THE SPONDYLITIS OF INFLAMMATORY BOWEL DISEASE

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1 1359 THE SPONDYLTS OF NFLAMMATORY BOWEL DSEASE Evidence for a Non-HLA Linked Axial Arthropathy ROGER W. ENLOW, WLMA B. BAS, and FRANK C. ARNETT Of 12 patients with inflammatory bowel disease (BD) and ankylosing spondylitis (AS) or sacroiliitis (S), only 4 (33%) had HLA-B27. Family studies revealed 3 B27-negative relatives with AS, 1 with S, 1 with S and BD, and with BD alone. HLA hap lotypes did not segregate with disease. These data suggest a non-hla linked genetic predisposition to BD which also confers susceptibility to spondylitis, even in the absence of expression of bowel disease. The association of inflammatory bowel disease (BD) with arthritis is well recognized. Both Crohn s disease and ulcerative colitis have two clinically defined articular subsets: ) peripheral arthritis alone, characterized by a predominantly asymmetrical, non-deforming large joint pattern with activity corresponding to that of the inflammatory bowel disease process, and 2) axial arthritis, both ankylosing spondylitis and sacroiliitis (AS/ S), with a course seemingly unrelated to that of the bowel lesion (1-3). Familial aggregation has been demonstrated for From the Rheumatology Division and mmunogenetics Laboratory, Department of Medicine, The Johns Hopkins University School of Medicine and Hospital and The Good Samaritan Hospital, Baltimore. Maryland. Supported by OPD/CRC Grant 5MO-RR00722, The Johns Hopkins Multipurpose Arthritis Center Grant -P60AM Roger W. Enlow, MD: nstructor in Medicine, The Johns Hopkins University School of Medicine; Wilma B. Bias, PhD: Associate Professor of Medicine and Associate Professor of Surgery Research and Epidemiology, The Johns Hopkins University School of Medicine; Frank C. Arnett, MD: Associate Professor of Medicine, The Johns Hopkins University School of Medicine, and Clinical Scholar, the Arthritis Foundation. Address reprint requests to Frank C. Amett, MD, The Good Samaritan Hospital, 5601 Loch Raven Blvd. Baltimore, MD Submitted for publication April 23, 1980 accepted in revised form August 4, both inflammatory bowel disease and idiopathic ankylosing spondylitis, suggesting, at least in part, a genetic basis for each separate disorder (4-8). The striking association of HLA-B27 with idiopathic spondylitis seen in of affected individuals provides a marker with which to evaluate other clinically related disorders in families with more than one affected member (9). Although no HLA associations have been convincingly demonstrated for inflammatory bowel disease alone, a definite relationship exists between HLA- B27 and inflammatory bowel disease with spondylitis (10). The strength of this association, however, is clearly less than that for idiopathic spondylitis, raising the possibility of additional genetic or environmental factors which contribute to disease susceptibility and expression. The family studies described here attempted to better elucidate the genetic relationships between inflammatory bowel disease and ankylosing spondylitis or sacroiliitis, especially as they relate to the HLA system. PATENTS AND METHODS Over the period September, 1974 to December 30, 1978, 14 patients with inflammatory bowel disease were referred to one of us (FCA) for evaluation of back pain. All had had barium contrast radiographs and/or bowel biopsy evidence of either Crohn s disease or ulcerative colitis. Clinical and radiographic evaluation of these 14 patients revealed that 2 had sacroiliitis (Grade V by New York criteria) ( 1) and 10 had ankylosing spondylitis. The remaining 2 patients had low back syndromes which seemed inflammatory in character, but their sacroiliac joints were normal by x-ray. AU 14 patients underwent HLA typing at the time of evaluation. A detailed family history was obtained from each patient regarding any relatives also known to have inflammatory bowel disease, symptoms of back pain, or known ankylosing spondylitis. Those who gave a positive family history for ei- Arthritis and Rheumatism, Vol. 23, No. 12 (December 1980)

