PRACTICAL THERAPEUTICS
Clin. Immunother. 3 (4): 271-286 , 1995 1172-7039/95/0C/J4-Q271 /$0800/0
© Adis International Limited. All rights reserved.
Corticosteroids in Rheumatoid Arthritis How Best To Use Them? Johannes WJ. Bijlsma, Amalia A. van Everdingen and Johannes WC. Jacobs Department of Rheumatology, University Hospital, Utrecht, The Netherlands
Contents Summary , , , , , , . 1, Mechanisms of Action . , . . . . . 1.1 Effects on the Immune System 1,2 Hypothalamic-Pituitary-Adrenal Axis and Stress Response 2. Clinical Studies . . . .. . . . . . . . . . . . , ' , . . . . . . . . 2,1 Oral Low Dosage Corticosteroids, , .......... . 2,2 Pulse Therapy with High Dosage Intravenous Corticosteroids 2,3 Intra-Articular Corticosteroids .. 3, Adverse Effects of Long Term Corticosteroid Use . . . .. . . 3.1 Peptic Ulcer Disease . . . . . . . . . . . 3.2 Suppression of the Hypothalamic-Pituitary-Adrenal Axis 3.3 Predisposition to Infections .. . 3.4 Atherosclerosis . , , . ... . 4, Corticosteroid-Induced Osteoporosis 4.1 Effects of Corticosteroids on Bone 4.2 Is Corticosteroid-Induced Osteoporosis Preventable? , 5. Guidelines, ... ... . " . . . . . . . . . . . .
Summary
271 272 272 274 275 275 276 277 279 279 280 280 280 280 281 281 282
Glucocorticosteroids are widely used in the treatment of patients with rheumatoid arthritis. Initially there was much enthusiasm for their use, arising from the striking relief of symptoms seen in patients with rheumatoid arthritis treated with corticosteroids. When the wide array of potentially serious adverse effects became apparent, the use of corticosteroids decreased. More recently, however, the careful use of corticosteroids in patients with rheumatoid arthritis has been generally accepted. New insights into the mechanisms of action of corticosteroids, especially their effects on the immune system and the hypothalamic-pituitary-adrenal axis, have provided more insight into, and rationale for, the use of corticosteroids in rheumatoid arthritis. Clinical data on the effectiveness of low dosage oral corticosteroids, high dosage systemic corticosteroids and intra-articular injections of corticosteroids are scarce. In contrast, data on the adverse effects of oral low dosage corticosteroids are abundant. In the last few years, strategies have been developed to at least partially prevent 2 of the main adverse effects: peptic ulcer disease and osteoporosis. Some practical guidelines on the use of corticosteroids in the management of rheumatoid arthritis conclude this review.
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Since the initial report by Hench et al.[I] that cortisone dramatically ameliorated the symptoms of rheumatoid arthritis, attitudes towards a therapeutic role for corticosteroids have swung through periods of enthusiasm, condemnation and, more recently, a guarded renaissance)2] Despite the continuing debate about the risks and benefits of corticosteroids, their central role in the treatment of rheumatoid arthritis remains undisputed. Corticosteroids are considered by many patients with rheumatoid arthritis, as well as by their physicians, to be most effective drugs, and their anti-inflammatory properties are well established. Studies continue to unravel the complexity of their biological effects, such as on gene transcription, and careful clinical observations refine their therapeutic use)31 In this review: (a) some aspects of their mechanisms of action are discussed, with emphasis on the effects of corticosteroids on the immune system and on the hypothalamic-pituitary-adrenal axis and stress response; (b) clinical studies and adverse effects are reviewed; and (c) some practical guidelines are formulated.
1. Mechanisms of Action Corticosteroids exert most of their effects through specific, ubiquitously distributed intracelhilar receptors. Corticosteroids circulate in blood in either the free form or bound to cortisol-binding globulin. The free form of the steroid can readily diffuse through the plasma membrane and bind with high affinity to cytoplasmic glucocorticoid receptors. The formation of the ligand-receptor complex is followed by its activation, i.e. translocation into the nucleus and binding to what are called acceptor sites. The bound complex modulates transcription of specific genes that encode proteins responsible for the action of glucocorticoids.[4] The human glucocorticoid receptor contains 3 main functional domains: (a) the DNA-binding domain in the centre of the molecule; (b) the ligandbinding domain in the C-terminal region; and (c) the immunogenic domain in the N-terminal region.[5] Specific receptors for corticosteroids are common in cells of the immune system, including monocytes and lymphocytes.l 6 ] The number of specific receptors © Adis International Limited. All rights reserved ,
varies with the stage of the cell cycle and, for instance, with the T lymphocyte subpopulation.[5] The corticosteroid-receptor complex enters the nucleus of a cell and binds to specific corticosteroidresponsive elements within DNA)7] The complex modulates the transcription rate of a corresponding corticosteroid-responsive gene)S] The complex may act both positively and negatively on transcription, depending on the gene on which the complex acts. [9] In addition to modulating transcription, corticosteroids also have effects on later cellular events, including RNA translation, protein synthesis and secretion. They can alter the stability of specific messenger RNAs for several cytokines and other proteins)IO] Corticosteroids also influence the secretion rates of specific proteins such as Iipocortin, through as yet unknown mechanisms. Corticosteroids influence nearly all cells and organ systems. In clinically evident rheumatoid arthritis, the immune system plays a pivotal role. The effects of corticosteroids on the immune system in patients with rheumatoid arthritis may be direct or indirect, for example by influencing the hypothalarnicpituitary-adrenal (HPA) axis and stress response. This review will concentrate on the effects of corticosteroids on the immune system as well as on the HPA axis and stress response. 1.1 Effects on the Immune System
Before different types of inflammatory cells are discussed separately, it is relevant to note that each cell type of the immune system is actually involved in complex interactions with other cells of the immune system. Corticosteroids thus provoke a wide range of changes that involve many cell types concurrently. 1. 1. 1 TLymphocytes
