American College of Rheumatology/Spondylitis Association of America/Spondyloarthritis Research and Treatment Network 2015: recommendations for the treatment of ankylosing spondylitis and nonradiographic axial spondyloarthritis

OBJECTIVE: To provide evidence-based recommendations for the treatment of patients with ankylosing spondylitis (AS) and nonradiographic axial spondyloarthritis (SpA). METHODS: A core group led the development of the recommendations, starting with the treatment questions. A literature review group conducted systematic literature reviews of studies that addressed 57 specific treatment questions, based on searches conducted in OVID Medline (1946-2014), PubMed (1966-2014), and the Cochrane Library. We assessed the quality of evidence using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) method. A separate voting group reviewed the evidence and voted on recommendations for each question using the GRADE framework. RESULTS: In patients with active AS, the strong recommendations included use of nonsteroidal antiinflammatory drugs (NSAIDs), use of tumor necrosis factor inhibitors (TNFi) when activity persists despite NSAID treatment, not to use systemic glucocorticoids, use of physical therapy, and use of hip arthroplasty for patients with advanced hip arthritis. Among the conditional recommendations was that no particular TNFi was preferred except in patients with concomitant inflammatory bowel disease or recurrent iritis, in whom TNFi monoclonal antibodies should be used. In patients with active nonradiographic axial SpA despite treatment with NSAIDs, we conditionally recommend treatment with TNFi. Other recommendations for patients with nonradiographic axial SpA were based on indirect evidence and were the same as for patients with AS. CONCLUSION: These recommendations provide guidance for the management of common clinical questions in AS and nonradiographic axial SpA. Additional research on optimal medication management over time, disease monitoring, and preventive care is needed to help establish best practices in these areas.(AU)

Association study of genes related to bone formation and resorption and the extent of radiographic change in ankylosing spondylitis.

OBJECTIVE: To identify genetic associations with severity of radiographic damage in ankylosing spondylitis (AS). METHOD: We studied 1537 AS cases of European descent; all fulfilled the modified New York Criteria. Radiographic severity was assessed from digitised lateral radiographs of the cervical and lumbar spine using the modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS). A two-phase genotyping design was used. In phase 1, 498 single nucleotide polymorphisms (SNPs) were genotyped in 688 cases; these were selected to capture >90% of the common haplotypic variation in the exons, exon-intron boundaries, and 5 kb flanking DNA in the 5' and 3' UTR of 74 genes involved in anabolic or catabolic bone pathways. In phase 2, 15 SNPs exhibiting p<0.05 were genotyped in a further cohort of 830 AS cases; results were analysed both separately and in combination with the discovery phase data. Association was tested by contingency tables after separating the samples into 'mild' and 'severe' groups, defined as the bottom and top 40% by mSASSS, adjusted for gender and disease duration. RESULTS: Experiment-wise association was observed with the SNP rs8092336 (combined OR 0.32, p=1.2×10(-5)), which lies within RANK (receptor activator of NFκB), a gene involved in osteoclastogenesis, and in the interaction between T cells and dendritic cells. Association was also found with the SNP rs1236913 in PTGS1 (prostaglandin-endoperoxide synthase 1, cyclooxygenase 1), giving an OR of 0.53 (p=2.6×10(-3)). There was no observed association between radiographic severity and HLA-B*27. CONCLUSIONS: These findings support roles for bone resorption and prostaglandins pathways in the osteoproliferative changes in AS.

Adherence to oral bisphosphonates and the risk of subtrochanteric and femoral shaft fractures among female medicare beneficiaries.

