IDH-mutant myeloid neoplasms are associated with seronegative rheumatoid arthritis and innate immune activation.

ABSTRACT: High prevalence of IDH mutations in seronegative rheumatoid arthritis (RA) with myeloid neoplasm, elevated 2-hydroxyglutarate, dysregulated innate immunity, and proinflammatory microenvironment suggests causative association between IDH mutations and seronegative RA. Our findings merit investigation of IDH inhibitors as therapeutics for seronegative IDH-mutated RA.

Immune checkpoints in rheumatoid arthritis: progress and promise.

Rheumatoid arthritis (RA) is one of the most prevalent autoimmune inflammatory conditions, and while the mechanisms driving pathogenesis are yet to be completely elucidated, self-reactive T cells and immune checkpoint pathways have a clear role. In this review, we provide an overview of the importance of checkpoint pathways in the T cell response and describe the involvement of these in RA development and progression. We discuss the relationship between immune checkpoint therapy in cancer and autoimmune adverse events, draw parallels with the involvement of immune checkpoints in RA pathobiology, summarise emerging research into some of the lesser-known pathways, and the potential of targeting checkpoint-related pathways in future treatment approaches to RA management.

Medicamentos antinflamatorios no esteroideos para casos agudos de gota / Non-steroidal anti-inflammatory drugs for acute gout

Pregunta: ¿Qué es una crisis de gota aguda, y qué son los AINE? La gota surge del depósito de cristales de urato monosódico en las articulaciones y se presenta normalmente como episodios autolimitados de artritis aguda. Los AINE son medicamentos que reducen el dolor y la inflamación, pero podrían incrementar el riesgo de úlceras y sangrado gastrointestinal. Los inhibidores selectivos de la cicloxigenasa (COX-2) son un subgrupo de AINE que provocan menos úlceras estomacales. Fundamento: Fecha de investigación. El estudio es una actualización de una revisión que se publicó inicialmente en 2014 y revisada el 28 de agosto de 2020. Características del estudio y resultados clave: Esta revisión de 28 ensayos cuenta con 3.406 participantes. La mayoría eran hombres (de un 69% a un 100%) entre 44 y 66 años con casos de gota aguda que han durado menos de 48 horas. Un estudio con 30 participantes comparó placebo con un AINE, 13 estudios con 518 participantes compararon un AINE con otro, 6 estudios con 1.244 participantes comparaban AINE con inhibidores selectivos de la COX-2, 5 estudios con 772 participantes compararon glucocorticoides con AINE, 1 estudio con 225 participantes comparó inhibidores interleukina-1 con AINE, 1 estudio con 163 participantes comparó acupuntura y radiación infrarroja con AINE, y 1 estudio con 399 participantes comparó colchicina con AINE. (AU)

Transcriptomic profiling of programmed cell death 1 (PD-1) expressing T cells in early rheumatoid arthritis identifies a decreased CD4 + PD-1 + signature post-treatment.

Programmed cell death protein 1 (PD-1)-expressing T cells are expanded in individuals with established rheumatoid arthritis (RA). However, little is known about their functional role in the pathogenesis of early RA. To address this, we investigated the transcriptomic profiles of circulating CD4+ and CD8+ PD-1+ lymphocytes from patients with early RA (n = 5) using fluorescence activated cell sorting in conjunction with total RNA sequencing. Additionally, we assessed for alterations in CD4+PD-1+ gene signatures in previously published synovial tissue (ST) biopsy data (n = 19) (GSE89408, GSE97165) before and after six-months of triple disease modifying anti-rheumatic drug (tDMARD) treatment. Comparisons of gene signatures between CD4+PD-1+ vs. PD-1- cells identified significant upregulation of genes including CXCL13 and MAF, and in pathways including Th1 and Th2, cross talk between dendritic cells and NK cells, B cell development and antigen presentation. Gene signatures from early RA ST before and after six-month tDMARD treatment revealed downregulation of the CD4+PD-1+ signatures following treatment, identifying a mechanism through which tDMARDs exert their effect by influencing T cell populations. Furthermore, we identify factors associated with B cell help that are enhanced in the ST compared with PBMCs, highlighting their importance in driving synovial inflammation.

Female reproductive status and exogenous sex hormone use in rheumatoid arthritis patients treated with tocilizumab and csDMARDs.

