_JMed Genet 1995;32:497-501 497 Review article J Med Genet: first published as 10.1136/jmg.32.7.497 on 1 July 1995. Downloaded from HLA-B27 and spondyloarthropathy: value for early diagnosis?

Jan Tore Gran, Gunnar Husby

The seronegative spondyloarthropathy REACTIVE ARTHRITIS complex Reactive arthritis (ReA) is a term introduced The seronegative spondyloarthropathy com- by Aho et al2 in 1973. It denotes an asym- plex embraces a group of inflammatory rheum- metrical non-infectious arthritis in a few joints, atic disorders linked together by certain clinical, appearing days or weeks after infection else- laboratory, and radiological manifestations. where in the body, most often in the genito- Clinically, the disorders are characterised by urinary or gastrointestinal system. Previously, asymmetrical peripheral oligoarthritis and in- the term postinfectious arthritis was preferred. volvement of the sacroiliac joints (table 1). Manifestations in the eyes, mucocutaneous membranes, and genitourinary system not in- PSORIATIC ARTHRITIS frequently accompany the often predominant The arthritis associated with psoriasis is most arthritis. The patients lack detectable rheum- often localised to a few joints in an asymmetrical atoid factors in serum, hence the term "sero- pattern, frequently affecting the distal in- negative". Other serum autoantibodies, often terphalangeal joints of the hands.3 It oc- found in inflammatory rheumatic diseases, are casionally manifests radiological sacroiliitis, but notably absent in the spondyloarthropathies. complete ankylosis of the spine ("bamboo Unlike in rheumatoid arthritis, radiological spine") is definitely less frequent than in AS. examinations of peripheral joints rarely show Psoriatic arthritis (PsA) may also present a destructive changes. However, radiological clinical picture almost indistinguishable from sacroiliitis is essential for the diagnosis of many

that of rheumatoid arthritis. Although serum http://jmg.bmj.com/ of these diseases. rheumatoid factors are notably absent, this form of psoriatic arthritis affecting peripheral joints bears little resemblance to the other spon- ANKYLOSING SPONDYLITIS dyloarthropathies. Ankylosing spondylitis (AS) is regarded as the prototype of the seronegative spondylo- arthropathies (table 1). In its classic but quite

rare form, complete ankylosis of the whole INFLAMMATORY BOWEL DISEASES on September 23, 2021 by guest. Protected copyright. spine develops within a few years. More often, A seronegative arthritis may also accompany however, the clinical picture is dominated by the inflammatory bowel disorders ulcerative pain and stiffness of the back with radiological colitis and Crohn's disease.4 As in other spon- examination showing sacroiliitis and varying dyloarthropathies, radiological sacroiliitis may degrees of spinal inflammation.' be seen. A striking feature of the seronegative spon- Table 1 The seronegative spondyloarthropathy complex: dyloarthropathies is the association with the disorders, common disease manifestations, and frequencies histocompatibility antigen HLA-B27. of HLA-B27 Disorders % Ankylosing spondylitis 90-95 The association between HLA-B27 and Reiter's disease 70-85 Reactive arthritis 36-100 spondyloarthropathy Psoriatic arthritis 54 The study of products of genes located on a Arthritis in inflammatory bowel diseases 50 Department of region of chromosome 6, known as the major Rheumatology, Aust Manifestations histocompatibility complex, has provided valu- Agder Central Seronegativity for rheumatoid factors able insight into many diseases of as yet un- Hospital, 4800 Absence of antinuclear antibodies known aetiology. In 1973, two independent Arendal, Norway Absence of rheumatic nodules J T Gran groups of workers found a striking association Peripheral arthritis between one of these genes, HLA-B27 and *Oslo Sanitetsforening Genitourinary (urethritis, vaginitis, balanitis) Rheumatism Hospital, Mucocutaneous (stomatitis, dermatitis) AS.56 Subsequently, associations between Oslo, Norway Intestinal (enteric infections or chronic inflammation) HLA-B27 and ReA and PsA were established.78 G Husby Radiological sacroiliitis Why subjects carrying HLA-B27 are prone to Correspondence to: Genetic develop spondyloarthropathy is not fully Dr Gran. (familial aggregation, HLA-B27) understood.9 498 Gran, Husby Table 2 Diagnostic criteria and tentative disease obtained by expressing the test sensitivity. definitions for varzous seronegative spondyloarthropathies Sensitivity is defined as the proportion of New York criteria for ankylosing spondylitis patients with positive test results, and is be- (1) Limitation of motion of the lumbar spine in all three tween 90 and 95% in AS. The specificity of