2 ENLOW ET AL Table 1..Type of axial disease, HLA-B27 status, and positive family histories for back pain or spondylitis in 14 patients with idammatory bowel disease No. BD probands with positive No. Rheumatic diagnosis No. family families in BD probands (no.)* B27+ history studied Ankylosing spondylitis (10) 4 ~~ ~ 4 3 Sacroiliitis (2) Low back pain (normal x-rays) (2) 0 1 Totals (14) BD = inflammatory bowel disease, ther bowel disease or axial skeletal complaints were asked to participate in this family study. An attempt was made to study all first-degree relatives of any patient (designated as the proband) who gave such a positive family history. Pedigrees were extended to include second-degree relatives when the family history indicated back or bowel disease in these relatives. After informed consent was granted, each relative was examined with special attention to musculoskeletal and gastroenterologic symptoms and signs. Laboratory studies included complete blood counts, a Wintrobe erythrocyte sedimentation rate, a latex fixation test for rheumatoid factor, serum antinuclear antibody screening, and HLA typing. n addition, x-rays of the sacroiliac joints (Ferguson views) were obtained on all family members except for those whose recent back x-rays were available for review, asymptomatic minors younger than 18, and young women who might be pregnant. Sacroiliac x-rays were assessed for sacroiliitis by using the New York criteria ( ), and only those with Grade 11 or V changes were considered to have definite sacroiliitis. A diagnosis of ankylosing spondylitis was applied when there was radiographic evidence for inflammatory arthritis of the spine above the sacroiliac joints (12). All radiographs were graded without the examiner s knowledge of pedigree analysis or HLA results. HLA typing for 16 A, 35 B, and 5 C alleles with the Amos modified lymphocytotoxicity dye exclusion test was performed (13). For clarification of an essential haplotype in one family, a series of mixed lymphocyte cultures (MLC) as well as B cell alloantigens (HLA-DRw locus antigens) were studied (14,15). RESULTS Of the 14 patients with inflammatory bowel disease (BD) and back pain, 12 had either sacroiliitis (S) (2 patients) or ankylosing spondylitis (AS) (10 patients), and 2 had normal sacroiliac radiographs (Table ). HLA-B27 was found in 4 of the 10 patients (40%) with BD and AS, but 2 with S and 2 with low back pain and normal sacroiliac x-rays were B27-negative. Thus, of 12 with definite axial inflammatory arthritis and BD, only 4 (33%) had the B27 marker. Family histories were positive for back disease, BD, or both in 6 of these 14 BD patients, including 3 with AS, 2 with S, and 1 with only back pain (Table ). n two of these families with a total of 5 living first-degree relatives, no definite axial inflammatory disease or BD could be found clinically or radiographically. Studies in the remaining four families revealed 5 relatives with definite inflammatory axial arthritis (2 with S and 3 with AS) and 1 with Reiter s syndrome (Table 2). Only 1 of these 6 relatives with spondylarthritis had concomitant bowel disease. An additional relative had BD without arthritis. HLA-B27 was found in only one of these four families (Family 4), occurring in the proband with BD and sacroiliitis and his brother with Reiter s disease. The remaining three families had no B27-positive members, including the 4 relatives with Table 2. HLA-B27 status of 4 informative BD probands and their relatives with spondylitis, BD, or both BD probands, First- and second-degree relatives. Family No. no. HLA-B27 Diagnosis studied Diagnoses HLA-B27 Relation - S 7 AS - Uncle S - Sister S, BD - Sister BD - Nephew AS 5t AS Brother 3 LBP 5 AS Father S 5 RS + Brother BD = inflammatory bowel disease; S = sacroiliitis; AS = ankylosing spondylitis; RS = Reiter s syndrome; LBP = low back pain with normal sacroiliac x-rays. t One sister has seropositive rheumatoid arthritis.

