Ann Rheum Dis: first published as 10.1136/ard.42.6.640 on 1 December 1983. Downloaded from Annals of the Rheumatic Diseases, 1983, 42, 640-643 HLA B27 related 'unclassifiable' seronegative spondyloarthropathies S. PRAKASH, N. K. MEHRA, S. BHARGAVA, AND A. N. MALAVIYA From the All-India Institute ofMedical Sciences, New Delhi-110029, India SUMMARY Twenty-five patients (22 males and 3 females) are described who had 'unclassifiable' seronegative peripheral arthritis affecting mainly the large joints of the lower limbs with other typical features of spondyloarthropathies such as heel pain, low back pain, and mucosal ulcers. But their disorders could not be diagnosed as any specific spondyloarthropathy such as ankylosing spondylitis, Reiter's disease, etc. The mean age of onset of disease was 21 *4 years and 60 % of them had mono- or oligoarthritis; 60% had arthritis ofonly lower limb joints. Knee, ankle, and hip joints were most commonly involved, often asymmetrically (mean degree of asymmetry = 0.28). Mini- mal radiographic sacroiliitis was present in 4 patients, though 13 had low back pain. HLA B27 antigen was detected in 21 (84%) ofthese patients and only 5 9% of 118 controls (relative risk 83). In addition to these 25 patients there were 4 others whose only symptom was severe bilateral heel pain: 3 of them were positive for HLA B27. copyright. Seronegative polyarthritis is a heterogeneous clinical Materials and methods entity frequently seen in rheumatological practice. The condition in most of the patients may ultimately Consecutive unrelated Indian patients attending the evolve into seropositive erosive rheumatoid arthritis immunology clinic of the All-India Institute of Medi- or into one of the group of diseases collectively iden- cal Sciences Hospital were selected for study. All of tified as seronegative spondyloarthropathies, usually them were seen by 2 of the authors (A.N.M. and S.P.) associated with the genetic marker HLA B27.1-4 and questioned in detail about their joint symptoms, http://ard.bmj.com/ Over the past 5 years this laboratory has been study- heel pain, low back pain or stiffness, mucosal and skin ing the latter group of rheumatic syndromes as seen lesions, symptoms of acute anterior uveitis, conjunc- in the north Indian population.5 6 It was repeatedly tivitis, urethritis, inflammatory bowel disease, and observed that some patients did not fit into any of the venereal exposure. Their past and family histories of well defined rheumatic categories of this broad these disorders were also recorded, and wherever group-namely, classical ankylosing spondylitis, Rei- possible the affected relatives were examined. A ter's disease, psoriatic spondylarthropathy, arthritis thorough physical examination was done, with on September 28, 2021 by guest. Protected of inflammatory bowel disease, and Behcet's syn- special attention to the joints, spine, skin, eyes, drome. Yet their clinical presentation has been so buccal mucosa, and genitalia. uniform that the diagnosis is easy-but of course Tests for rheumatoid factor in sera by a standard without name. To the best of our knowledge this latex agglutination test with the Rheuma-Welcotest entity remains unnamed. kit (Burroughs-Wellcome, UK), postero-anterior Here we report our experience with 29 patients (prone) and oblique (15°) x-rays of the sacroiliac with this clinical entity seen during a prospective joints, and tissue typing for HLA A and B loci an- study of 2 years. In the absence of any recognised tigens employing the NIH 2-stage microlympho- name for the disease these patients were identified as cytotoxicity test7 were done on all the patients. The 'unclassifiable' seronegative spondylarthropathy. clinical diagnosis was made independently of the result of the histocompatibility test. The controls for histocompatibility testing were 118 unrelated Accepted for publication 18 November 1982. Correspondence to Dr A. N. Malaviya, Clinical Immunology Divi- healthy volunteers. sion, Department of Medicine, All-India Institute of Medical The patients who could be given the diagnosis of Sciences, New Delhi-110029, India. the following diseases were excluded: (1) Ankylosing 640 Ann Rheum Dis: first published as 10.1136/ard.42.6.640 on 1 December 1983. Downloaded from HLA B27 related 'unclassifiable' seronegative spondyloarthropathies 641 spondylitis according to the Rome criteria8; (2) Rei- 6- ter's disease-seronegative peripheral arthritis with nonspecific urethritis or dysentery or conjunctivitis or anterior uveitis; (3) psoriatic arthritis as diagnosed or suspected by the presence or past history of characteristic skin lesions or nail pits or involvement of distal interphalangeal joints; (4) inflammatory t 4- bowel disease; (5) Beh,et's syndrome as diagnosed z by the triad of recurrent oral and genital ulcerations w and recurrent iritis. After the exclusion of patients with the above dis- LL eases, most of