Glucocorticoids and Rheumatoid Arthritis




Glucocorticoids (GCs) were discovered in the 1940s and were administered for the first time to patients with rheumatoid arthritis in 1948. However, side effects were subsequently reported. In the last 7 decades, the mechanisms of action for both therapeutic properties and side effects have been elucidated. Mechanisms for minimizing side effects were also developed. GCs are the most frequently used class of drugs in the treatment of rheumatoid arthritis because of their efficacy in relieving symptoms and their low cost. A review of clinical applications, side effects, and drug interactions is presented.


Key points








  • Endogenous glucocorticoids (GCs) are produced in the adrenal cortex.



  • GCs exert their effect by genomic and nongenomic mechanisms.



  • GCs improve pain, morning stiffness, and fatigue.



  • In early rheumatoid arthritis (RA), low-dose to medium-dose GCs can prevent joint damage.



  • In clinical practice, low doses of GCs can be used in RA as a maintenance therapy. Medium and high doses are used initially as a bridge therapy. Very high doses or pulse therapy are reserved for acute life-threatening or organ-threatening complications.






Introduction


Glucocorticoids (GCs) were discovered in the 1940s by Kendal and Hench and were administered for the first time to patients with rheumatoid arthritis (RA) in 1948. Two years later, Drs Kendal and Hench won the Nobel Prize.


This was the first time a medication had ever brought relief to patients with arthritis. However, in the following years, side effects were reported.


In the last 7 decades, the mechanism of action has been elucidated. There are 2 fundamental modes of actions: genomic and nongenomic action. The genomic mechanism starts with diffusion of the free plasmatic hormone through the membrane lipids. A binding site for the hormone is situated on cytoplasmic and nuclear receptors. The GC receptor (GCR) complex enters through nuclear pores and binds to the DNA, resulting in modification of gene transcription and messenger RNA production, and the subsequent translation and protein synthesis. The GCR complex also affects posttranscription events, resulting in alteration of cellular structure and activity, such as leukocytosis with neutrophil increase and reduction of all other leukocyte subsets.


Nongenomic effects are complex; they occur more rapidly and involve membrane-bound receptors. This mechanism needs further clarification but it is hoped that doing so will lead to new therapeutic targets.




Introduction


Glucocorticoids (GCs) were discovered in the 1940s by Kendal and Hench and were administered for the first time to patients with rheumatoid arthritis (RA) in 1948. Two years later, Drs Kendal and Hench won the Nobel Prize.


This was the first time a medication had ever brought relief to patients with arthritis. However, in the following years, side effects were reported.


In the last 7 decades, the mechanism of action has been elucidated. There are 2 fundamental modes of actions: genomic and nongenomic action. The genomic mechanism starts with diffusion of the free plasmatic hormone through the membrane lipids. A binding site for the hormone is situated on cytoplasmic and nuclear receptors. The GC receptor (GCR) complex enters through nuclear pores and binds to the DNA, resulting in modification of gene transcription and messenger RNA production, and the subsequent translation and protein synthesis. The GCR complex also affects posttranscription events, resulting in alteration of cellular structure and activity, such as leukocytosis with neutrophil increase and reduction of all other leukocyte subsets.


Nongenomic effects are complex; they occur more rapidly and involve membrane-bound receptors. This mechanism needs further clarification but it is hoped that doing so will lead to new therapeutic targets.




Clinical applications in rheumatoid arthritis


Inflammation Under Control


Administration of GCs results in diminished activation, proliferation, differentiation, and survival of various inflammatory cells. The higher the dose, the stronger is the effect. In RA, low doses are effective; however, in life-threatening events, high doses are often used. Although, the absolute number of inflammatory cell subsets is decreased, the total blood leukocyte count increases. This increase could be explained by reduction of the adhesion molecules, which subsequently prevents migration of neutrophils from the circulation to the tissues and increases their levels in plasma. Leukocyte subsets all decrease except B cells, which remain stable. GCs inhibit T-helper 1 (Th1) cells, resulting in a reduction of proinflammatory cytokine levels, such as interleukin (IL)-1β, IL-2, IL-3, IL-6, tumor necrosis factor alpha, interferon gamma, and IL-17 and explaining their antiinflammatory effect.


Pain Relief and Structural Progression


Relief of arthritis symptoms, including pain and swelling, is the predominant effect of GCs. New therapeutic strategies target rapid relief of symptoms but also aim to change the course of the disease (ie, preventing joint damage). A high-quality Cochrane Review identified 15 studies with 1414 patients and confirmed that treatment with GCs provided not only symptom relief but also reduction of radiographic progression with low doses of GCs in patients with early arthritis (RA<2 years). All these studies chose low doses of GCs (<7.5 mg/day) to minimize side effects.


