI 1.53–2.07) for peripheral arterial disease, 1.32 (95% CI 1.15–1.50) for cerebrovascular disease, and 1.93 (95% CI 1.47–2.53) for abdominal aortic aneurysm.
The lack of hospital medication records and drug adherence data might have led to underestimation of the dose prescribed when specialists provided care and overestimation of the dose taken during periods of low disease activity. The resulting dose misclassification in some patients is likely to have reduced the size of dose–response estimates.
Conclusions
In this study, we observed an increased risk of CVDs associated with glucocorticoid dose intake even at lower doses (<5 mg) in 6 immune-mediated diseases. These results highlight the importance of prompt and regular monitoring of cardiovascular risk and use of primary prevention treatment at all glucocorticoid doses.
Author summary
Why was this study done?
Glucocorticoids (steroids) are widely used to reduce disease activity and inflammation in patients with a range of immune-mediated inflammatory diseases, such as rheumatoid arthritis, polymyalgia rheumatica, giant cell arteritis, and inflammatory bowel disease.
Adequate assessment of cost-effectiveness of new steroid-sparing treatments for immune and inflammatory diseases require modelling of estimates of risk and cost of the main treatment complications of steroids.
It is widely recognised that high-dose steroids may increase the risk of cardiovascular disease (CVD; heart disease, stroke, or other vascular diseases), but it is debated whether this increase also applies to lower steroid doses.
Earlier studies of CVD risk associated with glucocorticoid therapy failed to account for changes in dose over time and for use of non-oral steroids and other potentially confounding therapies.
What did the researchers do and find?
In 87,794 adults with immune-mediated inflammatory diseases and no prior CVD (5-year median follow-up), we studied the risk of 6 common CVDs associated with the steroid dose prescribed, quantified either as current or as cumulative dose.
We found strong dose-dependent risks of all CVDs, including myocardial infarction, heart failure, atrial fibrillation, and cerebrovascular disease, in patients diagnosed with the 6 inflammatory diseases studied.
After 1 year, the overall absolute risk of CVD doubled for individuals using less than 5 mg prednisolone per day and was 6 times higher for users of 25 mg or greater.
Many individuals had known modifiable cardiovascular risk factors, including current smoking (24%), obesity (25%), or hypertension (25%).
What do these findings mean?
We have provided evidence that individuals receiving steroids have an increased risk of developing a broad spectrum of fatal and nonfatal CVDs and that this risk increases with the dose of steroids and with the duration of steroid treatment.
It was previously believed that less than 5 mg of prednisolone was safe long term, but even at this “low dose” patients with immune-mediated inflammatory diseases have a doubling of their underlying risk of CVD.
New treatment approaches that avoid the need for long-term steroid treatment and have better cardiovascular safety profile are required for immune-mediated inflammatory diseases.
All patients requiring long-term steroid treatment should be prescribed the lowest effective steroid dose and have a personalised CVD risk prevention plan that takes into account current and prior steroid use.
As potent endocrine disrupters, we know that corticosteroids can mediate CVD via several mechanisms. From Ng and Celermajer (2004)26:
CARDIOVASCULAR EFFECTS OF GLUCOCORTICOIDS
From a cardiovascular standpoint, the propensity of glucocorticoids to produce hyperglycaemia, hypertension, dyslipidaemia, and central obesity has long produced concern regarding possible adverse cardiovascular events.5Glucocorticoid administration increases blood pressure in a dose dependent fashion. The mechanisms of glucocorticoid mediated hypertension are incompletely understood but appear to be principally related to increased peripheral vascular resistance rather than to mineralocorticoid receptor mediated effects of increased sodium retentionand plasma volume expansion.6 Dyslipidaemia in the context of long term glucocorticoid use is characterised by increased total cholesterol, low density lipoprotein cholesterol, and triglycerides.2 Corticosteroid treatment increases the risk of glucose intolerance in patients without known diabetes and is associated with deterioration of glycaemic control in diabetic patients.7 Glucocorticoid treatment therefore contributes to the exacerbation of a cluster of cardiovascular risk factors that are central to the metabolic syndrome. However, as inflammation plays a central role in the pathogenesis in atherosclerosis,8 it is also possible that glucocorticoids may exert some anti-atherosclerotic effects. Indeed, dexamethasone has been shown to reduce atherosclerosis9,10 and restenosis11 in experimental animal models. Furthermore, high dose glucocorticoid treatment has been shown to protect the myocardium from acute ischaemic injury in some animal models.12,13
And the kind of paper I respect greatly by Cruz-Topete et al from as recently as 2020, because even now we are prescribing drugs to the elderly whilst not really knowing all the signalling pathways, interactions and pathologies involved27.
In other words we do yet not have sufficient understanding of how they actually work or if they are shortening lifespans in ways additional to the above, but we are prescribing nonetheless.
This long review considers the effects of glucocorticoid signalling on the aging heart and cardiovascular system. If you read my Substack about mRNA expressed stabilised oncogenic miR-21 and the effects on the circadian rhythm (CR) and cardiovascular disease you see that the CR is closely related to cardiovascular health, and induced imbalances can lead to atherosclerotic plaque formation, aortic dissection and cardiomyopathy:
A decline in normal physiological functions characterizes the aging process. While some of these changes are benign, the decrease in the function of the cardiovascular system that occurs during aging leads to the activation of pathological processes associated with an increased risk for heart disease and its complications. Imbalances in endocrine function are also common occurrences during the aging process. Glucocorticoids are primary stress hormones and are critical regulators of energy metabolism, inflammation, and cardiac function. Glucocorticoids exert their actions by binding the glucocorticoid receptor (GR) and, in some instances, to the mineralocorticoid receptor (MR). GR and MR are members of the nuclear receptor family of ligand-activated transcription factors. There is strong evidence that imbalances in GR and MR signaling in the heart have a causal role in cardiac disease. The extent to which glucocorticoids play a role in the aging heart, however, remains unclear.
As elegantly discussed by McEwen BS (30), depending on the context, glucocorticoids can exert both protective and deleterious effects on the body. An acute increase in glucocorticoids in response to stress is critical to maintaining homeostasis and allostasis (survival) (30). However, imbalances in glucocorticoid secretion patterns and levels due to exogenous administration (increased levels) or pathological states (overproduction or deficiency) can lead to or accelerate disease processes, including metabolic and cardiovascular complications (30), which are commonly found in the elderly. During the aging process, glucocorticoid secretion patterns undergo several modifications characterized by impairments in their circadian profile.While cortisol increases early during the day in the young, a flattening in glucocorticoid rhythm is seen in a subpopulation of the elderly in particular on those suffering from chronic disease, including cognitive impairments such Alzheimer's disease (2, 31, 32). This dysregulation in natural glucocorticoid rhythm seems attributable to a reduction in sensitivity to hypothalamic-pituitary-adrenal (HPA) axis negative feedback control due to an increased glucocorticoid level (32). However, there is no cause and effect relationship established between HPA axis dysregulation and cognitive impairments, dementia, depression, anxiety, as well as an increased risk of Alzheimer's disease, diabetes, and hypertension in the elderly (33–36). Studies are needed to fully establish if there is a physiological effect between the HPA axis dysregulation and increased glucocorticoid levels and the risk for cognitive impairments, anxiety, depression, and chronic inflammatory disorders in the elderly.
How aging alters the molecular mechanisms of glucocorticoid signaling remains largely unknown. A study by Murphy et al. (54) found that intracellular GR trafficking is impaired in the aging hippocampus due to a deficit in chaperone proteins, which diminish GR signaling within this area of the brain. A later study showed that GR mRNA levels in the cortex of the brain rise between infancy and adolescence and decline between adulthood and advanced age (55). The same study found that GR mRNA levels remain stable across the life span in the hippocampus (55). However, the mechanism that causes this aged-related change in GR expression in the cortex is unknown.
Little is also known about the effects of aging on GR signaling in the cardiovascular system. For example, no studies have been performed to test whether the expression of GR isoforms changes with age or whether there are alterations in GR phosphorylation or in other PTMs that affect GR cellular signaling. Additionally, no data exist on how activation of GR signaling by exposure to acute or chronic stressors alters the gene expression profile of the aging heart.
Glucocorticoids and the Heart
In the last decade, studies have shown that depending on the physiological context (e.g., sex, disease state, etc.), type and duration of the stress (e.g., environmental, psychological, acute or chronic), and mechanisms of signaling (via GR or the closely related MR) glucocorticoids have many effects on the heart. Some of these effects are positive and essential for life, whereas other effects can be detrimental for cardiac health. Clinical data suggest that decreased systemic GR signaling is associated with a reduction in cardiac contractile force, systolic dysfunction, coronary artery disease, dilated cardiomyopathy, and progression to heart failure (77–81). Similarly, overactivated glucocorticoid signaling has been shown to lead to negative cardiac outcomes. For example, prenatal exposure to glucocorticoids due to increased stress levels during pregnancy increases the risk for developing cardiovascular disease in adulthood (82). Additionally, excessive glucocorticoid levels due to endocrine disorders or pharmacological treatment are linked to major risk factors for cardiovascular disease, including metabolic syndrome and hypertension, and to pathological cardiac hypertrophy and failure (83–86). A limitation of many these studies is that they do not distinguish between systemic actions of glucocorticoids and direct local actions of glucocorticoids on the heart and the vasculature.
FIGURE 3. Schematic representation of the phenotypes of transgenic mice targeting GR in cardiomyocytes. Shown are the major morphological and functional phenotypes associated with GR overexpression (GR+), GR inactivation (GR–), and GR and MR inactivation (GR/MR–) in the whole heart, vascular smooth muscle cells (VSMC), and cardiomyocytes.
Regarding the role of glucocorticoids in the aging process, some studies show that an increase in glucocorticoid levels accelerates the aging process and increases the risk of premature mortality due to negative effects on vasculature, adipose tissue, and lipid and carbohydrate metabolism (102–104). There are no studies, however, on the direct effects of glucocorticoid signaling on aging cardiomyocytes and the heart. Therefore, it is still unclear whether increased glucocorticoid levels directly contribute to cardiovascular complications during aging or whether the interplay of glucocorticoid signaling with additional risk factors, such as obesity, hypertension, and diabetes, drives the negative systemic actions of these hormones on the heart.
Collectively, these findings suggest that glucocorticoids can both positively and negatively influence the function of the heart through direct effects on cardiomyocytes. Future research needs to be focused on elucidating the mechanisms by which glucocorticoids exert these positive/negative actions on cardiomyocytes, in which context glucocorticoids signal through GR and/or MR, and whether the majority of their beneficial effects on the heart are mediated by cardiomyocyte GR signaling or MR signaling.
Corticosteroids and cancer
Corticosteroids frequently are needed for pain management in cancer patients, especially at later stages. And anticancer effects are seen with some blood cancers such as leukaemia or lymphoma, due to the signalling pathways discussed previously.
Steroids are widely used in oncology and have been demonstrated to possess an anticancer effect or antiswelling effect. They are considered to improve refractory symptoms such as dyspnea or gastrointestinal (GI) obstruction. However, their roles in nonspecific indications are not well proved. Clinical practice and several studies suggest that corticosteroids may be effective in the treatment of bone and neuropathic pain, when administered along with opioids and with other adjuvant analgesics. The decrease in pain intensity is probably connected with both anti-inflammatory and antiswelling effects as well as modulation of neuroimmune interactions and an inhibition of angiogenesis.
Key words: steroids, cancer, pain, indication
Introduction
Steroids are widely used in oncology, from cancer curative treatment to supportive care. They have a demonstrated anticancer effect (i.e., leukemia or lymphoma management) or antiswelling effect (i.e., brain tumor or brain metastases) and are considered to improve refractory symptoms such as dyspnea or gastrointestinal (GI) obstruction. Although this could contribute to the assertion that they are always useful, there is little evidence for the effectiveness and toxicity of corticosteroids in cancer.
Pain
Pain is a major problem in cancer as it occurs in 30–50% patients in earlier stages and in 70–90% of these patients with advanced disease. The three-step framework for cancer-related pain management was published for the first time in 1986. Step I recommends nonopioid analgesics (nonsteroidal anti-inflammatory drugs [NSAIDs], paracetamol) for mild pain. Step II specifies the use of weak opioids for moderate pain (codeine, tramadol). Step III comprises the use of strong opioids for severe pain (morphine, methadone, fentanyl, hydromorphone).
Once indicated, moderate to high doses are administered:
The superiority of steroids over NSAIDs has not been demonstrated and side effects are of concern. Only case reports have demonstrated the effectiveness of corticosteroids in bone pain treatment. Given the present knowledge, a weak recommendation for the use of corticosteroids in cancer patients with pain is found.The evidence supports that a moderate dose of corticosteroids, such as methylprednisolone 32 mg, may contribute to analgesia and seems to be well tolerated. The corticosteroid medication should be discontinued after a week if there is no pain relief.[1] There is at least one complete review on the role on steroids in cancer-related pain management.[2] The conclusions are quite clear: “Clinical practice and several studies suggest that corticosteroids may be effective in the treatment of bone and neuropathic pain, when administered along with opioids and with other adjuvant analgesics. The decrease in pain intensity is probably connected with both the anti-inflammatory and anti-swelling effects as well as modulation of neuroimmune interactions. It seems that dexamethasone may be commonly used for cancer pain management due to its high potency, long duration of action and minimal mineralocorticoid effect. A proposed starting daily dose is 8 mg (orally, subcutaneously, or intravenously) with subsequent adjustment to the analgesia achieved and adverse effects. It is estimated that positive effect of steroids lasted from 3 to 6 weeks.”
The lowest effective dose should be used and patients must be followed up regularly to assess benefits and risks associated with the therapy. In the situation when the general condition of a patient deteriorates and the patient is no longer able to swallow medications that are taken orally, it is rather recommended not to stop the treatment abruptly but to continue dexamethasone administration by the subcutaneous route.
Patients with severe pain intensity of bone and neuropathic origin should also be considered for the use of analgesic ladder step 3 opioids (opioids for moderate to severe pain, strong opioids) without moving up the analgesic ladder. Other co-analgesics appropriate for bone and neuropathic pain should also be considered.
Corticosteroids and p53
The evidence for anti-tumour effects for other types of cancer is lacking. This is to be expected as steroid induced immunosuppression is, objectively, the last course of action you would recommend for a cancer patient.
The same principle applies to the use of experimental anti-Covid gene therapy agents. These have something in common with corticosteroids in that both can suppress the “guardian of the genome”, a key tumour suppressing protein called p5329:
p53, also known as Tumor protein P53, cellular tumor antigen p53 (UniProt name), or transformation-related protein 53 (TRP53) is a regulatory protein that is often mutated in human cancers. The p53 proteins (originally thought to be, and often spoken of as, a single protein) are crucial in vertebrates, where they prevent cancer formation. As such, p53 has been described as "the guardian of the genome" because of its role in conserving stability by preventing genome mutation. Hence TP53[note 1] is classified as a tumor suppressor gene.
