Metabolic bone health considerations in giant cell arteritis and polymyalgia rheumatica.

Giant cell arteritis (GCA) and polymyalgia rheumatica (PMR) are two common systemic inflammatory conditions with a combined lifetime risk of approximately 3.5% in women and 1.5% in men. They are intimately associated with the aging process, virtually never occurring prior to 50 years of age and becoming more common over time. The reasons for this are unclear, but likely relate in part to factors related to aging of the immune system. The treatment of both GCA and PMR is traditionally based on glucocorticoids, frequently requiring a prolonged treatment course over long periods of time. Other medications are belatedly entering our treatment armamentarium, but their exact place in treatment algorithms remains to be fully defined and it is likely glucocorticoids will remain a cornerstone of our treatment in GCA and PMR for the foreseeable future. As a result, people with GCA and PMR will continue to be exposed to a significant cumulative glucocorticoid burden with all of the attendant potential adverse events, including osteoporosis. The predominantly post-menopausal female population that most commonly develops PMR and GCA is also the population that is most affected by osteoporosis. Given the risk of glucocorticoid-induced osteoporosis and subsequent fragility fractures, a planned treatment approach from glucocorticoid initiation is needed in these conditions. For the majority of patients, this will entail ensuring sufficiency of calcium and vitamin D as well as antiresorptive treatments. In this article, we discuss considerations around optimisation of metabolic bone health in GCA and PMR.

Outcomes of COVID-19 in people with rheumatic and musculoskeletal disease in Ireland over the first 2 years of the pandemic.

BACKGROUND: Poor COVID-19 outcomes occur with higher frequency in people with rheumatic and musculoskeletal diseases (RMD). Better understanding of the factors involved is crucial to informing patients and clinicians regarding risk mitigation. AIM: To describe COVID-19 outcomes for people with RMD in Ireland over the first 2 years of the pandemic. METHODS: Data entered into the C19-GRA provider registry from Ireland between 24th March 2020 and 31st March 2022 were analysed. Differences in the likelihood of hospitalisation and mortality according to demographic and clinical variables were investigated. RESULTS: Of 237 cases included, 59.9% were female, 95 (41.3%) were hospitalised, and 22 (9.3%) died. Hospitalisation was more common with increasing age, gout, smoking, long-term glucocorticoid use, comorbidities, and specific comorbidities of cardiovascular and pulmonary disease, and cancer. Hospitalisation was less frequent in people with inflammatory arthritis and conventional synthetic or biologic disease-modifying antirheumatic drug use. Hospitalisation had a U-shaped relationship with disease activity, being more common in both high disease activity and remission. Mortality was more common with increasing age, gout, smoking, long-term glucocorticoid use, comorbidities, and specific comorbidities of cardiovascular disease, pulmonary disease, and obesity. Inflammatory arthritis was less frequent in those who died. CONCLUSION: Hospitalisation or death were more frequently experienced by RMD patients with increasing age, certain comorbidities including potentially modifiable ones, and certain medications and diagnoses amongst other factors. These are important 'indicators' that can help risk-stratify and inform the management of RMD patients.

Temporal trends in COVID-19 outcomes in people with rheumatic diseases in Ireland: data from the COVID-19 Global Rheumatology Alliance registry.

OBJECTIVES: Although evidence is accumulating globally, data on outcomes in rheumatic disease and COVID-19 in Ireland are limited. We used data from the COVID-19 Global Rheumatology Alliance (C19-GRA) to describe time-varying COVID-19 outcomes for people with rheumatic disease in Ireland. METHODS: Data entered into the C19-GRA provider registry from Ireland between 24 March 2020 and 9 July 2021 were analysed. Differences in the likelihood of hospitalization and mortality according to demographic and clinical variables were investigated using Chi-squared test or Fisher's exact test, as appropriate. Trends in odds of hospitalization and mortality over time were investigated using logistic regression with the time period as a categorical variable. RESULTS: Of 212 cases included, 59.4% were female and median age was 58.0 years (range 13-96). Of the 212 cases, 92 (43%) were hospitalized and 22 (10.4%) died. Increasing age, a diagnosis of gout, ever smoking, glucocorticoid use, having comorbidities and specific comorbidities of cancer, cardiovascular and pulmonary disease were more common in those hospitalized. A diagnosis of inflammatory arthritis, csDMARD and/or b/tsDMARD use were less frequent in those hospitalized. Increasing age, a diagnosis of gout, ever smoking, having comorbidities and specific comorbidities of obesity, cardiovascular and pulmonary disease were more common in those who died. Odds of hospitalization or mortality did not change over time. CONCLUSION: No temporal trend was observed in either COVID-19-related hospitalization or mortality outcomes for people with rheumatic disease in Ireland.

