Prevalence and factors associated with flares following COVID-19 mRNA vaccination in patients with rheumatoid arthritis, psoriatic arthritis and spondyloarthritis: a national cohort study.

OBJECTIVE: To determine prevalence and factors associated with flares post Coronavirus disease 2019 (COVID-19) mRNA vaccination in patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA) and spondyloarthritis (SpA). METHODS: A retrospective multi-centre study was conducted (January 2021 to February 2022). Data were collected during index visit, defined as first post-vaccine visit in which the patient had a physician-defined flare, or if at least 3 months had elapsed since first vaccine dose, whichever came first. Factors associated with flares were identified using mixed effects Cox regression and expressed as hazard ratio (HR) and 95% confidence interval (CI). RESULTS: Total of 2377 patients were included (1563 RA, 415 PsA and 399 SpA). Among patients with RA, PsA and SpA, 21.3%, 24.1% and 21.8% experienced a flare respectively. Of those who experienced a flare, only 10.2%, 11.0% and 14.9% were severe in patients with RA, PsA and SpA respectively. Patients with low or moderate/high disease were more likely to flare compared to those in remission in patients with RA only (HR: 1.68, 95% CI 1.22-2.31; HR: 2.28, 95% CI 1.50-3.48, respectively). Receiving the Moderna vaccine was associated with a higher HR of flare compared to the Pfizer vaccine in patients with PsA only (HR: 2.21, 95% CI 1.20-4.08). Patients who had two vaccine doses were found to be less likely to flare (HR: 0.08, 95% CI 0.06-0.10). HRs of flares were not significantly different among RA, PsA and SpA. CONCLUSION: About one-fifth of patients experienced a disease flare post COVID-19 mRNA vaccination, but most flares were non-severe. Patients with active disease prior to vaccination should be monitored closely for disease flares, especially in patients with RA.

Recommendations for enhanced primary series (third dose) COVID-19 vaccination for people with rheumatic diseases: Chapter of Rheumatologists, College of Physicians, Singapore.

Introduction: This review aims to provide evidence-based recommendations for an enhanced primary series (third dose) coronavirus disease 2019 (COVID-19) vaccination in people with rheumatic diseases (PRDs) in the local and regional context. Methods: Literature reviews were performed regarding the necessity, efficacy, safety and strategies for enhanced primary series COVID-19 vaccination in PRDs. Recommendations were developed based on evidence according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology. Evidence was synthesised by eight working group members, and the consensus was achieved by a Delphi method with nine members of an expert task force panel. Results: Two graded recommendations and one ungraded position statement were developed. PRDs have impaired immunogenicity from the COVID-19 vaccine and are at an increased risk of postvaccine breakthrough severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and poor clinical outcomes, compared to the general population. We strongly recommend that PRDs on immunomodulatory drugs be offered a third dose of the messenger RNA (mRNA) vaccine as part of an enhanced primary series, after the standard two-dose regimen. We conditionally recommend that the third dose of mRNA vaccine against SARS-CoV-2 be given at least 4 weeks after the second dose or as soon as possible thereafter. There is insufficient data to inform whether the third mRNA vaccine should be homologous or heterologous in PRDs. Conclusion: These recommendations that were developed through evidence synthesis and formal consensus process provide guidance for an enhanced primary series COVID-19 vaccination in PRDs.

The Singapore Experience With Uncontrolled Gout: Unmet Needs in the Management of Patients.

Gout is the most common type of inflammatory arthritis, and its impact on cardiovascular health and quality of life is often underestimated. The prevalence and incidence of gout are increasing globally. Further, ischemic heart disease (IHD) and chronic kidney disease (CKD) are prevalent in gout patients. Some unmet needs for gout management include physicians' low initiation rate of urate-lowering therapy (ULT) and poor treatment adherence in patients with gout. There is also a lack of randomized controlled trials that establish safe doses of acute and long-term treatment for gout, particularly in patients with IHD and stage 4 CKD and above (including end-stage renal failure). Furthermore, there is also a lack of studies showing optimal serum uric acid (SUA) target and validated clinical outcome measures, including disease activity and remission criteria for gout tailored to treat-to-target approaches and the high cost of newer gout medications. The causal relationship between asymptomatic hyperuricemia or gout with comorbidities such as IHD and CKD has yet to be fully elucidated. There is a pressing need for collaborative international efforts to address the overall suboptimal management of gout.

