A SERIAL STUDY OF ANTICARDIOLIPIN ANTIBODY AND ANTIMITOCHONDRIAL ANTIBODY TYPE M5 IN A PATIENT WITH POLYARTHRITIS AND POLYMYOSITIS

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1 British Journal of Rheumatology 1989;28: CASE REPORT A SERIAL STUDY OF ANTICARDIOLIPIN ANTIBODY AND ANTIMITOCHONDRIAL ANTIBODY TYPE M5 IN A PATIENT WITH POLYARTHRITIS AND POLYMYOSITIS By A. KEANE', R. WOODSf, D. FOLEY-NOLAN*, D. RODEN*, R. COUGHLAN* AND C. BARRY* * Department of Rheumatology and 1Department of Immunology, Mater Misericordiae Hospital, Dublin 7, Eire SUMMARY A 22-year-old female presented with polyarthritis and subsequent polymyositis. Initially, she had moderately high levels of anticardiolipin (acl) and antimitochondrial antibody (AMA) type M5. Following corticosteroid therapy, the anticardiolipin antibody rapidly fell to background levels but reappeared with the onset of two significant clinical events. KEY WORDS: Anticardiolipin antibody, Antimitochondrial antibody, Polymyositis. THERE have been previous reports of patients with connective tissue disease and antimitochondrial antibody (AMA) type M5 with and without anticardiolipin antibodies (acl). We document here a young woman with arthritis, polymyositis and the presence of both AMA type M5 and acl. CASE REPORT A 22-year-old female presented with a 1-year history of polyarthritis. She was 6 weeks post partum. This was her first pregnancy which was uncomplicated apart for a flare in her arthritis during the first and last trimester. During the antenatal period, she had a false positive VDRL test. Physical examination revealed an acute arthritis involving the right shoulder and wrist and a flexion contracture of the left elbow. There was no evidence of any skin rash or Raynaud's phenomenon. The following laboratory investigations were normal: full blood count, platelets, urea, electrolytes, creatinine, liver and muscle enzymes, rheumatoid factor and electromyography (EMG). The erythrocyte sedimentation rate (ESR) was 51 mm/h (normal less than 20) and C-reactive protein (CRP) was 0.7 mg/dl (normal less than 0.6). An autoantibody screen by indirect immunoflorescence using rat liver, kidney and stomach substrates was negative for antinuclear factor (ANF) but positive for anti- Received 25 February; revised edition accepted 5 June Correspondence to Dr. C. Barry. 158 mitochondrial antibody (AMA), 1:320 titre (normal less than 40). Subsequent testing for AMA pattern using Bio Dx (Lambourn House, Malvern Wells, Worcs.) rat kidney substrate slides identified this AMA as type M5. The immunoglobulins were measured by rate nephelometry: IgG 2200 mg/dl (normal ), IgM 477 mg/dl (normal ). IgA was within the normal range. Radiological assessment confirmed an inflammatory arthropathy with erosions in the right shoulder joint. The patient was treated with naproxen and physiotherapy. Six weeks after presentation, her ESR remained elevated and arthritis moderately active. Further immunological parameters were measured at this stage: anticardiolipin antibody (acl) by ELISA [1] which was positive; IgG 1:320 titre; IgM 1:80 titre; IgA 1:40 titre (normal less than 40). The VDRL test was repeated and was positive with a negative Treponema pallidum haemagglutinin test and fluorescent Treponema antibody test. The prothrombin time and activated partial thromboplastin time were normal with no evidence of the lupus anticoagulant. A full blood count including platelets and CRP were within the normal range. A direct Coombs' test was positive (IgG, C3d) and cold agglutinins were present with an anti-pi specificity. On week 14, there was an abrupt deterioration in the patient's arthritis and the development of proximal muscle weakness involving the shoulder girdle. Repeated muscle enzymes and EMG were normal. Pulmonary function tests were also normal. A muscle biopsy showed focal

2 KEANE ETAL.: ANTICARDIOLIPIN AND ANTIMITOCHONDRIAL ANTIBODY 159 FIG. 1. Serial study of acl (ACA), AMA, ESR and CRP levels during therapy with prednisolone. *Prednisolone (mg). necrotic muscle fibres with an associated lymphocitic inflammatory infiltrate but with no vascular necrosis identifiable. These changes were those of polymyositis. Further immunological tests were carried out at this time: extractable nuclear antigen antibody determined by counterelectrophoresis using rabbit thymus extract for anti-rnp, anti-sm and La (SS-B) antibodies were negative. Human spleen extract was used as antigen source for anti-ro (SS-A) antibodies. This test was positive at 1:40 titre (normal less than 4) and identified using Centre for Disease Control (Atlanta, Georgia, USA) reference sera. Anti- DNA antibody was negative using a radioimmunoassay kit supplied by Amersham International (Amersham, Bucks.). Treatment was commenced with prednisolone 50 mg/day. This produced a dramatic clinical improvement which has persisted. The patient's subsequent haematological (ESR and CRP) and immunological (acl and AMA) results are shown in Fig. 1. Prednisolone treatment brought about a fall in acl and ESR with no change in AMA levels. There were two subsequent acl peaks; IgG 1:40 titre, associated with a synovitis of her elbow at week 27 and a respiratory tract infection at week 76. The CRP level increased at this time with a subsequent rise in ESR values at week 80. The AMA titre fell to near background levels with increased prednisolone, only to rise again to pretreatment levels as prednisolone was reduced. DISCUSSION A report describing patients with collagen vascular disease and AMA type M5 antibodies [2] suggested these may characterize a group of patients with symptoms suggestive of SLE with some of the more prominent findings absent. Cold agglutinins were present in the majority of these patients and AMA activity was removed by cardiolipin absorption in the patients studied, suggesting cross-reactivity between acl and

