Safety of the Methotrexate-leflunomide Combination in Rheumatoid Arthritis: Results of a Multicentric, Registry-based, Cohort Study (BiobadaBrasil).

OBJECTIVE: To evaluate the safety of the methotrexate (MTX)-leflunomide (LEF) combination in rheumatoid arthritis (RA), comparing it with other therapeutic schemes involving conventional synthetic (cs-) and biologic (b-) disease-modifying antirheumatic drugs (DMARDs) or Janus kinase inhibitors (JAKi). METHODS: Patients with RA starting a treatment course with a csDMARD (without previous use of bDMARD or JAKi) or their first bDMARD/JAKi were followed up in a registry-based, multicentric cohort study in Brazil (BiobadaBrasil). The primary outcome was the incidence of serious adverse events (SAEs); secondary outcomes included serious infections. Multivariate Cox proportional hazards models and propensity score matching analysis (PSMA) were used for statistical comparisons. RESULTS: In total, 1671 patients (5349 patient-years [PY]) were enrolled; 452 patients (1537 PY) received MTX + LEF. The overall incidence of SAEs was 5.6 per 100 PY. The hazard of SAEs for MTX + LEF was not higher than for MTX or LEF (adjusted HR [aHR] 1.00, 95% CI 0.76-1.31, P = 0.98). MTX + LEF presented a lower hazard of SAEs (aHR 0.56, 95% CI 0.36-0.88, P = 0.01) and infectious SAEs (aHR 0.48, 95% CI 0.25-0.94, P = 0.03) than bDMARDs/JAKi with MTX or LEF. MTX + LEF presented lower hazard of SAEs than MTX + sulfasalazine (SSZ; aHR 0.33, 95% CI 0.16-0.65, P = 0.002). Analysis using PSMA confirmed the results obtained with traditional multivariate Cox analysis. CONCLUSION: In our study, MTX + LEF presented a relatively good overall safety profile in comparison to MTX + SSZ and schemes involving advanced therapies in RA.

Plasma kinetics of an LDL-like non-protein nanoemulsion and transfer of lipids to high-density lipoprotein (HDL) in patients with rheumatoid arthritis.

BACKGROUND: Rheumatoid arthritis (RA) is a systemic inflammatory disease associated with cardiovascular risk, but with normal plasma lipids. OBJECTIVE: The aim was to investigate low-density lipoprotein (LDL) and high-density lipoprotein (HDL) metabolism in RA patients using radioactive nanoemulsions resembling an LDL lipid structure (LDE) as metabolic probes. METHODS: Thirty patients with RA, 16 in remission and 14 in high activity, and 30 healthy controls were studied. LDE labeled with (14)C-cholesteryl ester ((14)C-CE) and (3)H-unesterified cholesterol ((3)H-UC) was intravenously injected followed by 24-hour plasma sampling. Fractional clearance rates (FCR, h(-1)) were calculated by compartmental analysis. Lipid transfers to HDL were assayed by incubating plasma samples with a donor nanoemulsion labeled with radioactive lipids; % lipids transferred to HDL were quantified after chemical precipitation. RESULTS: LDL cholesterol, triglycerides, unesterified cholesterol, and oxidized LDL were equal in RA and controls, and HDL cholesterol was even higher in RA. Compared with controls, apolipoprotein B was lower, apolipoprotein A1 was equal, and apolipoprotein E was higher in RA. Decay curves of LDE labels were faster in RA patients than in controls ((14)C-CE: 0.072 ± 0.066 and 0.038 ± 0.027, P = .0115; (3)H-UC: 0.066 ± 0.042 and 0.035 ± 0.039; P < .0044). FCRs were equal in 2 RA subgroups. Transfer of UC, triglycerides, and phospholipids to HDL was equal between RA and controls, but CE transfer was lower in RA. HDL size was smaller in RA patients than in controls (8.5 ± 0.5 nm; 9.2 ± 0.8 nm, P < .0001). CONCLUSION: RA patients were more efficient in removing atherogenic LDL from plasma, as indicated by higher CE and UC FCR, with in lower apolipoprotein B. This was unexpected because of the higher cardiovascular risk in RA.

Immunogenicity and reactogenicity of 2009 influenza A (H1N1) inactivated monovalent non-adjuvanted vaccine in elderly and immunocompromised patients.