Post-mRNA vaccine flares in autoimmune inflammatory rheumatic diseases: Results from the COronavirus National Vaccine registry for ImmuNe diseases SINGapore (CONVIN-SING).

BACKGROUND: Studies of flares of autoimmune inflammatory rheumatic diseases (AIIRD) after COVID-19 mRNA vaccination are limited by small sample size, short follow up or at risk of selection bias. METHODS: A national retrospective cohort study of consecutive AIIRD patients ≥12 years old, across 8 hospitals who received at least one dose of a COVID-19 mRNA vaccine. Patients were included from the date of 1st vaccine dose and censored at the time of flare or on the date of the clinic visit at least 3 months from cohort entry, whichever came first. Predictors of flare were determined by Cox proportional hazards analysis. FINDINGS: 4627 patients (73% Chinese, 71% female) of median (IQR) age 61 (48, 70) years were included; 42% Rheumatoid arthritis, 14% Systemic lupus erythematosus and 11% Psoriatic arthritis. 47% were in remission, 41% low disease activity, 10% moderate disease activity and 1% in high disease activity. 18% patients flared, of which 11.7% were within the 3-month period of interest. 11.8% patients improved. Median (IQR) time-to-flare was 60 (30, 114) days. 25% flares were self-limiting, 61% mild-moderate and 14% severe. Older patients (53-65 years and >66 years) had a lower risk of flare [HR 0.6 (95% CI 0.5-0.8) and 0.7 (0.6-0.8) respectively]. Patients with inflammatory arthritis and with active disease had a higher risk of flare [HR 1.5 (1.2-2.0) and 1.4 (1.2-1.6), respectively]. Treatment with conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs), immunosuppression and prednisolone was also associated with an increased risk of flare [HR 1.5 (1.1-2), 1.2 (1.1-1.4) and 1.5 (1.2-1.8) for prednisolone ≤7.5 mg respectively]. INTERPRETATION: There was a moderately high rate of AIIRD flares after mRNA vaccination but also improvement in several patients. Severe flares and hospitalisation were rare. Thus, vaccination remains safe and highly recommended.

Prevalence and factors associated with flares following COVID-19 mRNA vaccination in patients with rheumatoid arthritis, psoriatic arthritis and spondyloarthritis: a national cohort study

Abstract Objective To determine prevalence and factors associated with flares post Coronavirus disease 2019 (COVID-19) mRNA vaccination in patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA) and spondyloarthritis (SpA). Methods A retrospective multi-centre study was conducted (January 2021 to February 2022). Data were collected during index visit, defined as first post-vaccine visit in which the patient had a physician-defined flare, or if at least 3 months had elapsed since first vaccine dose, whichever came first. Factors associated with flares were identified using mixed effects Cox regression and expressed as hazard ratio (HR) and 95% confidence interval (CI). Results Total of 2377 patients were included (1563 RA, 415 PsA and 399 SpA). Among patients with RA, PsA and SpA, 21.3%, 24.1% and 21.8% experienced a flare respectively. Of those who experienced a flare, only 10.2%, 11.0% and 14.9% were severe in patients with RA, PsA and SpA respectively. Patients with low or moderate/high disease were more likely to flare compared to those in remission in patients with RA only (HR: 1.68, 95% CI 1.22-2.31; HR: 2.28, 95% CI 1.50-3.48, respectively). Receiving the Moderna vaccine was associated with a higher HR of flare compared to the Pfizer vaccine in patients with PsA only (HR: 2.21, 95% CI 1.20-4.08). Patients who had two vaccine doses were found to be less likely to flare (HR: 0.08, 95% CI 0.06-0.10). HRs of flares were not significantly different among RA, PsA and SpA. Conclusion About one-fifth of patients experienced a disease flare post COVID-19 mRNA vaccination, but most flares were non-severe. Patients with active disease prior to vaccination should be monitored closely for disease flares, especially in patients with RA.

Latent Class Analysis Identifies Distinct Phenotypes of Systemic Lupus Erythematosus Predictive of Flares after mRNA COVID-19 Vaccination: Results from the Coronavirus National Vaccine Registry for ImmuNe Diseases SINGapore (CONVIN-SING).