3 160 BRITISH JOURNAL OF RHEUMATOLOGY VOL. XXVIII NO. 2 AMA. Although we did not test our patient's sera for such cross-reactivity, our monitoring of acl and AMA shows these antibodies were behaving independently. More recently a report of six patients positive for acl and AMA [3] whose sera were absorbed with cardiolipin micelles, described removal of the acl activity but not the AMA activity. This study suggested that the AMA type M5 antigen is different from the cardiolipin antigen and that the AMA titre was not related to the ag titre of the IgG class. These patients had clinical and biological symptoms of thrombosis (three cases), haemolytic anaemia (one case) and thrombocytopenia (four cases) with all patients' ANF tests negative. In our patient, there was no clinical evidence of an autoimmune haemolytic anaemia, thrombocytopenia, thrombosis, ANA negative anti-ro antibody positive SLE, or Sjogren's syndrome. During the 80 weeks of our study period acl and AMA titres acted independently. The acl rapidly returned to background levels within 5 days after treatment with high dose steroids with no concomitant fall in AMA. The relationship of acl titres to disease activity agrees with our observations in a group of 90 patients with RA [1] and Fort's findings in a prospective study of patients with RA [4], but conflicts with the observations in a group of SLE patients treated with steroids where variable effects on acl titres were noted [5]. The fall in acl within 5 days suggests effects on metabolism and/or tissue fixation of the acl rather than an effect on acl synthesis. Vaarala et al. [6] also reported that acl disappeared more rapidly than specific viral antibody after acute viral infection. In conclusion, we describe a patient with an overlap connective tissue syndrome of polyarthritis/polymyositis with an elevated acl titre responsive to steroid treatment within 5 days of its commencement. The fall in acl titre was associated with a marked clinical improvement. Levels of acl were found to vary independently of AMA levels. The other serological markers detected were anti-ro (SS-A) antibody, cold agglutinins, and a direct positive Coombs' test which were not serially monitored. These markers have also been reported in other 'overlap' connective tissues diseases [2, 3, 7]. The acl findings are in agreement with recently published work on these antibody levels in RA [1, 4] and in conflict with observations in SLE patients [5] probably reflecting acl heterogeneity. Our patient remains well without disease suppressive treatment. Further correlative studies are, however, needed to clarify the role of acl in collagen vascular diseases. ACKNOWLEDGEMENTS We wish to thank Paula Shyne for typing the manuscript, Evelyn O'Keeffe and George Scully for their expert help in preparing the illustrations. This study was financially supported by the Mater College Research Fund. REFERENCES 1. Keane A, Woods R, Dowding V, Roden D, Barry C. Anticardiolipin antibodies in rheumatoid arthritis. Br J Rheumatol 1987;26: Norberg R, Gardlund B, Thorstensson R, Lidman K. Further immunological studies of sera containing antimitochondrial antibodies, type M5. Clin Exp Immunol 1984; 58: Meyer O, Abuaf N, Cyna L, Homberg JC, Khan MF, Ryckewaert A. Antimitochondrial type 5 antibodies and anticardiolipin antibodies in systemic lupus erythematosus and autoimmune disease. Clin Exp Immunol 1987; 69: Fort JG, Cowchock FS, Abruzzo JL, Smith JB. Anticardiolipin antibodies in patients with rheumatic diseases. Arthritis Rheum 1987; 30: Derksen RHWM, Biesma D, Bouma BN, Meyling-Ghelig FHJ, Kater L. Discordant effects of prednisolone on anticardiolipin antibodies and the lupus anticoagulant. Arthritis Rheum 1986;29: Vaarala O, Palosvo T, Kleemola M, Aho K. Anticardiolipin response in acute infections. Clin Immunol Immunopathol 1986;41: Bernstein RM, Mathews MB. Autoantibodies to intracellular antigens with particular reference to transfer RNA and related proteins in myoshis. J Rheumatol 1987;14(Suppl l3):83-8.

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