Clinical and Experimental Dermatology 1992; 17; 127-131.
Systemic sclerosis sine scleroderma presenting with vitiligo-like depigmentation and interstitial pulmonary fibrosis W.J.S.DE VILLIERS,* H.F.JORDAANf AND W.BATESt * Department of Internal Medicine, •f Department of Dermatology, XDepartment of Anatomical Pathology, University of Stellenbosch Medical School, P.O. Box 19063, Tygerherg 7505, Republic of South Africa Accepted for publication 2\ June 1991
white-cell count revealed a marked eosinophilia of 24% (normal 1-6%). Lung function studies showed a moderWe report a ease of systemic sclerosis sine scleroderma in ately severe restrictive pattern with markedly reduced whieh vitiligo-like depigmentation and early interstitial transfer factor. A chest X-ray showed a bilateral basal pulmonary fibrosis predominated. The pigmentary reticulonodular pattern as well as small pleural effusions. changes occurring in systemic sclerosis are reviewed and This was later confirmed by computed tomography ofthe the distinctive features ofthe case diseussed. thorax. The following investigations were normal or negative: biochemical profile, blood gases, anti-nuclear antibodies, anti-double stranded DNA antibodies, antiThe hallmark of systemie selerosis (SS), a generalized ribonuelear protein antibodies, anti-Sm antibodies, rheudisorder of connective tissue, is hide-bound fibrosis of matoid factor (latex and SCAT), RPR and TPHA, skin (seleroderma).' Rarely, the earliest clue to the electrocardiogram (ECG), X-rays of the hands and feet diagnosis is visceral involvement and oesophageal symp- and echocardiography. Her stools showed Entamoeba toms especially may precede the development of cuta- histolytica cysts. neous changes which may be absent (SS sine scleroSystemic lupus erythematosus (ANA-negative) with derma).^'' The lung is the second most common organ interstitial lung involvement was diagnosed and treated affected and 10 eases have been described in the literature with prednisone 60 mg daily and non-steroidal inflammawhere pulmonary disease presented without selerotory drugs. The eosinophilia and raised ESR normalized derma.** We report a case of SS with predominant early rapidly on treatment. Her pulmonary function remained pulmonary involvement where vitiligo-like skin lesions stable, but Raynaud's phenomenon and worsening arthriunassociated with deep sclerosis indicated the correet tis ofthe hands developed. Repeated serological screendiagnosis. ing remained negative. She defaulted from further follow-up in May 1989. Case report In May 1990 the patient presented at this hospital acutely ill with a 2-week history of fever, progressive In July 1988, a 30-year-old woman presented with a 6dyspnoea to Grade 4 and right-sided pleuritic ehest pain. month history of symmetrical polyarthralgia, intermitShe also complained of 15 kg weight loss over the tent pleuritis and increasing dyspnoea. She was not on preceding 6 months, increasing palpitations and dysphamedication, including L-tryptophan-containing preparagia for solids. tions and had not been exposed to toxins. On examination she weighed 40 kg, her temperature Initial examination showed active synovitis of several was Z^-X'Q and she was tachypnoeie with a respiratory proximal interphalangeal joints and bilateral basilar rate of 24/min. Her blood pressure was 120/90 mmHg eoarse crepitations on chest auscultation. Cutaneous and the radial pulse rate was 120/min with multiple examination was normal. extrasystolic beats. She appeared pale and had marked The erythrocyte sedimentation rate (ESR) was 52 mm/ ankle and sacral oedema. Skin lesions were present on the h Westergren (normal 0-7 mm/h) and a differential medial aspects ofthe thighs, suprapubieally (Fig. 1), the Correspondence: Dr H.F.Jordaan, Department of Dermatology, upper anterior chest and back. These lesions had enlarged University of Stellenhosch Medical Scbool, P.O. Box 19063, Tyger- over the previous 2 years, and apart from varying in shape berg 7505, Republic of South Africa. and size, appeared morphologieally similar. The rec127
W.J.S.DE VILLIERS et
Figure 1. Suprapubic lesion sbowing vitiligo-like hypopigmentation and foUicular repigmentatioti.
