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Home , CREST syndrome, Lupus erythematosus, Sclerodactyly, Scleroderma

Annals ofthe Rheumatic Diseases 1991; 50: 323-327 323

The progressive systemic sclerosis/systemic Ann Rheum Dis: first published as 10.1136/ard.50.5.323 on 1 May 1991. Downloaded from overlap: an unusual clinical progression

Ronald A Asherson, Heather Angus, John A Mathews, Orlando Meyers, Graham R V Hughes

Abstract matosus. At this time she was given Synacthen Three patients with the unusual combinations depot. At age 42 a clinical diagnosis of progres- ofdiscoid lupus, systemic sive systemic sclerosis (PSS) was made. She now (SLE), and progressive systemic sclerosis had thickening of her , predominantly (PSS) are reported. The firstpatient developed affecting the , as well as Raynaud's PSS eight years after a diagnosis of discoid phenomenon. She was initially given predniso- lupus had been made and this was compli- lone 5 mg twice a day. Progressive thickening of cated by six years later. The second the skin continued, however, with 'cracking' of patient developed PSS more than 20 years the tips. Despite the prednisolone, after being diagnosed as having SLE. The sloughing of the tips of three occurred in third patient developed SLE with predominant 1983, and she was admitted to hospital for features of urticarial six years after treatment and the steroids were stopped. The PSS. Mild myositis also ensued. There were DNA binding at this time was normal (7 5 no to UIRNP demonstrable in any U/ml) but the antinuclear titre was of these patients. The clinical progression of raised at 1/160. Ketanserin was given without SLE to PSS or vice versa in the absence of any appreciable response. In 1985 a prosta- features of mixed disease is glandin infusion was given intravenously with distinctly uncommon. some improvement in the skin thickening and warmth of the hands, but the improvement was not sustained for longer than a few weeks. Although the connective tissue diseases can In 1987 she complained of of the usually be clinically and serologically defined as shoulders, and, predominantly, the distinct and separate entities, such as rheu- wrists. She was found to have soft tissue matoid , systemic lupus erythematosus, swelling of the knees and wrists, microstomia progressive systemic sclerosis, and dermato- (fig 1), and dry thick fingers with pseudo- myositis, overlap between these conditions may clubbing, but no were seen. The http://ard.bmj.com/ be encountered. A specific overlap termed haemoglobin was 95 g/l with a low serum mixed connective tissue disease is one such ferritin (5-5 mmol/l), the count condition.' Others are simply termed undif- ferentiated connective tissue disease.2 Sjogren's syndrome, fibrosing alveolitis, and Raynaud's phenomenon may accompany all of the above

but may also exist on their own as 'primary' on October 1, 2021 by guest. Protected copyright. conditions. The association of lupus and (with or without myositis), one condition merg- ing into the other, without the presence of antibodies to UlRNP or any clinical features of mixed connective tissue disease, is distinctly uncommon. We report three such patients seen over the past five years.

The Lupus Arthritis Case reports Research Unit and PATIENT ONE: DISCOID LUPUS DEVELOPING INTO PROGRESSIVE SYSTEMIC SCLEROSIS WITH LATE Departments, St Thomas's Hospital, COMPLICATING London SE1 A 48 year old white woman of Austrian ancestry R A Asherson had a single discoid lesion aged 21 which was J Mathews confirmed as being discoid lupus erythematosus G R V Hughes in 1975 at the age of 34. Clinical details are Rheumatology Unit, Groote Schuur Hospital, sketchy, but skin manifestations had pre- Cape Town, South Africa dominated. At this time her antinuclear anti- H Angus bodies were positive (1/320). A biopsy specimen 0 Meyers from non-lesional skin showed positive im- Correspondence to: Dr Asherson. munofluorescence for IgG and complement, Accepted for publication and a lesional biopsy specimen showed typical 28 August 1990 histological features of discoid lupus erythe- Figure I Patient No I showing microstomia. 324 Asherson, Angus, Mathews, Meyers, Hughes