A single dose of corticosteroids produces a marked but transient lymphocytopenia, involving all lymphocyte sUbpopulations. This lymphocytopenia is due to redistribution of circulating lymphocytes to other lymphoid compartments such as the bone marrow,[II] but also to depression of adhesion molecules on lymphocytes. Corticosteroids downregulate the expression of the adhesion molecules Clin, Immunother, 3 (4) 1995
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LFA-I and CD2 following activation, with a consequent decrease in adhesion to endotheliumJl2] Recently, 2 functionally different types of T helper (T H) cells were identified based on their different cytokine secretion profiles: T Hi, which primarily secrete interferon-y, and T H2, which primarily secrete interleukin (IL)-4. It is hypothesised that in rheumatoid arthritis THI (cellmediated) activity predominates and that corticosteroids may enhance a shift from predominantly T HI to predominantly T H2 (antibody-mediated immunity))13] In addition to their effects on cell distribution, corticosteroids also affect the initiation and the progression of the T cell cycle. Corticosteroids inhibit several events associated with T cell activation, such as the production of IL-2 and of other cytokines secreted by activated T cells (IL-3, -4 and -6, and interferon-y).l14] Since cytokines are essential for T cell functions, the inhibition of these cytokines results in inhibition of the function of all T cells: helper and suppressor T cells as well as cytotoxic T cells.l 6] 1.1.28 Lymphocytes
In contrast to T cells, B cells are relatively resistant to the immunosuppressive effects of corticosteroids. Thus, low dosages of corticosteroids (prednisone 20 mg/day or less) do not affect serum immunoglobulin levels or antibody synthesis, but a brief course of high dosage corticosteroids will decrease serum immunoglobulin levels.[15] The mechanism of this may be inhibition of the production of cytokines involved in immunoglobulin synthesis (IL-l to -6, and interferon-y). 1.1.3 Macrophages
Corticosteroids antagonise macrophage differentiation and inhibit many of their functions,[ 161 such as: • expression of class II major histocompatibility complex antigens • release of numerous cytokines, for example IL-l, IL-6 and tumour necrosis factor-a • production and release of proinflammatory prostaglandins and leukotrienes. © Adis International Limited. All rights reserved.
Corticosteroids also impede the tumouricidal and microbicidal activities of activated macrophages. 1. 1.4 Neutrophils
Corticosteroids inhibit adhesion of neutrophils to endothelial cells, and thus the trapping of neutrophils in the inflamed site. Consequently neutrophilia may be found in the peripheral blood of a patient treated with corticosteroids. At pharmacological dosages, corticosteroids only modestly impair neutrophil functions; at lower dosages (prednisone 20 mg/day or less) these functions are not affected at all by corticosteroids. 1. 1.5 Other Immune Cells
Other immune cells also play an important role in the persistent inflammation of rheumatoid arthritis. These cells are also influenced by corticosteroids. Corticosteroids decrease circulating eosinophil and basophil counts. They decrease the accumulation of eosinophils and mast cells at sites of allergic reactions. They also inhibit release of histamines, leukotrienes and degranulation of mast cells.l41 1. 1.6 Other Mechanisms of Action
In inflammation, endothelial cells play an important regulatory role in the inflammatory cascade. They affect haemostasis, vascular permeability, trapping and exudation of leucocytes into inflammatory sites. Corticosteroids have an inhibitory effect on these processes. Another important part of the inflammatory cascade is arachidonic acid metabolism, leading to the production of prostaglandins and leukotrienes, most of which are strongly pro inflammatory. Through the induction of lipocortin, corticosteroids inhibit the formation of arachidonic acid metabolites. Recent data have shown the existence of at least 2 cyclo-oxygenase genes, COX-l and COX-2, coding for 2 related but unique isoenzymes that lead to the production of different prostaglandins. COX-I is the principal enzyme involved in producing prostaglandins that regulate cellular housekeeping functions such as gastric cytoprotection, vascular homeostasis and kidney function. In contrast, COX-2 appears only to be expressed in inflamed Un. Immunother. 3 (4) 1995
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tissue or following exposure to growth factors, lymphokines or other mediators of inflammation. An interesting finding is that COX-2, but not COXI, is inhibited by corticosteroids, whereas nonsteroidal anti-inflammatory drugs (NSAIDs) seem to inhibit both COX-I and COX_2.[17.18] In summary, lower dosages of corticosteroids inhibit leucocyte traffic and cellular immune response, whereas higher dosages are required to suppress the functions of leucocytes and the humoral immune response. Apart from this dosage response, there is also a heterogeneity of response among different persons with rheumatoid arthritis. 1.2 Hypothalamic-Pituitary-Adrenal Axis and Stress Response
The hypothalamic-pituitary unit plays a crucial role in the homeostasis of the human body, including the regulation of inflammation. Corticosteroids have potent anti-inflammatory actions through their influence on the HPA axis and the ensuing stress response. In the hypothalamus, signals to corticotrophin releasing hormone (CRH) neurons promote the release of CRH into the hypophyseal portal system and thus activate the pituitary to release corticotrophin (ACTH), which stimulates adrenal glands to release corticosteroids. This neuroendocrine system plays an important role in the regulation of the immune system: cytokines produced by immune inflammatory cells, such as IL-l, -2, -3, -6, tumour necrosis factor, prostaglandin F2 and platelet activating factor, stimulate the hypothalamus to secrete CRH. Corticosteroids suppress the inflammation and the immune response, completing a negative feedback circuit.[19] CRH not only activates the pituitary-adrenal axis, but also initiates a coordinated series of behavioural responses as well as the central autonomic-arousal system. The central autonomic-arousal system consists of the central limbic system [locus coeruleus, norepinephrine (noradrenaline) system] in the central nervous system. This system sets into motion a coordinated series of behavioural and physiological responses that are adaptive during stressful situations PO] The autonomic response, © Adis International Limited . All rights reserved.