tangular lesions on the thighs measured 17x7 cm, the eircular trunk lesions 5 x 7 em and the rectangular suprapubic lesion 16x7 cm in diameter. They were sharply circumscribed and morphologieally indistinguishable from repigmenting vitiligo. No sclerosis or telangieetases were deteeted. There wereflexioneontractures of the distal and proximal interphalangeal joints of both hands, without calcinosis or selerodactyly, and nailfold capillaroscopy showed enlarged capillary loops and a paucity of nail-fold vessels. She had a 5 em raised jugular venous pressure, bilateral basal coarse crepitations, a grade 3/6 tricuspid incompetence murmur and a pericardial rub. Initial special investigations showed a normoehromie normocytic anaemia with Hb 8 7 g/dl (normal 11-5-15-5 g/dl) without eosinophilia. The ESR was 105 mm/h Westergren. Chest roentgenogram showed bilateral pleura! effusions, eardiomegaly and interstitial oedema. The ECG showed a sinus taehyeardia of 120/min, multifocal ventricular extrasystoles numbering up to 10/ min and pathological Q^waves in V] to V4 indicative of a previous anteroseptal Q^wave infarction. Echocardiography revealed a decreased left ventrieular ejection fraction of 40% and pulmonary hypertension with a pulmonary artery pressure of 55 mmHg (normal 15-30 mmHg). A skin biopsy of the thigh lesion showed focal parakeratosis, mild acanthosis and pigmentary incontinence in the papillary dermis. A miid perivaseular lymphocytic infiltrate was evident (Fig. 2). Melanin was mostly contained within melanophages, and foeally, melanoeytes and melanin were absent from the overlying epidermis. The Masson-Fontana stain highlighted these findings (Fig. 3). Mild fibrosis was evident within the papillary dermis, but the reticular dermis and subcutaneous fat appeared normal. The suprapubie lesion was
Figure 2. Photomicrograph of lesion on left tbigh displaying laminated ortbokeratosis, mild acanthosis, melanin incontinence, a mild lymphocytic infiltrate and mild fibrosis of the pillary dermis. Note dilated lymphatics (H&E, x40).
Figure 3. Biopsy of a vitiligo-like macule showing absence of melanoeytes and melanin in the central portion. Note normal pigmentation ofthe periphery (Masson-Fontana Stain).
SYSTEMIC SCLKROSIS SINE SCLERODERMA histologically virtually similar, but the papillary dermis appeared more homogeneous due to selerosis of collagen. The following investigations were normal or negative: repeated serological screening including anti-ribonuclear protein antibodies, anti-ccntromcrc and anti-cardiolipin antibodies. The patient was treated with digoxin, frusemide, heparin, theophylline, cefoxitin sodium, piperacillin and gentamiein, but became progressively more dyspnoeic and cyanotic. Her renal function deteriorated with the urea increasing from 5-2 to 35 8 mmol/I and ereatinine from 102 /^mol/l to 500 /fmoI/1. She was started on prednisone and cyclophosphamide but remained in severe congestive heart failure despite the use of inotropic support, captopril, mexilctine hydrochloride and lignocaine. She developed resistant hypertension and was haemodialy/ed, but died 19 days after admission. Prominent post-mortem macroscopic findings included widespread renal cortical necrosis, a left lower lobe pulmonary infarct, fibrinous pericarditis, multiple gastric stress ulcers, ulceration ofthe lower third ofthe oesophagus and severe congestion ofthe liver and spleen. Microscopically increased collagen was found in the oesophagus, small bowel and myocardium. Interstitial lung disease consistent with systemie selerosis was confirmed by the presence of fibrosis, inflammation and arterial intimal proliferation. The most striking vascular change was present in the kidneys where the majority of the interlobular arteries showed prominent intimal proliferation and fibrinoid necrosis. Discussion The ample histological evidence for a diagnosis of SS in our patient is at variance with the absence of the American Rheumatism As.sociation's major clinical criterion (proximal scleroderma). One definite criterium, namely pulmonary fibrosis, was however present.^ These
and other classification criteria are intended for description of a large series of patients, and not for the diagnosis of individual patients. The major differential diagnosis is mixed connective tissue disease (MCTD) in which unusual features for SS, such as pleural effusions, pericardial rub and areas of hypopigmentation may occur more commonly. MCTD can be disregarded because of: (i) the absence on repeated screening of antinuclear and high titrc anti-U] ribonuclear protein antibodies which arc generally considered a sine qua non for the diagnosis'" and (ii) the histological presence of fibrinoid change, small vessel intimal proliferation and severe fibrosis all of which suggest fundamental differenees from MCTD.' Table 1 shows ihe clinical characteristics of patients with systemic sclerosis sine scleroderma presenting with lung disea.ses as described in the literature (adapted from Lomco (•/ (il.*). Skin thickness usually increases early in diffuse cutaneous SS, peaks after 2-4 years and then slowly recedes. In a few instances, this regression is marked, but always begins centrally and proceeds distally with improvement in distal finger skin thickening occurring only rarely.^ Three patterns of pigmentary disturbance occur in SS,** namely: (i) generalized hyperpigmentation simulating adrenal insufficiency; (ii) focal hyper- and hypopigmentation in areas of sclerosis; and (iii) patches of perifotticular pigmentation on a background of complete pigment loss, mimicking repigmenting vitiligo. The cause of the Addisonian type of pigmentation, which is not restricted to regions of sclerosis and develops in ihc presence of normal adrenoeortical function, is unknown. The focal hyperpigmentation or hypopigmentation in areas of sclerosis probably represents postinflammatory changes.'" The vitiligo-like depigmentation is considered to be a variant of ordinary vitiligo and has simitar histological, histochemical, immunopathological and electron microscopic findings." These changes are
Table I. Clinical characteristics of paticnt.s presenting with systemic sclero^ sine sclcrodernu Current patient Oesophageal dysfunction Restrictive pulmonary function tests DIxo decreased Telangiectasis Raynaud's phenomenon Nuilfold capillary changes Fihrosis and inflammation on lung histology Oevel()pmcni of taut skin within 7 years Antinuclear antihodv
8/9 6/8 6/7 -I-
DLco: diflusing lung capacity for carbon monoxide. • Numbers in parentheses are percentages.
