Annals of the Rheumatic Diseases 1994; 53: 323-326 323

CONCISE REPORTS Ann Rheum Dis: first published as 10.1136/ard.53.5.323 on 1 May 1994. Downloaded from in patients with systemic sclerosis and *** * ~~~~~** e9 severe digital ischaemla requiring amputation

A L Herrick, P K Oogarah, A J Freemont, R Marcuson, M Haeney, M I V Jayson

Abstract and aCL antibody status. When no aCL Objectives-To document the incidence of antibody result was available, then this was histological vasculitis in amputation assayed either retrospectively on serum stored specimens from patients with severe at -20°C or at the patient's next clinic visit. digital ischaemia secondary to systemic Blocks were taken from the skin and soft sclerosis (SSc), and to look for an tissue resection margins of the amputated association between anticardiolipin (aCL) specimens and sections stained with haema- antibodies and severe digital ischaemia in toxylin and eosin and elastic Van Geison for SSc. histological examination. Additional blocks Methods-This was a retrospective review were taken from the soft tissues of the digits of patients with SSc who underwent where appropriate, always from sites remote amputation for digital ischaemia over a from necrotic areas. three year period. Antibodies to cardiolipin were analysed Results-Five of nine patients had histo- using an ELISA technique as previously logical vasculitis, four of whom had aCL described.2 All results were calculated using antibodies, although these were not the same standard sera. The values of the present in high titre. individual isotypes were expressed as IgG and Conclusion-Vasculitis does occur in SSc, IgM aCL: the upper reference limits were 5 at least in that subgroup with severe and 3 units respectively. peripheral ischaemia. These findings could have implications for treatment of this subgroup ofpatients with SSc. Results PATIENTS CLINICAL CHARACTERISTICS (Ann Rheum Dis 1994; 53: 323-326) Nine patients with SSc required amputation during the three year period because of severe http://ard.bmj.com/ peripheral ischaemia. All were female and their Ischaemia is a predominant manifestation of median age at the time of the first amputation systemic sclerosis (SSc), and characteristically was 40 years, range 27 to 61 years. All had the the digits are most obviously affected. Severely limited cutaneous variant of SSc (eight were affected patients progress to permanent digital anticentromere antibody positive) and all had ischaemia and a minority may require severe disease. Several patients had had amputation. amputations before the three year study period on September 30, 2021 by guest. Protected copyright. The characteristic histological finding in and over 30 amputations, mostly of digits, had involved blood vessels is non-inflammatory been performed in this patient group (table). intimal thickening and fibrosis: unlike in other Three patients had dry eyes and a dry mouth connective tissue disorders, an inflammatory (patients 3, 4 and 9, all anti-Ro and anti-La Hope Hospital, component is rarely recognised. However, we antibody negative), and patients 3 and 4 had Salford, report histological vasculitis in several patients had histologically proven . Patients 3 United Kingdom with SSc undergoing amputation because of and 4 had and nail pitting, and Rheumatic Diseases Centre, severe digital ischaemia. Because of a possible patient 9 had had proximal skin involvement. University of association between anticardiolipin (aCL) All three had telangiectasiae and oesophageal Manchester antibodies and arterial and venous disease involvement, and none had anti-RNP anti- A L Herrick P K Oogarah these antibodies were sought in patients who bodies. Therefore clinically these three patients A J Freemont required amputations. fulfilled the ARA criteria for SSc and were not M I V Jayson felt to have an : the myositis Department of and symptoms of sicca syndrome were in all Vascular Surgery Patients and methods cases believed to be a manifestation of the SSc. R Marcuson A large number of patients with SSc are Patient 7 was unusual as she had a left Department of Clinical referred to The Rheumatic Diseases Centre. subclavian stenosis which was surgically Immunology artery M Haeney We reviewed the case notes and histological treated and which may have contributed to left Correspondence to: findings of all patients fulfilling the American sided digital ischaemia. However, clinically she Dr A L Herrick, Rheumatism Association Criteria for SSc' who had limited cutaneous SSc and was anticentro- Rheumatic Diseases Centre, University of Manchester, had amputation for severe peripheral ischaemia mere antibody positive, and both upper limbs Hope Hospital, over a three year period (1988-91), with showed similar ischaemic features. Salford M6 8HD, United Kingdom. particular reference to disease subtype (diffuse Antibodies to the extractable nuclear Accepted for publication or limited disease, and possibility of an overlap antigens Ro, La, Sm, RNP and Scl-70 were not 16 November 1993 syndrome), severity of peripheral ischaemia present in any of the patients' sera. Four of the 324 Herrick, Oogarah, Freemont, Marcuson, Haeney, 3'ayson