This Cochrane Review provides support that GCs behave as disease-modifying antirheumatic drugs (DMARDs) and should be included as the first line of therapy in early arthritis.


Fatigue, Anxiety, and Depression


Other debilitating RA symptoms are fatigue, anxiety, and depression. In contrast with pain and morning stiffness, which correlate with the presence of proinflammatory cytokines, the pathophysiology of these symptoms is unclear.


An analysis of 388 patients with early arthritis suggested an association between morning stiffness and fatigue. Both symptoms improved after taking GCs, underscoring a potential common pathway. Consistent with these results, modified-release prednisone treatment for 12 weeks significantly reduces fatigue scores compared with placebo circadian administration of prednisone in rheumatoid arthritis (CAPRA-2).


Depression and anxiety are sometimes related to disease activity and pain; amelioration of the disease activity and pain improves these symptoms. However, GCs can also have a psychological side effect that paradoxically results in increased anxiety ( Table 1 ).



Table 1

Glucocorticoid dosage and treatment regiments is RA






















Dose Definition
Low dose ≤7.5 mg prednisone equivalent per day
Medium dose >7.5 but ≤30 mg prednisone equivalent per day
High dose >30 mg but ≤100 mg prednisone equivalent per day
Very high dose >100 mg prednisone equivalent per day
Pulse therapy ≥250 mg prednisone equivalent per day for 1 d or a few days

Data from Buttgereit F, da Silva JA, Boers M, et al. Standardised nomenclature for glucocorticoid dosages and glucocorticoid treatment regimens: current questions and tentative answers in rheumatology. Ann Rheum Dis 2002;61(8):720.




Dosing in rheumatoid arthritis


There are very different doses of GC’s used in RA, depending of clinical manifestations, treatment objectives and duration of therapy. In order to standardized nomenclature for GC dosages and GC treatment regimens a set of definitions was proposed, summarized in Table 1 .


Equivalents of Prednisone


Steroid hormones, including sex hormones, mineralocorticoids, and GCs, are all derived from cholesterol. Mineralocorticoids (mainly aldosterone) and GCs (mainly cortisol) are synthesized in the adrenal cortex. Sex hormones are produced in the adrenal cortex but are predominantly produced in the gonads.


Classification of mineralocorticoids and GCs depends on the main effect of the hormones. There is an overlap in function between the naturally produced hormones; however, the synthetic drugs are more restricted to a GC effect.


GCs, as alcohols, are insoluble in water. They can be taken as oral tablets and are absorbed in 30 minutes with high bioavailability. GCs, as esters, are lipid soluble and can be used for intramuscular, intra-articular, and peritendinous administrations. GC salts are water soluble and can be administered intravenously.


Circulating GCs are bound to proteins, mostly to corticosteroid-binding globulin or transcortin, but they also can be bound to albumin. The free form, which represents 5% to 10%, is the active form. Therefore, all patients with low levels of plasma proteins are more susceptible to GC effects, both adverse and therapeutic, and should be considered for a dose reduction. Cortisone and prednisone are inactive forms; they are metabolized in the liver to active hormones, cortisol and prednisolone, which have high affinity to GCR. The active forms are recommended when severe liver insufficiency exists. In all other situations the prohormones are preferred.


Prednisolone has a plasma half-life of 2.5 to 5 hours, depending on transcortin-binding body distribution, affinity to GCR, and rate of metabolism. It can be administered once daily, with a maximum effect after peak serum concentration. In the normal circadian rhythm, natural GC levels start to increase after 6 am and reach the highest peak in the morning. They tend to gradually decline throughout the day and increase again, to a smaller peak, around 6 pm . This small peak is followed by a gradual decline, reaching a plateau around 11 pm , concurrent with normal sleep time. The CAPRA study, with modified-release prednisone, showed that the administration of prednisone at night resulted in an earlier peak with subsequent pain and morning stiffness relief, allowing a better outcome with even low doses and thus fewer side effects. Nevertheless, further studies are needed to verify whether this regimen is equally effective in preventing joint damage in early RA. ( Table 2 ).



