Development of prediction models to select older RA patients with comorbidities for treatment with chronic low-dose glucocorticoids.

OBJECTIVE: To develop prediction models for individual patient harm and benefit outcomes in elderly patients with RA and comorbidities treated with chronic low-dose glucocorticoid therapy or placebo. METHODS: In the Glucocorticoid Low-dose Outcome in Rheumatoid Arthritis (GLORIA) study, 451 RA patients ≥65 years of age were randomized to 2 years 5 mg/day prednisolone or placebo. Eight prediction models were developed from the dataset in a stepwise procedure based on prior knowledge. The first set of four models disregarded study treatment and examined general predictive factors. The second set of four models was similar but examined the additional role of low-dose prednisolone. In each set, two models focused on harm [the occurrence of one or more adverse events of special interest (AESIs) and the number of AESIs per year) and two on benefit (early clinical response/disease activity and a lack of joint damage progression). Linear and logistic multivariable regression methods with backward selection were used to develop the models. The final models were assessed and internally validated with bootstrapping techniques. RESULTS: A few variables were slightly predictive for one of the outcomes in the models, but none were of immediate clinical value. The quality of the prediction models was sufficient and the performance was low to moderate (explained variance 12-15%, area under the curve 0.67-0.69). CONCLUSION: Baseline factors are not helpful in selecting elderly RA patients for treatment with low-dose prednisolone given their low power to predict the chance of benefit or harm. TRIAL REGISTRATION: https://clinicaltrials.gov; NCT02585258.

Age at onset in axial spondyloarthritis around the world: data from the Assessment in SpondyloArthritis international Society Peripheral Involvement in Spondyloarthritis study.

OBJECTIVE: Age at onset is useful in identifying chronic back patients at an increased risk of axial SpA (axSpA). However, the majority of data on which the criterion of age at onset <45 years is based originates from Europe. Therefore it is unknown if this criterion applies in other parts of the world. We aimed to assess the age at onset of axSpA and its relationship with HLA-B27 and gender across the world. METHODS: Analyses were applied to patients from 24 countries across the world with an axSpA diagnosis and known age at onset of axial complaints. Cumulative probability plots were used to display the cumulative distribution of age at onset of axial symptoms. Linear regression models were built to assess the effect of HLA-B27 and gender on age at onset of axial symptoms. RESULTS: Of 2579 axSpA patients, 92% had an age at onset of axial symptoms <45 years, with only small variations across the geographical regions [Asia, n = 574 (94%); Europe and North America, n = 988 (92%); Latin America, n = 246 (89%); Middle East and North Africa, n = 771 (91%)]. Age at onset of axial symptoms was consistently lower in HLA-B27-positive patients {median 25 years [interquartile range (IQR) 19-32] vs 31 [IQR 22-39]} and male patients [median 25 years (IQR 19-33) vs 28 (IQR 21-37)], but in multivariable models an additional statistically significant effect of male gender independent of HLA-B27 was only found in Asia. CONCLUSION: Around the world, the great majority of axSpA patients had an age at onset of axial disease of <45 years, with HLA-B27 and male gender associated with earlier disease onset.

Automated joint space width quantification of hand and wrist joints: a proof of concept study.

