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Objective: To assess prospectively the rates and to explore predictors of spinal radiographic progression over 2 years in a cohort of patients with early axial spondylarthritis (SpA)., Methods: Two hundred ten patients with axial SpA from the German Spondyloarthritis Inception Cohort were selected for this analysis based on the availability of radiographs at baseline and after 2 years of followup. Spinal radiographs were scored by 2 trained readers in a blinded, randomly selected order according to the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS). Spinal radiographic progression was defined as worsening of the mean mSASSS by ≥2 units over 2 years., Results: Among the patients with axial SpA, 14.3% showed spinal radiographic progression after 2 years (20% of those with AS and 7.4% of those with nonradiographic axial SpA). The following parameters were independently associated with spinal radiographic progression: presence of syndesmophytes at baseline (odds ratio [OR] 6.29, P < 0.001), elevated levels of markers of systemic inflammation (for the erythrocyte sedimentation rate, OR 4.04, P = 0.001; for C-reactive protein level time-averaged over 2 years, OR 3.81, P = 0.001), and cigarette smoking (OR 2.75, P = 0.012). These associations were confirmed by multivariate logistic regression analysis. No clear association with spinal radiographic progression was observed for HLA-B27 status, sex, age, disease duration, Bath Ankylosing Spondylitis Disease Activity Index, Bath Ankylosing Spondylitis Functional Index, presence of peripheral arthritis, enthesitis, psoriasis, treatment with nonsteroidal antiinflammatory drugs, or treatment with disease-modifying antirheumatic drugs at baseline., Conclusion: The presence of radiographic damage at baseline (syndesmophytes), elevated levels of acute-phase reactants, and cigarette smoking were all independently associated with spinal radiographic progression in patients with early axial SpA., (Copyright © 2012 by the American College of Rheumatology.)

Objective: Remission in rheumatoid arthritis (RA) is an increasingly attainable goal, but there is no widely used definition of remission that is stringent but achievable and could be applied uniformly as an outcome measure in clinical trials. This work was undertaken to develop such a definition., Methods: A committee consisting of members of the American College of Rheumatology, the European League Against Rheumatism, and the Outcome Measures in Rheumatology Initiative met to guide the process and review prespecified analyses from RA clinical trials. The committee requested a stringent definition (little, if any, active disease) and decided to use core set measures including, as a minimum, joint counts and levels of an acute-phase reactant to define remission. Members were surveyed to select the level of each core set measure that would be consistent with remission. Candidate definitions of remission were tested, including those that constituted a number of individual measures of remission (Boolean approach) as well as definitions using disease activity indexes. To select a definition of remission, trial data were analyzed to examine the added contribution of patient-reported outcomes and the ability of candidate measures to predict later good radiographic and functional outcomes., Results: Survey results for the definition of remission suggested indexes at published thresholds and a count of core set measures, with each measure scored as 1 or less (e.g., tender and swollen joint counts, C-reactive protein [CRP] level, and global assessments on a 0-10 scale). Analyses suggested the need to include a patient-reported measure. Examination of 2-year followup data suggested that many candidate definitions performed comparably in terms of predicting later good radiographic and functional outcomes, although 28-joint Disease Activity Score-based measures of remission did not predict good radiographic outcomes as well as the other candidate definitions did. Given these and other considerations, we propose that a patient's RA can be defined as being in remission based on one of two definitions: (a) when scores on the tender joint count, swollen joint count, CRP (in mg/dl), and patient global assessment (0-10 scale) are all ≤ 1, or (b) when the score on the Simplified Disease Activity Index is ≤ 3.3., Conclusion: We propose two new definitions of remission, both of which can be uniformly applied and widely used in RA clinical trials. We recommend that one of these be selected as an outcome measure in each trial and that the results on both be reported for each trial., (Copyright © 2011 by the American College of Rheumatology.)

Objective: Osteocytes are considered to be sensors of bone damage and regulators of bone mass by specifically expressing sclerostin, an inhibitor of bone formation. The contribution of osteocytes in regulating local bone remodeling in arthritis is unknown. The aim of this study was to investigate the role of osteocytes as contributors to bone remodeling in ankylosing spondylitis (AS)., Methods: Sclerostin expression and osteocyte death were assessed by immunohistochemistry in joints derived from patients with AS, patients with rheumatoid arthritis (RA), and patients with osteoarthritis (OA), as well as from control subjects. In addition, the serum level of sclerostin was assessed by enzyme-linked immunosorbent assay in healthy subjects and patients with AS; this assessment included the longitudinal correlation of sclerostin serum levels and radiographic progression in the spine of patients with AS., Results: Sclerostin expression was confined exclusively to osteocytes. Whereas the majority of osteocytes in healthy individuals and patients with RA were sclerostin positive, expression was significantly reduced in patients with OA and was virtually absent in patients with AS. Moreover, serum levels of sclerostin were significantly lower in patients with AS than in healthy individuals. Importantly, low serum sclerostin levels in patients with AS were significantly associated with the formation of new syndesmophytes (P = 0.007)., Conclusion: Sclerostin expression is impaired in patients with AS, suggesting a specific alteration of osteocyte function in this disease. A low serum level of sclerostin in the setting of AS is linked to increased structural damage, emphasizing the role of sclerostin in the suppression of bone formation.

