Biomedical subjects
Publications and source records attributed to J Sieper.
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Patients with ankylosing spondylitis (AS) are characterised by a wide range of clinical presentations, radiographic profiles, and outcomes, which are not well differentiated by current diagnostic and classification systems for the disorder. Inadequacies in these systems may limit clinicians' ability to manage their patients with AS appropriately and act as an obstacle to reasonable comparison of therapeutic trial results. A standardised staging system for AS is therefore proposed that would provide a more detailed categorisation of patients based on assessment of structural damage, peripheral joint and organ involvement, presence of concomitant diseases, and the severity and extent of disease activity and functional impairment. The proposed system needs to be evaluated closely and amended as needed to assure its usefulness in clinical and research settings.
The conventional approach to treatment of patients with spondyloarthritis (SpA), particularly ankylosing spondylitis (AS), has serious limitations, adding a sense of urgency to the evaluation of new treatments for these rheumatic disorders. Tumour necrosis factor alpha (TNFalpha) is a cytokine that has been shown to mediate inflammatory and regulatory activities in SpA and other immune mediated diseases, including other arthritides and inflammatory bowel disease. Positive results have been reported in several international open label and randomised controlled trials of infliximab and etanercept, the two main biological agents targeting TNFalpha, which have included approximately 300 patients with SpA. Specifically, TNFalpha-directed therapy resulted in significant improvements in disease activity, function, and quality of life in these patients, most of whom had AS and received infliximab. Preliminary evidence from open label, long term extension trials suggests clinical benefit with continued use. Serious side effects were rare and consistent with experience from patient groups receiving infliximab or etanercept treatment for inflammatory bowel disease or rheumatoid arthritis. Together, these findings herald an age of more effective treatment of patients with AS with anti-TNFalpha and other emerging biological agents.
BACKGROUND: There is currently no universal consensus on nomenclature for spondyloarthropathy (SpA), or on activity and severity criteria for ankylosing spondylitis (AS). METHOD: Points of agreement and majority opinions among 28 international experts in the field were identified by questionnaire. Agreement was defined as >80% concurrence, clear majority as >60% concurrence, and a majority or trend as >50% concurrence. RESULTS: Respondents agreed on the need for one term that reflects the inflammatory nature of the disease, but no agreement was reached on a specific term. Agreement included subdivision of patients with SpA into AS, psoriatic arthritis, inflammatory bowel disease associated arthritis, and undifferentiated spondyloarthritis/spondyloarthropathy. A majority of experts defined active disease as fulfilling classification criteria for AS and/or a SpA, and disease activity measured by a Bath AS Disease Activity Index (BASDAI) score >4 determined by two patient visits during a two month period, but no maximum radiographic score. The majority of participants considered failure of treatment response to non-steroidal anti-inflammatory drugs (NSAIDs) alone to be a prerequisite for active/severe AS, and 15/28 (54%) thought that NSAID treatment failure should be defined as lack of response to two or more NSAIDs. CONCLUSIONS: Respondents agreed that a two to five year study is the ethical method to demonstrate effects of anti-tumour necrosis factor alpha (TNFalpha) therapy on radiographic progression of AS, and that inclusion criteria should include a certain level of disease activity (measured by BASDAI) and failure of certain treatments. After the efficacy of anti-TNFalpha therapy in AS and psoriatic arthritis is proved, respondents agreed that more studies will be needed to show efficacy for other SpA subsets.
