Objective
To investigate liver enzyme abnormalities and hepatic adverse events (AEs) during long‐term tocilizumab treatment for rheumatoid arthritis in clinical trials.
Methods
Data were pooled from ...patients who received intravenous tocilizumab (4, 8, or 10 mg/kg with or without disease‐modifying antirheumatic drugs DMARDs) in phase III or IV clinical trials, long‐term extensions, and a pharmacology study. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were measured routinely in these trials. AE rates were measured per 100 patient‐years of tocilizumab exposure for this pooled analysis.
Results
Overall, 16,204.8 patient‐years of tocilizumab exposure (mean ± SD duration of exposure 3.9 ± 2.0 years) were evaluated for 4,171 patients. ALT and AST elevations greater than the upper limit of normal (ULN) occurred in 70.6% and 59.4% of patients, respectively. ALT/AST elevations were >1–3× ULN in 59%/55% of patients, >3–5× ULN in 8.9%/3.3% of patients, and >5× ULN in 2.9%/0.9% of patients. Most elevations occurred during the first year of treatment. Single ALT/AST elevations >3× ULN occurred in 7.7%/3.6% of patients, and ≥2 consecutive elevations >3× ULN occurred in 1.9%/0.4% of patients. Elevations >3× ULN returned to normal in 80% of patients (median of 5.6 weeks to normalization). A total of 2.5% of patients withdrew from tocilizumab treatment following ALT/AST elevations. A total of 7 hepatic serious AEs (SAEs) (0.04 per 100 patient‐years 95% confidence interval 0.02–0.09) occurred in the tocilizumab studies.
Conclusion
Transaminase elevations with tocilizumab were frequent, but rates of hepatic SAEs were low in this clinical trial data set. Regular monitoring, with dose adjustment of tocilizumab/DMARDs for persistent elevations, is recommended.
Heart involvement is the leading cause of death of patients with eosinophilic granulomatosis with polyangiitis (EGPA; formerly Churg-Strauss syndrome) and is more frequent in anti-neutrophil ...cytoplasm antibody (ANCA)-negative patients. Post-transplant outcome has only been reported once.
We conducted a retrospective international multicenter study. Patients satisfying the criteria of the American College of Rheumatology and/or revised Chapel Hill Consensus Conference Nomenclature were identified by collaborating vasculitis and transplant specialists, and the help of the Churg-Strauss Syndrome Association.
Nine ANCA(-) patients who received transplants between October 1987 and December 2009 were identified. The vasculitis and cardiomyopathy diagnoses were concomitant for 5 patients and separated by 12 to 288 months for the remaining 4 patients. Despite ongoing immunosuppression, histologic examination of 7 (78%) patients' explanted hearts showed histologic patterns suggestive of active vasculitis. The overall 5-year survival rate was low (57%), but rose to 80% when considering only the 6 patients transplanted during the last decade. After survival lasting 3 to 60 months, 4 (44%) patients died sudden deaths.
The search for EGPA-related cardiomyopathy is mandatory early in the course of this type of vasculitis. Indeed, prompt treatment with corticosteroids and cyclophosphamide may achieve restore cardiac function. Most patients in this series were undertreated. For patients with refractory EGPA, heart transplantation should be performed, which carries a fair prognosis. No optimal immunosuppressive strategy has yet been identified.
Systemic lupus erythematosus is an autoimmune disease with diverse clinical manifestations that cannot always be regulated by steroids and immunosuppressive therapy. Intravenous immunoglobulin is an ...optional immunomodulatory agent for the treatment of SLE, but the appropriate indications for its use, duration of therapy and recommended dosage are yet to be established. In SLE patients, most publications report the utilization of a high dose (2 g/kg body weight) protocol.
To investigate whether lower doses of IVIg are beneficial for SLE patients.
We retrospectively analyzed the medical records of 62 patients who received low dose IVIg (approximately 0.5 g/kg body weight).
The treatment was associated with clinical improvement in many specific disease manifestations, along with a continuous decrease in SLEDAI scores (SLE Disease Activity Index). However, thrombocytopenia, alopecia and vasculitis did not improve following IVIg therapy.
Low dose IVIg is a possible therapeutic option in SLE and is associated with lower cost than the high dose regimen and possibly fewer adverse effects.
: Rheumatoid arthritis (RA) is a chronic inflammatory disease with predominant joint involvement and possible systemic compromise, which leads to a handicapped status and poor quality of life. An ...optimal approach to treat RA requires early and intensive intervention with close monitoring of treatment response. Tumor necrosis factor (TNF) blockers are recommended in cases of active RA after the unsuccessful use of effective disease‐modifying antirheumatic drugs (DMARDs); even adding them to treatment or replacing these drugs. Anti‐TNF therapies have been demonstrated to reduce significant joint damage and to relieve symptoms during a prolonged time (see Scott and Kingsley, 2006). The efficacy of infliximab in an open‐label trial is summarized with respect to speed of onset of action, durability of response, and its correlation between clinical and laboratory parameters. Safety for long‐term treatment is also summarized. We studied 105 RA patients with more than 3 years' history of disease during 24 months on i.v. infliximab (75 completed study). We evaluated ACR responses at base line, and at 1, 6, 12, 16, 52, 77, and 104 weeks. Morning stiffness, swollen and tender joints, HAQ, SF‐36% (PCS/MCS), polymerase chain reaction (PCR), erythrosedimentation rate (ESR), transaminases, rheumatoid factor (RF) levels, hemogram, and adverse events profile were all assessed. The treatment offered rapid and sustained clinical improvements as revealed by ACR responses and marked changes in the parameters previously described. Important changes were made in functional status and acute‐phase reactants. Finally, infliximab was considered well tolerated and did not affect the safety profile of this trial.
: Psoriatic spondyloarthropathy (PsSA) is a common and relatively typical form of spondyloarthropathy, affecting the axial skeleton with peripheral synovitis. Also, extraarticular as well as skin ...manifestations are sometimes difficult to diagnose and to treat. Recent studies demonstrated that anti‐tumor necrosis factor therapies are useful in treating and controlling disease activity. We conducted an open‐label 2‐year study in 16 patients to evaluate the efficacy and safety of long‐term compliance with intravenous infliximab therapy in patients with severe skin and refractory PsSA, with an incomplete response to methotrexate, azathioprine, cyclosporine, and/or sulfasalazine. Patients continued to receive only weekly methotrexate therapy during the study that included 16 patients (9 men, 7 women; mean age 38 ± 12.5 years SD) with psoriatic spondyloarthropathy for 16.4 ± 9.2 years. Each patient underwent complete physical examination before treatment and at each visit until the end of the study. Results of patient global pain assessment (VAS scale), investigator opinion on global assessment of disease activity (100 mm VAS), patient body weight and blood pressure, ACR response (20%, 50%, and 70%), laboratory parameters (CRP, ESR, WBC, RBC, liver enzymes, etc.), and PASI (skin score) were recorded. We conclude that infliximab therapy was effective in controlling joint and skin disease, having an acceptable safety profile and very good compliance when considering this type of patient. However, further long‐term, double‐blind, placebo‐controlled trials are necessary to validate these results.
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