Matthijs Janssen

Use of oral prednisolone or naproxen for the treatment of gout arthritis: a double-blind, randomised equivalence trial

BACKGROUND Non-steroidal anti-inflammatory drugs and colchicine used to treat gout arthritis have gastrointestinal, renal, and cardiovascular adverse effects. Systemic corticosteroids might be a beneficial alternative. We investigated equivalence of naproxen and prednisolone in primary care. METHODS We did a randomised clinical trial to test equivalence of prednisolone and naproxen for the treatment of monoarticular gout. Primary-care patients with gout confirmed by presence of monosodium urate crystals were eligible. 120 patients were randomly assigned with computer-generated randomisation to receive either prednisolone (35 mg once a day; n=60) or naproxen (500 mg twice a day; n=60), for 5 days. Treatment was masked for both patients and physicians. The primary outcome was pain measured on a 100 mm visual analogue scale and the a priori margin for equivalence set at 10%. Analyses were done per protocol and by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN14648181. FINDINGS Data were incomplete for one patient in each treatment group, so per-protocol analyses included 59 patients in each group. After 90 h the reduction in the pain score was 44.7 mm and 46.0 mm for prednisolone and naproxen, respectively (difference 1.3 mm; 95% CI -9.8 to 7.1), suggesting equivalence. The difference in the size of change in pain was 1.57 mm (95% CI -8.65 to 11.78). Adverse effects were similar between groups, minor, and resolved by 3 week follow-up. INTERPRETATION Oral prednisolone and naproxen are equally effective in the initial treatment of gout arthritis over 4 days.

A Diagnostic Rule for Acute Gouty Arthritis in Primary Care Without Joint Fluid Analysis

BACKGROUND Most cases of acute gouty arthritis are diagnosed in primary care and without joint fluid analysis in many instances. Our objectives were to estimate the validity of this diagnosis by family physicians and to develop a diagnostic rule. METHODS Patients with monoarthritis recruited in an open Dutch population with gout by family physician diagnosis were enrolled in a diagnostic study (March 24, 2004, through July 14, 2007). Validity variables were estimated using 2 x 2 tables, with the presence of synovial monosodium urate crystals as the reference test. For development of the diagnostic rule, clinical variables (including the presence of synovial monosodium urate crystals) were collected within 24 hours. Statistically significant variables and predefined variables were separately entered in multivariate logistic regression models to predict the presence of synovial monosodium urate crystals. Diagnostic performance of the models was tested by receiver operating characteristic curve analysis. The most appropriate model was transformed to a clinically useful diagnostic rule. RESULTS Three hundred twenty-eight patients were included in the study. The positive and negative predictive values of family physician diagnosis of gout were 0.64 and 0.87, respectively. The most appropriate model contained the following predefined variables: male sex, previous patient-reported arthritis attack, onset within 1 day, joint redness, first metatarsophalangeal joint (MTP1) involvement, hypertension or 1 or more cardiovascular diseases, and serum uric acid level exceeding 5.88 mg/dL (to convert serum uric acid level to micromoles per liter, multiply by 59.485). The area under the receiver operating characteristic curve for this model was 0.85 (95% confidence interval, 0.81-0.90). Performance did not change after transforming the regression coefficients to easy-to-use scores and was almost equal to that of the statistically optimal model (area under the receiver operating characteristic curve, 0.87; 95% confidence interval, 0.83-0.91). CONCLUSIONS The validity of family physician diagnosis of acute gouty arthritis was moderate in this study. An easy-to-use diagnostic rule without joint fluid analysis was developed for their use.

Pulmonary Mycobacterium szulgai infection and treatment in a patient receiving anti-tumor necrosis factor therapy

Background A 54-year-old man with a 22-year history of rheumatoid arthritis and an 8-year history of chronic obstructive pulmonary disease presented with dyspnea on exertion, nonproductive cough and fatigue of 1 months duration. His medication at presentation consisted of etanercept, azathioprine, naproxen and inhaled fluticasone and salbutamol.Investigations At presentation, the patient underwent physical examination, chest X-ray and high-resolution CT, blood tests, and bronchoalveolar lavage fluid analysis including auramine stains and gene sequence analysis of cultured Mycobacterium szulgai. The patient underwent minithoracotomy after 6 months, and bronchoalveolar lavage fluid analysis, culture and chest X-ray after 18 months. Further chest imaging and culture of sputum samples were performed another year later.Diagnosis Pulmonary M. szulgai infection.Management Triple drug therapy with rifampicin, ethambutol hydrochloride and clarithromycin. Anti-tumor necrosis factor treatment was continued.