OBJECTIVES: Sex is well known to influence risk, severity and treatment outcomes of RA, although the underlying causes are uncertain. The aim of this research was to examine whether factors influencing female sex hormones (reproductive status and exogenous sex hormone use) are associated with the efficacy of DMARDs. METHODS: Individual participant data were pooled from five phase 3 clinical trials where RA patients were treated with tocilizumab and/or conventional synthetic DMARDs. The primary outcome was the time to first remission according to the Simplified Disease Activity Index. The relationship between menopausal status or use of exogenous sex hormones and the time of first remission was assessed via Cox proportional analysis. Analysed data included sex, baseline menopausal status (premenopausal, perimenopausal, early postmenopausal and postmenopausal), participant age, body mass index, race, number of previous DMARDs and baseline disease activity. RESULTS: Analysis included 4474 female patients, of whom 2817 (62.9%) were postmenopausal, 202 (4.5%) were early postmenopausal, 1021 (22.8%) were premenopausal and 414 (9.2%) were perimenopausal. Of these, 221 (7.8%), 13 (6.4%), 255 (25%) and 47 (11.4%), respectively, were taking exogenous sex hormones. In the pooled analysis, perimenopausal status was associated with reduced remission compared with premenopausal status [adjusted HR 0.78 (95% CI 0.61, 0.99)]. Sex hormone use was associated with significantly higher remission [adjusted HR 1.20 (95% CI 1.01, 1.43)]. CONCLUSION: Perimenopausal women were less likely to achieve remission compared with premenopausal RA patients. The use of exogenous sex hormones appeared to be associated with more frequent remission in female RA patients, particularly those who were perimenopausal and early postmenopausal, although further research is required to confirm and identify the drivers for this observation and how it interacts with menopausal status.

Artificial intelligence and the future of radiographic scoring in rheumatoid arthritis: a viewpoint.

Rheumatoid arthritis is an autoimmune condition that predominantly affects the synovial joints, causing joint destruction, pain, and disability. Historically, the standard for measuring the long-term efficacy of disease-modifying antirheumatic drugs has been the assessment of plain radiographs with scoring techniques that quantify joint damage. However, with significant improvements in therapy, current radiographic scoring systems may no longer be fit for purpose for the milder spectrum of disease seen today. We argue that artificial intelligence is an apt solution to further improve upon radiographic scoring, as it can readily learn to recognize subtle patterns in imaging data to not only improve efficiency, but can also increase the sensitivity to variation in mild disease. Current work in the area demonstrates the feasibility of automating scoring but is yet to take full advantage of the strengths of artificial intelligence. By fully leveraging the power of artificial intelligence, faster and more sensitive scoring could enable the ongoing development of effective treatments for patients with rheumatoid arthritis.

Differential expansion of T peripheral helper cells in early rheumatoid arthritis and osteoarthritis synovium.

OBJECTIVES: Programmed cell death protein 1 (PD-1)-expressing T cells are implicated in the pathogenesis of autoimmune inflammatory diseases such as rheumatoid arthritis. A subset of CXCR5- T cells, termed T peripheral helper (Tph) cells, which drive B cell differentiation, have been identified in ectopic lymphoid structures in established rheumatoid arthritis synovial tissue. Here, we aimed to characterise these in treatment-naïve, early rheumatoid arthritis to determine whether these cells accumulate prior to fully established disease. METHODS: Fresh dissociated tissue and peripheral blood mononuclear cell (PBMC) suspensions were stained with Zombie UV, followed by anti-CD45RO, PD-1, CD3, ICOS, CD8, CD4, CD20, CXCR5, TIGIT and CD38 antibodies prior to analysis. For histology, rheumatoid arthritis synovial sections were prepared for Opal multispectral immunofluorescence with anti-CD45RO, CD20, PD-1 and CXCR5 antibodies. Images were acquired on the Perkin Elmer Vectra V.3.0 imaging system and analysed using InForm Advanced Image Analysis software. RESULTS: Flow cytometry revealed T cell infiltration in the rheumatoid arthritis synovium with differential expression of PD-1, CD45RO, ICOS, TIGIT and CD38. We observed a higher frequency of PD1hiCXCR5- Tph in rheumatoid arthritis synovial tissue and PBMCs versus controls, and no significant difference in T follicular helper cell frequency. Microscopy identified a 10-fold increase of Tph cells in early rheumatoid arthritis synovial follicular and diffuse regions, and identified Tph adjacent to germinal centre B cells. CONCLUSIONS: These data demonstrate that PD-1hi Tph cells are present in early rheumatoid arthritis, but not osteoarthritis synovium, and therefore may provide a target for treatment of patients with early rheumatoid arthritis.