BACKGROUND: Immunosuppressed individuals present serious morbidity and mortality from influenza, therefore it is important to understand the safety and immunogenicity of influenza vaccination among them. METHODS: This multicenter cohort study evaluated the immunogenicity and reactogenicity of an inactivated, monovalent, non-adjuvanted pandemic (H1N1) 2009 vaccine among the elderly, HIV-infected, rheumatoid arthritis (RA), cancer, kidney transplant, and juvenile idiopathic arthritis (JIA) patients. Participants were included during routine clinical visits, and vaccinated according to conventional influenza vaccination schedules. Antibody response was measured by the hemagglutination-inhibition assay, before and 21 days after vaccination. RESULTS: 319 patients with cancer, 260 with RA, 256 HIV-infected, 149 elderly individuals, 85 kidney transplant recipients, and 83 with JIA were included. The proportions of seroprotection, seroconversion, and the geometric mean titer ratios postvaccination were, respectively: 37.6%, 31.8%, and 3.2 among kidney transplant recipients, 61.5%, 53.1%, and 7.5 among RA patients, 63.1%, 55.7%, and 5.7 among the elderly, 59.0%, 54.7%, and 5.9 among HIV-infected patients, 52.4%, 49.2%, and 5.3 among cancer patients, 85.5%, 78.3%, and 16.5 among JIA patients. The vaccine was well tolerated, with no reported severe adverse events. CONCLUSIONS: The vaccine was safe among all groups, with an acceptable immunogenicity among the elderly and JIA patients, however new vaccination strategies should be explored to improve the immune response of immunocompromised adult patients. (ClinicalTrials.gov, NCT01218685).

Immunogenicity and Reactogenicity of 2009 Influenza A (H1N1) Inactivated Monovalent Non-Adjuvanted Vaccine in Elderly and Immunocompromised Patients

Immunosuppressed individuals present serious morbidity and mortality from influenza, therefore it is important to understand the safety and immunogenicity of influenza vaccination among them. This multicenter cohort study evaluated the immunogenicity and reactogenicity of an inactivated, monovalent, non-adjuvanted pandemic (H1N1) 2009 vaccine among the elderly, HIV-infected, rheumatoid arthritis (RA), cancer, kidney transplant, and juvenile idiopathic arthritis (JIA) patients. Participants were included during routine clinical visits, and vaccinated according to conventional influenza vaccination schedules. Antibody response was measured by the hemagglutination-inhibition assay, before and 21 days after vaccination. 319 patients with cancer, 260 with RA, 256 HIV-infected, 149 elderly individuals, 85 kidney transplant recipients, and 83 with JIA were included. The proportions of seroprotection, seroconversion, and the geometric mean titer ratios postvaccination were, respectively: 37.6%, 31.8%, and 3.2 among kidney transplant recipients, 61.5%, 53.1%, and 7.5 among RA patients, 63.1%, 55.7%, and 5.7 among the elderly, 59.0%, 54.7%, and 5.9 among HIV-infected patients, 52.4%, 49.2%, and 5.3 among cancer patients, 85.5%, 78.3%, and 16.5 among JIA patients. The vaccine was well tolerated, with no reported severe adverse events. The vaccine was safe among all groups, with an acceptable immunogenicity among the elderly and JIA patients, however new vaccination strategies should be explored to improve the immune response of immunocompromised adult patients.

Reduced seroprotection after pandemic H1N1 influenza adjuvant-free vaccination in patients with rheumatoid arthritis: implications for clinical practice.

BACKGROUND: Reduced response to pandemic (2009) H1N1 (pH1N1) vaccine in patients with rheumatoid arthritis (RA) was recently reported. OBJECTIVES: To evaluate the contribution of age, disease activity, medication and previous antibody levels to this reduced response. METHODS: 340 adult RA patients and 234 healthy controls were assessed before and 21 days after adjuvant-free influenza A/California/7/2009 (pH1N1) vaccine. Disease activity (DAS28), current treatment and pH1N1 antibody titres were collected. Seroprotection, seroconversion and factor increase in geometric mean titre (GMT) were calculated and adverse events registered. RESULTS: RA and controls showed similar (p>0.05) prevaccination GMT (8.0 vs 9.3) and seroprotection (10.8% vs 11.5%). After vaccination a significant reduction (p<0.001) was observed in all endpoints: GMT and factor increase in GMT, seroprotection and seroconversion rates. Disease activity did not preclude seroconversion or seroprotection and remained unchanged in 97.4% of patients. Methotrexate was the only disease-modifying antirheumatic drug associated with reduced responses (p=0.001). Vaccination was well tolerated. CONCLUSIONS: The data confirmed both short-term anti-pH1N1 vaccine safety and, different from most studies with seasonal influenza, reduced seroprotection in RA patients, unrelated to disease activity and to most medications (except methotrexate). Extrapolation of immune responses from one vaccine to another may therefore not be possible and specific immunisation strategies (possibly booster) may be needed. Clinicaltrials.gov no NCT01151644.

