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Chapter 20. Therapeutic Approaches to Rheumatoid Arthritis and Other Autoimmune Diseases
Chapter 20. Therapeutic Approaches t o Rheumatoid Arthritis and Other Autoimmune Diseases Michael C. Venuti Institute of Bio-Organic Chemistry Syntex Research, Palo Alto, CA 94304 Introduction - The management of autoimmune disease, particularly rheumatoid arthritis (RA) and other related chronic, systemic and articular inflammatory diseases, is based upon current understanding of the pathogenic mechanisms involved. 1 The immune-based chronic inflammation, triggered by persistent bacterial, viral or autoantigens, or by an aberration in cytokine regulation of T-cells,2 forms the underlying pathophysiology of RA and other autoimmune diseases, such as systemic lupus erythematosus (SLB), psoriasis and psoriatic artMtis, atopic dermatitis, ankylosing spondylitis (AS) and chronic inflammatory bowel disease. Current therapy for RA is divided into two main categories dependent on the severity of the disease. Symptomatic relief of the effects of acute inflammation is readily accomplished using non-steroidal anti-inflammatory drugs (NSAIDs), now well-established as the primary line of treatment.3 In order t o slow or halt tissue destruction, and more specifically joint damage, agents now classified as disease-modifying antirheumatic drugs (DMARDs),~,~ such as gold, D-penicillamine (DPA) and the antimalarials, while not necessarily providing a cure, do retard the progress of the underlying disease in a less than predictable manned-8 by mechanisms as y e t only poorly understood.9~10 Since excellent reviews of the established NSAIDs3911 and DMARDs12s13 have recently appeared, this report will focus on potential DMARD candidates operating by a variety of mechanisms, with brief updates on agents cited here previously.l4,15 Where appropriate, application of these and similar drugs t o the treatment of other autoimmune disorders will be summarized. Recent DMARD Candidates - The difficulties inherent in discovering new DMARDs for RA and other autoimmune diseases are two-fold. First, there exists no single biological model of RA which can consistently predict DMARD-type activity. Secondly, an extended clinical trial of a potential DMARD double-blind against placebo is considered unethical since a statistical number of RA patients, whose disease is severe enough t o be otherwise treated, will go untreated for upwards of a year or more. Hence, most potential DMARDs are screened and clinically evaluated against the standard agents cited above. Alternatively, clinical agents of approved therapeutic utility in other autoimmune diseases are examined in the treatment of RA. A number of such crossover DMARD candidates are currently being evaluated. Sulfasalazine, useful in the treatment of ulcerative colitis,16,17 has been evaluated against other DMARDs in a number of RA studies, which indicate that long-term sulfasalaaine treatment of R A is a viable option, especially in patients resistant t o gold or DPA.18-20 A controlled double-blind study of etretinate, an oral retinoid used in the treatment of psoriasis, provided modest confirmation of previously uncontrolled studies in psoriatic artMtis.21 13-&- Retinoic acid and N-4-hydroxyphenylretinamide (fenretinide) both significantly reduced r a t adjuvant arthritis (rat AA).22123 The latter also suppressed streptococcal cell wall-induced arthritis.24 Another DMARD candidate, thalidomide, previously used as a sedative, hypnotic and antiemetic until withdrawal because of its severe teratological side effects, showed therapeutic utility in a form of leprosy, discovered while a patient ANNUAL REPORTS IN MEDICINAL CHEMISTRY-21
Copyright 0 1986 by Academic Press, Inc. All rights of reproduction in any form reserved.
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received it as a sedative. Its anti-inflammatory properties in rat A A have prompted investigation into its DMARD potential for other autoimmune states.25~26 In a small, open PA clinical study, oral administration of thalidomide led to marked clinical improvement, which, in some cases, lasted long after discontinution of dosing. Adverse reactions, mainly associated with sedative effects, disappeared a t the completion of dosing.27 Although its extreme profile of side effects limits the potential use of thalidomide in BA, chemical modifications designed to retain the anti-inflammatory properties while eliminating adverse effects are ongoing.28 Finally, the biological and pharmacological profile of clobuzarit (Clozic.), a compound originally taken into clinical trials for atherosclerosis but later found to possess distinct DMARD properties in RA, has been summarized.29 A weak anti-inflammatory agent, clobuzarit inhibits the acute phase of rat AA, and may be acting by antiproliferative pathways. Adverse side effects observed in clinical trials have forced the withdrawal of clobuzarit from further consideration.30 Immunomodulatozy Drug T h e r a n - Perturbation of the delicate balance in the cellular and humoral immunoregulatory network results in a net expression of aberrant hyperreactivity in most autoimmune diseases.31 Thus, although immunosuppression might seem warranted for diseases of chronic inflammation and immunologic hyperreactivity, immunomodulation (immunoregulation), the dampening of hyperactive responses or enhancing defective negative influences, particularly through manipulation of the soluble mediators interleukins 1 and 2 (IL-1 and -2),32 is the required therapeutic strategy.33@ Two immunomodulators discussed here previously have gained limited approval for use in BA and other autoimmune diseases. Levamisole was shown to be superior to placebo35 and comparable to gold and DPA36 in two large RA trials, .ad of possible use in Chon's disease, herpetic keratitis37 and AS.38 Although patient withdrawals for toxicity reasons were frequent with levamisole, the side effects were found to be most rapidly reversible. Variations in the immunomodulatory effect of thymopentin CTP-5) and other thymic hormone