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Home , Serositis, Systemic scleroderma

Analls ofthe Rheumatic Diseases 1990; 49: 735-737 735

REVIEW ARTICLE Ann Rheum Dis: first published as 10.1136/ard.49.9.735 on 1 September 1990. Downloaded from

Systemic sclerosis: Is there a treatment yet?

Carol M Black

Systemic sclerosis is, as yet, an untreatable An important international step in classifi- disase and the choice and evaluation of any cation has been the agreement by a number of modifying treatment are extremely difficult. doctors, as outlined in a recent editorial,' that This is because: (a) the disorder is heterogeneous there are two major variants ofsystemic sclerosis: and its severity and rate of progression highly the diffuse cutaneous and the limited cutaneous variable; (b) there is a tendency towards spon- subtypes (table). Choice of any treatment and taneous improvement during the later stages of design ofany therapeutic trial should be planned the disease, particularly within the more benign with these distinct variants taken into account; and numerically larger subset; (c) the cause is if not, the results may well be meaningless. For unknown, its pathogenesis uncertain, and the example, patients with late stage diffuse disease relation between the vascular damage, immune are usually not suitable for clinical trials as dysfunction, and speculative; (d) there measurable improvement can hardly be expected is a paucity of objective criteria for ascertain- when advanced fibrosis, vascular damage, and ing improvement (or deterioration) in the tissue atrophy are present; equally, aggressive disease, particularly with respect to visceral disease modifying drugs are hardly justified in change. patients who have indolent disease with limited This review will not seek to describe the extensions and in whom measurable change will numerous ways in which systemic sclerosis has probably be absent. been treated nor to comment on the vast Recognition of the at risk group before the number of , alternative disease cascade gathers momentum is equally products, hormones, and surgical procedures important. Possible helpful clues are circulating that have been used (most of which have been antibodies, production, and nailfold heralded with great enthusiasm only to be changes. Such identification allows for 'protec- abandoned after critical evaluation) but to tive' therapeuticintervention. These ideas should suggest a logical approach to the use of drugs in also be extended to the earliest possible diagnosis systemic sclerosis and then to discuss some of internal involvement, which again recent therapeutic ventures. might allow for its containment. For example, http://ard.bmj.com/ Before a treatment is decided upon for any fine cut (3 mm) computed tomography scans of aspect of the disease the two most important the , measurement of , growth tasks for the doctor are to classify the patients factors and procollagen peptides in broncho- and to endeavour to recognise the 'at risk' alveolar lavage fluid might, in the future, aid population. the recognition of disease, now the major cause of death in . No single drug or combination of drugs has on September 25, 2021 by guest. Protected copyright. proved satisfactory in the treatment of systemic Subsets of systemic sclrosis (Reproduced, uith permsion, sclerosis in suitably controlled prospective trials. from J Rheumatol 1988; 15: 202-5.') This is perhaps understandable when one con- DtfiSse cutse Must scerosis* siders that concepts of systemic sclerosis are still Onset of Raynaud's phenomenon within one year of onset of skin changes (puffy or hidebound) evolving. Truncal and acral skin involvement Obviously, development of the scleroderma Presence of tendon friction rubs Early and significant incidence of interstitial lung disease, lesion is complicated and entails several events oliguric renal failure, diffuse gastrointestinal disease, and that may occur simultaneously or in sequence. myocardial disease Absence of anticentromere antibodies These almost certainly include , Nailfold capillary dilatation and capillary destructiont autoimmune attack, vascular damage, Antitopoisomerase antibodies (30% of patients) activation by cytokines and growth factors, and Limid cuneous ssmi sclerosis interaction between different components of the Raynaud's phenomenon for years (occasionaliy decades) Skin disease limited to hands, face, feet, and forearms (acral) extracellular matrix. There are, therefore, or absent several different potential points of therapeutic A significant lte incidence ofpulmonary hypertension with or without interstitial lung disease, trigeminal neuralgia, skin intervention. calcifications, telangectasia Although there is no good evidence for a A high incidence of anticentromere antibodies (70-80%) Diated nailfold capillary loops, usually without capillary generalised derangement of immune cell func- dropout tion, specific immune impairment may be 3 *Experienced observers note some patients with diffuse systemic important,2 and immunosuppression might sclerosis who do not develop organ insufficiency and suggest the play a part, especially if used at the right stage term chronic diffuse systemic sclerosis for these patients. of the disorder: such drugs could tNailfold capillary dilatation and destruction may also be seen in hypothetically Royal Free Hospital, patients with , overlap syndromes, and alter suggested interactions between immuno- Pond Street, undifferentiated connective tissue disease. These syndromes may London NW3 be considered as part of the spectrum of scleroderma associated competent cells, their cytokine products, and C M Black disorders. fibroblast function. Lack of mechanistic 736 Black

