Response to Tumor Necrosis Factor Inhibition in Male and Female Patients with Ankylosing Spondylitis: Data from a Swiss Cohort.

OBJECTIVE: To investigate sex differences in connection with the effectiveness of tumor necrosis factor inhibitors (TNFi) in patients with ankylosing spondylitis (AS). METHODS: A total of 440 patients with AS (294 men; 146 women) initiating a first TNFi in the prospective Swiss Clinical Quality Management Cohort were included. We evaluated the proportion of patients achieving the 20% and 40% improvement in the Assessment of Spondyloarthritis international Society criteria (ASAS20 and ASAS40) as well as Ankylosing Spondylitis Disease Activity Score (ASDAS) improvement and status scores at 1 year. Patients having discontinued TNFi were considered nonresponders. Logistic regression analyses were performed to adjust for important predictors of response. RESULTS: Compared to men, female patients had lower mean C-reactive protein levels, better spinal mobility, and more peripheral disease at the start. There was no sex disparity with regard to the ASDAS, the Bath Ankylosing Spondylitis Disease Activity and Functional indices, and the quality of life. At 1 year, 52% of women and 63% of men achieved an ASAS20 response (OR 0.63, 95% CI 0.37-1.07, p = 0.09). An inactive disease status (ASDAS < 1.3) was reached by 18% of women and 26% of men (OR 0.65, 95% CI 0.32-1.27, p = 0.22). These sex differences in response to TNFi were more pronounced in adjusted analyses (OR 0.34, 95% CI 0.16-0.71, p = 0.005 for ASAS20 and OR 0.10, 95% CI 0.03-0.31, p < 0.001 for ASDAS < 1.3) and confirmed for all the other outcomes assessed. CONCLUSION: In AS, fewer women respond to TNFi and women show a reduced response in comparison to men.

TNF blockers inhibit spinal radiographic progression in ankylosing spondylitis by reducing disease activity: results from the Swiss Clinical Quality Management cohort.

OBJECTIVES: To analyse the impact of tumour necrosis factor inhibitors (TNFis) on spinal radiographic progression in ankylosing spondylitis (AS). METHODS: Patients with AS in the Swiss Clinical Quality Management cohort with up to 10 years of follow-up and radiographic assessments every 2 years were included. Radiographs were scored by two readers according to the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS) with known chronology. The relationship between TNFi use before a 2-year radiographic interval and progression within the interval was investigated using binomial generalised estimating equation models with adjustment for potential confounding and multiple imputation of missing values. Ankylosing Spondylitis Disease Activity Score (ASDAS) was regarded as mediating the effect of TNFi on progression and added to the model in a sensitivity analysis. RESULTS: A total of 432 patients with AS contributed to data for 616 radiographic intervals. Radiographic progression was defined as an increase in ≥2 mSASSS units in 2 years. Mean (SD) mSASSS increase was 0.9 (2.6) units in 2 years. Prior use of TNFi reduced the odds of progression by 50% (OR 0.50, 95% CI 0.28 to 0.88) in the multivariable analysis. While no direct effect of TNFi on progression was present in an analysis including time-varying ASDAS (OR 0.61, 95% CI 0.34 to 1.08), the indirect effect, via a reduction in ASDAS, was statistically significant (OR 0.75, 95% CI 0.59 to 0.97). CONCLUSION: TNFis are associated with a reduction of spinal radiographic progression in patients with AS. This effect seems mediated through the inhibiting effect of TNFi on disease activity.

Impact of obesity on the response to tumor necrosis factor inhibitors in axial spondyloarthritis.