Neutrophils Require Activation to Express Functional Cell-Surface Complement Receptor Immunoglobulin.

The phagocytosis-promoting complement receptor, Complement Receptor Immunoglobulin (CRIg), is exclusively expressed on macrophages. It has been demonstrated that expression in macrophages could be modulated by inflammatory mediators, including cytokines. This raised the possibility that a major phagocyte, the neutrophil, may also express CRIg following activation with inflammatory mediators. Here we show that resting peripheral blood neutrophil lysates subjected to protein analysis by Western blot revealed a 35 kDa CRIg isoform, consistent with the expression of CRIg mRNA by RT-PCR. By flow cytometry, CRIg was detected intracellularly and in very minor amounts on the cell surface. Interestingly, expression on the cell surface was significantly increased to functional levels after activation with inflammatory mediators/neutrophil activators; N-Formylmethionine-leucyl-phenylalanine, tumor necrosis factor (TNF), Granulocyte-Macrophage Colony stimulating Factor (GM-CSF), bacterial lipopolysaccharide, leukotriene B4 and phorbol myristate acetate. The increase in expression required p38 MAP kinase and protein kinase C activation, as well as intracellular calcium. Neutrophils which were defective in actin microfilament reorganization due to a mutation in ARPC1B or inhibition of its upstream regulator, Rac2 lose their ability to upregulate CRIg expression. Inhibition of another small GTPase, Rab27a, with pharmacological inhibitors prevented the increase in CRIg expression, suggesting a requirement for the actin cytoskeleton and exocytosis. Engagement of CRIg on TNF-primed neutrophils with an anti-CRIg monoclonal antibody increased the release of superoxide and promoted the activation of p38 but not ERK1/ERK2 or JNK MAP kinases. The TNF-induced increase in killing of Staphylococcus aureus was blocked by the anti-CRIg antibody. Adding to the anti-microbial role of CRIg, it was found that GM-CSF priming lead to the release of neutrophil extracellular traps. Interestingly in contrast to the above mediators the anti-inflammatory cytokine IL-10 caused a decrease in basal expression and GM-CSF induced increase in CRIg expression. The data demonstrate that neutrophils also express CRIg which is regulated by inflammatory mediators and cytokines. The findings show that the neutrophil antimicrobial function involving CRIg requires priming as a means of arming the cell strategically with microbial invasion of tissues and the bloodstream.

Attenuation of the BTLA/HVEM Regulatory Network in the Circulation in Primary Sjögren's Syndrome.

Primary Sjögren's syndrome (SjS) is an inflammatory autoimmune disorder which targets the lacrimal and salivary glands, resulting in glandular dysfunction. Currently, the immune drivers of SjS remain poorly understood and peripheral biomarkers of disease are lacking. The present study therefore sought to investigate the immune cell constituents of the SjS peripheral blood, and to assess the role of the BTLA/HVEM/CD160 co-stimulatory network by characterizing expression within the periphery. Peripheral blood mononuclear cells (PBMCs) were isolated from whole blood of n = 10 patients with SjS and n = 10 age- and sex-matched healthy control donors. Cells were divided and stained with three panels of antibodies, allowing assessment of T, B, and myeloid cell subsets, and measurement of BTLA, HVEM, and CD160 surface expression by flow cytometry. We identified distinct alterations in proportions of peripheral T, B, and myeloid cell types in SjS compared with healthy controls. Expression of BTLA/CD160/HVEM and frequency of BTLA/CD160/HVEM-expressing cells were significantly altered in peripheral SjS lymphocytes. The proportion of T cells co-expressing BTLA/HVEM and CD160/HVEM were significantly reduced in SjS. We found decreased BTLA and HVEM levels on peripheral B and T cells of SjS patients, and decreased BTLA/HVEM and CD160/HVEM co-expression, demonstrating dysregulation of the BTLA/HVEM axis in the peripheral blood of SjS patients. These results indicate the potential of targeting the BTLA-HVEM axis for the treatment of SjS.