OBJECTIVES: To compare as proof of concept the sensitivity to change of automated quantification of radiographic wrist and hand joint space width (JSW) with scoring JSW according to the Sharp/van der Heijde scoring method (SHS) in two strategy groups of a treat-to-target and tight-control early rheumatoid arthritis (RA) study. METHODS: Digital radiographs were assessed for JSW changes of 134 patients of the 236 patients participating in the second Computer Assisted Management in Early Rheumatoid Arthritis trial, of whom both baseline and year 2 radiographs were available (year 1 radiographs n=125). Of those 134 patients, 70 started with methotrexate and prednisone (MTX+Pred) and 64 with MTX and placebo (MTX+Plac). JSW change over 1 and 2 years of the hands and wrists was assessed, applying both the joint space narrowing (JSN) subscore of the SHS by 2 readers and the automated assessment with the JSW quantification software 'JSQ'. For both methods, progression of JSW change of the hand and wrist was analysed using linear mixed modelling (dependent variable 'JSW', factor 'strategy group', covariate 'follow-up time in years', interaction term 'strategy group*follow-up time'; radiographs of baseline, year 1 and year 2 were used). For each method the standardised mean difference (SMD) for the change in JSW from baseline to year 2 between the treatment strategies was obtained using a non-parametric method. RESULTS: Patient characteristics of the current subpopulation were similar to those of the whole study population. JSN of the hand and wrist according to SHS at 2 years was present in 16 vs. 23% in the MTX+Pred group vs. the MTX+Plac group. The mean yearly progression rates of JSW change of the hands and wrists using JSQ were -0.00mm (95% confidence interval (CI) -0.01; 0.01) for MTX+Pred vs. -0.02mm (95%CI -0.03; -0.01) for MTX+Plac, p=0.045, and using SHS JSN they were 0.19 units (95%CI 0.09; 0.30) vs. 0.30 units (95%CI 0.14; 0.45) for MTX+Pred vs. MTX+Plac, p=0.271. The SMD for the change from baseline to year 2 between the treatment strategies was 0.37 for JSQ and 0.13 for SHS JSN. CONCLUSIONS: In this proof of concept study the yearly progression rate of JSW change of hand and wrist joints, according to the automated JSW quantification software package 'JSQ', was higher in the group initiating MTX+Plac than in the group initiating MTX+Pred. A similar trend was seen with the JSN assessment according to the SHS method of the hand and wrist. However, JSN of the hand and wrist according to SHS, the current gold standard to assess radiographic progression, was seen in only about 20%. Therefore, further studies are needed to conclude firmly that JSQ should be incorporated into quantitative scoring of radiographs in RA.

The unmet need in rheumatology: reports from the Targeted Therapies meeting 2016.

The 18th annual international Targeted Therapies meeting brought together over 100 leading scientists and clinicians from around the world in the field of rheumatology. During the meeting, breakout sessions were held consisting of 5 disease-specific groups each with 20-40 experts assigned to each group based on clinical or scientific expertise. Specific groups included: rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis/spondyloarthritis, systemic lupus erythematous, and other connective tissue diseases (e.g. Sjögren's, Behçet's, others). In each group, experts were asked to identify unmet needs in 3 categorical areas: basic/translational science, clinical science and therapeutic development, and clinical care. Needs were prioritised as primary or secondary. Overall, similar primary unmet needs were identified within each disease foci. Within translational science, these included the need for better understanding the heterogeneity within each disease, such that predictive tools for therapeutic response could be developed. Within clinical science and therapeutic trials, the ability to prevent progression to disease onset in those at risk, and the ability to cure disease were identified. A further unmet need was to develop new and accessible therapeutics, as well as to conduct strategic trials of currently approved therapies. Within the clinical care realm, improved co-morbidity management and patient-centered care were identified as unmet needs. Lastly, it was strongly felt there was a need to develop a scientific infrastructure for well-characterised, longitudinal cohorts married with biobanks and mechanisms to support data-sharing. This infrastructure could facilitate many of the unmet needs identified within each disease area.

Frequency of joint involvement in juvenile idiopathic arthritis during a 5-year follow-up of newly diagnosed patients: implications for MR imaging as outcome measure.

To assess the sequence and type of active joints in a cohort of newly diagnosed juvenile idiopathic arthritis (JIA) patients with full access to current treatment at first visit and during a follow-up period of 5-years, in order to identify an index joint/group of joints for magnetic resonance imaging in JIA. Patient charts of all consecutive newly diagnosed JIA patients with a follow-up duration of at least 5 years were analyzed. Patients were derived from two tertiary pediatric rheumatology centers. Patient characteristics and data concerning the presence of joints with arthritis and the use of medication were recorded. Findings from 95 JIA patients [39 (41 %) oligoarticular and 56 (59 %) polyarticular] were analyzed. At first visit, distribution of active joints among patients was as follows: knee (n = 70, 74 %), ankle (n = 55, 58 %), elbow (n = 23, 24 %), wrist (n = 23, 24 %), metacarpophalangeal (MCP) (n = 20, 21 %), proximal interphalangeal (PIP) (n = 13, 14 %), hip (n = 6, 6 %), shoulder (n = 5, 5 %), and distal interphalangeal (DIP) (n = 4, 4 %) joints. After a follow-up period of 5 years, the cumulative percentage of patients with specific joint involvement changed into: knee (n = 88, 93 %), ankle (n = 79, 83 %), elbow (n = 43, 45 %), wrist (n = 38, 40 %), MCP (n = 36, 38 %), PIP (n = 29, 31 %), shoulder (n = 20, 21 %), hip (n = 17, 19 %), and DIP (n = 9, 10 %) joints. Despite changes in treatment strategies over the years, the knee remains the most commonly involved joint at onset and during follow-up in JIA, followed by the ankle, elbow, and wrist. For the evaluation of outcome with MRI, the knee appears the most appropriate joint in JIA.