Objective: Ankylosing spondylitis (AS) is diagnosed late, because radiographs of the sacroiliac joints often do not show definite sacroiliitis at the time of disease onset. The aim of this study was to investigate whether patients without definite radiographically defined sacroiliitis, referred to as nonradiographic axial spondylarthritis (SpA), are different from patients with AS with regard to clinical manifestations and disease activity measures. Moreover, we sought to identify determinants of the development of radiographic sacroiliitis., Methods: In a cross-sectional analysis of 462 patients, we compared 226 patients with nonradiographic axial SpA (symptom duration < or =5 years) and 236 patients with AS (symptom duration < or =10 years) who are participants in the German Spondyloarthritis Inception Cohort. Radiographs of the sacroiliac joints and the spine were assessed by 2 readers in a blinded manner. Logistic regression analysis was applied to identify parameters associated with structural damage., Results: The 2 groups did not differ in the frequency of HLA-B27 positivity, inflammatory back pain, arthritis, enthesitis, and uveitis and had similar levels of disease activity, using measures such as the Bath Ankylosing Spondylitis Disease Activity Index. In both groups, HLA-B27 positivity determined the age at disease onset. Male sex (adjusted odds ratio [OR] 2.38, 95% confidence interval [95% CI] 1.19-4.73 [P = 0.014]) and an elevated C-reactive protein (CRP) level (adjusted OR 1.85, 95% CI 0.96-3.56 [P = 0.066]) were associated with radiographic sacroiliitis. In patients with AS, male sex and an elevated CRP level were also associated with the presence of syndesmophytes., Conclusion: Clinical manifestations and disease activity measures are highly comparable between patients with early nonradiographic axial SpA and those with early AS, suggesting that these 2 entities are part of the same disease. Male sex and an elevated CRP level are associated with structural damage on radiographs, whereas HLA-B27 positivity determines the age at disease onset.

Objective: To evaluate the efficacy and safety of the tumor necrosis factor (TNF) antagonist adalimumab in patients with axial spondylarthritis (SpA) without radiographically defined sacroiliitis refractory to conventional treatment., Methods: Patients with active axial SpA (n = 46) were randomized to receive placebo or adalimumab at a dosage of 40 mg subcutaneously every other week for 12 weeks, followed by an open-label extension that continued up to week 52. The diagnosis of axial SpA required the presence of 3 of 6 diagnostic criteria, including 2 of the following 3 criteria: inflammatory back pain, HLA-B27 positivity, or acute inflammation of the spine or sacroiliac joints on magnetic resonance imaging, in the absence of radiographic evidence of sacroiliitis. The primary end point was a 40% response according to the improvement criteria of the Assessment of SpondyloArthritis international Society (ASAS40)., Results: All 46 patients (22 receiving adalimumab and 24 receiving placebo) completed the 12-week trial; 38 patients completed the extension period to week 52. At week 12, an ASAS40 response was achieved by 54.5% of the adalimumab-treated patients, as compared with 12.5% of the placebo-treated patients (P = 0.004). After switching to adalimumab, a similar degree of efficacy was also achieved by the patients who were initially treated with placebo. Efficacy was maintained in all patients until week 52. Young age at study entry and an elevated C-reactive protein concentration were the best predictors of achieving an ASAS40 response. Serious adverse events occurred in 5 patients, none of which was related to the study drug., Conclusion: Adalimumab is the first TNF antagonist to demonstrate good clinical efficacy and safety in patients with axial SpA without radiographically defined sacroiliitis.