derivatives approved for use in thymic deficiency, have been found to be dependent on the mode of administration,39 and there are conflicting reports on its clinical effectiveness in RA.40~41 Hypoxanthine derivatives hydroerythranol (NPT-15393, 1) and isoprinosine (INPX, 2) were found to enhance T-cell lymphocyte differeitiation and natural killer (NK) cell i~ctivity.42-~6One of these studies,45 carried out in patients with prolonged generalized lymphadenopathy, and other similar studies have prompted the investigation of INPX as a treatment in the early stages of acquired immune deficiency syndrome (AIDS). While INPX has been suggested as a treatment for RA47 and for SLB,48 no controlled trials have been carried out. In a small trial, however, INPX was found to be highly efficacious in the treatment of aphtous stomatitis, a result attributed to increased IL-2 production.49 Lobensarit (CCA, a), previously reported to inhibit rat AA, was examined in vitro a t non-toxic levels, and was found to block IL-1 and Ig production without effect on IL-2, and to induce y-interferon (1-IP).50 The therapeutic effect obsenred is postulated to be mediated by short-lived, thymus-derived lymphocytes,51 rather than macrophages.52 In a double-blind study, CCA was significantly superior to placebo, although a number of side effects were noted.53 The isoxazole HWA-486 (s), currently in clinical trials, prevents the onset of rat AA, provided therapy is initiated within the first 12 days
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of induction. After this point, it behaves as a classic NSAID, reducing inflammation only as long as administered.54 This response is correlated with improved lymphocyte response to both T- and B-cell mitogens and enhanced monocyte activity.55 Thiol-containing compounds based on the lead provided by DPA continue to be investigated. Tiobutarit (SA-96, 31, currently in advanced trials, differed from DPA in various immunopharmacological models, was more potent than DPA as an inhibitor of macropha e migration,56 and inhibited rat AA alone or in conjunction with indomethacin.57 A summary of the immunological profile58 and the results of a preliminary clinical trial59 have appeared. In in vitn, and viyi studies sodium diethyldithiocarbamate (DTC, Immuthiol@) enhanced T-cell specific functions in mice, and, in certain instances, IL-2 production in human T-lymphocytes,60 prompting limited studies in both AIDS61 and chronically infected patients.62 ADA 202-718 activated lymphocytes both in vim and in vivo, potentiating IL-2 and IF release in response to allogenic stimulation.63964 While it did not decrease swelling in rat AA, both pain and locally induced edema were reduced.64 Ristianol(2) has been registered as an Hs&coNH-w
(Ho4s-s4
H o / s c n 2 c N-
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7
COOH
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antiinflammatory immunoregulator in Europe, but no further information is available.65 In a six-month open trial of the angiotensin-converting enzyme (ACE) inhibitor captopril in RA, the results compared favorably with similar DPA or gold studies.66 A control study using enalapril, a non-sulfhydryl ACE inhibitor, was completely negative, suggesting that the observed antirheumatoid activity of captopril is due to the thiol group and not to ACE inhibition.67 Increased emphasis on immunomodulatory RA therapy has produced a number of new agents of widely varying structural types. PCE 20696 exhibits antiviral activity mediated by IF induction,68 and is orally active in three models of autoimmunity [rat AA, experimental allergic encephalomyelitis (EAE) and NZBNF1 micel.69 LF- 1695 Q), which potentiates suppressor T-cell mechanisms70 and induces both IL-1 and -2 synthesis,71,72 is being evaluated in
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clinical t r i a l ~ . ~ sTEI-3096 r~~ shown to suppress rat AA without effects on acute inflammation by restoration of suppressor T-cell activity,75 is currently in advanced clinical trials as an antirheumatic agent. Roquinimex (LS-2616, augmented mouse NK cell activity but did not increase serum IF levels,76 and enhanced responses t o T-cell mitogens and the delayed-type hypersensitivity (DTH) reaction.77 Lymphocytes from treated rats also showed enhanced IL-2 production, and restoration of immunosuppression characteristic of inhibition of IL-1 production. Ciamexon (BM 41.332, produces significant reduction of symptoms in rat AA, but differed clearly from standard antirheumatic agents. Its effect was attributed to a selective stimulation of the maturation of T-cells, such that helper T-cells cannot be developed and the differentiation to suppressor
a)
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T-cells is increased.78 An increase in DTH response79 and in the survival rate of immunocompromised mice80 have also been observed. Diphosphonate SR-41319 (19) is effective in the suppression of rat AA, likely by alteration of hydroxyadipate crystal disposition,81 and inhibits activities characteristic of IL- 1 stimulation.82 The immunomodulatory activity of retinoids has been reviewed,Bd and is likely the mechanism of action of etretinate and other retinoids in the treatment of psoriatic arthritis mentioned above. Immunosuppressive agents such as methotrexate (MTX), cyclophosphamide (CP) and aaathioprine (AT) are limited in their use due to associated toxicities,84 whereas non-cytotoxic agents offer another possibility in autoimmune therapy. Cyclosporin A (CS), an immunosuppressive agent approved for post-trans lant use,85 was highly efficacious as a potential DMABD in RA in two trlals,86,8 and has been proposed for use in psoriatic arthritis,88 SLB and insulin-dependent diabetes.89 The prospect of further modifications to CS to narrow its immunosuppressive profile has been proposed.90 Other synthetic immunosuppressive agents have also been shown t o be potential RA treatments. Mitoxantmne (14) inhibited helper T-cell function while enhancing suppressor activity,91 and suppressed the BAR reaction in rats.92 In rat AA, it displayed potency and efficacy comparable to MTX and greater than CP.93 ABAD (CL-232,468, &l a derivative of mitoxsntrone, is considerably more potent, inhibiting in vitro induction of alloreactivity and impairing both the proliferative response of lymphocytes to antigen and the generation of cytolytic T-cells. &Q, the suppression persisted for as long as 30 days after a single i.p. dose, consistent with the induction of suppressor T-cells as the mechanism of acti0n.