The effect of antimalarials on the safety and persistence of treatment with biologic agents or Janus kinase inhibitors in rheumatoid arthritis.

OBJECTIVES: To test the association of use of antimalarials with the overall safety of treatment in RA patients receiving one or multiple courses of biologic (b)DMARDs or a Janus kinase inhibitor (JAKi). METHODS: BiobadaBrasil is a multicentric registry-based cohort study of Brazilian patients with rheumatic diseases starting their first bDMARD or JAKi. The present analysis includes RA patients recruited from January 2009 to October 2019, followed up over one or multiple (up to six) courses of treatment (latest date, 19 November 2019). The primary outcome was the incidence of serious adverse events (SAEs). Total and system-specific adverse events (AEs) and treatment interruption served as secondary outcomes. Negative binomial regression with generalized estimating equations (to estimate multivariate incidence rate ratios, mIRR) and frailty Cox proportional hazards models were used for statistical analyses. RESULTS: The number of patients enrolled was 1316 (2335 treatment courses, 6711 patient-years [PY]; 1254.5 PY on antimalarials). The overall incidence of SAEs was 9.2/100 PY. Antimalarials were associated with reduced risk of SAEs (mIRR: 0.49; 95% CI: 0.36, 0.68; P < 0.001), total AEs (0.68; 95% CI: 0.56, 0.81; P < 0.001), serious infections (0.53; 95% CI: 0.34, 0.84; P = 0.007) and total hepatic AEs (0.21; 95% CI: 0.05, 0.85; P = 0.028). Antimalarials were also related to better survival of treatment course (P = 0.003). There was no significant increase in the risk of cardiovascular AEs. CONCLUSION: Among RA patients on treatment with bDMARDs or JAKi, concomitant use of antimalarials was associated with reduced the incidence of serious and total AEs and with longer treatment course survival.

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.

Incidence of Infectious Adverse Events in Patients With Rheumatoid Arthritis and Spondyloarthritis on Biologic Drugs-Data From the Brazilian Registry for Biologics Monitoring.

BACKGROUND: The safety profile of biologic drugs might present substantial regional differences. Since 2009, the Brazilian Society of Rheumatology has maintained BIOBADABRASIL (Brazilian Registry for Biologic Drugs), a registry for monitoring of biologic therapies in rheumatic diseases. OBJECTIVES: The aim of this study was to verify the incidence rate (IR) of serious infections in rheumatoid arthritis (RA) and spondyloarthritis (SpA) patients on biologic drugs. METHODS: BIOBADABRASIL prospectively included patients with rheumatic diseases who started the first biologic drug or a synthetic disease-modifying antirheumatic drug as a parallel control group. This study focuses on serious infectious adverse events (SIAEs) in RA and SpA patients on biologic drugs compared with controls, from January 2009 to June 2015. Time of exposure was set from initiation of the drug to the date of last administration or censorship. Serious infectious adverse events IR was calculated per 1000 patient/years with 95% confidence interval (CI). RESULTS: A total of 1698 patients (RA, 1121; SpA, 577) were included, 7119 patient/years. Serious infectious adverse events were more common among patients on tumor necrosis factor inhibitors (TNFi's) than controls (adjusted IR ratio, 2.96 [95% CI, 2.01-4.36]; p < 0.001). Subsequent TNFi was associated with a higher SIAEs incidence when compared with first TNFI (adjusted IR ratio, 1.55 [95% CI, 1.15-2.08]; p = 0.004). Serious infectious adverse events were associated with age and corticosteroids intake. Serious infectious adverse events were more frequent in the respiratory tract in all subgroups. CONCLUSIONS: In BIOBADABRASIL, biologic drugs, especially the subsequent TNFi, were associated with a higher risk of serious infections compared with synthetic DMARDs. Corticosteroid intake and age represented risk factors for SIAEs. Constant monitoring is required to follow the safety profile of drugs in the clinical setting of rheumatic conditions in Brazil.

Evaluation of Bone Metabolism Biomarkers in Paget's Disease of Bone.

OBJECTIVE: To evaluate serum levels of bone metabolism biomarkers in patients with Paget's disease of bone (PDB). METHODS: Serum levels of osteopontin, sclerostin, receptor activator of nuclear factor kappa-Β ligand (RANKL), osteoprotegerin, Dickkopf-related protein 1 (DKK-1), and soluble frizzled-related protein 1 (sFRP-1) were measured in 57 patients with Paget's disease of bone and 24 controls with primary osteoarthritis. Subgroup analysis was employed to identify any differences in bone metabolism biomarker levels according to disease activity or current treatment. RESULTS: Patients with PDB presented higher levels of osteopontin and RANKL. When compared with patients with inactive disease, patients with active disease presented higher levels of bone-specific alkaline phosphatase (BAP) and osteopontin. There was a significant correlation between serum levels of BAP and osteopontin. There was no significant correlation between levels of BAP and other bone metabolism biomarkers. Current disease extension on bone scintigraphy had a significant correlation with serum levels of osteopontin and BAP. There was no significant correlation between current disease extension and other bone metabolism biomarkers. Serum levels of osteopontin and RANKL were correlated to serum levels of BAP and disease extension. CONCLUSION: Patients with PDB presented higher levels of osteopontin and RANKL. Osteopontin could be a useful biomarker for activity and extension of PDB.

Acute dermatomyositis with subcutaneous generalized edema.

The authors report a 40-year-old Caucasian man with relapsing muscle and skin involvement of dermatomyositis treated with high-dose corticosteroids, taken orally, and methotrexate and human gamma globulin, both administered intravenously. After 4 months of aggressive treatment, he presented with generalized edema, considered secondary to dermatomyositis. Aggressive immunosuppression did not stop disease progression. The literature concerning anasarca due to inflammatory myopathies is revised.

Protein-losing enteropathy associated with systemic lupus erythematosus: response to cyclophosphamide.

Protein-losing enteropathy is a rare manifestation of systemic lupus erythematosus (SLE) leading to hypoalbuminemia and anasarca. We report the case of a woman with SLE who presented chronic hypoalbuminemia diagnosed as protein-losing enteropathy associated with SLE. She was refractory to prednisone and azathioprine administration but showed good response to cyclophosphamide. The diagnosis and management of hypoalbuminemia in lupus-associated enteropathy are discussed.

Differential diagnosis of optic neuritis in a patient with ankylosing spondylitis.

The authors report a 38-year-old white man with ankylosing spondylitis (AS) who presented with recurrent ischaemic optic neuritis. The initial diagnosis was of multiple sclerosis, but further investigation showed serology and cerebrospinal fluid culture positive for syphilis. After treatment for tertiary syphilis with penicillin, there was complete remission of the ocular symptoms. This case illustrates the differential diagnosis of optic neuritis in AS and supports the relevance of investigating infectious diseases in the management of ischaemic optic neuritis.