SARS-CoV-2 Infection and COVID-19 Outcomes in Rheumatic Diseases: A Systematic Literature Review and Meta-Analysis.

OBJECTIVE: The relative risk of SARS-CoV-2 infection and COVID-19 disease severity among people with rheumatic and musculoskeletal diseases (RMDs) compared to those without RMDs is unclear. This study was undertaken to quantify the risk of SARS-CoV-2 infection in those with RMDs and describe clinical outcomes of COVID-19 in these patients. METHODS: We conducted a systematic literature review using 14 databases from January 1, 2019 to February 13, 2021. We included observational studies and experimental trials in RMD patients that described comparative rates of SARS-CoV-2 infection, hospitalization, oxygen supplementation/intensive care unit (ICU) admission/mechanical ventilation, or death attributed to COVID-19. Methodologic quality was evaluated using the Joanna Briggs Institute critical appraisal tools or the Newcastle-Ottawa scale. Risk ratios (RRs) and odds ratios (ORs) with 95% confidence intervals (95% CIs) were calculated, as applicable for each outcome, using the Mantel-Haenszel formula with random effects models. RESULTS: Of the 5,799 abstracts screened, 100 studies met the criteria for inclusion in the systematic review, and 54 of 100 had a low risk of bias. Among the studies included in the meta-analyses, we identified an increased prevalence of SARS-CoV-2 infection in patients with an RMD (RR 1.53 [95% CI 1.16-2.01]) compared to the general population. The odds of hospitalization, ICU admission, and mechanical ventilation were similar in patients with and those without an RMD, whereas the mortality rate was increased in patients with RMDs (OR 1.74 [95% CI 1.08-2.80]). In a smaller number of studies, the adjusted risk of outcomes related to COVID-19 was assessed, and the results varied; some studies demonstrated an increased risk while other studies showed no difference in risk in patients with an RMD compared to those without an RMD. CONCLUSION: Patients with RMDs have higher rates of SARS-CoV-2 infection and an increased mortality rate.

Predictors of hospitalization in patients with rheumatic disease and COVID-19 in Ireland: data from the COVID-19 global rheumatology alliance registry.

OBJECTIVES: Given the limited data regarding the risk of hospitalization in patients with rheumatic disease and coronavirus disease 2019 (COVID-19) in Ireland, we used the COVID-19 Global Rheumatology Alliance (GRA) registry data to study outcomes and their predictors. The primary objective was to explore potential predictors of hospitalization. METHODS: We examined data on patients and their disease-related characteristics entered in the COVID-19 GRA provider registry from Ireland (from 24 March 2020 to 31 August 2020). Multivariable logistic regression was used to assess the association of demographic and clinical characteristics with hospitalization. RESULTS: Of 105 patients, 47 (45.6%) were hospitalized and 10 (9.5%) died. Multivariable logistic regression analysis showed that age [odds ratio (OR) = 1.06, 95% CI 1.01, 1.10], number of co-morbidities (OR = 1.93, 95% CI 1.11, 3.35) and glucocorticoid use (OR = 15.01, 95% CI 1.77, 127.16) were significantly associated with hospitalization. A diagnosis of inflammatory arthritis was associated with lower odds of hospitalization (OR = 0.09, 95% CI 0.02, 0.32). CONCLUSION: Increasing age, co-morbidity burden and glucocorticoid use were associated with hospitalization, whereas a diagnosis of inflammatory arthritis was associated with lower odds of hospitalization.

Pathogenic, glycolytic PD-1+ B cells accumulate in the hypoxic RA joint.