Aziz et al (2012) conducted an in vitro study and demonstrated that glucocorticoid receptor agonists (ie GR promoters) could inhibit the apoptosis-inducing effects of p53 on 2 different breast cancer cell lines. And when they used a small interfering RNA (siRNA) to knockdown expression of the protein kinase epsilon (PKCϵ) normally induced by dexamethasone they found that the cells again became susceptible to apoptosis:
Glucocorticoid receptor (GR) is a ligand-dependent transcription factor that can promote apoptosis or survival in a cell-specific manner. Activated GR has been reported to inhibit apoptosis in mammary epithelial cells and breast cancer cells by increasing pro-survival gene expression. In this study, activated GR inhibited p53-dependent apoptosis in MCF10A cells and human mammary epithelial cells that overexpress the MYC oncogene. Specifically, GR agonists hydrocortisone or dexamethasone inhibited p53-dependent apoptosis induced by cisplatin, ionizing radiation, or the MDM2 antagonist Nutlin-3. In contrast, the GR antagonist RU486 sensitized the cells to apoptosis by these agents. Apoptosis inhibition was associated with maintenance of mitochondrial membrane potential, diminished caspase-3 and -7 activation, and increased expression at both the mRNA and protein level of the anti-apoptotic PKC family member PKCϵ. Knockdown of PKCϵ via siRNA targeting reversed the protective effect of dexamethasone and restored apoptosis sensitivity. These data provide evidence that activated GR can inhibit p53-dependent apoptosis through induction of the anti-apoptotic factor PKCϵ.
GR is able to induce apoptosis in lymphocytes, leukemia, lymphoma, and multiple myeloma cells (26, 27). However, in other cell types such as hepatocytes, vascular endothelial cells, osteoclasts, and particularly in mammary epithelial cells, GR can inhibit apoptosis induced by a variety of signaling events (18). Several groups have observed that glucocorticoids can inhibit chemotherapy-induced apoptosis in vitro (18, 19) and in vivo (28).
We wished to gain insight into the mechanisms by which GR activation inhibits apoptosis and promotes survival in breast epithelial cells. To this end, we addressed the involvement of protein kinase Cϵ (PKCϵ) as a potential mediator, because overexpression of PKCϵ is found in various cancers, including breast cancer, and is considered an important marker of negative disease outcome (29). PKC is a family of serine/threonine kinases involved in several processes, including proliferation, differentiation, survival, apoptosis, and migration (30, 31, 32).
Caspases (cysteine-aspartic proteases, cysteine aspartases or cysteine-dependent aspartate-directed proteases) are a family of protease enzymes playing essential roles in programmed cell death. They are named caspases due to their specific cysteine protease activity – a cysteine in its active site nucleophilically attacks and cleaves a target protein only after an aspartic acid residue. As of 2009, there are 12 confirmed caspases in humans[note 1] and 10 in mice, carrying out a variety of cellular functions.30
Here, we demonstrate that the GR agonists Dex and hydrocortisone can protect MCF10Amyc and HMEC+myc mammary epithelial cells from p53-induced apoptosis. Activation of GR by hydrocortisone/Dex and attenuation of p53-induced apoptosis is associated with increased expression of PKCϵ mRNA and protein, maintenance of mitochondrial membrane potential, and diminished caspase-3/7 activation. In contrast, the GR antagonist RU486 suppressed the anti-apoptotic effect of GR and enhanced apoptosis in MCF10Amyc cells. Finally, siRNA-mediated knockdown of PKCϵ reversed the protective effect of Dex, rendering the cells susceptible to apoptosis. These data suggest that PKCϵ plays an important role in the signaling pathway activated by Dex during GR-induced inhibition of apoptosis.
Nutlins are cis-imidazoline analogs which inhibit the interaction between mdm2 and tumor suppressor p53, and which were discovered by screening a chemical library by Vassilev et al. Nutlin-1, nutlin-2, and nutlin-3 were all identified in the same screen;however, Nutlin-3 is the compound most commonly used in anti-cancer studies. Nutlin small molecules occupy p53 binding pocket of MDM2 and effectively disrupt the p53–MDM2 interaction that leads to activation of the p53 pathway in p53 wild-type cells. Inhibiting the interaction between mdm2 and p53 stabilizes p53, and is thought to selectively induce a growth-inhibiting state called senescence in cancer cells. These compounds are therefore thought to work best on tumors that contain normal or "wild-type" p53. Nutlin-3 has been shown to affect the production of p53 within minutes.31
In sum, GR agonists (hydrocortisone and Dex) inhibited Nutlin-induced apoptosis, whereas GR antagonists (RU486) sensitized cells to Nutlin. We conclude activated GR inhibits Nutlin-induced apoptosis in MCF10Amyc cells.
FIGURE 2. GR activation protects against Nutlin-induced apoptosis and mitochondrial depolarization in MCF10Amyc cells. MCF10Amyc cells were starved of FBS/hydrocortisone/EGF/insulin (−ALL) or grown in hydrocortisone, EGF, and insulin without serum (+ALL), and these cells were treated with either vehicle, Dex (1 μm), Dex (1 μm)/RU486 (0.1 μm), or Dex (1 μm)/RU486 (1.0 μm) for 30 min. After 30 min of treatment, MCF10Amyc cells were further treated with or without Nutlin (Nut) (5 μm) in the same condition. A, percentage of sub-G1 cells (propidium iodide staining) was analyzed 72 h post-treatment. B, percentage of cells with low ΔΨm (tetramethylrhodamine ethyl ester staining) was analyzed 72 h post treatment. C, caspase-Glo-3/7 assay was performed with (+Dex) or without (−Dex) Dex for 30 min, and these cells were further treated with or without indicated Nutlin doses (2.5, 5.0, or 10.0 μm) for 24 h. The analysis was done in triplicate assays, and data are presented as mean ± S.E. (n = 3).
In total, the results suggest activated GR inhibits Nutlin-induced apoptosis by maintaining mitochondrial membrane potential (Fig. 2B) and diminishing caspase-3 activation (Fig. 3A), but not by inhibiting p53 transcriptional activity or targeting p53 for degradation.
FIGURE 3. Dexamethasone protects against cell death but without altering p53 induction or transcriptional activity. MCF10Amyc cells starved of FBS/hydrocortisone/EGF/insulin (−ALL) were exposed to Dex (1 μm) for 30 min. The cells were then treated with Nutlin (Nut) (5 μm) or untreated for 2, 4, 8, 12, and 24 h in the continued presence of Dex. A, cell lysates were collected and analyzed by immunoblot analysis with indicated antibodies. B, total RNA was extracted from each treated group after 24 h and quantitative real time PCR (qRT-PCR) was performed using p21, PUMA, Bax, and Noxa-specific primer pairs.
The effectiveness of radiotherapy is also diminished by corticosteroids due to the upregulated expression of apoptosis-inhibiting PKCϵ protein:
Cis: Cisplatin, is in the platinum-based antineoplastic family of medications. It works in part by binding to DNA and inhibiting its replication.32
IR: Ionising radiation therapy is commonly applied to the cancerous tumor because of its ability to control cell growth. Ionizing radiation works by damaging the DNA of cancerous tissue leading to cellular death. To spare normal tissues (such as skin or organs which radiation must pass through to treat the tumor), shaped radiation beams are aimed from several angles of exposure to intersect at the tumor, providing a much larger absorbed dose there than in the surrounding healthy tissue.33
Next, we wished to test whether GR activation could inhibit apoptosis induced by conventional therapy agents, Cis and IR, and, if yes, whether this requires PKCϵ. To this end, MCF10Amyc cells were treated with Cis (0, 5, and 15 μm) or IR (0, 4, and 10 Gy) for 72 h, and percent apoptosis was determined by sub-G1 DNA content. Results in Fig 10, A and B, show that both Cis and IR could induce abundant apoptosis. Importantly, Dex treatment diminished Cis- and IR-induced apoptosis in both untransfected cells and cells transfected with control siRNA (siCon) but did not inhibit apoptosis in cells transfected with PKCϵ siRNA (Fig 10, A and B; DNA histograms in supplemental Fig. 7, A and B).
Immunoblotting showed PKCϵ was effectively knocked down in siRNA-transfected cells (Fig 10, C and D). p53 was induced comparably by Cis or IR, regardless of whether PKCϵ was knocked down (Fig 10, C and D), consistent with the notion that PKCϵ inhibits Cis- and IR-induced apoptosis without altering p53 levels.
FIGURE 10. GR activated PKCϵ also protects against Cisplatin/Irradiation induced apoptosis in MCF10Amyc. MCF10Amyc cells were transfected with nontargeting siRNA (siCon) or PKCϵ-specific siRNA (siPKCϵ). After 24 h, Dex (1 μm) was added for 30 min before treating. A, Cis (Cis; 5, 15 μm); B, irradiation (IR; 4, 10 Gy) in −ALL condition. After 48 h post-treatment, cells were harvested and stained with propidium iodide to measure DNA content. C and D, cell lysates were collected and analyzed by immunoblot analysis with indicated antibodies. The analysis was done in duplicate assays, and data are presented in C as means ± S.E. (n = 2).
In breast cancer, increased PKCϵ is linked with high histologic grade and poor disease-free survival.
PKCε has been originally described as an oncogenic kinase [123, 153–154], and is known to signal via the Ras-Raf-1 signaling pathway [155–158] as well as other pathways. PKCε-transformed fibroblasts secrete increased amounts of TGF-β and possibly other mitogens, an indication that growth autocrine loops may account for its oncogenic activity [159–160]. PKCε is overexpressed in a large number of cancers. For example, PKCε is overexpressed in ~75% of primary tumors from invasive ductal breast cancer patients [7]. Increased PKCε staining correlates with high histologic grade, positive ErbB2/Her2 status, and negative estrogen and progesterone receptor status [7]. Overexpression of PKCε has been reported in the majority (>90%) of primary NSCLC cancers relative to normal lung epithelium [5]. PKCε levels are elevated in prostate cancer relative to benign prostatic epithelia [161], and a correlation with aggressiveness of human prostate cancer has been found [4]. PKCη, an isoform related to PKCε, has also been shown to be up-regulated in some cancers [162–163] but down-regulated in others [164].
Although p53 levels may not be altered there are studies showing that p53 can form complexes with dexamethasone-activated glucocorticoid receptors, inhibiting cell cycle arrest and apoptosis.
Neuroblastoma is a rare type of cancer that mostly affects babies and young children.
It develops from specialised nerve cells (neuroblasts) left behind from a baby's development in the womb.
Neuroblastoma most commonly occurs in 1 of the adrenal glands situated above the kidneys, or in the nerve tissue that runs alongside the spinal cord in the neck, chest, tummy or pelvis.
It can spread to other organs, such as the bone marrow, bone, lymph nodes, liver and skin.
It affects around 100 children each year in the UK and is most common in children under the age of 5.35
From an in vitro study by Sengupta et al (2000)36:
Abstract
The tumour suppressor p53 and the glucocorticoid receptor (GR) respond to different types of stress. We found that dexamethasone-activated endogenous and exogenous GR inhibit p53-dependent functions, including transactivation, up- (Bax and p21WAF1/CIP1) and down- (Bcl2) regulation of endogenous genes, cell cycle arrest and apoptosis. GR forms a complex with p53 in vivo, resulting in cytoplasmic sequestration of both p53 and GR. In neuroblastoma (NB) cells, cytoplasmic retention and inactivation of wild-type p53 involves GR. p53 and GR form a complex that is dissociated by GR antagonists, resulting in accumulation of p53 in the nucleus, activation of p53-responsive genes, growth arrest and apoptosis. These results suggest that molecules that efficiently disrupt GR–p53 interactions would have a therapeutic potential for the treatment of neuroblastoma and perhaps other diseases in which p53 is sequestered by GR.
And from 2006, Zhang et al also conducted an in vitro study . But this time they investigated GR complexes with both p53 and its relative, the structural and functional homolog p7337.
Unlike p53, p73 also possesses context sensitive oncogenic potential38.
Abstract
Background
p53 is a tumor suppressor and potent inhibitor of cell growth. P73 is highly similar to p53 at both the amino acid sequence and structural levels. Given their similarities, it is important to determine whether p53 and p73 function in similar or distinct pathways. There is abundant evidence for negative cross-talk between glucocorticoid receptor (GR) and p53. Neither physical nor functional interactions between GR and p73 have been reported. In this study, we examined the ability of p53 and p73 to interact with and inhibit GR transcriptional activity.
Results
We show that both p53 and p73 can bind GR, and that p53 and p73-mediated transcriptional activity is inhibited by GR co-expression. Wild-type p53 efficiently inhibited GR transcriptional activity in cells expressing both proteins. Surprisingly, however, p73 was either unable to efficiently inhibit GR, or increased GR activity slightly. To examine the basis for this difference, a series of p53:p73 chimeric proteins were generated in which corresponding regions of either protein have been swapped. Replacing N- and C-terminal sequences in p53 with the corresponding sequences from p73 prevented it from inhibiting GR. In contrast, replacing p73 N- and C-terminal sequences with the corresponding sequences from p53 allowed it to efficiently inhibit GR. Differences in GR inhibition were not related to differences in transcriptional activity of the p53:p73 chimeras or their ability to bind GR.
Conclusion
Our results indicate that both N- and C-terminal regions of p53 and p73 contribute to their regulation of GR. The differential ability of p53 and p73 to inhibit GR is due, in part, to differences in their N-terminal and C-terminal sequences.
Dexamethasone acts as a ligand to enhance binding between GRs and p53, in this case to form a complex.
In coordination chemistry, a ligand[a] is an ion or molecule (functional group) that binds to a central metal atom to form a coordination complex.39
Glucocorticoid receptor (GR) is a nuclear receptor and ligand-dependent transcription factor (reviewed in [21, 22]). GR belongs to the superfamily of steroid nuclear receptors that also includes estrogen receptor (ER), androgen receptor (AR), and progesterone receptor (PR). In the absence of ligand, GR is inactive and resides in the cytoplasm in complex with chaperones such as Hsp90. Ligand-binding promotes dissociation of GR from cytoplasmic complexes and its translocation to the nucleus, where it can then activate transcription of its target genes. The effect of activating GR appears to be cell-type specific. GR activation has been reported to promote survival and inhibit apoptosis in mammary epithelial cells, breast cancer cells, neuroblastoma cells, and other cell types [23–28]. In contrast, GR activation in thymocytes triggers apoptosis (reviewed in [29]). There is compelling evidence for cross-talk between GR and p53. Binding between GR and p53 has been demonstrated both in vitro and in vivo, and their interaction can lead to the mutual inhibition of both proteins [27, 28]. The GR ligand dexamethasone has been reported to enhance binding between GR and p53 and, under certain conditions, to cause their cytoplasmic sequestration and degradation [28]. Complexes of p53 and GR may also contain MDM2, a p53-responsive protein that can act as an E3 ubiquitin ligase to promote degradation of both p53 and GR [28]. These findings have suggested that GR could enhance survival by sequestering p53 in the cytoplasm and, conversely, that p53 might enhance cell death by sequestering GR in the cytoplasm and blocking its survival function.
If you are on chemotherapy or radiotherapy for a type of cancer malignancy that correlates positively with increased PKCϵ expression or decreased p53 levels then corticosteroids may be contraindicated.
Somebody just needs to tell this to the cancer charities and NHS. I won’t reproduce their webpages in full here but take it from me that in-your-face suppression of the effectiveness of chemo or radiotherapy is not discussed:
Even the British National Formulary (BNF) doesn’t mention the C-word, not even once, not even as a remotely related consideration or contraindication.
This is somewhat curious considering the widespread, long term systemic effects on the endocrine and immune system.
