854 Annals of the Rheumatic Diseases 1991; So: 854-861 Ann Rheum Dis: first published as 10.1136/ard.50.Suppl_4.854 on 1 November 1991. Downloaded from

Clinical aspects of systemic sclerosis ()

Richard M Silver

Systemic sclerosis (scleroderma) is a disease of course of the illness, one hopes to identify unknown cause, the hallmark of which is patients at greater or lesser risk of developing induration of the skin. Although long regarded certain visceral complications, as well as provide as a bland fibrotic process, there is now ample a more homogeneous group of patients for evidence of an active inflammatory process studies of the pathogenesis, clinical manifesta- underlying thepathogenesisofsystemic sclerosis. tions, and treatment. In addition, microvascular disease and immuno- logical abnormalities are present in most cases. It remains to be determined just how the Clinical features immunological and microvascular changes RAYNAUD'S PHENOMENON relate to the overproduction of collagen and Raynaud's phenomenon refers to episodic digital other matrix elements by the fibroblast, but ischaemia provoked by cold or emotion. recent data suggest that products of the immune Although classically described as triphasic- response may directly affect fibroblasts and that is, pallor followed by cyanosis, and then endothelial cells in vitro. hyperaemia accompanied by numbness and This review will focus on recent advances in pain, such a three colour response does not the understanding of several clinical aspects of occur universally. Pallor seems to be the most systemic sclerosis. The reader is referred to reliable sign and hyperaemia the least reliable several recent chapters and textbooks for a more sign in subjects who lack the classic triphasic extensive review. 1-3 response. A recently described questionnaire and colour chart may facilitate the diagnosis of Raynaud's phenomenon.6 Classification Establishment of the presence or absence of Scleroderma may exist as a localised or a Raynaud's phenomenon is important when systemic disease process. The latter has been evaluating a patient with scleroderma-like skin. delineated 'progressive systemic sclerosis' in the The absence of Raynaud's phenomenon should past, but use of this term has been decried as the raise the possibility that one might be dealing

disease is not always progressive and because of with a disease other than systemic sclerosis http://ard.bmj.com/ the emotional burden that this term may (table 2) as 95% of patients with systemic place on the patient and the patient's family.4 sclerosis have Raynaud's phenomenon. This In its localised form scleroderma is confined distinction is illustrated by the recentlydescribed to the skin and adjacent tissues, and it can be eosinophilia-myalgia syndrome associated with classified as linear scleroderma or morphoea L-tryptophan ingestion, in which scleroderma- (see below). In its systemic form scleroderma like skin lesions commonly accompanied

may affect a number of visceral organs. Here on September 29, 2021 by guest. Protected copyright. the classification is somewhat controversial and Table I Subsets of systemic sclerosis. Reproduced, with is based on the extent of cutaneous involvement. permission, from ref 4 Table 1 shows a widely accepted classification, Diffuse cutaneous systemic sclerosis* where diffuse Onset of Raynaud's phenomenon within one year of onset of skin (particularly truncal) skin disease changes (puffy or hidebound) is distinguished from limited skin involvement; Truncal and acral skin involvement the latter encompasses Presence of tendon friction rubs and replaces the CREST Early and significant incidence of interstitial lung disease, (calcinosis, Raynaud's phenomenon, oeso- oliguric renal failure, diffuse , and myocardial disease phageal dysmotility, sclerodactyly, and tel- Absence of anticentromere antibodies angiectasia) variant of scleroderma. Limited Nailfold capiLary dilatation and capillary destructiont cutaneous systemic sclerosis also includes what Antitopoisomerase antibodies (30% of patients) has been variously designated acrosclerosis, Limited cutaneous systemic sclerosis types I and II types Raynaud's phenomenon for years (occasionally decades) scleroderma of Barnett, I Skin involvement limited to hands, face, feet, and forearms and II of the German classification, inter- (acral) or absent mediate cutaneous A significant late incidence of pulmonary hypertension, with or systemic sclerosis of without interstitial lung disease, trigeminal neuralgia, skin Giordano, and systemic sclerosis without calcifications, A high incidence of anticentromere antibody (70 80%) scleroderma.4 Dilated nailfold capillary loops, usually without capillary dropout A recent editorial summarises data which Division of Immunology support a three sub- *Experienced observers note some patients with diffuse and Rheumatology, conceptual framework of cutaneous systemic