Progression From Subclinical Inflammation to Overt Spondyloarthritis in First-Degree Relatives of Patients in Association With HLA-B27: The Pre-Spondyloarthritis Cohort.

OBJECTIVE: As first-degree relatives (FDRs) of HLA-B27-positive patients with axial spondyloarthritis (SpA) have an increased risk of developing axial SpA, the objectives were 1) to evaluate the presence of highly specific imaging features as well as clinical signs of SpA at baseline and after 1 year of follow-up, and 2) to describe the evolution toward clinical disease within 1 year of follow-up in a cohort of seemingly healthy FDRs of HLA-B27-positive axial SpA patients. METHODS: The Pre-SpA cohort is a 5-year prospective inception cohort of seemingly healthy FDRs of HLA-B27-positive axial SpA patients. Clinical and imaging features were collected and recorded. RESULTS: At baseline, 19% of the FDRs reported inflammatory back pain, 32% current arthralgia, 3% arthritis (ever), 5% enthesitis (ever), and 1% dactylitis (ever), and 3% had an extraarticular manifestation. C-reactive protein level was elevated in 16%, and erythrocyte sedimentation rate was elevated in 7%. On magnetic resonance imaging (MRI) views of sacroiliac joints, 10% had a Spondyloarthritis Research Consortium of Canada score of ≥2, 4% had a score of ≥5, and 4% had deep lesions. In total, 1% fulfilled the modified New York criteria for radiographic sacroiliitis. Clinical, MRI, and acute phase findings were equally distributed between HLA-B27-positive and -negative FDRs. After 1 year of follow-up, clinical parameters did not change on the group level, but 6% of the FDRs were clinically diagnosed with axial SpA, of whom 86% were HLA-B27-positive. CONCLUSION: Features associated with SpA or imaging abnormalities were found in up to 32% of seemingly healthy FDRs, with an equal distribution between HLA-B27-positive and -negative FDRs. Progression to clinical axial SpA within 1 year of follow-up was mainly observed in HLA-B27-positive FDRs.

Multi-biomarker disease activity score as a predictor of disease relapse in patients with rheumatoid arthritis stopping TNF inhibitor treatment.

OBJECTIVE: Successfully stopping or reducing treatment for patients with rheumatoid arthritis (RA) in low disease activity (LDA) may improve cost-effectiveness of care. We evaluated the multi-biomarker disease activity (MBDA) score as a predictor of disease relapse after discontinuation of TNF inhibitor (TNFi) treatment. METHODS: 439 RA patients who were randomized to stop TNFi treatment in the POET study were analyzed post-hoc. Three indicators of disease relapse were assessed over 12 months: 1) restarting TNFi treatment, 2) escalation of any DMARD therapy and 3) physician-reported flare. MBDA score was assessed at baseline. Associations between MBDA score and disease relapse were examined using univariate analysis and multivariate logistic regression. RESULTS: At baseline, 50.1%, 35.3% and 14.6% of patients had low (<30), moderate (30-44) or high (>44) MBDA scores. Within 12 months, 49.9% of patients had restarted TNFi medication, 59.0% had escalation of any DMARD and 57.2% had ≥1 physician-reported flare. MBDA score was associated with each indicator of relapse. At least one indicator of relapse was observed in 59.5%, 68.4% and 81.3% of patients with low, moderate or high MBDA scores, respectively (P = 0.004). Adjusted for baseline DAS28-ESR, disease duration, BMI and erosions, high MBDA scores were associated with increased risk for restarting TNFi treatment (OR = 1.85, 95% CI 1.00-3.40), DMARD escalation (OR = 1.99, 95% CI 1.01-3.94) and physician-reported flare (OR = 2.00, 95% 1.06-3.77). CONCLUSION: For RA patients with stable LDA who stopped TNFi, a high baseline MBDA score was independently predictive of disease relapse within 12 months. The MBDA score may be useful for identifying patients at risk of relapse after TNFi discontinuation.

Risk of rheumatoid arthritis development in patients with unclassified arthritis according to the 2010 ACR/EULAR criteria for rheumatoid arthritis.

