9 Corticosteroid therapy in rheumatoid arthritis EMMANUEL GEORGE JOHN R. KIRWAN

T h e first p a t i e n t with r h e u m a t o i d arthritis ( R A ) to b e t r e a t e d with cortic o s t e r o i d s w a s a 2 9 - y e a r - o l d w o m a n w h o l a y b e d r i d d e n following 4 y e a r s o f s e v e r e , p r o g r e s s i v e disease. A l t h o u g h suffering f r o m w i d e s p r e a d synovitis, a f t e r o n l y t h r e e d a i l y i n t r a m u s c u l a r ( i . m . ) i n j e c t i o n s o f 100rag h y d r o c o r t i s o n e she was s y m p t o m l e s s a n d fully a m b u l a n t . Such a d r a m a t i c r e s p o n s e was a fitting c o n c l u s i o n to 20 y e a r s of clinical a n d l a b o r a t o r y effort b y H e n c h a n d his c o l l e a g u e s ( H e n c h et al, 1949), which e a r n e d t h e m t h e N o b e l P r i z e in M e d i c i n e a n d P h y s i o l o g y f o r t h e i r w o r k on s t e r o i d s a n d R A . S o m e h i s t o r i c a l m i l e s t o n e s a r e n o t e d in T a b l e 1. T h e i n t r o d u c t i o n o f c o r t i c o s t e r o i d s for t h e t r e a t m e n t of R A was g r e e t e d w i t h w i d e s p r e a d e n t h u s i a s m . A l t h o u g h t h e initial m e d i c a l l i t e r a t u r e s t r e s s e d

Table 1. Some milestones in the history of steroids in RA.

1925

Hench

Associated the weakness, fatigue and hypotension of RA with that found in adrenal failure

1929-38

Hench

Noticed improvement in RA during pregnancy and jaundice

1935

Mason (1936a,b)

Isolated compound E

1941

Hench

Treated three patients with the new adrenal cortex extract 'cortin' with little effect

1943

Reichsten and Shoppie

Elucidation of structure of 28 adrenal cortex steroids

1947

Kendall (1949)

Synthesis of compound E

1948

Hench et al (1949)

Treatment of first patient with hydrocortisone on 21 September

1950

Hench Sprague Empire Rheumatism Council

Descriptions of beneficial and adverse clinical effects of cortisone and ACTH

1967

West

First suggestions that steroids may reduce radiological progression

1980

Leibling

Use of large, pulsed doses of methylprednisolone

1957

BailliOre's Clinical Rheumatology-Vol. 4, No. 3, December 1990 ISBN 0-7020-1484-2

Controlled trial of corticosteroids in RA suggested medium-term benefit but many adverse reactions

621 Copyright 9 1990, by Bailli6re TindalI All rights of reproduction in any form reserved

622

E. GEORGEAND J. R. KIRWAN

the investigational nature of the studies, the general press emphasized the remarkable therapeutic responses. Their use and fame spread rapidly, and many patients gained f r o m short-term i m p r o v e m e n t s in their disease. But it gradually became clear that at doses required to maintain significant clinical benefit the adverse reactions seemed unacceptable, and investigators sought new ways of separating the two. In this review we will concentrate on what is known of the m o d e of action of corticosteroids and how this might relate to their beneficial clinical effects and adverse reactions. W e critically assess the data available and conclude that more work remains to be done before we can be confident that we understand the potential of these drugs, and we point to future directions of enquiry.

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Figure 1. Structures of some natural and synthetic glucocorticoids.

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623

CORTICOSTEROID THERAPY IN RHEUMATOID ARTHRITIS

STRUCTURE The principal glucocorticoid hormone of the human adrenal cortex is cortisol (hydrocortisone) (Sweab, 1955), which is derived from cortisone (Peterson et al, 1957). Steroid hormones are synthesized from cholesterol and have a basic structure of four interconnected carbon rings (Figure 1). The two hydroxyl groups, 1113 and 17oLare important for glucocorticoid activity and are probably necessary for interaction with steroid receptors (see below) (Mills, 1971). Like cortisone, the synthetic corticosteroid prednisone is an 11-keto compound but is converted to the ll-hydroxyl compounds, prednisolone in vivo (Jenkins 1966; Schalm et al, 1976). The additional double bond in ring A of prednisolone provides four times the glucocorticoid activity of cortisol and slightly less mineralocorticoid activity. Synthetic substitution to give 6a methylation produces methylprednisolone, which has even greater glucocorticoid activity and less mineralocorticoid activity (Jenkins, 1961), an effect similar to that of 9-~-fluorination (Jenkins, 1961) to produce triamcinolone. Dexamethasone has both 16-methylation and 9-o~fluorination. The synthetic derivatives of cortisol have the advantage of reduced mineralocorticoid activity, inducing less sodium retention at equipotent glucocorticoid doses (Table 2), but it has not yet proved possible to separate the different glucocorticoid effects (see below). Table 2. C o m p a r i s o n of c o m m o n l y used glucocorticoids.