sclerosis who do not develop organ insuf- Medical University of types of systemic sclerosis: digital, proximal ficiency and suggest the term chronic diffuse cutaneous systemic South Carolina, extremity, and truncal,5 but at the present time sclerosis for these patients. tNailfold capillary dilatation and destruction may also be seen Charleston, serological and microvascular data support the in patients with dermatomyositis, overlap syndromes, and un- South Carolina 1.4 differentiated connective tissue disease. These syndromes may 29425 2229, USA simpler classification shown in table By be considered as part of the spectrum of scleroderma associated R M Silver classifying patients into subsets early in the disorders. Clinical aspects ofsystemic sclerosis (scleroderma) 855 Ann Rheum Dis: first published as 10.1136/ard.50.Suppl_4.854 on 1 November 1991. Downloaded from Table 2 Diseases with cutaneous features resembling limited cutaneous systemic sclerosis (see table sclroderma i). 12 Eosinophilic fasciitis The other marker which may be useful in Tryptophan associated eosinophilia-myalgia syndrome Chemical induced disorders predicting the presence or eventual development Bleomycin fibrosis of connective tissue disease in a subject with Vinyl chloride disease Trichloroethylene fibrosis Raynaud's phenomenon is the antinuclear anti- Toxic oil syndrome body. Here the predictive value depends on the Graft versus host disease Digital sclerosis of diabetes mellitus method and substrate used. Two recent studies Infiltrating carcinomas showed that the immunoblot technique was Scleroedema Scleromyxoedema (papular mucinosis) more sensitive than indirectimmunofluorescence Werner's syndrome and, furthermore, antibody specificity of anti- Rothmund's syndrome nuclear antibodies as determined by immuno- Acrodermatitis chronica atrophicans blots was predictive of the development of Lichen sclerosis et atrophicus syndrome specific subtypes of systemic sclerosis. 13 4 In a Phenylketonuria prospective study of patients with Raynaud's Congenital porphyria phenomenon and undifferentiated connective Primary amyloidosis tissue disease Kallenberg et al found that the Acromegaly presence of antinuclear antibodies detected by immunoblots at the time of entry into the study was associated with the evolution of symptoms of a connective tissue disease, usually systemic myalgia, eosinophilia, and fasciitis (see below).7 sclerosis.'3 Furthermore, anticentromere anti- Few of such cases were accompanied by body was associated with limited cutaneous Raynaud's phenomenon, nor had other diseases systemic sclerosis (sensitivity 60%, specificity which may mimic systemic sclerosis. 98%) and anti-Scl-70 antibody was associated The duration of Raynaud's phenomenon with diffuse cutaneous systemic sclerosis (sensi- before skin involvement is important. Patients tivity 38%, specificity 100%). Based on the with diffuse cutaneous systemic sclerosis and a aforementioned studies, it is recommended that tendency to early visceral organ damage usually all patients with Raynaud's phenomenon have a have a briefduration ofRaynaud's phenomenon complete clinical evaluation, including nailfold before development of skin changes, whereas capillary microscopy and antinuclear antibody patients with limited cutaneous systemic studies which, preferably, test for specific sclerosis usually have many years (often decades) antigens associated with subtypes of systemic of Raynaud's phenomenon before overt skin sclerosis. and visceral involvement. An important issue for the clinician is the evaluation of the subject with Raynaud's pheno- SKIN DISEASE menon for the presence of an underlying con- Sclerosis of the skin is the hallmark of systemic nective tissue disease. Raynaud's phenomenon sclerosis, though rare patients may have typical itselfis quite common in the general population, visceral organ involvement in the absence of http://ard.bmj.com/ yet only a fraction of such subjects will develop skin disease (systemic sclerosis without sclero- a connective tissue disease.8 One survey found derma). 15 Skin thickening is the definitive the prevalence of Raynaud's phenomenon to be diagnostic criterion of systemic sclerosis in the 4-6% among adults living in South Carolina.9 vast majority of cases, and the distribution of The prevalence may be higher in colder climates. affected skin serves as the means of classifying As Raynaud's phenomenon may herald the patients into one or another subset of systemic development of serious disease, especially con- sclerosis (see above). Such classification may on September 29, 2021 by guest. Protected copyright. nective tissue disease, studies have been under- have important implications for the risk of taken to determine which ancillary tests may be developing visceral organ involvement and for predictive of the evolution to an overt connec- mortality (table 3).4 tive tissue disease. Two markers