5/8 6/6 6/6 7/10 T f 41 / / (1
9/10 (90)» 7/9(77) 7/8 (87) 5/8 (62) 6/9 (66) 7/7(100) 7/7(100) 7/11 (63) 7/9 (77)
W.J.S.DE VILLIERS et al.
most commonly found on the upper chest, scalp, hairline, pinnae and dorsa ofthe hands and forearms and may also occur in areas of normal skin. TuffaneUi and Winkelmann'^ found 30-5% of patients with diffuse eutaneous scleroderma had pigmentary changes, with scattered areas of depigmentation oceurring frequently. Morphea or localized scleroderma is also associated with an increased incidence of ordinary and/or segmental vitiligo. Vitiligo and the depigmented lesions of SS have similar as well as distinguishing features. Both are characterized by chalk-white macules with possible perifollicular repigmentation, have well-defined borders and are usually located over the extensor bony surfaees. The Wood's light findings are similar. The extent of involvement however, tends to be more focal and symmetrical in SS with mucosal involvement occurring in vitiligo, but not in SS. The white macules of SS tend to be stable and do not enlarge as in progressing vitiligo. Although the vitiligolike maeules noted by Sanchez^^ oeeurred in sclerotic areas, our patient did not show any underlying sclerosis involving the retieular dermis. Pigmentary incontinence could be ascribed to previous T-lymphocyte mediated melanocyte damage and although fibrosis ofthe papillary dermis is diffieult to explain, T-lymphocyte mediated fibroplasia and intermittent rubbing may have been contributory. Spontaneous remission is common in vitiligo, but was noted in only one patient documented by Sanchez. Treatment with psoralens plus ultraviolet light, although not often used in patients with SS, resulted in complete repigmentation in one patient. Early in the disease, skin biopsy is less reliable for diagnosis than careful physical examination, although biopsy of oedematous skin thiekening might identify the eellular phase of scleroderma.'^ The typieal selerodermatype capillaries found on nail-fold capillaroscopy have been suggested as a useful discriminatory sign for SS compared to systemic lupus erythematosus and rheumatoid arthritis.'^ Synovitis may be the first manifestation of SS and the flexion contractures ('bowed fingers') could be caused by tendinous and periarticularfibrosis.'*"The development of pulmonary symptoms and signs preceding cutaneous disease in this patient is unusual, but not unique."^''^ Similarly, the repeated episodes of pleuritis and survival for over 2 years is unusual, but have been reported previously. Differentiation from idiopathic pulmonary fibrosis can be difficult and SS should be considered when interstitial lung disease develops subaeutely, as in this case, especially in the presence of Raynaud's phenomenon, dysphagia, and/or a positive anti-nuclear antibody.*^ Most deaths in SS occur in the autumn and winter months,'** whieh suggests that cold-induced vasospasm may contribute to the reduced diffusing capacity and pulmonary hypertension.