~4 and & v i a immunomodulatory CL-246,738 (16) possesses a broad spectrum, including activation of NK cells and macrophages, and induction of IF.95~96 A structurally unrelated compound from the same group, CL-259,763 (17))stimulated macrophages and cytolytic T-cells.97 Sch-24,937 (18)suppressed the secondary response in rat AA, and was more potent than AT but less potent than CP in BAB. In contrast to many other immunosuppressive agents, it did not cause a reduction in circulating lymphocytes, indicating that its mode of action is not cytotoxic.98
Q
14 R=(NH-/C),OH
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R=NH./"H,
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NSAIDs as Immunomodulatorv DMABDs Although NSAIDs are thought to operate by a common mechanism of action, observed interpatient differences in drug efficacy have raised questions about additional modes of anti-inflammatory action independent of prostaglandin (PG) synthetase inhibition.99 Since arachidonic acid metabolites are known to exert a range of immunoregulatory activities,100 the examination of the interrelationship of NSAIDs and other mediators of inflammation present in R A revealed a link between these agents and both humoral and cellular immune response. NSAID inhibition of the production of PGB2, the PG shown to tonically inhibit suppressor T-cell activity, allows suppressor T-cells to mature and control B-cell mediated rheumatoid yii studies, NSAIDs inhibited a factor production.1019102 In in vitro and number of markers of neutrophil activation, such as migration, superoxide generation and aggregation.103-105 The patterns of this inhibition vary from drug to drug, suggesting that NSAIDs may directly effect neutrophil activation by pathways independent of their shared inhibition of PG synthesis, such as their capacity to inhibit movements of calcium and enhance intracellular cyclic AMP
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(CAMP) levels.106
The combination of NSAID and DMARD profiles has been suggested as the ideal drug treatment for RA. A number of NSAIDs either established or under investigation have been found to display this profile. Of the acidic drugs, fenclofenac,l07 diclofenac sodium108 and the new agents piraaolac (MY-309, 191109 and RS-2131 ( a ) 1 1 0 display evidence of modest immunomodulatory activity. Wy-18,251 (211, originally identified as an antimetastatic agent with immunomodulatory activity,lll is similar to levamisole both in vitro and k m . 1 1 2 In acute anti-inflammatory studies, 22. demonstrated activity comparable to aspirin, but without antipyretic activity, and also inhibited rat AA. In & studies, it was a modest cyclooxygenase (CO) inhibitor lacking lipoxygenase (LO) inhibitory activity.113 Wy-41,770 (221,an anti-inflammatory agent devoid of GI side effects, was active in rat AA, but was a weak inhibitor of PG synthetase activity.114 In type 11 collagen-induced arthritis, 22 was more potent than indomethacin, methylprednisolone or DPA in reducing both hind paw edema and bone pathology.1159116
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Imidaaole- and thiaaole-containing compow, constitute another LASS of NSAIDs which possess immunomodulatory activity. Tiflamiaole (231,117 structurally related to the platelet aggregation inhibitors flumiaolel and f e n f l u m i a o l e , ~is~ ~a potent CO inhibitor which inhibits rat AA,120 and displays immunomodulatory activity in models of lymphocyte blast transformation and SLB.1218122 Imidarothiazole a hybrid structure derived from flumizole and levamisole, is an inhibitor of both phases of rat AA, and is active in a number of immunoregulato assays.123 Lotifarole (P-1686, XI124 and fanetirole 5 both weak CO inhibitors inactive in rat AA, display properties (CP-48810, of immunostimulants in other assays. Lotifaaole reduces DTH-induced pleurisy
3
in guinea pigs and oxasolone-induced contact hypersensitivity in mice. Panetizole
specifically suppressed de novo IgE synthesis in atopic subjects. Both compounds show a stimulstory effect on T-lymphocytes. Another member of this chemical class, tomoxiprole (MDL-035, 2 1 , is active in rat AA and a potent PG synthetase inhibitor, but as yet no indication of immunomodulatory activity has been reported. 126,127
Antioxidants and Peroxvnenase Inhibitors - Arachidonic acid peroxidation products and reactive oxygen species, both responsible for inflammation and tissue damage, can be inhibited by a wide range of stnactural types. In addition to the nutritional antioxidants such as vitamins A and B, selenium and eicosapentaenoic acid, 12&129 many anti-inflammatory agents such as phenylbutarone, phenidonelb0 and CCAIS1 also act as general antioxidants. Interference with polymorphonuclear leukocyte ( P a - d e p e n d e n t oxygen
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intermediate generation has been suggested as the mechanism of action of thalidomide in RA.132 Four phenols recently prepared as antioxidants also exhibit marked anti-inflammatory activity. lS0 MK-447 (281 enhanced PGB2 synthesis, but exhibited marked antihypertensive and diuretic effects in man.133,134 ONO-3144 (39)acts a8 a eneral free radical scavenger and weak inhibitor of thromboxane synthetase.13t In clinical trials, 29 has been well tolerated, providing improvement in RA and lumbago with only minor GI side effects.136