planes (anterior flexion, lateral flexion, and extension). J Med Genet: first published as 10.1136/jmg.32.7.497 on 1 July 1995. Downloaded from (2) HistQry or the presence of pain at the dorsolumbar the test gives the proportion of healthy subjects junction or in the lumbar spine. with negative test results (HLA-B27 negative). (3) Limitation of chest expansion to 2-5 cm or less, measured With a prevalence of AS of 0 1 %, a population at the level of the fourth intercostal space. frequency of HLA-B27 of 10%, and a sensit- The diagnosis of ankylosing spondylitis requires the presence the of grade 3-4 bilateral sacroiliitis with at least one clinical ivity of 95%, the specificity of HLA-B27 criterion, or grade 3-4 unilateral or grade 2 bilateral with test in AS is 90- 1%. If the prevalence of AS criterion 1 or with both clinical criteria 2 and 3. amounts to 1%, the specificity is 90-8%. Reactive arthritis A seronegative arthritis occurring shortly after infection in the genitourinary or gastrointestinal canal. PREDICTIVE VALUE OF A POSITIVE HLA-B27 TEST Reiter's syndronie indicates the proportion of One or more episodes of urethritis or conjunctivitis in The predictive value connection with seronegative arthritis. HLA-B27 positive AS patients among persons Psonratic spondylitis with HLA-B27. Populations who have a pre- Pain/stiffness of the spine with radiological examination valence of HLA-B27 of 10%, disease pre- showing sacroiliitis/spondylitis in a patient with psoriasis. valences of 0 1 % and 1%, would give predictive Spondylitis in iniflanmnmatory bowel disease values of 0 95% and 9 5%, respectively. These Pain/stiffness of the spine with radiological examination well to the findings in epi- showing sacroiliitis/spondylitis in a patient with either Crohn's figures correspond disease or ulcerative colitis. demiological surveys, in which it has been cal- culated that between 1 and 6% of persons with HLA-B27 suffer from AS.'0 HLA-B27 IN SPONDYLOARTHROPATHIES Approximately 95% of white patients with AS are HLA-B27 positive'0 (table 1). The pre- PREDICTIVE VALUE OF A NEGATIVE HLA-B27 TEST valence of HLA-B27 among patients with ReA This figure gives the proportion of persons appears somewhat less, about 70-85%7 (table without HLA-B27 who are healthy. It can be 1). In PsA, there is a clear association between calculated that the probability of not having HLA-B27 and the group of patients exhibiting AS for a HLA-B27 negative person is about radiological sacroiliitis,8 whereas the frequency 99.9%. of this tissue antigen among cases with sym- metrical polyarthritis resembling rheumatoid arthritis equals that in the general population.8 INTERPRETATIONS OF THE STATISTICAL In the inflammatory bowel disorders, HLA- CALCULATIONS B27 does not confer an increased risk of con- From the above mentioned statistical con- tracting peripheral arthritis,4 but a moderate siderations, it can be concluded that although association between HLA-B27 and spondylitic the HLA-B27 test exhibits both high sensitivity http://jmg.bmj.com/ disease is present.4 and specificity, the test cannot be used to diag- nose AS in randomly selected persons. The predictive value of a positive test which is be- HLA-B27 IN VARIOUS POPULATIONS tween 0 95 and 9-5% indicates that the over- The distribution of HLA-B27 among various whelming majority of HLA-B27 positive ethnic groups appears strikingly uneven.'' persons do not suffer from AS. Thus, HLA- Among certain North American Indians, B27 appears not to be useful as a screening on September 23, 2021 by guest. Protected copyright. Lapps, and inhabitants ofnorthern Scandinavia test for AS among randomly selected persons. the frequency of HLA-B27 ranges from 26 to However, the predictive value of a negative 50%." Most European populations show B27 test result for the absence of AS reaches ex- prevalences between 7 and 10%." In blacks, ceptionally high values. Consequently, the HLA-B27 is virtually absent." chance ofhaving AS for a person without HLA- B27 is extremely low. The HLA-B27 test may therefore possess some value in clinical practice Diagnostic value of HLA-B27 in when dealing with randomly selected persons. spondyloarthropathy A negative test result should be interpreted as DEFINITE DIAGNOSES an exclusion criterion for the diagnosis of AS. The diagnostic criteria and tentative definitions However, this is unrealistic as there is no reason of various seronegative spondyloarthropathies to test for HLA-B27 in randomly selected per- are given in table 2. Clearly, none ofthe diseases sons. The HLA-B27 test should always be under consideration requires a positive HLA- performed after clinical suspicion of sero- B27 test for a definite diagnosis. All diagnoses negative spondyloarthropathy has been evoked. are based on the appearance of certain clinical Thus, the discussion of the potential use of signs and symptoms, and for AS the de- this test is reserved for cases presenting with monstration of radiological sacroiliitis is man- symptoms and signs suggestive of seronegative datory for diagnosis.'2 spondyloarthropathy.