Eosinophilic Vasculitis and Arteritic Anterior Ischemic Optic Neuropathy Associated With Anti-PD-L1 Therapy.

Immune checkpoint inhibitor therapy is frequently associated with immune-related adverse events, which occasionally manifest with visual symptoms. Here, we describe a case of unilateral and sudden-onset painless vision loss in an 82-year-old man with metastatic non-small cell lung cancer receiving immunotherapy with the anti-programmed death-ligand 1 agent atezolizumab. Examination demonstrated a right-sided relative afferent pupillary defect, diffusely swollen optic disc, and delayed choroidal and retinal arterial filling on fundus fluorescein angiography, consistent with an arteritic anterior ischemic optic neuropathy. Histology of an ipsilateral temporal artery biopsy revealed a transmural eosinophilic infiltrate without granulomas, while serology revealed the presence of antineutrophil cytoplasmic antibodies. Peripheral eosinophilia was also noted, which preceded treatment by several months. This report highlights the importance of clinician awareness of immune checkpoint inhibitors and their systemic and ophthalmic complications, which rarely appear to extend to eosinophilic temporal arteritis.

Non-steroidal anti-inflammatory drugs for acute gout.

BACKGROUND: Gout is an inflammatory arthritis resulting from the deposition of monosodium urate crystals in and around joints. Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used to treat acute gout. This is an update of a Cochrane Review first published in 2014. OBJECTIVES: To assess the benefits and harms of non-steroidal anti-inflammatory drugs (NSAIDs) (including cyclo-oxygenase-2 (COX-2) inhibitors (COXIBs)) for acute gout. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and Embase for studies to 28 August 2020. We applied no date or language restrictions. SELECTION CRITERIA: We considered randomised controlled trials (RCTs) and quasi-RCTs comparing NSAIDs with placebo or another therapy for acute gout. Major outcomes were pain, inflammation, function, participant-reported global assessment, quality of life, withdrawals due to adverse events, and total adverse events. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures as expected by Cochrane. MAIN RESULTS: We included in this update 28 trials (3406 participants), including 5 new trials. One trial (30 participants) compared NSAIDs to placebo, 6 (1244 participants) compared non-selective NSAIDs to selective cyclo-oxygenase-2 (COX-2) inhibitors (COXIBs), 5 (712 participants) compared NSAIDs to glucocorticoids, 13 compared one NSAID to another NSAID (633 participants), and single trials compared NSAIDs to rilonacept (225 participants), acupuncture (163 participants), and colchicine (399 participants). Most trials were at risk of selection, performance, and detection biases. We report numerical data for the primary comparison NSAIDs versus placebo and brief results for the two comparisons - NSAIDs versus COX-2 inhibitors and NSAIDs versus glucocorticoids. Low-certainty evidence (downgraded for bias and imprecision) from 1 trial (30 participants) shows NSAIDs compared to placebo. More participants (11/15) may have a 50% reduction in pain at 24 hours with NSAIDs than with placebo (4/15) (risk ratio (RR) 2.7, 95% confidence interval (CI) 1.1 to 6.7), with absolute improvement of 47% (3.5% more to 152.5% more). NSAIDs may have little to no effect on inflammation (swelling) after four days (13/15 participants taking NSAIDs versus 12/15 participants taking placebo; RR 1.1, 95% CI 0.8 to 1.5), with absolute improvement of 6.4% (16.8% fewer to 39.2% more). There may be little to no difference in function (4-point scale; 1 = complete resolution) at 24 hours (4/15 participants taking NSAIDs versus 1/15 participants taking placebo; RR 4.0, 95% CI 0.5 to 31.7), with absolute improvement of 20% (3.3% fewer to 204.9% more). NSAIDs may result in little to no difference in withdrawals due to adverse events (0 events in both groups) or in total adverse events; two adverse events (nausea and polyuria) were reported in the placebo group (RR 0.2, 95% CI 0.0, 3.8), with absolute difference of 10.7% more (13.2% fewer to 38% more). Treatment success and health-related quality of life were not measured. Moderate-certainty evidence (downgraded for bias) from 6 trials (1244 participants) shows non-selective NSAIDs compared to selective COX-2 inhibitors (COXIBs). Non-selective NSAIDs probably result in little to no difference in pain (mean difference (MD) 0.03, 95% CI 0.07 lower to 0.14 higher), swelling (MD 0.08, 95% CI 0.07 lower to 0.22 higher), treatment success (MD 0.08, 95% CI 0.04 lower to 0.2 higher), or quality of life (MD -0.2, 95% CI -6.7 to 6.3) compared to COXIBs. Low-certainty evidence (downgraded for bias and imprecision) suggests no difference in function (MD 0.04, 95% CI -0.17 to 0.25) between groups. Non-selective NSAIDs probably increase withdrawals due to adverse events (RR 2.3, 95% CI 1.3 to 4.1) and total adverse events (mainly gastrointestinal) (RR 1.9, 95% CI 1.4 to 2.8). Moderate-certainty evidence (downgraded for bias) based on 5 trials (712 participants) shows NSAIDs compared to glucocorticoids. NSAIDs probably result in little to no difference in pain (MD 0.1, 95% CI -2.7 to 3.0), inflammation (MD 0.3, 95% CI 0.07 to 0.6), function (MD -0.2, 95% CI -2.2 to 1.8), or treatment success (RR 0.9, 95% CI 0.7 to 1.2). There was no difference in withdrawals due to adverse events with NSAIDs compared to glucocorticoids (RR 2.8, 95% CI 0.5 to 14.2). There was a decrease in total adverse events with glucocorticoids compared to NSAIDs (RR 1.6, 95% CI 1.0 to 2.5). AUTHORS' CONCLUSIONS: Low-certainty evidence from 1 placebo-controlled trial suggests that NSAIDs may improve pain at 24 hours and may have little to no effect on function, inflammation, or adverse events for treatment of acute gout. Moderate-certainty evidence shows that COXIBs and non-selective NSAIDs are probably equally beneficial with regards to improvement in pain, function, inflammation, and treatment success, although non-selective NSAIDs probably increase withdrawals due to adverse events and total adverse events. Moderate-certainty evidence shows that systemic glucocorticoids and NSAIDs probably are equally beneficial in terms of pain relief, improvement in function, and treatment success. Withdrawals due to adverse events were also similar between groups, but NSAIDs probably result in more total adverse events. Low-certainty evidence suggests no difference in inflammation between groups. Only low-certainty evidence was available for the comparisons NSAID versus rilonacept and NSAID versus acupuncture from single trials, or one NSAID versus another NSAID, which also included many NSAIDs that are no longer in clinical use. Although these data were insufficient to support firm conclusions, they do not conflict with clinical guideline recommendations based upon evidence from observational studies, findings for other inflammatory arthritis, and expert consensus, all of which support the use of NSAIDs for acute gout.