Gout, not induced by diuretics? A case-control study from primary care

Background: It is taken for granted that diuretics may induce gout, but there is a general lack of evidence on this topic. Objectives: To determine the incidence of gout in patients who use diuretics, taking into account concurrent hypertension and cardiovascular diseases. Methods: A case-control study was designed. From a primary care population all patients with a first gout registration (59 men, 11 women; mean (SD) age 55.1 (13.5)) were identified as cases. To relate the occurrence of gout to diuretic use a matched reference series of three controls for each case was compiled. Conditional logistic regression analyses were applied to estimate incidence rate ratios (IRRs) of gout, and 95% confidence intervals (CIs), in subjects with and without diuretic treatment, hypertension, and cardiovasculardiseases. Additional stratification analyses were made, particularly in the subjects not using diuretics. Results: The IRRs of gout in subjects with v those without diuretic treatment, hypertension, heart failure, and myocardial infarction were 2.8 (95% CI 1.2 to 6.6), 2.6 (95% CI 1.2 to 5.6), 20.9 (95% CI 2.5 to 173.8), and 1.9 (95% CI 0.7 to 4.7), respectively. After adjustment, the IRR of gout for diuretic use dropped to 0.6 (95% CI 0.2 to 2.0), while the IRRs of gout for hypertension, heart failure, and myocardial infarction were still >1. This was also the case for subjects with hypertension or myocardial infarction, who had not used diuretics. Conclusion: The results suggest that diuretics do not actually increase the risk of gout. Cardiovascular indications for treatment may have confounded previous inferences.

Performance of classification criteria for gout in early and established disease

Objectives To compare the sensitivity and specificity of different classification criteria for gout in early and established disease. Methods This was a cross-sectional study of consecutive rheumatology clinic patients with joint swelling in which gout was defined by presence or absence of monosodium urate crystals as observed by a certified examiner at presentation. Early disease was defined as patient-reported onset of symptoms of 2 years or less. Results Data from 983 patients were collected and gout was present in 509 (52%). Early disease was present in 144 gout cases and 228 non-cases. Sensitivity across criteria was better in established disease (95.3% vs 84.1%, p<0.001) and specificity was better in early disease (79.9% vs 52.5%, p<0.001). The overall best performing clinical criteria were the Rome criteria with sensitivity/specificity in early and established disease of 60.3%/84.4% and 86.4%/63.6%. Criteria not requiring synovial fluid analysis had sensitivity and specificity of less than 80% in early and established disease. Conclusions Existing classification criteria for gout have sensitivity of over 80% in early and established disease but currently available criteria that do not require synovial fluid analysis have inadequate specificity especially later in the disease. Classification criteria for gout with better specificity are required, although the findings should be cautiously applied to non-rheumatology clinic populations.

Study for Updated Gout Classification Criteria: Identification of Features to Classify Gout

To determine which clinical, laboratory, and imaging features most accurately distinguished gout from non‐gout.

Multiplicative interaction of functional inflammasome genetic variants in determining the risk of gout.