mediated by catecholamines, especially norepinephrine, is manifested in changes in cardiovascular function and metabolism, called peripheral adaptation, and in changes in behaviour, called behavioural adaptation. Behavioural adaptation includes an improved alertness and attention span level, a decrease in reflex time, and suppression of feeding and sexual behaviour. Peripheral adaptation, on the other hand, consists primarily of a redirection of energy (oxygen and nutrition are shunted towards organs that require additional energy to function under stress), the fight or flight response. It has been suggested that the principal role of corticosteroids during the stress response is to contain or counter-regulate it. [21] Nearly 40 years ago the hypothesis that rheumatoid arthritis might be associated with adrenal insufficiency was put forward. 1221 It is time to look at this hypothesis in the light of our increased understanding of the HPA axis and the stress response. In this respect, the following observations have been made. (a) In patients with severe rheumatoid arthritis, the normal circadian rhythm of plasma cortisol levels is lost. In patients with mild to moderate disease activity, the diurnal maxima and minima are shifted to earlier times of the day, and the arithmetic mean of daily cortisol levels correlates with disease activity.[23] In patients with rheumatoid arthritis, cortisol levels were studied before and after a moderate exacerbation of their disease activity: when disease acti vity increased, cortisol levels decreased.l 241 These findings are in accordance with the idea that in patients with rheumatoid arthritis the regulation of cortisol levels to restrict inflammation might be inadequate. (b) Some inflammatory cell responses to corticosteroids differ in patients with rheumatoid arthritis compared with those in healthy controls, such as cell proliferation[25] and the induction of various proteinsJ26 1 (c) The number of specific corticosteroid receptors on mononuclear cells in the peripheral blood Clin. Immunother. 3 (4) 1995
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of patients with rheumatoid arthritis is diminished, especially during active disease.£27] (d) Rheumatoid arthritis patients may have an abnormality of the HPA axis response to immunoinflammatory stimuli. Patients with active rheumatoid arthritis were compared with patients with active osteomyelitis, another chronic inflammatory disease. The diurnal plasma cortisol level was low for the degree of inflammation in rheumatoid arthritis patients, and these patients failed to show a cortisol response to major surgery, despite adequately increased levels of IL-l and -6. Interestingly, the ACTH and cortisol response to infusion of CRH was similar in rheumatoid arthritis patients and in healthy controls, suggesting that the deficit in cortisol response in rheumatoid arthritis does not reside in the pituitary or adrenal glands, but might be due to a hypothalamic abnormality[28] (e) Early autopsy studies in patients with rheumatoid arthritis, not treated with corticosteroids, did show an increased frequency of pituitary hypoplasia and panhypopituitarism.£29] These findings suggest that a dysfunction of the HPA axis might be present in rheumatoid arthritis. It is, however, unknown whether this is a consequence of the active disease or a predisposing factor. This possible dysfunction of the HPA axis at the hypothalamic level may influence the stress response, modifying the autonomic system and behavioural adaptation. These findings, if confirmed, may give more rationale to the widespread use of corticosteroids in the treatment of patients with rheumatoid arthritis. Therefore, the effects of corticosteroids probably reach beyond inhibition of inflammation and suppression of symptoms of disease .
2. Clinical Studies 2.1 Oral Low Dosage Corticosteroids
The use of oral low dosage corticosteroids in the treatment of rheumatoid arthritis gives rise to continued debate. Low dosage corticosteroids (prednisone 5 mg/day or greater) effectively and rapidly suppress signs and symptoms of inflammation in rheuma© Adis International Limited. All rights reserved.