While autoantibodies are used in the diagnosis of rheumatoid arthritis (RA), the function of B cells in the inflamed joint remains elusive. Extensive flow cytometric characterization and SPICE algorithm analyses of single-cell synovial tissue from patients with RA revealed the accumulation of switched and double-negative memory programmed death-1 receptor-expressing (PD-1-expressing) B cells at the site of inflammation. Accumulation of memory B cells was mediated by CXCR3, evident by the observed increase in CXCR3-expressing synovial B cells compared with the periphery, differential regulation by key synovial cytokines, and restricted B cell invasion demonstrated in response to CXCR3 blockade. Notably, under 3% O2 hypoxic conditions that mimic the joint microenvironment, RA B cells maintained marked expression of MMP-9, TNF, and IL-6, with PD-1+ B cells demonstrating higher expression of CXCR3, CD80, CD86, IL-1ß, and GM-CSF than their PD-1- counterparts. Finally, following functional analysis and flow cell sorting of RA PD-1+ versus PD-1- B cells, we demonstrate, using RNA-Seq and emerging fluorescence lifetime imaging microscopy of cellular NAD, a significant shift in metabolism of RA PD-1+ B cells toward glycolysis, associated with an increased transcriptional signature of key cytokines and chemokines that are strongly implicated in RA pathogenesis. Our data support the targeting of pathogenic PD-1+ B cells in RA as a focused, novel therapeutic option.

Monocyte-Derived Dendritic Cell Differentiation in Inflammatory Arthritis Is Regulated by the JAK/STAT Axis via NADPH Oxidase Regulation.

Monocyte-derived Dendritic cells (Mo-DC) are a distinct DC subset, involved in inflammation and infection, they originate from monocytes upon stimulation in the circulation and their activation and function may vary in autoimmune diseases. In this study we investigate the differences in Mo-DC differentiation and function in patients with Rheumatoid (RA) compared to Psoriatic arthritis (PsA). A significant increase in the Mo-DC differentiation marker CD209, paralleled by a corresponding decrease in the monocytic marker CD14, was demonstrated in RA compared to PsA, as early as 1 day post Mo-DC differentiation. RA monocytes ex-vivo were phenotypically different to PsA, displaying a more mature phenotype associated with altered cellular-morphology, early dendrite formation, and a significant increase in the CD40 marker. In addition, SPICE algorithm flow cytometric analysis showed distinct differences in chemokine receptors distribution in HC compared to PsA and RA CD14+ cells in the blood, with increased expression of the chemokine receptors CCR7 and CXCR4 observed in PsA and RA. In addition CD14+ cells at the site of inflammation showed a different chemokine receptor pattern between PsA and RA patients, with higher expression of CXCR3 and CXCR5 in RA when compared to PsA. The early priming observed in RA resulted in monocyte-endocytosis and antigen-uptake mechanisms to be impaired, effects that were not observed in PsA where phagocytosis capacity remained highly functional. Tofacitinib inhibited early Mo-DC differentiation, decreasing both CD209 and CD40 activation markers in RA. Inhibition of Mo-DC differentiation in response to Tofacitinib was mediated via an imbalance in the activation of NADPH-oxidases NOX5 and NOX2. This effect was reversed by NOX5 inhibition, but not NOX2, resulting in suppression of NOX5-dependent ROS production. In conclusion, RA monocytes are already primed ex vivo to become DC, evident by increased expression of activation markers, morphological appearance and impaired endocytosis capacity. Furthermore, we demonstrated for the first time that NOX5 mediates Mo-DC differentiation and function in response to Tofacitinib, which may alter DC functions.

A quality improvement intervention failed to significantly increase pneumococcal and influenza vaccination rates in immunosuppressed inflammatory arthritis patients.