90 years after they were first developed and its turtles all the way down. Even now the mechanisms aren’t fully understood and effects on cancer progression are almost never discussed or investigated clinically:
Data Bridge Market Research analyses that the chemotherapy drug market was valued at USD 42,909.37 million in 2021 and is expected to reach USD 89,338.07 million by 2029, registering a CAGR of 9.60% during the forecast period of 2022 to 202941.
More is better for the health of your shareholders, if not for the patient.
If they worked so well shouldn’t the trend go in the opposite direction?
The subscription model pays well, whatever the industry:
Shantanu Narayen is chair and chief executive officer of Adobe, one of the largest and most diversified software companies in the world.
…As CEO, Shantanu has transformed the company into an industry innovator by pioneering a cloudbased subscription model for its creative suite.
…Shantanu is vice chairman of the US-India Strategic Partnership Forum and sits on the board of Pfizer.42
An in vivo study
In 1997, Bronson & Matherine conducted an in vivo study into the effects of anabolic steroids on adult mice43. The results were startling:
Abstract
Adult male laboratory mice were exposed for 6 months to a combination of four anabolic-androgenic steroids of the kinds and at the relative levels to which human athletes and body builders expose themselves. The four steroids included testosterone, two 17-alkylated steroids, and an ester, and they were given at doses that totaled either 5 or 20 times normal androgenic maintenance levels for mice. By the time the survivors were 20 months old (1 yr after the termination of steroid exposure), 52% of the mice given the high dose of steroids had died compared with 35% of the mice given the low dose and only 12% of the control mice given no exogenous hormones (P < 0.001). Autopsy of the steroid-treated mice typically revealed tumors in the liver or kidney, other kinds of damage to these two organs, broadly invase lymphosarcomas, or heart damage, and usually more than one of these conditions.It can be concluded that the life span of male mice is decreased dramatically by exposing them for 6 months to the kinds and relative levels of anabolic steroids used by many athletes and body builders.
Anabolic androgenic steroids are often used by athletes and body builders in an effort to improve their performance or appearance, in many cases starting in high school(9,10,16,26). Athletes and body builders often take as many as five different steroids simultaneously, usually including testosterone, injectable esters of testosterone, and analogues that can be taken orally (17,23). The combined doses of these hormones typically total 10-40 times normal androgenic maintenance levels(15,17), and often the steroids are taken in combination with growth hormone and IGF-1 (12). Usually the steroids are taken in cycles, starting several weeks or months prior to competition, followed by a washout period of weeks or months. This pattern of use can continue for years(15).
The potential pathological consequences of exposure to such high levels of steroids have been of continuing concern for some time now(11,12,14,17). In an overview of the state of our knowledge about this subject, Friedl (11) concludes that “.... an athlete would be foolish to conclude that there is a safe way to use anabolic steroids; although no disease of androgen excess has ever been described for men, the long-term consequences of androgen supplementation have not been investigated and are simply unknown.” Reviews of case histories suggest that men using steroids may show a marked increase in liver disorders, including liver tumors, a decrease in fertility, and a shift in the serum lipoprotein profile in a way that could indicate an increased risk of heart disease(11,12,19).
You need to exercise caution in interpreting the results, but some of the induced pathologies do indeed correlate well with case reports from athletes and body builders:
DISCUSSION
The object of this study was to use the male laboratory mouse as an animal model with which to suggest potential pathological consequences of steroid abuse by male athletes and body builders. The degree to which the results are relevant to humans depends on two factors: the degree to which the parameters of exposure in this experiment mimic those occurring in humans and the degree to which the specific pathological effects seen in mice mimic those seen in humans.
As detailed earlier, the numbers, kinds, and relative doses of steroids to which our mice were exposed are quite like the numbers, kinds, and relative doses of steroids to which athletes and body builders expose themselves. Indeed, the low dose we gave our mice is quite a bit lower than the doses typically used by athletes and body builders. As noted earlier, athletes and body builders usually take steroids in doses totally 10-40 times maintenance level (15,17), while our mice were given doses of either 5 or 20 times maintenance level (for mice).
On the other hand, the duration of exposure to which our mice were subjected may not be typical of that occurring in humans, depending on how one evaluates duration in relation to life span. Most male mice live to 30 months(and a few are still functioning sexually at 3 yr of age)(6). Thus 6 months of exposure to steroids is about one-fifth of a male mouse's life expectancy. This is undoubtedly longer than the duration to which most athletes and body builders expose themselves. Constant exposure over this period of time, without periodic washout periods, is also atypical of human use. Given all of these comparisons, we are probably only safe in concluding that the exposure parameters used in this experiment may be generalized for extreme steroid abusers.
Some of the pathological conditions seen in steroid-treated mice are similar to those seen in athletes and body builders and some are not. In the latter category are the two kinds of kidney damage seen in mice-the direct toxic effect on the glomeruli that killed many mice during the first year of their lives and the development of kidney tumors at later ages. There is only one report of a kidney tumor in a human athlete (18) and no suggestion of a direct nephrotoxic effect in either athletes(11,12) or nonathletes given higher-than-maintenance levels of androgens in clinical trials (e.g., in tests of the utility of androgens to act as male contraceptives(21)).
In contrast, the kinds of liver damage seen here in mice, most typically hepatocytic carcinoma and peliosis hepatis, are some of the most common pathological effects seen in athletes and body builders(19). The fact that suprapharmacological amounts of anabolic steroids can damage the liver of rodents in a variety of ways, including the induction of tumors, has been reported previously(22). The results of the present experiment demonstrate that the kinds of liver damage seen in athletes can be induced in mice using the same numbers, kinds, and relative amounts of steroids used routinely by athletes and weight lifters. Thus, our results with mice support the hypothesis that steroid abuse can result in serious liver damage. Friedl's(11) analysis of case histories suggests that 17-alkyl-substituted androgens cause liver damage while androgen esters do not. Thus, ultimately the effects seen in mice in this experiment may be traceable only to exposure to methyltestosterone and norethandrolone.
Perhaps the most important result of the present study is the demonstration that exposure to steroids produces a broad array of pathological effects that do not appear until long after exposure to steroids ceases. There is little comparable data for humans (7). Widespread use of steroids did not occur until the 1970s and, probably more germane, the practice of“stacking” or combining several analogues of testosterone at suprapharmacological levels did not become common until the 1980s(25). Thus, the delayed effects of steroid abuse seen here in mice and the consequent dramatic effect on life span may ultimately prove to be a concern for athletes and body builders abusing steroids regardless of specific pathological condition.
Although reports of aggressive turbo-cancers are becoming more common due to mass exposure to spike protein from various sources, the latency period of cancers is usually measured in decades:
One of the few publications that is actually critical of their use in cancer patients and got past the censors was an editorial by Rescigno & di Lorenzo (2014)44:
The potential detrimental effect of corticosteroids in prostate cancer
Diagnosis of prostate cancer (PC) at local or regional stages is associated with an excellent prognosis [1]; however, patients with metastatic PC generally achieve only temporary disease control with hormonal therapy and they eventually develop disease progression despite castrate serum androgen levels. In the last years the number of drugs available for metastatic castration-resistant prostatic cancer (mCRPC), such as abiraterone, cabazitaxel, enzalutamide and sipuleucel-T, has rapidly increased [2]. Some of them, such as the classic chemotherapeutic docetaxel, require the concomitant use of corticosteroids. The large use of corticosteroids should lead physicians to question themselves regarding the long-term use of glucocorticoids and their role in PC and especially in advanced disease.
Corticosteroids are commonly used in the treatment of cancer due to their anti-inflammatory activities, and they have a direct effect on tumor-induced pain, secondary to bone metastases. [3] Thus, corticosteroids are used both to manage tumor-related symptoms and to counteract toxic effects and side effects associated with prostatic anticancer drugs; they delay the onset of fluid retention induced by docetaxel [4] and they can also help to prevent the mineralocorticoid syndrome secondary at abiraterone acetate administration [5].
AR: androgen receptor.
Grade 3 events are serious and interfere with a person's ability to do basic things like eat or get dressed. Grade 3 events may also require medical intervention.
Grade 4 events are usually severe enough to require hospitalization.45
The AFFIRM trial demonstrated the efficacy of enzalutamide, an irreversible AR inhibitor, as a second-line therapy in mCRPC after docetaxel failure [14]. Analyzing demographic characteristics of the AFFIRM population, patients who received corticosteroids were generally sicker and had more advanced disease. In multivariate analysis of baseline prognostic factors, the corticosteroid use was associated with reduced survival and adverse side effects, such as the presence of visceral metastases and anemia.
Moreover, although enzalutamide showed its efficacy compared with placebo in both the noncorticosteroid- and corticosteroid-treated groups, overall survival, radiologic progression-free survival and prostate-specific antigen progression were all inferior in the corticosteroid-treated group.With regard to toxicity, patients on corticosteroids had higher rates of grade 3–4 adverse events compared with no corticosteroid patients (63.3 vs 34.4%, respectively) [15].
Similarly, in the COUAA-301 trial, which evaluated the efficacy of abiraterone after docetaxel in mCRPC [16], the role of corticosteroids at baseline was studied. Corticosteroids at baseline included prednisone, dexamethasone and other corticosteroids (n = 489), while 797 patients were not treated with corticosteroids. In this study, corticosteroids at baseline was not a strong independent prognostic factor in mCRPC postdocetaxel treatment, but was associated with worse baseline disease characteristics and inferior overall survival [17].
Alternatives are available:
At present, we have medical options that do not need the additional use of steroids such as enzalutamide or alpharadin. As previously stated, enzalutamide demonstrated the efficacy as a second-line therapy in CRPC in the AFFIRM trial [14].
…Alpharadin is a calcium-mimetic radiopharmaceutical that accumulates in bones and emits α-radiation from radium-223 decay and releases relatively high energy with a narrow range (2–10 cells). Following promising results in a Phase II trial, the Phase III ALSYMPCA trial was conducted in mCRPC patients with symptomatic bone metastases, who either had received or were ineligible for docetaxel. Patients received six doses of alpharadin 50 kBq/kg intravenously every 4 weeks.
At the interim analysis, which involved 809 patients, radium-223, as compared with placebo, significantly improved overall survival (median: 14.0 vs 11.2 months; hazard ratio: 0.70; p = 0.002). The updated analysis involving 921 patients confirmed the radium-223 survival benefit (median: 14.9 vs 11.3 months; hazard ratio: 0.70; p < 0.001). Assessments of all main secondary efficacy end points also showed a benefit of radium-233 compared with placebo. Radium-223 was associated with low myelosuppression rates and fewer adverse events [18]. However radium-233 is effective only in patients with bone metastases and cannot be used in visceral or lymph node disease.
As at 2014, no randomized trials had been conducted to investigate the efficacy of alternatives to using corticosteroids:
Treatment options for CRPC patients have greatly increased in recent years and several active agents can be offered to our patients [19]. To date, there are no randomized trials comparing these agents and no predictive models or biomarkers are able to identify patients who are likely to benefit from any of these drugs. Therefore, the choice of therapy is based on clinical expertise. Physicians should take greater account of late sequelae related to long-term corticosteroid use; a patient history should be collected and corticosteroids should be managed carefully in diabetic, hypertensive or obese patients, weighing the pros and cons of their use. Chemotherapeutic agents that require concomitant use of corticosteroids should be avoided, or it proposal of eliminating concomitant steroid use or other available medical options that do not require the additional use of steroids, should be preferred.
No financial & competing interests disclosures were made.
Late breaking story
Self explanatory, and of course the previously discussed pathology shows that it may well have been a factor in his lung cancer origin and later metastasis, especially as this correlates strongly with p53 suppression.
Actor Dolph Lundgren Questions Whether Steroids Are to Blame for Cancer Diagnosis
Hollywood actor Dolph Lundgren has revealed that he has been battling cancer for the past eight years and has said the condition could have been brought on by his past steroid use.
The actor, who's best known for his portrayal of Ivan Drago in Rocky IV and Creed 2, opened up about his condition with interviewer Graham Bensinger on his show In Depth with Graham Bensinger.
In the interview, he explained how he was first diagnosed with lung cancer in 2015. Following a period in remission, his cancer returned in 2020, and Lundgren was told by one doctor that he only had a couple of years left to live.
However, the star sought a second opinion and his current treatment has resulted in his tumours shrinking.
Lundgren first revealed the news while also paraphrasing a memorable line from Rocky IV. Speaking in 2020 and still wearing a hospital gown, he said: ‘It's the day after my surgery, they took out one tumour, then they took out another two they found and another three small ones.
‘Hopefully it's cleaned out. If it dies, it dies.’
Sitting down for an interview with Bensinger, Lundgren went on to share how he's not sure the impact his past steroid use had on his current condition, revealing that he was on steroids – on and off – for around 10 years.
‘I tried steroids back in the 80s, 90s. I don't know if that is something to do with the cancer, of course it struck me as it could have something to do with it,’ Lundgren said.
‘I thought about it, you always think you've made a mistake. I think maybe there is some connection between testosterone therapy and cancer.
‘I was on steroids when I was younger, on and off for maybe ten years. Depending on the kind of movie I made.’
Alternatives to steroids
Apart from diseases caused by the immune system itself, steroids are something of a sledgehammer to crack a nut and do little to target the underlying causes of the disease, they mostly target the symptoms.
From a review by Baughman & Lower (1997) alternatives to steroids are discussed as treatments for sarcoidosis47.
Sarcoidosis is an inflammatory disease in which the immune system overreacts, causing clusters of inflamed tissue called "granulomas" to form in different organs of the body. Sarcoidosis most commonly affects the lungs and lymph nodes, but it can also affect the eyes, skin, heart and nervous system48.
One of the proposed alternatives you will have heard of:
The treatment of sarcoidosis is controversial and complicated because therapy must be tailored to the individual patient. Some patients require no specific therapy, whereas others may require a lifetime of treatment. Corticosteroids have been the standard form of treatment for symptomatic sarcoidosis patients since the early observations regarding their benefit in that disease.52, 100, 122Randomized trials have not been able to demonstrate long-term benefit for corticosteroid therapy.48, 98, 121 Because of side effects associated with corticosteroid therapy, many have sought alternatives.
The choice of an alternative agent for sarcoidosis depends on the expected duration of therapy. For patients with acute disease such as erythema nodosum, the use of nonsteroidal anti-inflammatory drugs (NSAIDs) may be useful. Whether or not the patient is treated, her symptoms often resolve within 2 to 4 months and further therapy becomes unnecessary. Other manifestations of the disease require different strategies.
The full review is paywalled:
Section snippets
CYTOTOXIC AGENTS
For patients with chronic or refractory disease, cytotoxic drugs are used to avoid further complications with corticosteroids. In that situation, the treating physician may be willing to trade off speed of drug onset for the long-term benefit of lowered toxicity. Drugs such as methotrexate and azathioprine may take several months to affect the disease.
Cytotoxic drugs have been used for many years for non-neoplastic inflammatory diseases such as rheumatoid arthritis, lupus erythematosus, and
Antimalarial Agents
Chloroquine and hydroxychloroquine were originally developed as antimalarial agents. They were noted to have anti-inflammatory activity, especially in rheumatoid arthritis. The use of chloroquine and hydroxychloroquine for sarcoidosis has a relatively long history.102 They have been described primarily in anecdotal reports and few series have reported their usefulness. In studies of cutaneous sarcoidosis,56 these drugs seem to have about a 35% response rate.
Aspirin
For this paper we are going back to 195949, and salicylate use to treat RA can be traced back much earlier50.