Multinational evidence-based recommendations for the diagnosis and management of gout: integrating systematic literature review and expert opinion of a broad panel of rheumatologists in the 3e initiative.

We aimed to develop evidence-based multinational recommendations for the diagnosis and management of gout. Using a formal voting process, a panel of 78 international rheumatologists developed 10 key clinical questions pertinent to the diagnosis and management of gout. Each question was investigated with a systematic literature review. Medline, Embase, Cochrane CENTRAL and abstracts from 2010-2011 European League Against Rheumatism and American College of Rheumatology meetings were searched in each review. Relevant studies were independently reviewed by two individuals for data extraction and synthesis and risk of bias assessment. Using this evidence, rheumatologists from 14 countries (Europe, South America and Australasia) developed national recommendations. After rounds of discussion and voting, multinational recommendations were formulated. Each recommendation was graded according to the level of evidence. Agreement and potential impact on clinical practice were assessed. Combining evidence and clinical expertise, 10 recommendations were produced. One recommendation referred to the diagnosis of gout, two referred to cardiovascular and renal comorbidities, six focused on different aspects of the management of gout (including drug treatment and monitoring), and the last recommendation referred to the management of asymptomatic hyperuricaemia. The level of agreement with the recommendations ranged from 8.1 to 9.2 (mean 8.7) on a 1-10 scale, with 10 representing full agreement. Ten recommendations on the diagnosis and management of gout were established. They are evidence-based and supported by a large panel of rheumatologists from 14 countries, enhancing their utility in clinical practice.

Diagnostic value of clinical, laboratory, and imaging findings in patients with a clinical suspicion of gout: a systematic literature review.

OBJECTIVE: To analyze the diagnostic utility of clinical, laboratory, and imaging items for gout. METHODS: A systematic literature search was performed in MEDLINE, EMBASE, and The Cochrane Library; and a manual search of abstracts from the 2010/2011 meetings of the American College of Rheumatology (ACR) and the European League Against Rheumatism, as well as the reference lists of retrieved papers. Studies were included if they evaluated the diagnostic utility of clinical, laboratory, or imaging features or criteria for the diagnosis or classification of gout in adult patients. Two independent reviewers selected papers, extracted the data, and assessed the risk of bias. RESULTS: Nineteen studies were included in the review; 4 used the identification of monosodium urate (MSU) crystals as the reference standard (RS) and the rest used expert opinion or the ACR preliminary criteria. Most features were evaluated in a single study. Evidence for diagnostic utility, using MSU crystals as RS, of over 50 individual clinical, laboratory, and radiographic features was retrieved. Most items showed a positive likelihood ratio (LR+) < 3, except for the following: response of arthritis to colchicine (LR+ 4.3); presence of tophi on physical examination (LR+ 15.6-30.9); identification of the double-contour sign in ultrasound (US) (LR+ 13.6); and detection of urate deposits by dual-energy computed tomography (DECT) (LR+ 9.5). CONCLUSION: Individual clinical features show low diagnostic utility, with the exception of tophi and response to colchicine. Some US and DECT findings show better performance than most clinical features.

Treatment target and followup measures for patients with gout: a systematic literature review.