seem to have Three phases of dermal involvement have predictive value for the subsequent develop- been described. Firstly, there is an oedematous ment of connective tissue disease (usually phase, often presenting as stiffand puffy fingers systemic sclerosis): (a) abnormal nailfold capil- and hands. In this initial phase the condition is laries and (b) antinuclear antibodies. often difficult to distinguish from other connec- Definitely abnormal capillary patterns, tive tissue diseases or carpal tunnel syndrome; detected by nailfold capillary microscopy, nailfold capillary microscopy and determination indicate an increased risk for the presence or of the presence and type ofantinuclear antibody eventual transition to a connective tissue are of greatest diagnostic value in patients in disease.'0 A recent prospective study of patients this disease phase. Secondly, an indurative with Raynaud's phenomenon confirmed this phase, characterised by tightness of the skin, finding and concluded that the presence of usually follows the oedematous phase. Here, abnormal capillaries was the most significant predictor of the subsequent development Table 3 Survival in systemic sclerosis (%). Reproduced, of systemic sclerosis (odds ratio, 26-82, with permission, from ref4 p=0 001)." In addition, the degree of capillary loss assessed by nailfold Systemic sclerosis I year 6 years 12 years capillary microscopy subtpe may be correlated with clinical and serological features and may assist in the subclassification Limited cutaneous 98 80 50 Diffuse cutaneous 80 30 15 of systemic sclerosis as diffuse cutaneous or 856 Silver Ann Rheum Dis: first published as 10.1136/ard.50.Suppl_4.854 on 1 November 1991. Downloaded from sclerodactyly and the classic expressionless face relatively insensitive tests of lung disease. make the diagnosis unmistakable. Ultimately, Recent studies using thin section computed an atrophic phase occurs, when the skin may tomography have shown abnormalities before actually soften. the onset of dyspnoea or the detection of Pitting scars over the fingertips, often accom- abnormalities on routine chest radiograph.'9 panied by loss of substance of the finger pad, Tests of pulmonary function often disclose are characteristic findings in both limited and restrictive lung disease with reduced lung diffuse cutaneous systemic sclerosis. The volumes and decreased diffusing capacity. As presence of digital pitting scars is one of the lung disease progresses, hypoxia and cor minor criteria for systemic sclerosis.'6 Tel- pulmonale may occur. angiectasias are commonly found on the hands Recently, a number of studies have demon- and face, especially in the limited cutaneous strated an inflammatory component to the lung form of systemic sclerosis. Calcinosis occurs disease in a significant percentage of patients commonly on the volar aspect of the fingertips with systemic sclerosis. Gallium-67 lung scans and over joints such as the metacarpophalangeal often show increased uptake,20 but gallium and interphalangeal joints, where it may scans are non-specific and not recommended. ulcerate. Studies using bronchoalveolar lavage have shown that a significant proportion of patients with systemic sclerosis have evidence of an GASTROINTESTINAL TRACT DISEASE 'alveolitis', often before the onset of dyspnoea Gastrointestinal disease is the most commonly or abnormal pulmonary function tests or chest recognised visceral manifestation of systemic radiograph,'9 21 and most studies concur that sclerosis. Dysphagia and heartburn, the most the alveolitis is characterised by an increased common symptoms, are due to oesophageal number of total cells (mostly alveolar macro- dysmotility and oesophageal reflux. Nearly 85% phages) and an increased percentage and of patients with systemic sclerosis have been absolute number of neutrophils and eosino- found to have oesophageal reflux using 24 hour phils-similar increases to those described in pH monitoring of the distal oesophagus.'7 The cryptogenic fibrosing alveolitis.22-26 A few oesophagus is not affected in localised sclero- patients may have a lymphocytic alveolitis, derma. particularly patients with Sjogren's syndrome. Peristaltic abnormalities may delay gastric In our study of 43 patients with systemic emptying and may also affect motility of the sclerosis (all non-smokers) an increased bron- small and large intestines, at times giving rise to choalveolar lavage cell count or an increased pseudo-obstruction or secondary percentage of neutrophils, or both, was as- to bacterial overgrowth. Malabsorption may sociated with poorer pulmonary function.27 The rarely result from pancreatic insufficiency. A course of interstitial lung disease in patients recent study concluded that pancreatic exocrine with systemic sclerosis has been shown not to be function is often reduced in patients with predicted by traditional tests, such as initial systemic sclerosis, but rarely to an extent that is clinically important.18 Primary biliary cirrhosis 4- http://ard.bmj.com/ may occur, usually in association with long- standing limited cutaneous systemic sclerosis. Palliative treatment of gastrointestinal disease is based upon the prevention of gastric reflux 3- and stricture formation by using combinations of antacids, H2 blockers, sucralfate, with > elevation of the head of the bed. Severe 2- 8-----,O on September 29, 2021 by guest. Protected copyright. reflux oesophagitis may respond to treatment ,--..o with omeprazole. Malabsorption and pseudo- obstruction are treated with antibiotics, bowel rest and, at times, parenteral hyperalimentation. I - Initial Follow up Initial Follow up

