Biomarkers in spondyloarthropathies.

The study of biomarkers in spondyloarthropathy (SpA) has emerged to be a very important field of research. This is particularly because the two commonly used biomarkers, erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), are of very low sensitivity and specificity. The second reason is, with advances in the treatment of SpA by the very expensive tumor necrosis factor-alpha (TNF-alpha) blockers, for cost-effectiveness, clinicians need to be much more accurate in predicting disease progression, evaluating disease activity and monitoring therapeutic efficacy. This review focuses on several biomarkers of promise: matrix metalloproteinases 3 (MMP-3), Type II collagen neoepitope (C2C and C1-2C), C-propeptide of Type II collagen (CPII), aggrecan 846 epitope, macrophage colony stimulating factor (M-CSF), serum amyloid A (SAA) and Interleukin-6 (IL-6). The results summarized in Table 1 call for a co-ordinated effort for systematic studies of existing biomarkers and for search for new candidates.

Identification of acute phase reactants and cytokines useful for monitoring infliximab therapy in ankylosing spondylitis.

Although most ankylosing spondylitis patients show an apparent clinical response to infliximab therapy, there is considerable individual variation. Because current clinical assessment relies heavily on subjective patient self-evaluation, biomarkers of high sensitivity and specificity are much needed. Here, we assessed potential biomarkers in 47 ankylosing spondylitis patients who received three standard pulses of infliximab. Before each infusion and at week 10, the following were measured: erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), platelet count, serum levels of metalloproteinase-3 (MMP-3), and 22 different cytokines. We discovered that, 2 weeks after the first infusion, the combination of ESR, CRP, and platelet count distinguished responders from non-responders with 81.3% sensitivity and 72.7% specificity. The distinguishing power was much less when each acute phase reactant was used alone. Among the 22 cytokines, serum IL-1alpha was able to distinguish responders from non-responders at week 6, with sensitivity of 84.9% and specificity of 53.8%. Serum IL-1alpha was probably generated from the joint compartments, as synovial fluid levels were much higher than corresponding serum levels. Although infliximab infusions led to rapid and significant suppression of serum MMP-3 levels, serum MMP-3 levels did not distinguish responders from non-responders. Besides identifying potential biomarkers, our results also demonstrate the usefulness of using sensitivity and specificity to assess usefulness of potential biomarkers.

Matrix metalloproteinase expression in the spondyloarthropathies.

PURPOSE OF REVIEW: Expression of matrix metalloproteinases and their tissue inhibitors has been an active area of investigation in rheumatoid arthritis and osteoarthritis. Only recently have investigators started to study these factors in spondyloarthropathy. The purpose of this review is to summarize these recent findings. RECENT FINDINGS: Multiple matrix metalloproteinases and their tissue inhibitors are expressed in the synovial fluid as well as serum samples of spondyloarthropathy patients. Their degrees of expression in the synovia correlate with parameters of arthritis activity such as cell infiltration. In the synovial fluids, the factor which is expressed in very high level is matrix metalloproteinase-3. Two separate cohorts demonstrate that serum levels of matrix metalloproteinase-3 correlate with disease activity in ankylosing spondylitis. Their usefulness appears to exceed those of erythrocyte sedimentation rate and C-reactive protein. Multiple studies also indicate that serum levels of matrix metalloproteinase-3 are suppressed when patients are treated with the anti-tumor necrosis factor-alpha antibody infliximab. SUMMARY: New biomarkers are in demand for spondyloarthropathy in deciding whether patients would benefit from treatment with tumor necrosis factoralpha blockers, monitoring response to treatment, or predicting potential of joint damage if untreated. Recent studies show that among the matrix metalloproteinase and their tissue inhibitors, serum MMP-3 is the one with potential usefulness.

One-year open-label trial of thalidomide in ankylosing spondylitis.

OBJECTIVES: To test in a large open study whether thalidomide is potentially useful in treating ankylosing spondylitis, and to see if thalidomide induces any change in expression of genes in peripheral blood mononuclear cells (PBMC). METHODS: Thirty male patients with treatment-refractory ankylosing spondylitis were recruited into a 12-month open study using thalidomide at a dosage of 200 mg/day. Seven indices were measured as primary outcome measures, and 6 other indices as secondary outcome measures. Transcripts in the PBMC of some of these patients were first screened with microarray, and then measured with reverse transcriptase-polymerase chain reaction. RESULTS: Twenty-six patients completed the study. Of these, 80% showed a >20% improvement in 4 of 7 primary indices. Sharp declines in several parameters were noticed at 3-6 months. Nine patients became pain-free. There was also a statistically significant decrease in tumor necrosis factor alpha transcripts in the PBMC. CONCLUSION: Thalidomide is a reasonably promising drug in treatment-resistant ankylosing spondylitis.

Clues to pathogenesis of spondyloarthropathy derived from synovial fluid mononuclear cell gene expression profiles.

OBJECTIVE: To use gene expression profiles of spondyloarthropathy (SpA) synovial fluid mononuclear cells (SFMC) to determine if there are transcripts that support the unfolded protein response (UPR) hypothesis, and to identify which cytokines/chemokines are being expressed and which cell fractions are involved. METHODS: Gene expression profiles were generated by microarray screening of SFMC of 5 patients with SpA, 5 patients with rheumatoid arthritis (RA), and peripheral blood mononuclear cells (PBMC) of 6 controls. Results were validated by reverse transcription polymerase chain reaction using samples from a larger panel of subjects. RESULTS: The repertoires of proinflammatory cytokines/chemokines expressed by SpA and RA SFMC were very similar: monocyte chemotractant protein 1 (MCP-1), interleukin 8 (IL-8), IL-1beta, endothelial-monocyte activating polypeptide II, interferon-gamma, and tumor necrosis factor-alpha. MCP-1 was highly expressed in SpA SFMC. There was enhanced expression of immunoglobulin heavy chain binding protein (BiP) in SpA, which is compatible with the UPR hypothesis. BiP was most highly expressed in the adherent fraction of SpA SFMC. CONCLUSION: Previous data postulating UPR in SpA are based on in vitro experiments with transfected cell lines. Our patient derived data suggest that it also occurs in vivo in the macrophages of SpA joints.