SENSITIVITY AND SPECIFICITY PRETEST LIKELIHOOD The diagnostic value of the HLA-B27 test In epidemiological surveys it has been found for AS in a randomly selected person can be that the prevalence of AS among HLA-B27 HLA-B27 and spondyloarthropathy: value for early diagnosis? 499

positive persons with back pain or stiffness is probands, should be re-evaluated. Until the as high as 22-5%. ' This figure clearly contrasts aetiology of AS has been described, these sug- the estimate of a 1 to 6% prevalence of AS gestions cannot be proven nor refuted. among a random sample ofB27 positive people. However, the eventual clinical usefulness of Thus, selecting people with back pain and expanding the diagnostic net of spondylo- J Med Genet: first published as 10.1136/jmg.32.7.497 on 1 July 1995. Downloaded from stiffness for B27 testing increases the likelihood arthropathies may be disputed. Evidently, no of finding AS. effective prophylaxis is available for either the However, more than 75% of cases with back classical spondyloarthropathies or for the pain and stiffness suffer from diseases other "new" group of spondylitics. Thus, adding a than AS. Thus, the pretest likelihood must new group of patients to the already existing be increased further to meet the cost-benefit cases of AS does not help to solve the primary demands. It has been calculated'3 that for a task of medicine, to prevent disease de- positive HLA-B27 test to provide an acceptable velopment. 95% chance that the diagnosis is correct, the Moreover, we do not know the effect of physician must be more than 50% certain of therapy on these new syndromes. To diagnose the diagnosis before the test is performed. Un- "spondylitic disease" for the benefit of early fortunately, the many attempts at constructing therapy, whether physical therapy or ad- useful clinical diagnostic criteria for AS in- ministration of drugs, does not seem justified. dependent of radiological examination have Furthermore, whether or not undifferentiated all been unsuccessful.'415 At present it seems spondyloarthropathy in due time will lead to difficult to diagnose AS clinically with a 50% restricted mobility of the spine and chest as chance of correct diagnosis. Consequently, seen in AS is not yet known, so the purpose of HLA-B27 does not appear helpful in differ- physical therapy directed at increasing spinal entiating spondyloarthropathies meeting tra- mobility appears limited. ditional definitions from other causes of back Finally, another important problem is ad- complaints. equate patient information. At present, the possible risk of developing disease com- plications, such as cardiac conduction dis- THE CONCEPT OF UNDIFFERENTIATED turbances, dislocations of the upper cervical SPONDYLOARTHROPATHY AND SPONDYLITIC spine, and renal amyloidosis has not been stud- DISEASE ied properly. Thus, defining a new group of It has been suggested recently that the tra- spondylitics creates the problem of offering ditional clinical view on diagnosing seroneg- adequate patient information regarding disease ative spondyloarthropathies should be broad- outcome. However, the concept of a wider ened.'6 Some workers have suggested that spectrum of HLA-B27 associated spon- AS may manifest with clinical symptoms of dyloarthropathy is intriguing and the cases inflammatory back pain but without the radio- under consideration should be subjected to follow up and further clinical logical features of classical AS.'6 In family stud- research based http://jmg.bmj.com/ ies this clinical picture appears significantly and laboratory analyses. associated with HLA-B27. It has been found It should also be stressed that the new cri- that between 13 and 18% of B27 positive first teria'7 were primarily meant to serve as clas- degree relatives of B27 positive cases express sification criteria and not as a diagnostic aid in clinical symptoms of inflammatory spinal dis- everyday clinical practice. Unfortunately, ease without concomitant radiological signs of classification criteria are often confused with the disease. The clinical picture has been en- diagnostic criteria and