Duration of action Short tv28-12 hours Intermediate tv2 12-36 hours

Long tl/2 36-72 hours

Equivalent oral or intravenous doses (mg) Cortisone Cortisol

Relative sodium-retaining action

25 20

0.8 1

Prednisone Prednisolone Methyl prednisolone Triamcinolone

5 5 4 4

0.8 0.8 0.5 0

Paramethasone Dexamethasone Betamethasone

2 0.75 0.60

0 0 0

MODE OF ACTION

Glucocorticoid receptors Under the influence of the hypothalamus and the pituitary gland the plasma cortisol concentration is maintained at 5-25 pLg/ml, of which 80% is tightly bound to the oL-globulin transcortin (corticosteroid-binding globulin). Of

624

E. GEORGEAND J. R. KIRWAN

the remainder, half is bound to albumin, and half is unbound, existing in equilibrium with bound cortisol (Baxter and Forsham, 1972). It is only this free c o m p o n e n t that is active. The synthetic analogues do not compete for binding sites on transcortin and are less extensively bound to plasma albumin and therefore diffuse into tissues m o r e completely than does cortisol (Melby, 1974). T h e relative potencies of the glucocorticoids correlate with their plasma half-lives (Table 2); and the duration of anti-inflammatory activity of cortisol and its analogues given orally approximates to the

Figure 2. Steps in glucocorticoid action. S = steroid; R = receptor. Outline of a glucocorticoid responsive cell. Unbound steroid(s) diffuses across the cell membrane and binds to a specific cytoplasmic receptor (R). The steroid-receptor complex (RS) undergoes a conformational change and moves into the nucleus and becomes attached to chromosomal DNA, thereby increasing (or reducing) the synthesis of corresponding messenger RNA.

CORTICOSTEROIDTHERAPYIN RHEUMATOIDARTHRITIS

625

duration of suppression of the hypothalamic-pituitary-adrenal axis. This suggests that the molecular binding sites needed for attachment to the receptors in the hypothalamus are the same as those needed for attachment to receptors in peripheral tissues (Melby, 1974). Free cortisol diffuses into individual cells, where specific receptor proteins are found in the cytoplasm of glucocorticoid-responsive tissues (Figure 2). The human glucocorticoid receptor is a 95-kD phosphorylated protein with steroid-binding, DNA-binding and strongly antigenic regions each of roughly equal size. The receptor gene has now been cloned and sequenced, confirming and extending the general description of this protein. The glucocorticoid receptor belongs to a superfamily of regulatory proteins that include receptors for thyroid hormones and the vitamin A-related metabolite retinoic acid (Evans, 1988). The genetics of glucocorticoid receptors have been reviewed by Gehring (1986). The steroid and receptor form a complex that undergoes a conformational change, leaves the cytoplasm and moves to the nucleus, where it binds reversibly to specific sites on chromatin. This results in the production of a mRNA, which codes for enzymes or other proteins that produce the hormonal effects (Baxter, 1972). Most cellular responses can be detected within 2 hours of corticosteroid exposure and some within 10 minutes (Baxter and Forsham, 1972). In general, steroid response is not observed if RNA synthesis is inhibited and the concentration of a specific steroid required for optimal response is lower when it has a higher affinity for the corticosteroid receptor. Although there are wide differences between the number of steroid receptors present in different cell types, corticosteroid responsiveness or sensitivity does not appear to directly correlate with receptor-related parameters (Ballard et al, 1974). Glucocorticoid resistance and defective glucocorticoid receptors in man have been reviewed by Lipsette et al (1985).

