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Ann Rheum Dis: first published as 10.1136/ard.46.11.853 on 1 November 1987. Downloaded from

Annals of the Rheumatic Diseases, 1987; 46, 853-858 Concurrence of rheumatoid and systemic erythematosus: report of 11 cases

MICHAEL G COHEN AND JOHN WEBB From the Sydney University Department, The Royal North Shore Hospital of Sydney, St Leonards, NSW 2065, Australia

SUMMARY The concurrence of rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) has been reported infrequently. Eleven patients are described here with both RA and SLE, in whom the diagnoses were separated by one to 24 years. Because of the difficulty in diagnosing RA occurring subsequent to SLE, only patients with classical RA as their initial diagnosis were included. Further difficulties arise because arthritis is common to both diseases and may be deforming in SLE, antinuclear (ANA) are not uncommon in RA, and (RF) may be seen in SLE. Nonetheless, judicious application of the American Association (ARA) criteria allows both diagnoses to be made in the individual patient. In our patients there was erosive arthritis in nine, rheumatoid nodules in five, and urinary abnormalities in 10. Serological evidence of RA and SLE with positive RF and ANA and raised DNA antibodies was universal, all patients had evidence of and all haematological SLE, copyright. but one decreased serum complement levels. These cases suggest that the concurrence of RA and SLE is not as rare as previously considered and may occur more often than expected by chance alone. Key words: overlap syndromes, antinuclear antibodies, rheumatoid factor. Despite the clinical and laboratory similarities of SLE have been defined and updated.4 On the other rheumatoid arthritis (RA) and systemic lupus , the diagnostic criteria of RA5 have remained

erythematosus (SLE) distinction between the two unchanged since 1958 and contain the specific http://ard.bmj.com/ diseases can usually be made, though at times this exclusion of SLE. may be difficult. It might also be expected that some We presently report 11 patients with classical RA patients would have both diseases, but the paucity of who subsequently developed SLE. We believe that such reported instances has led to the suggestion these cases probably underestimate the true preva- that the concurrence of RA and SLE is lence of concurrence of the two diseases in our coincidental.' Were this so, however, about 1% of patient population. We describe these patients to patients with SLE would be expected to have support the notion that RA and SLE may be concurrent RA as this represents the prevalence of concurrent, and to show the diagnostic difficulties on October 1, 2021 by guest. Protected definite or classical RA in most communities.2 If the that may arise. small numbers of published cases truly reflect the prevalence of associated RA and SLE then it would Patients and methods imply that there is a negative association between these diseases.3 Given the clinical and serological All patients attending the rheumatology department overlap between RA and SLE, this seems unlikely, at the Royal North Shore Hospital of Sydney during and thus the apparent under-reporting probably the past 17 years who had the dual diagnoses of RA reflects the difficulty of making both diagnoses in and SLE entered separately or simultaneously were of reviewed. the individual patient. Criteria for the diagnosis The hospital is a secondary referral institution for the lower north shore of Sydney (population Accepted for publication 10 May 1987. Correspondence to Dr Michael G Cohen, Sydney University 160 000) and a tertiary referral centre for the Rheumatology Department, The Royal North Shore Hospital of northern region of New South Wales (population Sydney, St Leonards, NSW 2065, Australia. 800 000). Because of the specialised interest that we 853 Ann Rheum Dis: first published as 10.1136/ard.46.11.853 on 1 November 1987. Downloaded from

854 Cohen, Webb have in SLE, patients having this syndrome are Careful review of the case records was sup- more likely to be referred to us than those having plemented by current clinical evaluation, serology, other rheumatic complaints, including RA. During and radiographs of all surviving patients. All the past 17 years 309 patients have been seen in our serology, during the period reviewed, has been done unit in whom SLE has been diagnosed. in our laboratory without any major changes in Only those who fulfilled the ARA criteria, firstly, technological procedures. Estimation of RF titre for classical RA5 and, subsequently, for SLE4 was by a commercial sensitised sheep cell agglutina- (excluding ) were further studied. Be- tion technique (Rheumaton, Denver Laboratories). cause of the occurrence of nodules,6 rheumatoid Antinuclear (ANA) was detected using rat factor (RF),7 and, rarely, erosions' in SLE we have liver substrate as previously described.9 Native- not included those patients in whom the initial DNA antibody (anti-DNA) was measured as per- diagnosis was SLE. Also, no patient having clinical centage binding in the Farr assay, with the upper or laboratory features (abnormal urine sediment, level of normal being 20%.10 Antibodies to extract- raised levels of DNA antibodies, or hypocom- able nuclear antigens (anti-ENA) were detected by plementaemia) to suggest SLE at the time of counterimmunoelectrophoresis using rabbit thymus diagnosis of RA was included in this study. (Pel Freeze Biologicals, AR, USA) and guinea pig