Amputations and aCL antibody status in nine patients with SSc was the only one of the eight patients tested Patient Age* Amputations ACL antibody titre for this antibody who was known to be significantly ANCA positive, titre >1/64 Ann Rheum Dis: first published as 10.1136/ard.53.5.323 on 1 May 1994. Downloaded from IgG (n

ACL ANTIBODIES ACL antibodies were detected in four patients; all had histological vasculitis. The fifth patient 4M1 X...... , shown to have vasculitis has since died and whether she had aCL antibodies is unknown.

' ,@,.'"a Three of the four patients with histological thrombosis had aCL antibodies. In three ofthe four patients with aCL antibodies these were of the 1gM isotype (table). Because this was a retrospective study, aCL antibodies were not always assayed at the time of admission for amputation. ACL antibodies were assayed within three months of ampu- Figure 1 Vasculitic rash ofthigh ofpatient 4 - this responded to oral steroids. tation in five patients, and 15 months, two Vasculitis in patients with systemic sclerosis and severe digital ischaemia requiring amputation 325

antiphospholipid syndrome (in our laboratory . IZ such patients would typically have aCL IgG

levels in excess of 50 units/ml). Three of the Ann Rheum Dis: first published as 10.1136/ard.53.5.323 on 1 May 1994. Downloaded from four patients with aCL antibodies had evidence of thrombosis histologically, but not in association with vasculitis in individual biopsies. Admittedly patient numbers are small and vasculitis was not a consistent finding in every amputation specimen from patients with aCL antibodies, but SSc is a rare disease and only a very small minority of affected patients require amputation. We therefore feel that our findings in this rare group of patients are important. By requiring amputation these patients provided a unique opportunity for ,. - histological examination. ACL antibodies have now been reported in a wide variety of disorders, including SSc.' The .- proportion of SSc patients found to have aCL Figure 2 Focal chronic inflammatory cell infiltrate of an arterial wall (ha and antibodies varies greatly between studies,5-9 eosin stain, magnification X 400). ematoxylin and the well recognised interlaboratory variability in aCL methodology will have contributed to these differences. Whether occlusive vascular disease associated with anti- phospholipid antibodies is primarily due to thrombosis or vasculitis had been debated,'0 but not specifically in patients with SSc. A small number of patients with vasculitis in association with antiphospholipid antibodies Qg- have been reported." '4 It is recognised that various infective and inflammatory states are associated with rises in aCL antibodies4 which may be transient. Similarly in our patients low grade inflammation, such as we have demonstrated histologically, appears to be associated with aCL antibodies. What is unclear at present is whether the vasculitis leads to the formation of http://ard.bmj.com/ aCL antibodies, or whether low levels of these antibodies can, in the long term, predispose to

a I the chronic vascular problems present in this Figure 3 An artery with a recanalised organised thrombus (haematoxylin and eosin stain, patient group. Perhaps a combination of both magnification x 1000). factors occurs. It may well be that these aCL antibodies are not pathogenic, but a marker of vascular events occurring in patients with SSc. on September 30, 2021 by guest. Protected copyright. years and three years later in thLe three other A prospective study is required to clarify the patients. relationship between systemic sclerosis, vasculitis, thrombosis, and aCL antibodies. If a definite association is shown, then the Discussion demonstration of aCL antibodies may indicate Our observations suggest that vasculitis does prophylaxis with long term low dose aspirin as occur in SSc, and that at least in the subgroup in coagulopathies associated with other aCL with severe digital ischaemia vas,culitis occurs syndromes. histologically when not appare nt clinically. The most important finding from our study, Previously it has been thought that vasculitis is however, is that inflammatory change does a rare finding in SSc, and that when it does occur in the blood vessels of a significant occur this is usually in associaltion with the proportion of SSc digits that are so ischaemic CREST variant and features of Sjogren's that they require amputation. Evidence for syndrome.3 vasculitis should be carefully looked for in this We have also found that a Iproportion of patient group. Perhaps in patients with SSc at patients with severe peripheral ischaemia have risk of severe digital ischaemia immuno- aCL antibodies (four of the e~ight patients suppressant treatment to suppress this tested), and in our experiencee these were inflammation may be justified, in an attempt to always associated with at least onte amputation minimise digit loss. However, caution is specimen showing vasculitis. These patients indicated because of the potential toxicity of had levels of aCL antibodies outside the these drugs, and of particular concern is that reference range for normal hea lthy controls, steroid therapy may, in some instances, be but did not have the very high lewvels found in associated with worsening of vasculitis.'5 acute arterial and venous thro:mbotic states Unfortunately, the small number of SSc sometimes associated with SLE or a primary patients with peripheral ischaemia so severe as 326 Hemck, Oogarah, Freemont, Marcuson, Haeney, 3rayson