UNLABELLED: Previous studies have shown an association between duration of bisphosphonate use and atypical femur fractures. This cohort study showed an increasingly higher risk of subtrochanteric and femoral shaft fractures among those who were more adherent to oral bisphosphonates. INTRODUCTION: Long-term use of oral bisphosphonates has been implicated in an increased risk of atypical femur fractures located in subtrochanteric and femoral shaft regions. Another measure of drug exposure, medication adherence, however, has not been investigated. METHODS: Among all Medicare fee-for-service female beneficiaries from 2006-2010, we followed 522,287 new bisphosphonate users from their index prescription until being censored or having a primary diagnosis of closed subtrochanteric/femoral shaft or intertrochanteric/femoral neck fractures. Data about radiographs of fracture site and features were not available. Adherence was classified according to the medication possession ratio (MPR) as the following: MPR < 1/3 as less compliant, MPR ≥ 1/3- < 2/3 as compliant, and MPR ≥ 2/3 as highly compliant. Alternative cutoff points at 50 and 80% were also used. Survival analysis was used to determine the cumulative incidence and hazard of subtrochanteric/femoral shaft or intertrochanteric/femoral neck fractures. RESULTS: There was a graded increase in incidence of subtrochanteric/femoral shaft fractures as the level of adherence increased (Gray's test, P < 0.001). The adjusted hazard ratio (HR) for the highly compliant vs. the less compliant was 1.23 (95% Confidence Interval [CI] 1.06-1.43) overall, became significant after 2 years of follow-up (HR = 1.51, 95% CI 1.06-2.15) and reached the highest risk in the fifth year (HR = 4.06, 95% CI 1.47-11.19). However, age-adjusted incidence rates of intertrochanteric/femoral neck fractures were significantly lower among highly compliant beneficiaries, compared to less compliant users (HR = 0.69, 95% CI 0.66-0.73). Similar results were obtained when the cutoff points for being compliant and highly compliant were set at 50 and 80 %, respectively. CONCLUSIONS: Subtrochanteric/femoral shaft fractures, unlike intertrochanteric/femoral neck fractures, are positively associated with higher adherence to long-term (≥3 years) oral bisphosphonates in the elderly female Medicare population.

Tetrathiomolybdate-associated copper depletion decreases circulating endothelial progenitor cells in women with breast cancer at high risk of relapse.

BACKGROUND: Bone marrow-derived endothelial progenitor cells (EPCs) are critical for metastatic progression. This study explores the effect of tetrathiomolybdate (TM), an anti-angiogenic copper chelator, on EPCs in patients at high risk for breast cancer recurrence. PATIENTS AND METHODS: This phase 2 study enrolled breast cancer patients with stage 3 and stage 4 without evidence of disease (NED), and stage 2 if triple-negative. TM 100 mg orally was administered to maintain ceruloplasmin <17 mg/dl for 2 years or until relapse. The primary end point was change in EPCs. RESULTS: Forty patients (28 stage 2/3, 12 stage 4 NED) were enrolled. Seventy-five percent patients achieved the copper depletion target by 1 month. Ninety-one percent of triple-negative patients copper-depleted compared with 41% luminal subtypes. In copper-depleted patients only, there was a significant reduction in EPCs/ml by 27 (P = 0.04). Six patients relapsed while on study, of which only one patient had EPCs maintained below baseline. The 10-month relapse-free survival was 85.0% (95% CI 74.6%-96.8%). Only grade 3/4 toxicity was hematologic: neutropenia (3.1% of cycles), febrile neutropenia (0.2%), and anemia (0.2%). CONCLUSIONS: TM is safe and appears to maintain EPCs below baseline in copper-depleted patients. TM may promote tumor dormancy and ultimately prevent relapse.

Development of quality indicators to evaluate the monitoring of SLE patients in routine clinical practice.

The assessment of systemic lupus erythematosus (SLE) patients in routine clinical practice is mainly based on the experience of the treating physician. This carries the risk of unwanted variability. Variability may have an impact on the quality of care offered to SLE patients, thereby affecting outcomes. Recommendations represent systematically developed statements to help practitioners in reducing variability. However, major difficulties arise in the application of recommendations into clinical practice. In this respect, the use of quality indicators may raise the awareness among rheumatologists regarding potential deficiencies in services and improve the quality of health care. The aim of this study was to develop a set of quality indicators (QI) for SLE by translating into QIs the recently developed EULAR Recommendations for monitoring SLE patients in routine clinical practice and observational studies. Eleven QIs have been developed referring to the use of validated activity and damage indices in routine clinical practice, general evaluation of drug toxicity, evaluation of comorbidities, eye evaluation, laboratory assessment, evaluation of the presence of chronic viral infections, documentation of vaccination and of antibody testing at baseline. A disease specific set of quality assessment tools should help physicians deliver high quality of care across populations. Routine updates will be needed.

Nephritis and the risk of acute myocardial infarction in patients with systemic lupus erythematosus.