OBJECTIVE: To systematically review the validity of serum uric acid (SUA) as a treatment target for patients with gout, and the clinimetric properties of the potential tools for monitoring these patients. METHODS: A search was performed in Medline, Embase and the Cochrane Library from inception to October 2011, and the 2010-2011 American College of Rheumatology and European League Against Rheumatism meeting abstracts. Studies evaluating different SUA levels or SUA reduction with the achievement of outcomes, and studies assessing clinimetric properties of instruments used to follow patients with gout were selected. Intervention studies were also included in order to estimate responsiveness. Titles and abstracts of the identified references were screened, and included articles were reviewed in detail and data collected using ad hoc standard forms. RESULTS: In total, 4575 articles were retrieved, 120 articles reviewed in detail, and 54 articles were included in the systematic literature review. SUA reduction was significantly associated with a reduction in acute attacks (6 studies), tophi regression (2 studies), and crystal clearance (3 studies). SUA 6.0 mg/dl was used as cutoff point in most of studies, but this level was found to be arbitrary. For followup of patients with gout, tophus measurement by caliper and ultrasound, the physical component of the Medical Outcomes Study Short Form-36 Survey, and Health Assessment Questionnaire have shown excellent clinimetric properties for this purpose. CONCLUSION: Reducing SUA is a valid treatment target for patients with gout, but the target level of reduction (cutoff point) is not clear. Some tools were found suitable for following patients with gout.

Interventions for tophi in gout: a Cochrane systematic literature review.

OBJECTIVE: To systematically review the available literature on the management of tophi in gout. This article is based on the Cochrane Review Interventions for Tophi in Gout published in the Cochrane Database of Systematic Reviews. METHODS: Medline, Embase, and The Cochrane Library were searched using a strategy developed with an experienced librarian. We also searched American College of Rheumatology and European League Against Rheumatism conference abstracts from 2010-2011. Included articles were reviewed in detail and a risk of bias (using the Cochrane tool) and quality assessment were performed. RESULTS: In total, 3206 references were recovered. Of these, 72 articles were selected based on our inclusion criteria. This included 1 report of 2 randomized controlled trials, 2 nonrandomized studies, and 69 case series and reports. The study with 2 randomized controlled trials looked at pegloticase. This showed improvement in tophi with treatment. One observational prospective trial looked at allopurinol and benzbromarone individually and in combination. It noted that achieving lower serum urate levels was associated with a faster reduction of tophi. An open-label extension trial noted that longterm maintenance of serum uric acid < 6.0 mg/dl with febuxostat led to a reduction in tophi. The case series and reports looked at surgical, pharmacological, and other interventions, as well as combination therapies. All surgical interventions reported improvement in pain and/or function. No report had objective measures of outcome. CONCLUSION: Treatment with urate-lowering therapy such as allopurinol, benzbromarone, allopurinol + benzbromarone in combination, febuxostat, or pegloticase can lead to reduction in tophi. There is some evidence that achieving a lower serum urate level leads to a faster rate of tophi reduction.

Treatment of asymptomatic hyperuricemia for the prevention of gouty arthritis, renal disease, and cardiovascular events: a systematic literature review.

OBJECTIVE: To systematically review available literature on treatment of hyperuricemia (HU) as a measure of preventing gouty arthritis, renal disease, or cardiovascular events in asymptomatic patients. METHODS: A systematic literature search was conducted in the Cochrane Library, Medline, Embase, clinical trials registries of the World Health Organization and the US National Institutes of Health, and abstracts from American College of Rheumatology/European League Against Rheumatism meetings, for interventional studies involving adults with no history of gouty arthritis, who were treated for HU. Outcomes of interest included gouty arthritis, renal disease (i.e., renal insufficiency, urate nephropathy, nephrolithiasis), and cardiovascular events (i.e., myocardial infarction, heart failure, ischemic stroke). RESULTS: A total of 3 studies met the inclusion criteria, 2 studies assessing the prevention of renal disease and 1 study evaluating the potential for delaying progression of preexisting renal disease. In hyperuricemic patients without renal disease, treatment resulted in increased estimated glomerular filtration rate. In hyperuricemic patients with preexisting renal disease, treatment resulted in no significant elevation of serum creatinine over a 1-year followup. However, differences in renal function between the treatment and no-treatment groups were not statistically significant in any of the identified studies. CONCLUSION: Very limited data are available on the treatment of HU in asymptomatic patients. There is currently insufficient empiric evidence to suggest that lowering serum uric acid level in asymptomatic patients with HU can prevent gouty arthritis, renal disease, or cardiovascular events.

Cardiovascular risk factors and comorbidities in patients with hyperuricemia and/or gout: a systematic review of the literature.

