Ankylosing Spondylitis Clinical Trial
Official title:
Open Label Clinical Trial With Rituximab (MabThera ®) in Ankylosing Spondylitis
To evaluate the efficacy and safety of rituximab when added to NSAIDs and/ or methotrexate both for TNFalpha inhibitor naïve or TNFalpha inhibitor failure patients with moderate to severe ankylosing spondylitis
Indication: Moderate to severe ankylosing spondylitis who have had an inadequate response to
or do not tolerate conventional therapy including NSAIDs, DMARDs and TNF alpha inhibitors.
Rationale: We 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 4,5 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 5.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 proteogkycan (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.This
was further backed by recent studies from our group demonstrating mononuclear infiltrates of
cartilage by investigating femoral heads and facette joints (small joints of the spine)
obtained by surgery from a number of AS patients). The presence of mononuclear cell
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. However, rather surprisingly there were also dense infiltrations of B cells in the
subchondral bone marrow in these patients. In comparison to immunohistological stainings from
controls without spinal disease, the number of B cells in AS was even higher than the T
cells. At the moment it is not clear whether this indicates that autoantibodies do play a
role in the pathogenesis or whether these B cells might rather act as important local antigen
presenting cells. In any case, given the assumed autoimmune pathogenesis in AS and the
presence of B cells aggregates in inflammatory cellular infiltrates the study of potential
effects of an immunotherapy which targets B cells in AS is justified and needed.
Objectives: To evaluate the efficacy and safety of rituximab when added to NSAIDs and/ or
methotrexate both for TNFalpha inhibitor naïve or TNFalpha inhibitor failure patients with
moderate to severe ankylosing spondylitis.
Study design: Open label clinical trial with a study duration of 48 weeks
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