BACKGROUNDS: Patients with systemic lupus erythematosus (SLE) have an increased risk of acute myocardial infarction (AMI). We examined if nephritis or other clinical manifestations of SLE identified patients at increased risk. METHODS: In this population-based case-control study, we identified patients with SLE hospitalized with an AMI in California in 1996-2000. We compared the frequency of six manifestations of SLE (nephritis, pleuritis, hemolytic anemia, thrombocytopenia, psychosis/major depression, seizures) and of venous thrombosis/pulmonary embolism, in this group (n=535) to the frequency of these manifestations in two control groups: patients with SLE hospitalised for pulmonary disease (n=529), and patients with SLE hospitalised for gastrointestinal bleeding (n=349). RESULTS: Nephritis was present in 23.7% of patients with AMI, 11.0% of patients with pulmonary disease and 25.2% of patients with gastrointestinal bleeding. In adjusted analyses, nephritis was more common in the AMI group (odds ratio (OR) 2.85, 95% confidence interval (CI) 1.97-4.14; p<.0001) than in the pulmonary disease control group. Among women, nephritis was more common in the AMI group (OR 2.83; 95% CI 1.33-6.01; p=0.007) than in the gastrointestinal bleeding control group. Psychosis/major depression was less common among patients with AMI. CONCLUSIONS: Among patients with SLE, nephritis was associated with 2.8-fold increased risk of AMI.

Predictors of efficacy after stereotactic radiosurgery for medial temporal lobe epilepsy.

BACKGROUND: Stereotactic radiosurgery (RS) is a promising treatment for intractable medial temporal lobe epilepsy (MTLE). However, the basis of its efficacy is not well understood. METHODS: Thirty patients with MTLE were prospectively randomized to receive 20 or 24 Gy 50% isodose RS centered at the amygdala, 2 cm of the anterior hippocampus, and the parahippocampal gyrus. Posttreatment MRI was evaluated quantitatively for abnormal T2 hyperintensity and contrast enhancement, mass effect, and qualitatively for spectroscopic and diffusion changes. MRI findings were analyzed for potential association with radiation dose and seizure remission (Engel Ib or better outcome). RESULTS: Despite highly standardized dose targeting, RS produced variable MRI alterations. In patients with multiple serial imaging, the appearance of vasogenic edema occurred approximately 9-12 months after RS and correlated with onset of seizure remission. Diffusion and spectroscopy-detected alterations were consistent with a mechanism of temporal lobe radiation injury mediated by local vascular insult and neuronal loss. The degree of these early alterations at the peak of radiographic response was dose-dependent and predicted long-term seizure remission in the third year of follow-up. Radiographic changes were not associated with neurocognitive impairments. CONCLUSIONS: Temporal lobe stereotactic radiosurgery resulted in significant seizure reduction in a delayed fashion which appeared to be well-correlated with structural and biochemical alterations observed on neuroimaging. Early detected changes may offer prognostic information for guiding management.

European League Against Rheumatism recommendations for monitoring patients with systemic lupus erythematosus in clinical practice and in observational studies.

OBJECTIVES: To develop recommendations for monitoring patients with systemic lupus erythematosus (SLE) in clinical practice and observational studies and to develop a standardised core set of variables to monitor SLE. METHODS: We followed the European League Against Rheumatism (EULAR) standardised procedures for guideline development. The following techniques were applied: nominal groups, Delphi surveys for prioritisation, small group discussion, systematic literature review and two Delphi rounds to obtain agreement. The panel included rheumatologists, internists, dermatologists, a nephrologist and an expert related to national research agencies. The level of evidence and grading of recommendations were determined according to the Levels of Evidence and Grades of Recommendations of the Oxford Centre for Evidence-Based Medicine. RESULTS: A total of 10 recommendations have been developed, covering the following aspects: patient assessment, cardiovascular risk factors, other risk factors (osteoporosis, cancer), infection risk (screening, vaccination, monitoring), frequency of assessments, laboratory tests, mucocutaneous involvement, kidney monitoring, neuropsychological manifestations and ophthalmology assessment. A 'core set' of minimal variables for the assessment and monitoring of patients with SLE in clinical practice was developed that included some of the recommendations. In addition to the recommendations, indications for specific organ assessments that were viewed as part of good clinical practice were discussed and included in the flow chart. CONCLUSIONS: A set of recommendations for monitoring patients with SLE in routine clinical practice has been developed. The use of a standardised core set to monitor patients with SLE should facilitate clinical practice, as well as the quality control of care for patients with SLE, and the collection and comparison of data in observational studies.

Challenges comparing functional limitations in rheumatoid arthritis and ankylosing spondylitis.