Objective: To determine the hazard risk of developing or worsening heart failure in rheumatoid arthritis (RA) patients treated with tumor necrosis factor alpha (TNFalpha) inhibitors., Methods: RA patients ages 18-75 years who started treatment with infliximab, etanercept, or adalimumab (n = 2,757), or conventional disease-modifying antirheumatic drugs (controls; n = 1,491) at the time of enrollment in a German biologics register were studied. Cox proportional hazards models were applied to investigate the influence of disease-related and treatment-specific risk factors on the incidence or worsening of heart failure., Results: The 3-year incidence rates of heart failure in patients with and patients without cardiovascular disease at the start of treatment were 2.2% and 0.4%, respectively. After adjustment for traditional cardiovascular risk factors, an increased risk of developing heart failure was found in patients who had a higher 28-joint Disease Activity Score at followup (hazard ratio [HR] 1.47 [95% confidence interval 1.07-2.02], P = 0.019). A residual nonsignificant risk related to treatment with TNFalpha inhibitors remained (adjusted HR 1.66 [95% confidence interval 0.67-4.1], P = 0.28). This residual risk was balanced by the efficacy of the anti-TNF treatment. When only baseline characteristics were taken into account, the HR related to TNFalpha inhibitor treatment decreased to 0.70 (95% confidence interval 0.27-1.84)., Conclusion: The findings of this study indicate that TNFalpha inhibitor treatment that effectively reduces the inflammatory activity of RA is more likely to be beneficial than harmful with regard to the risk of heart failure, especially if there is no concomitant therapy with glucocorticoids or cyclooxygenase 2 inhibitors. Furthermore, the data suggest that TNFalpha inhibition does not increase the risk of worsening of prevalent heart failure.

Objective: Randomized clinical trials (RCTs) evaluate the efficacy of treatments in selected groups of patients defined by strict inclusion criteria. The value of these trials in predicting therapeutic effectiveness in "real world" patients is limited. This observational cohort study was designed to complement the knowledge obtained in RCTs by evaluating the effectiveness of tumor necrosis factor (TNF) inhibitors in patients with rheumatoid arthritis (RA) according to their eligibility for the major trials., Methods: Using the data from the German biologics register Rheumatoid Arthritis Observation of Biologic Therapy (RABBIT [in German]), we investigated how many of the RA patients who were treated with a TNF inhibitor (infliximab, etanercept, or adalimumab) would have been eligible for the major clinical trials that led to approval of the drugs. In addition, therapeutic effectiveness was compared in the eligible and ineligible patients using the American College of Rheumatology 20% (ACR20) and 50% (ACR50) improvement response criteria., Results: Only 21-33% of the patients in the RABBIT register would have been eligible for the major trials. In these patients, the ACR20 and ACR50 improvement responses, indicating therapeutic effectiveness, were comparable with the response rates in the published trials. ACR response rates were lower in those patients considered ineligible for the trials; however, absolute improvement was similar to that in eligible patients. Ineligible patients had lower baseline disease activity, more comorbidity, and lower functional status., Conclusion: RCT cohorts reflect only a minor proportion of the patients treated with biologic agents in routine care. In the clinic setting, the indications for treatment with biologic agents are not identical to the inclusion criteria for trials. Despite the smaller relative improvement achieved in these patients with longstanding, severe RA who would not fulfill the inclusion criteria of a major trial, the majority of such patients would nevertheless benefit from biologic therapy.

Objective: Back pain associated with ankylosing spondylitis (AS) is referred to as inflammatory back pain (IBP). The value of the clinical history in differentiating IBP from mechanical low back pain (MLBP) has been investigated in only a few studies. In this exploratory study, we sought to evaluate the individual features of IBP and to compose and compare various combinations of features for use as classification and diagnostic criteria., Methods: We assessed the clinical history of 213 patients (101 with AS and 112 with MLBP) younger than 50 years who had chronic back pain. Single clinical parameters and combinations of parameters were compared between the AS and MLBP patient groups., Results: Morning stiffness of >30 minutes' duration, age at onset of back pain, no improvement in back pain with rest, awakening because of back pain during the second half of the night only, alternating buttock pain, and time period of the onset of back pain were identified as independent contributors to IBP. Importantly, none of the single parameters sufficiently differentiated AS from MLBP. In contrast, several sets of combined parameters proved to be well balanced between sensitivity and specificity. Among these, a new candidate set of criteria for IBP, which consisted of morning stiffness of >30 minutes' duration, improvement in back pain with exercise but not with rest, awakening because of back pain during the second half of the night only, and alternating buttock pain, yielded a sensitivity of 70.3% and a specificity of 81.2% if at least 2 of these 4 parameters were fulfilled (positive likelihood ratio 3.7). If at least 3 of the 4 parameters were fulfilled, the positive likelihood ratio increased to 12.4., Conclusion: A new set of criteria for IBP performed better than previous criteria in AS patients with established disease. A prospective study is needed to validate the diagnostic properties of the new candidate criteria set in patients with early disease.