Figure 2 PatientNo 1. was treated with prednisolone (60 mg/day) and Radiograph ofthe hands (125 mg/day orally) with shoi resorptin ofthe Cyclophosphamide was stopped trminalphalamges. improvement. Ann Rheum Dis: first published as 10.1136/ard.50.5.323 on 1 May 1991. Downloaded from after three months because of the development of haemorrhagic cystitis. He was lost to follow up until 1982 when he was admitted with right middle lobe pneumonia. Extensive skin lesions of chronic discoid lupus affecting the scalp, face, and upper trunk with scarring and alopecia were noted. A loud pericardial friction rub was noted, and echocardiography confirmed a . The haemoglobin was reduced at 82 g/l, the total white cell count was 11 3x 109/1 with 17% lymphocytes, and platelets were 729x 109/1. The ESR was 125 mm/h. The urea was 3-8 mmol/l, creatinine 71 pmol/l, with an uncorrected clear- ance of 132-3 ml/min and a 24 hour urinary protein excretion of 0-12 g. The antinuclear was normal but the erythrocyte sedimentation antibody titre was low positive (1/10), and anti- rate (ESR) was raised at 44 mm/h. The anti- DNA antibodies raised at 10 mg bound nuclear antibody titre was still positive (1/320), DNA/ml serum (normal 0-5). Radiographs of immune complexes were increased (IgG the hands were normal. He was treated with 102 mg/i), she had negative latex and Rose- prednisolone (40 mg/day) and antibiotics for his Waaler tests for rheumatoid factor, but sur- infection. prisingly antibodies to Sm were present. The In 1985 he presented to the outpatient clinic serum IgG concentration was raised (17 9 g/l) with pleuritic and arthralgia. Syno- (normal 5-316-5 g/l). She was given diclofenac vitis of the wrists and the metacarpophalangeal sodium 100 mg twice a day for the pains. and proximal interphalangeal ofthe hands Throughout 1988 and 1989 various other was noted, and radiographs showed juxta- non-steroidal anti-inflammatory drugs were articular osteoporosis, but no erosions. Sclero- prescribed (ketoprofen, indomethacin) with no dactyly was noted for the first time. The major clinical effects. A chest radiograph was antinuclear antibody titre was positive (1/100; normal, but radiography of her hands now 1/500) (homogeneous), and anti-DNA antibodies showed resorption of the terminal phalanges were raised at 18 mg bound DNA/ml serum. (fig 2). There was no soft tissue calcification Treatment with phosphate (250 evident. In October 1989 she complained of mg/day) was started for control of his arthritis. http://ard.bmj.com/ muscle pain and her muscle enzymes were Throughout 1986 and 1987 he continued to raised. Electromyography showed fibrillation have pain in the hands and wrists, but no active and small polyphasic units characteristic of arthritis was reported. The inflammatory muscle disease. A diagnosis of became more marked, however, and he myositis was made. Her creatine kinase was developed proximal scleroderma with skin 608 U/i (normal <250), and hydroxybutyric changes extending onto the forearms. Marked dehydrogenase 238 U/i (normal <182). The resorption of the digits resulted in significant on October 1, 2021 by guest. Protected copyright. ESR was raised at 82 mm/h and the rheumatoid loss of function. Radiographs of the hands factor test was also positive. Tissue typing over a three year period showed progression of showed her to be A11,28, B14,56, C4,5, Bw6, erosions and marked resorptive changes at the and DRI and 6. The muscle symptoms have interphalangeal and metacarpophalangeal joints, responded to prednisolone 5 mg twice daily. as well as the wrists (figs 3A, B, and C). The patient has never had Raynaud's pheno- menon. The nailfold capillaries could not be PATIENT TWO: SYSTEMIC LUPUS ERYTHEMATOSUS clearly seen owing to the pigmentation and DEVELOPING INTO PROGRESSIVE SYSTEMIC thickening of the skin. There was no evidence SCLEROSIS of skin or . He did not The patient, a South African man of mixed have , and a barium swallow done in descent was diagnosed as having systemic lupus September 1988 was normal. Tolerance of erythematosus (SLE) at the age of 9 years, but exercise was normal and the chest was clinically clinical details are available only from 1973, and radiologically clear. when at the age of 17 he presented with There had been no evidence of active lupus alopecia, discoid skin lesions, and an erythe- for the past two years. The skin lesions were matous malar . Blood and protein were quiescent, he did not have serositis, and the noted in the urine, and a renal biopsy showed urine was clear. The most recent laboratory focal nephritis, with wire looping, focal hyper- investigations showed haemoglobin 154 g/l, cellularity, and subendothelial deposits on elec- white blood cell count 7 6x I09/1 with a normal tron microscopy. The haemoglobin was 105 g/l, differential, platelets 275 x 109/1, ESR 12 mm/h, urea 23 mmol/l, and creatinine 272 pmol/l. urea 4-6 mmol/l, and creatinine 77 ,imol/l. A 24 Lupus erythematosus cells were positive, anti- hour urine collection was negative for protein, nuclear antibodies were positive at a titre of and the uncorrected clearance was 131 ml/min. 1/100, and rheumatoid factor was negative. He Recent serological tests showed a negative The progressive systc scerosis/lystemic lupus overlap 325 Ann Rheum Dis: first published as 10.1136/ard.50.5.323 on 1 May 1991. Downloaded from