Single measurements of C-reactive protein and disease activity scores are not predictors of carotid atherosclerosis in rheumatoid arthritis patients.

BACKGROUND: Although inflammation has a defined role in the pathogenesis of atherosclerosis, the link between rheumatoid arthritis (RA) parameters of disease activity and atherosclerotic findings are not defined. OBJECTIVE: To investigate the association between subclinical carotid atherosclerosis and clinical/laboratorial parameters of RA systemic inflammatory activity. METHODS: Seventy-one RA patients were consecutively selected and compared to 53 healthy controls. Smoking, diabetes and hypertension were excluded, as well as the use of statins or fibrates. B-mode carotid ultrasound was performed in all subjects. CRP, ESR and fibrinogen were determined in both groups. Clinical assessment of RA activity included DAS 28 and SDAI. Correlation between plaques and intima-media thickness (IMT) of common carotid arteries and inflammatory parameters was evaluated. RESULTS: Carotid plaques were more prevalent in RA patients than in controls (14.1% vs. 1.9 %, p=0.02) and marginally increased IMT was observed (0.72 +/- 0.17 vs. 0.67 +/- 0.15 mm, p=0.07). RA patients with plaques had older age (p=0.001) and increased IMT (p<0.001), but low SDAI (p=0.025) compared to those without plaques. RA patients with plaques had also longer disease duration, although this difference did not reach statistical significance (p=0.06). No significant correlations were found between IMT and ESR (p=0.80), CRP (p=0.75), fibrinogen (p=0.94), HAQ (p=0.89) and DAS 28 (p=0.13). CONCLUSIONS: Carotid atherosclerosis is more frequently detected in RA but its prevalence was not correlated with isolated inflammatory markers measurement or noncumulative activity scores. These findings reinforce the need to evaluate subclinical atherosclerosis in RA patients, and to find predictors of atherosclerotic lesions.

Brazilian version of the foot health status questionnaire (FHSQ-BR): cross-cultural adaptation and evaluation of measurement properties.

OBJECTIVE: To conduct a cross-cultural adaptation of the Foot Health Status Questionnaire into Brazilian-Portuguese and to assess its measurement properties. INTRODUCTION: This instrument is an outcome measure with 10 domains with scores ranging from 0-100, worst to best, respectively. The translated instrument will improve the examinations and foot care of rheumatoid arthritis patients. METHODS: The questions were translated, back-translated, evaluated by a multidisciplinary committee and pre-tested (n = 40 rheumatoid arthritis subjects). The new version was submitted to a field test (n = 65) to evaluate measurement properties such as test-retest reliability, internal consistency and construct validity. The Health Assessment Questionnaire, Numeric Rating Scale for foot pain and Sharp/van der Heijde scores for foot X-rays were used to test the construct validity. RESULTS: The cross-cultural adaptation was completed with minor wording adaptations from the original instrument. The evaluation of measurement properties showed high reliability with low variation coefficients between interviews. The alpha-Cronbach coefficients varied from 0.468 to 0.855, while correlation to the Health Assessment Questionnaire and Numeric Rating Scale was statistically significant for five out of eight domains. DISCUSSION: Intra- and inter-observer correlations showed high reliability. Internal consistency coefficients were high for all domains, revealing higher values for less subjective domains. As for construct validity, each domain revealed correlations with a specific group of parameters according to what the domains intended to measure. CONCLUSION: The FHSQ was cross-culturally adapted, generating a reliable, consistent, and valid instrument that is useful for evaluating foot health in patients with rheumatoid arthritis.

Brazilian version of the foot health status questionnaire (FHSQ-BR): cross-cultural adaptation and evaluation of measurement properties