3 SPONDYLTS AND BOWEL DSEASE 1361 ankylosing spondylitis or sacroiliitis who did not have inflammatory bowel disease. The clinical features along with HLA genotypes for the 4 probands and their relatives are detailed in the following case presentations and figures. Family 1. (Figure.) The 52-year-old proband, subject 11-4, has had biopsy proven ulcerative colitis for 20 years. At age 45 he developed pain and stiffness with subsequent fusion of his entire spine. He is B27-negative. His 62-year-old maternal uncle (-3), who is also B27-negative, has had classic ankylosing spondylitis clinically and radiographically for 40 years duration without inflammatory bowel disease. Thirty years ago he had a brief episode of diarrhea which resolved without specific therapy. A recent barium enema and proctoscopy were normal. The proband s 2 sisters both have had symptomatic sacroiliitis, 1 (11-3) with ulcerative colitis and the other (11-2) without BD. The latter s son (111-), nephew of the proband, has had Crohn s disease for 17 years confirmed at laparotomy. His sacroiliac x- rays remain normal despite mild persistent bowel symptoms. Of note, the proband s wife (11-5) and son (111-4) both have HLA-B 13 and psoriasis without arthritis (16). Of particular interest was the occurrence of HLA- B5 in this family including the proband, his 2 affected sisters, and nephew. n the latter (111-), B5 is part of the paternal haplotype A2,B5,Cw4. Because two other B5 containing haplotypes (A 1,B5 and A 1,B5) were defined in the affected sisters and the proband, the possibility that A 1,B5 represented an intra-hla-recombinant between the A and B loci was considered. Though B cell alloantigens (DR types) were defined for several family members, the proband s (11-4) DR typing failed. Mixed lymphocyte culture (MLC) studies, however, demonstrated stimulation of the proband s lymphocytes by irradiated cells from 11-3 but not 11-2, suggesting different D-locus antigens. Thus, in addition to A-locus antigens, these two haplotypes differ at the D-locus as well, making recombination unlikely. n short, the same HLA haplotype did not segregate with disease for the affected members of the family. Family 2. (Figure 2.) n this previously reported family (17), the 53-year-old proband (11-5) has had Crohn s disease since age 41, but back symptoms antedated the onset of her BD by 8 years. She now has bilateral sacroiliitis, a syndesmophyte at L4, and has had one episode of intis. Her 59-year-old brother (11-2) has severe ankylosing spondylitis complicated by the cauda equina syndrome, but no bowel symptoms. Both are B27-negative and have identical HLA haplotypes. Other siblings who are unaffected by either BD or AS/ S share the A2,BS haplotype but not A28,Bw35, which is present in the 2 affected individuals. Of interest, 1 sister (11- ) has seropositive, nodular rheumatoid arthritis. Family 3. (Figure 3.) The 19-year-old proband (11-2) has had Crohn s disease, confirmed at laparotomy, since age 14. He has experienced low back pain, but results of an examination and sacroiliac x-rays were normal. Treatment with prednisone and azulfidine has controlled his BD. His father (1-1) has classic ankylosing spondylitis with complete fusion of lumbar, thoracic, and cervical spine as well as bilateral obliteration of sacroiliac joints. Both are B27-negative, though they share the A 1,B8 haplotype. Of interest, the proband s 17-year-old brother (11-3) also shares the same haplotype and has had significant low back pain but nor A2.85.CW4 A.85 A11.85 A.85 A2.813 DRWS A2,8W49,CW6 AW26.BW38 A3.8W39 X.88 m A2, B5.CW4 A2.8W49.CW6 DRW4 A26.0W30 A,BS A3,8W39 A A2.813 X,B8 Figure 1. Family HLA genotypes. The proband (t). 11-4, has ulcerative colitis and ankylosing spondylitis (AS), while his uncle 1-3. has idiopathic AS without inflammatory bowel disease (BD). Two sisters, 11-2 and 11-3, have sacroiliitis (S), with and without BD. The probands nephew, 111-1, has Crows disease without arthritis. 0 = BD: 0 = AS or S; X = no antigen defined; NS = not studied; t = deceased.