Table 1 Clinical and laboratory details

Patient No 2 3 4 5 6 7 8 9 10 11 Sex F F F F F F F M F M F Present age (years) 33 45 67 79* 58 57 78* 63 76 73 40 Age of onset: RA 22 34 49 69 31 44 53 40 29 63 19 Age of onset: SLE 27 39 57 73 48 47 77 46 67 64 33 6 I 14 Interval RA-SLE 5 5 8 4 17 3 24 38 copyright. RA criteria 1-5 5 5 5 5 5 5 5 5 5 5 5 6 Nodules + + + + 7 x Ray erosions + + + + + + 8 RFt 128 32 128 2048 2048 512 128 256 128 256 2048 9 + + + + 10 Synovial biopsy + 11 Nodule biopsy Total RA count 8 8 9 8 8 8 8

SLE criteria http://ard.bmj.com/ 1 Malar rash + + + + + + 2 Discoid lupus + 3 Photosensitive + 4 Oral ulcers +~~~~~~~ 5 6 Renal + + + + + -biopsy V III V llA IllB IIA + 7 CNS disease§

8 Haematological on October 1, 2021 by guest. Protected 9 DNA binding (%) 41 47 41 27 36 30 35 26 81 57 47 10 ANAt 2560 2560 2560 1000 2560 200() 256 4000 4000 1000 2560 -patternt H H S S S,R S S S S S H Total SLE count 5 S s 6 6 4 4 s S s 8 Other features Sicca syndrome + + + + + + + + Skin + + ENA antibodies§ SS-A SS-A SS-A SS-A SS-A SS-B SS-B RNP SS-B Complement decreased C4 C4 C3, 4 C3, 4 C4 C4 C4 C4 C4 C4 DIF§ skin-lupus band + + + + + -in vivo ANA + + *Deceased. tReciprocal titre. 1H=homogeneous, S=speckled, R=rim. §CNS=central nervous system, ENA=cxtractable nuclear antigen. DIF=direct immunofluorescence. Ann Rheum Dis: first published as 10.1136/ard.46.11.853 on 1 November 1987. Downloaded from

RA with concurrent SLE 855 kidney (Sigma Chemicals, St Louis, MO, USA) and in eight it was deforming. Among the patients extracts9 and identified by immunodiffusion against with the greatest deformity, a spectrum of mild (Fig. known reference sera in agarose gels. Synovial fluid 1) to marked erosive disease was observed. Of the analysis was by standard techniques. Renal biopsy five patients with rheumatoid nodules, only patient specimens were assessed by light and electron No 11 had biopsy verification. Synovial fluid analy- microscopy and by direct immunofluorescence and sis was performed in six patients and was consistent categonsed according to the WHO classification.'1 with RA in all, including a synovial RF titre equal to Skin biopsy specimens were obtained from unin- or higher than that found in the corresponding sera. volved skin on the inner aspect of the upper arm and Each of the patients had at least seven criteria examined by light microscopy and direct im- (mean eight) and may thus be classified as having munofluorescence . classical RA.

Results CHARACTERISTICS OF SYSTEMIC LUPUS ERYTH EM ATO S U S CLINICAL AND LABORATORY FINDINGS The onset of SLE was most commonly marked by The ages of onset of RA and SLE, the ARA criteria the detection of urinary abnormalities, and seven for the two diseases4 5 fulfilled by each patient, and patients had renal biopsies, all of which were other clinical and laboratory findings are shown in consistent with lupus glomerulonephritis (LGN). Table 1. The mean age of onset of RA was 41-2 Only patients Nos 2 and 3 required cytotoxic years (range 19-69) and that of SLE was 52-5 years therapy for renal involvement. Malar rash was (range 27-77), giving a mean interval between the common, being present in six patients. All patients diagnoses of the two diseases of 11-3 years (range had haematological abnormalities that could not be 1-38). The mean follow up from the diagnosis of ascribed to drug therapy; lymphopenia (<109/1) was SLE has been 8-2 years (range 1-17). present in all, leucopenia (<4x 109A1) in four (patients 1, 3, 5, and 10), thrombocytopenia in copyright. CHARACTERISTICS OF RHEUMATOID patient No 6 (40x 109/l), and four had positive direct ARTHRITIS Coombs' tests (patients 1, 2, 10, and 11). Partial All patients had morning stiffness, joint and thromboplastin times with kaolin were normal in the tenderness, and symmetrical polyarthritis, thus ful- 10 patients in which it was sought. High titre ANA filling critena one to five for RA. Similarly, a positivity and raised anti-DNA were a universal positive RF was detected in all patients and was, finding. The patients had a mean of 5-3 criteria for with the exception of patient No 2, in moderate or SLE, with the exclusion of arthritis. high titre. Erosive arthritis was seen in nine patients As D- is associated with drug related http://ard.bmj.com/