R-830 (901, currently in clinical trials for topical treatment of inflammatory dermatoses,130 is orally active in rat AA, reversed passive Arthus reaction, and oxasolone-induced DTH, and inhibits both CO and L0.137 Reports on KME-4 (911 show a similar dual inhibitor profile of anti-inflammatory activity.138~139 The combination of the anti-inflammatory effect of CO inhibition with the potential immunomodulatory effects140 of LO inhibition has been proposed as a new treatment for RA.141~142 BW-540C (321 is active against carrageenan-induced edema in rats, and has been selected for evaluation in the treatment of psoriasis.143 CBS-1108 (831144 and CBS-1114 (941145 both exhibit a wide range of anti-inflammatory activities, especially in models in which CO inhibitors are not effective. The former exhibited a marked effect on leukocyte chemotaxis.146 The products of &LO, particularly leukotriene B4 (LTBq), are potent chemotactic agents which elicit a variety of acute147 and itnmune-based138 inflammatory responses. Both REV-5901 (Q51148*149 and RS-43179 (961150-152 were potent and selective 5-LO inhibitors both vitro and in vivo in the topical arachidonic acid-induced mouse ear edema m ~ d e l w -In~clinical ~ ~ trials, was effective as a topical treatment for psoriasis.156 The lipophilic benaoquinone AA-861 (571, also a selective 5-LO inhibitor, exhibited effects on asthmatic and inflammatory reactions.157 Although the reported LO inhibition by sulfrsalarine has been disputed,l58,159 one primary metabolite, 5-aminosalicylic acid, inhibits
5-LO16O and is thought to contribute to the first line effect in RA, while the other metabolite, sulphapyridine, is the active moiety responsible for second line effects.161 Both prodnrg162 and controlled delivery163,164 systems for 5-aminosalicylic acid release in ulcerative colitis treatment have been described. Although benoxaprofen has been demonstrated to be a LO inhibitor of some effect in psoriasis,l65 a small trial in ulcerative colitis proved unencouraging.166 Regulation of glutathione peroxidase, responsible for the decomposition of hydrogen peroxide into toxic oxygen species, was proposed as the mechanism of action for the novel organoselenium compound ebselen (PZ-51, Q8),167 but a more recent report indicates that 5-LO inhibition is the probable mechanism of action.168 Ancillary to the direct inhibition of &LO, the potential utility of antagonists of LTBa69 and platelet activating factorl70~171in inflammation has been discussed.
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Phomholipase and Phomhodiesterase Inhibitors - Glucocorticoids are known to exert their anti-inflammatory action by inhibition of the release of arachidonic acid from phospholipids by phospholipase A2 (PLA2).172 Detection of PLA2 in the sera and synovial fluids in RA173 reinforced the search for non-steroidal PLA2 inhibitors for chronic inflammation, even though the list of known inhibitors is short174 and recent detailed inhibition studies have raised questions concerning PLA activity.175 Timegadine (991, shown previously to inhibit rat AA, may exert its 2 -1 CO-LO inhibition by inhibition of PLA2.176 A small clinical trial has established its potential effectiveness in the remissive control of RA.177 Glucocorticoids inhibit PLA2 by stimulation of a 15 ldlodalton cell membrane protein variously referred to as macrocortin, lipomodulin or (the now preferred) lipocortin (LC), the endogenous inhibitor of PLA2.178 Highly purified LC exhibits steroid-like effects and an acute anti-inflammatory activity in rat carrageenan pleurisy edema.179~180 Monoclonal antibodies to LC reversed the biological effects of steroids in vim and to a certain extent in vivo.1818182 Cyclic nucleotides (CAMP or cGMP) are known to affect a multitude of biochemical regulatory processes, including the immune system. 183 Inhibition of the phosphodiesterases (PDBs) present in inflammatory cells would consequently raise intracellular levels of CAMP or cGMP, which in turn influence many cellular processes responsible for inflammation, including chemotaxis, aggregation and release of lysosomal enzymes and inflammatory mediators. Recently, nitraquaaone (TVX-2706, has been found to be a selective non-competitive inhibitor of cAMP PDB from a variety of cell sources, includixy PMN,184 possibly accounting for its potent anti-inflammatory activity.1 5 The observed immunomodulatory activity of J. may be due to selective inhibition of lymphocyte cGMP PDE.186 In vivo administration of CS was also found to raise cAMP levels in rat lymphocyte^.^
Inhibition of Comdement - The normally beneficial effects of the complement cascade, an immunostimulated process, lead to the adverse symptoms of chronic inflammation in autoimmune disease. Inhibition of the complement alternative pathway (CS transform6tion) or the terminal complement reaction (C5a activation) has been proposed as a possible treatment for RA, SLB, atopic dermatitis, psoriasis and other immune complex diseases.188,189 The sesquiterpene E-76COONa (41)interferes with C5a activation, and inhibits leukocyte migration and release of histamine in inflammatory models.190,191 Nafamstat mesilate (PUT-175, 421, a synthetic protease inhibitor, inhibits the alternative complement pathwag92 and has both rophylactic and curative effects on the development of.lupus nephritis in mice.lg3 Rosmarinic acid (491, a natural product exhibiting weak effects on mediators of acute inflammation, inhibits many inflammatory responses associated with complement activation, and is under development as a topical treatment for various autoimmune-based skin disorders. 194 Conclusion - Recent research has allowed a better definition of the basis of autoimmune disease, even though the precise details of the pathogenesis and etiology of most of these disorders remain unknown. Advances in immunology, in
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particular the complexity of the requirements for self-recognition, have shown that this internal regulatory system is subject to a myriad of controlling mechanisms and multiple pathways by which these mechanisms may be rendered abnormal.1 Pharmacological manipulation of even one of these regulatory systems might provide the means to control and eventually reverse the abnormal anti-self immune responses characteristic of autoimmune disease. I. 2.