The initial dose of aspirin is huge (6.0g) and may have skewed the side effects profile somewhat:
A COMPARISON OF PREDNISOLONE WITH ASPIRIN OR OTHER ANALGESICS IN THE TREATMENT OF RHEUMATOID ARTHRITIS
REPORT BY THE JOINT COMMITTEE OF THE MEDICAL RESEARCH COUNCIL AND NUFFIELD FOUNDATION ON CLINICAL TRIALS OF CORTISONE, ACTH, AND OTHER THERAPEUTIC MEASURES IN CHRONIC RHEUMATIC DISEASES*
The results of previous trials conducted by the Joint Committee (1954, 1955, 1957a) showed that there was little to choose between cortisone and aspirin in the long-term management of patients with rheumatoid arthritis, and a similar result was obtained in a trial conducted by the Empire Rheumatism Council (1955, 1957). Since the time of these trials many analogues of cortisone have been introduced, and, of these, prednisone and prednisolone appeared to be particularly suitable for the treatment of rheumatic diseases. Further trials were therefore initiated by the Joint Committee in 1955. In the first of these prednisone was compared with cortisone in the long-term treatment of rheumatoid arthritis. The results of this trial, which have already been published (1957b), showed that for this purpose prednisone was better than cortisone. The present report concerns another trial in which prednisolone was compared with aspirin or other analgesics in the treatment of patients with rheumatoid arthritis.
Methods and Material
Diagnostic Criteria
The criteria for entry into the trial were similar to those used previously, and patients of either sex between the ages of 17 and 59 years were admitted if they had a rheumatoid type of arthritis of from 3 to 24 months' duration affecting more than three joints with bilateral involvement of hands or feet, ankles or wrists. A sheep cell agglutination test was done on all patients entering the trial, but the results of this test were not included in the criteria for entry.
Treatment
The general management of the patients in terms of rest, splintage, exercise, and physiotherapy was to be that used currently in each participating centre. Within each centre one group of patients received prednisolone in an initial dosage of 20 mg. daily, to be adjusted subsequently on an individual basis to give the maximum therapeutic response obtainable without serious side-effects. To a second group aspirin or other analgesics were given; most patients in this group received aspirin in an initial daily dose of 6.0 g. though seven of the 39 patients received phenylbutazone instead with an initial daily dose of 400 mg. For allocation to one or other group, randomized treatment orders, stratified for sex and for disease duration of under or over 9 months, were prepared for each of the eight participating centres separately.
Hypertension threshold was defined as 160/90:
Complications and Side-Effects
The incidence of the defined side-effects of therapy listed on the record form is shown in Table XI. These were mainly of a minor character and require no comment. The changes in blood pressure are shown in Table XII. There was a greater tendency for the blood pressure to rise in the prednisolone group, but hypertension did not become a therapeutic problem in any patient during the period of the trial.
…Of the eight patients in the trial who received 20 mg. prednisolone daily over 3 months, four had evidence of peptic ulceration and a fifth developed psychosis-a proportion of serious complications which is clearly unacceptable, and this high incidence of complications with high dosage accords with the experience of others (Howell and Ragan, 1956; Black, Yielding, and Bunim, 1957).
The differential sheep-cell agglutination test gave a positive indication in 60% of cases of confirmed RA back in 1949:
The results of more than 700 tests on more than 300 patients and controls were analysed. A positive test was obtained on at least one occasion from 60 per cent, of 124 patients with clinical rheumatoid arthritis of adult type. A strongly positive result was almost pathognomonic of rheumatoid arthritis, if disseminated lupus erythematosus and hepatitis were excluded. A negative result was less useful, since 40 per cent, of cases of rheumatoid arthritis were negative51.
Conclusions
From the results of this trial it may be concluded that the administration of prednisolone instead of, or in addition to, analgesics, such as aspirin, to certain patients with rheumatoid arthritis for a period of 2 years will, on average, improve their functional capacity and general well-being and reduce the incidence of erosive joint damage; but more patients are likely to show a rise in sheep cell agglutinating titre, and the significance, if any, for the patients' future is not yet known. If the daily dose of prednisolone approaches 20 mg., undesirable side-effects are likely to occur and the highest acceptable daily dose for long-term therapy is probably in the region of 10 mg.
Although possibly less effective than prednisolone for treating RA, aspirin has some significant advantages over steroids which aren’t limited just to cost and availability.
Not only is the side effects profile much more benign, but significant anti-cancer effects were found in this large scale cohort analysis from Hong Kong by Tsoi et (2019)52:
Abstract
Aspirin, commonly used for prevention of cardiovascular and cerebrovascular diseases, has been found to possess protective effects against cancer development in the Western populations. Such effects among Asian populations remain uncertain. The objective of this study is to investigate the use of aspirin on prevention of different cancers among Chinese users. This population-based study utilized database from the Hong Kong Hospital Authority; adults with aspirin prescription for at least 6 months between 2000 and 2004 were included and followed up until 2013. Aspirin users were age-sex matched with non-aspirin users at a 1:2 ratio. Incidences of cancer were the primary outcome measured by relative risk (RR). A total of 204,170 aspirin users and 408,339 non-aspirin users were included, with the mean age 67.5 years, 7.7 years average duration of aspirin prescription and 80 mg as the median dose of aspirin. Cancer incidences were found in 26,929 (13.2%) aspirin users and 70,755 (17.3%) non-aspirin users. Compared with patients who had not been prescribed aspirin, aspirin usage led to significant reduction of cancers in liver (RR: 0.49), stomach (RR: 0.42), colorectum (RR: 0.71), lung (RR: 0.65), pancreas (RR: 0.54), oesophagus (RR: 0.59) and leukaemia (RR: 0.67). There was no demonstrable reduction of kidney cancer, bladder cancer, prostate cancer and multiple myeloma in association with the usage of aspirin. Risk of breast cancer was shown to marginally increase (RR: 1.14) with aspirin usage.This study demonstrated that the long-term use of low-dose aspirin is associated with the reduction in risk of various cancers but not for breast cancer. Further investigation is needed before promoting aspirin as a primary chemoprotective agent.
Keywords: Chinese; Hong Kong; aspirin; cancer incidence; long-term.
Cardioprotective aspects of low dose aspirin were discussed by Patrono (2013) and are significant53. I won’t go into great detail here as it’s a little out of scope and worthy of its own write up, but the message is that aspirin has a much more favourable therapeutic profile than CSs for some conditions:
Abstract
Low-dose aspirin has been shown to be effective in preventing about one-fifth of atherothrombotic vascular complications (non-fatal myocardial infarction, non-fatal stroke, or vascular death) in a meta-analysis of 16 secondary prevention trials in patients with previous myocardial infarction, stroke, or transient cerebral ischaemia. This corresponds to an absolute reduction of about 10-20 per 1000 patients in the yearly incidence of non-fatal events, and to a smaller, but still definite, reduction in vascular death. Against this benefit, the absolute increase in major extracranial bleeding complications [mostly, gastrointestinal (GI)] is 20- to 50-fold smaller, depending on age and sex. Hence, for secondary prevention, the benefits of antiplatelet therapy substantially exceed the risks. For primary prevention, the balance between vascular events avoided and major bleeds caused by aspirin is substantially uncertain because the risks without aspirin, and hence the absolute benefits of antiplatelet prophylaxis, are at least an order of magnitude lower than in secondary prevention. The aim of this article is to review the updated evidence for the efficacy and safety of low-dose aspirin in primary prevention and to discuss additional health benefits resulting from prolonged antiplatelet therapy in apparently healthy people at low average risk of vascular events.
Keywords: Aspirin; Chemoprevention of cancer; Major bleeding complications; Major vascular events; Primary prevention
Some mechanistic considerations to interpret clinical trial results
Before discussing the results of aspirin trials in primary prevention, it seems appropriate to review briefly the unique features of aspirin's pharmacokinetics (PK) and pharmacodynamics (PD) in inhibiting platelet function.4,5The drug permanently inactivates the cyclooxygenase (COX) activity of the platelet enzyme, prostaglandin (PG)G/H-synthase-1 (also referred to colloquially as COX-1), responsible for the first committed step in prostanoid biosynthesis. In human platelets, this results in dose- and time-dependent inhibition of thromboxane (TX)A2 formation. Platelet TXA2 production represents an important amplification mechanism of platelet activation, by virtue of its being triggered in response to any platelet agonist and in turn inducing further platelet recruitment and aggregation.6In healthy subjects, inhibition of platelet TXA2 production by aspirin is cumulative upon repeated daily dosing and saturable at low doses (≥30 mg) because of its irreversible nature.7In contrast to the uniform effectiveness of low-dose aspirin in blocking platelet COX-1 activity in healthy individuals,8some clinical conditions are associated with suboptimal antiplatelet effects of aspirin. These include patients following coronary artery bypass surgery,9 patients with essential thrombocythaemia,10 patients with coronary artery disease who have metabolic syndrome (independently of diabetes mellitus),11 and type 2 diabetes mellitus.12 The mechanisms of suboptimal aspirin effect in these conditions are likely related to the fact that they all are associated with increased in vivo platelet activation.6 Thus, impaired acetylation of platelet COX-1 could result from accelerated platelet turnover,10 or from platelet activation-induced generation of hydroperoxides that are known to impair the acetylation of COX-isozymes by aspirin.13Given the short half-life (∼20 min) of aspirin in the human circulation, the long-lasting duration of its antiplatelet effect is ensured by acetylation of COX-1 in bone-marrow megakaryocytes and limited de novo protein synthesis in blood platelets.4,5 These factors typically allow a once daily regimen of aspirin administration, when the drug is used as an antiplatelet agent. However, changes in the systemic bioavailability of the drug, as may occur with some enteric-coated formulations and in association with obesity,14 or faster renewal of the drug target, as may occur in association with altered megakaryopoiesis,15 may limit the duration of its antiplatelet effect and require a different (e.g. bid) dosing regimen.15,16
Hydroxychloroquine
HCQ’s track record is long established for treating RA effectively, with a much more benign side effects profile.
As with ivermectin, HCQ is somewhat demonized of late for obvious reasons. You tend to find that most of the more objective, unbiased papers are not recent!
Setting: Ambulatory referral clinic in a Mexico City, Mexico, teaching hospital.
Patients: A total of 126 patients with early rheumatoid arthritis were randomly assigned to receive hydroxychloroquine, 400 mg/d, or placebo; 121 patients completed the study.
Results: Hydroxychloroquine showed a clinically and statistically significant improvement over placebo in joint score (20% greater mean improvement; 10% more patients improved by > 50%); pain (40% greater mean improvement; 19% more patients improved by > 50%); grip strength (22% greater mean improvement; 21% more patients improved by > 50%); patient global assessment (16% more patients stated they had improved); and physician global assessment (12% more patients were judged to have improved). Side effects were mild, and no patients in the hydroxychloroquine group required discontinuation of therapy. Patient compliance with the study medication was high.
Conclusion: Hydroxychloroquine is moderately effective in early rheumatoid arthritis.
And from 2007 arandomized, double-blind, placebo controlled clinical trial from India found similar results. There are several other papers I could include but these are quite representative.
Objective: Hydroxychloroquine (HCQ) has been used for a long time worldwide as a therapy for rheumatoid arthritis (RA). This trial was designed to determine whether HCQ was efficacious and safe in Indian patients with RA.
Research design and methods: The trial was a multicentre, placebo controlled, randomized and double-blind study. One hundred and twenty-two patients with RA were enrolled in 3 different centres for the trial (26 males and 96 females in the age group of 18-60 years). Patients were randomized to receive either hydroxychloroquine tablets (n = 61) two tablets of 200 mg daily or placebo (n = 61) two tablets daily. After 8 weeks all patients received one tablet of hydroxychloroquine 200 mg daily for 4 weeks. Every patient also received one tablet of Nimesulide 100 mg twice daily.
Main outcome measures: Assessment of response at 12 weeks using modified ACR 20 (American College of Rheumatology 20) criteria where Health Assessment Questionnaire (HAQ) was replaced by ARA (American Rheumatology Association) functional class.
Results: 40.4% of patients on hydroxychloroquine showed improvement by modified ACR response criteria whereas only 20.7% (p = 0.02) showed improvement in the placebo group. No significant side effects were observed in any of the patients. There were no ocular toxicities.
Conclusions: Hydroxychloroquine was found to be an effective and well-tolerated drug in rheumatoid arthritis in Indian patients.
Hydroxychloroquine works almost as well as steroids for treating proteinuria (excess proteins in the urine) caused by immunoglobulin A antibody induced nephropathy (kidney damage, often caused by diabetes).
Most importantly it is safer long term, and what adverse effects have been reported appear to have been caused by or increased significantly by drug interactions. Plus you need to dig deep through meta-analysis to find a signal54.
Safety of Long term use of Hydroxychloroquine Therapy Further Verified for People with Lupus
Hydroxychloroquine (Plaquenil®) was approved by the Food and Drug Administration for symptoms of lupus. The greatest concern people with lupus have when taking hydroxychloroquine is related to vision and an increase in risk for retinal damage. A new investigation analyzed the retinal changes over a five-year period in people with lupus and did not find clinically relevant retinal changes in the group. The study concludes that hydroxychloroquine therapy is safe for long-term use at doses <5 mg/kg/day.56
From a case controlled study by Yang et al (2019)57:
Abstract
Background
Hydroxychloroquine (HCQ), a well-known immunomodulator, has recently been found to be a promising and safe anti-proteinuric agent for treating IgA nephropathy (IgAN). We aimed to compare the efficacy and safety of HCQ and corticosteroid treatment in patients with IgAN.
Methods
This is a case-control study. Ninety-two patients with IgAN who received HCQ in addition to routine renin-angiotensin-aldosterone system inhibitors (RAASi) therapy were included. Ninety-two matched historical controls who received corticosteroids were selected by propensity score matching. The clinical data over 6 months were compared.
Results
Baseline proteinuria levels were comparable between the HCQ and corticosteroid groups (1.7 [1.2, 2.3] vs. 1.8 [1.3, 2.5] g/d, p = 0.96). The percentage reduction in proteinuria at 6 months was smaller in the HCQ group than in the corticosteroid group (− 48.5% [− 62.6, − 31.4] vs. -62.9% [− 81.1, − 34.9], p = 0.006). The time averaged proteinuria within the 6 months of observation was comparable for the HCQ and corticosteroid groups (1.1 [0.8, 1.5] vs. 1.1 [0.5, 1.8] g/d, p = 0.48). The cumulative frequency of patients with a 50% reduction in proteinuria during the study was also comparable between the two groups (52.2% vs. 62.0%, p = 0.25). However, six of the 92 (6.5%) patients suffered from severe adverse events (SAEs) in the corticosteroid group, while no SAEs were observed in the HCQ group (6.5% vs. 0%, p = 0.03).
Conclusions
The antiproteinuric effect of HCQ might be slightly inferior to that of corticosteroids over 6 months in patients with IgAN who were deemed to be candidates for HCQ and not corticosteroids treatment. However, HCQ treatment was safer than corticosteroid treatment.
Metformin
From 2020 and Pernicova et al published the results of a randomised, double-blind, placebo controlled trial which investigated the use of metformin for reducing the symptoms and complications of treating Cushing's syndrome with the steroid prednisolone.