OBJECTIVE: To review the available literature on the likelihood of having cardiovascular (CV) risk factors and on developing CV comorbidities in patients with gout and/or asymptomatic hyperuricemia as an evidence base for generating multinational clinical practice recommendations in the 3e (Evidence, Expertise, Exchange) Initiative in Rheumatology. METHODS: A systematic literature search was carried out using MEDLINE, EMBASE, and The Cochrane Library, and abstracts presented at the 2010/2011 meetings of the American College of Rheumatology (ACR) and the European League Against Rheumatism, searching for CV risk factors and new CV comorbidities in patients with asymptomatic hyperuricemia and/or a diagnosis of gout. Trials that fulfilled predefined inclusion criteria were systematically reviewed. RESULTS: A total of 66 out of 8918 identified publications were included in this review. After assessment of the risk of bias, 32 articles with a high risk of bias were excluded. Data could not be pooled because of clinical and statistical heterogeneity. In general, both for asymptomatic hyperuricemia and for gout the hazard ratios for CV comorbidities were only modestly increased (1.5 to 2.0) as were the hazard ratios for CV risk factors, ranging from 1.4 to 2.0 for hypertension and from 1.0 to 2.4 for diabetes. CONCLUSION: Unlike the common opinion that patients with gout or hyperuricemia are at higher risk of developing CV disease, the actual risk to develop CV disease is either rather weak (for hyperuricemia) or poorly investigated (for gout).

Lifestyle interventions for the treatment of gout: a summary of 2 Cochrane systematic reviews.

OBJECTIVE: To determine the efficacy and safety of lifestyle interventions for treating gout. METHODS: Two Cochrane systematic reviews assessed the efficacy and safety of lifestyle interventions for the treatment of acute and chronic gout. We searched MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials up to September 2011, and the 2010-2011 American College of Rheumatology and European League Against Rheumatism conference abstracts. Primary outcomes of interest were joint pain for acute gout, frequency of gout attacks for chronic gout, and withdrawals due to adverse events for both reviews. RESULTS: One trial met inclusion criteria for each review. An unblinded trial (19 participants), at high risk of bias, found that topical ice added to prednisolone and colchicine for acute gout resulted in significantly greater pain reduction at 1 week [mean difference (MD) -3.33 cm, 95% confidence interval (95% CI) -5.84 to -0.82 on 10 cm visual analog scale]. Adverse events were not described. The second trial (120 participants), at moderate risk of bias, compared enriched skim milk powder (glycomacropeptide and G600 milk fat extract) to non-enriched skim milk and lactose powders for treating chronic gout. There were no between-group differences in gout attack frequency over 3 months [MD -0.21 (95% CI -0.76 to 0.34)] or withdrawals due to adverse events [relative risk 1.27 (95% CI 0.53 to 3.03)]. CONCLUSION: While there is observational evidence for an association between lifestyle risk factors and gout development, there are no high quality trials to support or refute the use of lifestyle interventions for treating acute or chronic gout.

Urate-lowering therapy for the management of gout: a summary of 2 Cochrane reviews.

OBJECTIVE: To systematically review the evidence on the efficacy, safety, and cost-effectiveness of urate-lowering therapy for gout: xanthine oxidase inhibitors (allopurinol and febuxostat), uricosuric medications (benzbromarone, probenecid and sulfinpyrazone), and uricases (pegloticase and rasburicase). METHODS: A systematic review was performed as part of the 3e (Evidence, Expertise, Exchange) Initiative on Gout. The primary efficacy outcomes were frequency of acute gout attacks, study participant withdrawal due to adverse events, and cost-effectiveness. Serum urate-lowering was a secondary outcome and was the most commonly reported outcome in the included trials. RESULTS: The search identified 17 articles for efficacy, 31 for safety, and 3 for cost-effectiveness. The main outcome described in these studies was serum urate-lowering. Allopurinol, febuxostat, and pegloticase are all effective at lowering serum urate compared to placebo and febuxostat (≥ 80 mg) was more effective at lowering serum urate than allopurinol. Compared to probenecid, benzbromarone was more effective at lowering serum urate. Regarding acute gout attacks, pegloticase and febuxostat (≥ 120 mg) resulted in more acute attacks than placebo. Regarding the primary safety outcome, more withdrawals due to adverse events were seen only when pegloticase was compared to placebo. The two trials of cost-effectiveness were inconclusive. CONCLUSION: There is currently moderate quality data supporting the efficacy and safety of allopurinol, febuxostat, benzbromarone, and probenecid in gout. Pegloticase, while efficacious, is associated with more withdrawals due to adverse events and infusion reactions. There is insufficient evidence currently with respect to the cost-effectiveness or the most optimal sequencing of urate-lowering therapy.