Figure 3 Patient No 2. Radiograph ofthe right hand in (A) December 1986; (B) November 1987; (C) October 1988.

antinuclear antibody and anti-Ro antibody. loss started some three years after the onset of Anti-DNA antibodies were normal (<3 mg her illness. She was given steroid treatment, bound DNA/ml serum) and other antibodies to but in 1987 developed steroid induced glaucoma. extractable nuclear were also negative. To reduce her steroid requirements, hydroxy- http://ard.bmj.com/ The patient was once again lost to follow up and chloroquine and naproxen were added to her specimens were unobtainable. regimen for relief of her arthritic pains. Several 'flares' of disease had occurred over the six year period, which were associated with increased PATIENT THREE: PROGRESSIVE SYSTEMIC shortness of breath but without cough, and the SCLEROSIS DEVELOPING INTO SYSTEMIC LUPUS dyspnoea was accompanied by severe . ERYTHEMATOSUS These 'flares' had previously been treated on October 1, 2021 by guest. Protected copyright. The patient, a 42 year old white woman with no with temporary increases in steroid dose. She family history of note, had a six year history had recently had more frequent episodes of of and polyarthralgias affecting retrosternal chest pains radiating to her neck mainly the ankles, knees, and small joints of the and occurring particularly at night. She was hands, thickening of the skin, particularly admitted to St Thomas's Hospital for assess- affecting the face, upper arms, and shoulders, ment in April 1987. Alopecia was noted as well accompanied by Raynaud's phenomenon. Exer- as a widespread fading urticarial rash affecting tional dyspnoea had recently developed over the limbs and trunk. There was a purpuric one year as well as '', which con- element present on the edges of the soles of the sisted of substernal burning and discomfort feet and toes. Microstomia was obvious but no postprandially. Additionally, she was lethargic. sclerodactyly was present. She had a longstanding history of dermato- Investigations showed a normal blood count graphism. with an ESR of 17 mm/h and a raised platelet When seen in 1985 she had the typical count of 519x 109/l. Coombs' test was negative. features of scleroderma-including shiny and The Crithidia DNA test taught skin over the digits and loss of digital was positive. Antinuclear antibodies were posi- creasing-accompanied by , particu- tive at 1/320 and the DNA binding antibody larly of the metacarpophalangeal joints of both was more than 97 U/ml (normal <25 U/ml). hands. There were no associated pigmentary The Venereal Disease Research Laboratory test changes, but microstomia was present. She was negative. Immune complexes were raised at additionally had livedo reticularis. 116 g IgG/l (normal <49). The aspartate trans- From 1987 she had an intermittent burning aminase was minimally raised and the hydroxy- purpuric rash generalised in distribution, which butyric dehydrogenase activity was also in- was diagnosed as urticarial vasculitis, for which creased. The creatine kinase was persistently she was given a course of dapsone in 1986. Hair normal. Liver function and renal function tests 326 Asherson, Angus, Mathews, Meyers, Hughes

