OBJECTIVE: To evaluate the long-term effectiveness and tolerability of adalimumab in the treatment of psoriatic arthritis (PsA). METHODS: Patients with PsA who completed a 24-week, double-blind study of adalimumab versus placebo were eligible to enroll in an open-label extension study and receive adalimumab 40 mg subcutaneously every other week for up to an additional 120 weeks. At the time of this analysis, available efficacy evaluations through 2 years of treatment (n=245) included American College of Rheumatology (ACR) 20%, 50%, and 70% improvement scores, measures of joint disease and skin disease, disability, and quality of life; modified total Sharp score (mTSS) were available through 2.75 years of treatment for patients who received adalimumab in the 24-week study. RESULTS: After 24 weeks of double-blind treatment, the mean change in mTSS was -0.2 for the adalimumab group (N = 144) and 1.0 for the placebo group (N = 152)(p<0.001), and outcomes for all individual ACR component variables were significantly improved in adalimumab- compared with placebo-treated patients. Compared with 24-week responses, inhibition of radiographic progression and improvements in joint disease were maintained in most patients during long-term, open-label adalimumab treatment. Also, improvements in skin disease were maintained, with >20% of patients achieving the strict criterion of Psoriasis Area and Severity Index (PASI) 100. The nature and frequency of adverse events during long-term adalimumab treatment were consistent with the safety profile during short-term treatment. CONCLUSIONS: The clinical and radiographic efficacy of adalimumab demonstrated during short-term treatment was sustained during long-term treatment. Adalimumab has a favorable risk-benefit profile in patients with PsA.

OBJECTIVE: To compare the efficacy of adalimumab versus placebo in reducing spinal and sacroiliac (SI) joint inflammation, by magnetic resonance imaging (MRI) in patients with active ankylosing spondylitis (AS). METHODS: This was a randomized, multicenter, double-blind, placebo-controlled study. Patients (n = 82) received 40 mg adalimumab or placebo every other week during an initial 24-week double-blind period. MRIs of both the spine and SI joints were obtained at baseline, week 12, and week 52. Spinal and SI joint inflammation were measured using the Spondyloarthritis Research Consortium of Canada (SPARCC) MRI index. RESULTS: The spine SPARCC score in placebo-treated patients increased by a mean of 9.4% from baseline, compared with a mean decrease of 53.6% in adalimumab-treated patients (P < 0.001); the SI joint SPARCC score decreased by a mean of 12.7% from baseline in placebo-treated patients and by 52.9% in adalimumab-treated patients (P = 0.017). The response in adalimumab-treated patients was maintained at week 52. Placebo-treated patients were switched to open-label adalimumab treatment at week 24 and experienced similar reductions in spinal and SI joint inflammation by week 52. Similar large reductions in the spine and SI joint SPARCC scores were noted, even in patients who failed to meet the ASsessment in Ankylosing Spondylitis (International Working Group) criteria (nonresponders) at 12 weeks. In adalimumab-treated patients, a reduced C-reactive protein concentration at week 12 was significantly associated with improvement in the spine SPARCC score (P = 0.018). CONCLUSION: Adalimumab significantly reduced both spinal and SI joint inflammation in patients with active AS after 12 weeks of treatment, and these improvements were maintained for up to 52 weeks.

BACKGROUND: Traditional non-steroidal anti-inflammatory drugs (NSAIDs) are a widely used class of therapy in the treatment of chronic pain and inflammation. The drugs are effective and can be relatively inexpensive thanks to available generic versions. Unfortunately the traditional NSAIDs are associated with gastrointestinal complications in a small proportion of patients, requiring costly co-therapy with gastro-protective agents. Recently, a new class of non-steroidal anti-inflammatory agents known as coxibs has become available, fashioned to be safer than the traditional NSAIDs but priced considerably higher than the traditional generics. To help physicians choose appropriately and cost-effectively from the expanded number of anti-inflammatory therapies, scientific bodies have issued clinical practice guidelines and third party payers have published restricted reimbursement policies. The objective of this study is to determine whether an educational intervention can prompt physicians to adjust their prescribing in accordance with these expert recommendations. METHODS: This is an ongoing, randomized controlled trial. All primary care physicians in Manitoba, Canada have been randomly assigned to a control group or an intervention study group. The educational intervention being evaluated consists of an audit and feedback mechanism combined with optional participation in a Continuing Medical Education interactive workshop. The primary outcome of the study is the change, from pre-to post-intervention, in physicians' appropriate prescribing of non-steroidal anti-inflammatory therapies for patients requiring chronic treatment. Three classes of non-steroidal anti-inflammatory therapies have been identified: coxib therapy, traditional NSAID monotherapy, and traditional NSAID therapy combined with gastro-protective agents. Appropriate prescribing is defined based on international clinical practice guidelines and the provincial drug reimbursement policy in Manitoba.