Preventing attacks of acute gout when introducing urate-lowering therapy: a systematic literature review.

OBJECTIVE: To systematically review the evidence on treatment available to prevent an acute attack of gout when initiating a urate-lowering therapy (ULT) and for how long this treatment should be continued. To also evaluate the evidence on the optimal time to start a ULT after an acute attack of gout. METHODS: A systematic review as part of the 3e (Evidence, Expertise, Exchange) Initiative on Diagnosis and Management of Gout was performed using Medline, Embase, Cochrane Central Register of Controlled Trials (from 1950 to October 2011), and the European League Against Rheumatism (EULAR) and American College of Rheumatology (ACR) 2010/2011 meeting abstracts. Two reviewers independently screened titles and abstracts for selection criteria. Included articles were reviewed in detail, and a risk of bias assessment (using the Cochrane tool) was performed. RESULTS: The search identified 8168 articles and 197 abstracts, from which 4 randomized controlled trials were included in the review. Two of these studies compared placebo with colchicine, 1 compared differing durations of colchicine, and 1 compared colchicine with canakinumab. CONCLUSION: Two randomized controlled trials have shown that colchicine prophylaxis for at least 6 months, when starting a ULT, reduces the risk of acute attacks. Canakinumab, although not currently licensed for gout, has been shown to provide prophylaxis superior to colchicine, when starting a ULT. There is no evidence on the optimum time to start a ULT after an acute gout attack.

Treatment of gout patients with impairment of renal function: a systematic literature review.

OBJECTIVE: To assess the efficacy and safety of gout-specific medications in gout patients with a comorbidity and/or comedication. METHODS: A systematic literature search for gout, its medication, and the most common comorbidities and comedications, using serum uric acid (SUA) levels as the primary, and adverse events as the secondary outcomes. RESULTS: Eight trials met inclusion criteria. Trials covered treatment with allopurinol, benzbromarone, rasburicase, or febuxostat in a gout population with mild or moderate renal insufficiency. High risk of bias (5/8 trials) and heterogeneity precluded formal metaanalysis. The trials showed the following hierarchy in efficacy (lowering the SUA below 6.0 mg/dl): febuxostat 80 mg (44%-71%) > febuxostat 40 mg (43%-52%) > allopurinol 100 mg or 200 mg (0-46%) after 6 months of therapy; rasburicase (46%) > allopurinol 300 mg (16%) after 7 days of therapy; benzbromarone 100-200 mg (93%) > allopurinol 100-200 mg (63%) after 9-24 months of therapy. The combination of allopurinol and benzbromarone seemed to be effective, with a significant reduction in the SUA from 7.8 to 5.7 mg/dl (p < 0.05) after 1 month. One study showed that 89% achieved the target SUA using higher doses of allopurinol than usually recommended for patients with renal impairment without an apparent increase in adverse events. In addition, allopurinol and benzbromarone significantly improved renal function. CONCLUSION: In gout patients with renal insufficiency febuxostat, rasburicase, benzbromarone, and allopurinol + benzbromarone seemed to be effective and safe; allopurinol may be cautiously titrated until the target uric acid level has been reached, and may improve renal function.

The efficacy and safety of treatments for acute gout: results from a series of systematic literature reviews including Cochrane reviews on intraarticular glucocorticoids, colchicine, nonsteroidal antiinflammatory drugs, and interleukin-1 inhibitors.