Lipocortin Glucocorticoids act through a variety of mechanisms (Table 3). Their main effect is achieved by controlling the rate of synthesis of mRNA and proteins as described above. Although reduced protein synthesis has been recognized in some tissues (e.g. lymphoid cells, muscle, bone and skin), the main glucocorticoid effect is through increased rates of synthesis of certain proteins and especially of lipocortin. The anti-inflammatory effect of lipocortin is mediated through its inhibition of the enzyme phospholipase A2. Table 3. Someactionsof glucocorticoid. Increased synthesisof lipocortinand subsequent inhibitionof phospholipaseA2 Reducedproductionof cytokinesand inflammatoryenzymes Alteration in T and B cell functions Reductionof Fc receptor expression Changes in white cell traffic

626

E. GEORGEAND J. R. KIRWAN

In vitro many pro-inflammatory cellular responses depend upon phospholipase A2, which converts membrane-bound phospholipids to arachidonic acid with the subsequent intracellular production of prostaglandins, leukotrienes and oxygen radicals (Blackwell et al, 1980; Rothbut and RussoMarie, 1984) (see Figure 3). These products leave the cell and are themselves able to stimulate the release of phospholipase A2 from adjacent cells. Thus, a positive feedback loop is established and this reaction could continue unabated. In practice this does not occur, implying the existence of an inhibitory mechanism forming an important part of the control of inflammation. It was the search for this inhibitor which led to the discovery of lipocortin, which now underpins our understanding of the fundamental biochemical and cellular anti-inflammatory mechanisms of glucocorticoids. Thus glucocorticoids inhibit pro-inflammatory cytokine production, including that of interleukin 1 (IL-1) (Dinarello, 1984; Snyder et al, 1982), interleukin 2 (IL-2) (Gillis et al, 1979; Grabstein et al, 1986), the IL-2 receptor (Grabstein et al, 1986), interferon e~(IFN-e0 (Grabstein et al, 1986), turnout necrosis factor (TNF) (Beutler et al, 1986), and perhaps various colonystimulating factors (CSFs) such as IL-3 (Grabstein et al, 1986). Steroids are

CortJcosteroids

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Lipocortin ( LM:Crm~ /

Inhi!ition //

Phospholipase A 2

Arachidonicacid Lipoxygenase ~Z/~~~

Cyclooxygenase

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Leukotrienes

Prostaglandins O" radicals

Figure 3. Glucocorticoidsinduce the synthesisof macrocortin, which inhibits the enzyme phospholipase A2. Arachidonicacid release from membranephospholipidsis thus blocked. The productionof pro-inflammatorysubstances via cyclooxygenaseand lipoxygenaseis thus reduced.

C O R T I C O S T E R O I D T H E R A P Y IN R H E U M A T O I D ARTHRITIS

627

antipyretic, probably because they impair the production of endogenous pyrogen (Dillard and Bodel, 1970), so reducing the rise in temperature that is a prominent accompaniment of inflammation and that may represent part of the body's inflammatory response. This has been characterized as tumour necrosis factor (Beutler et al, 1986). In addition, corticosteroids even in very low concentrations inhibit the production of a variety of pro-inflammatory enzymes, including the macrophage products collagenase, elastase and plasminogen activator (Werb, 1978). Plasminogen activator converts plasminogen to plasmin, an action which is thought to facilitate the entrance of leukocytes into areas of inflammation by hydrolysis of fibrin and other proteins (Granelli-Piperino et al, 1977). Some of the effects of corticosteroids have been attributed to stabilization of neutrophil lysosomal membranes (Weissmann and Thomas, 1963), but these experiments used rabbit liver lyosomes and high in vitro steroid concentrations. Doubts about the applicability of these studies to man have been reinforced by suggestions that human neutrophil lysosomes are rather resistant to steroids (Weissmann and Thomas, 1963) but the question remains unresolved (Goldstein et al, 1975; Ignarro, 1977).

Lymphocyte function Current models of immunoregulation indicate that antigen presentation to T cells occurs via cells bearing Class II major histocompatibility complex (MHC) molecules on their surface. Steroids inhibit the expression of murine Class II MHC antigens (Snyder et al, 1982), but the effects on human cells are more complex. Steroids may inhibit antigen presentation by human monocytes but there seems to be no relation between the reduction in Class II expression and suppression of antigen presentation (Gerrard et al, 1985). In fact, some experiments show that steroids increase Class II expression in human monocytes (Gerrard et al, 1984a,b). Lymphocyte proliferation is inhibited by steroids; for example, the in vivo expression of delayed-type hypersensitivity reactions. A well-documented study has shown that it requires an average of 13.6 days for oral prednisolone (4 mg/day) to inhibit the tuberculin test (Bovornkitti et al, 1960). In vitro cell proliferation such as that produced by phytohaemagglutination is also suppressed. These effects may be largely due to inhibition of IL-1 production. Information about the differential effects of steroids on T cell subsets is scarce. Hydrocortisone inhibits activity in cultured peripheral human blood T cells (Lipsky et al, 1978), yet there appears to be no difference in the number of steroid receptors present in cells possessing the CD3 marker (all T cells), CD4 T cells (helpers) and CD8 T cells (suppressors) (Martins et al, 1987). With regard to cytotoxic T cell (CTL) function, it is clear that this can be inhibited by steroids in vitro but (at least in the mouse) preincubation of primed CTL is needed (Schleimer et al, 1984), suggesting that glucocorticoids appear to modulate early events as opposed to significantly affecting an established response.