4 1362 ENLOW ET AL A2, B8 A2,B8 A2.812 A28, BW35 A2,B8 A2,B8 A2, 812 A2, 812 A3, BX m A2,B8 A9, 812 Figure 2. Family 2 HLA genotypes. The proband (7) has Crohn s disease and ankylosing spondylitis (AS), while her brother, 11-2, has idiopathic AS. Their sister. 11-1, has seropositive nodular rheumatoid arthritis. 0 = AS or sacroiliitis; X = no antigen defined; NS = not studied; t = deceased. (This figure reprinted with permission of Medicine.) ma1 sacroiliac x-rays. The mother (1-2) has had low back pain, and x-rays demonstrated narrowing and sclerosis of the L5-S intervertebral disc space and osteitis condensans ilii. Both sisters (11-1 and 11-4) were asymptomatic and no x-rays were obtained. Family 4. (Figure 4.) The 35-year-old proband has had Crohn s disease for 16 years and asymptomatic sacroiliitis which was documented in nflammatory bowel disease was confirmed by laparotomy and involved his terminal ileum and caecum. He has also had recurrent iritis and erythema nodosum. His 43- year-old brother has had Reiter s syndrome with low back pain, but no bowel symptoms. Another 37-yearold brother has had back pain with normal sacroiliac joints on x-ray. This is the only family in which HLA- B27 is found and segregates into those who have symptoms and arthritis. DSCUSSON The association of arthritis with inflammatory bowel disease has been investigated periodically since White s observations in 895 (1-3,18-24). Despite the attention, the reasons for this relationship have remained elusive, although genetic factors have been proposed. Ankylosing spondylitis and inflammatory bowel disease both exhibit familial aggregation. Additionally, studies of patients with inflammatory bowel disease, both ulcerative colitis and Crohn s disease, and their families have confirmed the increased prevalence of ax- All, BW40*2,CW3 Al.88 Al, 88 A, 8 W 40.2,C W 3 A CW3 A2,815*2,CW3 A2,BW15-2, CW3 No XRay?3,B7 No XRay Figure 3. hamily 3 HLA genotypes. The proband (t), 11-2, has Crohn s disease with low back pain but normal sacroiliac joints on x-ray His father, 1-1, has ankylosing spondylitis (AS) without inflammatory bowel disease (BD). 0 = BD. 0 = AS or sacroiliitis.

5 SPONDYLTS AND BOWEL DSEASE 1363 n AW31,840 Al, 88 AW26, 827 AW26,827 Al, A29,812, BW22 1 T 2 4 RS & LBP LBP AW31,B40 AW31,840 Al, 88 AW26,827 AW26,827 AW26,827 f Figure 4. Family 4 HLA genotypes. The proband (T), 11-4, has Crohn s disease and sacroiliitis (S), while his brother, -, has Reiter s syndrome (RS) with normal sacroiliac joints on x-ray. Another brother, 11-2, who is also B27-positive, has low back pain with normal sacroiliac joints on x-ray (LBP). NS = not studied. ial arthritis in blood relatives, often asymptomatic and unrecognized. The studies of Macrae and Wright (25) which evaluated 9 1 consecutive probands with ulcerative colitis, 236 blood relatives, and 56 spouses demonstrated spondylitic stigmata in 20% of the male probands, 7.7% of the female probands, 5.1% of the male relatives, 2.6% of the female relatives, and none in the spouses of either sex. n a similar study of 116 probands with Crohn s disease, Haslock (26) noted that 7% had spondylitis and 9% sacroiliitis; an increased prevalence of sacroiliitis was found in blood relatives, 8.3% for first-degree and 1.9% for second-degree relationships. The recognition of the strong HLA-B27 association with idiopathic ankylosing spondylitis by Brewerton et a1 (27) and Schlosstein et a1 (28) provided a genetic marker with which to evaluate clinically similar disorders. This discovery raised important considerations about the role of histocompatibility antigens and disease susceptibility in humans. While HLA-B27 occurs in 85-90% of patients with ankylosing spondylitis, its frequency is lower in those who have spondylitis accompanying inflammatory bowel disease (29). This form of spondylitis is clinically and radiographically indistinguishable from the idiopathic variety, yet it appears to differ genetically. n our series of 12 patients with bowel disease and spondylitis, only 4 (33%) had B27. Other studies have also shown a reduced B27 frequency