OBJECTIVE: To determine the efficacy and safety of glucocorticoids (GC), colchicine, nonsteroidal antiinflammatory drugs (NSAID), interleukin-1 (IL-1) inhibitors, and paracetamol to treat acute gout. METHODS: We searched MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials to September 2011. Randomized controlled trials (RCT) or quasi-RCT in adults with acute gout that compared GC, colchicine, NSAID, IL-1 inhibitors, and paracetamol to no treatment, placebo, another intervention, or combination therapy were included. Two authors independently extracted data and assessed risk of bias. Primary endpoints were pain and adverse events. Data were pooled where appropriate. RESULTS: Twenty-six trials evaluating GC (N = 5), NSAID (N = 21), colchicine (N = 2), and canakinumab (N = 1) were included. No RCT assessed paracetamol or intraarticular (IA) GC. No RCT compared systemic GC with placebo. Moderate quality evidence (3 trials) concluded that systemic GC were as effective as NSAID but safer. Low quality evidence (1 trial) showed that both high- and low-dose colchicine were more effective than placebo, and low-dose colchicine was no different to placebo with respect to safety but safer than high-dose colchicine. Low quality evidence (1 trial) showed no difference between NSAID and placebo with regard to pain or inflammation. No NSAID was superior to another. Moderate quality evidence (1 trial) found that 150 mg canakinumab was more effective than a single dose of intramuscular GC (40 mg triamcinolone) and equally safe. CONCLUSION: GC, NSAID, low-dose colchicine, and canakinumab all effectively treat acute gout. There was insufficient evidence to rank them. Systemic GC appeared safer than NSAID and lower-dose colchicine was safer than higher-dose colchicine.

Epistasis between two HLA antigens defines a subset of individuals at a very high risk for ankylosing spondylitis.

OBJECTIVES: Susceptibility to spondyloarthritis (SpA) is largely genetically determined. To understand increasingly complex genetic associations, one approach is to study epistasis or genetic interactions. Several associations between HLA antigens and SpA including HLA-B27 have been reported. In this study, we investigated epistasis between common HLA class I risk antigens in ankylosing spondylitis (AS), the most typical form of SpA. METHODS: In 154 patients with AS and 5584 controls, HLA class I antigens were analysed for association with AS. Biological interaction was analysed by investigating whether the effects of the risk factors combined departed from additivity. RESULTS: Apart from the association with HLA-B27, we found an association between HLA-B60 and AS (OR 1.8; 95% CI 1.2 to 2.8). This was confirmed in a meta-analysis (OR 2.2; CI 1.8 to 2.8). While 18.2% of AS patients had both HLA-B27 and HLA-B60, this combination was found in only 0.4% of controls. Using AS patients without HLA-B27 and HLA-B60 as a reference, the relative risk (RR) for disease in HLA-B27-/HLA-B60+ patients was 1.2 (95% CI 0.3 to 4.1). For HLA-B27+/HLA-B60- the RR was 69 (95% CI 40 to 111) but increased to 342 (95% CI 147 to 708) in HLA-B27+/HLA-B60+ patients. For the interaction, the relative excess risk due to interaction was 251, the attributable proportion was 0.8 and the synergy index was 4.7. The interaction was confirmed in an independent cohort. CONCLUSIONS: There is a strong epistatic interaction between HLA-B60 and HLA-B27 in AS susceptibility. As a result, individuals with the HLA-B27+/HLA-B60+ genotype are at a very high risk of developing AS.

Association of joint space narrowing with impairment of physical function and work ability in patients with early rheumatoid arthritis: protection beyond disease control by adalimumab plus methotrexate.

OBJECTIVES: Tumour necrosis factor inhibition plus methotrexate is believed to inhibit radiographic progression independent of inflammation. This analysis assessed whether these protective effects are exerted on bone (joint erosion; JE) and/or cartilage (joint space narrowing; JSN), and what the independent effects of JE/JSN progression are on longer-term patient-reported outcomes. METHODS: PREMIER was a 2-year, randomised, controlled trial of adalimumab plus methotrexate (ADA+MTX) versus the monotherapies. The impact of treatment on the relationships between time-averaged disease activity (TA-DAS28(CRP)) and changes in JE/JSN and associations of JE/JSN with the disability index of the health assessment questionnaire (HAQ-DI) at baseline and weeks 52 and 104 were assessed through non-parametric approaches of analysis of variance and quantile regression. JE/JSN association with employment status was evaluated at baseline and weeks 52 and 104 through logistic regression. RESULTS: Increasing tertiles of TA-DAS28(CRP) were associated with JE and JSN progression in the monotherapy groups, a phenomenon largely absent in ADA+MTX-treated patients. Although JSN was not associated with HAQ-DI at baseline, it was at 52 and 104 weeks. In contrast, JE was not associated with HAQ-DI at any time point examined. Odds of being employed at baseline, 52 weeks and 104 weeks were significantly associated with lower JSN, but not JE, scores. CONCLUSIONS: ADA+MTX inhibited both JE and JSN progression independently of disease activity. JSN played a more prominent role in patient-reported outcomes than JE. Preventing the onset or worsening of JSN probably represents a critical aspect of effective disease management of early rheumatoid arthritis patients.