IntroductionThe acute gout flare results from a localised self-limiting innate immune response to monosodium urate (MSU) crystals deposited in joints in hyperuricaemic individuals. Activation of the caspase recruitment domain-containing protein 8 (CARD8) NOD-like receptor pyrin-containing 3 (NLRP3) inflammasome by MSU crystals and production of mature interleukin-1β (IL-1β) is central to acute gouty arthritis. However very little is known about genetic control of the innate immune response involved in acute gouty arthritis. Therefore our aim was to test functional single nucleotide polymorphism (SNP) variants in the toll-like receptor (TLR)-inflammasome-IL-1β axis for association with gout.Methods1,494 gout cases of European and 863 gout cases of New Zealand (NZ) Polynesian (Māori and Pacific Island) ancestry were included. Gout was diagnosed by the 1977 ARA gout classification criteria. There were 1,030 Polynesian controls and 10,942 European controls including from the publicly-available Atherosclerosis Risk in Communities (ARIC) and Framingham Heart (FHS) studies. The ten SNPs were either genotyped by Sequenom MassArray or by Affymetrix SNP array or imputed in the ARIC and FHS datasets. Allelic association was done by logistic regression adjusting by age and sex with European and Polynesian data combined by meta-analysis. Sample sets were pooled for multiplicative interaction analysis, which was also adjusted by sample set.ResultsEleven SNPs were tested in the TLR2, CD14, IL1B, CARD8, NLRP3, MYD88, P2RX7, DAPK1 and TNXIP genes. Nominally significant (P < 0.05) associations with gout were detected at CARD8 rs2043211 (OR = 1.12, P = 0.007), IL1B rs1143623 (OR = 1.10, P = 0.020) and CD14 rs2569190 (OR = 1.08; P = 0.036). There was significant multiplicative interaction between CARD8 and IL1B (P = 0.005), with the IL1B risk genotype amplifying the risk effect of CARD8.ConclusionThere is evidence for association of gout with functional variants in CARD8, IL1B and CD14. The gout-associated allele of IL1B increases expression of IL-1β – the multiplicative interaction with CARD8 would be consistent with a synergy of greater inflammasome activity (resulting from reduced CARD8) combined with higher levels of pre-IL-1β expression leading to increased production of mature IL-1β in gout.

A Delphi Exercise to Identify Characteristic Features of Gout — Opinions from Patients and Physicians, the First Stage in Developing New Classification Criteria

Objective. To identify a comprehensive list of features that might discriminate between gout and other rheumatic musculoskeletal conditions, to be used subsequently for a case-control study to develop and test new classification criteria for gout. Methods. Two Delphi exercises were conducted using Web-based questionnaires: one with physicians from several countries who had an interest in gout and one with patients from New Zealand who had gout. Physicians rated a list of potentially discriminating features that were identified by literature review and expert opinion, and patients rated a list of features that they generated themselves. Agreement was defined by the RAND/UCLA disagreement index. Results. Forty-four experienced physicians and 9 patients responded to all iterations. For physicians, 71 items were identified by literature review and 15 more were suggested by physicians. The physician survey showed agreement for 26 discriminatory features and 15 as not discriminatory. The patients identified 46 features of gout, for which there was agreement on 25 items as being discriminatory and 7 items as not discriminatory. Conclusion. Patients and physicians agreed upon several key features of gout. Physicians emphasized objective findings, imaging, and patterns of symptoms, whereas patients emphasized severity, functional results, and idiographic perception of symptoms.

The validation of a diagnostic rule for gout without joint fluid analysis: a prospective study

OBJECTIVE The gold standard for diagnosing gout is the identification of MSU crystals in joint fluid. In secondary care, the facilities or expertise to analyse joint fluid are not always available and gout is diagnosed clinically. To improve the predictive value of the clinical diagnosis of gout in secondary care, a diagnostic rule developed in primary care could be helpful. The aim of this study was to validate this diagnostic rule in a secondary care population with the gold standard as reference test. METHODS Three hundred and ninety patients with monoarthritis were included. The variables of the diagnostic rule (male sex, previous arthritis attack, onset <1 day, joint redness, involvement of the first MTP joint, hypertension or one or more cardiovascular disease, and serum uric acid >5.88 mg/dl) were collected and scored. The affected joint was aspirated and joint fluid was analysed for the presence of MSU crystals. RESULTS In 219 patients (56%) MSU crystals were found. The positive predictive value of a score of ≥8 points was 0.87, the negative predictive value of a score of ≤4 points was 0.95. The area under the receiver operating characteristic curve for the diagnostic rule was 0.86 (95% CI 0.82, 0.89). The Hosmer-Lemeshow goodness-of-fit test showed that the difference between the expected and the observed probability was non-significant (P = 0.64), indicating good agreement. CONCLUSION An easy-to-use diagnostic rule for gout developed in primary care shows good performance in secondary care and improves the predictive value of the clinical diagnosis of gout when joint fluid analysis is not available.

Performance of Ultrasound in the Diagnosis of Gout in a Multicenter Study: Comparison With Monosodium Urate Monohydrate Crystal Analysis as the Gold Standard

To examine the performance of ultrasound (US) for the diagnosis of gout using the presence of monosodium urate monohydrate (MSU) crystals as the gold standard.