Fig. 1 Patient No 5. There is and obvious deformity on October 1, 2021 by guest. Protected with or dislocation involving several metacarpophalangeal (MCP) , the interphalangealjoint of the left thumb, and the rightfifth proximal interphalangeal (PIP) joint. Relatively minor erosions involve a number ofthe MCP and PIPjoints. Ann Rheum Dis: first published as 10.1136/ard.46.11.853 on 1 November 1987. Downloaded from

856 Cohen, Webb

Fig. 2 Patient No 8. A deep necrotic ulcer is apparent on the lower leg.

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lupus erythematosus and is unique in that it will were given and later stopped over a induce antibodies to double stranded DNA'2 13 we year before the diagnosis of SLE with Sjogren's reviewed the possible relation between D- syndrome. After a further six years,=malabsorptioncopyright. penicillamine and the development of SLE in the with protein losing enteropathy was recorded and two patients that received it. Patient No 1 had oral considered secondary to exocrine pancreatic insuffi- ulceration that preceded the administration of D- ciency and which was demonstrated by penicillamine, and the serological abnormalities rectal biopsy. Whether the pancreatic disease is together with the renal biopsy showing membranous secondary to Sjogren's syndrome or amyloidosis is LGN were found a year after this drug was stopped unknown. Patient No 4 developed a monoclonal owing to lack of efficacy. Patient No 2 developed the IgM x paraproteinaemia one year after the onset of nephrotic syndrome, which was due to membranous SLE and subsequently died of an aggressive im- LGN and settled upon withdrawal of D- munoblastic . Patient No 6 had familial penicillamine, which was not reintroduced. Two IgA deficiency detected when she was evaluated for http://ard.bmj.com/ years later, however, she developed malar rash and RA. She later developed definite dermatomyositis decreasing renal function associated with increased three months before the diagnosis of SLE, and four numbers of urinary casts. Renal biopsy showed a years later developed Hodgkin's disease, which re- focal and segmental proliferative LGN with quired treatment with and from sclerosed glomeruli but no evidence of residual which she is currently in remission. membranous changes. Discussion on October 1, 2021 by guest. Protected OTHER DISEASES AND AUTOIMMUNE FEATURES Reports of the concurrence of adult RA and SLE Other features in our patients included the sicca are rare, with Fischman et al finding only five syndrome in nine and digital vasculitis or vasculitic instances in their review of the published work and leg ulcers (Fig. 2) in four. Anti-ENA were found in contributing a further case.' We could find only two five, their specificities being to SS-A and SS-B in other well documented cases,'5 16 though 10 cases of three, SS-A and RNP in one, and SS-A alone in 'apparent' juvenile rheumatoid arthritis that pro- another. All but one patient had hypocom- gressed to SLE have also been reported.17 plementaemia and only two lacked positive skin To obtain a combined diagnosis of RA and SLE is biopsy direct immunofluorescence findings ('lupus set about by a number of difficulties and therefore band' or in vivo ANA, or both). we elected to include only those patients who first Significant other diseases were noted in three developed classical RA and subsequently SLE. The patients. Four years after the onset of RA patient criteria for RA lack the specifcity to distinguish this No 3 developed definite polymyositis,14 for which disease from many other inflammatory arthritides Ann Rheum Dis: first published as 10.1136/ard.46.11.853 on 1 November 1987. Downloaded from

