Influence of humanized anti-IL-6R antibody, tocilizumab on the activity of soluble gp130, natural inhibitor of IL-6 signaling

Tocilizumab, humanized anti-IL-6R antibody is a novel anti-rheumatic drug. In the present study, we examined the influence of tocilizumab on the inhibitory activity of soluble gp130 (sgp130) against IL-6 signaling. BAF-h130 cells, human gp130 transfected mouse pro-B cell line, were cultured with the mixture with IL-6, sIL-6R and sgp130 for 72 h. BAF-h130 cells proliferated by the addition of both IL-6 and sIL-6R, but not IL-6 or sIL-6R alone. The proliferation induced by IL-6/sIL-6R complex was inhibited by sgp130 concentration-dependently. Tocilizumab inhibited IL-6/sIL-6R-induced cell proliferation. On the other hand, it did not affect the suppressive property of sgp130. To examine if tocilizumab can dissociate IL-6/sIL-6R/sgp130 complex, we established an ELISA system to detect IL-6/sIL-6R/sgp130 complex using anti-IL-6R coated ELISA plate. The results clearly indicated that ELISA system established was detectable IL-6/sIL-6R/sgp130 complex in a concentration dependent manner. Tocilizumab was added to IL-6/sIL-6R/sgp130 complex-fixed plate and then remaining IL-6/sIL-6R/sgp130 complexes on the plate were measured. The amount of IL-6/sIL-6R/sgp130 complexes on the plate was not changed by the addition of tocilizumab. In conclusion, tocilizumab exerts its inhibitory effect through the inhibition of IL-6R directly without affecting natural inhibitor sgp130.     

Japan College of Rheumatology 2009 guidelines for the use of tocilizumab,a humanized anti-interleukin-6 receptor monoclonal antibody,in rheumatoid arthritis

Abstract

The introduction of biological agents targeting tumor necrosis factor-alpha (TNF-α) has brought about a paradigm shift in the treatment of rheumatoid arthritis (RA). Although these anti-TNF agents have excellent efficacy against RA, a substantial number of patients still show inadequate responses. In Western countries, such patients are already being treated with new classes of antirheumatic drugs such as abatacept and rituximab. Tocilizumab (TCZ) is a humanized monoclonal antibody developed in Japan against the human interleukin-6 (IL-6) receptor. TCZ does not only alleviate the signs and symptoms of RA but also seems to prevent progressive bone and joint destruction. However, there is a concern that TCZ might increase the risk of adverse events such as infections since IL-6 plays a pivotal role in the immune system. Calculating the relative risks of specific adverse outcomes with TCZ use remains difficult, due to insufficient patient numbers enrolled in clinical trials to date. This review presents tentative guidelines for the use of TCZ for RA patients prepared by the Japan College of Rheumatology and based on results of clinical trials in Japan and Western countries. The guidelines are intended as a guide for postmarketing surveillance and clinical practice, and will be revised periodically based on the surveillance.     

Japan College of Rheumatology 2009 guidelines for the use of tocilizumab, a humanized anti-interleukin-6 receptor monoclonal antibody, in rheumatoid arthritis

The introduction of biological agents targeting tumor necrosis factor-alpha (TNF-α) has brought about a paradigm shift in the treatment of rheumatoid arthritis (RA). Although these anti-TNF agents have excellent efficacy against RA, a substantial number of patients still show inadequate responses. In Western countries, such patients are already being treated with new classes of antirheumatic drugs such as abatacept and rituximab. Tocilizumab (TCZ) is a humanized monoclonal antibody developed in Japan against the human interleukin-6 (IL-6) receptor. TCZ does not only alleviate the signs and symptoms of RA but also seems to prevent progressive bone and joint destruction. However, there is a concern that TCZ might increase the risk of adverse events such as infections since IL-6 plays a pivotal role in the immune system. Calculating the relative risks of specific adverse outcomes with TCZ use remains difficult, due to insufficient patient numbers enrolled in clinical trials to date. This review presents tentative guidelines for the use of TCZ for RA patients prepared by the Japan College of Rheumatology and based on results of clinical trials in Japan and Western countries. The guidelines are intended as a guide for postmarketing surveillance and clinical practice, and will be revised periodically based on the surveillance.     

Successful treatment with tocilizumab of pericarditis associated with rheumatoid arthritis

Abstract

Rheumatoid arthritis (RA) is a systemic inflammatory disease often complicated by vasculitis. Pericarditis is a serious complication caused by vasculitis, resulting in retention of pericardial effusion that sometimes induces cardiac tamponade. We report a patient with RA in whom pericarditis improved after tocilizumab administration. A male patient was diagnosed with RA and chronic renal failure in 1980 and was treated with salazosulfapyridine, but disease activity remained high. In January 2012, at the age of 73 years, he developed organizing pneumonia as a complication and was admitted to our hospital. Treatment with prednisolone 30 mg/day was initiated. However, 20 days after initiation of treatment, chest pain and palpitation developed, and chest computed tomography (CT) and echocardiography (ECG) revealed retention of pericardial effusion without cardiac tamponade. Rheumatoid nodules and interstitial pneumonia were also observed, and serum C3 level was decreased. A diagnosis of pericarditis caused by vasculitis was made based on these findings, and tocilizumab 8 mg/kg was administered. His symptoms improved gradually, and chest CT and ECG showed no pericardial effusion after about 3 weeks. No adverse effects of tocilizumab were observed during the clinical course. Although there are only a few reports of the effects of tocilizumab on vasculitis associated with RA, tocilizumab administration appears worthwhile in RA patients with vasculitis who do not respond to conventional treatment.     