3. 4.
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23. 24.
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28. 29.
M. 31. 32.
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u. 35.
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Copyright 0 1986 by Academic Press, Inc. All rights of reproduction in any form reserved.
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Section I V
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received it as a sedative. Its anti-inflammatory properties in rat A A have prompted investigation into its DMARD potential for other autoimmune states.25~26 In a small, open PA clinical study, oral administration of thalidomide led to marked clinical improvement, which, in some cases, lasted long after discontinution of dosing. Adverse reactions, mainly associated with sedative effects, disappeared a t the completion of dosing.27 Although its extreme profile of side effects limits the potential use of thalidomide in BA, chemical modifications designed to retain the anti-inflammatory properties while eliminating adverse effects are ongoing.28 Finally, the biological and pharmacological profile of clobuzarit (Clozic.), a compound originally taken into clinical trials for atherosclerosis but later found to possess distinct DMARD properties in RA, has been summarized.29 A weak anti-inflammatory agent, clobuzarit inhibits the acute phase of rat AA, and may be acting by antiproliferative pathways. Adverse side effects observed in clinical trials have forced the withdrawal of clobuzarit from further consideration.30 Immunomodulatozy Drug T h e r a n - Perturbation of the delicate balance in the cellular and humoral immunoregulatory network results in a net expression of aberrant hyperreactivity in most autoimmune diseases.31 Thus, although immunosuppression might seem warranted for diseases of chronic inflammation and immunologic hyperreactivity, immunomodulation (immunoregulation), the dampening of hyperactive responses or enhancing defective negative influences, particularly through manipulation of the soluble mediators interleukins 1 and 2 (IL-1 and -2),32 is the required therapeutic strategy.33@ Two immunomodulators discussed here previously have gained limited approval for use in BA and other autoimmune diseases. Levamisole was shown to be superior to placebo35 and comparable to gold and DPA36 in two large RA trials, .ad of possible use in Chon's disease, herpetic keratitis37 and AS.38 Although patient withdrawals for toxicity reasons were frequent with levamisole, the side effects were found to be most rapidly reversible. Variations in the immunomodulatory effect of thymopentin CTP-5) and other thymic hormone derivatives approved for use in thymic deficiency, have been found to be dependent on the mode of administration,39 and there are conflicting reports on its clinical effectiveness in RA.40~41 Hypoxanthine derivatives hydroerythranol (NPT-15393, 1) and isoprinosine (INPX, 2) were found to enhance T-cell lymphocyte differeitiation and natural killer (NK) cell i~ctivity.42-~6One of these studies,45 carried out in patients with prolonged generalized lymphadenopathy, and other similar studies have prompted the investigation of INPX as a treatment in the early stages of acquired immune deficiency syndrome (AIDS). While INPX has been suggested as a treatment for RA47 and for SLB,48 no controlled trials have been carried out. In a small trial, however, INPX was found to be highly efficacious in the treatment of aphtous stomatitis, a result attributed to increased IL-2 production.49 Lobensarit (CCA, a), previously reported to inhibit rat AA, was examined in vitro a t non-toxic levels, and was found to block IL-1 and Ig production without effect on IL-2, and to induce y-interferon (1-IP).50 The therapeutic effect obsenred is postulated to be mediated by short-lived, thymus-derived lymphocytes,51 rather than macrophages.52 In a double-blind study, CCA was significantly superior to placebo, although a number of side effects were noted.53 The isoxazole HWA-486 (s), currently in clinical trials, prevents the onset of rat AA, provided therapy is initiated within the first 12 days
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of induction. After this point, it behaves as a classic NSAID, reducing inflammation only as long as administered.54 This response is correlated with improved lymphocyte response to both T- and B-cell mitogens and enhanced monocyte activity.55 Thiol-containing compounds based on the lead provided by DPA continue to be investigated. Tiobutarit (SA-96, 31, currently in advanced trials, differed from DPA in various immunopharmacological models, was more potent than DPA as an inhibitor of macropha e migration,56 and inhibited rat AA alone or in conjunction with indomethacin.57 A summary of the immunological profile58 and the results of a preliminary clinical trial59 have appeared. In in vitn, and viyi studies sodium diethyldithiocarbamate (DTC, Immuthiol@) enhanced T-cell specific functions in mice, and, in certain instances, IL-2 production in human T-lymphocytes,60 prompting limited studies in both AIDS61 and chronically infected patients.62 ADA 202-718 activated lymphocytes both in vim and in vivo, potentiating IL-2 and IF release in response to allogenic stimulation.63964 While it did not decrease swelling in rat AA, both pain and locally induced edema were reduced.64 Ristianol(2) has been registered as an Hs&coNH-w
(Ho4s-s4
H o / s c n 2 c N-
6
7
COOH
5