We recently reported that messenger ribonucleic acid (mRNA) coronavirus disease 2019 (COVID-19) vaccination was associated with flares in 9% of patients with systemic lupus erythematosus (SLE). Herein, we focused our analysis on patients from a multi-ethnic Southeast Asian lupus cohort with the intention of identifying distinct phenotypes associated with increased flares after mRNA COVID-19 vaccination. METHODS: Six hundred and thirty-three SLE patients from eight public healthcare institutions were divided into test and validation cohorts based on healthcare clusters. Latent class analysis was performed based on age, ethnicity, gender, vaccine type, past COVID-19 infection, interruption of immunomodulatory/immunosuppressive treatment for vaccination, disease activity and background immunomodulatory/immunosuppressive treatment as input variables. Data from both cohorts were then combined for mixed effect Cox regression to determine which phenotypic cluster had a higher risk for time to first SLE flare, adjusted for the number of vaccine doses. RESULTS: Two clusters were identified in the test (C1 vs. C2), validation (C1' vs. C2') and combined (C1″ vs. C2″) cohorts, with corresponding clusters sharing similar characteristics. Of 633 SLE patients, 88.6% were female and there was multi-ethnic representation with 74.9% Chinese, 14.2% Malay and 4.6% Indian. The second cluster (C2, C2' and C2″) was smaller compared to the first. SLE patients in the second cluster (C2 and C2') were more likely to be male, non-Chinese and younger, with higher baseline disease activity. The second cluster (C2″) had more incident flares (hazard ratio = 1.4, 95% confidence interval 1.1-1.9, p = 0.014) after vaccination. A higher proportion of patients in C2″ had immunomodulatory/immunosuppressive treatment interruption for vaccination as compared to patients in C1″ (6.6% vs. 0.2%) (p < 0.001). CONCLUSION: We identified two distinct phenotypic clusters of SLE with different patterns of flares following mRNA COVID-19 vaccination. Caution has to be exercised in monitoring for post-vaccination flares in patients with risk factors for flares such as non-Chinese ethnicity, young age, male gender and suboptimal disease control at the time of vaccination.

Idiopathic recurrent serositis-Off the beaten track.

A 63-year-old female presented with chest pain and fever, and was found to have recurrent pleuropericardial effusions. Extensive investigations including infection screen and serologies, autoimmune screen and pleural and pericardial biopsy revealed no secondary aetiologies. She was diagnosed with idiopathic recurrent serositis (IRS). Our patient developed rash to naproxen, so she was started on colchicine monotherapy and responded well clinically. A review of the literature demonstrated that pleuropericardial effusions are rare occurrences, with patients occasionally being perceived as a medical enigma. This case study recommends an approach to guide physicians in their diagnosis and management of patients with pleuropericardial syndrome. Our case had an inflammatory phenotype, either autoimmune or seronegative serositis of unclear aetiology, which was recurrent and required pharmacological treatment. While the treatment for IRS lies in combined therapy with Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) and colchicine, monotherapy with colchicine was effective in the treatment and preventing recurrence in our unique case.

Interventions for tophi in gout.