Clinically apparent congestive failure and arrythmias due to diffuse atrophy and fibrous replacement of functioning myocardium or conduction system occur in less than 10% of patients with SS, most of whom display diffuse cutaneous scleroderma.''' Electrocardiographic evidence of myocardial ischaemia and/or necrosis (anteroseptal pathological Q^waves in our patient) may occur in the absence of the clinical syndrome of myocardial infarction, possibly caused by multiple vasospastic ischaemic episodes ('intramyocardial Raynaud's phenomenon') leading to myocardial fibrosis.^"•^' The abrupt onset of malignant hypertension and rapidly progressive renal insufficiency is typical of scleroderma renal crises which could develop dramatically in up to 20% of diffuse cutaneous scleroderma patients.^^ The classical pathologicalfindingsof scleroderma kidney, namely cortical infarction, subintimal hyperplasia with occlusion of the interlobular arteries and fibrinoid necrosis were present.^^ The initial profound peripheral eosinophilia posed a diagnostic challenge as impressive eosinophilia (> 500 cells/mm-') in SS, although described, is unusual.^'* Eosinophilia-myalgia syndrome, eosinophilic fasciitis and 'toxic oil syndrome' could be dismissed as possibilities because of dissimilar clinical features.^^ ^' Amoebic cysts were found in the patients's stools and this, together with the transient nature ofthe eosinophilia, might argue for a parasitic infestation as cause. In conclusion, we describe a patient with SS in whom severe renal, pulmonary and cardiac involvement led to her demise and where the presenee of vitiligo-like depigmentation, unassociated with reticular dermal sclerosis, pointed to the correct diagnosis. The only indication of possible cutaneous sclerosis was the presence of digital contractures without aeroselerosis. To our knowledge vitiligo-like depigmentation in a patient with SS sine scleroderma has not been reported previously. Furthermore, this form of depigmentation, unassociated with sclerosis of the reticular dermis, seems to be unique. Acknowledgment We thank Corena de Beer for typing the manuscript. References 1. Medsger TA, Jr. Systemic sclerosis (scleroderma), localized scleroderma, eosinophilic fasciitis, and calcinosis. In: McCarty DJ, ed. Arthritis and allied conditions. Philadelphia: Lea & Febiger, 1989; 1118-U65. 2. Rodnan GP, Fennel! RH, Jr. Progressive systemic sclerosis sine scleroderma. JAMA 1962; 180: 665-670. 3. Le Roy EL. Scleroderma (systemic sclerosis). In: Kelly WN, Harris F.D, Ruddy S, Sledge CB, eds. Textbook of Rheumatology. Philadelphia: WBSaunders, 1985; 1183-1205. 4. Lomeo RM, Cornelia RJ, Schabel SI, Silver RM. Progressive systemic sclerosis sine scleroderma presenting as pulmonary
SYSTEMIC SCLKROSIS SINK SCil.ERODERMA interstitial fihrosis. Amcricafi Journal af Medicine 1989; 87: .^25527. 5. Subcummiitev lor sclcntdcrma criierij of the American Rheumatism .^ssnciatiiin I }ia|[nMic jnJ Thcrapcuiic Criteria Committee, Prcliminar> criteria f, Rudd> S. Sledge CB.edv Texthoiik of Rheumatnln^r. Philadelphia: WII .Saunders, 198.>; 1115-1136. 7. Sharp GC, SinfiEscn HI I. Mixed cunncctivc tissue disease. In: McCart\ DJ, cd. trt/iritn iindalliedcnndiluins. Philadelphia: I,ca & Febiger, l'W>; lOHO HWl. 8. Black C;, Dieppe PK. llusLissonT, Hart I'D, Regressive systemic sclerosis. .UtiuiU nl Rheum,itu ihseases 1986; 45: 384-388. 9. Braverman lM. Connective tissue (rheumatic) diseases. In: Bravcrman l.\l ud. Skin sipn uf systemic diseases. Philadelphia: WHSauiulors, l'JHl; i.'i.T .177. ' 10. Kricft T. Mcurer M. Systemic scleriiticrmu. Clinical anil pathophysidliigic aspects. Journul»/ the hnerinin .-hademy ofDcrnuitnIo^y I98K; 18:457 48L U. Bolognia JL. PawclckJ.M. Binltigy of hypopigmentation. jr»«rH(i/ ofthe .Imeruan Uademy nfDermalolai^y I9S8; 19: 217-255. 12. Tutfanclli DL. Winkelmann RK. .Systemic scleroderma: a clinical stud> of 727 cast', inhiiet ofDermjiuh^r 1%1; 84: 359-371. 13. Sanchez Jl.. \asqucs M, Sanchez \ . \itiligi>-Iike macules in systemic scleroderma, ,(r.Aiirj uf ntrmatolo^y 1963; 119: 129 133. 14. Fleischmajcr R, Perlish JS, Reeves JRT. Cxllular infiltrates in scler: .\ hiinded study oC its discriminatory value in sclenKJcrnia. systemic lupus cry thematosus and rheumatoid arthrilis, Auitrahan and \eir Zealand Journut of .Medtntie VHiiy, 1ft: 457 4(i(I, 16. Palmer IHi. 1 l,ik- (iM. (irain.in DM. l*ollcK;k .\1. Bowed fingers. A hdpiul sign in ihc carls dia^no.sis of sysiemic sclerosis. of Rheumattihuv 1981; 8: 266 272.
17. Hetiman MA. Kantrowits I-', Rapid (m.seroflung jnviilvcnient in pnujressive sysiemic sclerosis. Chest 1979; 75: 5(W 510, 18. Petcrs-Goldcn \\, Wise RA. Ilochberg M. Stevens .MB. Wiglcy F.M, (.arbon monoxide ditfucing capacity as prediaor of outcome in systemic scler