the confusion is not titled "spondylitic disease".'6 infrequently enhanced by the general ac- on September 23, 2021 by guest. Protected copyright. A new set of classification criteria for spon- cessibility of the HLA-B27 test. Therefore, it dyloarthropathies has also been suggested'7 seems necessary to review the individual clinical (table 3). According to these criteria, a diag- syndromes of the seronegative spondylo- nosis of undifferentiated spondyloarthropathy arthropathy complex and their associations is preferred in patients who complain of in- with HLA-B27. flammatory spinal pain or synovitis and in ad- dition have psoriasis, inflammatory bowel disease, positive familial history, or en- VALUE OF THE B27 TEST IN PATIENTS WITH thesopathy. 17 ASYMMETRICAL PERIPHERAL OLIGOARTHRITIS If the concept of AS is broadened to include The presence of asymmetrical peripheral arth- such clinical pictures, the value of HLA-B27 ritis in a few joints may raise the suspicion testing, especially in first degree relatives ofAS of either psoriatic arthritis (PsA) or reactive arthritis (ReA). In young and middle aged patients with an Table 3 European Spondylarthropathy Study Group (ESSG) preliminary classification criteria for *acute onset of oligoarthritis in the absence of spondyloarthropathies psoriasis, ReA is a likely diagnosis. A definite diagnosis is based on the findings of serological Inflammatory spinal pain or synovitis Asymmetrical or microbiological evidence of genitourinary or Predominantly in the lower limb gastrointestinal infection antedating the arth- And one of the following ritis. As the prevalence of HLA-B27 among Positive family history cases with ReA is lower than in AS, the pre- Psoriasis Inflammatory bowel disease dictive value of both a positive and a negative Alternate buttock pain test is less when compared to AS. Although Enthesopathy the presence of HLA-B27 may increase the 500 Gran, Husby suspicion of ReA, it remains unhelpful as an so significant that HLA-B27 typing based on aid to diagnosis. the assumption of clinical spondylitic disease In PsA, the association between spondylitis is not justified. and HLA-B27 is less pronounced than that of AS and ReA.8 At most, the frequency of HLA- J Med Genet: first published as 10.1136/jmg.32.7.497 on 1 July 1995. Downloaded from B27 in psoriatic spondylitis is about 50%.8 HLA-B27 AS A CONFIRMATORY TEST IN AS Consequently, the predictive diagnostic value The diagnosis ofAS rests on the demonstration of the HLA-B27 test in psoriatic spondylitis of radiological sacroiliitis in patients having does not meet the demands ofclinical medicine. pain or stiffness ofthe back. The demonstration of a negative HLA-B27 test in such cases will not alter the diagnosis. The absence of HLA- THE VALUE OF HLA-B27 IN JUVENILE CHRONIC B27 in a patient with AS should, however, alert ARTHRITIS the physician to the possibility of concurrent In contrast to adult AS, juvenile AS less fre- psoriasis or inflammatory bowel disease. There quently causes symptoms of axial skeleton dis- are undoubtedly, however, true cases of HLA- ease at onset.'8 Perhaps as few as 24% ofchildren B27 negative cases of AS.showing no signs of complain of pain and stiffness of the lumbar concurrent dermatological or intestinal disease. spine.'8 Instead, manifestations from the peri- pheral joints often dominate the initial clinical picture. The association between juvenile AS and HLA-B27 AND PROGNOSIS IN AS HLA-B27 is, however, as strong as that in adult Apart from a higher prevalence ofAAU in B27 disease.'8 In patients with established juvenile positive subjects compared to B27 negative chronic arthritis a positive HLA-B27 test can be cases, the clinical picture appears similar in of help in focusing the diagnosis towards de- B27 positive and B27 negative AS.22 As more velopment of AS later on. However, the test than 90% of AS patients carry B27, and only shows the same limitations as in adult AS, and 25% contract AAU, tissue typing is of no help cannot be regarded as ofdiagnostic value. in selecting those cases that are prone to de- velop eye complications.

