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 fibrosis 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 vitamins, alternative medicine 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, cytokine 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 organ 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 lungs, measurement of cytokines, 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 lung disease, now the major cause of death in scleroderma. 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 inflammation, Nailfold capillary dilatation and capillary destructiont autoimmune attack, vascular damage, fibroblast 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 dermatomyositis, 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 collagen 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 fibroblasts 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, cyclophosphamide, 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 plasmapheresis 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