OBJECTIVES: Pneumococcal and influenza vaccination rates have been suboptimal in studies of immunosuppressed patients. We aimed to assess barriers to and increase rates of 23-valent pneumococcal polysaccharide vaccine (PPSV23) and influenza vaccination in this group. The primary endpoint was a statistically significant increase in adequate PPSV23 and influenza vaccination. METHODS: In 2017, rheumatology outpatients completed an anonymous questionnaire recording vaccination knowledge, status, and barriers. Simultaneously, a low-cost multifaceted quality improvement (QI) intervention was performed. All outpatients on oral steroids, immunosuppressant conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) or biologics disease-modifying antirheumatic drugs (bDMARDs) were included in the study. In 2018, post-intervention, the clinic was re-assessed. Demographics, diagnosis, medications, smart phone access, and willingness to use this for vaccination reminders were assessed for independent vaccination predictors using binary logistic regression analysis. RESULTS: Four hundred twenty-five patients were included (72.6% rheumatoid arthritis, 74% women, 45.6% ≥ 60 years old). From 2017 to 2018, PPSV23 vaccination rates changed from 41.0 to 47.2% (P = 0.29) and influenza from 61.8 to 62.1% (P = 0.95). The most common reason for non-vaccination was lack of awareness. Following the intervention, this changed for influenza (36.7 to 34.2%) and PPSV23 (82.1 to 76.4%). General practitioners performed most vaccinations, only 3.6% were delivered in the hospital. Significant predictors of PPSV23 vaccination were older age {≥ 80 years had an OR 41.66 (95% CI 3.69-469.8, P = 0.003), compared with ≤ 39 years}, bDMARD use (OR 2.80, 95% CI 1.24-6.32, P = 0.013), and adequate influenza vaccination (OR 9.01, 95% CI 4.40-18.42, P < 0.001). Up-to-date PPSV23 vaccination (OR 8.93, 95% CI 4.39-18.17, P < 0.001) predicted influenza vaccination. CONCLUSIONS: PPSV23 and influenza vaccination rates were suboptimal. The intervention did not cause a statistically significant change in vaccination rates. Point-of-care vaccination may be more effective.Key Points• Low vaccination rates amongst immunosuppressed inflammatory arthritis outpatients• Less than 5% of vaccinations occurred in hospital• There was no statistically significant difference in the rates of adequate PPSV23 (41.0 to 47.2%) or influenza (61.8 to 62.1%) vaccination following our intervention.

Readability and Quality of Online Information on Osteoarthritis: An Objective Analysis With Historic Comparison.

BACKGROUND: Osteoarthritis (OA) is the most common cause of disability in people older than 65 years. Readability of online OA information has never been assessed. A 2003 study found the quality of online OA information to be poor. OBJECTIVE: The aim of this study was to review the readability and quality of current online information regarding OA. METHODS: The term osteoarthritis was searched across the three most popular English language search engines. The first 25 pages from each search engine were analyzed. Duplicate pages, websites featuring paid advertisements, inaccessible pages (behind a pay wall, not available for geographical reasons), and nontext pages were excluded. Readability was measured using Flesch Reading Ease Score, Flesch-Kincaid Grade Level, and Gunning-Fog Index. Website quality was scored using the Journal of the American Medical Association (JAMA) benchmark criteria and the DISCERN criteria. Presence or absence of the Health On the Net Foundation Code of Conduct (HONcode) certification, age of content, content producer, and author characteristics were noted. RESULTS: A total of 37 unique websites were found suitable for analysis. Readability varied by assessment tool from 8th to 12th grade level. This compares with the recommended 7th to 8th grade level. Of the 37, 1 (2.7%) website met all 4 JAMA criteria. Mean DISCERN quality of information for OA websites was "fair," compared with the "poor" grading of a 2003 study. HONcode-endorsed websites (43%, 16/37) were of a statistically significant higher quality. CONCLUSIONS: Readability of online health information for OA was either equal to or more difficult than the recommended level.

Current advances in the treatment of giant cell arteritis: the role of biologics.