varying from 50-75% (30,3 1). Furthermore, Crohn s disease and ulcerative colitis without spondylitis have not been found to be associated with B27 or other HLA-A, B, or C locus antigens (32,33). Similarly, idiopathic spondylitis with its striking B27-positivity does not appear to result from occult inflammatory bowel disease. Recent gastroenterologic studies by Meuwissen et a1 failed to detect any subclinical bowel disease in 76 patients with idiopathic ankylosing spondylitis (34). Thus although B27 appears to increase the risk of spondylitis in patients with inflammatory bowel disease, other factors appear inherent to these intestinal diseases which promote axial inflammation. The family studies reported herein examined the intrafamilial relationships between spondylitis, inflammatory bowel disease, and the HLA system in order to elucidate these factors. These families of probands with inflammatory bowel disease and axial symptoms with or without spondylitis were selected on the basis of strong history suggesting axial arthritis in relatives. From three such families (Families 1-3), relatives were found to have sacroiliitis (1 subject) or frank ankylosing spondylitis (3 subjects) in the absence of bowel disease. A fifth relative had both sacroiliitis and ulcerative colitis. HLA-B27 was not present in any of these spondylitic relatives or their respective probands. Only in Family 4 did the proband and his relative with Reiter s disease have B27. The likelihood of!inding four HLA-B27-negative subjects with idiopathic ankylosing spondylitis in a sample of the same size as this study is low. By comparison, the frequency of B27 in our total population of 93 patients with idiopathic spondylitis is 84% (PtO.001; 2 analysis with Yates correction). Thus, the spondylitis in these relatives may relate to a genetic predisposition to bowel disease within these families. Such a genetic predisposition would appear to also confer susceptibility

6 1364 ENLOW ET AL to spondylitis even in the absence of expression of the bowel lesion, since they themselves have no evident bowel disease even after many years of spondylitis. Further analysis of the HLA data in Families 1-3 showed no particular HLA antigen to be common to this group of subjects. A common HLA haplotype was shared by the affected siblings in Family 2 and the father and son in Family 3. Family 1, however, is most informative because of the many affected members in three generations. n this family there is complete dissociation of spondylitis and bowel disease from any HLA haplotype. Thus, it is likely that the proposed genetic predisposition to both inflammatory bowel disease and spondylitis is not HLA linked. Finally, these data suggest that ankylosing spondylitis is a genetically heterogeneous disease. The majority of patients with this disorder have HLA-B27, a genetic marker segregating to affected relatives of such patients. There are, however, other patients with B27- negative spondylitis who have relatives with inflammatory bowel disease. Disease susceptibility in these families does not appear to be HLA-linked. Studies of the families of additional patients with B27-negative ankylosing spondylitis may yield further insight into the pathogenesis of this complex disease. ADDENDUM After completion of these studies, an additional family was found. A 28-year-old white man with B27- negative sacroiliitis was followed by one of the authors (FCA) for the last 5 years. Three years earlier he had been referred to a gastroenterologist for abdominal bloating. Sigmoidoscopy, barium enema, and upper gastrointestinal series with small bowel examination were normal, and his symptoms resolved. n 1979 his 9- year-old son developed severe diarrhea and was found to have ulcerative colitis by the same gastroenterologist. ACKNOWLEDGMENTS The authors wish to thank our colleagues who referred us their patients for this study, especially Drs. Theodore Bayless, Thomas Hendrix, Marshall Bedine, and Stanley Rosen REFERENCES Wright V, Watkinson G: The arthritis of ulcerative colitis. Medicine 38: , 1959 Haslock, Wright V: The