PULMONARY DISEASE 0 The prevalence of lung disease ranks second to that of the gastrointestinal tract. Dyspnoea and hypoxiamayresultfrominterstitial inflammation zxI and fibrosis, or may be the result of pulmonary E hypertension occurring in the absence of E parenchymal lung disease. Severe pulmonary hypertension is seen most often in patients with E limited cutaneous systemic sclerosis. With recent advances in the treatment of scleroderma renal disease, scleroderma lung disease has become the most common cause of death. Dyspnoea on exertion is the most common up v up pulmonary complaint and is often accompanied Changes inforced vital capacity (FVC) and carbon by a non-productive cough. Chest radiographs monoxide transferfactor(TLco) in 10 patients with systemic sclerosis classified according to bronchoalveolar lavage often show diffuse linear and nodular fibrosis in findings as those without (0) and those with (O) alveolitis. the lower two thirds of the lung fields, but are Solid symbols represent means." Clinical aspects ofsystemic sclerosis (scleroderma) 857

chest radiograph or pulmonary function tests, introduction of dialysis and potent antihyper- Ann Rheum Dis: first published as 10.1136/ard.50.Suppl_4.854 on 1 November 1991. Downloaded from nor by demographic data. In a prospective tensive drugs, renovascular hypertension was study of scleroderma lung disease we found that uniformly fatal. The characteristic histopatho- normal bronchoalveolar lavage findings were logical finding is that of concentric, subendo- associated with a stable course, but abnormal thelial intimal proliferation of small arcuate and findings were associated with worsening interlobular arteries. A functional correlate of dyspnoea, worsening chest radiograph, and this structural abnormality is the reduction in significantly greater decline in forced vital renal cortical blood flow, which may be further capacity and carbon monoxide transfer factor compromised by vasospasm associated with (see figure).27 Thus bronchoalveolar lavage-may Raynaud's phenomenon.30 prove to be a useful predictor of the course of Significant risk factors for the onset of scleroderma lung disease. scleroderma renal crisis include anaemia, peri- Treatment of the interstitial lung disease of cardial effusion, congestive , and systemic sclerosis has been disappointing. Our rapid progression of skin thickening.3' The preliminary studies suggest that patients with renin-angiotensin system plays a major part in systemic sclerosis with alveolitis may benefit the pathogenesis of malignant hypertension from treatment with cyclophosphamide, but secondary to systemic sclerosis. Many such controlled prospective trials are needed.27 patients have increased plasma renin activity, Perhaps bronchoalveolar lavage and high which may precede or coincide with rapid resolution computed tomography will prove deterioration in renal function, and many will useful in selecting patients with potentially respond to angiotensin converting enzyme reversible disease, as well as helpful in monitor- inhibitor treatment with normalisation of blood ing responses to drug treatment. pressure and, sometimes, reversal of renal Bronchoalveolar lavage does provide infor- failure. The use of captopril and other convert- mation about cells and proteins obtained from ing enzyme inhibitors has been associated with a the lung, a common site of active disease. marked reduction in mortality from scleroderma Products of alveolar macrophages such as renal crisis,32 but not all cases will respond fibronectin, a glycoprotein that may serve as despite normalisation of blood pressure.33 3 A a chemoattractant and growth factor for fibro- recent report described a small percentage blasts, may play a part in the pathogenesis of (11%) of patients with systemic sclerosis with scleroderma lung disease. We have found that renal crisis not accompanied by hypertension.35 scleroderma alveolar macrophages release When compared with patients with systemic significantly more fibronectin than controls and sclerosis with hypertensive renal crisis, such that the concentration of fibronectin correlates cases were more likely to have had microangio- with the degree of