were normal. Electromyography showed evi- of discoid lupus erythematosus and then a dence of a mild myositis with some polyphasi- clinical picture of PSS seemed to evolve with city. Radiographs showed normal size and marked resorption of digits. An unusual feature fields. Barium swallow and meal examina- was the fact that he never experienced Raynaud's Ann Rheum Dis: first published as 10.1136/ard.50.5.323 on 1 May 1991. Downloaded from tions were normal. No erosive changes were phenomenon. He lived in a warm climate, evident in the hands, and there was no terminal however, and the fact that he was naturally resorption of bone and no calcinosis. There was racially pigmented might have made any obser- minor subluxation of the distal interphalangeal vations of colour changes associated with vaso- joints of both little fingers. Respiratory function spasm difficult. tests showed a mild restrictive defect with a Patient three developed typical features of significant reduction in gas transfer (transfer SLE six years after manifesting PSS. The SLE factor 5 3) (predicted mean value (SD) 8&5 was heralded by the appearance of the typical (2 4)). rash of urticarial vasculitis, which has persisted Several months later the Coombs' test became for three years and has been unresponsive to any positive. This positivity was accompanied, how- form of treatment to date. ever, by a normal reticulocyte count and a In patients one and three a myositis eventu- haemoglobin concentration at the lower end of ally complicated their clinical course. normal (125 g/l). Mixed connective tissue disease was originally A diagnosis of SLE was made with compli- described by Sharp et al3 and by Mattioli and cating urticarial vasculitis, myositis, and inter- Reichlin in the early 1970s.' Patients with this mittent Coombs' positivity. Steroid treatment disease seem to show features of SLE, poly- was continued. Postprandial epigastric pains myositis, and progressive systemic sclerosis, persisted, but an endoscopy was normal. Rani- accompanied by a chronic arthritis at one time tidine 150 mg twice a day was added and she or another. There is a high incidence of was also given nifedipine 20 mg twice a day for Raynaud's phenomenon, swollen or 'sausage' the Raynaud's phenomenon. Because of the fingers, and tenosynovitis clinically. All these recurrent chest pains an echocardiogram was patients have high titres of antibodies to performed in 1988. This showed the presence of U1RNP and are negative for antibodies to mitral regurgitation, confirmed on Doppler double stranded DNA (dsDNA). A speckled scanning. pattern of antinuclear antibodies is a useful clue When seen in late 1988 she had developed to the presence of antibodies to UIRNP. The marked telangiectasias of the face and hands but incidence of renal disease and neuropsychiatric there was no evidence of a CREST syndrome, illness in this group seems to be low according such as pigmentation or sclerodactyly, and the to some studies. Younger patients with the telangiectasis were ascribed to her long term condition tend to develop SLE, whereas older steroid treatment. Microstomia was still present. patients develop features ofprogressive systemic Immunological testing now showed antibodies sclerosis. Many, however, remain in the cat- to extractable nuclear antigens (unidentified), egory of mixed connective tissue disease. http://ard.bmj.com/ and the rheumatoid factor was positive. The C4 The familial occurrence of SLE and sclero- concentration was reduced at 0 11 g/l (normal derma is well described. Flores et al reported 0-16-0-45) with a low normal CH100 of 60% eight families containing members with both (normal 50-125) and C3 at 0-8 g/l (normal disorders.4 Relatives with PSS, however, had at 0-7-1[8). Antimitochondrial antibodies were least one serological abnormality more charac- negative and the Coombs' test was now negative. teristic of SLE, such as antibodies to Sm, anti- Clq precipitins were present in serum. A RNP, anti-dsDNA, haemolytic anaemia, leuco- on October 1, 2021 by guest. Protected copyright. lymphopenia of 0-9x l09/1 had developed penia, or hypocomplementaemia. Two mem- (normal I 5-3 5x109/1). bers of different families had enough clinical The patient continues to have episodes of evidence of both diseases simultaneously to recurrent urticarial vasculitis unresponsive to classify them as such. most treatments. Other authors have also drawn attention to the coexistence of both PSS and SLE within families,57 and these patients are discussed in Discussion detail by Flores et al.4 The three patients described present unusual Dubois et al reported PSS and SLE coexisting overlap features of two well defined connective in the same patients.7 These authors reviewed tissue diseases. Patient one originally presented the incidence of coexistent SLE and sclero- with discoid lupus and there was no convincing derma, as well as cases reported by other evidence of . Eight years later authors, and were able to discover only 10 she had features of PSS predominantly affecting previously published cases. They recorded 12 of the skin, and severe Raynaud's phenomenon. 78 patients with PSS from their own clinics, Interestingly, in 1987, 12 years after the initial nine with PSS and three with morphoea only. development of discoid lupus erythematosus Defmite skin changes of scleroderma were and still with predominant features of PSS, confirmed by biopsy in nine of the 12. Discoid antibodies to Sm were present, indicating that lupus erythematosus lesions were present in at least serologically there was some evidence of four, pleurisy in six, pleural effusions in five, antibody production against ribonucleoproteins, and pericarditis in five. Seven had a leucopenia not usually seen in PSS, indicative and diagnostic (<4-5x109/1) and the diagnosis of the two of coexisting SLE. conditions in single patients was confirmed by Patient two developed SLE at a young age. necropsy in four. Eight years later he presented extensive features In an appendix to their paper Dubois et al The progressive systemic sclerosis/systemic lupus overlap 327