BACKGROUND: Few studies have investigated the impact of obesity on the response to tumor necrosis factor inhibitors (TNFi) in patients with axial spondyloarthritis (axSpA). The aim of our study was to investigate the impact of different body mass index (BMI) categories on TNFi response in a large cohort of patients with axSpA. METHODS: Patients with axSpA within the Swiss Clinical Quality Management (SCQM) program were included in the current study if they fulfilled the Assessment in Spondyloarthritis International Society (ASAS) criteria for axSpA, started a first TNFi after recruitment, and had available BMI data as well as a baseline and follow-up visit at 1 year (±6 months). Patients were categorized according to BMI: normal (BMI 18.5 to <25), overweight (BMI 25-30), and obese (BMI >30). We evaluated the proportion of patients achieving the 40% improvement in ASAS criteria (ASAS40), as well as Ankylosing Spondylitis Disease Activity Score (ASDAS) improvement and status scores at 1 year. Patients having discontinued the TNFi were considered nonresponders. We controlled for age, sex, HLA-B27, axSpA type, BASDAI, BASMI, elevated C-reactive protein (CRP), current smoking, enthesitis, physical exercise, and co-medication with disease-modifying antirheumatic drugs, as well as with nonsteroidal anti-inflammatory drugs in multiple adjusted logistic regression analyses. RESULTS: A total of 624 axSpA patients starting a first TNFi were considered in the current study (332 patients of normal weight, 204 patients with overweight, and 88 obese patients). Obese individuals were older, had higher BASDAI levels, and had a more important impairment of physical function in comparison to patients of normal weight, while ASDAS and CRP levels were comparable between the three BMI groups. An ASAS40 response was reached by 44%, 34%, and 29% of patients of normal weight, overweight, and obesity, respectively (overall p = 0.02). Significantly lower odds ratios (ORs) for achieving ASAS40 response were found in adjusted analyses in obese patients versus patients with normal BMI (OR 0.27, 95% confidence interval (CI) 0.09-0.70). The respective adjusted ASAS40 OR in overweight versus normal weight patients was 0.62 (95% CI 0.24-1.14). Comparable results were found for the other outcomes assessed. CONCLUSIONS: Obesity is associated with significantly lower response rates to TNFi in patients with axSpA.

Magnetic Resonance Imaging Findings in the Knee Before and After Long-Distance Running-Documentation of Irreversible Structural Damage? A Systematic Review.

BACKGROUND: Various studies have investigated structural knee changes after running, with conflicting results. PURPOSE: To perform a systematic review of acute changes in knee structures as detected by magnetic resonance imaging (MRI) after running and assess the reversibility of these changes. STUDY DESIGN: Systematic review. METHODS: A systematic literature search in Medline, Cochrane, Embase, and Scopus was performed. Articles that fulfilled predefined inclusion criteria were included and systematically reviewed according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement. RESULTS: A total of 19 studies were included in this review. All studies performed standard knee MRI; 6 studies additionally performed T1ρ and T2 mapping. Sixteen studies assessed cartilage or meniscal morphological changes. Ten found no significant morphological changes after running. Six studies showed significant changes at the first follow-up. Six performed a second follow-up. Five showed no change compared with baseline and the first follow-up, and 1 showed a significant recovery compared with the first follow-up and no significant difference compared with baseline. Five of the 6 studies performing T1ρ and T2 mapping found significant changes in T2 and T1ρ values at the first follow-up. Three performed a second follow-up. Two found a significant recovery of T2 but no recovery of T1ρ. One study did not find a significant change compared with baseline. Ten studies assessed the patellar tendon, ligaments, synovial fluid, or subchondral bone. Changes at the first follow-up were not significant. A second follow-up was performed in 5 studies. All studies discovered recovery from the first follow-up. CONCLUSION: These data suggest that healthy athletes who have no risk factors for degenerative joint disease may present fleeting quantitative alterations after running. No irreversible, qualitative harmful effects seemed to occur, with the exception of persistent T1ρ elevation representing a proteoglycan depletion. Whether T1ρ changes need more than 3 months to recover or represent permanent structural damage remains to be investigated.

Computer-based diagnostic expert systems in rheumatology: where do we stand in 2014?

Background. The early detection of rheumatic diseases and the treatment to target have become of utmost importance to control the disease and improve its prognosis. However, establishing a diagnosis in early stages is challenging as many diseases initially present with similar symptoms and signs. Expert systems are computer programs designed to support the human decision making and have been developed in almost every field of medicine. Methods. This review focuses on the developments in the field of rheumatology to give a comprehensive insight. Medline, Embase, and Cochrane Library were searched. Results. Reports of 25 expert systems with different design and field of application were found. The performance of 19 of the identified expert systems was evaluated. The proportion of correctly diagnosed cases was between 43.1 and 99.9%. Sensitivity and specificity ranged from 62 to 100 and 88 to 98%, respectively. Conclusions. Promising diagnostic expert systems with moderate to excellent performance were identified. The validation process was in general underappreciated. None of the systems, however, seemed to have succeeded in daily practice. This review identifies optimal characteristics to increase the survival rate of expert systems and may serve as valuable information for future developments in the field.