antiinflammatory immunoregulator in Europe, but no further information is available.65 In a six-month open trial of the angiotensin-converting enzyme (ACE) inhibitor captopril in RA, the results compared favorably with similar DPA or gold studies.66 A control study using enalapril, a non-sulfhydryl ACE inhibitor, was completely negative, suggesting that the observed antirheumatoid activity of captopril is due to the thiol group and not to ACE inhibition.67 Increased emphasis on immunomodulatory RA therapy has produced a number of new agents of widely varying structural types. PCE 20696 exhibits antiviral activity mediated by IF induction,68 and is orally active in three models of autoimmunity [rat AA, experimental allergic encephalomyelitis (EAE) and NZBNF1 micel.69 LF- 1695 Q), which potentiates suppressor T-cell mechanisms70 and induces both IL-1 and -2 synthesis,71,72 is being evaluated in
8
C
I
W
(u),
10
clinical t r i a l ~ . ~ sTEI-3096 r~~ shown to suppress rat AA without effects on acute inflammation by restoration of suppressor T-cell activity,75 is currently in advanced clinical trials as an antirheumatic agent. Roquinimex (LS-2616, augmented mouse NK cell activity but did not increase serum IF levels,76 and enhanced responses t o T-cell mitogens and the delayed-type hypersensitivity (DTH) reaction.77 Lymphocytes from treated rats also showed enhanced IL-2 production, and restoration of immunosuppression characteristic of inhibition of IL-1 production. Ciamexon (BM 41.332, produces significant reduction of symptoms in rat AA, but differed clearly from standard antirheumatic agents. Its effect was attributed to a selective stimulation of the maturation of T-cells, such that helper T-cells cannot be developed and the differentiation to suppressor
a)
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T-cells is increased.78 An increase in DTH response79 and in the survival rate of immunocompromised mice80 have also been observed. Diphosphonate SR-41319 (19) is effective in the suppression of rat AA, likely by alteration of hydroxyadipate crystal disposition,81 and inhibits activities characteristic of IL- 1 stimulation.82 The immunomodulatory activity of retinoids has been reviewed,Bd and is likely the mechanism of action of etretinate and other retinoids in the treatment of psoriatic arthritis mentioned above. Immunosuppressive agents such as methotrexate (MTX), cyclophosphamide (CP) and aaathioprine (AT) are limited in their use due to associated toxicities,84 whereas non-cytotoxic agents offer another possibility in autoimmune therapy. Cyclosporin A (CS), an immunosuppressive agent approved for post-trans lant use,85 was highly efficacious as a potential DMABD in RA in two trlals,86,8 and has been proposed for use in psoriatic arthritis,88 SLB and insulin-dependent diabetes.89 The prospect of further modifications to CS to narrow its immunosuppressive profile has been proposed.90 Other synthetic immunosuppressive agents have also been shown t o be potential RA treatments. Mitoxantmne (14) inhibited helper T-cell function while enhancing suppressor activity,91 and suppressed the BAR reaction in rats.92 In rat AA, it displayed potency and efficacy comparable to MTX and greater than CP.93 ABAD (CL-232,468, &l a derivative of mitoxsntrone, is considerably more potent, inhibiting in vitro induction of alloreactivity and impairing both the proliferative response of lymphocytes to antigen and the generation of cytolytic T-cells. &Q, the suppression persisted for as long as 30 days after a single i.p. dose, consistent with the induction of suppressor T-cells as the mechanism of acti0n.~4 and & v i a immunomodulatory CL-246,738 (16) possesses a broad spectrum, including activation of NK cells and macrophages, and induction of IF.95~96 A structurally unrelated compound from the same group, CL-259,763 (17))stimulated macrophages and cytolytic T-cells.97 Sch-24,937 (18)suppressed the secondary response in rat AA, and was more potent than AT but less potent than CP in BAB. In contrast to many other immunosuppressive agents, it did not cause a reduction in circulating lymphocytes, indicating that its mode of action is not cytotoxic.98
Q
14 R=(NH-/C),OH
15
R=NH./"H,
18 17
-
NSAIDs as Immunomodulatorv DMABDs Although NSAIDs are thought to operate by a common mechanism of action, observed interpatient differences in drug efficacy have raised questions about additional modes of anti-inflammatory action independent of prostaglandin (PG) synthetase inhibition.99 Since arachidonic acid metabolites are known to exert a range of immunoregulatory activities,100 the examination of the interrelationship of NSAIDs and other mediators of inflammation present in R A revealed a link between these agents and both humoral and cellular immune response. NSAID inhibition of the production of PGB2, the PG shown to tonically inhibit suppressor T-cell activity, allows suppressor T-cells to mature and control B-cell mediated rheumatoid yii studies, NSAIDs inhibited a factor production.1019102 In in vitro and number of markers of neutrophil activation, such as migration, superoxide generation and aggregation.103-105 The patterns of this inhibition vary from drug to drug, suggesting that NSAIDs may directly effect neutrophil activation by pathways independent of their shared inhibition of PG synthesis, such as their capacity to inhibit movements of calcium and enhance intracellular cyclic AMP
Chap. 20 Rheumatoid Arthritis and Other Auto-immune Diseases Venuti
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(CAMP) levels.106