Table 2

Equivalents of prednisone
















































































Equivalent to Hydrocortisone Dose (mg) Relative GC Activity Protein Binding Plasmatic Half-life (h) Biological Half-life (h)
Short Acting
Cortisone 25 0.8 0.5 8–12
Cortisol 20 1 ++++ 1.5–2 8–12
Intermediate Acting
Methylprednisolone 4 5 >3.5 18–36
Prednisolone 5 4 ++ 2.1–3.5 18–36
Prednisone 5 4 +++ 3.4–3.8 18–36
Deflazacort 6 6 ++ 12–36
Triamcinolone 4 5 ++ 2 to >5 18–36
Long Acting
Dexamethasone 0.75 20–30 ++ 3–4.5 36–54
Betamethasone 0.6 20–30 ++ 3–5 36–54

Adapted from Jacobs JVdGM, Buttgereit F. Glucocorticoid in rheumatic diseases. In: WJ Bijlsma J, editor. EULAR textbook on rheumatic diseases. 1: BMJ Group; 2012. p. 1224.




Administration in rheumatoid arthritis


In patients with RA, the recommended plan of treatment is based on the current disease manifestations, the desired therapeutic effect, and the potential side effects. The prescribed GCs should include the recommended type, dose, route, administration time, frequency, and the duration of therapy.


Systemic


Oral


Oral GCs are frequently used in early RA as a bridge therapy for other DMARDs but they can also be used in low doses, as a maintenance therapy, concurrent with other DMARDs. It is preferable for oral GCs to be administered once daily in intermediate-acting or short-acting forms. The rationale for initiation and maintenance of low-dose GCs as additional therapy is the probable relative adrenal insufficiency in patients with active RA. As previously described, the role of low-dose GCs administered for 2 years in delaying the radiographic progression of RA has been highlighted in the last 2 decades and was thought to be superior to the use of DMARDs alone. Current practice is to use GCs as bridging therapy until stable state, ideally remission, is reached, then to taper ideally to no therapy. Modifications of the daily oral regimens have been devised to alternate-day regimens in an attempt to reduce the hypothalamic-pituitary-adrenal (HPA) suppression. However, these regimens proved unsuccessful in controlling the symptoms. In practice, they are used in juvenile idiopathic arthritis, in which the alternate-day regimen causes less inhibition of growth.


Parenteral


Parenteral administration is usually by the intramuscular route to control flares or as a bridge therapy in early RA, providing a symptom-free period until other DMARDs become efficacious when patient compliance with the oral regimens is questionable. Note that the long-acting lipid-soluble forms of GCs may be efficacious for 3 to 4 months. It is recommended not to repeat more than 3 to 4 times a year to avoid side effects.


Intravenous administration, as pulse therapy, is another form of parenteral use, reserved for induction of remission in major flares, particularly with initiation of new DMARDs strategy or for serious disease manifestations such as vasculitis with specific regimens. The soluble form, given in a very high dose, is administered once daily (it is sometimes given on 3 successive days but without good evidence for efficacy) followed by oral GCs. The duration of action of intravenous methylprednisolone is variable but it normally lasts for up to 6 weeks. Pulse therapy can be used as a bridge therapy for symptoms relief with reduced risks of side effects because many side effects depend more on the cumulative dose.


Intra-articular


The intra-articular administration of GCs in patients with RA is often used, particularly when the disease is active in a limited number of joints. The outcome of the intra-articular treatment is variable depending on several factors: the size of the joint, the amount of weight bearing on the joint, the degree of activity in the joint in terms of synovial fluid volume or presence of synovial hypertrophy, and history of previous joint aspiration. The more of these factors that are present, the less favorable an outcome is anticipated. It also depends on the type and dose of the administered GCs, injection technique, and on the duration of rest permitted after the injection. Rest is always recommended and the period of rest should be longer in weight-bearing joints. There is no evidence-based recommendation for the duration of rest; however, it is usually recommended to rest for 24 hours after injection and avoid overuse of the joint, even when it becomes pain free, for 3 to 6 weeks.


Concurrent administration of GCs with local anesthetics is usually preferred because the latter helps to relieve pain immediately. Soluble forms have the advantages of reduced risk of subcutaneous tissue atrophy and rapid onset of action, albeit the duration of symptoms relief is shorter. Lipid-soluble forms have a delayed onset of action but a more prolonged effect. A mixture of both forms of GCs can be used, combining the advantages of each.


The frequency of injection should not be more than once every 3 to 4 weeks with a total of 3 to 4 injections per year to minimize GC-induced cartilage injury.


Infection, as a cause of synovitis, should be excluded before the administration of intra-articular GCs. Infection can be a potential complication of the injection, but is rare when the procedure is done with stringent aseptic technique. Other local complications include subcutaneous fat atrophy, local skin depigmentation, tendon slip or rupture, and injury of other local structures such as nerves. Systemic effects also can occur, similar to other forms of GCs, but are rare.

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Sep 28, 2017 | Posted by in RHEUMATOLOGY | Comments Off on Glucocorticoids and Rheumatoid Arthritis
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