toid arthritis,[30] but adverse effects limit their role. Weighting the risks and benefits, many rheumatologists use low dosage corticosteroids in the management of individual patients with rheumatoid arthritis in order to improve quality of life. However, scientific data to confirm the effectiveness of corticosteroids in rheumatoid arthritis are scarce. 2. 1. 1 Evidence for Efficacy
The Medical Research Council was the first to conduct a study in 122 patients with early rheumatoid arthritis, comparing the effect of cortisone 80 mg/day, equivalent to prednisone 16 mg/day, with aspirin (acetylsalicylic acid) 4.5 g/day for 2 years. After 1 year there was no difference in effect between both groups. After 2 years the corticosteroid group had some better clinical results, but radiological deterioration had still occurred. [3 I] Following this initial study, the Medical Research Council compared the effecti veness of prednisone 12 mg/day during the first year and 10 mg/day during the second year with aspirin and other NSAIDs in 77 patients. After 2 years there was a statistically significant reduction of progression of erosions in the prednisone-treated group.l3 2] The same group was evaluated up to 7 years later, and at that time a statistically significant radiological difference was still noted in favour of the prednisone-treated patients.[33] The Empire Rheumatism Council performed a similar study in 100 patients, comparing the effect of cortisone 75 mg/day (equivalent to prednisone 15 mg/day) with aspirin 3.3 g/day for 3 years. No clinical or radiological difference between treatment groups was found at 2 and 3 years. However 'well-being' was better maintained on cortisone.£34] It is relevant to note that the dosage of aspirin used in this study is rather low, and perhaps not even anti-inflammatory. A more recent study compared the efficacy of prednisone 5 mg/day with placebo in 34 patients during 24 weeks. Despite the small number of patients, a slight functional improvement and an increase in a global sense of well-being was found in the group treated with prednisone. The number of Clin. lmmunother. 3 (4) 1995
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erosions increased in 1 prednisone-treated patient and in 4 patients treated with placebo.l3 5] In addition, numerous short term studies have described the beneficial effects of corticosteroids in patients with rheumatoid arthritis, especially in very active disease. Ritchie used the beneficial effects of corticosteroids to assess the sensitivity to change of the articular index for clinical use in patients with rheumatoid arthritis.[36] In another study, a prompt flare in arthritis activity occurred in patients treated for 3 months with prednisone 2.5 to 5 mg/day when corticosteroids were withdrawn, suggesting the efficacy of corticosteroids even at very low dosage.[37] However, an alternative explanation could be that flaring of the arthritis does not suggest efficacy but only steroid dependence. It is remarkable that the widespread use of low dosage corticosteroids in rheumatoid arthritis is based on such scarce, not very convincing and rather old scientific data. New studies with longer treatment duration and better defined outcome measurements, including adverse effects, are needed. 2. 1.2 Clinical Effects
In daily practice, corticosteroids seems to have greatest effect on morning stiffness and other systemic symptoms, such as fatigue , weakness and anorexia. An increase in haemoglobin concentration is noted, together with a decrease in erythrocyte sedimentation rate (ESR) and C-reactive protein. Walking time and grip strength of the hands often improve. Joint inflammation itself is more variably affected. Whether steroids can in fact retard the progression of erosive disease remains, as yet, unclear.[38] In case of extra-articular disease, such as pericarditis and pleuritis, low dosage corticosteroids may be effective, but sometimes higher dosages are necessary. For most physicians and patients, the beneficial effects of low dosage corticosteroids seem to outweigh their adverse effects (see section 3).[39] At present, about 25% of patients with long standing rheumatoid arthritis are receiving long term treatment with low dosage corticosteroidsJ40] © Adis International Limited. All rights reserved.
2.2 Pulse Therapy with High Dosage Intravenous Corticosteroids Long term treatment of rheumatoid arthritis with relatively high dosages of corticosteroids, 20 mg/day or more, has been disappointing because of incomplete responses, severe complications or, quite often, both. Accordingly, regimens have been modified to improve the therapeutic index of higher dosage corticosteroids. One such approach is the use of intravenous pulse therapy. Infusion of high dosage corticosteroids, for example methylprednisolone up to 1.0 g/m2/day for I to 5 days, has become widely used in different rheumatic diseases, such as systemic lupus erythematosus[41] and rheumatoid arthritis. [42] In rheumatoid arthritis, high dosage intravenous corticosteroids are used: • in treatment-resistant crippling rheumatoid arthritis • to bridge the time before onset of action of slowacting and disease-modifying agents • in life-threatening vasculitis or other serious extraarticular symptoms, often in combination with a cytotoxic agent. It is thought that pulsed high dosage corticosteroids may avoid to some extent adverse effects such as suppression of the HPA axis and osteoporosis, and may have specific therapeutic effects on the immune system (see section 1.1)J43.441 2.2. 1 Efficacy When corticosteroid pulse therapy is used in treatment-resistant rheumatoid arthritis, there is usually a striking clinical benefit, as measured by pain, morning stiffness, joint score, ESR, C-reactive protein and other measuresJ42,45] Although within a few days corticosteroids are metabolised and excreted, and after 1 week the suppression of the HPA axis is restored,l46] the beneficial effects are generally sustained for 4 to 12 weeks. After this period, little further effect is observed. Whether pulse therapy with corticosteroids is able to bridge the time to onset of action of the slow-acting or disease-modifying agents is still an area of controversy. The results seem to depend on Clin. lmmunother. 3 (4) 1995
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the dosage and schedule of the corticosteroids and on the particular disease-modifying agent used. In most clinical trials, corticosteroid pulse therapy was able to bridge the time to onset of action of newly started penicillamine, sulfasalazine, parenteral gold and methotrexate, but not of azathioprine.f 47 -51 ] Comparison of intramuscular pulse therapy with oral pulse therapy showed greater efficacy of intramuscular corticosteroids during induction of chrysotherapy.[52] Based on the available data in the literature, it seems probable that corticosteroid pulse therapy can bridge the time to onset of action of newly started disease-modifying agents as long as the time to onset is not too long. This may be the case with azathioprine, especially if the dosage schedule known as 'going low, going slow' is employed)53] No clinical comparative studies have been performed in patients with life-threatening extra-articular complications of rheumatoid arthritis treated with corticosteroid pulse therapy. In these cases, high dosage pulsed corticosteroids are usually combined with a cytotoxic agent. The efficacy of pulse treatment regimens depends on the dosage and schedule used. However, striking individual differences in the effects of corticosteroid pulse therapy are noted. Based on the literature reviewed[54] and our own experience, we suggest as the most effective treatment methylprednisolone 1000mg (or equivalent) 3 times within a period of 3 to 5 days , i.e. every day or every other day. 2.2.2 Adverse Effects
Recently we published a follow-up study of 50 rheumatoid arthritis patients undergoing a total of 87 corticosteroid pulses.[54] A remarkable number of short term and long term adverse effects were noted (table I). However, most of the short term adverse effects were mild and transient. Despite the adverse effects, many patients preferred this treatment, especially with regard to their quality of life. It is reassuring to note that corticosteroid pulse therapy has no evident effect on bone metabolism in the long term. Changes that have been observed © Adis International Limited. All rights reserved.