MRI of hand and foot joints of patients with anticitrullinated peptide antibody positive arthralgia without clinical arthritis.

BACKGROUND: Anticitrullinated peptide antibodies (ACPA) and acute phase reactants may be increased before arthritis becomes clinically detectable, suggesting that the processes underlying rheumatoid arthritis (RA) start preclinically. Whether local inflammation occurs in the preclinical phase is unknown. Therefore, we studied the small joints of ACPA positive arthralgia patients for local subclinical inflammation. METHODS: Imaging was performed using 1.5 T extremity MRI. Painful hand or foot joints of 21 ACPA positive arthralgia patients without clinical arthritis were imaged. For comparison, hand and foot joints of 22 ACPA positive RA patients and 19 symptom free controls were studied. Within ACPA positive arthralgia patients, painful and symptom free joint regions were imaged. Scoring was performed according to the Outcome Measures in Rheumatology Clinical Trials (OMERACT) Rheumatoid Arthritis Magnetic Resonance Imaging Scoring (RAMRIS) method. Analyses were performed on joint region level and focused on inflammation (synovitis plus bone marrow oedema). RESULTS: The mean combined inflammation scores of the metacarpophalangeal/proximal interphalangeal joints of controls, painful joints of ACPA positive arthralgia patients and ACPA positive RA patients were 0.1, 0.7 and 3.7, respectively (p<0.001). Likewise, the mean combined inflammation scores of the wrist were 0.9, 2.3 and 10.3, respectively (p<0.001) and that of the metatarsophalangeal joints 0.5, 0.9 and 3.8, respectively (p=0.10). At the MCP joints, the combined inflammation score was significantly correlated with C reactive protein and erythrocyte sedimentation rate levels (rs=0.83 and rs=0.78, respectively) CONCLUSIONS: The present data suggest that local subclinical inflammation occurs in ACPA positive arthralgia patients.

Improvement in deployment of MRI of the sacroiliac joints in patients suspected for spondyloarthritis using a targeted intervention: a case study.

OBJECTIVE: To assess characteristics of deployment of MRI of the SI joints (MR-SI) in patients with suspected axial spondyloarthritis (SpA) before and after a targeted intervention. METHODS: In a retrospective chart review study, all MR-SI performed in the period 1 April 2004 to 31 December 2010 were collected. Inclusion criteria were complete patient data and MR-SI ordered by a rheumatologist for suspicion of axial SpA. MR-SI reports were graded as normal, suspected sacroiliitis or sacroiliitis. In April 2007 an intervention was made to improve deployment. Rheumatologists were provided with data on ordering behaviour, patient characteristics and MRI outcomes. An introduction on the effect of pretest chance on positive and negative predictive value was given; the burden for patients and costs was illustrated. An alternative behavioural strategy was offered in the form of a simple diagnostic algorithm. Percentages of MRIs and positive MRI for sacroiliitis were compared before and after intervention. RESULTS: From April 2004 to April 2007, 198 MR-SIs were performed, of which 166 (83.9%) were normal, 5 (2.5%) were suspicious and 27 (13.6%) were positive. After the intervention, patients displayed significantly more SpA features. More optimal patient selection resulted in 79 MR-SI requests, a decrease of 60.1%. Fifty-seven (72.2%) reports were normal, 0 were suspicious and 22 (27.8%) were positive. CONCLUSION: A simple, one-time, five-step feedback intervention resulted in a 60% reduction in MR-SI requests with a doubling of the percentage of MR-SI positive for sacroiliitis. This approach may benefit future research in areas with diagnostic uncertainty and suboptimal testing.