Real-Life Retention Rates and Reasons for Switching of Biological DMARDs in Rheumatoid Arthritis, Psoriatic Arthritis, and Ankylosing Spondylitis.

Aims: To determine real-life biologic/targeted synthetic disease-modifying anti-rheumatic drug (b/tsDMARD) retention rates in rheumatoid arthritis (RA), psoriatic arthritis (PsA), and ankylosing spondylitis (AS), explore reasons for switching and to compare results to previously published data. Methods: Time-to-event analysis for mean treatment duration (estimated as the Restricted Mean Survival Time), b/tsDMARD failure, and b/tsDMARDs switching was performed for 230 patients (n = 147 RA, 46 PsA, 37 AS) who commenced their first b/tsDMARD between 2008 and 2018. Patients were managed in a dedicated "biologics" clinic in a tertiary hospital; the choice of b/tsDMARD was clinician driven based on medical factors and patient preferences. The effect of covariates on switching risk was analysed by a conditional risk-set Cox proportional-hazards model. Treatment retention data was compared to a historical analysis (2002-2008). Results: The proportions remaining on treatment (retention) were similar, throughout follow-up, for the first, second and third b/tsDMARDs across all patients (p = 0.46). When compared to RA patients, the risk of b/tsDMARD failure was halved in PsA patients [Hazard Ratio (HR) = 0.50], but no different in AS patients (HR = 1.0). The respective restricted mean (95%CI) treatment durations, estimated at 5 years of follow-up, were 3.1 (2.9, 3.4), 4.1 (3.7, 4.6), and 3.3 (2.8, 3.9) years, for RA, PsA, and AS, respectively. Age, gender, disease duration, smoking status and the use of concomitant csDMARDS were not associated with the risk of bDMARD failure. The most common reasons for switching in the first and subsequent years were secondary (n = 62) and primary (n = 35) failure. Comparison with historical data indicated no substantive differences in switching of the first biologic for RA and PsA. Conclusion: Similar retention rates of the second and third compared to the first b/tsDMARD in RA, PsA, and AS support a strategy of differential b/tsDMARDs use informed by patient presentation. Despite greater availability of b/tsDMARDs with differing mechanisms of action, retention rates of the first b/tsDMARD remain similar to previous years.