Ankylosing spondylitis (AS) is a complex, potentially debilitating disease that is insidious in onset, progressing to radiological sacroiliitis over several years. Patients with symptomatic AS lose productivity owing to work disability and unemployment, have a substantial use of healthcare resources, and reduced quality of life. The pathogenesis of AS is poorly understood. However, immune mediated mechanisms involving human leucocyte antigen (HLA)-B27, inflammatory cellular infiltrates, cytokines (for example, tumour necrosis factor alpha and interleukin 10), and genetic and environmental factors are thought to have key roles. The detection of sacroiliitis by radiography, magnetic resonance imaging, or computed tomography in the presence of clinical manifestations is diagnostic for AS, although the presence of inflammatory back pain plus at least two other typical features of spondyloarthropathy (for example, enthesitis and uveitis) is highly predictive of early AS. Non-steroidal anti-inflammatory drugs (NSAIDs) effectively relieve inflammatory symptoms and are presently first line drug treatment. However, NSAID treatment has only a symptomatic effect and probably does not alter the disease course. For symptoms refractory to NSAIDs, second line treatments, including corticosteroids and various disease modifying antirheumatic drugs, are employed but are of limited benefit. Emerging biological therapies target the inflammatory processes underlying AS, and thus, may favourably alter the disease process, in addition to providing symptom relief.
The association of HLA-B27 with ankylosing spondylitis and reactive arthritis is the strongest one known between an MHC class I Ag and a disease. We have searched the proteome of the bacterium Chlamydia trachomatis for HLA-B27 binding peptides that are stimulatory for CD8(+) cells both in a model of HLA-B27 transgenic mice and in patients. This was done by combining two biomathematical computer programs, the first of which predicts HLA-B27 peptide binding epitopes, and the second the probability of HLA-B27 peptide generation by the proteasome system. After preselection, immunodominant peptides were identified by Ag-specific flow cytometry. Using this approach we have identified for the first time nine peptides derived from different C. trachomatis proteins that are stimulatory for CD8(+) T cells. Eight of these nine murine-derived peptides were recognized by cytotoxic T cells. The same strategy was used to identify B27-restricted chlamydial peptides in three patients with reactive arthritis. Eleven peptides were found to be stimulatory for patient-derived CD8(+) T cells, of which eight overlapped those found in mice. Additionally, we applied the tetramer technology, showing that a B27/chlamydial peptide containing one of the chlamydial peptides stained CD8(+) T cells in patients with Chlamydia-induced arthritis. This comprehensive approach offers the possibility of clarifying the pathogenesis of B27-associated diseases.
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Osteoporosis due to steroid therapy is one of the most frequent and serious adverse events of antirheumatic therapy. The greatest loss of bone occurs during the 1st year of steroid intake, with the largest loss in the spine. Up to 50% of the patients, mostly postmenopausal women, suffer vertebral fractures. The prevalence of osteoporosis in 60-year-old patients with rheumatoid arthritis (RA) is more than double compared to the normal population. There are more risk factors other than age, gender, and menopause. Independent from the underlying disease, glucocorticoid therapy is associated with a high risk of osteoporosis development. Among the clinical manifestations of osteoporosis, fractures of the vertebrae, hips, and ribs are the most common. In clinical practice, bone density measurements are mostly performed with the dual-energy X-ray absorptiometry (DXA) technique. Since prevalent vertebral fractures are strongly predictive of new fractures, X-rays of the lumbar and thoracic spine are indicated in patients who are scheduled to receive steroid therapy for > 3 months. The value of serologic bone markers has not yet been clearly established. On the basis of these risks and the high prevalence of already manifest osteoporosis, there is a clear indication for osteoprotective therapy in RA. Bisphosphonates and active vitamin D metabolites play an important role for therapy and prophylaxis of steroid-induced osteoporosis. In rheumatology it is often necessary to administer bisphosphonates intravenously due to the disability of the patients. The clear necessity for prophylaxis and therapy of steroid-induced osteoporosis must be stressed. Efforts should be intensified to ensure even more consistent application in daily practice. Doctors should treat their steroid patients on the basis of the clear-cut indications for intervention despite budget problems.