those included under the group 0 'unclassifiable' seronegative spondyloarthropathy w m had seronegative peripheral arthritis and/or heel pain 2- with the clinical low back following features (1) pain z and/or stiffness with or without minimal sacroiliitis; (2) buccal or genital ulcerations; (3) family history of any of the specific spondyloarthropathies; (4) peripheral arthritis which was to some extent assym- metrical, often oligoarticular, and- 1 mainly affect- 0 ing the lower limbs. The degree of asymmetry of 10 20 30 40 50 peripheral arthritis was calculated as the proportion AGE IN YEARS of joints involved asymmetrically.9 Fig. 1 Age at onset of'unclassifiable' seronegative peripheral arthritis in 25 patients. Results copyright. A total of 133 patients with seronegative spondylo- 3 2 (range 1-22). The number of joints involved was arthropathies were seen: ankylosing spondylitis 51; 1 in 5 patients, 2 in 14, 4 in 1, and more than 4 in 3 Reiter's disease 36; 'unclassifiable' seronegative patients. Weight bearing joints of the lower limbs spondyloarthropathy (SSA) 29; 'inflammatory' low were affected commonly (Fig. 2, Table 1). The mean back pain without x-ray changes of sacroiliitis 11; degree of asymmetry of peripheral arthritis at the ulcerative colitis with arthritis 3; and Beh,et's disease onset of disease was 0-48. 3. Depending on the major presenting manifestations During the course of the disease all the 25 patients the patients with 'unclassifiable' SSA were divided had peripheral arthritis. The average number of http://ard.bmj.com/ into 2 groups: (a) seronegative peripheral arthritis; joints affected was 6*8 (range 1-26). The number of and (b) enthesopathy (Achilles tendonitis). joints involved was 1 in 2 (8%) patients, 2 in 6 (24%), 3 in 5 (20%), 4 in 2 (8%), 5-10 in 5 (20%), (A) 'UNCLASSIFIABLE' SERONEGATIVE and more than 10 in 5 (20%) patients (Fig. 3). The SPON DYLOARTHROPATHY-PERIPHERAL disease affected mainly the lower limb joints (Fig. 2, ARTHRITIS Table 1). Often the arthritis was asymmetrical (the This group included 25 patients-22 males and 3 mean degree of asymmetry was 0.28). females. The mean age of onset of disease was 21-4 Seven of the 25 patients had heel pain over the on September 28, 2021 by guest. Protected years and in 68% of them the disease started in the insertion of the tendo Achillis or os calcaneum, and 3 second and third decades (Fig. 1). The onset of disease was insidious in 13 (52%), subacute in 10 (40 %), and acute in 2 (4 %) cases. The Table 1 Distribution ofperipheral arthritis in patients with first manifestation was peripheral arthritis in 23 'unclassifiable' seronegative spondyloarthropathy patients, bilateral heel pain in one, and low back pain (peripheral arthritis) in one. The average duration of symptoms was 4-7 years (range 3 weeks to 24 years); it was less than 1 At onset (n = 23) During the course year in 7 (28 %), 1 to 5 years in 11 (44 %), 6-10 years ofdisease (n = 25) in 5 (20%), and more than 10 years in 2 (8%) patients. Number Percent Number Percent Peripheral arthritis was the major manifestation in Only upper limbs 3 13-0 0 0 these 25 patients. Twenty-three (92 %) had Only lower limbs 19 82-6 15 60.0 Both upper and peripheral arthritis at the onset aver- of disease. The lower limbs 1 4.4 10 40.0 age number of joints affected in the 23 patients was Ann Rheum Dis: first published as 10.1136/ard.42.6.640 on 1 December 1983. Downloaded from 642 Prakash, Mehra, Bhargava, Malaviya PERIPHERAL KNEE ARTHRITIS MONO -2 ANKLE 1 15 OLIGO 13 HIP 8 POLY 10 HEEL PAIN ~~~~~7 SHOULDER LOW BACK PAIN 1 13 WRIST X- RAY SACROILIITIS MC P 4 E1 AT ONSET M DURING THE COURSE OF DISEASE MOUTH ULCERS " 2 M T P 2 copyright. 0 1 20 30 40 SO 6C P (TOES) PERCENT Fig. 3 Clinical manifestations in 25 patients with 'unclassifiable' seronegative peripheral arthritis. ELBOW 0 3 6 9 12 IS 18 http://ard.bmj.com/ NUMBER OF PATIENJTS Histocompatibility testing results revealed the pre- sence of HLA B27 antigen in 21 (84%) of 25 patients Fig. 2 Pattern ofperipheral joint involvement at the onset and 5 9% of 118 controls with a relative risk of 83*2 (23 patients) and during the course (25 patients) of (corrected Fisher's test, p = 6*55 E-14). None of the 'unclassifiable' seronegative peripheral arthritis. other HLA A or B loci antigens deviated significantly IP = interphalangeal. MCP = metacarpophalangeal. MTP = metatarsophalangeal. from the expected frequency in these patients, though the relative risks were slightly high for some of the other antigens: All, 3-4; AW30, 2-7; A28, on September 28, 2021 by guest. Protected 2-6; BW63, 5-3; BW41, 2-6; B37, 1-7; and BW35, had sole pain (Fig. 3). Though more than half the 1 3. The number of HLA B27 negative patients is so patients (13) had low back pain or stiffness, only 4 of small that their comparison with HLA B27 positive them had radiographic changes of minimal sacro- patients is not justified.