Giant cell arteritis (GCA) is the most common form of systemic vasculitis. It is a potentially severe disease with 25% of patients suffering vision loss or stroke. Our treatment paradigm is based on glucocorticoids. Glucocorticoids are required in high doses for prolonged periods and subsequently are associated with a significant amount of treatment-related morbidity. Alternative treatment options are urgently needed to minimize these glucocorticoid adverse events. Many other agents, such as methotrexate and tumour necrosis factor alpha inhibitors have been used in GCA, with limited or no evidence of benefit. Our emerging understanding of the pathogenic processes involved in GCA has led to an increased interest in the use of biologic agents to treat the disease. Two randomized controlled trials have recently reported dramatic effects of the use of the interleukin-6 targeted biologic tocilizumab in GCA, with significant increases in remission rates and decreases in glucocorticoid burden. While encouraging, longer-term and additional outcomes are awaited to clarify the exact positioning of tocilizumab in the treatment approach. Emerging data for other biologic agents, particularly abatacept and ustekinumab, are also encouraging but less well advanced. We are at the dawn of a new era in GCA treatment, but uncertainties and opportunities abound.

Association of synovial tissue polyfunctional T-cells with DAPSA in psoriatic arthritis.

OBJECTIVE: This study examines polyfunctional T-cells in psoriatic arthritis (PsA) synovial tissue and their associations with clinical disease and implications for therapy. METHODS: PsA synovial tissue was enzymatically/mechanically digested to generate synovial tissue single cell suspensions. Frequencies of polyfunctional CD4, CD8, T-helper 1 (Th1), Th17 and exTh17 cells, using CD161 as a marker of Th17 plasticity, were determined by flow cytometry in matched PsA synovial tissue and peripheral blood. Synovial T-cell polyfunctionality was assessed in relation to Disease Activity in PSoriatic Arthritis (DAPSA) and in synovial cell suspensions cultured with a current mode of treatment, phosphodiesterase 4 (PDE4) inhibitor. RESULTS: PsA synovial tissue infiltrating CD4+ T-cells expressed higher levels of interleukin (IL)-17A, interferon gamma (IFN-γ), GM-CSF and CD161, with parallel enrichment of Th1, Th17 and exTh17 T-helper subsets (all p<0.05). Interestingly, a significant proportion of synovial T-cell subsets were triple-positive for GM-CSF, tumour necrosis factor (-TNF), -IL-17 or IFN-γ compared with matched blood (all p<0.05). Importantly, frequencies of polyfunctional T-cells correlated with DAPSA: Th1-GM-CSF+/TNF+/IFN-γ+ (r=0.7, p<0.01), Th17-GM-CSF+/TNF+/IL-17+ (r=0.6, p<0.057) and exTh17-GM-CSF+/TNF+/IFN-γ+ (r=0.7, p=0.0096), with no associations observed for single cytokine-producing T-cells. Following ex vivo culture of PsA synovial tissue cell suspensions, polyfunctional GM-CSF+TNFα+IL-17A+ or/IFN-γ+-producing T-cells (p<0.05), but not single cytokine-producing T-cells, were inhibited with a PDE4 inhibitor. CONCLUSION: These data demonstrate enrichment of polyfunctional T-cells in PsA synovial tissue which were strongly associated with DAPSA and ex vivo therapeutic response.

JAK/STAT Blockade Alters Synovial Bioenergetics, Mitochondrial Function, and Proinflammatory Mediators in Rheumatoid Arthritis.