musculo-skeletal complications of Crohn s disease. Medicine 52: , 1973 Palumbo PJ, Ward LE, Sauer WG, Scudamore HH: The musculoskeletal manifestations of inflammatory bowel disease. Mayo Clin Proc 48:411416, Kellgren JH: The epidemiology of rheumatic disease. Ann Rheum Dis 23: , Emery AE, Lawrence JS: Genetics of ankylosing spondylitis. J Med Genet 4: , Kirsner JB, Spenser JA: Family occurrences of ulcerative colitis, regional enteritis, and ileocolitis. AM ntern Med 59~ , Moms PJ: Familial ulcerative colitis. Gut 6: , McConnell RB: The Genetics of Gastrointestinal Disorders. London, The Oxford University Press, 1966, pp Woodrow JC: Histocompatibility antigens and rheumatic diseases. Semin Arthritis Rheum 6: , Russell AS: Arthritis, inflammatory bowel disease, and histocompatibility antigens. AM ntern Med 86:82O-82 1, Gofton JP Report from the subcommittee on diagnostic criteria for ankylosing spondylitis in population studies of rheumatic diseases, Proceedings of the 11 nternational Symposium. Edited by PH Bennett, PNH Wood. Amsterdam, Excerpta Medica, 1966, p Kellgren JH: Diagnostic criteria for pepulation studies. Bull Rheum Dis 13: , Amos DB, Bashir H, Boyle W, MacQueen M, Tiilikainen A: A simple micro-cytotoxicity test. Transplantation 7: , Hartzman RJ, Segall M, Bach ML, Bach FH: Histo- compatibility matching. V. Miniaturization of the mixed leukocyte culture test: a preliminary report. Transplantation 11: , van Rood JJ, van Leeuwen A, Ploem JS: Simultaneous detection of two cell populations by two-colour fluorescence and application to the recognition of B-cell determinants. Nature 262(557 1): , Lobitz WC, Civatte J, Thivolet J, Betuel H, Thorsby E: Dermatology, HLA and Disease. Edited by J Dausset, A Svejgaard. Baltimore, Williams and Wilkins Co, 1977, pp Hochberg MC, Bias WB, Arnett FC: Family studies in HLA-B27 associated arthritis. Medicine , White WH: Colitis. Lancet 1537, Steinberg VL, Storey C: Ankylosing spondylitis and chronic inflammatory lesions of the intestines. Br Med J 2: , Ansell BM, Wigley RAD: Arthritic manifestations in regional enteritis. AM Rheum Dis 23:6472, Wilkiison M, Bywaters EGL: Clinical features and course of ankylosing spondylitis. Ann Rheum Dis 17: , McBride JA, King MJ, Baikie AG, Cream GP, Sircus W: Ankylosing spondylitis and chronic inflammatory diseases of the intestines. Br Med J , Jayson M, Bouchier LA Ulcerative colitis with ankylosing spondylitis. AM Rheum Dis 27: , 1968

7 SPONDYLTS AND BOWEL DSEASE Jayson M, Salmon PR, Hamson WJ: nflammatory bowel disease in ankylosing spondylitis. Gut 11: , Macrae, Wright V: A family study of ulcerative colitis with particular reference to ankylosing spondylitis and sacroiliitis. Ann Rheum Dis 32:16-20, Haslock : Arthritis and Crohn s disease: a family study. Ann Rheum Dis 32:479486, Brewerton DA, Hart FD, Nicholls A, CaErey M, James DCO, Sturrock RD: Ankylosing spondylitis and HL-A27. Lancet 1: , Schlosstein L, Terasaki P, Bluestone R, Pearson CM: High association of an HL-A antigen, W27, wih ankylosing spondylitis. N Engl J Med 288: , Morris R, Metzger AL, Bluestone R, Terasaki P: HL-A- W27-a useful discriminator in the arthropathies of inflammatory bowel disease. N Engl J Med 290: , Jacoby RK, Jayson M: HLA-27 in Crohn s disease. AM Rheum Dis 33:422424, Huaux JP, Faisse R, DeBruyere M, Nagant de Deauxchaisnes A: HLA-B27 in regional enteritis with and without ankylosing spondylitis or sacroiliitis. J Rheumatol 4 (Suppl 3):60-63, Mallas EG, Mackintosh P, Asquith P, Cooke WT: Histocompatibility antigens in inflammatory bowel disease: their clinical significance and their association with arthropathy with special reference to HLA-B27. Gut 17(11): , van den Berg-Loonen EM, Dekker-Saeys BJ, Meuwissen SG, Nijenhuis LE, Englefriet CP: Histocompatibility antigens and other genetic markers in ankylosing spondylitis and inflammatory bowel disease. J mmunogenet , Meuwissen SG, Dekker-Saeys BJ, Agenant D, Tytgat GNJ: Ankylosing spondylitis and inflammatory bowel disease.. Prevalence of inflammatory bowel disease in patients suffering from ankylosing spondylitis. Ann Rheum Dis 37:30-41, 1978