Colchicine for acute gout.

BACKGROUND: This is an updated Cochrane Review, first published in 2006 and updated in 2014. Gout is one of the most common rheumatic diseases worldwide. Despite the use of colchicine as one of the first-line therapies for the treatment of acute gout, evidence for its benefits and harms is relatively limited. OBJECTIVES: To update the available evidence of the benefits and harms of colchicine for the treatment of acute gout. SEARCH METHODS: We updated the search of CENTRAL, MEDLINE, Embase, Clinicaltrials.gov and WHO ICTRP registries to 28 August 2020. We did not impose any date or language restrictions in the search. SELECTION CRITERIA: We considered published randomised controlled trials (RCTs) and quasi-randomised controlled trials (quasi-RCTs) evaluating colchicine therapy compared with another therapy (placebo or active) in acute gout; low-dose colchicine at clinically relevant doses compared with placebo was the primary comparison. The major outcomes were pain, participant global assessment of treatment success (proportion with 50% or greater decrease in pain from baseline up to 32 to 36 hours), reduction of inflammation, function of target joint, serious adverse events, total adverse events and withdrawals due to adverse events. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures as expected by Cochrane in this review update. MAIN RESULTS: We included four trials (803 randomised participants), including two new trials, in this updated review. One three-arm trial compared high-dose colchicine (52 participants), low-dose colchicine (74 participants) and placebo (59 participants); one trial compared high-dose colchicine with placebo (43 participants); one trial compared low-dose colchicine with non-steroidal anti-inflammatory drugs (NSAIDs) (399 participants); and one trial compared low-dose colchicine with Chuanhu anti-gout mixture (traditional Chinese Medicine compound) (176 participants). We did not identify any trials comparing colchicine to glucocorticoids (by any route). The mean age of participants ranged from 51.2 to 70 years, and trial duration from 48 hours to 12 weeks. Two trials were at low risk of bias, one was possibly susceptible to selection bias (random sequence generation), reporting bias and other bias, and one open-label trial was at high risk of performance and detection bias. For the primary comparison, low-quality evidence from one trial (103 participants, downgraded for imprecision and bias) suggests low-dose colchicine may improve treatment outcome compared to placebo with little or no increased risk of adverse events. The number of people who reported treatment success (50% or greater pain reduction) at 32 to 36 hours was slightly larger with low-dose colchicine (418 per 1000) compared with placebo (172 per 1000; risk ratio (RR) 2.43, 95% confidence interval (CI) 1.05 to 5.64; absolute improvement 25% more reported success (7% more to 42% more, the 95% CIs include both a clinically important and unimportant benefit); relative change of 143% more people reported treatment success (5% more to 464% more). The incidence of total adverse events was 364 per 1000 with low-dose colchicine compared with 276 per 1000 with placebo: RR 1.32, 95% CI 0.68 to 2.56; absolute difference 9% more events with low-dose colchicine (9% fewer to 43% more, the 95% CIs include both a clinically important effect and no effect); relative change of 32% more events (32% fewer to 156% more). No participants withdrew due to adverse events or reported any serious adverse events. Pain, inflammation and function were not reported. Low-quality evidence (downgraded for imprecision and bias) from two trials (124 participants) suggests that high-dose colchicine compared to placebo may improve symptoms, but with increased risk of harms. More participants reported treatment success at 32 to 36 hours with high-dose colchicine (518 per 1000) compared with placebo (240 per 1000): RR 2.16, 95% CI 1.28 to 3.65, absolute improvement 28% (8% more to 46% more); more also had reduced inflammation at this time point with high-dose colchicine (504 per 1000) compared with placebo (48 per 1000): RR 10.50, 95% CI 1.48 to 74.38; absolute improvement 45% greater (22% greater to 68% greater); but more adverse events were reported with high-dose colchicine (829 per 1000 compared with 260 per 1000): RR 3.21, 95% CI 2.01 to 5.11, absolute difference 57% (26% more to 74% more). Pain and function were not reported. Low-quality evidence from a single trial comparing high-dose to low-dose colchicine indicates there may be little or no difference in benefit in terms of treatment success at 32 to 36 hours but more adverse events associated with the higher dose. Similarly, low-quality evidence from a single trial indicates there may also be little or no benefit of low-dose colchicine over NSAIDs in terms of treatment success and pain reduction at seven days, with a similar number of adverse events reported at four weeks follow-up. Reduction of inflammation, function of target joint and withdrawals due to adverse events were not reported in either of these trials, and pain was not reported in the high-dose versus low-dose colchicine trial. We were unable to estimate the risk of serious adverse events for most comparisons as there were few events reported in the trials. One trial (399 participants) reported three serious adverse (one in a participant receiving low-dose colchicine and two in participants receiving NSAIDs), due to reasons unrelated to the trial (low-quality evidence downgraded for bias and imprecision). AUTHORS' CONCLUSIONS: We found low-quality evidence that low-dose colchicine may be an effective treatment for acute gout when compared to placebo and low-quality evidence that its benefits may be similar to NSAIDs. We downgraded the evidence for bias and imprecision. While both high- and low-dose colchicine improve pain when compared to placebo, low-quality evidence suggests that high-dose (but not low-dose) colchicine may increase the number of adverse events compared to placebo, while low-quality evidence indicates that the number of adverse events may be similar with low-dose colchicine and NSAIDs. Further trials comparing colchicine to placebo or other treatment will likely have an important impact on our confidence in the effect estimates and may change the conclusions of this review. There are no trials reporting the effect of colchicine in populations with comorbidities or in comparison with other commonly used treatments, such as glucocorticoids.