Table I. Adverse effects of corticosteroid pulse therapy. Data are from a study of 87 pulse treatments in 50 patientsI5.] Complication
Frequency (%)
Short term effects Increased diastolic blood pressure Hypoglycaemia or glucosuria Facial flushing Headache Bitter taste Vertigo Palpitationsltachycardia Urinary tract infections Euphoria Tired/malaise Insomnia Erythema/urticaria Jitteriness/fear Hypokalaemia Other infections Peptic ulcer
51
16 14
12 10 6 6 5
5 2 2 2
2 2
Long term effects, possibly attributable to corticosteroid pulse therapy Cushingoid face 18 Peptic ulcer 14 Cataract 6 Symptomatic osteoporosis 4 Purpura 6 Skin atrophy 2
suggest a transient decrease in bone formation and no relevant effect on bone resorptionJ55-57] 2.2.3 OveNiew
High dosage intravenous corticosteroid therapy may be very effective in well-selected patients with treatment-resistant rheumatoid arthritis or with life-threatening extra-articular disease. However, the most frequent use is in patients with active rheumatoid arthritis to bridge the time between the start of therapy and onset of effect of diseasemodifying agents. Contraindications are uncontrolled hypertension, peptic ulcer and/or concurrent infectious disease. [54] Careful consideration of the benefits and risks of corticosteroid pulse therapy is essential in each patient. 2.3 Intra-Articular Corticosteroids
Since 1950, several long-acting corticosteroid preparations have been used intra-articularly to Clin. lmmunother. 3 (4) 1995
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suppress synovitis in rheumatoid arthritis joints. The symptom-modifying value of these intra-articular injections has been confirmed in many studies.l 581 2.3. 1 Efficacy
Injection of corticosteroids into inflamed joints can provide prolonged (several months) relief from pain and swelling, and can markedly improve function. There is, however, no evidence that these injections hamper progression of erosive disease. After a follow-up of 17 years, radiographic progression was observed in 61 of 82 injected knee joints.[59] In patients with active rheumatoid arthritis this is to be expected, and does not exclude a positive effect of these injections. No other long term studies are available. Regardless of the question of slowing down erosive disease, synovitis is suppressed in the vast majority of patients receiving intra-articular corticosteroid injections. Duration of action is probably related to the insolubility of the corticosteroid preparation, leading to prolonged retention at the site of injection. Intra-articular corticosteroids may have some systemic effect, as shown by frequently observed flushing and joint improvement at distant sites from the injection. 2.3.2 Administration It is generally accepted that ajoint may be injected
several times, but at least for weight-bearing joints injections should preferably not be administered more than 3 times a year. All joints can be injected, but some joints, for example the hip joints, are difficult to approach. In such cases, radiological visualisation in guiding the positioning of the needle may be helpful. The need for rest of the joint after injection is not proven, but it seems prudent to avoid major strain or overuse of the joint.[60] Frequently used preparations are triamcinolone acetonide, dexamethasone acetate, methylprednisolone acetate and paramethasone. The dosage of the intra-articular injection depends on the size of the joint, and may range from 2.5 to 40mg of, for example, triamcinolone acetonide. No adequate comparative clinical trials have been done to compare the efficacy of the different preparations and dosages. © Adis International limited. All rights reserved.
2.3.3 Adverse Effects
The following adverse effects of local corticosteroid injections have been described: • cartilage damage • cutaneous atrophy • destructive arthritis • infectious arthritis • postinjection synovitis • tendon rupture.l 61 ] Infectious arthritis is a potentially serious, but extremely rare, complication, estimated at < 1 in 10 ()()() injections.[59] Reports of tendon or ligament rupture after corticosteroid injection into a joint are also very rare. Attention to injection technique is of course always important. Destructive arthritis may be due to the analgesic effect of corticosteroid injections, to a direct biochemical action on cartilage, or to ischaemic necrosis. Case reports have suggested that repeated intraarticular injections could result in a destructive arthropathy, indistinguishable from a Charcot joint. [62] However, in these patients it was impossible to disentangle the effects of corticosteroid injections from the natural history of the underlying arthropathy. More frequently encountered is postinjection synovitis, an acute self-limiting synovitis occurring in up to 1% of joints injected with corticosteroids. There is some suggestion that this postinjection synovitis may be attributable to crystals present in the steroid preparations.l 63 ] Perhaps the greatest concern over the widespread use of intra-articular corticosteroid injections is about the effect that these agents might have on cartilage. Evidence of a possible deleterious effect has largely come from animal models and in vitro studies. Intra-articular steroid injections in young rabbits, for instance, showed a reduction in protein synthesis.[64] However, other more recent studies with human cartilage even show a beneficial effect of corticosteroids.l 65 ] In the clinical situation it is quite likely that the possible negative effects of corticosteroids on cartilage are outweighed by their anti-inflammatory properties, which might lead to a reduction in joint destruction. The positive effects Clin. Immunother. 3 (4) 1995
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of the injection generally exceed the negative effects.