RA with concurrent SLE 857 which are exclusions to the diagnosis. Further, the RA subsequent to SLE, though it may be argued possibility that 5-23% of patients with SLE may that these are a subgroup of SLE. Thus we believe have a non-erosive, deforming, Jaccoud-type of that the true prevalence of the concurrence of RA arthritis'8 and 21-57% have positive RF7 compli- and SLE in our patient population has been under- cates the distinction. Two of our patients had stated. It seems logical to expect that some patients non-deforming, non-erosive arthritis. The remain- with SLE would subsequently develop RA. Indeed ing nine, however, had erosions, thus precluding this might even be anticipated to be more common a diagnosis of Jaccoud-type arthritis, though in than RA occurring first as the peak age of onset of patients 5 and 10 the erosive changes were dispro- RA is characteristically in the fourth and fifth portionately minor when compared with the degree decades,23 which is a decade older than that of of deformity. Erosive changes are rarely accepted as SLE7. Should an equal number of patients have SLE occurring in SLE,7 8 l though 5-7% may have and then RA, as have the converse, then some 7-2% nodules which, histologically, may be similar to of our SLE patients would be predicted to have rheumatoid nodules.6 Importantly, in these 11 concurrent RA. patients the initial disease was RA, and its features Further difficulty in making the dual diagnoses as exemplified by the classical diagnostic criteria may arise because the conditions that allow the were indistinguishable from those of our other expression of one disease may mask the other. For patients with RA. None had clinical features or example, oestrogens or pregnancy may improve serological evidence of SLE at the time of diagnosis RA24 while worsening or precipitating SLE.25 Simi- of classical RA. larly, it is possible that one disease may modify the It is likely that the diagnosis of SLE can be made other, and the fact that some of our patients either with greater assurance. The 1982 criteria for SLE4 failed to develop erosions or had minor erosive allow this disease to be distinguished from a control changes after several years of RA supports this. group of inflammatory arthritides with a high degree Moreover, these patients may represent a more of confidence. Notably, most of the control group complex subgroup of autoimmune copyright. had RA. When the individual criteria were assessed, disease, with episodes of specific syndromes occur- arthritis was the least discriminatory. Antinuclear ring at separate times or concurrently, as nine antibody (ANA) was also a poor discriminatory patients had coexistent sicca syndrome, two had factor as 51% of the control group and 61% of our definite dermatopolymyositis, and five had anti- own patients with RA were positive.20 Although ENA. In the presence of such a clustering of positive ANA is of little value in distinguishing syndromes it may be difficult to delineate individual between RA and SLE, a negative ANA mitigates diagnoses and instead patients may be classified as strongly against the latter diagnosis. Nonetheless, having a multisystem connective tissue disease.26

the occurrence of LGN, raised anti-DNA, and In conclusion, we believe that the concurrence of http://ard.bmj.com/ hypocomplementaemia, all of which are distinctly RA and SLE is more common than previously uncommon in RA, strongly support the diagnoses suggested. Although it is difficult to correct for of SLE in our patients. selection bias in patient referrals to our hospital, our The mean age of onset of SLE in our patients data, in association with the well described serolo- (52-5 years) reflects our requirement that RA be the gical overlap, support the contention that the two initial diagnosis. Some 12% of patients with SLE diseases do coexist more often than expected by may have their onset of disease in the fifth decade or chance alone. later,2' and such patients usually follow a benign on October 1, 2021 by guest. Protected course with a good prognosis.-' 22 Most of our MGC is in receipt of the Frank G Spurway Scholarship of the patients had mild disease with two deaths in the Arthritis Foundation of Australia. Work done was in part supported by Sutton Rheumatism Research Funds, the Royal mean follow up period of 8-2 years. Although renal North Shore Hospital. We thank Mr R Money for the photography involvement was a feature in eight patients, only two and Ms D Carey for secretarial assistance. required cytotoxic therapy for LGN. This is consis- tent with the previous observation that renal in- volvement tends to be mild in patients with RA and References SLE.' 1 Fischman A S. Abeles M. Zanetti M. Weinstein A. Rothfield N F. The coexistence of rheumatoid arthritis and systemic lupus These 11 patients represent 3-6% of our patients erythematosus: a case report and review of the literature. J with SLE, which is greater than the 1% or less of the Rheutnatol 1981; 8: 405-15. population that would be predicted to have classical 2 Hochberg M C. Adult and juvenile rheumatoid arthritis: RA. We consider that some of our reviewed patients current epidemiologic concepts. Epidemiol Rev, 1981; 3: 27-44. 3 Mawson A R. Are rheumatoid arthritis and systemic lupus with SLE who later developed erosive or nodular erythematosus inversely related diseases? Med Hvpotheses 1985; arthritis, or both, and became seropositive represent 18: 377-86. Ann Rheum Dis: first published as 10.1136/ard.46.11.853 on 1 November 1987. Downloaded from