OBJECTIVE: To examine the effects of tofacitinib on metabolic activity, mitochondrial function, and proinflammatory mechanisms in rheumatoid arthritis (RA). METHODS: Ex vivo RA synovial explants and primary RA synovial fibroblasts (RASFs) were cultured with 1 µM tofacitinib. RASF bioenergetics were assessed using an XF24 analyzer, and key metabolic genes were assessed by reverse transcription-polymerase chain reaction (RT-PCR) analysis. Mitochondrial function was assessed using specific cell fluorescent probes and by mitochondrial gene arrays. Mitochondrial mutagenesis was quantified using a mitochondrial random mutation capture assay, and lipid peroxidation was quantified by enzyme-linked immunosorbent assay (ELISA). The effect of tofacitinib on spontaneous release of proinflammatory mediators from RA whole tissue synovial explants was quantified by ELISAs/MSD multiplex assays, and metabolic markers were quantified by RT-PCR. Finally, RASF invasion, matrix degradation, and synovial outgrowths were assessed by transwell invasion/Matrigel outgrowth assays and ELISA. RESULTS: Tofacitinib significantly decreased mitochondrial membrane potential, mitochondrial mass, and reactive oxygen species production by RASFs and differentially regulated key mitochondrial genes. Tofacitinib significantly increased oxidative phosphorylation, ATP production, and the maximal respiratory capacity and the respiratory reserve in RASFs, an effect paralleled by a decrease in glycolysis and the genes for the key glycolytic enzymes hexokinase 2 (HK2), glycogen synthase kinase 3α (GSK-3α), lactate dehydrogenase A, and hypoxia-inducible factor 1α. Tofacitinib inhibited the effect of oncostatin M (OSM) on interleukin-6 (IL-6) and monocyte chemotactic protein 1 and reversed the effects of OSM on RASF cellular metabolism. Using RA whole tissue synovial explants, we found that tofacitinib inhibited the key metabolic genes for glucose transporter 1, 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3, 3'-phosphoinositide-dependent protein kinase 1, HK2, and GSK-3α, the proinflammatory mediators IL-6, IL-8, IL-1ß, intercellular adhesion molecule 1, vascular endothelial growth factor, and TIE-2, and RASF outgrowth from synovial explants, RASF invasion, and matrix metalloproteinase 1 activity. CONCLUSION: This study demonstrates that JAK/STAT signaling mediates the complex interplay between inflammation and cellular metabolism in RA pathogenesis.

Leflunomide Use and Risk of Lung Disease in Rheumatoid Arthritis: A Systematic Literature Review and Metaanalysis of Randomized Controlled Trials.

OBJECTIVE: To evaluate the relative risk (RR) of pulmonary disease among patients with rheumatoid arthritis (RA) treated with leflunomide (LEF). METHODS: We searched PubMed, Embase, and the Cochrane Central Register of Controlled Trials to April 15, 2014. We included double-blind randomized controlled trials (RCT) of LEF versus placebo or active comparator agents in adults with RA. Studies with fewer than 50 subjects or shorter than 12 weeks were excluded. Two investigators independently searched both databases. All authors reviewed selected studies. We compared RR differences using the Mantel-Haenszel random-effects method to assess total respiratory adverse events, infectious respiratory adverse events, noninfectious respiratory adverse events, interstitial lung disease, and death. RESULTS: Our literature search returned 5673 results. A total of 8 studies, 4 with placebo comparators, met our inclusion criteria. There were 708 respiratory adverse events documented in 4579 participants. Six cases of pneumonitis occurred, all in the comparator group. Four pulmonary deaths were reported, none in the LEF group. LEF was not associated with an increased risk of total adverse respiratory events (RR 0.99, 95% CI 0.56-1.78) or infectious respiratory adverse events (RR 1.02, 95% CI 0.58-1.82). LEF was associated with a decreased risk of noninfectious respiratory adverse events (RR 0.64, 95% CI 0.41-0.97). CONCLUSION: Our study found no evidence of increased respiratory adverse events in RCT of LEF treatment.

Risk of liver injury among methotrexate users: A meta-analysis of randomised controlled trials.

OBJECTIVE: Methotrexate is an effective treatment for a variety of inflammatory diseases. Robust evidence on the risk of serious liver injury is lacking. The aim of this study was to evaluate the relative risk and severity of liver disease among patients treated with methotrexate. METHODS: We searched PubMed and the Cochrane Central Register of Controlled Trials from 1 January 1990 to 24 April 2014 for double-blind randomised controlled trials of methotrexate versus comparator agents in adults with rheumatoid arthritis, psoriasis, psoriatic arthritis or inflammatory bowel disease. Studies with less than 100 subjects or of less than 24 weeks' duration were excluded. Two investigators independently searched both the databases. All authors reviewed the selected studies. We compared relative risk (RR) differences using the Mantel-Haenszel random effects method to assess total liver adverse events, minor liver enzyme abnormalities (≤ 3 ULN), major liver enzyme abnormalities (>3 ULN or treatment withdrawal) and a composite outcome of liver failure, fibrosis, cirrhosis or death. RESULTS: A total of 32 studies with 13,177 participants met our inclusion criteria. Methotrexate was associated with an increased risk of total adverse liver events, RR = 2.19 (95% CI: 1.73-2.77, I(2) = 68%), as well as minor and major liver enzyme abnormalities, RR = 2.16 (95% CI: 1.67-2.79, I(2) = 68%) and RR = 2.63 (95% CI: 1.90-3.64, I(2) = 10%), respectively. Patients treated with methotrexate were not at increased risk of liver failure, cirrhosis or death, RR = 0.12 (95% CI: 0.01-1.09, I(2) = 0%). CONCLUSION: Our study found an increased risk of elevated transaminases but not liver failure, cirrhosis or death with methotrexate compared to other agents. We were unable to assess long-term liver toxicity due to the short duration of included clinical trials.

