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New treatment options in ankylosing spondylitis: a role for anti-TNFα therapy
  1. J Siepera,
  2. J Braunb
  1. aMedical Department I, Rheumatology, University Hospital Benjamin Franklin, Berlin, Germany, bRheumazentrum Ruhrgebiet, Herne, Germany
  1. Professor J Sieper, Medical Department I, Rheumatology, University Hospital Benjamin Franklin, Hindenburgdamm 30, 12200 Berlin, Germanyhjsieper{at}zedat.fu-berlin.de

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The spondyloarthropathies (SpA) comprise ankylosing spondylitis (AS), reactive arthritis, some forms of psoriatic arthritis/spondylitis, arthritis/spondylitis associated with inflammatory bowel disease, and undifferentiated SpA. AS is the most common subgroup with the most severe course of the disease. In two studies from Germany, one performed among blood donors and one in an outpatient clinic with special interest in SpA, AS was slightly more common than undifferentiated SpA.1 2 The prevalence for the whole group of SpA has been estimated in recent studies at between 0.6% and 1.9%.1 3 4 Thus it can be assumed that the SpA have a similar prevalence to rheumatoid arthritis (RA).

Only recently, researchers have started to investigate the burden of disease in patients with AS, both personally and economically. Although a direct comparison between RA and AS is difficult, because there are far more studies in RA and AS usually starts considerably earlier in life, some studies have now been performed. When age and sex matched patients with severe AS were compared with patients with severe RA the grade of disability was similar.5 Furthermore, work disability is clearly greater in patients with AS than in normal subjects.6 Thus SpA, in general, and AS, especially, is more prevalent than previously thought and active disease has a clear socioeconomic impact.

With this background it is rather surprising that there are no established disease modifying antirheumatic drugs (DMARDs) for AS. Although some of the treatments, such as sulfasalazine, seem to be effective for peripheral arthritis in patients with SpA, there is no such treatment for the axial manifestation. Not only is there no accepted DMARD treatment for this chronic rheumatic disease but also most of the few studies are—in comparison with RA treatment trials—of bad quality with small patient numbers and without control groups.

Treatment of AS with NSAIDs

Non-steroidal anti-inflammatory drugs (NSAIDs) are the only accepted drug treatment for AS. They are highly effective in about 70% of patients with AS and a good response to NSAID treatment has been suggested as a criterion for the diagnosis of inflammatory back pain and spondyloarthropathies.7 However, similar to other rheumatic diseases, NSAIDs only improve the symptoms and there is no evidence that permanent antiphlogistic treatment improves radiological outcome and function. There is now evidence that the new COX-2 selective drugs, such as meloxicam and celecoxib,8 9 are also effective in treating back pain in AS.

Treatment of AS with DMARDs

The best investigated DMARD for the treatment of AS is sulfasalazine. In the two largest placebo controlled studies no effect was seen on the axial symptoms.10 11 However, in these studies only patients with longstanding disease (disease duration >14 years) were treated. One smaller placebo controlled trial (including 85 patients) showed that sulfasalazine might have an effect on spinal symptoms in patients with a disease duration of less than six years, 60% of whom had peripheral arthritis.12 In contrast with axial symptoms, peripheral arthritis showed an improvement when treated with sulfasalazine in several studies.10 11 However, again, these patients already had disease of long duration. There is also evidence that sulfasalazine prevents attacks of AS associated uveitis.13 Taken together, at the moment there is only limited evidence that sulfasalazine has an overall efficacy in AS, with a possible effect in early disease. Presently, we are performing a placebo controlled study in Germany treating patients with early AS (duration of symptoms less than six years) with sulfasalazine for six months. The result of this study will allow better conclusions to be reached about the efficacy of sulfasalazine in early AS.

Fewer data are available for other DMARDs. A few small open studies with methotrexate report a potential effect in AS.14-17No placebo controlled studies have been performed so far. There are no studies beyond case reports on the treatment of patients with AS with other DMARDs which are effective in the treatment of RA such as gold, azathioprine, cyclosporin A, or leflunomide. There have been reports of a positive result in small open studies in the treatment of AS with pamidronate18 19 and with thalidomide.20However, these reports have to be confirmed. In Germany, radium-224 chloride has recently been approved for severe AS, mainly on the basis of older studies.21 Again, controlled trials need to be done.

Two conclusions can be drawn: (a) attempts to find an effective treatment for AS have been neglected in the past; or (b) clinicians have been reluctant to perform treatment trials because none of the above mentioned drugs showed convincing efficacy in clinical practice. Interestingly, it is also generally believed—in contrast with RA and other inflammatory rheumatic diseases—that glucocorticoids do not work in low or moderate doses in AS despite the good effect of NSAID treatment.

TNFα blockade in the treatment of AS

The sacroiliac joint and the entheses are the most characteristic and almost pathognomonic sites involved in SpA.22 Although there is currently no good long term anti-inflammatory or immunosuppressive treatment for AS available, inflammation at the interphase of cartilage and bone has been convincingly shown by magnetic resonance imaging (MRI)22-24 and immunohistological investigations from biopsy specimens taken from the sacroiliac joint and other sites.25-28 Especially in cases of early AS, dense mononuclear infiltrates can be seen which invade the cartilage.27 We could also show that many of the cells in these infiltrates secrete TNFα.25 Thus an inflammation is present. In view of this background, we decided to investigate the efficacy of the TNFα blocking monoclonal antibody, infliximab, in patients with AS. This decision was supported by two further sets of data:

  • AS and the whole group of SpA are clearly associated with chronic inflammatory bowel disease (IBD)29 because patients with IBD can develop AS and up to 50% of patients with primary AS show histological gut lesions similar to Crohn's disease. TNFα is strongly expressed in the inflamed gut of patients with IBD, and anti-TNFα treatment is effective and approved for Crohn's disease.30

  • Anti-TNFα treatment is effective in other inflammatory rheumatic diseases, such as psoriatic arthritis31 and RA,32 33 which are, however, pathogenetically different.