Whether physical functioning in patients with rheumatoid arthritis (RA) differs from that in patients with ankylosing spondylitis (AS) is presently uncertain. Such a comparison poses challenges, not only because the two diseases differ in the domains of functioning affected, but also because of the different instruments used to measure functional limitations. Limiting our analysis to studies using similar self-report questionnaires, we examined published observational studies of unselected cohorts of patients with RA and patients with AS to compare and contrast the severity of functional limitations. Available studies from a few direct comparisons, and mostly indirect comparisons, suggested that patients with RA are generally more severely limited in physical functioning throughout the disease course than patients with AS. Since most studies did not adjust adequately for potentially important confounders, such as age, gender, comorbidity, and disease duration, reported differences in functional disability between patients with RA and patients with AS must be interpreted cautiously.

An exploratory study measuring verbal order content and context.

BACKGROUND: The use of verbal orders, while essential in some healthcare settings, has been identified as a potential contributor to poor quality and less safe care. Despite the widespread use of verbal orders, little research attention has been paid to understanding and measuring the content of verbal orders or variables related to the context in which verbal orders are made. AIM: This paper first identifies variables related to verbal order content and context, and then provides detailed analyses from two exploratory studies conducted in one community hospital. METHODS: The data presented were collected using both a paper-based manual audit, and an analysis of data generated from a computerised order entry system. DISCUSSION: Selected analyses focus of variations in types and timing of verbal orders hospital-wide as well as for specific inpatient units, changes in verbal order utilisation following implementation of a computerised provider order entry system, and an analysis of the presence of sound-alike and high-alert medications in verbal orders.

Neuronal and glial cell expression of angiotensin II type 1 (AT1) and type 2 (AT2) receptors in the rat retina.

The bio-active peptide, angiotensin II (Ang II), has been suggested to exert a neuromodulatory effect on inner retinal neurons. In this study, we examined the distribution of angiotensin receptors (ATRs) in the developing and mature rat retina and optic nerve using immunofluorescence immunocytochemistry. Double-labeling experiments were performed with established markers to identify different retinal cell populations. In adult retinae, ATRs were observed on neurons involved in "ON" pathways of neurotransmission. Angiotensin II type 1 receptors (AT(1)Rs) were expressed by a sub-population of "ON" cone bipolar cells that also labeled for G alpha(0) and islet-1. Extra-neuronal expression of AT(1)Rs was evident on retinal astrocytes, Müller cells and blood vessels. Immunoreactivity for the angiotensin II type 2 receptor (AT(2)R) was observed on conventional and displaced GABAergic amacrine cells. Co-localization studies showed that AT(2)R-expressing amacrine cells constituted at least two separate sub-populations. Cell counts revealed that all wide-field amacrine cells expressing protein kinase C-alpha were also AT(2)R-positive; a further subset of amacrine cells expressing AT(2)Rs and stratifying in sublamina "b" of the inner plexiform layer (IPL) was identified. Developmental expression of AT(1)Rs was dynamic, involving multiple inner neuronal classes. At postnatal day 8 (P8), AT(1)R immunoreactivity was observed on putative ganglion cells. The characteristic bipolar cell labeling observed in adults was not evident until P13. In contrast, AT(2)Rs were detected as early as P2 and localized specifically to amacrine cells from this age onward. These data provide further evidence for the potential role of angiotensin II in the modulation of retinal neurons and glia. The differential pattern of expression of these receptors across these cell types is similar to that observed in the brain and suggests that a similar functional role for Ang II may also exist within the retina.

Perception of improvement in patients with rheumatoid arthritis varies with disease activity levels at baseline.