THE VALUE OF HLA-B27 IN ACUTE UVEITIS It has been found that the prevalence of HLA- Conclusions B27 is increased to about 50% in acute anterior HLA-B27 is essential to the aetiopathogenesis uveitis (AAU),'9 and that between 15 and 25% of spondyloarthropathies. This statement has of the patients have clinical and radiographic been so widely accepted that the term "HLA- evidence of AS.'9 Thus, even in the absence of B27 associated disease" is sometimes used to concomitant AS, AAU seems to be associated replace "the seronegative spondyloarthropathy with HLA-B27, and the test appears to be of complex" introduced by Moll et al.21 However, limited value in diagnosing coexisting AS. for the practising physician it is important to Patients with AAU should not undergo rou- bear in mind that only a minority of HLA-B27 http://jmg.bmj.com/ tine rheumatological examinations. Only those positive subjects contract a "B27 associated cases with AAU who report significant stiffness disease" and that the overwhelming majority or pain of the back or peripheral joints should of patients with musculoskeletal complaints do be referred to a rheumatologist for further ex- not suffer from inflammatory rheumatic dis- amination. ease. These two simple facts should serve as guidelines to the use of the HLA-B27 test in everyday clinical practice. on September 23, 2021 by guest. Protected copyright. SCREENING FOR HLA-B27 IN FAMILIES OF AS It is our conviction that the benefit of the PROBANDS HLA-B27 test is very limited. The test cannot As HLA-B27 is inherited in a codominant be used for confirming a diagnosis of spon- fashion, the prevalence of HLA-B27 among dyloarthropathy or predicting the prognosis in first degree family members will be in the order patients with an established diagnosis of in- of 25 to 100%, depending on homozygosity flammatory rheumatic disease. The test can be and HLA status of the mate. The prevalence used in three ways. of AS among first degree relatives of AS prob- First, if the likelihood of spondylo- ands has been estimated as 1-3 to 11%.2021 arthropathy based on symptoms and signs is Consequently, only a small proportion ofHLA- greater than 50%, a B27 positive test result B27 positive probands will develop AS as de- significantly increases the chance of a correct fined by traditional diagnostic criteria. More- diagnosis. Such a high pretest likelihood, how- over, as no prophylaxis is available to prevent ever, requires reliable clinical diagnostic criteria the development of AS, there is no cause for which are not readily available in rheumatology. routine testing of HLA-B27 among family It is, however, our hope that such criteria will members. The determination of HLA-B27 in be developed in the near future. first degree relatives of AS probands will only Secondly, in patients with back pain and increase the risk of introducing "iatrogenic stiffness, a negative B27 test result very strongly HLA-B27-itis". indicates that the complaints are caused by As discussed earlier, clinical spondylitic dis- diseases other than AS. In the absence of con- ease is suggested to occur quite frequently current psoriasis or inflammatory bowel dis- among HLA-B27 positive family members of ease, a negative B27 test result virtually AS probands.'6 It is the authors' opinion that excludes a diagnosis of AS, provided the test the prbblems associated with this diagnosis are is properly done. HLA-B27 and spondyloarthropathy: value for early diagnosis? 501

10 Gran JT, Husby G, Hordvik M. Prevalence of ankylosing Thirdly, a positive B27 test in children with spondylitis in males and females in a young middle-aged established inflammatory joint disease may help population in Troms0, northern Norway. Ann Rheum Dis 1985;44:359-67. the physician focus on a possible development 11 Gran JT, Husby G. The epidemiology of ankylosing spon- of seronegative spondyloarthropathy. dylitis. Semin Arthritis Rheum 1993;22:319-34.

