Efficacy and tolerability of tocilizumab in rheumatoid arthritis patients seen in daily clinical practice in Japan: results from a retrospective study (REACTION study)

Tocilizumab, a humanized monoclonal antibody to the interleukin 6 (IL-6) receptor, was approved for use as rheumatoid arthritis (RA) therapy in Japan in 2008, but its efficacy and tolerability in daily practice has not yet been reported. We report the results of a multicenter retrospective study on the efficacy and safety of tocilizumab involving all patients (n = 229) who were started on tocilizumab therapy at three rheumatology institutes in Japan from April 2008 through to March 2009. Tocilizumab was infused every 4 weeks at a dose of 8 mg/kg according to the drug labeling. Among the 229 patients, 55% concomitantly received methotrexate (MTX) and 63% had previously received anti-tumor necrosis factor (TNF) therapy. Average disease activity score (DAS) 28 of all 229 patients significantly decreased from 5.70 to 3.25 after 24 weeks of therapy. A European League Against Rheumatism (EULAR) good response and DAS28 remission was achieved in 57.4 and 40.7% of the patients, respectively, at 24 weeks. White blood cell counts significantly decreased and liver enzymes and total cholesterol slightly but significantly increased; however, liver enzyme levels did not increase in patients without MTX. Tocilizumab was discontinued in 47 cases (20.5%) due to lack of efficacy (5.2%), adverse events (11.4%), and other reasons (3.9%). The overall retention rate at 24 weeks was 79.5%. Based on these results, we conclude that tocilizumab therapy in daily rheumatology practice appears to be highly efficacious and well tolerated among active RA patients, including the anti-TNF therapy-refractory population. Tocilizumab infusion is therefore applicable not only as an alternative approach for anti-TNF therapy-resistant patients, but also as primary biologic therapy for active RA patients

Relevance of interferon-gamma in pathogenesis of life-threatening rapidly progressive interstitial lung disease in patients with dermatomyositis

Abstract Background Dermatomyositis (DM) with rapidly progressive interstitial lung disease (DM RP-ILD) is a life-threatening condition. Serum cytokine levels are potentially suitable biomarkers for DM RP-ILD. However, the relationships among cytokine levels, lung imaging findings, and lung pathology have not been investigated. The aim of the present retrospective study was to determine the association between hypercytokinemia and lung inflammation in patients with DM RP-ILD. Methods The study subjects were nine patients with life-threatening DM RP-ILD and severe hypoxemia (partial arterial oxygen pressure (PaO2)/fraction of inspired oxygen (FiO2) ratio ≤ 200) before receiving intensive care management, who were admitted to our hospital between 2006 and 2015. The controls included 10 patients with DM without RP-ILD and 19 healthy subjects. We assessed the association between serum cytokine levels and computed tomography (CT) scores of the lung (ground glass opacity-score, G-score; fibrosis-score, F-score). Lung, hilar lymph nodes, and spleen from two autopsies were examined by hematoxylin-eosin (H&E) staining and immunostaining. Results Serum interferon (IFN)-γ, interleukin (IL)-1β and IL-12 levels were significantly higher in patients with DM RP-ILD than in the other two groups, whereas serum IL-6 levels were elevated in the two patient groups but not in the healthy subjects. Serum levels of IL-2, IL-4, IL-8, IL-10, IFN-α, and TNF (tumor necrosis factor)-α were not characteristically elevated in the DM RP-ILD group. Serum IFN-γ levels correlated with G-scores in patients with DM RP-ILD, while IL-1β was negatively correlation with F-scores. Immunohistochemical staining showed infiltration of numerous IFN-γ-positive histiocytes in the lung and hilar lymph nodes; but not in the spleen. Serum IL-6 levels did not correlate with the CT scores. Numerous IL-6-positive plasma cells were found in hilar lymph nodes, but not in the lungs or spleen. Conclusions Our results suggest strong IFN-γ-related immune reaction in the lungs and hilar lymph nodes of patients with life-threatening DM RP-ILD, and potential IFN-γ involvement in the pathogenesis of DM, specifically in the pulmonary lesions of RP-ILD

Association of the multi-biomarker disease activity score with joint destruction in patients with rheumatoid arthritis receiving tumor necrosis factor-alpha inhibitor treatment in clinical practice

<p><i>Objective</i>: Evaluate the association between the multi-biomarker disease activity (MBDA) score and radiographic progression in patients with rheumatoid arthritis (RA) treated with tumor necrosis factor (TNF)-α inhibitors.</p> <p><i>Methods</i>: Change (Δ) in modified total Sharp score (mTSS) over 52 weeks and disease activity scores were examined retrospectively by Spearman's rank correlation coefficient in patients (<i>N</i> = 83) with RA initiating TNF-inhibitor treatment. Relative risk (RR) of ΔmTSS >0.5 for low MBDA score and 28-joint count disease activity score (DAS28) categories and associations between ΔmTSS and MBDA score categories conditional on DAS28 categories were assessed.</p> <p><i>Results</i>: At 52 weeks, 34% of patients had ΔmTSS >0.5 and 12% had ΔmTSS >3. Strongest correlations were observed between ΔmTSS and MBDA score (<i>r</i> = 0.47) or DAS28 (<i>r</i> = 0.42) at Week 24 and for area under the curve at Week 52 (MBDA score: <i>r</i> = 0.44, DAS28: <i>r</i> = 0.41), all <i>p</i> < 0.001. At Week 24, RR of ΔmTSS >0.5 for moderate/high MBDA score (≥30) or DAS28 (>3.2) were 6.6 (<i>p</i> < 0.001) and 2.7 (<i>p</i> = 0.005), respectively. Low DAS28 had greater risk of ΔmTSS >0.5 at 52 weeks when MBDA score was ≥30 (<i>p</i> < 0.05).</p> <p><i>Conclusion</i>: Higher MBDA score or DAS28 at Week 24 was associated with greater radiographic progression over 52 weeks of TNF-inhibitor treatment. MBDA score improved risk discrimination for radiographic progression within DAS28 categories.</p