Precision Medicine With Leflunomide: Consideration of the DHODH Haplotype and Plasma Teriflunomide Concentration and Modification of Outcomes in Patients With Rheumatoid Arthritis.

OBJECTIVE: Leflunomide is a commonly used disease-modifying drug in the treatment of rheumatoid arthritis (RA). Its effects are mediated via inhibition of dihydroorotate dehydrogenase (DHODH) by its active metabolite teriflunomide, and the pharmacokinetics of teriflunomide are highly variable. Our objective was to examine the association between the DHODH haplotype and plasma teriflunomide concentration with response to leflunomide in patients with RA where leflunomide was added to an existing disease-modifying drug regimen after failure to achieve an adequate response with conventional triple therapy. METHODS: Patients with RA who were taking, or were about to initiate, leflunomide were included. Participant characteristics, including the DHODH haplotype, were determined. Up to 5 plasma samples were collected after leflunomide was initiated for assays of total and free teriflunomide concentration. Disease activity was determined via the 28-joint Disease Activity Score (DAS28). The association between DAS28 scores and patient covariates was determined by linear mixed-effects modeling. RESULTS: A total of 67 patients were included in the study. The DAS28 score after initiation of leflunomide was associated with the baseline DAS28 score (ß = 0.70, P < 0.001) and was higher in those who carried the DHODH haplotype 2 (ß = 0.56. P = 0.01) and did not carry the shared epitope (ß = 0.56, P = 0.013). As total and free plasma teriflunomide concentration increased, the DAS28 score was significantly lower (P < 0.001 and P = 0.001, respectively). When considering threshold concentrations, teriflunomide concentrations >16 mg/liter were associated with a DAS28 score that was 0.33 lower, and when free teriflunomide concentration was >35 µg/liter, the DAS28 score was 0.32 lower. CONCLUSION: Teriflunomide concentration and carriage of the DHODH haplotype 2 are associated with response to leflunomide in patients with RA, and a total plasma teriflunomide concentration of at least 16 mg/liter is needed to maximize the likelihood of response.