BACKGROUND: Tophi develop in untreated or uncontrolled gout. This is an update of a Cochrane Review first published in 2014.  OBJECTIVES: To assess the benefits and harms of non-surgical and surgical treatments for the management of tophi in gout. SEARCH METHODS: We updated the search of Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and Embase databases to 28 August 2020. SELECTION CRITERIA: We included all published randomised controlled trials (RCTs) or controlled clinical trials examining interventions for tophi in gout in adults. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. MAIN RESULTS: We included one trial in our original review. We added four more trials (1796 participants) in this update. One had three arms; pegloticase infusion every two weeks (biweekly), monthly pegloticase infusion (pegloticase infusion alternating with placebo infusion every two weeks) and placebo. Two studies looked at lesinurad 200 mg or 400 mg in combination with allopurinol. One trial studied lesinurad 200 mg or 400 mg in combination with febuxostat. One trial compared febuxostat 80 mg and 120 mg to allopurinol. Two trials were at unclear risk of performance and detection bias due to lack of information on blinding of participants and personnel. All other trials were at low risk of bias. Moderate-certainty evidence (downgraded for imprecision; one study; 79 participants) showed that biweekly pegloticase resolved tophi in 21/52 participants compared with 2/27 on placebo (risk ratio (RR) 5.45, 95% confidence interval (CI) 1.38 to 21.54; number needed to treat for a benefit (NNTB) 3, 95% CI 2 to 6). Similar proportions of participants receiving biweekly pegloticase (80/85) had an adverse event compared to placebo (41/43) (RR 0.99, 95% CI 0.91 to 1.07). However, more participants on biweekly pegloticase (15/85) withdrew due to an adverse event compared to placebo (1/43) (RR 7.59, 95% CI 1.04 to 55.55; number needed to treat for a harm (NNTH) 7, 95% CI 4 to 16). More participants on monthly pegloticase (11/52) showed complete resolution of tophi compared with placebo (2/27) (RR 2.86, 95% CI 0.68 to 11.97; NNTB 8, 95% CI 4 to 91). Similar numbers of participants on monthly pegloticase (84/84) had an adverse event compared to placebo (41/43) (RR 1.05, 95% CI 0.98 to 1.14). More participants on monthly pegloticase (16/84) withdrew due to adverse events compared to placebo (1/43) (RR 8.19, 95% CI 1.12 to 59.71; NNTH 6, 95% CI 4 to 14). Infusion reaction was the most common reason for withdrawal. Moderate-certainty evidence (2 studies; 103 participants; downgraded for imprecision) showed no clinically significant difference for complete resolution of target tophus in the lesinurad 200 mg plus allopurinol arm (11/53) compared to the placebo plus allopurinol arm (16/50) (RR 0.40, 95% CI 0.04 to 4.57), or in the lesinurad 400 mg plus allopurinol arm (12/48) compared to the placebo plus allopurinol arm (16/50) (RR 0.79, 95% CI 0.42 to 1.49). An extension study examined lesinurad 200 mg or 400 mg in combination with febuxostat, or placebo (low-certainty evidence, downgraded for indirectness and imprecision). Participants on lesinurad in the original study continued (CONT) on the same dose. Lesinurad 400 mg plus febuxostat may be beneficial for tophi resolution; 43/65 in the lesinurad 400 mg CONT arm compared to 38/64 in the lesinurad 200 mg CONT arm had tophi resolution (RR 1.11, 95% CI 0.85 to 1.46). Lesinurad 400 mg plus febuxostat may result in no difference in adverse events; 57/65 in the lesinurad 400 mg CONT arm had an adverse event compared to 50/64 in lesinurad 200 mg CONT arm (RR 1.12, 95% CI 0.96 to 1.32). Lesinurad 400 mg plus febuxostat may result in no difference in withdrawals due to adverse events; 10/65 participants in the lesinurad 400 mg CONT arm withdrew due to an adverse event compared to 10/64 participants in the lesinurad 200 mg CONT arm (RR 0.98, 95% CI 0.44 to 2.20). Lesinurad 400 mg plus febuxostat may result in no difference in mean serum uric acid (sUA), which was 3 mg/dl in the lesinurad 400 mg CONT group compared to 3.9 mg/dl in the lesinurad 200 mg CONT group (mean difference -0.90, 95% CI -1.51 to -0.29). Participants who were not on lesinurad in the original study were randomised (CROSS) to lesinurad 200 mg or 400 mg, both in combination with febuxostat. Low-certainty evidence downgraded for indirectness and imprecision showed that lesinurad 400 mg (CROSS) may result in tophi resolution (17/34) compared to lesinurad 200 mg (CROSS) (14/33) (RR 1.18, 95% CI 0.70 to 1.98). Lesinurad 400 mg in combination with febuxostat may result in no difference in adverse events (33/34 in the lesinurad 400 mg CROSS arm compared to 27/33 in the lesinurad 200 mg (CROSS); RR 1.19, 95% CI 1.00 to 1.41). Lesinurad 400 mg plus febuxostat may result in no difference in withdrawals due to adverse events, 5/34 in the lesinurad 400 mg CROSS arm withdrew compared to 2/33 in the lesinurad 200 mg CROSS arm (RR 2.43, 95% CI 0.51 to 11.64). Lesinurad 400 mg plus febuxostat results in no difference in sUA (4.2 mg/dl in lesinurad 400 mg CROSS) compared to lesinurad 200 mg (3.8 mg/dl in lesinurad 200 mg CROSS), mean difference 0.40 mg/dl, 95% CI -0.75 to 1.55. AUTHORS' CONCLUSIONS: Moderate-certainty evidence showed that pegloticase is probably beneficial for resolution of tophi in gout. Although there was little difference in adverse events when compared to placebo, participants on pegloticase had more withdrawals due to adverse events. Lesinurad 400 mg plus febuxostat may be beneficial for tophi resolution compared with lesinurad 200 mg plus febuxostat; there was no difference in adverse events between these groups. We were unable to determine whether lesinurad plus febuxostat is more effective than placebo. Lesinurad (400 mg or 200 mg) plus allopurinol is probably not beneficial for tophi resolution, and there was no difference in adverse events between these groups. RCTs on interventions for managing tophi in gout are needed, and the lack of trial data is surprising given that allopurinol is a well-established treatment for gout.