OBJECTIVE: To examine single-nucleotide polymorphisms (SNPs) in the 3' region of the IL1RN gene in a large Caucasoid case-control series and in ankylosing spondylitis (AS) families from Western Canada by use of high-throughput MassArray matrix-assisted laser desorption ionization-time-of-flight (MALDI-TOF) mass spectrometry SNP typing. METHODS: An association analysis was performed in a case-control cohort of 394 AS cases and 500 controls. Family-based association analysis was performed in 58 simplex and 13 multiplex families. Three SNPs located in the 3' region of the IL1RN gene (T/C at position 27810 in exon 4, T/C at position 30735 in exon 6, and G/C at position 31017 in exon 6) were examined by high-throughput MassArray MALDI-TOF mass spectrometry. Haplotype inference software programs were used to infer the most likely haplotypes and to compare haplotype frequencies, which were then further analyzed in family-based association studies by transmission disequilibrium tests. RESULTS: The frequency of allele C at SNP position 30735 in exon 6 was significantly increased in AS cases (35.1%) versus controls (27.8%), as was the phenotype frequency (61.7% versus 48.6%). A significantly increased frequency of SNP allele G at position 31017 in exon 6 in cases (32.9%) versus controls (28.3%) was also noted. A highly significant difference in the overall distribution of haplotype frequencies was evident between cases and controls, with significant increases in the frequencies of the 27810C/30735C/31017C and 27810C/30735T/31017G haplotypes, but a significant reduction in the estimated frequency of the 27810C/30735T/31017C haplotype, in the AS cases. Estimation of haplotype frequencies based on 2 SNP markers indicated a highly significant increase in the 30735C/31017C haplotype and a highly significant decrease in the 30735T/31017C haplotype in cases compared with controls. Preliminary evidence for reduced transmission of the 27810C/30735T/31017C 3-marker haplotype was also found in family-based association analyses. CONCLUSION: Our data establish a highly significant disease association with markers in the IL1RN gene. In the absence of nonsynonymous coding sequence substitutions, it is possible that the primary disease-associated locus regulates gene expression. Association with specific haplotypes raises the possibility that the primary disease locus is in linkage disequilibrium with a specific combination(s) of markers in the IL1RN gene.

OBJECTIVE: Pain is the cardinal feature of osteoarthritis (OA), and with advancing disease there is loss of function and increasing pain even at times of joint rest. Few studies have evaluated the role of opioid analgesics in treating the pain of OA. METHODS: This randomized, double blind, parallel group study compared the efficacy and safety of a 12 hourly controlled release codeine formulation (Codeine Contin) with placebo in patients with chronic pain due to OA of the hips and/or knees. The 4 week treatment period, following an analgesic washout phase of 2-7 days, included weekly clinic evaluations, at which the dose was escalated as appropriate, and daily patient diary completion. Pain (daily), stiffness, and physical function (weekly) were assessed using the multidimensional, self-administered WOMAC (visual analog scale version) questionnaire. RESULTS: Sixty-six eligible patients completed the study. The mean initial and final daily doses of controlled release codeine were 50 mg every 12 h at baseline and 159 mg every 12 h at the final assessment. All variables in the efficacy analysis indicated superiority of controlled release codeine over placebo. The WOMAC pain scale showed an improvement of 44.8% over baseline in the controlled release codeine group compared with 12.3% taking placebo (p = 0.0004). For the WOMAC stiffness and physical function scales the improvements over baseline on controlled release codeine were 47.7% and 49.3%, respectively compared with 17.0% and 17.0%, respectively, with placebo (p = 0.003; p = 0.0007). Controlled release codeine was also significantly better than placebo on measures of sleep quality and requirement for supplemental acetaminophen. CONCLUSION: Single entity controlled release codeine is an effective treatment for pain due to OA of the hip or knee.