alveolitis and correlates pathic haemolytic anaemia and thrombocyto- negatively with the carbon monoxide transfer penia, and were more likely to have received factor.28 Other growth factors secreted by high doses of corticosteroids during the two alveolar macrophages are currently under months immediately preceding the renal crisis. investigation. Renal disease in patients who develop renal Pulmonary hypertension (in the absence of failure despite treatment has been managed http://ard.bmj.com/ significant interstitial fibrosis) occurs in about with haemodialysis and transplantation, but 5% of patients with limited cutaneous systemic experience is limited and success has been sclerosis but rarely in patients with the diffuse variable. Haemodialysis often presents technical cutaneous subtype. A recent case-control problems with vascular access. Contrary to necropsy study showed that intimal thickening some earlier reports, we and others have found and luminal narrowing occur in both subsets of continuous ambulatory peritoneal dialysis to be

systemic sclerosis, but that such pulmonary effective and well tolerated in patients with on September 29, 2021 by guest. Protected copyright. vascular changes are most pronounced in systemic sclerosis with end stage renal disease.36 patients with limited cutaneous systemic sclerosis.29 By the time that patients present with dyspnoea and hypoxia significant pul- CARDIAC DISEASE monary vascular resistance might have occurred The landmark paper by Weiss et al established owing to structural luminal narrowing. Thus the entity of scleroderma heart disease 48 years vasodilator treatment is often unsuccessful at ago.37 Heart disease may present as heart this point. Perhaps the early use of vasodilator failure, arrhythmias, conduction disturbances, or other drug treatment in patients identified as or chest pain, all of which may be the result of being at risk for pulmonary hypertension vascular disease and fibrosis. Weiss et al noted (limited cutaneous systemic sclerosis, dilated an unusual type of myocardial scarring in the nailfold capillaries with minimal capillary loss, presence ofnormal extramural coronary arteries. anticentromere antibody) will forestall the Such scarring is probably antedated by contrac- development of this often fatal complication of tion-band necrosis, the classic finding in sclero- systemic sclerosis. derma heart disease, which has been produced experimentally by transient interruption of blood flow. Once again, the functional correlate RENAL DISEASE of this structural abnormality may be reversible Proteinuria, azotaemia, or hypertension occurs vasospasm affecting small coronary arteries. in 45% of patients with systemic sclerosis.30 Of Evidence exists for left ventricular dysfunction all the visceral organs potentially affected by induced by cold,38 as well as cold induced systemic sclerosis, renal disease has been as- regional perfusion defects.39 Structural lesions sociated with the highest mortality. Until the of the coronary microcirculation may also be 858 Silver Ann Rheum Dis: first published as 10.1136/ard.50.Suppl_4.854 on 1 November 1991. Downloaded from major determinants ofcardiac disease in systemic the vascular and interstitial lesions of systemic sclerosis. Some patients with primary sclero- sclerosis.54 derma heart disease have reduced coronary blood flow and coronary reserve after maximal VASCULAR ASPECTS coronary vasodilatation with intravenous The physiological (Raynaud's phenomenon) dipyridamole.' and pathological (in vivo and postmortem) Coronary vasospasm seems to be reversible features of vascular disease in systemic sclerosis with calcium channel blockers such as nife- have been discussed. Raised plasma concentra- dipine."' As in the case of pulmonary hyperten- tions of factor VIII/von Willebrand factor and a sion, some patients may not respond to vaso- platelet product, (3 thromboglobulin, further dilator treatment owing to the presence of fixed attest to microvascular and endothelial injury.55 structural lesions affecting the coronary micro- The mediator of endothelial injury in systemic circulation. Studies are needed to identify sclerosis remains controversial. Two recently patients at risk of developing such lesions in the defined molecules which are capable of causing coronary microcirculation so that treatment endothelial injury are tumour necrosis factor a56 may be started before irreversible intimal and transforming growth factor (.53 Each has hypertrophy. the ability to stimulate fibroblast proliferation, as well as induce endothelial injury. Pathogenesis GENETIC ASPECTS IMMUNOLOGICAL ASPECTS A number of cases of familial scleroderma have The common occurrence of antinuclear anti- been reported.42 Although no common genetic bodies and the presence of mononuclear cell markers have been identified, asymptomatic infiltrates in the dermis suggest a role for altered relatives have