Clinical manifestations and prevalence of ankylosing spondylitisAnkylosing spondylitis (AS) is a chronic inflammatory disease which affects primarily the spine and the sacroiliac joints, but extraspinal structures such as peripheral joints, the enthesis (insertion of tendons/ligaments at bone), the eye (uveitis) and the aorta can also be involved. There is a strong association between AS and the MHC class I antigen HLA-B27 which is positive in 90-95% of patients. About 5% of HLA-B27-positve individuals do develop ankylosing spondylitis during lifetime, starting in more than 95% at an age younger than 45 years. The overall prevalence of AS has been estimated to be between 0.2 and 1.2%. These differences can mainly be explained by differences in the HLA-B27 prevalence in different populations. Current treatment of ankylosing spondylitisRecent ASAS/EULAR recommendations for the treatment of AS state that for the predominant axial manifestations there are only two groups of effective drugs: the NSAIDs and, more recently, the TNF-blockers 1. Thus, in contrast to rheumatoid arthritis and other inflammatory rheumatic diseases such as SLE treatment with DMARDs does not play a role in the mangement of AS. Most recently, we could show in three open label studies that drugs such as leflunomide2, the IL-RA anakinra3 and methotrexate 4 are not effective in AS. Sulfasalazine, the DMARD most often used for the treatment of AS, has, if at all, also only a very limited efficacy. About 20-30% of AS patients have been estimated to be potential candidates for treatment with TNF-blockers because their disease is still active despite an adequate therapy with NSAIDs. From the AS patients treated with TNF-blockers, about 50% show a 50% improvement in their disease acitivity (BASDAI), but 50% do not. Especially for the latter patients with no or only a suboptimal response to anti-TNF agents alternative treatment options are urgently needed. Evidence for ankylosing spondylitis as an autoimmune disease and thepotential role of T cells in the pathogenesisWe have argued already 10 years ago that autoimmunity plays an important role in the pathogenesis of ankylosing spondylitis (AS). Although there is no direct evidence, as in nearly all 'suspected' autoimmune diseases, of an autoimmune response in AS it has been proposed repeatedly over the last years that the cartilage is the most likely target of an autoimmune response in AS. Histological studies and magnet resonance imaging investigations suggest that the primary site of inflammation is the cartilage/bone interphase. Mononuclear cell infiltrates are mainly found in cartilage and the subchondral bone. In early and active sacroiliitis, T cells and macrophages are dominant in these infiltrates underlining the relevance of a specific cellular immune response . This was further backed by recent studies from our group demonstrating mononuclear infiltrates (including both CD4+ and CD8+ T cells) of cartilage by investigating femoral heads and facette joints (small joints of the spine) obtained by surgery from a number of AS patients 5,6. The presence of T cell and other MNC infiltrates was strongly dependent on the presence of cartilage on the surface of the femoral heads, suggesting that cartilage could be indeed the stimulus and target of a cellular immune response. Furthermore, T cell responses have been demonstrated against proteoglycan (an important cartilage protein) in human arthritides including ankylosing spondylitis . We could also recently demonstrate both a CD4+ and a CD8+ T cell response to proteoglycan (aggrecan) derived peptides in the peripheral blood and a CD8+ T cell response against a collagen VI derived peptide in the synovial fluid from AS patients. Thus, all these findings suggest that a chronic, probably T cell mediated, immune response against cartilage is relevant in the pathogenesis of AS.Further strong evidence for a crucial role of T cells in the pathogenesis of AS comes, in addition to the experimental data discussed above, from the association of AS with the MHC class I antigen HLA-B27. Because the natural function of HLA molecules is the presentation of peptides to T cells it has been postulated that the presentation of a yet unknown peptide to T cells might be the link to explain this HLA-B27 association , although direct evidence for this hypothesis is still missing. However, this hypothesis is backed by a lack of association with the HLA-B27 subtypes \*B2706 and \*B2709, which differ from the other susceptible subtypes by only 1 (or 2) amino acid substitution at the bottom of the peptide binding groove . Thus, these subtypes might not present an arthritogenic peptide. Based on the above described findings about the role of T-cells in ankylosing spondylitis we assume that Abatacept has the potential to be an effective drug for treating ankylosing spondylitis.The rheumatology group at the Charité, Campus Benjamin Franklin, has a large experience in the conduction of clinical trials, especially in ankylosing spondylitis, including treatment with biologicals . The infliximab trials finally led to the approval of infliximab for the indication ankylosing spondylitis. Most of these studies were conducted as investigators' initiated (sponsored) trials. From these trials we know that the placebo response rate is rather small in patients with active ankylosing spondylitis. The aim of the proposed trial is to evaluate the short-term efficacy and safety of treatment of active AS (BASDAI \> 4 despite adequate therapy with NSAIDs) in a pilot open label trial with abatacept. If a clear response (see sample size justification). with an acceptable safety can be reached this study would be followed by a double blind placebo-controlled trial.We propose to treat in this open label pilot study two groups of patients: 1. TNFa-blocker failures (meaning patients who did not show an adequate response to TNFa-blocker treatment according to the international ASAS recommendations 7; not meaning patients who had to be discontinued because of side effects) and 2. TNFa-blocker naïve patients. We expect to gain important information about potential indications for treatment of AS with abatacept already by a relatively simple study design and a small number of patients (N= 30 in total).Research hypothesis The aim of the proposed trial is to evaluate the short-term efficacy and safety of treatment of active AS (BASDAI \> 4 despite adequate therapy with NSAIDs) in a pilot open label trial with abatacept. If a clear response (see sample size justification) with an acceptable safety can be reached this study would be followed by a double blind placebo-controlled trial.