OBJECTIVE: To conduct a cross-cultural adaptation of the Foot Health Status Questionnaire into Brazilian-Portuguese and to assess its measurement properties. INTRODUCTION: This instrument is an outcome measure with 10 domains with scores ranging from 0-100, worst to best, respectively. The translated instrument will improve the examinations and foot care of rheumatoid arthritis patients. METHODS: The questions were translated, back-translated, evaluated by a multidisciplinary committee and pre-tested (n = 40 rheumatoid arthritis subjects). The new version was submitted to a field test (n = 65) to evaluate measurement properties such as test-retest reliability, internal consistency and construct validity. The Health Assessment Questionnaire, Numeric Rating Scale for foot pain and Sharp/van der Heijde scores for foot X-rays were used to test the construct validity. RESULTS: The cross-cultural adaptation was completed with minor wording adaptations from the original instrument. The evaluation of measurement properties showed high reliability with low variation coefficients between interviews. The a-Cronbach coefficients varied from 0.468 to 0.855, while correlation to the Health Assessment Questionnaire and Numeric Rating Scale was statistically significant for five out of eight domains. DISCUSSION: Intra- and inter-observer correlations showed high reliability. Internal consistency coefficients were high for all domains, revealing higher values for less subjective domains. As for construct validity, each domain revealed correlations with a specific group of parameters according to what the domains intended to measure. CONCLUSION: The FHSQ was cross-culturally adapted, generating a reliable, consistent, and valid instrument that is useful for evaluating foot health in patients with rheumatoid arthritis.

Chloroquine-induced bull's eye maculopathy in rheumatoid arthritis: related to disease duration?

Chloroquine diphosphate has been used in the treatment of various rheumatic diseases, including rheumatoid arthritis. The most important of its side effects is retinopathy. If not diagnosed early, this lesion can evolve into irreversible bull's eye maculopathy and visual loss. The aim of this study was to define the outcome of chloroquine-induced maculopathy after cessation of chloroquine therapy and also to identify the risk factors involved in case of retinopathy evolution. The design of this cohort study was longitudinal and retrospective. Over the period spanning 2000 to 2005, out of 607 medical records of patients with rheumatoid arthritis followed in our Division of Rheumatology, 27 had been diagnosed with chloroquine-induced maculopathy through clinical funduscopy with pupil dilation. In all cases, there was immediate chloroquine intake cessation. After a mean time of 5 years, 16 of these patients were available for follow-up and underwent a new ophthalmologic evaluation by funduscopy, using biomicroscopy and angiofluorescein when necessary. Sequelae maculopathy were reconfirmed in all 16 cases, but progression to advanced stage (bull's eye maculopathy) was found in half of the cohort, even though chloroquine had been suspended. All patients complained of visual alterations, but without progression. Comparison between patient groups with and without bull's eye maculopathy revealed a statistically significant longer rheumatoid arthritis disease history in the former group. Also, the bull's eye group had higher dose intakes of chloroquine and over a longer period compared to the other group, but not statistically significant. This study corroborates the progression of maculopathy even after cessation of chloroquine intake, pointing out the need for careful screening in the high-risk patients. Furthermore, it indicates that duration of rheumatoid arthritis disease could be a possible factor linked to worse prognosis of chloroquine-induced maculopathy.

Sources of discrepancy in patient and physician global assessments of rheumatoid arthritis disease activity.

OBJECTIVE: To investigate discrepancy in the perception of rheumatoid arthritis (RA) disease activity between patient and physician, and its possible sources. METHODS: Eighty patients with RA rated their level of disease activity on a visual analog scale (VAS). Physician global assessment (MDGA) of disease activity was performed blinded to the patient evaluation except for the results of laboratory tests. A discrepancy score (DS) was calculated by subtracting MDGA from patient global assessment (PTGA), leading to definition of 3 groups of patients: (1) no discrepancy when PTGA and MDGA were within 1.0 or 3.0 cm of each other; (2) negative discrepancy when PTGA was under-rated relative to the physician; and (3) positive discrepancy when PTGA was over-rated relative to the physician. Age, sex, disease duration, education, income, residence area, employment, use of antirheumatic drugs, comorbidity, pain score, Health Assessment Questionnaire (HAQ) rating, tender (TJC) and swollen (SJC) joint count, and Disease Activity Score (DAS28) were recorded. RESULTS: Negative discrepancy was found in 27.5% (VAS 1 cm) and 8.7% (VAS 3 cm) of patients, positive discrepancy in 43.7% (VAS 1 cm) and 23.7% (VAS 3 cm), and no discrepancy in 28.7% (VAS 1 cm) and 67.5% (VAS 3 cm). Patients were predominantly older (mean age near 50 yrs), female, with long disease duration and low income. The negative discrepancy group had a lower level of education and higher C-reactive protein (p < 0.05). The positive discrepancy group presented a higher pain score, HAQ score, and TJC (p < 0.0001). The no-discrepancy group had lower SJC (p < 0.05). CONCLUSION: Our results indicate that for disease activity in patients with RA assessed on pain score, HAQ, and TJC, the only important feature that determined perception of their RA disease activity was education.