OBJECTIVE: To analyze the minimum clinically important improvement (MCII) of disease activity measures in rheumatoid arthritis (RA) using patient-derived anchors, and to assess whether criteria for improvement differ with baseline disease activity. METHODS: We used data from a Norwegian observational database comprising 1,050 patients (73% women, 65% rheumatoid factor-positive, mean duration of RA 7.7 years). At 3 months after initiation of therapy, patients indicated whether their condition had improved, had considerably improved, was unchanged, had worsened, or had considerably worsened. We used receiver operating characteristic curve analysis to determine the MCII for the Disease Activity Score based on the assessment of 28 joints (DAS28), the Simplified Disease Activity Index (SDAI), and the Clinical Disease Activity Index (CDAI), and analyzed the effects of different levels of baseline disease activity on the MCII. RESULTS: On average, patients started with high disease activity and improved significantly during treatment (American College of Rheumatology 20%, 50%, and 70% improvement criteria responses were 37%, 17%, and 5%, respectively). The overall mean (95% confidence interval [95% CI]) thresholds for MCII after 3 months for the DAS28, SDAI, and CDAI were 1.20 (95% CI 1.18-1.22), 10.95 (95% CI 10.69-11.20), and 10.76 (95% CI 10.49-11.04), respectively, and the mean (95% CI) thresholds for major responses were 1.82 (95% CI 1.80-1.83), 15.82 (95% CI 15.65-16.00), and 15.00 (95% CI 14.82-15.18), respectively. With increasing disease activity, much higher changes in disease activity were needed to achieve MCII according to patient judgment. CONCLUSION: The perception of improvement of disease activity of patients with RA is considerably different depending on the disease activity level at which they start.

Subsets of retinal neurons and glia express P2Y1 receptors.

Recent evidence suggests that extracellular ATP modulates retinal processing and could play a role in modulating glial cells during retinal diseases. Here, we evaluated the localization of P2Y(1) receptors in the rat retina using indirect immunofluorescence immunocytochemistry. We observed labeling within defined populations of inner retinal neurons and Müller cell processes and end feet. Double labeling of P2Y(1) receptor with choline acetyltransferase revealed extensive colocalization indicating the expression of this receptor by cholinergic amacrine cells. Ganglion cell labeling for P2Y(1) receptors was also observed. Having established the normal pattern of immunolabeling within the retina, we next examined whether immunolabeling was altered by retinal disease. P2Y(1) receptor immunolabeling of Müller cells was of greater intensity following light-induced retinal degeneration, suggesting that Müller cell gliosis is accompanied by changes in P2Y(1) receptor expression. Overall, these data provide further evidence for a role of extracellular ATP in retinal signaling within subsets of retinal neurons as well as glia.

Localization and possible function of P2Y(4) receptors in the rodent retina.

Extracellular ATP acts as a neurotransmitter in the retina, via the activation of ionotropic P2X receptors and metabotropic P2Y receptors. The expression of various P2X and P2Y receptor subtypes has been demonstrated in the retina, but the localization of P2Y receptors and their role in retinal signaling remains ill defined. In this study, we were interested in determining the localization of the P2Y(4) receptor subtype in the rat retina, and using the electroretinogram (ERG) to assess whether activation of these receptors modulated visual transmission. Using light and electron microscopy, we demonstrated that P2Y(4) receptors were expressed pre-synaptically in rod bipolar cells and in processes postsynaptic to cone bipolar cells. Furthermore, we show that the expression of P2Y(4) receptors on rod bipolar cell axon terminals is reduced following dark adaptation, suggesting receptor expression may be dependent on retinal activity. Finally, using the electroretinogram, we show that intravitreal injection of uridine triphosphate, a P2Y receptor agonist, decreases the amplitude of the rod PII, supporting a role for P2Y receptors in altering inner retinal function. Taken together, these results suggest a role for P2Y(4) receptors in the modulation of inner retinal signaling.

Treatment-related improvement in physical function varies with duration of rheumatoid arthritis: a pooled analysis of clinical trial results.

BACKGROUND: Physical function in rheumatoid arthritis (RA) has reversible and irreversible components, and is typically assessed by the Health Assessment Questionnaire Disability Index (HAQ). Since irreversible components are expected to increase with longer duration of RA and reduce the ability for improvement in physical function, we analysed responsiveness of HAQ scores in patient populations with differing RA durations in randomised controlled trials (RCTs). METHODS: Data from all RCTs published between 1980 and 2005 that reported changes from baseline in HAQ at 6 and/or 12 months were analysed. Treatments were grouped as "biologics", or "traditional" disease modifying antirheumatic drugs (DMARDs), and "placebo". We computed effect sizes of HAQ in each trial, and contrasted the association between these effects and duration of RA among treatment groups using regression models. RESULTS: We identified 42 RCTs with complete data for the statistical models. The models indicate that discrimination of functional improvement between active drug groups and placebo is reduced in patients with a longer duration of RA (p = 0.02 for the change in discrimination over time). The placebo-adjusted HAQ responses decreased on average by 0.37 per year of RA duration. CONCLUSION: Responsiveness in HAQ scores is inversely associated with mean disease duration in RA. This impacts assessment of physical function, a key outcome measure in RCTs and practice, and impacts the ability to discriminate active treatment from placebo.