The combination of NSAID and DMARD profiles has been suggested as the ideal drug treatment for RA. A number of NSAIDs either established or under investigation have been found to display this profile. Of the acidic drugs, fenclofenac,l07 diclofenac sodium108 and the new agents piraaolac (MY-309, 191109 and RS-2131 ( a ) 1 1 0 display evidence of modest immunomodulatory activity. Wy-18,251 (211, originally identified as an antimetastatic agent with immunomodulatory activity,lll is similar to levamisole both in vitro and k m . 1 1 2 In acute anti-inflammatory studies, 22. demonstrated activity comparable to aspirin, but without antipyretic activity, and also inhibited rat AA. In & studies, it was a modest cyclooxygenase (CO) inhibitor lacking lipoxygenase (LO) inhibitory activity.113 Wy-41,770 (221,an anti-inflammatory agent devoid of GI side effects, was active in rat AA, but was a weak inhibitor of PG synthetase activity.114 In type 11 collagen-induced arthritis, 22 was more potent than indomethacin, methylprednisolone or DPA in reducing both hind paw edema and bone pathology.1159116
a)--
Fcoon \ /
CI
19
22
21
Imidaaole- and thiaaole-containing compow, constitute another LASS of NSAIDs which possess immunomodulatory activity. Tiflamiaole (231,117 structurally related to the platelet aggregation inhibitors flumiaolel and f e n f l u m i a o l e , ~is~ ~a potent CO inhibitor which inhibits rat AA,120 and displays immunomodulatory activity in models of lymphocyte blast transformation and SLB.1218122 Imidarothiazole a hybrid structure derived from flumizole and levamisole, is an inhibitor of both phases of rat AA, and is active in a number of immunoregulato assays.123 Lotifarole (P-1686, XI124 and fanetirole 5 both weak CO inhibitors inactive in rat AA, display properties (CP-48810, of immunostimulants in other assays. Lotifaaole reduces DTH-induced pleurisy
3
in guinea pigs and oxasolone-induced contact hypersensitivity in mice. Panetizole
specifically suppressed de novo IgE synthesis in atopic subjects. Both compounds show a stimulstory effect on T-lymphocytes. Another member of this chemical class, tomoxiprole (MDL-035, 2 1 , is active in rat AA and a potent PG synthetase inhibitor, but as yet no indication of immunomodulatory activity has been reported. 126,127
Antioxidants and Peroxvnenase Inhibitors - Arachidonic acid peroxidation products and reactive oxygen species, both responsible for inflammation and tissue damage, can be inhibited by a wide range of stnactural types. In addition to the nutritional antioxidants such as vitamins A and B, selenium and eicosapentaenoic acid, 12&129 many anti-inflammatory agents such as phenylbutarone, phenidonelb0 and CCAIS1 also act as general antioxidants. Interference with polymorphonuclear leukocyte ( P a - d e p e n d e n t oxygen
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intermediate generation has been suggested as the mechanism of action of thalidomide in RA.132 Four phenols recently prepared as antioxidants also exhibit marked anti-inflammatory activity. lS0 MK-447 (281 enhanced PGB2 synthesis, but exhibited marked antihypertensive and diuretic effects in man.133,134 ONO-3144 (39)acts a8 a eneral free radical scavenger and weak inhibitor of thromboxane synthetase.13t In clinical trials, 29 has been well tolerated, providing improvement in RA and lumbago with only minor GI side effects.136
R-830 (901, currently in clinical trials for topical treatment of inflammatory dermatoses,130 is orally active in rat AA, reversed passive Arthus reaction, and oxasolone-induced DTH, and inhibits both CO and L0.137 Reports on KME-4 (911 show a similar dual inhibitor profile of anti-inflammatory activity.138~139 The combination of the anti-inflammatory effect of CO inhibition with the potential immunomodulatory effects140 of LO inhibition has been proposed as a new treatment for RA.141~142 BW-540C (321 is active against carrageenan-induced edema in rats, and has been selected for evaluation in the treatment of psoriasis.143 CBS-1108 (831144 and CBS-1114 (941145 both exhibit a wide range of anti-inflammatory activities, especially in models in which CO inhibitors are not effective. The former exhibited a marked effect on leukocyte chemotaxis.146 The products of &LO, particularly leukotriene B4 (LTBq), are potent chemotactic agents which elicit a variety of acute147 and itnmune-based138 inflammatory responses. Both REV-5901 (Q51148*149 and RS-43179 (961150-152 were potent and selective 5-LO inhibitors both vitro and in vivo in the topical arachidonic acid-induced mouse ear edema m ~ d e l w -In~clinical ~ ~ trials, was effective as a topical treatment for psoriasis.156 The lipophilic benaoquinone AA-861 (571, also a selective 5-LO inhibitor, exhibited effects on asthmatic and inflammatory reactions.157 Although the reported LO inhibition by sulfrsalarine has been disputed,l58,159 one primary metabolite, 5-aminosalicylic acid, inhibits
5-LO16O and is thought to contribute to the first line effect in RA, while the other metabolite, sulphapyridine, is the active moiety responsible for second line effects.161 Both prodnrg162 and controlled delivery163,164 systems for 5-aminosalicylic acid release in ulcerative colitis treatment have been described. Although benoxaprofen has been demonstrated to be a LO inhibitor of some effect in psoriasis,l65 a small trial in ulcerative colitis proved unencouraging.166 Regulation of glutathione peroxidase, responsible for the decomposition of hydrogen peroxide into toxic oxygen species, was proposed as the mechanism of action for the novel organoselenium compound ebselen (PZ-51, Q8),167 but a more recent report indicates that 5-LO inhibition is the probable mechanism of action.168 Ancillary to the direct inhibition of &LO, the potential utility of antagonists of LTBa69 and platelet activating factorl70~171in inflammation has been discussed.