Cross-cultural adaptation of the German version of the spinal stenosis measure.

PURPOSE: To validate the German version of the spinal stenosis measure (SSM), a disease-specific questionnaire assessing symptom severity, physical function, and satisfaction with treatment in patients with lumbar spinal stenosis. METHODS: After translation, cross-cultural adaptation, and pilot testing, we assessed internal consistency, test-retest reliability, construct validity, and responsiveness of the SSM subscales. Data from a large Swiss multi-center prospective cohort study were used. Reference scales for the assessment of construct validity and responsiveness were the numeric rating scale, pain thermometer, and the Roland Morris Disability Questionnaire. RESULTS: One hundred and eight consecutive patients were included in this validation study, recruited from five different centers. Cronbach's alpha was above 0.8 for all three subscales of the SSM. The objectivity of the SSM was assessed using a partial credit approach. The model showed a good global fit to the data. Of the 108 patients 78 participated in the test-retest procedure. The ICC values were above 0.8 for all three subscales of the SSM. Correlations with reference scales were above 0.7 for the symptom and function subscales. For satisfaction subscale, it was 0.66 or above. Clinically meaningful changes of the reference scales over time were associated with significantly more improvement in all three SSM subscales (p < 0.001). Conclusion: The proposed version of the SSM showed very good measurement properties and can be considered validated for use in the German language.

Relevant baseline characteristics for describing patients with knee osteoarthritis: results from a Delphi survey.

BACKGROUND: Inclusion/exclusion criteria and baseline characteristics are essential for assessing the applicability of trial results to a given patient and the comparability of study populations for meta-analyses. This Delphi survey aimed to generate a set of baseline characteristics for describing patients with knee osteoarthritis enrolled in clinical studies. METHODS: Survey participants comprised clinical experts (n = 23; mean age 54 y; from 4 continents) that had authored at least two randomized trials on knee osteoarthritis. First, given a prepared list of baseline patient characteristics, the experts were asked to add characteristics they considered important for assessing comparability of patient populations in different trials that evaluated the efficacy of non-surgical interventions for treating knee osteoarthritis. Next, they were asked to rate the importance of each characteristic, on a scale of 0 (not important) to 10 (highly important), according to three outcome categories: pain, function, and structure. RESULTS: Participants identified 121 baseline characteristics. A rating ≥7 points was assigned to 39 characteristics (e.g., age, depression, global knee pain, daily dose of pain killers, Kellgren-Lawrence grading); of these, 20 were related to pain, 15 to function, and 23 to structural outcomes. Global knee pain was the only baseline characteristic that fulfilled among experts the predefined consensus criteria. CONCLUSIONS: Experts identified a large number of characteristics for describing patients with knee osteoarthritis. Disagreement and uncertainty prevailed over the relevance of these characteristics. Our findings justified further efforts to define appropriate, broadly acceptable sets of baseline characteristics for describing patients with knee osteoarthritis.

Total Knee Replacement as a Knee Osteoarthritis Outcome: Predictors Derived from a 4-Year Long-Term Observation following a Randomized Clinical Trial Using Chondroitin Sulfate.

OBJECTIVE: To predict, using clinical and qMRI data, the incidence of total knee replacement (TKR) during the long-term follow-up of knee osteoarthritis (OA) patients who formerly received chondroitin sulfate (CS) or placebo treatment. DESIGN: A post hoc intention-to-treat analysis to evaluate the incidence of TKR was done on knee OA patients who had participated in a 12-month trial evaluating the impact of CS (800 mg/d) versus placebo for 6 months, followed by a 6-month open-phase in which all patients received CS. Additionally, the clinical and qMRI predictors of TKR were determined. RESULTS: Thirteen TKRs were performed in the population after a 4-year follow-up. More TKRs were performed in the placebo group than in the CS group (69% vs. 31%, P = 0.150, logistic regression). The statistically significant predictors of TKRs were, at baseline, higher WOMAC pain and function scores, presence of bone marrow lesions (BMLs), and higher C-reactive protein levels. Loss of medial cartilage volume and increase in WOMAC pain and function at one-year were also predictors of TKR. Multivariate analyses revealed that baseline presence of BML and higher WOMAC pain score were independent predictors. Time to occurrence of the TKR also favored the CS group versus placebo (log-rank, P = 0.094). CONCLUSION: Symptoms such as knee pain and function, presence of BML, and cartilage volume loss predict the long-term occurrence of a "hard" outcome such as TKR.

