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• Response to Drs Healy and Helliwell
  Martin Rudwaleit
  Published on: 14 November 2005
• HLA B27 is not an appropriate screening tool for spondyloarthropathy
  Paul J Healy
  Published on: 9 August 2005

• Published on: 14 November 2005

  Response to Drs Healy and Helliwell

  • Martin Rudwaleit, Rheumatology
  • Other Contributors:
    • Joachim Sieper

  Dear Editor

  Our referral recommendations (1) for axial spondyloarthritis (SpA) that includes ankylosing spondylitis (AS) and early preradiographic forms of axial SpA were based on feasibility, costs, and effectiveness. Two screening parameters have been proposed: inflammatory back pain (IBP) and HLA-B27. According to data presented in an earlier publication (2) we assumed for IBP a sensitivity of 75% and a specific...

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  Dear Editor

  Our referral recommendations (1) for axial spondyloarthritis (SpA) that includes ankylosing spondylitis (AS) and early preradiographic forms of axial SpA were based on feasibility, costs, and effectiveness. Two screening parameters have been proposed: inflammatory back pain (IBP) and HLA-B27. According to data presented in an earlier publication (2) we assumed for IBP a sensitivity of 75% and a specificity of 76%, and for HLA -B27 a sensitivity of 90% and a specificity of 90%, resulting in positive likelihood ratios (LR+) of about 3 and 9, respectively. We are well aware that the figures for HLA-B27 will be somewhat different in Non-White/Non- Caucasian populations (discussed in ref. 2). Based on these figures and assuming a prevalence of about 5% of axial SpA among chronic back pain sufferers (3), a positive history of inflammatory back pain would give a posttest probability of axial SpA of about 14-16% whereas a positive test for HLA-B27 would yield a posttest probability of around 32% (2). Accordingly, 1 out of 7 patients with a history of IBP and 1 out of 3 chronic back pain patients who are HLA-B27 positive can be expected to have axial SpA.

  Drs Healy and Helliwell now question the diagnostic value of HLA-B27 if appropriate controls that is patients with chronic back pain of origin other than AS/SpA were considered, and refer to 3 studies (4-6). Two (4, 5) of the 3 studies, however, do not have the appropriate study design and, therefore, are not valid in this context. In the study by Mau et al. (4) no back pain controls were included at the start of the study. Rather, patients highly suspected to have AS based on HLA-B27 positivity (overall 76% of patients suspected to have AS were HLA-B27 positive), presence of IBP, and other clinical features of SpA but without radiographic sacroiliitis were included. After 5 and 10 years, the frequency of radiographic sacroiliitis rose to 36% and 59%, respectively. Among the patients classified as AS after 10 years 91% were HLA-B27 positive (confirming the proposed sensitivity of 90% for HLA-B27) whereas among the 12 patients who had other diagnosis after 10 years, 4 patients (33%) were HLA-B27 positive. However, these 12 patients were initially included as probably having SpA based on the presence of HLA-B27 and/or IBP, for example, and therefore, cannot be considered as an appropriate control group of patients with back pain of other origin (4). A second study (5) referred to by Drs Healy and Helliwell is also invalid in using the data as an argument against the diagnostic value of HLA-B27 in patients with chronic back pain. In this study conducted by Braun et al. (5) the frequency of clinical disease in blood donors stratified for the status of HLA-B27 was assessed. Thus, the starting point was the HLA-B27 status (positive or negative) in blood donors and not patients with chronic back pain - a fundamental difference. Altogether, neither the study by Mau et al. (4) nor the study by Braun et al. (5) can tell us the frequency of HLA -B27 in patients with mechanical low back pain nor do these two studies provide appropriate control groups.

  The study by Sadowska-Wróblenska et al. from Poland (6) Drs Healy and Helliwell refer to is the only study which may allow to calculate the diagnostic value of HLA-B27. In this study, the frequency of HLA-B27 was 83% among 70 patients with early AS (sensitivity 83%) compared to 5% among 32 mechanical back pain controls (6). Thus, a sensitivity of 83% and specificity of 95% (LR+ 16.6) from this study results in a posttest probability of 46% of having SpA if HLA-B27 is positive – a figure that is even better than the 32% probability we assumed in our calculations (1, 2).

  There is even more data available supporting the diagnostic value of HLA-B27. In an older small study from Sweden (7) 45 patients with chronic back pain were typed for HLA-B27. 6 out of 45 (13.3%) patients were found to be HLA-B27 positive, reflecting the population frequency of HLA-B27 in Sweden. Of note, 2 out of these 6 (33.3%) HLA-B27 positive patients with chronic back pain were found to have signs of ankylosing spondylitis when examined radiographically (7). This data is strong support for our hypothesis that 1 out of 3 patients with chronic back pain and positivity for HLA-B27 can be expected to have AS or axial SpA.

