Developments in ankylosing spondylitis management

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Sjef van der Linden
MD PhD
Professor of Rheumatology
Department of Internal Medicine
Division of Rheumatology University of Maastricht
The Netherlands
E:[email protected]

Ankylosing spondylitis (AS) is a chronic inflammatory rheumatological disorder of unknown aetiology that primarily affects the axial skeleton. The disease belongs to the spondyloarthropathies, which share common features (see Tables 1 and 2).

[[HPE09_table1_32]]

[[HPE09_table2_32]]

Sacroiliitis, the hallmark of the disease, is associated with the characteristic clinical symptoms of AS: chronic inflammatory low back pain and stiffness. These symptoms tend to worsen after prolonged periods of inactivity and may wake patients from sleep; exercise usually provides relief. Axial involvement comprises inflammation of the vertebral ligaments and spinal joints and may lead to complete ossification of the spine. This also causes loss of spinal mobility and reduced functional capacity. In approximately 25% of patients peripheral joints are also affected, especially shoulders and hips.

Patients may experience extra-articular features such as acute anterior uveitis. AS may be associated with psoriasis or chronic inflammatory bowel disease (Crohn’s disease or ulcerative colitis). Clinical manifestations usually begin in late adolescence or early adulthood. Functional limitations increase with duration of the disease. Acute-phase reactants such as sedimentation rate or C-reactive protein (CRP) levels are raised in about 30% of patients and are associated with active disease.

The prevalence of AS in European populations is approximately 0.1%, but a recent study using MRI techniques estimated a prevalence of 0.86%.(1) The disease is highly linked to the human leukocyte antigen HLA-B27. Approximately 90% of Caucasoid patients with AS are HLA-B27(+), in contrast to about 9% of the healthy European population. In the general population, AS is likely to develop in about 1–2% of B27(+) adults. The disease is much more common (10–30%) among B27(+) first-degree relatives of B27+ AS patients.(2)

The disease has a major socioeconomic impact. The age- and sex-adjusted withdrawal rate from labour force participation is about three times higher among patients than the general population.(3) AS patients have an important healthcare and non-healthcare resource utilisation, resulting in yearly mean total (direct and productivity) costs per patient of between e. 6,700 and e. 9,500.(4–6)

The precise aetiology of AS is still unclear. The strong association with HLA-B27 suggests that the disease is due to a genetically determined immune response to environmental factors in susceptible individuals. Currently two theories prevail. The first deals with autoimmune crossreactivity between bacterial antigens and human tissue. The role of Klebsiella pneumoniae bacterial polysaccharides in the aetiology of the disease is a matter of debate, as levels of IgG and IgA antibodies against these bacteria may be increased.(7) The second theory is the arthritogenic peptide hypothesis that postulates that AS occurs when an external antigenic challenge activates autoreactive T-cells that recognise endogenous peptides presented by HLA-B27.

Management
The objectives of AS treatment are to relieve pain and stiffness and to maintain good posture and good physical functioning.

Nonpharmaceutical interventions
There is now ample evidence that physiotherapy exercises are effective. These activities counteract the kyphotic effects of pain and fatigue on posture and reduce stiffness. A three-week spa-exercise therapy course may provide marked improvement. Health resource utilisation, in particular NSAID usage and sick leave, decrease in the nine-month follow-up period after such therapy. Clinical benefits can be reached at acceptable costs.(8,9)

Pharmaceutical interventions
NSAIDs constitute the mainstay of treatment with drugs. They reduce pain and stiffness and enable physical exercise. Other modalities comprise secondline drugs and newer treatments.

Nonsteroidal anti-inflammatory drugs
Many NSAIDs are effective in patients with AS. No NSAID has documented superiority in terms of efficacy. Selective cox-2 inhibitors show similar efficacy to conventional NSAIDs. Although not tested directly in AS, better gastrointestinal safety is expected.(10)

Secondline drugs
The rationale for the use of sulfasalazine in AS is twofold: first, there is a common association between inflammatory bowel diseases (Crohn’s disease and ulcerative colitis) and AS; and second, there are often inflammatory lesions in the ileum of patients with AS. Sulfasalazine may be effective in reducing inflammation of peripheral joints such as the knees, but has no results on spinal manifestations and may not retard the process of spinal ossification.(11)

Contrary to the situation in rheumatoid arthritis (RA), there is currently no convincing evidence that methotrexate works in AS.(12) Leflunomide showed little efficacy in an open trial.(13) Oral steroids are less effective than in RA.

Newer treatment modalities
Treatment with intravenously administered bisphosphonates has provided conflicting results.(14) Thalidomide administered orally has now also been used in AS with some positive results.(15)

The introduction of anti-TNFalpha therapy can be regarded as a milestone, as these biological drugs have often remarkable effects in the treatment of AS. Currently available anti-TNF agents infliximab (3–5mg/kg every six to eight weeks), and etanercept (25mg subcutaneously twice weekly) show substantial improvement in signs and symptoms of active AS.(16,17) The number of patients needed to treat with one of these expensive drugs in order that one patient will experience at least 50% improvement in disease activity is just two. Continuous treatment with these compounds is necessary in most patients. It is now well known that CRP levels normalise during treatment with anti-TNFa therapy.  It is not yet known whether patients with active disease but low CRP levels respond to the same degree as those with both active disease and high CRP levels.