3. Adverse Effects of Long Term Corticosteroid Use Given the diversity of their mechanisms and sites of action, it is not surprising that corticosteroids can cause a wide array of adverse effects. A partial list is given in table IJ,l41 in which an attempt has been made to group effects in order of practical importance. These adverse effects are commonplace and many of them cannot be completely avoided. Theoretically, the risk for most of these complications is dosage- and time-dependent; minimising the use of corticosteroids minimises the risk of complications. It is a striking clinical observation that some patients develop severe adverse effects with relatively small doses of corticosteroids, while other patients receive rather high doses without obvious serious adverse effects. This apparent individual susceptibility for adverse effects does not seem to parallel the individual's susceptibility for beneficial effects. The toxicity of prednisone 15 mg/day or less for at least 1 year in the treatment of rheumatoid arthritis was recently evaluatedJ 66 1 Although disease severity is an important confounding factor in interpreting this evaluation, 3 serious adverse events were identified that caused substantial morbidity: • gastrointestinal bleeding or ulcers • infections • osteoporosis. These and some other common adverse effects are discussed in this section. Corticosteroid-induced osteoporosis is discussed separately in section 4, since measures to, at least partially, prevent osteoporosis are now timely. 3.1 Peptic Ulcer Disease
Peptic ulcers have long been considered a complication of corticosteroid therapy. However, careful analysis of the literature leads to the conclusion that if any association exists between peptic ulcer © Adis Internotionollimited. All rights reserved.
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Table II. Adverse effects of corticosteroid therapy (after Boumpas et al. ,(4) with permission) Characteristic early in therapy: essentially unavoidable Emotional lability Enhanced appetite or weight gain or both Insomnia
In patients with underlying risk factors or concomitant use of other drugs Acne vulgaris Diabetes mellitus Hypertension Peptic ulcer disease When corticosteroid treatment is sustained and intense Cushingoid habitus Hypothalamic-pituitary-adrenal suppression Impaired wound healing Myopathy Osteonecrosis Predisposition to infections Delayed and insidious, probably dependent on cumulative dose Atherosclerosis Cataracts Fatty liver Growth retardation Osteoporosis Skin atrophy Rare and unpredictable Epidural lipomatosis Glaucoma Pancreatitis Pseudotumour cerebri Psychosis
and corticosteroids, it is likely to be small. A prospective study of 1400 patients receiving corticosteroid therapy showed an overall 2-fold increased risk for peptic ulcer disease. However, multivariate analysis showed that concomitant use of NSAIDs explained this increased riskJ 67 1 A smaller study showed a relative risk of 3.3 for corticosteroids as a risk factor for peptic ulcer disease; however, in this study 85% of these patients were also using NSAIDs, for which the risk factor was not corrected.[661 It may be concluded that there is no clear independent association of corticosteroids with peptic ulcer disease. However, corticosteroids in combination with NSAIDs should be considered as a risk factor for peptic ulcer diseaseJ 68 1 Clin.lmmunother. 3 (4) 1995
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3.2 Suppression of the Hypothalamic-Pituitary-Adrenal Axis
Suppression of the HPA axis is common with corticosteroid usage, and Addisonian crises may occur in patients whose dosage is tapered too rapidly, if the drug is abruptly withdrawn, or when stress response is needed, for instance in surgery. When patients are treated with prednisone:2:l0 mg/day or equivalent they are likely to have a blunted adrenal response to stressful stimuli. At prednisone < 10 mg/day or equivalent, many patients will have recovered at least partial HPA axis function, but those receiving prednisone 5 to 10 mg/day or equivalent should be considered to be at risk during the stress of emergency situations. [69] Patients receiving lower dosages of corticosteroids «5 mg/day) would be expected to have a normal HPA axis, although this is not al ways the case. It has been believed that the degree of HPA axis suppression depends on factors such as duration and dosage of corticosteroid treatment. However, recently 2 large studies have shown that HPA axis function in patients treated with corticosteroids cannot be reliably estimated from the dosage of corticosteroids, the duration of therapy or the basal cortisol concentration.[69.70] In such patients, testing with corticotrophin[70] or CRH[69] will predict HPA axis function. 3.3 Predisposition to Infections
As discussed in section 1.1, corticosteroids have a profound effect on cells of the immune system. Lower doses of corticosteroids inhibit leucocyte traffic and cellular immune response, while higher doses suppress the function of leucocytes and the humoral immune response. Indeed, corticosteroids can dramatically alter the course of most infectious diseases: fever is reduced, as are the malaise and toxicity from the illness, but the infection often worsenspl] By masking symptoms, corticosteroids not infrequently lead to underestimation of clinical problems, such as in diverticulitis or appendicitis. However, whether corticosteroids really increase the risk of infection is controversial. © Adis International Limited. All rights reserved.