knowledge has necessitated a 'blunderbuss' activities and is also a potent inhibitor of approach With non-specific agents. Both production by normal and scleroderma Ann Rheum Dis: first published as 10.1136/ard.49.9.735 on 1 September 1990. Downloaded from alkylating agents and antimetabolites have been dermal in vitro. A recent pilot study used. Chlorambucil studies have given mixed by Kahan et al suggests that interferon gamma results. Early reports were hopeful,4 but may be beneficial,25 and a blinded controlled Steigerwald, in an open study in 1985, could not study is indicated. Interferon alfa is a less potent substantiate these,5 and a recent three year, inhibitor of collagen synthesis than interferon double blind, controlled trial was negative.6 gamma but unlike interferon gamma it does not The same historical sequence was found with activate the class II cell surface antigens-this 5-fluorouracil; an initial pilot study by Casas may be a distinct advantage in scleroderma, showed significant objective improvement,7 but which is an HLA-DR linked disease. Interferon a subsequent controlled study by the same alfa is under trial in the United Kingdom, and a group failed to confirm their original results. A recent pilot study26 is encouraging enough to third alkylating agent, , warrant a definitive study. known to block humoral as well as certain To date there is obviously no general agree- cellular responses, has been inadequately ment on the place of these drugs. To use them investigated as a single agent,8`0 but these to the greatest effect more information is reports were not encouraging. Uncontrolled urgently needed on the specific immune defect data suggest that as part of a combination so that targeting can be achieved and the drugs treatment with steroids and it used at the most effective stage of the diffuse may be more effective." The extent to which disorder-one suspects this stage to be the cyclophosphamide contributed to improvement earliest possible beginnings. These drugs with this combination is, however, unclear. should not be used for late stage, stable diffuse Wollheim and Akesson tried to separate these or limited cutaneous disease. effects, but as all their patients received pred- Drugs which target collagen synthesis, such nisolone the results, which showed a tendency as colchicine and D-penicillamine, have been in favour ofthe triple theory, are not definitive. 2 used in the treatment of scleroderma for many Removal of cytokines rather than autoanti- years. Neither is the answer to the fibrotic bodies, which may be markers of subsets and deposition, but consensus opinion is that D- not pathogenic agents, is theoretically attractive. penicillamine is the most useful. The drug must There have been several uncontrolled (or be used correctly to derive the maximum inadequately controlled) studies of the efficacy benefit, and the most suitable subjects for of plasma exchange,'1'5 and a properly per- treatment are those with widespread active skin formed, randomised, controlled trial is needed. disease. Long term treatment in a dose around The theoretical rationale for lymphoplasma- 500-750 mg is needed. Skin changes in the pheresis may be sounder than plasma exchange, diffuse form of the disease are often rapid in the and a preliminary report by Weiner was en- first six to 12 months and show a limited couraging. 1 Considering the almost certain response to all known forms of treatment-D- need to target the immune system and the non- penicillamine included. The pace of change http://ard.bmj.com/ selectivity of the immunosuppressive drugs, then usually slows down with regression occur- O'Dell et al tried total lymphoid irradiation and ring in many areas. D-Penicillamine should be found it wanting with, in addition, the possible continued throughout this whole period and the acceleration of visceral disease in the irradiated dose maintained until there is no further patients. 17 improvement in skin thickening. The drug may Targeting the immune systems more specifi- then be reduced, but low dose treatment should cally is, however, still an attractive idea and the be maintained for many years-some recom- on September 25, 2021 by guest. Protected copyright. use of rabbit antithymocyte-globulin is worthy mend 10 years.27 The patients who present of investigation. To date only two cases have after spontaneous regression of skin changes been reported,'8 but other studies are currently should not be treated. in hand. Anti-inflammatory drugs have been tried and Use of the antimetabolites 6-thioguanine found wanting. Steroids are potentially toxic and has been reported in a few and their use has been restricted to patients with cases.9 20 The information is, however, too , symptomatic , the oede- scant to provide any useful conclusions. Aza- matous phase of skin disease, and, occasionally, thioprine has been more widely used-always, refractory . unfortunately, in uncontrolled studies8 21; the Raynaud's phenomenon is a prominentfeature authors considered the drug to be beneficial, of systemic sclerosis and may herald the however. development of the disease and precede it by Cyclosporin A has been used in a few patients many years. It is an aspect of the disease which with positive results,22 23 but high doses of the may be alleviated, though the response to drug have been followed by reports of hyper- treatment is variable. This idiosyncratic response tension and renal failure, both of which might may reflect the stage of the disease. It is be attributed to either the drug or scleroderma. conceivable that the Raynaud's phenomenon A lower dose regimen may be a sensible results from endothelial damage, subintimal compromise. Such a study is in progress,24 but thickening, and consequent reduction in vessel inadequate numbers of patients have been size and that this, rather than exaggerated studied to date. vasospasm, is the primary event. If this is so, The interferons alfa and gamma are currently the patients with structural damage will respond being evaluated in several countries. Recom- rather poorly to vasodilators alone. In un- binant interferon gamma has immunoregulatory complicated cases simple measures, such as Systemic sclerosis: Is there a treatmentyet? 737