  Another study mentioned by Drs Healy and Helliwell has now been accepted for publication (8). This study investigated primarily clinical features of inflammatory back pain in back pain patients with established diagnoses. In addition, the HLA-B27 status was determined in all patients (101 AS patients and 112 patients with mechanical low back pain). The frequency of HLA-B27 was 89.1% among AS patients and 5.5% among mechanical back pain patients resulting in a LR+ of 16.2. Hence, this this large study i) demonstrates convincingly that HLA-B27 is definitely not increased in patients with mechanical back pain, and ii) confirms again the high diagnostic value of HLA-B27 (8).

  Taken these studies together, there is ample evidence that HLA-B27 is not increased in patients with mechanical low back pain. Moreover, the resulting LRs + in the range of 9-16 if HLA-B27 is positive represent a major diagnostic gain according to evidence-based approaches (9, 10). Likewise, the LRs- (in case HLA-B27 is negative) in the range of 0.11-0.18 are diagnostically helpful in ruling out the disease.

  Regarding criteria for IBP we have not reduced the criteria from 5 to 2 as stated by Drs Healy and Helliwell. Instead we propose to use 2 of the 5 parameters Calin et al. (11) have developed already as obligatory entry parameters, and offer 3 more parameters (altogether 5 parameters for IBP). The 2 obligatory entry criteria are chronic back pain of > 3 months and age at onset of back pain < 45 years (Calin used 40 years but this is unlikely to make a major difference) since this group of young adults with chronic back pain is the target group in which axial SpA is a relevant differential diagnosis. We have further refined the 3 remaining parameters according to our own new data (8) in that ‘pain at night/ early morning’ has been added and ‘insidious onset’ has been removed from the list.

  The concern expressed by Dr. Helliwell that rheumatology clinics will be overwhelmed by patients if our proposed screening recommendations come into place is clearly a question of capacity and depends on local or regional modalities. However, in the interest of patients, the time span of 5 to 7 years from onset of symptoms to making the diagnosis (12) can only be significantly reduced if a well trained rheumatologist is prepared to diagnose patients early (13). Selecting those patients with chronic back pain who are at a relatively high risk of having axial SpA will help to limit the number of patients needed to be seen.

  References

  1. Sieper J, Rudwaleit M. Early referral recommendations for ankylosing spondylitis (including pre-radiographic and radiographic forms) in primary care. Ann Rheum Dis 2005;64:659-63

  2. Rudwaleit M, van der Heijde D, Khan MA, Braun J, Sieper J. How to diagnose axial spondyloarthritis early. Ann Rheum Dis 2004;63:535-43

  3. Underwood MR, Dawes P. Inflammatory back pain in primary care. Br J Rheumatol. 1995;34:1074-7

  4. Mau W, Zeidler H, Mau R, Majewski A, Freyschmidt J, Stangel W, et al. Clinical features and prognosis of patients with possible ankylosing spondylitis. Results of a 10-year followup. J Rheumatol. 1988;15:1109-14

  5. Braun J, Bollow M, Remlinger G, Eggens U, Rudwaleit M, Distler A, et al. Prevalence of spondylarthropathies in HLA-B27 positive and negative blood donors. Arthritis Rheum 1998;41:58-67

  6. Sadowska-Wróblewska M, Filipowicz A, Garwolinska H, Michalski J, Rusiniak B, Wróblewska T. Clinical signs and symptoms useful in the early diagnosis of ankylosing spondylitis. Clin Rheumatol. 1983;2:37-43

  7. Sandström J, Andersson GBJ, Rydberg L. HLA-B27 as a diagnostic screening tool in chronic low back pain. Scand J Rehab Med 1984;16:27-28

  8. Rudwaleit M, Metter A, Listing J, Sieper J, Braun J. Inflammatory back pain in ankylosing spondylitis – a reassessment of the clinical history for classification and diagnosis. Arthritis Rheum, in press

  9. Jaeschke R, Guyatt GH, Sackett DL. Users' guides to the medical literature. III. How to use an article about a diagnostic test. B. What are the results and will they help me in caring for my patients? The Evidence-Based Medicine Working Group. JAMA 1994;271:703-7

  10. Grimes DA, Schulz KF. Refining clinical diagnosis with likelihood ratios. Lancet 2005;365:1500-5

  11. Calin A, Porta J, Fries JF, Schurmann DJ. Clinical history as a screening test for ankylosing spondylitis. JAMA. 1977;237:2613-411.