628

E. G E O R G E A N D J. R. K I R W A N

Glucocorticoids easily suppress antibody synthesis in steroid-sensitive species. In man, however, the situation is more complex. A 5-day course of methylprednisolone (96 mg/day) was followed by a 20% lowering of serum immunoglobulin levels caused by both a decrease in immunoglobulin production and an increase in its catabolism (Butler and Rossen, 1973). In more chronic experiments, however, specific antibody production was not reduced in steroid-treated patients (Tuchinda et al, 1972). In vitro immunoglobulin production by cells taken from patients on high-dose steroids is decreased (McMillan et al, 1976), but B cells from normal subjects given a bolus of steroids actually produce more immunoglobulins (Cupps et al, 1984), and when exposed to steroids in vitro IgE synthesis increases (Ray et al, 1987). At the moment, there is no comprehensive schema which integrates all these findings, although one group believes that the effect of immunoglobulin production in vitro occurs by inhibition of leukotrienes (Goodwin and Atluru, 1986). Fc receptor suppression Many cells (including red blood cells (RBC)) carry a surface receptor for the Fc portion of immunoglobulin--the Fc receptor (FCR) (Schreiber and Frank, 1972). Corticosteroids inhibit FCR expression (Crabtree et al, 1979), which may explain the prompt improvement seen when patients with autoimmune haemolytic anaemia or autoimmune thrombocytopenia are given corticosteroids. By inhibiting FCR (and C3 receptors) in the reticuloendothelial system, the clearance of antibody-coated RBCs and platelets is reduced. Changes in white cell traffic Large intravenous doses of glucocorticoids given to normal human volunteers increase the numbers of circulating neutrophils but decrease peripheral lymphocytes, eosinophils, and monocytes (Parillo and Fauci, 1979). These changes reach their maximum in 4-6 hours and generally return to normal by 24 hours. Most of these effects reflect changes in patterns of cell traffic rather than changes in bone marrow function. Neutrophilia results from a combination of increased release of immature cells from the bone marrow, an increase in circulating half-life, reduced neutrophil egress from blood, and reduced vascular margination of cells, making them more accessible to the flow of blood which is sampled (Figure 4). Lymphopenia in man mainly reflects a rapid movement of blood lymphocytes into the tissues (Fauci, 1975) and does not, as previously suggested, result from lympholysis. Rapid recovery from steroid-induced lymphopenia (Fauci et al, 1976) is more easily attributed to redistribution effects of non-dividing T cells than to rapid regeneration of recirculating cells, which are known to have a long half-life. The monocytopenia and eosinopenia may also reflect the redistribution of cells into the tissues, but recent evidence indicates that steroids in vitro inhibit the growth of eosinophil precursors. The mechanism of basopenia is not known.

629

CORTICOSTEROID THERAPY IN RHEUMATOID ARTHRITIS

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Margination of white cells

:i i i; 9

il ~ 6

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It is possible to examine the effects of corticosteroids on cellular traffic patterns in inflammatory responses. A well-studied example is the effect of steroids on the influx of cells into an inflammatory focus, represented by a Rebuck skin window (Dale et al, 1974). Normally neutrophils migrate into the window first, followed by monocytes. In patients taking daily steroids, neutrophils and monocytes reach the coverslip in greatly diminished numbers. In patients taking alternate-day therapy, neutrophil migration is more impaired during the 'on-steroid day' as compared to the 'off-steroid' day. Monocyte migration is impaired on both days. Other effects

Topical steroid application results in decreased blood flow (Greeson et al, 1973) and vasodilatation (Ebert and Barclay, 1952). The mechanism is not fully understood but probably relates to a reduction in local cytokine production. Tables 3 and 4 (see below) summarize the immunological and anti-inflammatory effects of glucocorticoids. PHARMACOLOGY OF SYNTHETIC STEROIDS Pharmacokinetics

Prednisolone is rapidly absorbed from the gastrointestinal tract and is

630

E. G E O R G E A N D J. R. K I R W A N

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