Results were encouraging, considering the short duration of the trial (only 12 weeks). It would be interesting to have longer term data too58:
Cushing's syndrome is a disorder that occurs when your body makes too much of the hormone cortisol over a long period of time. Cortisol is sometimes called the “stress hormone” because it helps your body respond to stress. Cortisol also helps. maintain blood pressure. regulate blood glucose, also called blood sugar59.
Abstract
Background: An urgent need to reduce the metabolic side-effects of glucocorticoid overexposure has been recognised, as glucocorticoid excess can lead to Cushing's syndrome, which is associated with high morbidity. We aimed to evaluate the potential of metformin to reverse such effects while sparing the anti-inflammatory benefits of glucocorticoids.
Methods: We did a randomised, double-blind, placebo-controlled, proof-of-concept, phase 2 trial involving four hospitals in the UK. Patients without diabetes were eligible if they were between the ages of 18 and 75 years with an inflammatory disease treated with continuous prednisolone (≥20 mg/day for ≥4 weeks and remaining on ≥10 mg/day for the subsequent 12 weeks, or its cumulative dose-equivalent). Eligible patients were randomly allocated (1:1) to either the metformin or placebo groups, using a computer-generated randomisation table stratified according to age and BMI. Metformin and placebo were administered orally for 12 weeks in escalating doses: 850 mg/day for the first 5 days, 850 mg twice a day for the next 5 days, and 850 mg three times a day subsequently. The primary outcome was the between-group difference in visceral-to-subcutaneous fat area ratio over 12 weeks, assessed by CT. Secondary outcomes included changes in metabolic, bone, cardiovascular, and inflammatory parameters over 12 weeks. Our analysis followed a modified intention-to-treat principle for the primary outcome. This study is registered with ClinicalTrials.gov, NCT01319994.
Findings: Between July 17, 2012, and Jan 14, 2014, 849 patients were assessed for study eligibility, of which 53 were randomly assigned to receive either metformin (n=26) or placebo (n=27) for 12 weeks. 19 patients in the metformin group and 21 in the placebo group were eligible for the primary outcome analysis. Both groups received an equivalent cumulative dose of glucocorticoids (1860 mg prednisolone-equivalent [IQR 1060-2810] in the metformin group vs 1770 mg [1020-2356] in the placebo group); p=0·76). No change in the visceral-to-subcutaneous fat area ratio between the treatment groups was observed (0·11, 95% CI -0·02 to 0·24; p=0·09), but patients in the metformin group lost truncal subcutaneous fat compared with the placebo group (-3835 mm2, 95% CI -6781 to -888; p=0·01). Improvements in markers of carbohydrate, lipid, liver, and bone metabolism were observed in the metformin group compared with the placebo group. Additionally, those in the metformin group had improved fibrinolysis, carotid intima-media thickness, inflammatory parameters, and clinical markers of disease activity. The frequency of pneumonia (one event in the metformin group vs seven in the placebo group; p=0·01), overall rate of moderate-to-severe infections (two vs 11; p=0·001), and all-cause hospital admissions due to adverse events (one vs nine; p=0·001) were lower in the metformin group than in the placebo group. Patients in the metformin group had more events of diarrhoea than the placebo group (18 events vs eight; p=0·01).
Interpretation: No significant changes in the visceral-to-subcutaneous fat area ratio between the treatment groups were observed; however, metformin administration did improve some of the metabolic profile and clinical outcomes for glucocorticoid-treated patients with inflammatory disease, which warrants further investigation.
Funding: Barts Charity and Merck Serono.
Metformin has clinical value for treating rheumatoid arthritis (RA) too.
Gharib et al conducted a randomised controlled study (2021)60.
Adiponectin (also referred to as GBP-28, apM1, AdipoQ and Acrp30) is a protein hormone and adipokine, which is involved in regulating glucose levels as well as fatty acid breakdown. In humans it is encoded by the ADIPOQ gene and it is produced primarily in adipose tissue, but also in muscle, and even in the brain61.
Abstract
Objective: To evaluate the efficacy and safety of metformin use in rheumatoid arthritis (RA) patients receiving conventional synthetic disease modifying anti-rheumatic drugs (csDMARDs). Methods: A prospective, randomized, controlled, single blinded, study was carried on 66 RA patients with moderate and high disease activity state, receiving csDMARDs. Patients were simply randomized to receive either metformin 850 mg twice daily (Metformin group, n = 33), or placebo twice daily (Control group, n = 33) in addition to their stable anti-rheumatic regimen and followed up for 6 months. Serum C-reactive protein (CRP), disease activity of 28 joints based on CRP (DAS-28-CRP), and quality of life (QOL) were evaluated at baseline and then every 3 months. Moreover, serum adiponectin was assessed at baseline and after 6 months. Results: Sixty patients completed the study. Drop out was due to intolerance to metformin side effects (n = 3) and non-compliance (n = 3). Metformin significantly decreased CRP levels and DAS-28-CRP after 6 months compared to the control group (p-value <0.001). A significant improvement in QOL of metformin group was observed as early as after 3 months (p-value = 0.006) with a continued improvement observed at 6 months (p-value <0.001) compared to the control group. Despite the significantly higher serum adiponectin in the metformin group at baseline, it was significantly reduced after 6 months in the metformin group with median percent change of -63.49% compared to the significant increase in the control group with median percent change of 92.40%. Conclusion: Metformin significantly improved inflammation, disease severity, and QOL in RA patients with high safety profile. Clinical Trial Registration: Clinical-Trials.gov, identifier [NCT08363405].
Keywords: CRP; DAS–28; adiponectin; metformin; quality of life; rheumatoid arthritis.
Tripterygium wilfordii
From Textbook of Natural Medicine Fifth Edition by Joseph E. Pizzorno and Michael T. Murray:
In Chinese medicine, Tripterygium wilfordii Hook F, or thunder god vine, has a long history of use in RA and other autoimmune diseases. Although studies have focused almost exclusively on the root, both the folium and the radix of the plant appear to have anti-inflammatory, analgesic, and immunosuppressive effects that may be effective in treating RA. In a double-blind, placebo-controlled study involving patients with long-standing RA in whom conventional therapy had failed, 80% of those who received a high dose (380 mg/day) of ethanol/ethyl acetate root extract had a positive response (i.e., at least 20% improvement according to the ACR criteria).80 Forty percent of the low-dose (180 mg/day) group also responded positively, compared with none in the placebo group. Another trial demonstrated that 180 mg/day of Tripterygium extract was more effective than sulfasalazine 1 g twice a day.81
Side effects reported for this herb include GI upset, diarrhea, headache, hair loss, menstrual abnormalities, and hypertension. Randomized controlled trials have demonstrated efficacy and decreased adverse reactions from sustained-release tablet,82 topical applications,83 and coadministration with Glycyrrhiza glabra (licorice) root.84 Coadministration of Tripterygium with methotrexate may improve efficacy and decrease side effects compared with methotrexate alone.85
Tripterygium wilfordii Hook f. (TW, Thunder God Vine or Lei Gong Teng) is one of the most representative TTCM herb with great therapeutic potential that has been broadly studied by scientists, not only from China, but also in western laboratories due to its significant immunosuppressive effects and anti-cancer activity. Currently, several patented TCM, made only from TW (a single component TCM prescription), are approved by China FDA and are clinically available, including Tripterygium wilfordii tablets, Tripterygium wilfordii glycosides tablets, and Tripterygium hypoglaucum hutch tablets. These drugs are widely used in clinical settings with a daily dose of 1–1.5 mg tripterygium glycosides (including triptolide and celastrol)/kg/day for immunosuppression following organ transplantation and the treatment of autoimmune and inflammation-related diseases, such as rheumatoid arthritis (RA), multiple sclerosis, diabetic nephritic syndrome, Lupus, Behcet's disease, and central nervous system (CNS) diseases. Although occasional, but severe, adverse effects were found during clinical practice, these drugs are still not replaceable due to their significantly stronger efficacy against diseases when compared to other drugs.
In a 2016 review by Wang et al they performed meta-analysis on the use of T. wilfordii to treat RA instead of conventional synthetic disease modifying anti-rheumatic drugs (DMARDs)63:
Abstract
Background
Tripterygium wilfordii Hook F (TwHF), a medicinal plant that has been widely used in Chinese traditional medicine, is proven effective for treating rheumatoid arthritis (RA), but its clinical efficacy and safety remain largely undefined in comparison with conventional synthetic disease modifying anti-rheumatic drugs (DMARDs).
Methods
PubMed, Embase, Cochrane Library, CNKI, VIP, CBM, and WanFang Databases. Endpoints were ACR 20, 50, and 70, and the number of withdrawals due to adverse events. Initially, traditional pairwise meta-analysis was performed by using a random-effects model. Then, we performed network meta-analysis to compare different therapies by using frequentist approach.
Results
A total of 22 trials (5255 participants) were identified. By direct comparison, TwHF was superior to sulphasalazine according to ACR 20, 50 and 70. TwHF was superior to placebo according to ACR 20 and 50. By indirect comparisons, TwHF was superior to methotrexate, leflunomide, sulphasalazine, tacrolimus, minocycline and placebo according to ACR 20.Ranking by the Surface under the Cumulative Ranking curve (SUCRA) values showed that TwHF had the greatest probability for being the best treatment option according to ACR 20 (92.0 %) and ACR 50 (81.3 %), and the highest probability to be in the second (57.8 %) ranking position after leflunomide (69.6 %) according to ACR 70. By both direct and indirect comparisons, TwHF caused no more significant withdrawals than the placebo. The SUCRA values showed that TwHF had the highest probability to rank sixth (26.7 %) after the placebo (45.6 %) in causing withdrawals.
Conclusions
Our data suggest that TwHF is effective and safe in the treatment of RA and has better clinical efficacy in terms of ACR 20 and 50 than existing conventional synthetic DMARDs. In the absence of head-to-head treatment comparison, the confidence in these estimates is low. Future comparative efficacy studies are warranted.
Glucosamine
Published in 2022, Conrozier & Lohse conducted a mini review into the use of glucosamine as treatment for osteoarthritis. Again, findings were encouraging - the importance of addressing long term systemic inflammation cannot be overstated64:
Abstract
No disease-modifying treatments are currently available for osteoarthritis (OA). While many therapeutic approaches are now being investigated it is ethical to resort to alternative solutions as that we already possess. There are many reasons for thinking that, at sufficiently high doses, glucosamine (GlcN) sulphate possesses a clinically relevant effect on OA pain. Wide inter-individual variations in the symptomatic effects of GlcN are explained by the extreme variability of its bioavailability. In studies evaluating its structure-modifying effect, GlcN was more effective than placebo in reducing the rate of joint space narrowing in patients with knee OA. More recent data suggest that GlcN may be effective in the primary prevention of OA in sportsmen. There is no controversy concerning the safety of GlcN which does not differ to that of placebo. Several studies have recently revealed an unexpected effect of GlcN on cardiovascular mortality. After adjusting for confounding factors, the regular consumption of GlcN correlated with a 27% reduction in mortality and a 58% reduction in deaths from cardiovascular causes. These data confirm animal studies demonstrating a protective effect of GlcN against cancer and cardiovascular diseases due to modulation of the O-GlcNAcylation pathway. Disorders in O-GlcNAcylation are involved in diabetes, obesity and cancers, which all feature chronic low-grade inflammation (CLGI). By regulating CLGI, GlcN may be beneficial to the symptoms of OA, its outcome and to that of the concomitant chronic pathologies, making GlcN as a valuable candidate for the treatment of OA in patients with metabolic syndrome, diabetes or cardiovascular diseases.
Without overmedicating and using diet by preference my advice would be to live now as if you have the condition asymptomatically, especially if there is a familial (genetic) predisposition and you have reached a certain age!
To date no disease-modifying therapeutics are currently available for OA due to an insufficient understanding of the pathogenesis, and a delay in the therapeutic management, due to the lack of a sufficiently sensitive biomarker allowing to make the diagnosis during the early asymptomatic phase of the disease. At an advanced stage the treatment of OA is mainly based on symptomatic measures or joint replacement surgery. On the other hand, if the diagnosis is made early, developing treatments to slow the progression of joint degradation is a reasonable goal.
…Thanks to recent achievements in understanding the causes of the cartilage degradation many therapeutic approaches are now being investigated (Hochberg et al., 2019; Ghouri and Conaghan, 2019; Stevens et al., 2019; Thorup et al., 2020; Yazici et al., 2020; Fernández-Martín et al., 2021). However, we cannot hope for a structure-modifying treatment to be marketed for several years. In clinical daily practice all the care-givers must legitimately ask them the following question: Is it ethical not to bring forward patients anything at all (except symptomatic treatments, most of which having frequent and sometimes serious side effects) until a real chondroprotective agent has been launched on the market?
…The committed stance of the authors is to emphasize that, despite controversies, a number of data suggest that the long-term prescription of glucosamine could be beneficial for OA patients, both symptomatically and in terms of cardiovascular status.
Safety
In contrast to its efficacy, there is no controversy concerning the safety in use of glucosamine; all meta-analyses and systematic reviews conclude that its safety is excellent, not different from placebo (Zhu et al., 2018). Conventionally, glucosamine is not recommend in patients with shellfish allergy due to its origin (the chitin of crustaceans) but reports of allergic phenomena, skin or respiratory, are not found to any significant extent in the literature. As glucosamine is a molecule similar to glucose its use in diabetics has been discussed, but studies showed no effect on blood glucose levels and hyperinsulinism at the doses used, whether in healthy subjects or diabetics (Simon et al., 2011).
The reviewers conclude by saying that further research is needed to optimise bioavailability and structural efficacy, eg sulphate or hydrochloride?
Jafarinia et al published a review in 2020 of the potential effects of quercetin on allergic diseases65:
Abstract
Quercetin is a naturally occurring polyphenol flavonoid which is rich in antioxidants. It has anti-allergic functions that are known for inhibiting histamine production and pro-inflammatory mediators. Quercetin can regulate the Th1/Th2 stability, and decrease the antigen-specific IgE antibody releasing by B cells. Quercetin has a main role in anti-inflammatory and immunomodulatory function which makes it proper for the management of different diseases. Allergic diseases are a big concern and have high health care costs. In addition, the use of current therapies such as ß2-agonists and corticosteroids has been limited for long term use due to their numerous side effects. Since the effect of quercetin on allergic diseases has been widely studied, in the current article, we review the effect of quercetin on allergic diseases, such as allergic asthma, allergic rhinitis (AR), and atopic dermatitis (AD).
For treating asthma:
The significant inhibitory dose for quercetin was 40 µM [26] (Table 1). In vitro studies of quercetin suggest that quercetin in the concentration of 40 µM is useful for mucus hypersecretion, a common pathological change in chronic inflammatory diseases of the airway. In the future, quercetin might be a valuable treatment for mucin hypersecretion in chronic inflammatory airway diseases in the clinic.