a higher incidence of antinuclear immune responsiveness in the pathogenesis of antibodies than controls.43 Several population systemic sclerosis. Additional indirect support studies have shown an increase in the prevalence for this notion is the occurrence of scleroderma- of certain HLA types, including DRI, DR3, like lesions in patients with chronic graft versus and DR5, among patients with systemic host disease. These and other immunological sclerosis." A recent study showed that the features have been reviewed recently.' New increased chromosomal breakage rate reported data implicating the immune response in the in patients with systemic sclerosis and their first pathogenesis of systemic sclerosis are reviewed degree relatives is linked to one particular HLA below. haplotype, HLA Al, B8, DR3.45 Of interest is As noted above, antinuclear antibodies are the association of the same haplotype with the often found in patients with systemic sclerosis severe form of scleroderma-like disease induced and their first degree relatives, up to 95% of the by vinyl chloride.' former and 57% of the latter, when a rapidly dividing, human cell substrate such as HEp-2 is used.43 Two particular antinuclear antibodies

CONNECTIVE TISSUE ASPECTS deserve mention because of their subset specifi- http://ard.bmj.com/ The characteristic feature of systemic sclerosis city and potential role in pathogenesis. The first is excessive deposition of collagen and other is the anticentromere antibody, which recognises connective tissue matrix proteins. LeRoy noted three human chromosomal antigens, and which that scleroderma dermal fibroblasts synthesise is associated with limited cutaneous systemic excessive collagen in vitro and that this increased sclerosis and patients with Raynaud's pheno- ability to synthesise collagen persists in vitro for menon at risk of developing limited disease.57

a number of passages, before declining towards The association of anticentromere antibody on September 29, 2021 by guest. Protected copyright. normal.47 Increased synthesis of glycosamino- with certain nailfold capillary abnormalities has glycans and fibronectin has also been shown. been noted'2; both are useful in screening Increased concentrations of mRNA of each of patients with Raynaud's phenomenon for these matrix proteins exist in scleroderma underlying systemic sclerosis.'3 " The second, dermal fibroblasts. This may result from anti-Scl-70, found in about 30% of patients with increased rates of transcription, but increased diffuse cutaneous systemic sclerosis, is an auto- half lives of the mRNAs may also contribute antibody directed against the nuclear enzyme, to increased matrix synthesis in systemic DNA topoisomerase 1.58 Another autoantibody, sclerosis.48 49 found in a smaller percentage of patients with Recent studies have shown that transforming diffuse cutaneous systemic sclerosis, seems to growth factor ,B may enhance transcription of be directed against a nucleolar enzyme, RNA collagen mRNA through the activation of a polymerase V9 Recently it has been suggested promoter region of the collagen gene.50 When that topoisomerase I may accelerate collagen injected into experimental animals, transform- gene transcription by virtue of its ability to bind ing growth factor c causes a mononuclear cell to promoter regions and other sites on collagen inflammatory response and fibrosis.5' Also of genes, leading Douvas to propose that in- potential relevance to systemic sclerosis, trans- hibitors of topoisomerase I may ultimately forming growth factor ,B induces the autocrine prove useful in controlling the excessive production of a potent fibroblast mitogen, collagen synthesis which characterises systemic platelet derived growth factor,52 and it inhibits sclerosis.' endothelial cell proliferation in vitro.53 These Activation of the complement pathways has and other studies support a hypothetical role for been shown recently in patients with systemic transforming growth factor 3 in the induction of sclerosis.6' Newly developed techniques Clinical aspects ofsystemic sclerosis (scleroderma) 859

showed that concentrations of activated comple- with localised scleroderma react is unknown, Ann Rheum Dis: first published as 10.1136/ard.50.Suppl_4.854 on 1 November 1991. Downloaded from ment components were high in many patients but it differs from topoisomerase I and centro- with systemic sclerosis and these concentrations mere antigens.70 Eosinophilia is more common reflected the clinical severity. than in systemic sclerosis (31% v 7%), but less The presence of mononuclear cells in the common than in eosinophilic fasciitis.7' The dermis of patients with systemic sclerosis has degree of blood eosinophilia may reflect disease generated interest in the products of such cells activity. and their potential effects on fibroblasts. Mast The cause of localised scleroderma is un- cells are present in the dermis of