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.

The prevalence of aortic calcification on vertebral fracture assessment imaging among patients with rheumatoid arthritis.

Patients with rheumatoid arthritis (RA) are at increased risk of osteoporosis (OP) and cardiovascular disease (CVD). Dual-energy X-ray absorptiometry scans have been validated for identifying patients with RA at risk for fracture. Reliable CVD risk stratification remains an unmet need in this population. Vertebral fracture assessment (VFA)-detected abdominal aortic calcification (AAC) has been validated as a marker of CVD in other populations, but the prevalence among patients with RA is unknown. In this study, we determined the prevalence and severity of AAC on VFA scans in a cohort of patients with RA. AAC was detected in 211 of the 603 (35%) eligible subjects; 24% were graded as severe. In multivariable analyses, the presence of AAC was significantly associated with longer disease duration and higher disease activity (p<0.05). Further studies are needed on the relationship between AAC and CVD in patients with RA.

The prevalence of vertebral fracture on vertebral fracture assessment imaging in a large cohort of patients with rheumatoid arthritis.

OBJECTIVE: RA accelerates bone loss, increasing the risk of osteoporosis (OP) and fracture. DXA imaging has been validated for identifying RA patients at risk of fracture. The objective of this study was to assess the presence of asymptomatic vertebral fractures (VFs) in a cohort of patients with established RA referred for DXA using VF assessment (VFA) technology. METHODS: We determined the prevalence of VFs in a cohort of RA patients age ≥ 40 years fulfilling the 1987 ACR classification criteria. Two blinded radiologists independently reviewed all VFA scans to determine the presence and severity of VFs using Genant criteria. We compared the prevalence and severity of VFs between RA patients and determined the independent associations of different variables with VFs using multivariable logistic regression. RESULTS: Six hundred and three subjects fulfilled study inclusion criteria. Thirteen per cent of the entire cohort (77/603) had one or more vertebral deformities identified on VFA imaging: 58% were female with mean age 56 years. The prevalence of OP and osteopenia was 59% and 40%, respectively. The prevalence and severity of VFs showed significant correlation with spine T-scores (r = -0.37, P < 0.001) and femoral T-scores (r = -0.31, P < 0.001). In multivariable analyses VFs were significantly and independently associated with a longer duration of RA, markers of disease activity and severity. CONCLUSION: VFs were detected on VFA images in 13% of women and men with well-established RA referred for DXA testing. Longer duration and severity of RA disease were independent risk factors for fractures in our study.

Vertebral fracture assessment-detected abdominal aortic calcification and cardiovascular disease in rheumatoid arthritis.

OBJECTIVE: Individuals with rheumatoid arthritis (RA) are at increased risk for cardiovascular disease (CVD). Traditional prediction tools underestimate this risk. Vertebral fracture assessment (VFA)-detected aortic calcification enhances CVD risk stratification in the general population but its relationship in RA is unclear. We assessed the presence of abdominal aortic calcification (AAC) on VFA images, and its association with CVD in RA patients. METHODS: We determined the prevalence of cardiovascular events in a cohort of RA patients aged 40 years and older fulfilling the 1987 American College of Rheumatology classification criteria. Two blinded radiologists independently reviewed all VFA scans to determine the presence/severity of AAC using an established 24-point scale. Logistic regression analyses were performed to determine whether AAC could discriminate between RA patients with and without CVD, and to compare the ability of VFA-detected AAC to predict CVD to conventional CVD risk factors and the Framingham Risk Score. RESULTS: 603 subjects fulfilled study inclusion criteria. 230 (38%) subjects had 1 or more documented CVD event and 211 (35%) had AAC detected on VFA scans. Significantly more subjects with cardiovascular events had AAC on their VFA scans than controls (76% versus 10%; P < 0.05). VFA-detected AAC was a better predictor of CVD than traditional risk factors, and significantly out-performed the Framingham Risk Score for discriminating between the presence and absence of CVD (AUC 0.85 versus 0.58; P < 0.001). CONCLUSION: There was a significant association between VFA-detected AAC and CVD in our study population. This finding may enhance cardiovascular disease risk prediction in RA patients.

High prevalence of fibromyalgia in patients with HFE-related hereditary hemochromatosis.

OBJECTIVES: Subjects with HFE-related hereditary hemochromatosis (HH) may present with arthralgias, fatigue, and stiffness, yet little is known on the presence of fibromyalgia syndrome (FMS) in these subjects. We determined the prevalence of FMS in a cohort of subjects with HH and evaluated its relationship to subject demographics, disease status, and quality of life. METHODS: In a cross-sectional study we collected data on 395 consecutive subjects diagnosed with HH who were attending a tertiary referral Hepatology outpatient clinic at Galway University Hospital, Ireland (between October 2009 and June 2010). Subjects underwent a standard assessment including history, clinical examination, and functional assessments for pain and disability. Univariate logistic regression was applied to determine risk factors independently associated with prevalent FMS in these subjects. RESULTS: Three hundred ninety-five subjects met the inclusion criteria. Mean age was 43 years (range, 21 to 59 y) and 260 (66%) were males. One hundred seventy (43%) of the subjects were diagnosed with FMS. Among those with fibromyalgia fatigue and ≥ 11 tender points were present in all of the subjects, widespread pain in 150 (88%), depression in 70 (41%), and arthralgia/joint stiffness in 70 (41%). In subjects with FMS 33% reported some functional impairment (HAQ-DI>0), with 10% reporting moderate-severe functional impairment (HAQ-DI ≥ 1.5). CONCLUSIONS: This study reveals a high prevalence of FMS (43%) among subjects with HFE-related hemochromatosis. Prospective studies are needed to better understand the risk factors for FMS in such patients.