The relative risk for infection across a number of clinical settings was approximately 2 times that of controls in a meta-analysis of71 trials involving more than 2000 glucocorticosteroid-treated patients. In] The risk varied according to the type of disease being treated. In a study comparing 112 rheumatoid arthritis patients treated with low dosage (mean 6.1 mg/day) prednisone with 112 matched rheumatoid arthritis patients not treated with prednisone, 14 versus 4 serious infections were found (p = 0.04), including pneumonia (5 cases), septic arthritislbursitis (4 cases) and urinary tract infections (2 cases).l66 1 3.4 Atherosclerosis
More than 20 years ago an increased incidence of peripheral atherosclerosis was noted in rheumatoid arthritis patients who received long term corticosteroid therapy.[73] Although accelerated atherosclerosis seems to be associated with corticosteroid treatment, other processes operating in rheumatoid arthritis may also be atherogenic.l7 4 ] Evidence of increased atherosclerotic risk in corticosteroidtreated individuals without confounding systemic disease is not definitive. For example, in a study of normal volunteers, corticosteroids did not induce lipoprotein abnormalities associated with cardiovascular risk; no effect on total cholesterol or low density lipoproteins was noted,l75] In the study[66] that compared 112 rheumatoid arthritis patients treated with low dosage corticosteroids with matched rheumatoid arthritis patients not treated with corticosteroids, 4 myocardial infarctions were found in both groups, but 6 strokes occurred in the corticosteroid group versus only 1 stroke in the control group.l66] If corticosteroids themselves are indeed atherogenic, the process probably involves mechanisms other than a change in lipoprotein profiles, for example influences on the adhesion molecules of vascular endothelium.
4. Corticosteroid-Induced Osteoporosis Generalised osteoporosis is a feature of established rheumatoid arthritis, but this may be a consequence of treatment with corticosteroids, immobility or Clin. Immunother. 3 (4) 1995
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disease activity, or a combination of these factors. In 148 patients with early rheumatoid arthritis, before treatment with disease-modifying drugs or corticosteroids was started, measurement of bone mineral density by dual energy x-ray absorptiometry showed a significant amount of generalised skeletal bone loss. This bone loss was associated with disease activityJ76] This result illustrates the difficulty in defining the effect of corticosteroids on bone in patients with rheumatoid arthritis.
4.1 Effects of Corticosteroids on Bone Corticosteroids inhibit bone formation directly and perhaps also indirectly by decreasing gonadal steroid secretion.[77] Suppression of osteoblast function results in reduced synthesis of bone matrix and therefore in reduced bone formation, illustrated by the decreased rate of mineral apposition and the decrease in the width of trabecular packets in histomorphometric studiesP8] As shown by serum osteocalcin concentrations, osteoblast function decreases within a few days after the start of treatment with even low dosage (prednisone 10 mglday) corticosteroidsJ79] Apart from inhibiting bone formation, corticosteroids also increase bone resorption. This increased bone resorption is suggested by histomorphometric studies showing an increase in trabecular resorption surfaces and an increased urinary hydroxyproline excretion. [80] It may be caused by secondary hyperparathyroidism, the stimuli for which are decreased calcium absorption[81] and increased urinary calcium excretionJ82] The unfortunate combination of decreased bone formation and increased bone resorption leads to a significant loss of bone. As measured by changes in bone mass, bone loss is greatest in the first year of treatment, with rates approaching 10% per annum.[83] Bone loss probably continues for as long as corticosteroid treatment is being given. Measurement of bone loss is important, but osteoporotic fractures are the clinically relevant endpoint. Increased rates of vertebral fractures have been reported in many studies of patients with rheumatic diseases, but some of that increase may © Adis International Limited. All rights reserved.
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be attributable to the underlying rheumatoid arthritisJ84] Steroids affect cortical sites, such as the neck of the femur, as much as trabecular bone in the vertebra,[85] but whether there is an increased risk of hip fracture in addition to the commonly associated vertebral and rib fractures is unknown.[83] Some corticosteroid-induced bone loss is reversible.[86] The question of a 'safe' dosage that does not cause bone loss is controversial. Some investigators claim that corticosteroid dosages equivalent to prednisone ~7.5 mg/day are relatively free from these effects,[87] but others disagree.[88] It is likely that the total bone loss is related to the underlying disease, daily corticosteroid dosage, duration of treatment and especially cumulative dosage,[89] but this is not found in all studies.[90]
4.2 Is Corticosteroid-Induced OsteoporosiS Preventable? Of course one should try to use the lowest dosage of corticosteroids possible, but changing to alternate day treatment with corticosteroids has no beneficial effect on bone.[91] As discussed in section 2.2, pulse therapy has fewer effects on bone metabolism. However, a large number of patients with rheumatoid arthritis have been, are and will be treated with corticosteroids for a long period of time. What are the possibilities to prevent (further) bone loss in these patients? Based on the underlying mechanisms of corticosteroid-induced osteoporosis, one might try to increase bone formation and/or to decrease bone resorption. As is known from the international osteoporosis literature, there are no effective and safe methods to increase bone formation and thus restore bone.[92] Fluoride salts are reported to stimulate bone formation, and might be effective in treatment of corticosteroid-induced osteoporosis,[93] but the value of fluoride salts in the prevention of osteoporosis is not known. In order to prevent hypocalcaemia, because of decreased calcium absorption and increased calcium excretion, and secondary hyperparathyroidism, it seems sensible to supplement calcium, with or Clin. Immunother. 3 (4) 1995