OBJECTIVE: Early recognition and treatment of RA is associated with an improved outcome. The 2010 ACR/EULAR criteria for RA identify RA patients earlier than the 1987 ACR criteria. Nevertheless, we recently observed that 24% of the 2010 unclassified arthritis (UA) patients develop RA during follow-up. Here we studied this frequency in other cohorts and evaluated the prognostic accuracy of ACPA and the Leiden prediction rule in 2010 UA patients. METHODS: The 2010 UA patients from three Early Arthritis Clinics were studied: 776 from Leiden, 121 from Birmingham and 322 from Amsterdam. Fulfilment of the 1987 ACR criteria during follow-up was studied as the primary outcome. DMARD prescription during the year and having a persistent course of arthritis over 7 years were studied as secondary outcomes in one cohort. The presence of ACPA and the prediction score at baseline were evaluated in relation to these outcomes. RESULTS: In the three cohorts, 24%, 26% and 12%, respectively, of the 2010 UA patients fulfilled the 1987 criteria after 1 year. However, some of these patients already fulfilled the 1987 criteria at baseline. In 1987 and 2010 UA patients, 15%, 21% and 9%, respectively, developed RA (1987) at 1 year. In these patients, 0-6% of the patients were ACPA positive and 0-1% had high prediction scores. Consequently a large majority of the UA patients with an unfavourable outcome was not recognized by these prognostic tools. CONCLUSION: A proportion of 2010 UA patients progress to RA. ACPA and the Leiden prediction rule are not useful in identifying these patients. These results imply that other predictive markers should be developed for 2010 UA patients.

Genome-wide association analysis of anti-TNF drug response in patients with rheumatoid arthritis.

BACKGROUND: Treatment strategies blocking tumour necrosis factor (anti-TNF) have proven very successful in patients with rheumatoid arthritis (RA). However, a significant subset of patients does not respond for unknown reasons. Currently, there are no means of identifying these patients before treatment. This study was aimed at identifying genetic factors predicting anti-TNF treatment outcome in patients with RA using a genome-wide association approach. METHODS: We conducted a multistage, genome-wide association study with a primary analysis of 2 557 253 single-nucleotide polymorphisms (SNPs) in 882 patients with RA receiving anti-TNF therapy included through the Dutch Rheumatoid Arthritis Monitoring (DREAM) registry and the database of Apotheekzorg. Linear regression analysis of changes in the Disease Activity Score in 28 joints after 14 weeks of treatment was performed using an additive model. Markers with p<10(-3) were selected for replication in 1821 patients from three independent cohorts. Pathway analysis including all SNPs with p<10(-3) was performed using Ingenuity. RESULTS: 772 markers showed evidence of association with treatment outcome in the initial stage. Eight genetic loci showed improved p value in the overall meta-analysis compared with the first stage, three of which (rs1568885, rs1813443 and rs4411591) showed directional consistency over all four cohorts studied. We were unable to replicate markers previously reported to be associated with anti-TNF outcome. Network analysis indicated strong involvement of biological processes underlying inflammatory response and cell morphology. CONCLUSIONS: Using a multistage strategy, we have identified eight genetic loci associated with response to anti-TNF treatment. Further studies are required to validate these findings in additional patient collections.

Inter-observer reproducibility of measurements of range of motion in patients with shoulder pain using a digital inclinometer.

BACKGROUND: Reproducible measurements of the range of motion are an important prerequisite for the interpretation of study results. The digital inclinometer is considered to be a useful instrument because it is inexpensive and easy to use. No previous study assessed inter-observer reproducibility of range of motion measurements with a digital inclinometer by physical therapists in a large sample of patients. METHODS: Two physical therapists independently measured the passive range of motion of the glenohumeral abduction and the external rotation in 155 patients with shoulder pain. Agreement was quantified by calculation of the mean differences between the observers and the standard deviation (SD) of this difference and the limits of agreement, defined as the mean difference +/- 1.96*SD of this difference. Reliability was quantified by means of the intraclass correlation coefficient (ICC). RESULTS: The limits of agreement were 0.8 +/- 19.6 for glenohumeral abduction and -4.6 +/- 18.8 for external rotation (affected side) and quite similar for the contralateral side and the differences between sides. The percentage agreement within 10 degrees for these measurements were 72% and 70% respectively. The ICC ranged from 0.28 to 0.90 (0.83 and 0.90 for the affected side). CONCLUSIONS: The inter-observer agreement was found to be poor. If individual patients are assessed by two different observers, differences in range of motion of less than 20-25 degrees can not be distinguished from measurement error. In contrast, acceptable reliability was found for the inclinometric measurements of the affected side and the differences between the sides, indicating that the inclimeter can be used in studies in which groups are compared.