Objective: To estimate the incidence rates of serious and nonserious infections in patients with rheumatoid arthritis (RA) who start treatment with a biologic agent, and to compare these rates with those in patients with RA who receive conventional treatment., Methods: Patients enrolled in the German biologics register between May 2001 and September 2003 were included. Treating rheumatologists assessed adverse events and serious adverse events. All adverse events and serious adverse events experienced within 12 months after study entry were analyzed. Propensity score methods were applied to estimate which part of a rate increase was likely to be attributable to differences in patient characteristics., Results: Data were available for 512 patients receiving etanercept, 346 patients receiving infliximab, 70 patients receiving anakinra, and 601 control patients treated with disease-modifying antirheumatic drugs. The total number of adverse events per 100 patient-years was 22.6 (95% confidence interval [95% CI] 18.7-27.2) among patients receiving etanercept, 28.3 (95% CI 23.1-34.7) among patients receiving infliximab, and 6.8 (95% CI 5.0-9.4) among controls (P < 0.0001). Significant differences in the rate of serious adverse events were also observed. For patients receiving etanercept, those receiving infliximab, and controls, the total numbers of serious adverse events per 100 patient-years were 6.4 (95% CI 4.5-9.1), 6.2 (95% CI 4.0-9.5), and 2.3 (95% CI 1.3-3.9), respectively (P = 0.0016). After adjusting for differences in the case patient mix, the relative risks of serious adverse events were 2.2 (95% CI 0.9-5.4) for patients receiving etanercept and 2.1 (95% CI 0.8-5.5) for patients receiving infliximab, compared with controls., Conclusion: Patients treated with biologic agents have a higher a priori risk of infection. However, our data suggest that this risk is increased by treatment with tumor necrosis factor inhibitors.

Objective: Rheumatoid arthritis (RA)-associated HLA class II genes are assumed to promote susceptibility to and/or progression of the disease. Among the various modes of action proposed so far is the effect of the differential expression of HLA class II genes in different types of antigen-presenting cells on the Th1/Th2 balance. The aim of this study was to investigate the differential expression of genes encoded within the RA-associated HLA-DR4 superhaplotype and within the neutral DR7 and DR9 superhaplotypes., Methods: The promoters encoded within these 3 haplotypes were first analyzed for sequence polymorphisms. To test for functional consequences, we assumed that the binding of nuclear factors to the promoter elements was correlated with the transcription activity, and we used surface plasmon resonance technology. To that end, oligonucleotides representing the polymorphic regulatory sequences and nuclear extracts from a monocyte cell line and a B cell line were used., Results: While the promoters of the highly polymorphic HLA-DRB1*04, *07, and *09 alleles showed comparable binding of nuclear factors, differential binding was observed for the 2 promoters that drive the relatively nonpolymorphic DRB4 alleles in linkage disequilibrium with DRB1. Interestingly, analysis of RA patients positive for DR4, DR7, and DR9 revealed the segregation of radiographic progression with the stronger of the 2 DRB4 promoters, independent of the DRB1 allele. Moreover, DRB1*04 alleles in RA patients showed a reduced association with the DRB4 splice variant, completely preventing DRB4 expression., Conclusion: Our findings represent the first evidence of a correlation between the differential expression of HLA class II genes and both the susceptibility and the progression of RA.

Objective: To describe the long-term outcome of juvenile idiopathic arthritis (JIA)., Methods: All patients with JIA referred to a pediatric rheumatology center between 1978 and 1988 were identified and invited to undergo an assessment. Patients with JIA from a population-based cohort from East Berlin were included. The outcome assessment considered changes in body function and structure (e.g., mortality, joint abnormalities, disease activity), activities at the individual level (Health Assessment Questionnaire), and participation in society (e.g., mobility, educational and vocational background)., Results: Of 260 eligible patients, 215 (83%) were evaluated. Subtypes of JIA at disease onset included oligoarthritis (40%), polyarthritis (14%), systemic arthritis (14%), psoriatic arthritis (1%), enthesitis-related arthritis (15%), and other arthritis (16%). Followup was conducted after a median of 16.5 years. No deaths occurred in this cohort. At followup, approximately half of the patients had active disease and/or changes in body structures to a variable extent. Approximately one-third of patients rated themselves as being functionally limited. Patients demonstrated good social integration: few mobility problems were reported, and the educational achievements of patients were higher and their rate of unemployment was lower compared with the age-matched population. No significant differences in outcome were found between the population-based and the referral-based cohorts., Conclusion: Even though approximately half of the JIA patients had more or less distinctive changes in body function and/or structure after a disease duration of >15 years, fewer than 10% were severely disabled or handicapped. Because JIA often persists into adulthood, long-term followup and care are necessary.