OBJECTIVE: Sulfasalazine (SSZ) has been found to have beneficial effects in the treatment of patients with spondyloarthropathy (SpA) with active disease. The effectiveness of SSZ is limited by both idiosyncratic and dose related side effects when treating SpA. Mesalamine is a drug used to treat inflammatory bowel disease. Case reports have suggested potential efficacy in SpA. We investigated the efficacy and safety of the Pentasa formulation of mesalamine in treating SpA. METHODS: Thirty patients with SpA as defined by the European Spondylarthropathy Study Group were recruited from a rheumatology specialty clinic. All subjects began 16 week open label therapy with mesalamine 1500 mg/day. Dose escalation for lack of efficacy was permitted after 8 weeks of therapy. Clinical, physical, and laboratory data were collected at baseline, at 8 weeks, and at the conclusion of the study at 16 weeks. RESULTS: Twenty-nine of the 30 patients completed the study. There was clinically and statistically significant improvement in all clinical measures (morning stiffness, night awakenings, quality of sleep, severity of stiffness, severity of pain, Dougados functional index, patient and physician global indices). Joint counts and enthesitis counts improved, but measures of axial flexibility did not. Erythrocyte sedimentation rate and C-reactive protein also improved over the duration of the study. CONCLUSION: In this population of patients with SpA, mesalamine was well tolerated in the dose range 1500 to 4000 mg/day. Improvements in clinical, physical, and laboratory measures indicate the efficacy of mesalamine in treating SpA.

OBJECTIVE: To study the clinical presentation, immunogenetics, and serum immune response to lipopolysaccharide (LPS) in a cohort of patients with post-Salmonella reactive arthritis (ReA). METHODS: A validate ReA screening questionnaire (Quest 2) was mailed to 919 individuals reporting symptoms of gastroenteritis to the health department after eating at a single restaurant. Three hundred twenty-one persons returned questionnaires; 170 reported symptoms outside the gastrointestinal tract; 23 of those 170 reporting persistent joint symptoms were seen 4 to 16 weeks after the outbreak and 5 of the 23 were seen in followup 12 to 20 weeks later. Clinical features, HLA Class I typing, serum soluble CD8 levels, and serum antibodies to gram negative LPS by ELISA were determined. RESULTS: Joint complaints were reported more frequently by individuals with a longer duration of diarrhea. Upper extremity joints were frequently involved, and 66% reported one or more extraarticular symptoms of Reiter's syndrome. Three of 5 typed individuals were HLA-B27 positive, including 3 of the 4 most severely involved. Serum soluble CD8 levels correlated poorly with disease activity measured either clinically or by C-reactive protein. Antibodies to Klebsiella and Shigella LPS rose over time, while antibodies to Salmonella LPS fell. CONCLUSION: The clinical picture of post-Salmonella ReA is less stereotyped than often assumed, although severity correlated with HLA-B27 status. The association of joint symptoms with duration of diarrhea and the kinetics of the anti-LPS antibody response support the hypothesis that abnormal gut permeability plays a role in the pathogenesis of post-Salmonella ReA.

Synovial fluid aspirates have been characterized by measuring their visible/near-infrared spectra (400-2500 nm). The hypothesis tested in this study is that the spectra contain sufficient information to serve as an aid in the diagnosis and/or staging of arthritic disorders. The concentrations of all major constituents are carried implicitly in the spectra, and in this sense this approach is similar in spirit to conventional synovial fluid analysis. The distinguishing feature of this method is that we have not converted the raw data (spectra) explicitly to analytical information. Rather, we have used automated pattern recognition methods to identify significant characteristics of the spectra themselves. A total of 109 spectra were measured and split into three classes according to the disease (osteoarthritis, rheumatoid arthritis, or spondyloarthropathy) affecting the patient from whom the synovial fluid sample was taken. An automated classification method was then trained by correlating features derived from these spectra to the clinical diagnoses. The robustness of the classification was validated using the leave-one-out cross-validation method, i.e., by training on all but one of the spectra and using the resulting model to predict the classification for the spectrum that is left out. The result derived by following this procedure for each of the spectra was that 105 of the 109 predicted classifications correctly matched the clinical diagnosis. These results suggest that the near-infrared spectrum of synovial fluid is sufficient to allow diagnosis of the disease affecting the joint from which the aspirate is drawn.