Anti-TNF therapy seems to be highly effective in AS. Based on the available results, this treatment seems to be at least as effective as in RA. Furthermore, because no other treatments are available for AS--in contrast to RA or psoriatic arthritis--infliximab might even become a first-line immuno-suppressive treatment in patients with severe, active AS. A dosage of 5 mg/kg seems to be required and intervals between 6-12 weeks seem to be necessary depending on the disease activity. It remains to be shown what the long-term effects are, whether the patients benefit from long-term therapy and whether radiological progression and ankylosis can be stopped. Allergy, lupus-like diseases and tuberculosis are rare side effects which need to be addressed. At first glance, the possible benefits of anti-TNF therapy seem to outweigh these shortcomings.
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Osteoarthritis (OA) is a degenerative joint disease characterised by the breakdown of the extracellular matrix of chondrocytes in the affected joints. Cytokines and growth factors which are known to play a role in the synthesis and degradation of cartilage matrix have been shown to be upregulated in osteoarthritic cartilage. This upregulation resulted in two different phenotypes, overexpressing either TNF-alpha and IL-6 or IL-1beta, TGFbeta1, IL-4 and IL-10. To investigate the hierarchy among growth factors and cytokines involved in cartilage metabolism, we analysed osteoarthritic cartilage explants for their responses to human recombinant (rh) cytokines and growth factors. The cytokine expression patterns of the explants before and after in vitro culture were compared by immunohistological staining of cartilage sections. We found a coordinate expression of TNF-alpha and IL-6 on the one hand, and of IL-1beta, TGFbeta1, IL-4 and IL-10 on the other. Although TNF-alpha and IL-6 stimulated each other's expression, they downregulated TGF beta1, IL-4 and IL-10 or IL-1beta, TGF beta1 and IFNdelta, respectively. IL upregulated the expression of TGF beta1, IL-4 and IL-10, and jointly these four cytokines and growth factors downregulated IL-6. Both of the expression patterns described for OA cartilage can be explained by these regulatory mechanisms. Interestingly, no cytokine efficiently downregulated TNF-alpha, and even though IL-1beta is upregulated in one of the OA phenotypes, none of the growth factors and cytokines tested--except for IL-1beta itself--seemed capable of mediating this upregulation. This unresponsiveness to cytokine stimulation might hint at a genetic cause for the elevated expression in the respective phenotypes.
There is good evidence that bacteria persist in vivo in patients with reactive arthritis (ReA). While Chlamydia seem to hide inside the joint, other areas such as gut mucosa or lymph nodes seem to be more likely places for Salmonella and Yersinia. T-helper (Th) 1 cells secreting cytokines such as IFN gamma and TNF alpha are crucial for an effective elimination of these bacteria. An inhibited Th1-response could be demonstrated in ReA, probably contributing to bacterial persistence. While HLA-B27 is found in only approximately 50% of patients with acute ReA, HLA-B27 seems to be crucial for the development of features typical with chronic spondyloarthropathy, such as sacroiliitis. Among several hypotheses to explain the interaction of bacteria with HLA-B27, the most likely seems to be that until now unknown bacterial or self- antigens were presented by HLA-B27 to CD8(+) T-cells. An important site where the immunopathology takes place seems to be at the insertion of tendons and ligaments at bone. Because antibiotics have failed so far in the treatment of ReA immunomodulatory therapies, based on a better understanding of the pathogenesis, alone or in combination with antibiotics might be an option for the future.
Tumor necrosis factor-alpha is a major effector and regulatory cytokine, which seems to have an outstanding position in rheumatic and other inflammatory states. Because TNF-alpha has been detected in the inflamed gut and sacroiliac joints of patients with chronic inflammatory bowel diseases and spondyloarthritides, like ankylosing spondylitis, there was need for studies of the efficacy of the modern biologic anti-TNF agents infliximab and etanercept in these diseases. Infliximab is approved for the treatment of Crohn disease. In addition, there are now also positive data for infliximab in the treatment of ankylosing spondylitis and for etanercept and infliximab in the treatment of psoriatic arthritis.