Adherence to uric acid treatment guidelines in a rheumatology clinic.

The aim of this study was to evaluate adherence to recommended serum uric acid levels in the rheumatology outpatients department of a university teaching hospital. We performed a retrospective study of all patients with a definitive diagnosis of gout attending our subspecialty gout clinic between 1 January 2010 and 31 December 2010. We evaluated adherence with two recently suggested uric acid thresholds, <300 µmol/L (<5 mg/dL) and <360 µmol/L (<6 mg/dL). Patient management was judged to adhere to the guidelines if either (1) the latest serum uric acid level was less than the specified guideline targets or (2) uric acid-lowering therapy was titrated upwards or the agent changed if the serum uric acid was above the guideline targets. One hundred two patients with a definitive diagnosis of gout attended the outpatients department between 1 January 2010 and 31 December 2010 and were included in the study. Median serum uric acid level was 331 µmol/L (IQR 276-456 µmol/L). Eighty-six patients (84 %) were treated with allopurinol, six patients (6 %) were treated with febuxostat (one of whom also received probenecid), and one with rasburicase. In 80 patients (78 %), the management adhered to a target guideline of <360 µmol/L (<6 mg/dL). In 66 patients (65 %), the management adhered to a target guideline of <300 µmol/L (<5 mg/dL). A treat-to-target approach has the potential to improve patient outcomes in the management of gouty arthritis. Our study shows encouraging results with the majority of patients on appropriate therapy and reaching recommended targets.

Prevalence of fibromyalgia among patients with chronic hepatitis C infection: relationship to viral characteristics and quality of life.

OBJECTIVES: We determined the prevalence of fibromyalgia syndrome (FMS) in a cohort of subjects with chronic hepatitis C virus (HCV), and the relationship to subject demographics, viral characteristics, and quality of life. METHODS: In a cross-sectional study of a cohort of HCV-infected individuals, all subjects underwent a standard assessment including history, clinical examination, and functional assessments for pain and disability. RESULTS: A total of 185 subjects met the inclusion criteria. Median age was 48.7 years, and 110 (59%) were women. A total of 106 (57%) of the subjects met criteria for the presence of FMS. Widespread pain and ≥11 tender points were present in all of the subjects with FMS, fatigue in 98 (92%), and depression in 60 (57%). Among those with FMS, mean pain score was 70±11.78 and 36% reported some functional impairment on (HAQ-DI>0), with 17% reporting moderate-to-severe functional impairment (HAQ-DI≥1.5). CONCLUSIONS: This study reveals a high prevalence of FMS (57%) among subjects with chronic HCV infection, one third of whom reported some degree of functional impairment. Recognition and management of this condition in such patients will help improve their quality of life.

Proinflammatory action of the antiinflammatory drug infliximab in tumor necrosis factor receptor-associated periodic syndrome.

OBJECTIVE: Tumor necrosis factor receptor (TNFR)-associated periodic syndrome (TRAPS) is an autosomal-dominant autoinflammatory condition caused by mutations in the TNFRSF1A gene. Unlike other autoinflammatory diseases in which anti-TNF therapy is largely a successful treatment option, therapy with the anti-TNF drug infliximab is often ineffective in patients with TRAPS. Moreover, in certain cases, infliximab actually triggers severe episodes of inflammation. The aim of this study was to elucidate the mechanisms underlying such a reaction. METHODS: Peripheral blood mononuclear cells (PBMCs) were obtained from patients with TRAPS. Both caspase 3 activity and NF-kappaB subunit activity were determined by enzyme-linked immunosorbent assay. Cytokine secretion was assessed using a specific customized human multiplex bead immunoassay kit. RESULTS: Unlike findings in controls, cells from a family of 9 patients, all of whom carried the T50M mutation in TNFRSF1A, failed to respond to infliximab through proapoptotic induction of caspase 3 activity. Instead, we observed enhanced antiapoptotic c-Rel subunit activity, accompanied by a significant increase in secretion of the proinflammatory cytokines interleukin- 1beta (IL-1beta), IL-1 receptor, IL-6, IL-8, and IL-12. CONCLUSION: Altered extracellular conformation of TNFRI, resulting from the T50M mutation in TNFRSF1A, results in failure of PBMCs to induce an apoptotic response to infliximab. We hypothesize that failure to shed infliximab-bound TNF/TNFRI from the cell surface of cells from patients with the T50M mutation triggers c-Rel activation, and that this leads to a marked increase in cytokine secretion and an increased proinflammatory response. In light of these findings, we strongly advise caution when prescribing infliximab as anti-TNF therapy to patients with TRAPS.