warm layered clothing, underwear, hats and 4 Mackenzie A H. Prolonged alkylating drug is beneficial in . Arthritis Rhewn 1970; Ann Rheum Dis: first published as 10.1136/ard.49.9.735 on 1 September 1990. Downloaded from scarves, electrically heated gloves, hand 13: 334. warmers, the avoidance of cold, skin care, and 5 Steigerwald J C. Chlorambucil in the treatment ofprogressive systemic sclerosis. In: Black C M, Myers A R, eds. Systemic abstention from tobacco, may suffice. For more sclerosis (scleroderma). New York: Gower Medical, 1985: frequent prolonged attacks, which interfere 423-7. 6 Furst D E, Clements P J, Hillis S, et al. Immunosuppression with daily living, a vasodilator may be tried, with chlorambucil versus placebo, for scleroderma. Results such as , ketanserin, thymoxamine, of a three year, parallel, randomized, double-blind study. Arthritis Rheum 1989; 32: 584-93. diltiazem, or captopril. If the attacks are accom- 7 Casas J A, Subhauste C P, Alarcon G S. A new promising panied by ulceration and threatened gangrene treatment in systemic sclerosis: 5-fluorouracil. Ann Rhewn Dis 1987; 46: 763-7. intravenous or prostaglandin may 8 Saporta L, Godeau P, Delrieu F, et al. La sclerodermie be needed. Secondary infection requires anti- g6neralis&. Traitement par les immunosuppresseurs. Nouv Presse Med 1972; i: 1929-30. biotics and, sometimes, . Frank gangrene 9 Hurd E R, Giuliano V J. The effect of cyclophosphamide on will also require surgery in many instances. B and T lymphocytes in patients with connective tissue diseases. Arthritis Rhewn 1975; 18: 67-75. Cervical sympathectomy should be avoided, 10 Tolchin S F, Winkelstein A, Rodnan G P, Pan S F, Nankin though lumbar sympathectomy still has a place. H R. Chromosome abnormalities from cyclophosphamide therapy in and progressive systemic Structural widespread vascular damage is sclerosis (scleroderma). Arthitis Rheum 1974; 17: 375-82. central to the pathogenesis of scleroderma and a 11 Dau P C, Kahaleh M B, Sagebiel R W. Plasmapheresis and therapy in scleroderma. Arthritis logical extension of this has been to seek for Rheum 1981; 24: 1128-36. drugs to protect injured endothelial cells and to 12 Wollheim F A. Akesson A. Treatment ofsystemic sclerosis in 1988. Semin Arthritis Rheum 1989; 18: 181-8. prevent aggregation and subsequent 13 McKune M A, Winkelmann R K, Osmundson P J, et al. A release of platelet derived mediators. This controlled study of plasmapheresis in scleroderma. J Clin 1983; 1: 206-14. search has been disappointing to date. Ketan- 14 O'Reilly M J, Talpos G, Roberts V C, White J M, Cotton serin, a serotonin antagonist, although useful in L T. Controlled trial of plasma exchange in treatment of Raynaud's syndrome. BrJ Med 1979; i: 1113-5. Raynaud's phenomenon, does not improve skin 15 Capodicasa G, De Santo N G, Galione A, et al. Clinical or visceral disease.28 Alphamethyldopa with effectiveness of apheresis in the treatment of progressive systemic sclerosis. IntJ Artif Organs 1983; 6: 81-6. propranolol was equally ineffective,29 and 16 Weiner S R, Kono D H, Osterman H A, Levy J, Paulus H E, dipyridamole and aspirin, although reducing Pitts W H. Preliminary report on a controlled trial of apheresis in the treatment of scleroderma [Abstract]. the circulating plasma concentrations of ,B Arthritis Rhewn 1987; 30: S27. thromboglobulin or circulating platelet aggre- 17 O'Dell J R, Steigerwald J C, Kennaugh R C, Hawkins R, Holers V M, Kotzin B L. Lack of clinical benefit after gates were not effective in a randomised double treatment of systemic sclerosis with total lymphoid irradia- blind trial.?0 Captopril, the angiotensin convert- tion. J Rhewnatol 1989; 16: 1050-4. 18 Goronzy J J, Weyand C M. Therapeutic effects of T- ing enzyme inhibitor, has been so successful in lymphocyte depletion in progressive systemic sclerosis the treatment of renal crisis that the use of this [Abstract]. Arthitis Rheum 1989; 32: S119. 19 Demis D J, Brown C S, Crosby W H. Thioguanine in the drug or another angiotensin converting enzyme treatment of certain autoimmune, immunologic and related inhibitor has been considered for the primary diseases. Am J Med 1964; 37: 195-205. 20 Van den Hoogen F H J, Boerbooms A M Th, Van de Putte and possibly prophylactic treatment of vascular L B A. Methotrexate treatment in systemic sclerosis. AmJ disease. Med 1989; 87: 116-7. 21 Kurwa A R, Denman A M. Scleroderma treated with