Clinical, radiographic and functional differences between juvenile-onset and adult-onset ankylosing spondylitis: results from the PSOAS cohort.

AIMS: Previous data suggests that patients with juvenile-onset ankylosing spondylitis (JoAS) have more severe disease and worse functional outcomes than adult-onset AS (AoAS). The purpose of this study was to evaluate clinical, functional and radiographic differences between patients with JoAS and AoAS in a large cohort of patients with long-standing disease. METHODS: A total of 402 subjects who met the Modified New York Criteria for definitive AS and had had disease >or=20 years were enrolled in a multi-centre cross-sectional study (Prospective Study of Outcomes in Ankylosing Spondylitis; PSOAS). JoAS was defined as initial symptoms

Impact of complications on outcomes following aortic and mitral valve replacements in the United States.

AIM: Heart valve replacement surgeries account for 20% of all cardiac procedures. In-hospital mortality rates are approximately 6% for aortic valve replacements and 10% for mitral valve replacements. The objectives of the study are to provide nationally representative estimates of complications following aortic and mitral valve replacements and to quantify the impact of different types of complications on in-hospital outcomes. METHODS: The Nationwide Inpatient Sample was analyzed for years 2000-2003. The effect of complications on in-hospital mortality, length of stay (LOS), and hospital charges were examined using bivariate and multivariable logistic and linear regression analyses. The confounding effects of age, sex, primary diagnosis, type of valve replacement, type of admission, comorbid conditions, and hospital characteristics were adjusted. RESULTS: A total of 43,909 patients underwent aortic valve replacement as the primary procedure during the study period and 16,516 patients underwent mitral valve replacement. Complications occurred in 35.2% of those undergoing aortic valve replacements and in 36.4% of those undergoing mitral valve replacements. Almost half of these are cardiac complications and a quarter involve hemorrhage/hematoma/seroma. Complications were significantly associated with in-hospital mortality, LOS, and hospital charges even after adjusting for patient and hospital characteristics. CONCLUSION: Complications are prevalent and exert a considerable influence on outcomes following aortic and mitral valve replacements. Quality initiatives should focus on minimizing complications and improving processes of care that would enable complications to be better resolved if they occur.

Outcomes in ankylosing spondylitis: what makes the assessment of treatment effects in ankylosing spondylitis different?

There are four major challenges in the assessment of outcomes in patients with ankylosing spondylitis (AS) that are particularly relevant to the evaluation of new therapies. Firstly, measures of symptoms and impairment in AS are not specific for inflammatory processes, they also capture mechanical symptoms and fixed limitations. The non-specific nature of these measures may cause them to be less responsive and therefore less useful in determining treatment efficacy. Secondly, acute phase reactants have limited value as measures of AS activity and other surrogate markers have not yet been established. Thirdly, the assessment of the disease modifying potential of new therapies is hampered by the slow rate of spinal fusion. Fourthly, work disability has not be studied as an endpoint in clinical trials in AS, despite the fact that work disability is an important outcome in patients with AS. Research into ways to overcome these challenges in outcome measurement will help identify useful therapies and define the range of outcomes that they influence.

Duration of rheumatoid arthritis influences the degree of functional improvement in clinical trials.

BACKGROUND: Functional capacity is an important outcome in rheumatoid arthritis and is generally measured using the Health Assessment Questionnaire disability index (HAQ). Functional limitation incorporates both activity and damage. Because irreversible damage increases over time, the HAQ may be less likely to show improvement in late than in early rheumatoid arthritis. OBJECTIVE: To determine the relation between sensitivity to change of the HAQ and duration of rheumatoid arthritis in reports of clinical trials. METHODS: Data were pooled from clinical trials that measured responses of HAQ scores at three or six months. The effect size of the HAQ was calculated and linear regression used to predict the effect size by duration of rheumatoid arthritis at group level. Treatment effect was adjusted for by including the effect sizes of pain scores and of tender joint counts as additional independent variables in separate models. Subgroup analysis employed contemporary regimens (methotrexate, leflunomide, combination therapies, and TNF inhibitors) only. RESULTS: 36 studies with 64 active treatment arms and 7628 patients (disease duration 2.5 months to 12.2 years) were included. The effect sizes of the HAQ decreased by 0.02 for each additional year of mean disease duration using all trials, and by 0.04/year in the subgroup analysis (p