858 Cohen, Webb

4 Tan E M, Cohen A S. Fries J F. et al. The 1982 revised criteria Mowbrav J. Erosive rheumatoid arthritis co-existing with for the classification of systemic lupus erythematosus. Artblritis systemic lupus erythematosus. A report of a case also showing Rheum 1982; 25: 1271-7. atlanto-axial subluxation. Clini Rlieu(tn(atol 1982; 1: 216-2). S Ropes M W. Bennett G A. Cobb S. Jacox R. Jessar R A. 1958 16 Bresnihan F P. Ansell B M. Rheumatoid arthritis followed bv revision of diagnostic criteria for rheumatoid arthritis. Bull systemic lupus erythematosus. Proc R Soc Med 1975: 68: 596-7. Rheum Dis 1958; 9: 175-6. 17 Ragsdalc C G. Petty R E. Cassidv J T, Sullivan D B. The 6 Dubois E L, Friou G J. Chandor S. Rheumatoid nodules and clinical progrcssion of apparcnt juvenilc rheumatoid arthritis to rheumatoid in systemic lupus erythematosus. systemic lupus erythematosus. J Rheumnatol 1980; 7: 5(-5. JAMA 1972; 220: 515-8. 18 Esdaile J M. Danoff D. Rosenthall L. Gutkowski A. Deform- 7 Lee P, Urowitz M B, Bookman A A M, et al. Systemic lupus ing arthritis in systemic lupus crvthematosus. Anni Rheuin Dis erythematosus. A review of 110 cases with reference to 1981; 40: 124-6. nephritis, the nervous system. infections, aseptic and 19 Labowitz R. Schumacher H R. Articular manifcstations of prognosis. Q J Med 1977; 46: 1-32. systemic lupus crythcmatosus. Annii lInterni Med 1971; 74: 8 Weissman B N, Rappoport A S. Sosman J L. Schur P H. 91 1-21. Radiographic findings in the in patients with systemic 21) Francis H. Kcndrick J. Bcll C. Wcbb J. Rheumatoid arthritis- lupus erythematosus. Radiology 1978; 126: 313-7. a revicw of 2t)4 patients. Aust NZ J Med 1984; 14: 351A. 9 Vivian Wells J, Webb J, Van Deventer M. et al. In vivo 21 Baker S B, Rovira J R. Campion E W. Mills J A. Latc onset anti-nuclear antibodies in epithelial biopsies in SLE and other systemic lupus erythematosus. Ain J Med 1979; 66: 727-32. connective tissue diseases. Clin Exp Immunol 1979; 38: 424-35. 22 Gossat D M. Walls R S. Systemic lupus erythematosus in later 10 Webb J. Whalcy K. Evaluation of the native DNA-binding lifc. Med J Aust 19822; 1: 297-9. assay for DNA antibodies in systemic lupus ervthcmatosus and 23 Buchanan W W. Kcan W F. Articular and systemic manifesta- other connective tissue diseases. Med J Aust 1974; 2: 324-8. tions of rheumatoid arthritis. In: Scott J T. ed. Copemna'sns 11 Appel G B, Silva F G. Pirani C L. Meltzer J 1. Estcs D. Rcnal textbook ofthe rheumnatic diseases. Edinburgh: Churchill Living- involvement in systemic lupus crythematosus (SLE). A study of stone. 1986: 653-71)5. 56 patients emphasizing histologic classification. Medicine 24 Cronin M E. Rheumatic aspects of endocrinopathies. In: (Baltimore) 1978; 57: 371-410. McCarty D J. cd. Arthritis atid allied coniditionts. Philadelphia: 12 Chalmers A. Thompson D, Stein H E. Rcid G. Pattcrson A C. Lca and Fcbiger. 1985: 160)7-23. Systemic lupus erythematosus during pcnicillaminc therapy for 25 Rothficld N. Clinical fcaturcs of systemic lupus crythematosus. rheumatoid arthritis. Anni Inttern Med 1982; 97: 659-63. In: Kellcy W N. Harris E D. Ruddy S. Sledgc C B. eds. 13 Webb J. Pollard K M. Induction of DNA-antibodics bV D- Textbook of rheuwnatolog,. 2nd cd. Philadelphia: Saunders. penicillamine. Clin Exp Rheutnatol 1985; 3: 213-9. 1985: 11)70-97. copyright. 14 Bohan A, Peter J B. Polymyositis and dcrmatomyositis. N Eigl 26 Cohen M G. Ho K K. Wcbb J. Fingcr joint calcinosis followed J Med 1975; 292: 344-7. 41)3-7. by ostcolysis in a paiticnt with multisystcm connectivc tissue 15 Isenberg D A. Tookman A. Whitc A GC. lIoffbrand B 1. discasc and anti-Jo-I antibody. J Rhieumnatol (in prcss). http://ard.bmj.com/ on October 1, 2021 by guest. Protected