The study of Rogerio et al. in 2007 have shown that in BALB/c receiving quercetin (10 mg/kg), eosinophil counts were lower in BALF, blood and lung parenchyma [29]. The same group in 2010 compared the anti-inflammatory effects of quercetin-loaded microemulsion (QU-ME) and quercetin suspension (QU-SP) in an experimental model of airways allergic inflammation. Mice received a daily oral dose of QU-ME (3 or 10 mg/kg) or QU-SP (10 mg/kg). Their results showed QU-ME reduced the eosinophil recruitment, IL-4 and IL-5 levels in the BALF, as well as, inhibited the nuclear transcription factor-kappa B (NF-κB) activation, P-selectin expression and the mucus production in the lung. As the plant-derived flavonoid quercetin is part of many foods and seems to be safe despite long-term use in animals and humans, therefore, its microemulsion would form an interesting and practical formulation to increase its oral bioavailability and, in turn, to evaluate its potential clinical advantage for treating certain inflammatory and allergic diseases [17]. In 2016, the influence of quercetin (16 mg/kg/day) on histopathological aspects and also airway epithelium in allergic airway inflammation on BALB/c mice has been evaluated by Sozmen et al. Quercetin treatment cause lower epithelial thickness, subepithelial smooth muscle thickness, goblet, and mast cell numbers compared to untreated mice with allergic airway inflammation. However, quercetin treatment was not effective in improving basal membrane thickness. Immunohistochemical scores of IL-25, IL-33, Thymic stromal lymphopoietin (TSLP), cysteine-dependent aspartate-specific proteases (caspase)-3 and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) were lower in quercetin-treated mice in comparison with untreated mice with allergic airway inflammation. IL-4, IL-25, IL-33, TSLP levels in BALF and OVA-specific IgE in serum were lower in quercetin treated mice compared with untreated mice. These results suggest that quercetin improves chronic histopathological changes except for basal membrane thickness in lung tissue and its beneficial effects on inflammation might be related to epithelium-derived cytokines modulators and epithelial apoptosis [31] (Table 2).
Similar to in vitro studies, in vivo studies suggest that quercetin plays a critical role in asthmatic reactions. Anti-inflammatory effects of quercetin such as reduction of IL-4 and IgE in serum could be useful on allergic asthma.
Fig. 2 Different effects of quercetin on immune cells involved in asthma
For treating allergic rhinitis (AR):
In vitro and in vivo studies
Thioredoxin (TRX) is a protein that regulates reactive oxidative metabolism and scavenges reacting oxygen species, which is implicated in the mechanism of asthma. Some studies have shown that TRX suppresses allergic inflammation [46]. In 2018, the effects of quercetin on AR symptoms and the role of the TRX production of nasal epithelial cells in vitro and in vivo have been investigated by Edo et al. The results showed that the oral administration of 20 mg/kg of quercetin significantly inhibited nasal symptoms and the same dose of quercetin significantly increased TRX levels in nasal lavage fluids. Quercetin’s ability to increase TRX production may be useful, at least in part, for its clinical efficacy toward AR [47] (Table 3). Similar to asthma allergic, quercetin seems to be a good therapeutic candidate for AR. However, the study of quercetin on AR is lower than asthma allergic. Similar to studies on asthma allergic, the dose of 25 mg/kg quercetin seems to be enough for inhibiting the symptoms in AR.
For treating Atopic dermatitis (AD or eczema):
In vitro studies
Two studies have examined the effect of quercetin on heme oxygenase (HO) and oxidative stress. In 2009, the role of HO-1 in the anti-allergic action of quercetin against the degranulation of rat basophilic leukemia (RBL-2H3) cells, rat peritoneal mast cells, and mouse bone marrow-derived mast cells has been investigated by Matsushima et al. HO activity was upregulated after short exposure to quercetin, followed by the induction of HO-1 expression after long exposure to quercetin. The results strongly suggest that quercetin exerted anti-allergic actions via activation of nuclear factor erythroid 2-related factor 2 (Nrf2(-HO-1 pathways [51]. The improvement of quercetin protective effect against oxidative stress skin damage by incorporation in nanovesicles has been evaluated by Manca et al. Quercetin was taking part in glycerosomes, new phospholipid-glycerol vesicles, and their protective effect against oxidative stress skin damages has been assessed. Quercetin incorporated into liposomal and glycerosomal nanoformulations showed a strong ability to scavenge free radicals and protect human keratinocytes in vitro against hydrogen peroxide damage. Moreover, quercetin-loaded vesicles were avidly taken up by keratinocytes in vitro. Overall, results indicate 40 and 50% glycerosomes as promising nanosystems for the improvement of cutaneous quercetin delivery and keratinocyte protection against oxidative stress damage [52]
In 2015, the effects of quercetin on skin lesion, high mobility group box (HMGB) 1 cascade signaling and inflammation in the AD mouse model have been investigated by Karuppagoundera et al. AD-like lesion was induced by the application of house dust mite extract to the dorsal skin of NC/Nga transgenic mice. Quercetin treatment weakened the development of AD-like skin lesions. Histological analysis showed that quercetin inhibited hyperkeratosis, parakeratosis, acanthosis, mast cells and infiltration of inflammatory cells. Furthermore, quercetin treatment down-regulated cytoplasmic HMGB1, receptor for advanced glycation end product (RAGE), nuclear p-NF-κB, p-extracellular signal-regulated kinase (ERK) 1/2, COX2, TNFα, IL-1β, IL-2Rα, IFN-γ and IL-4 and up-regulated nuclear Nrf2. Their data indicated that the HMGB1/RAGE/NF-κB signaling might play an important role in skin inflammation, and quercetin treatment could be a promising agent for AD by modulating the HMGB1/RAGE/NF-κB signaling and induction of Nrf2 protein [55] (Table 2).
In vitro and in vivo studies
In 2014, Castangia et al. developed biocompatible quercetin and curcumin nanovesicles as a novel approach to prevent and restore skin tissue defects on chronic cutaneous pathologies. Their results showed that nano entrapped polyphenols prevented skin lesions formation abrogating the various biochemical processes that cause epithelial loss and skin damage [56]. The effects of quercetin on AD seem to be similar to other allergic diseases. It suggested that quercetin affects different immune and non-immune cells in the same pathway (Table 3).
And in 2022 El-Said et al conducted an investigation into how quercetin mitigates rheumatoid arthritis by inhibiting adenosine deaminase in rats66:
Abstract
Rheumatoid arthritis (RA) is a chronic inflammatory joint disease characterized by synovial proliferation and bone destruction. Adenosine deaminase (ADA) is a key inflammatory enzyme that increases joint stiffness and pain in RA. In this study, we evaluated the in-silico, and in vivo inhibitory effect of quercetin isolated from Egyptian Fenugreek on ADA enzyme activity. We also determined the combinatorial effect of quercetin on methotrexate mediated anti-inflammatory efficacy and toxicity. In-silico molecular docking was conducted and confirmed in an in vivo RA rat model. The results showed that the inhibition constant of quercetin on joint ADA by docking and in-vitro was 61.9 and 55.5 mM, respectively. Therefore, quercetin exhibits anti-inflammatory effect in a rat RA model as evidenced by reducing the specific activity of ADA in joint tissues, lower jaw volume, enhance body weight, downregulate ADA gene expression, reduce levels of RA cytokines interleukin-1β, interleukin-6, tumor necrosis factor-α, also, rheumatoid factor, C-reactive protein, and anti-cyclic citrullinated peptide RA biomarker levels. These findings demonstrate that the purified quercetin has a promising anti-inflammatory effect against RA disease through its inhibitory effects on the ADA enzyme. Furthermore, isolated quercetin improved the anti-inflammatory efficacy of methotrexate, reduced its toxic effects by increasing antioxidant enzymes and reducing oxidative stress.
Fig.4 A Inhibition of ADA enzyme activity by various concentration of quercetin. B, C Lineweaver Burk blot and the inhibition constant (Ki) of ADA by quercetin
Fig.5 The body weight of rats at the start and at the end of the experiment after treatment with QUE, MTX or their combination. Values are expressed as the mean ± SE (n = 8) of experimental group. *p < 0.05 showed significance vs. normal control, +p < 0.05 showed significance vs. the RA control group, #p < 0.05 showed significance vs. the MTX control group
Fig 7 Levels of Il-6, 1β, TNF-α, CRP, CCP, and RF in the sera of different groups. Data are expressed as the means ± S.E. *p < 0.05 showed significance vs. the normal control, +p < 0.05 showed significance vs. the RA group
When arthritic rats were compared with their normal control counterparts, they showed signs of arthritis. In contrast to their arthritic control counterparts, QUE-treated arthritic rats reported a marked increase in body weight and decrease in PV. These results are consistent with that of other studies (Rasool et al. 2006; Roy et al. 2017; Kumar et al. 2009; Haleagrahara et al. 2017).
The anti-inflammatory efficacy of QUE alone or in combination with MTX was further confirmed by live imaging and X-ray examination of the animals. RA control rats showed mild to moderate cartilage damage and, bone erosion indicating bone destruction. This may result from the chronic exposure of ankle joints to proinflammatory mediators such as TNF-α and IL-1β, which stimulate the production of proteolytic enzymes which result in the degradation of cartilage (Roy et al. 2017). We observed that small joints such as the tarsal, metatarsal, and interphalangeal were more affected in RA rat control group. However, in case of QUE-treated and MTX alone or in the combinational groups, these abnormalities were ameliorated, and in the QUE/MTX combined group, it is bearing more resemblance to radiographic pattern of the joints of normal group. This indicates the enhanced anti-inflammatory efficacy of QUE and MTX.
Conclusion
Collectively, the isolated quercetin from Egyptian Fenugreek seeds exhibits a significant inhibitory effect on adenosine deaminase enzyme (ADA), and inflammatory cytokines biomarkers either alone or in combination with methotrexate (MTX) in a RA rat model. Moreover, Fenugreek quercetin reduced MTX—induced toxicity. Thus, we recommended Egyptian Fenugreek quercetin as a natural adjuvant in mitigating (RA) because of its antiarthritic properties and its ability to improve the therapeutic efficacy of MTX (Fig. 11).
Fig. 11 Systematic diagram showed the effect of Egyptian fenugreek quercetin either alone or in combination with MTX in rheumatoid arthritis disease
An article by Christina DeBusk (2020) provides a good overview with respect to corticosteroids67:
Studies show that as many as 30% of patients will not respond to steroid treatments, and at the present time there are 629 clinical studies on CBD, some pertaining to CBD and steroids
Corticosteroids (steroids) such as cortisone, prednisone, and hydrocortisone are prescribed to patients regularly. In some cases, these types of drugs are used to reduce inflammation. This makes them beneficial for individuals diagnosed with respiratory tract infections or allergic reactions. Steroids can also be helpful for those who are diagnosed with chronic inflammatory conditions such as asthma and various forms of arthritis. In the conversation of CBD and steroids, can CBD offer the same benefits for individuals who have issues with steroids?
CBD for inflammation, immunity, and pain relief
The cannabidiol CBD is found within the hemp plant that has been linked to a variety of health benefits. Inflammation, immunity, and pain relief are three that are most relevant in the replacement of steroid use when discussing CBD and steroids.
For example, one animal model involved rats with arthritic knee joints. After having transdermal CBD gel applied for four days, the test subjects had “significantly reduced joint swelling.” There were also indications that they experienced less pain.
An article published in the journal Cannabis and Cannabinoid Research in March 2020 adds that CBD has positive effects on both the innate and adaptive immune systems. Like steroids, it acts as an immunosuppressive, controlling immune response through actions such as T cell induction.
Still other pieces of research connect CBD with easier management of difficult to treat pain. Since some of the conditions that steroids are typically used to treat involve pain as a symptom — like arthritis and lupus — CBD can potentially assist with this as well. CBD research is booming, and more human trials are underway since certain types of CBD were made legal with the Hemp Farming Act of 2018.
CBD and steroids: resistance and studies
Another factor to consider when it comes to CBD and steroids in terms of replacement is that some people are resistant to steroids’ effects.
The University of Bristol, UK, indicates that as many as 30% of patients will not respond to steroid treatments. This can make their conditions more difficult to control and treat. In situations such as this, CBD may be a suitable alternative, providing patients relief when other drugs don’t seem to work.
The one factor that makes it difficult to know exactly what effect CBD has on patients who would typically be prescribed steroids is, until passage of the Farm Bill, industrial hemp was illegal. As a result, a number of studies in this area have been conducted on animals versus humans. This has made it harder to identify CBD’s full effects.
At this moment in time, there are 629 clinical studies that are hoping to provide more information in this area. As each one is completed, we will begin to learn more about this cannabinoid and how it influences inflammation, immunity, and pain.Once we do, we will also know about whether it is, in fact, a suitable replacement for prescription steroid drugs.
I am happy to post updates as the results from the clinical trials come through. I can do the same for other therapeutics.
Unfortunately these are unlikely to change allopathic prescribing practice any time soon unless someone can patent it and profit from it!
Updated 21st May ‘23:
Ribes nigrum
Shout-out to @D3Rahanne for this one:
Just to mention it: Ribes Nigrum (Black Currant) Buds Gemmotherapy May be worth a consideration due to the cortisone-like action, but also modulating aspect. While normal dose is about 2-3x 15 drops/d, in urgency dosing may go up to 15 drops/h max 2-3 days. Used since ages.
To go into the mechanisms and a suggested combo-stack we will start with an in vivo study using 7 week old mice, from 2019 by Lee & Lee68.
M1 macrophages are pro-inflammatory:
Abstract
Macrophages are polarized into different phenotypes depending on tissue microenvironment where they reside. In obesity-associated inflammation, M1-type macrophages are predominant in the inflamed tissue, exerting pro-inflammatory responses. Our previous studies demonstrate that blackcurrant consumption attenuates hepatic inflammation and lipopolysaccharide-stimulated inflammatory responses of splenocytes in obese mice. In this study, we determined whether blackcurrant modulates macrophage phenotypes to exert its anti-inflammatory action. Mouse bone marrow-derived macrophages (BMDM) and human THP-1 macrophages were polarized into M1 macrophages in the presence or absence of blackcurrant extract (BCE). BCE repressed M1 polarization of both murine and human macrophages. Also, to gain insight into the role of blackcurrant metabolites produced in vivo in the regulation of macrophage phenotypes, BMDM were treated with serum obtained from lean or obese mice fed blackcurrant. While serum from lean mice fed blackcurrant did not exert either anti-inflammatory actions or suppressive effects on M1 polarization, serum from obese mice fed blackcurrant reduced the expression of pro-inflammatory genes in BMDM. Our data demonstrate that BCE suppresses M1 polarization, with reduced pro-inflammatory responses. Moreover, this study suggests that blackcurrant metabolites may not exert their anti-inflammatory effect directly by altering macrophage phenotypes, but possibly by inhibiting the production of obesity-associated inflammatory factors.
The functional change or adaptation of macrophages in response to stimuli is referred to as macrophage polarization [4]. Polarized macrophages are broadly categorized into classically activated M1 macrophages and alternatively activated M2 macrophages [5]. Typical stimuli that induce M1 polarization are interferon γ (IFNγ), tumor necrosis factor α (TNFα), and lipopolysaccharide (LPS), while interleukin-4 (IL-4), IL-10, and IL-13 are known to stimulate M2 polarization [5,6]. M1 macrophages produce pro-inflammatory cytokines, e.g., TNF, IL-1β, IL-12, and IL-6, and reactive oxygen species (ROS) [5,6]. On the other hand, M2 macrophages are specialized to produce immune-modulatory and reparative mediators such as IL-10, transforming growth factor β (TGFβ), IL-4, and IL-13, and to clear apoptotic cells due to their high phagocytosis capacity [7].