Recommendations for COVID-19 vaccination in people with rheumatic disease: Developed by the Singapore Chapter of Rheumatologists.

AIM: People with rheumatic diseases (PRD) remain vulnerable in the era of the COVID-19 pandemic. We formulated recommendations to meet the urgent need for a consensus for vaccination against SARS-CoV-2 in PRD. METHODS: Systematic literature reviews were performed to evaluate: (a) outcomes in PRD with COVID-19; (b) efficacy, immunogenicity and safety of COVID-19 vaccination; and (c) published guidelines/recommendations for non-live, non-COVID-19 vaccinations in PRD. Recommendations were formulated based on the evidence and expert opinion according to the Grading of Recommendations Assessment, Development and Evaluation methodology. RESULTS: The consensus comprises 2 overarching principles and 7 recommendations. Vaccination against SARS-CoV-2 in PRD should be aligned with prevailing national policy and should be individualized through shared decision between the healthcare provider and patient. We strongly recommend that eligible PRD and household contacts be vaccinated against SARS-CoV-2. We conditionally recommended that the COVID-19 vaccine be administered during quiescent disease if possible. Immunomodulatory drugs, other than rituximab, can be continued alongside vaccination. We conditionally recommend that the COVID-19 vaccine be administered prior to commencing rituximab if possible. For patients on rituximab, the vaccine should be administered a minimum of 6 months after the last dose and/or 4 weeks prior to the next dose of rituximab. Post-vaccination antibody titers against SARS-CoV-2 need not be measured. Any of the approved COVID-19 vaccines may be used, with no particular preference. CONCLUSION: These recommendations provide guidance for COVID-19 vaccination in PRD. Most recommendations in this consensus are conditional, reflecting a lack of evidence or low-level evidence.

Singapore chapter of rheumatologists' updated consensus statement on the eligibility for government subsidization of biologic and targeted therapy for the treatment of psoriatic arthritis.

AIM: There have been major advances in biologic treatment options for psoriatic arthritis (PsA) since the publication of the 2015 consensus recommendations by the Chapter of Rheumatologists, College of Physicians, Academy of Medicine, Singapore, for government-assisted funding, thus warranting a revision of this guideline. METHODS: Recent trials and nine published guidelines on the use of biologic therapy for PsA were reviewed. Based on the synthesized evidence, a task force panel (TFP), consisting of 10 practicing rheumatologists in Singapore, rated the statements pertaining to the use of biologic therapy, using a modified Delphi approach. Consensus was obtained if >70% agreed on a statement. RESULTS: The TFP agreed on 10 recommendations pertaining to the initiation, choice and continuation of biologic therapy. A biologic is indicated in patients with PsA: (a) with at least three swollen and tender joints, digits or entheses; and (b) who have failed at least two conventional synthetic disease-modifying anti-rheumatic drug (csDMARD) strategies for a minimum of 3 months each. Any approved drug class including tumor necrosis factor inhibitors, interleukin-17 inhibitors (IL-17i), IL-12/23i or targeted synthetic DMARDs may be considered as first-line treatment, and continued only if a response is achieved by 6 months. CONCLUSION: These recommendations developed through a formal consensus method may be useful to guide funding considerations for appropriate and equitable use of biologic therapy for eligible patients with PsA.

Update on recommendations for eligibility of government subsidization of biologic disease-modifying antirheumatic drugs for the treatment of axial spondyloarthritis in Singapore.