Today there are two main biological agents used to target TNFα: the chimeric monoclonal IgG1 antibody infliximab (Remicade) and the 75 kDa IgG1 fusion protein etanercept (Enbrel). Both catch soluble TNFα in the plasma; etanercept also catches TNFβ. Infliximab also binds to cell membrane bound TNFα. It is not yet clear whether etanercept, in contrast with infliximab, is effective in Crohn's disease. Both might not work in colitis ulcerosa but both are effective in psoriasis.31 34

Effect of infliximab in patients with AS

In our open pilot study performed in Berlin, infliximab improved the disease activity of patients with severe AS with a mean disease duration of five years,35 as measured by the “Bath Ankylosing Spondylitis Disease Activitiy Index” (BASDAI).36 Eleven patients received three infusions of infliximab 5 mg/kg at weeks 0, 2, and 6. Significant efficacy was already noted on the first day of treatment. Spinal pain, fatigue, and morning stiffness, especially, but also peripheral arthritis, improved. Nine out of ten patients showed an improvement of >50% in the BASDAI; the median improvement of the BASDAI after four weeks was as much as 70%. Importantly, quality of life, as measured by the “short form” (SF) 36 instrument, was significantly better after four weeks. In comparison with an age and sex matched normal healthy German population, the patients with AS studied had clearly impaired initial assessments—in particular, their physical functioning ability was very low but could be increased by anti-TNFα treatment. One patient remains in remission at present after the first three infusions of infliximab. Major side effects occurred in three patients, who developed allergic reactions and could not receive further treatment.

These patients were then followed up for another nine months. The next infusion of infliximab was not given before a relapse occurred, defined as 80% of the initial activity (Brandt, unpublished data). First symptoms came back after a mean of six weeks and a relapse occurred after a mean of 12 weeks. These patients were treated again three more times. They all responded again, but, less well than at the start of the study, probably owing to the lack of the initial saturation phase.

In another open label study 21 patients with the whole spectrum of SpA were treated with infliximab in a similar fashion. Ten of these 21 patients fulfilled the criteria for AS and also showed an excellent response.37 This study is covered in more detail elsewhere in this issue (Veys et al, see p iii33).

These excellent data could now be confirmed in a controlled trial. A placebo controlled German multicentre study conducted over 12 weeks, organised by us, included 70 patients with AS who had to have a BASDAI >4 and spinal pain on a visual analogue scale >4. The effect of infliximab treatment was highly significant (again, 5 mg/kg body weight given at weeks 0, 2, and 6), with the primary outcome parameter of a 50% improvement of disease activity (BASDAI) achieved in the infliximab group compared with placebo (Braun et al, unpublished data). Again, other parameters showed a similar improvement. This suggests a major breakthrough in the short term treatment of severe AS. Since then these 70 patients have been treated after this placebo controlled phase of the study with infliximab 5 mg/kg body weight every six weeks for two years. This study is still continuing and will give us more information about the long term efficicacy and side effects of infliximab treatment in AS.

So far, only preliminary data of a study on the treatment of AS with the soluble TNFα receptor, etanercept, have been presented, which also indicate a favourable effect.38 Currently, further studies with this drug are in progress or are planned. These results are awaited before any firm conclusions can be made.

Definition of new outcome parameters for AS studies

Major progress for investigating effective drugs for the treatment of AS was achieved by the definition of outcome parameters for such studies by the “Assessment in Ankylosing Spondylitis” (ASAS) Working Group.39 Furthermore, similar to response criteria in AS, this group defined 20% response criteria and criteria for partial remission in AS based on the four domains of pain, disease activity, function, and patient's global assessment.40

Recent studies41 have shown that radiographic progression in AS is slow if the patients examined are not preselected by severe disease activity. Indeed, one needs two years to be able to detect differences using the BASRI42 or the SASSS.43Increasing evidence shows that acute sacroiliitis, spondylitis, and spondylodiscitis can be visualised by MRI using either contrast or STIR techniques.22 25 In contrast with conventional imaging byx rays, where mainly the result of inflammation, bony changes, and ankylosis but also erosions can be seen, acute spinal inflammation can be visualised by MRI. In Berlin, an improvement in spinal inflammation detected by MRI could already be shown in the open study.35 The MRI results of the multicentre study cited are just being evaluated. Preliminary results suggest that regression of spinal inflammation occurs after three months in patients treated with infliximab (about 40% improvement) but also with placebo (20% improvement).

Thus the availability of tools (both clinical and imaging) for the conduction of studies, and the finding that active AS can be effectively treated, as has now been shown for infliximab, will hopefully trigger research activities to find more effective treatments for AS.

Summary

Anti-TNFα treatment seems to be highly effective in AS. The results available indicate that this treatment is at least as effective as in RA. Furthermore, because no other treatments are available for AS—in contrast with RA or psoriatic arthritis—infliximab may even become a first line immunosuppressive treatment in patients with severe active AS. A dose of 5 mg/kg body weight seems to be required and intervals between 6 and 12 weeks seem to be necessary depending on the disease activity. It remains to be seen what the long term effects will be, whether the patients benefit from long term treatment, and whether radiological progression and ankylosis can be stopped. Allergy, lupus-like diseases, and tuberculosis are rare side effects which need to be considered. At first glance, the possible benefits of anti-TNFα treatment seem to outweigh these shortcomings, including the high cost.

References

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