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without additional vitamin D. In several studies it has been shown that supplementation of calcium inhibits (further) bone loss.[94,95] In a large study, additional supplementation with calcitriol was effective in further preventing corticosteroid-induced bone loss,l96] but other studies failed to note an additional effect of vitamin DJ94] The rationale for using vitamin 0 or its metabolites is not only to reverse the decrease in intestinal calcium absorption by antagon ising the effects of corticosteroids on gut cells, but also possibly to exert a direct stimulatory effect on osteoblasts.[97] Another way to counteract the detrimental effect of corticosteroids is to administer anti-bone resorptive agents, such as calcitonin, oestrogens or bisphosphonates. Calcitonin has not been shown to be very effective in this respect.[96,98] Oestrogens may prevent corticosteroid-induced osteoporosis,l99] but no large studies have been performed. The preventive effect of bisphosphonates is better documentedJloo-I02] It should be noted that none of the above-mentioned studies have used fracture rates as an outcome parameter; all used changes in bone mineral density. Deflazacort is an oxazoline derivative of prednisolone with reduced lipid solubility. It is claimed that this drug has fewer effects on calci um and bone metabolism than prednisone; it possibly also has smaller negative effects on carbohydrate and lipid metabolism. In a cross-sectional study of patients with rheumatoid arthritis treated with deflazacort or prednisone, the deflazacort group had no detectable negative changes in vertebral bone mass, whereas such changes were detected in the prednisone groupJI03] However, in another trial in premenopausal patients with rheumatoid arthritis, neither treatment caused a significant change in vertebral bone mineral density, in contrast to what would be expected.[104] As with the other drugs, no study has been published of deflazacort with osteoporotic fracture rate as an endpoint. Therefore the possible benefit of long term treatment with low dosage deflazacort over other corticosteroids has still to be proven. © Adis International Limited. All rights reserved.
In summary, corticosteroid-induced osteoporosis is a frequently occurring and serious adverse effect of therapy with corticosteroids. Preventive treatment is considered to be mandatory: at least an adequate supplementation of calcium, and in case of suspected vitamin 0 deficiency also vitamin D. In high risk patients, for instance those with low bone mass or who are severely immobilised, additional preventive measures are feasible, such as oestrogens (in women) or bisphosphonates. Further research is needed to determine whether all patients receiving treatment with corticosteroids should be given preventive treatment additional to calcium and vitamin D.
5. Guidelines Treatment of rheumatoid arthritis is complex and should be individualised. Corticosteroids probably only have effects on the symptoms and signs attributable to inflammation, and not on structural damage.[38] Therefore, corticosteroids should preferably be used as a part of a long term treatment strategy, including additionally an NSAID and a disease-modifying drug. Adequate control of rheumatoid arthritis with this combination strategy permits tapering and sometimes withdrawal of the steroid therapy. However, especially in elderly patients ~80 years of age with active rheumatoid arthritis, corticosteroids may be used as monotherapy, the advantages of corticosteroids outweighing the disadvantages. The recent interesting finding of a possible deficit in the HPA axis in rheumatoid arthritis merits further research, but has as yet no practical consequences for the use of corticosteroids in the management of rheumatoid arthritis. Clinical trials evaluating the efficacy of low dosage corticosteroid therapy in early rheumatoid arthritis are now underway. If oral corticosteroids are needed for the treatment of arthritis only, the dosage should be kept as low as possible and the duration of treatment as short as possible. In general, dosages up to 10 mg/day of prednisone, or equivalent, are effective. To treat systemic disease, higher dosages of 10 to 30 mg/day Clin. Immunother. 3 (4) 1995
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are sometimes necessary. In case of severe extraarticular complications, such as pericarditis or lifethreatening vasculitis, still higher dosages are often needed, quite often in combination with (other) immunosuppressive drugs. When corticosteroids are necessary in rheumatoid arthritis, the following preventive measures are prudent. • To inhibit development of osteoporosis, calcium (taken at bedtime) should be added to the treatment. If vitamin D levels in blood are low, or expected to be low, for example in elderly immobile patients, vitamin D (calcitriol) should be added. • If the patient also requires NSAIDs, and neither corticosteroids nor NSAIDs can be withdrawn, treatment, for example misoprostol, to prevent peptic ulcer disease has to be considered. This is especially the case in patients over 60 years of age, in those with a history of peptic ulcer and in immobile patients. • Active screening for potential adverse effects is advisable, for example regular measurement of blood pressure and blood glucose levels (see table II). Intra-articular use of corticosteroids, for example triamcinolone acetonide 2.5 to 40mg, is generally effective. Good injection techniques should be used, and a single weight-bearing joint should not be injected more frequently than 3 times a year. Pulse therapy with high dosage intravenous corticosteroids, for example methylprednisolone I g/day 3 times on alternate days, probably has a modest place in the management of recalcitrant rheumatoid arthritis, in bridging the gap before disease-modifying agents are effective, and in severe extra-articular complications. For each individual patient the advantages and disadvantages of this form of treatment should be carefully weighed.
Acknowledgements The continuous support of the Dutch Rheumatism Foundation ' Het Nationaal Reumafonds' is gratefully acknowledged.
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Correspondence and reprints: Professor Hans Bijlsma, Department of Rheumatology, F02.223, University Hospital Utrecht, P.O. Box 85500, 3508 GA Utrecht, The Netherlands.
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