AIMS: The field of axial spondyloarthritis (axSpA) has undergone significant changes recently in particular with disease classification, assessment of disease activity and increased treatment options for biologics. In order to reflect these developments, we aimed to update the local consensus recommendations for subsidization of biologics. METHODS: A modified Delphi approach was used. Six published guidelines from major rheumatology societies and healthcare authorities on axSpA were reviewed. Findings were synthesized and used in formulating updated recommendation statements. Recommendations were rated by 10 practicing rheumatologists in Singapore. Consensus was reached if there was more than 70% agreement or disagreement. RESULTS: Ten statements achieved consensus. Patients may be considered for subsidization of biologic therapy if they fulfill the Assessment of Spondyloarthritis International Society or modified New York criteria, with persistently active disease (defined either by Ankylosing Spondylitis Disease Activity Score ≥ 2.1 or Bath Spondylitis Disease Activity Index ≥ 4), despite 4 weeks of full-dose non-steroidal anti-inflammatory drugs and regular exercise. Either tumor necrosis factor inhibitors or interleukin 17 inhibitors may be used as first-line therapy, and should be continued if adequate response is achieved at 6 months. CONCLUSION: Recommendation statements were formulated through a formal consensus process by local experts with a view to assist relevant authorities in funding considerations and for use in clinical practice.

Singapore Chapter of Rheumatologists updated consensus statement on the eligibility for government subsidization of biologic and targeted-synthetic therapy for the treatment of rheumatoid arthritis.

INTRODUCTION: Approximately 30% of patients with rheumatoid arthritis (RA) respond inadequately to conventional-synthetic disease-modifying anti-rheumatic drugs (csDMARDs). However, widespread use of biologic DMARDs (bDMARDs) and targeted-synthetic (tsDMARDs) is limited by cost. We formulated updated recommendations for eligibility criteria for government-assisted funding of bDMARDs/tsDMARDs for RA patients in Singapore. MATERIALS AND METHODS: Published guidelines regarding use of bDMARD and tsDMARDs were reviewed. We excluded those without a systematic literature review, formal consensus process or evidence grading. Separately, unpublished national reimbursement guidelines were included. RESULTS: Eleven recommendations regarding choice of disease activity measure, initiation, order of selection and continuation of bDMARD/tsDMARDs were formulated. A bDMARD/tsDMARD is indicated if a patient has: (a) at least moderately active RA with a Disease Activity Score in 28 joints/erythrocyte sedimentation rate (DAS28-ESR) score of ≥3.2; (b) failed ≥2 csDMARD strategies, 1 of which must be a combination; (c) received an adequate dose regimen of ≥3 months for each strategy. For the first-line bDMARD/tsDMARD, either tumor necrosis factor inhibitors (TNFi), non-TNFi (abatacept, tocilizumab, rituximab), or tsDMARDs, may be considered. If a first-line TNFi fails, options include another TNFi, non-TNFi biologic or tsDMARDs. If a first-line non-TNFi biologic or tsDMARD fails, options include TNFi or another non-TNF biologic or tsDMARD. For continued bDMARD/tsDMARD subsidization, a patient must have a documented DAS28-ESR every 3 months and at least a moderate European League Against Rheumatism response by 6 months. CONCLUSION: These recommendations are useful for guiding funding decisions, making bDMARD/tsDMARDs usage accessible and equitable in RA patients who fail csDMARDs.

Acute interstitial pneumonia as first presentation of anti-synthetase syndrome: an atypical case.

Anti-synthetase syndrome is characterized by myositis associated with interstitial lung disease (ILD), the usual pattern of ILD being non-specific interstitial pneumonia type or usual interstitial pneumonia. We report a case of anti-synthetase syndrome presenting as acute interstitial pneumonia which is reported only once before. With this case, we emphasize the need to consider anti-synthetase syndrome even in patients presenting with acute onset ILD. Physicians should raise their index of suspicion in this clinical context as timely diagnosis, early treatment, and a multidisciplinary approach is paramount for optimal care of these patients.

Interventions for tophi in gout.