12 Moll JMH, Wright V. New York clinical criteria for an- J Med Genet: first published as 10.1136/jmg.32.7.497 on 1 July 1995. Downloaded from Today's increasing demands for an effective kylosing spondylitis. Ann Rheum Dis 1973;32:354-63. and rationalised health system do not allow 13 Hawkins BR, Dawkins RL, Christiansen FT, Zilko PJ. Use of the B27 test in the diagnosis of ankylosing spondylitis: uncritical use of expensive laboratory tests. a statistical evaluation. Arthritis Rheum 1981;24:743-6. The results of such tests may at worst lead to 14 Gran JT. An epidemiological survey of the signs and symp- toms of ankylosing spondylitis. Clin Rheumatol 1985;4: incorrect diagnoses and initiation oftherapeutic 161-9. strategies of virtually no benefit to the patients. 15 Baron M, Zeidel I. HLA-B27 testing in ankylosing spon- dylitis: an analysis of pretest assumptions. _7 Rheumatol 1989;16:631-6. 16 Khan MA, van der Linden SM, Kushner I, Valkenburg HA, 1 Gran JT, Husby G. Ankylosing spondylitis: a comparative Cats A. Spondylitic disease without radiologic evidence study of patients in an epidemiological survey and those of sacroiliitis in relatives of HLA-B27 positive ankylosing admitted to a department of rheumatology. .7 Rheumatol spondylitis patients. Arthritis Rheum 1985;28:40-3. 1984;11:788-93. 17 Khan MA, van der Linden SM. Ankylosing spondylitis and 2 Aho K, Ahvonen P, Lassus A, Sievers K, Tiilikainen A. other spondyloarthropathies. Rheunz Dis Clin North Am HLA antigen 27 and reactive arthritis. Lancet 1973; ii: 1990;16:551-79. 157. 18 Cassidy JT, Petty RE. Spondyloarthropathy. In: Cassidy JT, 3 Wright V. Arthropathia psoriatica. A clinical entity? Scand Petty RE, eds. Textbook ofpediatric rheumatology. 2nd ed. .7 Rheumatol 1980;suppl 32:25-30. New York: Churchill Livingstone, 1990:221-59. 4 Gran JT, Husby G. Joint manifestations in gastrointestinal 19 Brewerton DA, Webley M, Murphy AH, Ward AM. The diseases. Dig Dis 1992;10:274-94. alpha-1-antitrypsin phenotype MZ in acute anterior uve- 5 Brewerton DA, Hart FD, Nicholls A, Caffrey M, James itis. Lancet 1978;i:1103. DCO, Sturrock RD. Ankylosing spondylitis and HL-A27. 20 Rogoff B, Freyberg RH. The familial incidence of rheum- Lancet 1973;i:904-7. atoid spondylitis. Ann Rheum Dis 1949;8:139-42. 6 Schlosstein L, Terasaki PI, Bluestone R, Pearson CM. High 21 van der Linden SM, Valkenburg HA, de Jongh BM, Cats association of an HL-A antigen, w27, with ankylosing A. The risk of developing ankylosing spondylitis in HLA- spondylitis. N Engl J7 Med 1973;288:704-6. B27 positive individuals. Arthritis Rheum 1984;27:241-9. 7 Calin A. Reiter's syndrome: epidemiology and im- 22 Linssen A, Feltkamp TEW. B27 positive diseases versus munogenetics. ScandJ Rheumatol 1980;suppl 32:178-83. B27 negative diseases. Ann Rheum Dis 1988;47:431-9. 8 Scarpa R, Oriente P, Pucino A. The clinical spectrum of 23 Moll JM, Haslock I, Macrae IF, Wright V. Associations psoriatic spondylitis. Br _7 Rheumatol 1988;27: 133-7. between ankylosing spondylitis, psoriatic arthritis, Reiter's 9 Khan MA. Spondyloarthropathies. Curr Opin Rheumatol disease, the intestinal arthropathies and Behcet's syn- 1993;5:405-7. drome. Medicine (Baltimore) 1974;53:343-64. http://jmg.bmj.com/ on September 23, 2021 by guest. Protected copyright.