Future therapeutics for osteoarthritis.

Osteoarthritis (OA) is a disease of the joints that affects several million individuals worldwide. This disease, which involves mainly the diarthrodial joints, is chronic and develops slowly over decades, making it very difficult to precisely identify the different etiological and risk factors that influence its onset. At present, most therapies for OA are symptomatic. This review will focus on new OA therapeutics in development that are directed toward pain relief as well as others with the potential to reduce or stop the progression of the disease (DMOADs). This article is part of a Special Issue entitled "Osteoarthritis".

Risk factors predictive of joint replacement in a 2-year multicentre clinical trial in knee osteoarthritis using MRI: results from over 6 years of observation.

OBJECTIVE: To identify predictive factors for total knee replacement (TKR) using data from MRI of knee osteoarthritis patients in a phase III multicentre disease-modifying osteoarthritis drug (DMOAD) study. METHODS: Knee osteoarthritis patients from a 2-year clinical trial evaluating licofelone versus naproxen were investigated for the incidence of TKR of the study knee. Patients (n=161) who completed the study according to protocol were selected. Incidence of TKR was assessed blindly to the treatment following telephone interviews (n=123). RESULTS: 18 TKR (14.6%) were performed in 4-7 years following enrolment in the original study. More TKR were performed within the naproxen than the licofelone group (61% vs 39%, p=0.232). Baseline score of bone marrow lesions (BML) in the medial compartment (p=0.0001), medial joint space width (JSW) as assessed by standardised radiographs (p=0.0008), presence of severe medial meniscal tear (p=0.004), medial meniscal extrusion (p=0.013), and C-reactive protein level (p=0.049) were strong predictors of TKR. Changes at the end of the study also yielded strong predictors: change in cartilage volume of the medial compartment (p=0.005) and of the global knee (p=0.034), reduction in the JSW of greater than 7% (p=0.009), and WOMAC pain (p=0.009) and function (p=0.023) scores. Multivariate analysis showed that baseline severe medial meniscal tear (p=0.023) and presence of medial BML (p=0.025) were the strongest independent long-term predictors of TKR. CONCLUSION: This study shows that in the context of osteoarthritis trials, clinical data and structural changes identified by MRI allow prediction of a 'hard' outcome such as TKR. The findings support the usefulness and predictive value of MRI in defining study outcome in DMOAD trials.

Pseudocystic degeneration of the lumbar ligamentum flavum: a little known entity.

OBJECTIVE: The objective of this work was to investigate the clinical and histologic features of patients with pseudocystic lesions of the ligamentum flavum in the lumbar region of the spinal canal and ascertain the existence of genuine ligamentum flavum pseudocysts. METHODS: Retrospective chart and histologic study of a patient cohort with lumbar radiculopathy due to a cystic intraspinal lesion and who had undergone decompressive surgery was conducted. Intraoperatively, the stenosing process had been found to be different from common etiologic entities and had been submitted for histologic examination. RESULTS: The 33 patients with symptoms and signs of lumbar radiculopathy were between 48 and 85 years of age (mean 63.5 years). Twenty (61%) of them were women. All patients showed degenerative changes of the bony structures of the spine by conventional radiography. Segmental instability due to degeneration of the lumbar spine was present in 45%. Computed tomography and/or magnetic resonance imaging showed a cystic lesion. Clinical and histologic examination confirmed their origin from within the severely degenerated ligamentum flavum. CONCLUSIONS: Radiologic, surgical, and histologic findings suggest that the pseudocystic degeneration of the ligamentum flavum represents a genuine entity that is associated with degenerative changes of the structures of the respective lumbar spine segment. These pseudocystic lesions may compress the adjacent nerve roots, provoking symptoms and signs of radiculopathy. The findings suggest that the surgical treatment not only must consist of removal of the pseudocyst but must also include a radical extirpation of the ligamentum flavum surrounding the pseudocyst to avoid recurrence of such a lesion.