patients with known. Much excitement was generated by systemic sclerosis,62 and in a number of experi- reports suggesting a spirochaetal cause (Borrelia mental models and pathological states offibrosis, burgdorfern),72 but most subsequent investi- including graft versus host disease. Inhibitors of gations from other geographical locations have mast cell degranulation reduce the fibrosis failed to confirm this association.7374 which occurs spontaneously in one experimental Diffuse fasciitiswitheosinophilia (eosinophilic model ofscleroderma, the tight skin mouse.63 6 fasciitis or Shulman's disease) is a syndrome It remains to be determined whether such characterised by scleroderma-like skin changes, inhibitors can modify the course of systemic fasciitis, and blood eosinophilia. It falls within sclerosis. the spectrum of scleroderma, and histologically Soluble products of lymphocytes and mono- is similar in many respects to what has been cytes have recently been studied for their effects described as 'morphoea profunda'.75 The on vascular endothelium and fibroblasts. One characteristic histopathological features are such cytokine, interferon y, can down regulate thickening and hyalinisation of collagen bundles collagen synthesis by fibroblasts in vitro. Inter- in the deep dermis and of the septa in the feron y exerts its action at the level of transcrip- subcutis; an inflammatory cell infiltrate com- tion by decreasing mRNA for procollagen, and posed mainly of lymphocytes and sometimes has a longlasting effect.65 6 In one study a 72 eosinophils; and slight deposits of mucin. Such hour exposure to interferon y reduced pro- changes differ from conventional morphoea collagen mRNA concentrations in scleroderma because of deeper involvement and more pro- fibroblast cell lines to those shown by control nounced inflammatory cell infiltration. fibroblasts.' Clinical trials of recombinant Recently, an epidemic known as the eosino- interferon y in systemic sclerosis are currently philia-myalgia syndrome was reported, initially under way. and predominantly from the United States, Other cytokines are also potentially relevant associated with the ingestion of the essential to the pathogenesis of systemic sclerosis. Inter- amino acid L-tryptophan.76 This syndrome is leukin 1 is mitogenic to fibroblasts, as is an similar in some respects to sporadic cases of inhibitor to interleukin 1 produced by mono- eosinophilic fasciitis; in fact, retrospective nuclear cells from patients with systemic studies have shown that a significant proportion sclerosis.67 Lymphotoxin and tumour necrosis of cases of eosinophilic fasciitis were associated factor a, present in scleroderma serum samples, with the ingestion of L-tryptophan. The eosino- may also be important mediators.68 Tumour philia-myalgia syndrome also resembles in http://ard.bmj.com/ necrosis factor a has been shown in vitro to many respects the toxic oil syndrome, which injure endothelial cells and to stimulate fibro- occurred as an epidemic in Spain in 1981. blast proliferation.56 68 Future treatments may Thus far the eosinophilia-myalgia syndrome has use modifiers of the biological response(s) to affected over 1500 subjects and has been linked such cytokines. to more than 20 deaths. Many patients with eosinophilia-myalgia syndrome have scleroderma-like changes affect- on September 29, 2021 by guest. Protected copyright. Special considerations ing the skin and subcutaneous tissue, including Localised scleroderma is similar to systemic the fascia and adjacent muscles,7 similar to sclerosis histopathologically, but effects of the those described above in morphoea profunda or former condition are limited to the skin, sub- eosinophilic fasciitis. Unusual features of this cutaneous tissue, fascia, and adjacent muscle. syndrome include an eosinophilic pneumonitis, Depending upon the location and extent of hepatitis, and neuropathy in some patients. The affected skin, localised scleroderma may be last of these may be severe and debilitating, classified as linear or morphoea (plaque or resulting in respiratory failure, and has been generalised). In linear scleroderma sclerotic responsible for most of the deaths attributed to skin occurs in a band-like distribution, often the syndrome. A number of cases have also been crossing joint lines and resulting in contractures. described with clinical and histopathological Facial hemiatrophy may be regarded as a form evidence of pulmonary hypertension.78 Pneu- of linear scleroderma affecting the face and monitis, pulmonary hypertension, and neuro- scalp (en coup de sabre). Morphoea may occur pathy were also prominent features of the toxic as circumscribed plaques of sclerotic skin or as a oil syndrome. more generalised, symmetric process. Several cases of a similar illness were reported Raynaud's phenomenon is rare among patients in patients receiving L-5-hydroxytryptophan for with localised scleroderma, unlike