Methotrexate use and risk of lung disease in psoriasis, psoriatic arthritis, and inflammatory bowel disease: systematic literature review and meta-analysis of randomised controlled trials.

OBJECTIVE: To evaluate the relative risk of pulmonary disease among patients with psoriasis, psoriatic arthritis, and inflammatory bowel disease treated with methotrexate. DATA SOURCES: PubMed, Cochrane central register of controlled trials, and Embase to 9 January 2014. STUDY SELECTION: Double blind randomised controlled trials of methotrexate versus placebo or active comparator agents in adults with psoriatic arthritis, psoriasis, or inflammatory bowel disease. Studies with fewer than 50 participants or of less than 12 weeks' duration were excluded. DATA SYNTHESIS: Two investigators independently searched both databases. All authors reviewed selected studies. We compared relative risk differences using the Mantel-Haenszel random effects method to assess total respiratory adverse events, infectious respiratory adverse events, non-infectious respiratory adverse events, interstitial lung disease, and death. RESULTS: Seven studies met our inclusion criteria, six with placebo as the comparator. Heterogeneity across the studies was not significant (I(2)=0%), allowing combination of trial results. 504 respiratory adverse events were documented in 1630 participants. Methotrexate was not associated with an increased risk of adverse respiratory events (relative risk 1.03, 95% confidence interval 0.90 to 1.17), respiratory infections (1.02, 0.88 to 1.19), or non-infectious respiratory events (1.07, 0.58 to 1.96). No pulmonary deaths occurred. CONCLUSIONS: Findings suggested that there was no increased risk of lung disease in methotrexate treated patients with non-malignant inflammatory diseases. Given the limitations of the study, however, we cannot exclude a small but clinically important risk.

Methotrexate and lung disease in rheumatoid arthritis: a meta-analysis of randomized controlled trials.

OBJECTIVE: Methotrexate has shown efficacy for the treatment of several diseases, especially rheumatoid arthritis (RA). Methotrexate has also been implicated as a causative agent in interstitial lung disease. Patients with RA may develop pulmonary manifestations of their disease and are at increased risk of respiratory infection. The aim of this study was to evaluate the relative risk (RR) of pulmonary disease among patients with RA treated with methotrexate. METHODS: We searched the PubMed and Cochrane databases (publication dates January 1, 1990 to February 1, 2013) for double-blind, randomized, controlled trials of methotrexate versus placebo or active comparator agents in adults with RA. Studies with <100 subjects or with a duration of <24 weeks were excluded. Two investigators independently searched both databases, and all of the investigators reviewed the selected studies. We compared differences in the RR using the Mantel-Haenszel random-effects method. RESULTS: A total of 22 studies with 8,584 participants met the inclusion criteria. Heterogeneity across studies was not significant (I(2) = 3%), allowing combination of the trial results. Methotrexate was associated with an increased risk of all adverse respiratory events (RR 1.10, 95% confidence interval [95% CI] 1.02-1.19) and respiratory infection (RR 1.11, 95% CI 1.02-1.21). Patients treated with methotrexate were not at increased risk of death due to lung disease (RR 1.53, 95% CI 0.46-5.01) or noninfectious respiratory events (RR 1.02, 95% CI 0.65-1.60). A subgroup analysis of studies in which pneumonitis was described revealed an increased risk associated with methotrexate (RR 7.81, 95% CI 1.76-34.72). CONCLUSION: Our study demonstrated a small but significant increase in the risk of lung disease in patients with RA treated with methotrexate compared with other disease-modifying antirheumatic drugs and biologic agents.