BACKGROUND: Tophi develop in untreated or uncontrolled gout. Their presence can lead to severe and potentially fatal complications. To date there have been no systematic reviews focused on the management of tophi in gout. OBJECTIVES: To assess the benefits and harms of non-surgical and surgical treatments for the management of tophi in gout. SEARCH METHODS: We searched three databases: the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE. We handsearched American College of Rheumatology (ACR) and European League against Rheumatism (EULAR) abstracts from 2010 to 2011, references from included studies and trial registries. We completed the most recent search on 20 May 2013. SELECTION CRITERIA: All published randomised controlled trials (RCTs) or controlled clinical trials with quasi-randomised methods of allocating participants to treatment examining interventions for tophi in gout in adults. Possible interventions included urate-lowering pharmacological treatment (e.g. benzbromarone, probenecid, allopurinol, febuxostat, pegloticase), surgical removal or other interventions such as haemodialysis. DATA COLLECTION AND ANALYSIS: Two review authors extracted data from titles, abstracts and selected studies for detailed review, and extracted data and risk of bias independently. Major outcomes were number of participants with complete resolution of tophi, number of study participant withdrawals due to adverse events, joint pain reduction, function, quality of life, serum urate normalisation and total adverse events. MAIN RESULTS: Only one study, at low risk of all biases, met the inclusion criteria. This was the pooled results from two RCTs (225 participants, 145 with tophi at baseline) randomised to one of three arms; pegloticase infusion every two weeks (biweekly), monthly pegloticase infusion (pegloticase infusion alternating with placebo infusion every two weeks) and placebo. Moderate-quality evidence from one study indicated that biweekly pegloticase 8 mg infusion reduced tophi in the subset of participants with tophi, but increased withdrawals due to adverse events in all participants, and monthly infusion appeared to result in less benefit.Biweekly pegloticase treatment resulted in resolution of tophi in 21/52 participants compared with 2/27 who received placebo (risk ratio (RR) 5.45, 95% confidence intervals (CI) 1.38 to 21.54; number needed to treat for an additional beneficial outcome (NNTB) 3 (95% CI 2 to 6).Eleven of 52 participants with monthly pegloticase treatment had complete resolution of one or more tophi compared with 2/27 who received placebo (RR 2.86, 95% CI 0.68 to 11.97).Participant-reported pain relief of 30% or greater, function, quality of life, serum urate normalisation, were reported for all participants but not separately for those with tophi; therefore, we did not include the results.Pegloticase administered biweekly resulted in more withdrawals due to adverse events compared with placebo (15/85 participants with pegloticase versus 1/43 participants with placebo; RR 7.59, 95% CI 1.04 to 55.55; number needed to treat for an additional harmful outcome (NNTH) 7, 95% CI 4 to 17). Pegloticase administered monthly also resulted in more withdrawals due to adverse events than placebo (16/84 participants with pegloticase versus 1/43 participants with placebo; RR 8.19, 95% CI 1.12 to 59.71; NNTH 6, 95% CI 4 to 14). Most withdrawals were due to infusion reactions.Total adverse events were high in all treatment groups: 80/85 participants administered pegloticase biweekly reported an adverse event compared with 41/43 from the placebo group (RR 0.99, 95% CI 0.91 to 1.07); 84/84 participants administered pegloticase monthly reported an adverse event versus 41/43 in the placebo group (RR 1.05, 95% CI 0.98 to 1.14). As 80% of adverse events were due to flares of gout, probably unrelated to the drug treatment per se, this may explain the high rate of adverse events in the placebo group - who were essentially untreated. AUTHORS' CONCLUSIONS: This study showed pegloticase is probably beneficial in the management of tophi in gout, in terms of resolution of tophi, but with a high risk of adverse infusion reactions. However, there is a need for more RCT data considering other interventions, including surgical removal of tophi.

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.

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.

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.

Lifestyle interventions for acute gout.