It can be seen that there is as yet no treatment immunosuppressive drugs. Brj Dermatol 1979; 101: 56-7. http://ard.bmj.com/ for scleroderma. A careful consideration of the 22 Zachariae H, Zachariae E. Cyclosporin A in systemic sclerosis. BrJ Dermatol 1987; 116: 741-2. heterogenicity of the disorder and its natural 23 Appelboom T, Itzowitch D. Cyclosporine in successful history, together with the subset and stage of control ofrapidly progressive scleroderma. AmJ Med 1987; 82: 866-7. disease of the individual patient, can maximise 24 Russell M L, Schachter R A. Cyclosporin treatment of the use of the drugs currently available. Possibly scleroderma (PSS). [Abstract). Arthitis Rhewn 1988; 31 (suppl 4): S51. more importantly, the level and degree of 25 Kahan A, Amnor B, Menkes C J, Strauch G. Recombinant of research the world into interferon-y in the treatment of systemic sclerosis. Am J

activity throughout on September 25, 2021 by guest. Protected copyright. Med 1989; 87: 273-7. the cause and pathogenesis of the condition may 26 Stevens W M R, Black C M, Cohen M G, Maddison P, and eventually result in early rational effective the U.K. scleroderma study group multicentre pilot study of alpha interferon in recent onset diffuse cutaneous treatment. disease.Proceedigs oftheMedicalResearchSociety (in press). 27 Medsger T A Jr. Treatment of systemic sclerosis. Rheumatic Diseases Clinics ofNorth America 1989; 15: 513-31. 1 LeRoy E C, Black C M, Fleischmajer R, et al. Scleroderma 28 Siebold J R, Jageneau A H M. Treatment of Raynaud's (systemic sclerosis): classification, subsets and pathogenesis. phenomenon with ketanserin, a selective antagonist of the J Rheunatol 1988; 15: 202-5. serotonin 2 (5-HT2) receptor. Ardritis Rheum 1984; 27: 2 Kratz L E, Bongham J A, Needleman B W. Associations 139-46. between antigen receptor gamma gene restriction, 29 Fries J F, Wasner C, Brown J, Feignbaum P. A controlled- fragment length polymorphism and progressive systemic trial of antihypertensive therapy in systemic sclerosis sclerosis. Arthritis Rhewm 1989; 32: 534. (scleroderma). Ann Rheum Dis 1984; 43: 407-10. 3 Kahaleh M B, LeRoy E C. Interleukin-2 in scleroderma- 30 Beckett V L, Conn D L, Fuster V, et al. Trial of platelet- correlation of serum level with extent of skin involvement inhibiting drug in scleroderma. Double-blind study with and disease duration. Ann Intern Med 1989; 110: 446-50. dipyridamoleandaspirin.ArthritisRheum 1984;27: 1137-43.