Guidelines for the use of anti-TNFa therapies have recently been developed by the international ASsessment in Ankylosing Spondylitis (ASAS) working group.(18,19) Clearly, infliximab and etanercept have disease-modifying properties, but their long-term safety and disease- controlling effects (WHO definition: improvement or maintaining of function and prevention of structural damage) have still to be demonstrated. Advantages of treatment with these drugs should be weighted against disadvantages. Preliminary findings suggest that about 2–4% of serious infections, including tuberculosis, occur per 100 patient-years among AS patients who are being treated with anti-TNFalpha therapy.

Summary
Treatment with anti-TNFalpha therapy is very effective and may constitute the first therapy that really can control AS. The challenge now is to find out how to predict at an early stage of the disease those patients who will have a bad outcome and those who will respond favourably, weighting benefits against costs of any kind.

References

1. Braun J, Bollow M, Remlinger G, et al. Prevalence of spondylo-arthropathies in HLA-B27 positive and negative blood donors. Arthritis Rheum 1998;41:58-67.
2. Van der Linden SM, Valkenburg HA, de Jongh BM, et al. The risk of developing ankylosing spondylitis in HLA-B27 positive individuals: A comparison of relatives of spondylitis patients with the general population. Arthritis Rheum 1984;27:241-9.
3. Boonen A, Chorus A, Miedema H, et al. Withdrawal from labour force due to work disability in patients with ankylosing spondylitis. Ann Rheum Dis 2001;60:1033-9.
4. Boonen A, van der Heijde D, Landewe R, et al. Work status and productivity costs due to ankylosing spondylitis: comparison of three European countries. Ann Rheum Dis 2002;61:429-37.
5. Boonen A, van der Heijde D, Landewé R, et al. Direct costs of ankylosing spondylitis and its determinants. An analysis among three European countries. Ann Rheum Dis In press 2003;62.
6. Ward MM. Functional, disability predicts total costs in patients with ankylosing spondylitis. Arthritis Rheum 2002;46:223-31.
7. Ahmadi K, Wilson C, Tiwana H, et al. Antibodies to Klebsiella pneumoniae lipopolysaccharide in patients with ankylosing spondylitis. Br J Rheumatol 1998;37:1330-3.
8. van Tubergen A, Landewé R, van der Heijde D, et al. Combined spa-exercise therapy is effective in patients with ankylosing spondylitis: a randomised controlled trial. Arthritis Rheum 2001;45:430-8.
9. van Tubergen A, Boonen A, Landewé R, et al. Cost-effectiveness of combined spa-exercise therapy in ankylosing spondylitis: a randomized controlled trial. Arthritis Rheum 2002;47:459-67.
10. Dougados M,  Behier JM, Jolchine I, et al. Efficacy of celecoxib, a cyclooxygenase 2-specific inhibitor, in the treatment of ankylosing spondylitis: a six-week controlled study with comparison against placebo and against a conventional nonsteroidal antiinflammatory drug. Arthritis Rheum 2001;44:180-5.
11. Clegg DO, Reda DJ, Weisman MH, et al. Comparison of sulfasalazine and placebo in the treatment of ankylosing spondylitis: a Department of Veterans Affairs cooperative study. Arthritis Rheum 1996;39:2004-12.
12. Creemers MCW, Franssen MJAM, van de Putte LBA, et al. Methotrexate in severe ankylosing spondylitis: an open study. J Rheumatol 1995;22:1104-7.
13. Haibel H, Rudwaleit M, Braun J, Sieper J. Therapy of active ankylosing spondylitis with leflunomide. Ann Rheum Dis 2002;61 Suppl 1:301.
14. Maksymowych WP, Fitzgerald A, LeClercq S, et al. A 6-month randomized double-blinded dose response comparison of i.v. pamidronate (60mg vs 10mg) in the treatment of NSAID-refractory ankylosing spondylitis (AS). Arthritis Rheum 2002;46:766-73.
15. Huang F, Gu J, Zhao W, Zhu J, Zhang J, Yu DT. One-year open-label trial of thalidomide in ankylosing spondylitis. Arthritis Rheum 2002;47:249-54.
16. Braun J, Sieper J. Therapy of ankylosing spondylitis and other spondyloarthritides: established medical treatment, anti-TNF-alpha therapy and other novel approaches. Arthritis Res 2002;4:307-21.
17. Gorman JD, Sack KE, Davis JC Jr. Treatment of ankylosing spondylitis by inhibition of tumor necrosis factor alpha. N Engl J Med 2002;346:1349-56.
18. Maksymowych W, Inman RD, Gladman D, et al. Spondyloarthritis research consortium of Canada. Canadian rheumatology association consensus on the use of anti-TNF-alpha-directed therapies in the treatment of spondyloarthritis. J Rheumatol In press 2003;30.
19. Braun J, Pham T, Sieper J, et al, for the ASAS working group. International ASAS consensus statement for the use of biologic agents in patients with ankylosing spondylitis. Ann Rheum Dis In press 2003;62.