those with treatment of neurological disorders,79 raising systemic sclerosis. Antinuclear antibodies may the question ofthe role oftryptophan metabolism be positive in about 50% of patients with in these and other fibrosing conditions, includ- localised scleroderma, using the sensitive HEp- ing systemic sclerosis. Biochemical studies of 2 substrate.69 The nature of the nuclear anti- tryptophan metabolites have shown abnor- gen(s) with which serum samples from patients malities in these patients,7 79 as well as in 860 Silver Ann Rheum Dis: first published as 10.1136/ard.50.Suppl_4.854 on 1 November 1991. Downloaded from patients in the active phase of eosinophilic Raynaud's phenomenon. Long-term follow-up study of 73 cases. Am J Med 1987; 83: 494-9. fasciitis.80 These studies have shown increased 9 Maricq H R, Weinrich M C, Keil J E, LeRoy E C. Prevalence concentrations of tryptophan metabolites, of Raynaud's phenomenon in the general population. A preliminary study by questionnaire. J Chronic Dis 1986; 39: kynurenine and quinolinic acid, in the plasma 423-7. and urine. The pattern of increased kynurenine 10 Harper F E, Maricq H R, Turner R E, Lidman R W, LeRoy E C. A prospective study of Raynaud's phenomenon and and quinolnic acid concentrations in patients in early connective tissue disease. A five-year report. Am J7 the active phase of their is consistent with Med 1982; 72: 883-8. illness 11 Fitzgerald 0, Hess E V, O'Connor G T, Spencer-Green G. increased activity of the rate limiting enzyme Prospective study of the evolution of Raynaud's pheno- in the kynurenine pathway, indoleamine-2,3- menon. AmJ Med 1988; 84: 718-26. 12 Chen Z, Silver R, Ainsworth S K, Dobson R L, Rust P, dioxygenase. Inflammatory mediators, such as Maricq H R. Association between fluorescent antinuclear endotoxin and interferon y, are known to antibodies, capillary patterns and clinical features in scleroderma spectrum disorders. Am J Med 1984; 77: stimulate the activity of indoleamine-2,3- 812-22. dioxygenase. It remains to be determined 13 Kallenberg CG M, Wouda A A, Hoet M H, van Venrooij W J. Development of connective tissue disease in patients whether endotoxin or interferon y, or both, play presenting with Raynaud's phenomenon: a six year follow a part in the biochemical abnormalities and up with emphasis on the predictive value of antinuclear antibodies as detected by immunoblotting. Ann Rheum Dis pathogenesis of the current eosinophilia-myalgia 1988; 47: 634-41. syndrome epidemic. Further studies of trypto- 14 Wollersheim H, Thien Th, Hoet M H, van Venrooij W J. The diagnostic value of several immunological tests for phan metabolism in patients with eosinophilia- antinuclear antibody in predicting the development of myalgia syndrome or eosinophilic fasciitis may connective tissue disease in patients presenting with Raynaud's phenomenon. Eur J Clin Invest 1989; 19: provide information which is applicable to the 535-41. pathogenesis of systemic sclerosis. 15 Lomeo R M, Cornella R J, Schabel S I, Silver R M. Progressive systemic sclerosis sine scleroderma presenting The eosinophilia and oedematous skin as pulmonary interstitial fibrosis. Am J Med 1989; 87: changes, as well as the pneumonitis, associated 525-7. 16 Masi A T, Rodnan G P, Medsger T A Jr, et al. Preliminary with eosinophilia-myalgia syndrome generally criteria for the classification of systemic sclerosis (sclero- respond well to corticosteroid treatment. derma). Arthritis Rhewu 1980; 23: 581-90. 17 Zaninotto G, Peserico A, Costanini M, et al. Oesophageal Neuropathy and pulmonary hypertension may motility and lower oesophageal sphincter competence in persist, and chronic skin changes are now being progressive systemic sclerosis and localized scleroderma. ScandJ Gastroenterol 1989; 24:95-102. seen. The natural history of this new epidemic 18 Hendel L, Worning H. Exocrine pancreatic function in remains to be determined. patients with progressive systemic sclerosis. Scand J Gastroenterol 1989; 24: 461-6. 19 Harrison N K, Glanville AR, Strickland B, et al. Pulmonary involvement in systemic sclerosis: the detection of early changes by thin section CT scan, bronchoalveolar lavage Childhood scieroderma and 99mTc-DTPA clearance. Respir Med 1989; 83: 403-14. Scleroderma is rare in childhood, and the 20 Furst D E, Davis J A, Clements P J, Chopra S K, Theofilopoulos A N, Chia D. Abnormalities of pulmonary clinical presentation is even more varied than in vascular dynamics and inflammation in early progressive adult life.8" Juvenile onset scleroderma may systemic sclerosis. Arthritis Rheum 1981; 24:1403-8. 21 Wallaaert B, Hatron P Y, Grosbois J M, Tonnel A B, take the form of localised scleroderma (linear or Devulder B, Voison C. Subclinical pulmonary involvement morphoea), including eosinophilic fasciitis,82 or in collagen-vascular diseases assessed by bronchoalveolar lavage. 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