In obesity-associated inflammation, M1 macrophages are predominant in the inflamed tissue, producing ROS, nitric oxide (NO), and pro-inflammatory cytokines [8], which aggravate inflammation and damage tissue. Specifically, studies have reported that M1 macrophages in the liver and adipose tissue are increased in obesity [9,10,11,12]. Therefore, it is beneficial to inhibit macrophage polarization into M1 or to shift macrophage phenotype toward anti-inflammatory and pro-resolving M2 macrophages to prevent obesity-associated inflammation [13].
Blackcurrant (Ribes nigrum) is a type of berries originated from Northern Asia and Europe, and started to gain its popularity in the U.S. from the early 2000s [14]. Blackcurrant contains high phenolic compounds the majority of which are anthocyanins [14]. Specifically, we previously reported that the major anthocyanins in blackcurrant are delphinidin-3-rutinoside, cyanidin-3-rutinoside, delphinidin-3-glucoside, and cyanidin-3-glucoside [15]. The anthocyanins in blackcurrant contribute to its antioxidant, anti-inflammatory, and anti-microbial properties [14,15,16,17,18].
Lower is better:
Figure 1. Effect of blackcurrant extract (BCE) on the expression of inflammatory genes in RAW 264.7 macrophages. (A) mRNA levels of interleukin-1β (IL-1β) and IL-6 in RAW 264.7 macrophages. Cells were pre-treated with 0 (control; C), 25, 50, 75, or 100 µg/mL of BCE for 24 h, and then stimulated with 100 ng/mL of lipopolysaccharide (LPS) for 6 h. (B) mRNA levels of IL-1β, IL-6, and tumor necrosis factor α (TNFα) in RAW 264.7 macrophages. Macrophages were pre-treated with 0 (control; C) or 50 µg/mL of BCE for 24 h and then stimulated with 100 ng/mL of LPS for 0, 1, 4, 6, 12, or 24 h. Data were normalized by no LPS control. Data are shown as mean ± SEM. Different letters show significant differences (p < 0.05). *, p < 0.05 vs. control.
Although serum collected from blackcurrant-fed mice did not alter macrophage phenotypes, we speculate that the modulatory effect of blackcurrant polyphenols on macrophage phenotype is still valid at least in the intestine where macrophages are likely exposed to intact polyphenols. Importantly, intestinal macrophages are constantly renewed by Ly6Chi monocytes, which differentiate into M1 macrophages, in response to low inflammatory signals from luminal contents and gut microbiota [36]. Furthermore, hyporesponsiveness to bacterial ligands is one of the characteristics of intestinal macrophages for gut homeostasis [37]. Therefore, the suppressive effect on M1 polarization of polyphenols in blackcurrant may be beneficial for obesity-associated inflammation in intestinal macrophages, which could affect inflammatory states at the whole body level.
5. Conclusions
In this present study, we demonstrated that BCE suppresses M1 polarization of macrophages, leading to repressed pro-inflammatory responses. Furthermore, this study suggests that metabolites of blackcurrant may not exert the anti-inflammatory effect of blackcurrant directly by altering macrophage phenotypes, but it may attenuate inflammatory responses in macrophages by modulating levels of obesity-induced circulating pro-inflammatory factors.
In 2017, Ashigai et al confirmed that R nigrum extracts can suppress eczema in mice69:
Abstract
Atopic dermatitis (AD) is a chronic inflammatory skin disease that causes dry skin and functional disruption of the skin barrier. AD is often accompanied by allergic inflammation. AD patient suffer from heavy itching, and their quality of life is severely affected. Some pharmaceuticals for AD have some side effects such as skin atrophy. So it is necessary to develop mild solutions such as food ingredients without side effects. There are various causes of AD. It is especially induced by immunological imbalances such as IFN-γ reduction. IFN-γ has an important role in regulating IgE, which can cause an allergy reaction. NC/Nga mice develop AD and IgE hyperproduction. In a previous study, we revealed that administration of polysaccharide from black currant (R. nigrum) has an effect on immunomodulation. It induces IFN-γ production from myeloid dendritic cells. We named this polysaccharide cassis polysaccharide (CAPS). In this report, we studied the effect of administering CAPS on atopic dermatitis in NC/Nga mice. Thirty NC/Nga mice that developed symptoms of atopic dermatitis were used. We divided them into three groups (control, CAPS administration 12 mg/kg/day, CAPS administration 60 mg/kg/day). For 4 weeks, we evaluated clinical score, serum IgE levels, gene expression of spleen, and skin pathology. We revealed that CAPS administration improves atopic dermatitis symptoms. We also found that CAPS administration suppresses IgE hyperproduction and induces IFN-γ gene transcription in the spleen. Finally, we confirmed that CAPS administration suppresses mast cell migration to epidermal skin. These results indicated that CAPS has an effect on AD.
Keywords: black currant, polysaccharide, atopic dermatitis, NC/Nga mice
Fig. 1. Effect of CAPS on atopic dermatitis score. The results are expressed as mean ± standard error (n=10). The differences between the control and the CAPS administration groups were statistically significant by the Steel test (*p<0.05, **p<0.01).
In conclusion, we investigated the inhibitory effect of oral administration of CAPS on the development of AD-like skin lesions in NC/Nga mice. Ingestion of CAPS prevented the development of dermatitis and the increase of IgE hyperproduction in a dose-dependent manner. IFN-γ and IL-12p40 transcription levels in the spleen were increased by CAPS administration. The number of mast cells in skin lesions decreased after CAPS ingestion. These results clearly demonstrate that intake of CAPS is effective in preventing and alleviating the development of AD-like skin disease.
Conflict of Interest
HA, GW, YK, YK, RY, RT, MM, and TY are employees of Kirin Co., Ltd., the study sponsor. KS is an employee of Mercian Corporation.
And in a recently published paper by De Luca et al (2023) they conducted a case-control study using a combo-stack of R. nigrum, Boswellia serrata (Indian frankincense), bromelain (pineapple extract) and vitamin D to inhibit inflammation in chronic sinusitis70.
Abstract
Although chronic sinusitis widely affects the adult population, the treatments currently used did not always satisfactorily solve the symptoms. Traditional therapy with steroids and antibiotics presents risks and benefits and the new drugs, i.e., monoclonal antibody, are valid solutions despite being quite expensive. Natural molecules could be a valid treatment that combines good efficacy and low price. We conducted a case -control study to evaluate the benefit of an oral supplement with Ribes nigrum, Boswellia serrata, Bromelain and Vitamin D on chronic sinusitis symptoms. 60 patients were randomly assigned to one of the three groups: control using nasal steroids only, treatment 1 using nasal steroid and 1 dose of the oral supplement for 30 days and treatment 2 in which patients used nasal steroid and two oral supplement doses daily for 15 days. Conditions of the nasal mucosa and a blood sample (WBC, IgE and CRP) were analyzed at T0, T1 (15 days after treatment) and T2 (30 days after treatment. Patients treated with the supplement improved their nasal findings (hyperemia of mucosa and rhinorrhea) with statistically significant differences from the control. Our preliminary data suggest that the addition of supplement containing Ribes nigrum, Boswellia serrata, Vitamin D and Bromelain to the traditional local therapy (nasal spray with cortisone) can be a supporting therapy to modulate the local inflammation in the nose in patients affected by chronic sinusitis.
A vitamin D dose of 600 IU is low if you are deficient71, Boswellia 300mg is a touch low (300-500mg)72, bromelain 200mg is low (500-1000mg)73 and R nigrum extract at 300mg is also at the lower end of dosage guidelines (300mg-6g)74. If corrected for this then results may have demonstrated even more marked improvements:
The nutraceutical used in the study was an oral solution available on the market commercial name Flogostop Forte® produced by Humana® Italia S.p.A; the supplement contains in 4 gr sachet the following elements Vitamin D (15 microgram, 600 U.I.), Boswellia Casperome® (125 mg), Bromelain (200 mg), and Ribes nigrum (300 mg).
Even so, statistically significant differences were found:
Figure 4. Comparison of clinical aspects between the three groups in term of improvement at the end of the treatment. (A) shows the changes of the color of nasal mucosa (hyperemia) and (B) the improvement of nasal secretion (reduction of rhinorrhea) after treatments. “**” indicates p < 0.01.
Based on these current findings, we speculate that the supplement could have improved local inflammation (hyperemia and rhinorrhea) for different reasons related to its components. Bromelain has immunomodulatory effects and antibacterial properties; these two characteristics in chronic sinusitis allow us to (i) ameliorate the local immune response with reduction of nasal inflammation, (ii) reduce the secretion of pro-inflammatory agents during rhinitis, (iii) reduce mucus secretion and (iv) kill microbes responsible of the recurrent chronic nasal inflammation [22,23].
Vitamin D is a known immune-stimulating and immune-modulating element and the efficacy of supplements containing this vitamin to fight infection and inflammation of the upper respiratory tract has been recently shown in human clinical trials. [24]. A recent meta-analysis performed by Li et al. identified a deficit of this vitamin in a patient with chronic sinusitis [25] suggesting the supplementation with vitamin D as possible useful treatment. Our results confirm that vitamin D can be beneficial to reduce nasal inflammation in patients affected by chronic sinusitis [15].
Boswellia inhibits 5-lipoxygenase (5-LO), including 5-hydroxyeicosatetraenoic acid (5-HETE) and leukotriene B4 (LTB-4) that cause chemotaxis and vascular permeability [26]; in particular, the inhibition of 5-LO may reduce the inflammation in the nasal mucosa and consequently, the secretion of excessive mucus as we observed in this study. The nutraceutical we used contained Boswellia Casperome® based on a patented method able to improve the bioavailability of Boswellia ameliorating the efficacy of the product [27].
Ribes nigrum (Blackcurrants) has potent antioxidant, antimicrobial, and anti-inflammatory properties [28]. This element inhibits the M1 pro-inflammatory phenotype of macrophages [29], reducing the local inflammation and inhibiting the recurrence of nasal symptoms. Furthermore, Ribes nigrum inhibits the replication of a series of viruses, for example, influenza viruses, which sustain the chronicity of naso-sinusal inflammation [30].
5. Conclusions
This study showed that the addition of a supplement with Ribes nigrum, Boswellia serrata (Casperome®), Bromelain and Vitamin D to the standard local treatment in chronic sinusitis can improve the clinical findings, first by reducing the inflammation of nasal mucosa, then improving the general symptoms correlated with this disease. The use of the supplement, despite a different efficacy based on the different posology used, was always a benefit when compared with the standard therapy.
Conflicts of Interest
The authors declare no conflict of interest.
Finally, as is typical with many polyphenols (and flavonoids), R nigrum extract has anti-cancer properties.
Liu & Li (2016) demonstrated this in vitro using MKN-45 (gastric) and TE-1 (oesophagus) cancer cell lines75 (paywalled).
p38 mitogen-activated protein kinases are a class of mitogen-activated protein kinases (MAPKs) that are responsive to stress stimuli, such as cytokines, ultraviolet irradiation, heat shock, and osmotic shock, and are involved in cell differentiation, apoptosis and autophagy76.
c-Jun N-terminal kinases (JNKs), were originally identified as kinases that bind and phosphorylate c-Jun on Ser-63 and Ser-73 within its transcriptional activation domain. They belong to the mitogen-activated protein kinase family, and are responsive to stress stimuli, such as cytokines, ultraviolet irradiation, heat shock, and osmotic shock. They also play a role in T cell differentiation and the cellular apoptosis pathway77.
Abstract
Black currant extract (BCE) is rich in polyphenols and can induce apoptosis in various cancer cells, but the molecular mechanism by which BCE induces cancer cell apoptosis has not been reported. The aim of this work was to elucidate the antitumor effect of BCE and the signal transduction pathways involved. MTT test results revealed that the viability of MKN-45 and TE-1 cells treated with BCE gradually decreased in a concentration-dependent manner, with significant effects achieved after 12 h of treatment. MKN-45 and TE-1 cells clearly showed characteristics of apoptosis: shrinkage, cytoplasmic condensation, and formation of cytoplasmic filaments, even partial detachment. In addition, these results showed MKN-45 cells showed a higher level of apoptosis than TE-1 cells when treated with BCE. Western blot assays showed that the Bcl-2/Bax ratio decreased in both MKN-45 and TE-1 cells, indicating that BCE induced apoptosis through the mitochondrial pathway. In addition, BCE-induced apoptosis was mediated by mitochondrial dysfunction involving the PI3K/Akt pathway in both MKN-45 and TE-1 cells. However, BCE-induced cell apoptosis was mediated by the Fas receptor pathway in MKN-45 cells but not in TE-1 cells. BCE-induced apoptosis in MKN-45 cells was associated with the MAP-kinase signaling pathway through the activation of p38 and JNK and the inactivation of Erk1/2. However, it was associated with the MAP-kinase signaling pathway only by means of activation of p38 and JNK in TE-1 cells. These results showed that BCE induces apoptosis of MKN-45 and TE-1 cells through MAPK- and PI3K/Akt-mediated mitochondrial pathways. Thus, BCE may be a promising anticancer candidate.
Essential oils for topical application
I won’t go into great detail here as it could fill a Substack in its own right, but I will provide some links for further reading.
From the Pain Doctor website:
Why would you use essential oils for muscle pain?
Muscular pain can occur from a number of reasons. You may be dealing with muscle pain as a result of:
A long and particularly hard workout
Fatigue or pain after an illness
Tension or stress from work, especially in the neck, head, and shoulders
A long road trip or flight
A chronic condition, like fibromyalgia
A chronic pain condition, such as lower back pain, arthritis or tendonitis
An injury
For muscle pain caused by injuries or other conditions, it’s always important to talk to your doctor first. They’ll help you find treatments that can resolve the underlying condition causing your pain. But, if you’re suffering from pain in your muscles after a workout or something similar, essential oils for muscle pain after workout can be a great option. In some cases, these can help relieve the inflammation and improve blood flow to the area.
If you’re suffering from another condition, essential oils are a non-invasive option to be used alongside your other treatments. These can help complement other therapies and encourage rest, healing, and calm. Reducing stress in any capacity can also help reduce your pain. So, while essential oils will not treat your condition directly, they can help with your overall mood and stress levels.
As always, talk to your doctor before trying any of these oils. And make sure to follow the safety advice listed here and on the bottle itself. Essential oils are non-invasive and generally safe to use, but too much can lead to skin rashes or other side effects. Further, never ingest these oils unless you’ve been advised to do so by your doctor.
More:
These Are The 5 Best Essential Oils For Muscle Pain
The predominant natural ingredient in wintergreen oil is methyl salicylate, which is a compound closely related to acetylsalicylic acid, or aspirin. When applied to the skin, including tissues at the site of pain, wintergreen oil has analgesic properties. Mix with peppermint oil for enhanced absorption:
Treatment of Low Back Pain: The Potential Clinical and Public Health Benefits of Topical Herbal Remedies (2014)
To conclude this Substack we need to ask whether it is always best to intervene using anti-inflammatory drugs to reduce pain?
Inflammation is the trigger for the cascade of events that follow in wound and injury repair. In my opinion, the moment inflammation became the enemy of healing, is the moment chronic pain started becoming a billion-dollar business for drug companies. When Ibuprofen was introduced in 1974, it was heralded as one of the great steps in the management of pain. By 1976, two years after its introduction, 1.7 billion tablets had been produced. Today, millions of prescriptions for pain relievers are written annually and tons of aspirin are consumed each day. Yet chronic pain persists. Why? Because these drugs only mask the problem of pain and do not attempt to cure it.