  12. Feldtkeller E, Khan MA, van der Heijde D, van der Linden S, Braun J: Age at disease onset and diagnosis delay in HLA-B27 negative vs. positive patients with ankylosing spondylitis. Rheumatol Int 2003;23:61-6

  13. Rudwaleit M, Khan MA, Sieper J. The challenge of diagnosis and classification in early ankylosing spondylitis: do we need new criteria? Arthritis Rheum 2005;52:1000-8

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  Conflict of Interest:
  None declared.

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• Published on: 9 August 2005

  HLA B27 is not an appropriate screening tool for spondyloarthropathy

  • Paul J Healy, Rheumatology registrar
  • Other Contributors:
    • Philip S. Helliwell

  Dear Editor,

  Sieper et al. propose a set of early referral criteria for ankylosing spondylitis (AS) using HLAB27 as an central test.[1] The supporting data were presented in a previous paper.[2] The HLAB27 data were taken from six study populations. In two groups the control population were either symptom free blood donors or no clinical data was known.[3, 4] There are three published trials using back pain contro...

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  Dear Editor,

  Sieper et al. propose a set of early referral criteria for ankylosing spondylitis (AS) using HLAB27 as an central test.[1] The supporting data were presented in a previous paper.[2] The HLAB27 data were taken from six study populations. In two groups the control population were either symptom free blood donors or no clinical data was known.[3, 4] There are three published trials using back pain controls with ankylosing spondylitis (AS) patients.[5-7] When reviewed these produce lower figures for sensitivity and specificity than are quoted in the paper by Rudwaleit et al. A further trial with back pain controls has been seen only in abstract form and the patient numbers quoted do not match those from the abstract.[8] If using only the data from studies with back pain controls the recalculated post test probability is 19% so that the utility of HLAB27 as a screening and diagnostic tool is greatly reduced .

  The authors have used a history of inflammatory back pain[9] as the entry point for both their diagnostic and referral algorithms. However in the most recent paper the initial questions are reduced from five to two. The full set are suggested only if the HLAB27 is difficult to perform. This recommendation of HLAB27 as the primary test in determining referral is of concern. While it may ensure most patients are seen early by a rheumatologist it will certainly overwhelm many of the assessing clinics. Even in moderately well funded health systems the level of service provision is already far below recommendation.[10]

  Some years ago HLAB27 positive mechanical back pain was a regular cause for referral to rheumatology clinics [11] and we would not wish to return to this situation. Further, HLAB27 testing may not be routinely available in primary care in many areas. Given this we believe that a well taught clinical history is still the best (albeit poor) indicator of inflammatory spinal disease in primary care.

  References

  1. Sieper, J. and M. Rudwaleit, Early referral recommendations for ankylosing spondylitis (including pre-radiographic and radiographic forms) in primary care. Ann Rheum Dis, 2005. 64(5): p. 659-63.

  2. Rudwaleit, M., et al., How to diagnose axial spondyloarthritis early. Ann Rheum Dis, 2004. 63(5): p. 535-43.

  3. Schlosstein, L., et al., High association of an HL-A antigen, W27, with ankylosing spondylitis. N Engl J Med, 1973. 288(14): p. 704-6.

  4. Brewerton, D.A., et al., Ankylosing spondylitis and HL-A 27. Lancet, 1973. 1(7809): p. 904-7.

  5. Sadowska-Wroblewska, M., et al., Clinical symptoms and signs useful in the early diagnosis of ankylosing spondylitis. Clin Rheumatol, 1983. 2(1): p. 37-43.

  6. Mau, W., et al., Clinical features and prognosis of patients with possible ankylosing spondylitis. Results of a 10-year followup. J Rheumatol, 1988. 15(7): p. 1109-14.

  7. Braun, J., et al., Prevalence of spondylarthropathies in HLA-B27 positive and negative blood donors. Arthritis Rheum, 1998. 41(1): p. 58- 67.

  8. Rudwaleit, M., et al., Clinical parameters in the differentiation of inflammatory back pain from non-inflammatory back pain. Ann Rheum Dis, 2002. 61 ((suppl 1)): p. 57.

  9. Calin, A., et al., Clinical history as a screening test for ankylosing spondylitis. Jama, 1977. 237(24): p. 2613-4.

  10. Harrison, A., Provision of rheumatology services in New Zealand. N Z Med J, 2004. 117(1192): p. U846.

  11. Helliwell, P.a.W., V., Seronegative spondyloarthropathies, in Clinical Rheumatology International Practice and Research: Epidemiological, Sociological and Environmental Aspects of Rheumatology, J.A.D. Anderson, Editor. 1987, Balliere Tindall: London. p. 491-524.

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  Conflict of Interest:
  None declared.

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