BACKGROUND: Although lifestyle interventions are often recommended in the management of chronic gout, the evidence from trial data of the benefits and safety of using lifestyle interventions for treating acute gout attacks have not previously been examined in a systematic review. OBJECTIVES: The objective of this systematic review was to evaluate the benefits and safety of lifestyle interventions for the treatment of people with acute gout. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and EMBASE for studies (up to 5 April 2013). We also searched the 2010 to 2011 American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) abstracts and performed a handsearch of the reference lists of included articles. SELECTION CRITERIA: Studies were included if they were randomised or quasi-randomised controlled trials which compared lifestyle interventions to another therapy (active or placebo) in patients with acute gout. Outcomes of interest were the change in participant-reported pain in the target joint(s), target joint inflammation and function, health-related quality of life (HRQoL), patient global assessment, study participant withdrawals due to adverse events (AEs) and serious adverse events (SAEs). DATA COLLECTION AND ANALYSIS: Two review authors independently applied methods recommended by The Cochrane Collaboration for the selection, appraisal, data collection and synthesis of studies. We assessed the quality of the body of evidence for each outcome using the GRADE approach. MAIN RESULTS: Only one study (19 participants) at high risk of bias was included in the review. Patients were randomised to receive oral prednisolone and colchicine with or without concomitant topical ice therapy. Topical ice therapy provided significant additional benefit over oral prednisolone and colchicine alone with respect to pain, but did not significantly reduce swelling during acute gout episodes. Mean pain reduction with standard medical treatment was 4.4 cm on a 0 to 10 cm visual analogue scale (VAS) after one week; the addition of topical ice reduced pain by an additional 3.33 cm (95% CI 5.84 to 0.82), or an absolute reduction of 33% (8% to 58% reduction). Joint swelling was reduced by a mean of 3.8 cm in the standard medical treatment group; the addition of topical ice therapy did not reduce swelling significantly (mean difference (MD) 2.07 cm, 95% CI -1.56 to 5.70). Target joint function, HRQoL, patient global assessment, study participant withdrawals due to AEs and SEAs were not reported in this study. AUTHORS' CONCLUSIONS: There is low quality evidence, from a single trial at high risk of bias, that the addition of topical ice therapy to oral prednisolone and colchicine for oligoarticular attacks of acute gout results in significantly greater pain reduction at one week.

Lifestyle interventions for chronic gout.

BACKGROUND: Although lifestyle interventions are commonly recommended in the management of patients with chronic gout, the evidence from trial data for their benefits and safety has not been previously examined in a systematic review. OBJECTIVES: The objective of this systematic review was to evaluate the benefits and safety of lifestyle interventions for the treatment of people with chronic gout. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and EMBASE for studies on 5 April 2013. We also searched the 2010 to 2011 American College of Rheumatology (ACR) and European League against Rheumatism (EULAR) abstracts and performed a handsearch of the reference lists of included articles. SELECTION CRITERIA: Studies were included if they were randomised or quasi-randomised controlled trials (RCTs or CCTs) which compared lifestyle interventions to another therapy (active or placebo) in patients with chronic gout. Outcomes of interest were changes in gout attack frequency, joint pain, serum urate levels, tophus size, function, quality of life and adverse effects. DATA COLLECTION AND ANALYSIS: Two review authors independently applied methods recommended by The Cochrane Collaboration for the selection, appraisal, data collection and synthesis of studies. We assessed the quality of the body of evidence for each outcome using the GRADE approach. MAIN RESULTS: Only one study (120 participants), at moderate risk of bias, was included in the review. Patients were randomised to one of three interventions: either skim milk powder (SMP) enriched with glycomacropeptide (GMP) and G600, non-enriched SMP or lactose powder, over a three-month period. The frequency of acute gout attacks, measured as the number of flares per month, decreased in all three groups over the three-month study period. Low quality evidence indicated that there was no difference between the SMP/GMP/G600 group and combined control groups (SMP and lactose powder) at three months (mean difference (MD) -0.21, 95% confidence interval (CI) -0.76 to 0.34). There were no significant between-group differences in terms of withdrawals due to adverse effects (risk ratio (RR) 1.27, 95% CI 0.53 to 3.03), and serious adverse events resulting in hospitalisation (2/40 SMP/GMP/G600 group versus 3/80 controls; RR 1.33, 95% CI 0.23 to 7.66). Gastrointestinal adverse effects were the most commonly reported. Pain from self reported gout flares, measured on a 10-point Likert scale, improved more in the SMP/GMP/G600 group compared to controls (MD -1.03, 95% CI -1.96 to -0.10), an absolute difference of 10% (absolute risk difference -0.10, 95% CI -0.20 to -0.01). This is unlikely to be of clinical significance. Physical function, tophus regression and serum urate normalisation were not reported in this study. AUTHORS' CONCLUSIONS: While there is good evidence from observational studies of an association between various lifestyle risk factors and gout development, there is a paucity of high-quality evidence from randomised controlled trials to either support or refute the use of lifestyle modifications for improving outcomes in people with chronic gout.