This was principally a hypothesis until a ground-breaking study was published in 2022, which prompted the issue of a press release by McGill University, Canada78.
The source study is paywalled so this is probably the best summary of the research findings.
The sledgehammer effect of steroids onT-lymphocytes, macrophages, fibroblasts, neutrophils, eosinophils, and basophils cannot distinguish between helpful and harmful leukocytes. One of the consequences of this is that healing may be impaired and chronic pain remain unresolved for much longer than if CS or NSAID treatments had been withheld in the first place:
PUBLISHED: 11 May 2022
Using anti-inflammatory drugs and steroids to relieve pain could increase the chances of developing chronic pain, according to researchers from McGill University and colleagues in Italy. Their research puts into question conventional practices used to alleviate pain. Normal recovery from a painful injury involves inflammation and blocking that inflammation with drugs could lead to harder-to-treat pain.
“For many decades it’s been standard medical practice to treat pain with anti-inflammatory drugs. But we found that this short-term fix could lead to longer-term problems,” says Jeffrey Mogil, a Professor in the Department of Psychology at McGill University and E. P. Taylor Chair in Pain Studies.
The difference between people who get better and don’t
In the study published in Science Translational Medicine, the researchers examined the mechanisms of pain in both humans and mice. They found that neutrophils – a type of white blood cell that helps the body fight infection – play a key role in resolving pain.
“In analyzing the genes of people suffering from lower back pain, we observed active changes in genes over time in people whose pain went away. Changes in the blood cells and their activity seemed to be the most important factor, especially in cells called neutrophils,” says Luda Diatchenko a Professor in the Faculty of Medicine, Faculty of Dentistry, and Canada Excellence Research Chair in Human Pain Genetics.
Inflammation plays a key role in resolving pain
“Neutrophils dominate the early stages of inflammation and set the stage for repair of tissue damage. Inflammation occurs for a reason, and it looks like it’s dangerous to interfere with it,” says Professor Mogil, who is also a member of the Alan Edwards Centre for Research on Pain along with Professor Diatchenko.
Experimentally blocking neutrophils in mice prolonged the pain up to ten times the normal duration. Treating the pain with anti-inflammatory drugs and steroids like dexamethasone and diclofenac also produced the same result, although they were effective against pain early on.
Thesefindings are also supported by a separate analysis of 500,000 people in the United Kingdom that showed that those taking anti-inflammatory drugs to treat their pain were more likely to have pain two to ten years later, an effect not seen in people taking acetaminophen or anti-depressants.
Reconsidering standard medical treatment of acute pain
“Our findings suggest it may be time to reconsider the way we treat acute pain. Luckily pain can be killed in other ways that don’t involve interfering with inflammation,” says Massimo Allegri, a Physician at the Policlinico of Monza Hospital in Italy and Ensemble Hospitalier de la Cote in Switzerland.
“We discovered that pain resolution is actually an active biological process,” says Professor Diatchenko. These findings should be followed up by clinical trials directly comparing anti-inflammatory drugs to other pain killers that relieve aches and pains but don’t disrupt inflammation.”
About this study
“Acute inflammatory response via neutrophil activation protects against the development of chronic pain” by Marc Parisien et al. was published in Science Translational Medicine.
This site is strictly an information website about pathology, potential therapeutic agents and a review of the current state of research. It does not advertise anything, provide medical advice, diagnosis or treatment. This site is not promoting any of these as potential treatments or offers any claims for efficacy. Its content is aimed at researchers, registered medical practitioners, nurses or pharmacists. This content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read on this website. Always consult a qualified health provider before introducing or stopping any medications as any possible drug interactions or effects will need to be considered.
Ramamoorthy S, Cidlowski JA. Corticosteroids: Mechanisms of Action in Health and Disease. Rheum Dis Clin North Am. 2016 Feb;42(1):15-31, vii. doi: 10.1016/j.rdc.2015.08.002. PMID: 26611548; PMCID: PMC4662771.
Chmielnicka M, Woźniacka A, Torzecka JD. The influence of corticosteroid treatment on the OPG/RANK/RANKL pathway and osteocalcin in patients with pemphigus. Postepy Dermatol Alergol. 2014 Oct;31(5):281-8. doi: 10.5114/pdia.2014.44016. Epub 2014 Oct 22. PMID: 25395923; PMCID: PMC4221354.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4221354/
Gioia, U., Tavella, S., Martínez-Orellana, P. et al.SARS-CoV-2 infection induces DNA damage, through CHK1 degradation and impaired 53BP1 recruitment, and cellular senescence.Nat Cell Biol25, 550–564 (2023). https://doi.org/10.1038/s41556-023-01096-x
Mohammed, R.N., Tamjidifar, R., Rahman, H.S. et al. A comprehensive review about immune responses and exhaustion during coronavirus disease (COVID-19). Cell Commun Signal 20, 79 (2022). https://doi.org/10.1186/s12964-022-00856-w
Sicilia B, Arias L, Hontoria G, García N, Badia E, Gomollón F. Are Steroids Still Useful in Immunosuppressed Patients With Inflammatory Bowel Disease? A Retrospective, Population-Based Study. Front Med (Lausanne). 2021 Jun 25;8:651685. doi: 10.3389/fmed.2021.651685. PMID: 34249960; PMCID: PMC8267154.
Sheth, A., Reddymasu, S. & Jackson, R. Worsening of asthma with systemic corticosteroids.J Gen Intern Med21, C11–C13 (2006). https://doi.org/10.1007/s11606-006-0266-x
Kerzerho J, Wunsch D, Szely N, Meyer HA, Lurz L, Röse L, Wahn U, Akbari O, Stock P. Effects of systemic versus local administration of corticosteroids on mucosal tolerance. J Immunol. 2012 Jan 1;188(1):470-6. doi: 10.4049/jimmunol.1101405. Epub 2011 Nov 21. PMID: 22105997; PMCID: PMC3253659.
Roncoroni C, Baillet A, Durand M, Gaudin P, Juvin R. Efficacy and tolerance of systemic steroids in sciatica: a systematic review and meta-analysis. Rheumatology (Oxford). 2011 Sep;50(9):1603-11. doi: 10.1093/rheumatology/ker151. Epub 2011 Apr 27. PMID: 21525139.
Crossfield SSR, Buch MH, Baxter P, Kingsbury SR, Pujades-Rodriguez M, Conaghan PG. Changes in the pharmacological management of rheumatoid arthritis over two decades. Rheumatology (Oxford). 2021 Sep 1;60(9):4141-4151. doi: 10.1093/rheumatology/keaa892. PMID: 33404652; PMCID: PMC8409998.
Wu J, Mackie SL, Pujades-Rodriguez M. Glucocorticoid dose-dependent risk of type 2 diabetes in six immune-mediated inflammatory diseases: a population-based cohort analysis. BMJ Open Diabetes Research and Care 2020;8:e001220. doi: 10.1136/bmjdrc-2020-001220
Pujades-Rodriguez M, Morgan AW, Cubbon RM, Wu J. Dose-dependent oral glucocorticoid cardiovascular risks in people with immune-mediated inflammatory diseases: A population-based cohort study. PLoS Med. 2020 Dec 3;17(12):e1003432. doi: 10.1371/journal.pmed.1003432. PMID: 33270649; PMCID: PMC7714202.
Lossignol D. A little help from steroids in oncology. J Transl Int Med. 2016 Apr 1;4(1):52-54. doi: 10.1515/jtim-2016-0011. Epub 2016 Apr 14. PMID: 28191519; PMCID: PMC5290916.
Garg R, Benedetti LG, Abera MB, Wang H, Abba M, Kazanietz MG. Protein kinase C and cancer: what we know and what we do not. Oncogene. 2014 Nov 6;33(45):5225-37. doi: 10.1038/onc.2013.524. Epub 2013 Dec 16. PMID: 24336328; PMCID: PMC4435965.
Sengupta S, Vonesch JL, Waltzinger C, Zheng H, Wasylyk B. Negative cross-talk between p53 and the glucocorticoid receptor and its role in neuroblastoma cells. EMBO J. 2000 Nov 15;19(22):6051-64. doi: 10.1093/emboj/19.22.6051. PMID: 11080152; PMCID: PMC305812.
Zhang, L., Nie, L. & Maki, C.G. P53 and p73 differ in their ability to inhibit glucocorticoid receptor (GR) transcriptional activity.Mol Cancer5, 68 (2006). https://doi.org/10.1186/1476-4598-5-68
Stiewe T, Pützer BM. Role of p73 in malignancy: tumor suppressor or oncogene? Cell Death Differ. 2002 Mar;9(3):237-45. doi: 10.1038/sj.cdd.4400995. PMID: 11859406.
Ozaki T, Nakagawara A. Role of p53 in Cell Death and Human Cancers. Cancers (Basel). 2011 Mar 3;3(1):994-1013. doi: 10.3390/cancers3010994. PMID: 24212651; PMCID: PMC3756401.
Bronson FH, Matherne CM. Exposure to anabolic-androgenic steroids shortens life span of male mice. Med Sci Sports Exerc. 1997 May;29(5):615-9. doi: 10.1097/00005768-199705000-00005. PMID: 9140897.
Rescigno, Pasquale, and Giuseppe di Lorenzo. "The Potential Detrimental Effect of Corticosteroids in Prostate Cancer." Future Oncology 10.3 (2014): 325-27. Print.
A COMPARISON of prednisolone with aspirin on other analgesics in the treatment of rheumatod rthritis [sic]. Ann Rheum Dis. 1959 Sep;18(3):173-88. PMID: 13856637; PMCID: PMC1007099.
Hunder GG, Matteson EL. Rheumatology practice at Mayo Clinic: the first 40 years-1920 to 1960. Mayo Clin Proc. 2010 Apr;85(4):e17-30. doi: 10.4065/mcp.2009.0701. PMID: 20360289; PMCID: PMC2848437.
Brown R, Bunim JJ, McEwen C. Differential Sheep-Cell Agglutination Test in Rheumatoid Arthritis. Ann Rheum Dis. 1949 Dec;8(4):299-301. doi: 10.1136/ard.8.4.299. PMID: 18623829; PMCID: PMC1030744.
Tsoi KKF, Ho JMW, Chan FCH, Sung JJY. Long-term use of low-dose aspirin for cancer prevention: A 10-year population cohort study in Hong Kong. Int J Cancer. 2019 Jul 1;145(1):267-273. doi: 10.1002/ijc.32083. Epub 2019 Jan 7. PMID: 30575949.
Patrono C. Low-dose aspirin in primary prevention: cardioprotection, chemoprevention, both, or neither? Eur Heart J. 2013 Nov;34(44):3403-11. doi: 10.1093/eurheartj/eht058. Epub 2013 Jun 14. PMID: 23771843.
Clark P, Casas E, Tugwell P, Medina C, Gheno C, Tenorio G, Orozco JA. Hydroxychloroquine compared with placebo in rheumatoid arthritis. A randomized controlled trial. Ann Intern Med. 1993 Dec 1;119(11):1067-71. doi: 10.7326/0003-4819-119-11-199312010-00002. PMID: 8239224.
Das SK, Pareek A, Mathur DS, Wanchu A, Srivastava R, Agarwal GG, Chauhan RS. Efficacy and safety of hydroxychloroquine sulphate in rheumatoid arthritis: a randomized, double-blind, placebo controlled clinical trial--an Indian experience. Curr Med Res Opin. 2007 Sep;23(9):2227-34. doi: 10.1185/030079907X219634. PMID: 17692155.
Yang, Yz., Chen, P., Liu, LJ. et al.Comparison of the effects of hydroxychloroquine and corticosteroid treatment on proteinuria in IgA nephropathy: a case-control study.BMC Nephrol20, 297 (2019). https://doi.org/10.1186/s12882-019-1488-6
Pernicova I, Kelly S, Ajodha S, Sahdev A, Bestwick JP, Gabrovska P, Akanle O, Ajjan R, Kola B, Stadler M, Fraser W, Christ-Crain M, Grossman AB, Pitzalis C, Korbonits M. Metformin to reduce metabolic complications and inflammation in patients on systemic glucocorticoid therapy: a randomised, double-blind, placebo-controlled, proof-of-concept, phase 2 trial. Lancet Diabetes Endocrinol. 2020 Apr;8(4):278-291. doi: 10.1016/S2213-8587(20)30021-8. Epub 2020 Feb 25. PMID: 32109422.
Gharib M, Elbaz W, Darweesh E, Sabri NA, Shawki MA. Efficacy and Safety of Metformin Use in Rheumatoid Arthritis: A Randomized Controlled Study. Front Pharmacol. 2021 Sep 22;12:726490. doi: 10.3389/fphar.2021.726490. PMID: 34630103; PMCID: PMC8493211.
Liu, Runping, et al. "Chapter Eleven - Toxicity of Traditional Chinese Medicine Herbal and Mineral Products." Advances in Pharmacology. Ed. Du, Guanhua. Vol. 87: Academic Press, 2020. 301-46. Print.
Wang, HL., Jiang, Q., Feng, XH. et al.Tripterygium wilfordii Hook F versus conventional synthetic disease-modifying anti-rheumatic drugs as monotherapy for rheumatoid arthritis: a systematic review and network meta-analysis.BMC Complement Altern Med16, 215 (2016). https://doi.org/10.1186/s12906-016-1194-x
Conrozier T, Lohse T. Glucosamine as a Treatment for Osteoarthritis: What If It's True? Front Pharmacol. 2022 Mar 17;13:820971. doi: 10.3389/fphar.2022.820971. PMID: 35370756; PMCID: PMC8968913.
Jafarinia, M., Sadat Hosseini, M., kasiri, N. et al.Quercetin with the potential effect on allergic diseases.Allergy Asthma Clin Immunol16, 36 (2020). https://doi.org/10.1186/s13223-020-00434-0
Lee Y, Lee JY. Blackcurrant (Ribes nigrum)Extract Exerts an Anti-Inflammatory Action by Modulating Macrophage Phenotypes. Nutrients. 2019 Apr 28;11(5):975. doi: 10.3390/nu11050975. PMID: 31035378; PMCID: PMC6566326.
Ashigai H, Komano Y, Wang G, Kawachi Y, Sunaga K, Yamamoto R, Takata R, Miyake M, Yanai T. Effect of administrating polysaccharide from black currant (Ribes nigrum L.) on atopic dermatitis in NC/Nga mice. Biosci Microbiota Food Health. 2018;37(1):19-24. doi: 10.12938/bmfh.17-014. Epub 2017 Nov 16. PMID: 29387518; PMCID: PMC5787412.
De Luca P, D’Ascanio L, Cingolani C, Latini G, Grigaliute E, Di Mauro P, Ralli M, La Mantia I, Di Stadio A. A Supplement with Ribes Nigrum, Boswellia Serrata, Bromelain and Vitamin D to Stop Local Inflammation in Chronic Sinusitis: A Case-Control Study.Journal of Clinical Medicine. 2023; 12(8):2929. https://doi.org/10.3390/jcm12082929
Bingshuo Liu and Zhiwei Li. Black Currant (Ribes nigrum L.) Extract Induces Apoptosis of MKN-45 and TE-1 Cells Through MAPK- and PI3K/Akt-Mediated Mitochondrial Pathways. Journal of Medicinal Food.Apr 2016.365-373.http://doi.org/10.1089/jmf.2015.3521
.jpg){kind=link}
Well done
Second that , Must Watch . Great job 👏🏻