to need amputation means that controlled 7 Passaleva A, Massai G, Matucci-Cerinic M, et al. Immunologic abnormalities in a group of patients with clinical trials concerned with this issue are limited cutaneous systemic sclerosis and prominent vascular disease. Autoimmunity 1990; 6: 283-91. unlikely to be mounted. Ann Rheum Dis: first published as 10.1136/ard.53.5.323 on 1 May 1994. Downloaded from 8 Katayama I, Otoyama K, Kondo S, Nishioka K, Nishiyama S. Clinical manifestations in anticardiolipin 1 Subcommittee for Criteria of the American antibody-positive patients with progressive systemic Rheumatism Association Diagnostic and Therapeutic sclerosis. JAm Acad Dermatol 1990; 23: 198-201. Criteria Committee. Preliminary criteria for the 9 Fonollosa V, Selva A, Lima J, Simeon C P, Vilardell M. classification of systemic sclerosis (scleroderma). Arthritis Anticardiolipin antibodies in systemic sclerosis. 7 Am Rheum 1980; 23: 581 -90. Acad Dermatol 1991; 25: 133-4. 2 Loizou S, McCrea J D, Rudge A C, Reynolds R, 10 Lie J T. Vasculopathy in the antiphospholipid syndrome: Boyle C C, Harris E N. Measurements of anti-cardiolipin thrombosis or vasculitis, or both? Rheumatol 1989; 16: antibodies by an enzyme-linked immunosorbent assay 713-5. (ELISA): standardization and quantitation of results. Clin 11 Alarcon-Segovia D, Cardiel M H, Reyes E. Antiphospho- Exp Immunol 1985; 62: 738-45. lipid arterial vasculopathy. Rheumatol 1989; 16: 762-7. 3 Oddis C V, Eisenbeis C H, Reidbord H E, Steen V D, 12 Rallings P, Exner T, Abraham R. Coronary artery vasculitis Medsger T A. Vasculitis in systemic sclerosis: association and myocardial infarction associated with antiphospho- with Sjogren's syndrome and the CREST syndrome lipid antibodies in a pregnant woman. Aust NZ .7 Med variant. JRheumatol 1987; 14: 942-8. 1989; 19: 347-50. 4 Love P E, Santoro S A. Antiphospholipid antibodies: 13 Reyes E, Alarcon-Segovia D. Leg ulcers in the primary anticardiolipin and the anticoagulant in systemic antiphospholipid syndrome. Report of a case with a lupus erythematosus (SLE) and non-SLE disorders. Ann peculiar proliferative small vessel vasculopathy. Clin Exp Inten Med 1990; 112: 682-98. Rheumatol 1991; 9: 63-6. 5 Seibold J R, Knight P J, Peter J B. Anticardiolipin antibodies 14 Goldberger E, Elder R C, Schwartz R A, Phillips P E. in systemic sclerosis. Arthritis Rheum 1986; 29: 1052-3. Vasculitis in the antiphospholipid syndrome. Arthritis 6 Malia R G, Greaves M, Rowlands L M, et al. Anticardiolipin Rheum 1992; 35: 569-72. antibodies in systemic sclerosis: immunological and 15 Hart F D. Rheumatoid arthritis: extra-articular manifes- clinical associations. Clin Exp Immunol 1988; 73: 456-60. tations. BMJ 1969; 3: 131-6. http://ard.bmj.com/ on September 30, 2021 by guest. Protected copyright.