Chap. 20 Rheumatoid A r t h r i t i s and Other Auto-immune Diseases Venuti
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Phomholipase and Phomhodiesterase Inhibitors - Glucocorticoids are known to exert their anti-inflammatory action by inhibition of the release of arachidonic acid from phospholipids by phospholipase A2 (PLA2).172 Detection of PLA2 in the sera and synovial fluids in RA173 reinforced the search for non-steroidal PLA2 inhibitors for chronic inflammation, even though the list of known inhibitors is short174 and recent detailed inhibition studies have raised questions concerning PLA activity.175 Timegadine (991, shown previously to inhibit rat AA, may exert its 2 -1 CO-LO inhibition by inhibition of PLA2.176 A small clinical trial has established its potential effectiveness in the remissive control of RA.177 Glucocorticoids inhibit PLA2 by stimulation of a 15 ldlodalton cell membrane protein variously referred to as macrocortin, lipomodulin or (the now preferred) lipocortin (LC), the endogenous inhibitor of PLA2.178 Highly purified LC exhibits steroid-like effects and an acute anti-inflammatory activity in rat carrageenan pleurisy edema.179~180 Monoclonal antibodies to LC reversed the biological effects of steroids in vim and to a certain extent in vivo.1818182 Cyclic nucleotides (CAMP or cGMP) are known to affect a multitude of biochemical regulatory processes, including the immune system. 183 Inhibition of the phosphodiesterases (PDBs) present in inflammatory cells would consequently raise intracellular levels of CAMP or cGMP, which in turn influence many cellular processes responsible for inflammation, including chemotaxis, aggregation and release of lysosomal enzymes and inflammatory mediators. Recently, nitraquaaone (TVX-2706, has been found to be a selective non-competitive inhibitor of cAMP PDB from a variety of cell sources, includixy PMN,184 possibly accounting for its potent anti-inflammatory activity.1 5 The observed immunomodulatory activity of J. may be due to selective inhibition of lymphocyte cGMP PDE.186 In vivo administration of CS was also found to raise cAMP levels in rat lymphocyte^.^
Inhibition of Comdement - The normally beneficial effects of the complement cascade, an immunostimulated process, lead to the adverse symptoms of chronic inflammation in autoimmune disease. Inhibition of the complement alternative pathway (CS transform6tion) or the terminal complement reaction (C5a activation) has been proposed as a possible treatment for RA, SLB, atopic dermatitis, psoriasis and other immune complex diseases.188,189 The sesquiterpene E-76COONa (41)interferes with C5a activation, and inhibits leukocyte migration and release of histamine in inflammatory models.190,191 Nafamstat mesilate (PUT-175, 421, a synthetic protease inhibitor, inhibits the alternative complement pathwag92 and has both rophylactic and curative effects on the development of.lupus nephritis in mice.lg3 Rosmarinic acid (491, a natural product exhibiting weak effects on mediators of acute inflammation, inhibits many inflammatory responses associated with complement activation, and is under development as a topical treatment for various autoimmune-based skin disorders. 194 Conclusion - Recent research has allowed a better definition of the basis of autoimmune disease, even though the precise details of the pathogenesis and etiology of most of these disorders remain unknown. Advances in immunology, in
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particular the complexity of the requirements for self-recognition, have shown that this internal regulatory system is subject to a myriad of controlling mechanisms and multiple pathways by which these mechanisms may be rendered abnormal.1 Pharmacological manipulation of even one of these regulatory systems might provide the means to control and eventually reverse the abnormal anti-self immune responses characteristic of autoimmune disease. I. 2.
3. 4.
5. 6. 7. 8.
9. 10. II. 12. 13. 14. 15. 16. 17. IS. 19. 20. 21. 22.
23. 24.
25. 26. .27.
28. 29.
M. 31. 32.
33.
u. 35.
36. 37.
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n.
(mi).
i,
z.
L,
Chap. 20 Rheumatoid A r t h r i t i s and Other Auto-immune Diseases Venuti
3
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30 JU1y-3