then described several other patients in detail 1 Reichlin M, Mattioli M. Correlation ofa precipitin reaction to an RNA protein and a low prevalence of nephritis who seemed to have varying combinations of in patients with systemic lupus erythematosus. N Engi J Med 1972; 236: 908-11.

the two diseases; either PSS, later developing Ann Rheum Dis: first published as 10.1136/ard.50.5.323 on 1 May 1991. Downloaded from 2 Bennett R M. Mixed connective tissue disease and other features of SLE, or the reverse. These patients overlap syndromes. In: Kelly W M, Harris E D, Ruddy S, closely resemble the patients we have reported Sledgde M N, eds. Textbook of rhewmatlogy. 3rd ed. Philadelphia: Saunders, 1989: 1147-65. in this paper. 3 Sharp G C, Irving W S, Tan E. Mixed connective tissue Chorzelski and Jablonska also described three disease: an apparently distinct rheumatic disease syndrome associated with a specific antibody to an extractab.le nuclear cases of coexistent PSS and SLE,8 one with antigen (ENA). Am J Med 1972; 52: 148-59. discoid lupus erythematosus and two with SLE. 4 Flores R H, Stevens M B, Arnett F C. Familial occurrence of progressive systemic sclerosis and systemic lupus erythe- Jablonska et al subsequently reviewed the co- matosus. J Rheumatol 1984; 11: 321-3. existence of the two conditions and concluded 5 Hagberg B, Leonhardt T, Skogh M. Familial occurrence of diseases, progressive systemic sclerosis and that the association was most uncommon, systemic lupus erythematosus. Acta Medica Scandinavica occurring in less than 1% of cases of PSS.9 1%1; 169: 727-34. 6 Tuffanelli D L. Sckeroderma, immunologic and genetic In summary, therefore, although the associa- disease in three families. Dermatologica 1%9; 138: 93-104. tion of the two diseases in the same patient may 7 Dubois E L, Chandor S, Friou G J. Progressive systemic sclerosis and localised scleroderma (morphoea) with posi- occur rarely and sporadically, the familial tive LE cell test and unusual systemic manifestations occurrence of the two conditions may also be compatible with systemic lupus erythematosus. Medicine (Balimore) 1971; 50: 199-222. seen, albeit uncommonly. 8 Chorzelski T, Jablonska S. Co-existence of lupus erythe- matosus and scleroderma in light of immunopathological investigations. Acta Derm Venereol (Stockh) 1970; 50: 81-5. 9 Jablonska S, Chorzelski T, Blasczyck M. Relation between Thanks are due to Mrs Caroline Hesketh for the typing. This scleroderma and collagen diseases. In: Jablonska S, ed. work was supported by the British SLE Aid Group and the Jean Sckeroderma and psudosckroderma. 2nd ed. Warsaw: Polish Shanks Foundation. Medical Publishers, 1975: 35-51. http://ard.bmj.com/ on October 1, 2021 by guest. Protected copyright.