Clinical evaluation of tocilizumab for patients with active rheumatoid arthritis refractory to anti-TNF biologics: tocilizumab in combination with methotrexate

Abstract

We retrospectively observed the clinical efficacy and safety of tocilizumab (TCZ) in 74 patients with rheumatoid arthritis (RA) at 13 hospitals, without any restrictions on disease duration or stage, treatment history, and other influencing factors. TCZ was infused by the approved method, and disease activity was evaluated every 4 weeks until week 24 using a joint disease activity score (DAS28). Remission and treatment response were categorised using European League Against Rheumatism (EULAR) definitions. We also analysed the impact of previous treatment with other biologics and of concomitant methotrexate (MTX) therapy on the efficacy of TCZ. At week 24, the DAS28 had improved from 5.5 to 2.7 and the EULAR remission rate was 55.2%. Good and moderate responses according to the EULAR criteria were obtained in 61 and 36% of the patients, respectively. The biologic-naïve group had a significantly better DAS28 (2.1 vs. 2.8) and a significantly higher “good” response rate (86% vs. 54%) than the biologic-exposed group. Although the TCZ + MTX treatment group and the TCZ monotherapy group had a good response rate of 71 and 48%, respectively, the difference was not significant. Based on these results, we conclude that TCZ is able to significantly alleviate disease symptoms in a wide range of patients with RA in a normal clinical context.     

Masked early symptoms of pneumonia in patients with rheumatoid arthritis during tocilizumab treatment: a report of two cases

Although reports of serious infections in clinical trials for rheumatoid arthritis (RA) with tocilizumab, anti-interleukin6 (IL-6) receptor antibody, have been relatively few, there is still some concern about infections. We report here two cases of patients who developed severe pneumonia during tocilizumab treatment for RA. Both patients initially presented with only minimal clinical symptoms and modest elevations in serum C-reactive protein. Tocilizumab might suppress the early inflammatory symptoms of pneumonia.     

Masked early symptoms of pneumonia in patients with rheumatoid arthritis during tocilizumab treatment: a report of two cases

Abstract

Although reports of serious infections in clinical trials for rheumatoid arthritis (RA) with tocilizumab, anti-interleukin6 (IL-6) receptor antibody, have been relatively few, there is still some concern about infections. We report here two cases of patients who developed severe pneumonia during tocilizumab treatment for RA. Both patients initially presented with only minimal clinical symptoms and modest elevations in serum C-reactive protein. Tocilizumab might suppress the early inflammatory symptoms of pneumonia.     

Synovial fluid and serum levels of soluble interleukin-6 receptor in patients with rheumatoid arthritis

Our objective was to measure both synovial fluid (SF) and serum levels of soluble interleukin-6 receptor (sIL-6R) in patients with rheumatoid arthritis (RA) and patients with osteoarthritis (OA), and to investigate the amounts of sIL-6R protein produced by cultured synovial cells, chondrocytes and mononuclear cells (MNCs). We measured levels of sIL-6R using a sensitive and specific enzyme-linked immunosorbent assay. Synovial cells, chondrocytes and MNCs were cultured, and the supernatants were also measured for sIL-6R. SF levels of sIL-6R in RA were significantly higher than those in OA. SF levels of sIL-6R significantly correlated with SF levels of IL-6 in RA. The serum level of sIL-6R was approximately 3-fold higher than the SF level of sIL-6R. sIL-6R protein was not detected in the supernatants of synovial cells and chondrocytes. As compared to the SF levels of sIL-6R, a small amount of sIL-6R protein was produced by SF MNCs. The above findings suggest that increased amounts of sIL-6R form IL-6-sIL-6R complexes which mediate IL-6 function in RA joints and that SF sIL-6R protein might be not only produced in affected joints, but also supplied from the serum.     

Synovial fluid and serum levels of soluble interleukin-6 receptor in patients with rheumatoid arthritis

Abstract

Our objective was to measure both synovial fluid (SF) and serum levels of soluble interleukin-6 receptor (sIL-6R) in patients with rheumatoid arthritis (RA) and patients with osteoarthritis (OA), and to investigate the amounts of sIL-6R protein produced by cultured synovial cells, chondrocytes and mononuclear cells (MNCs). We measured levels of sIL-6R using a sensitive and specific enzyme-linked immunosorbent assay. Synovial cells, chondrocytes and MNCs were cultured, and the supernatants were also measured for sIL-6R. SF levels of sIL-6R in RA were significantly higher than those in OA. SF levels of sIL-6R significantly correlated with SF levels of IL-6 in RA. The serum level of sIL-6R was approximately 3-fold higher than the SF level of sIL-6R. sIL-6R protein was not detected in the supernatants of synovial cells and chondrocytes. As compared to the SF levels of sIL-6R, a small amount of sIL-6R protein was produced by SF MNCs. The above findings suggest that increased amounts of sIL-6R form IL-6-sIL-6R complexes which mediate IL-6 function in RA joints and that SF sIL-6R protein might be not only produced in affected joints, but also supplied from the serum.     

The efficacy and safety of reinstitution of tocilizumab in patients with relapsed active rheumatoid arthritis after long-term withdrawal of tocilizumab

Abstract

We have evaluated the efficacy and safety of tocilizumab (TCZ) re-administration in patients with active rheumatoid arthritis (RA) who had previously received TCZ treatment for about 31 months. Four patients whose RA had been well-controlled with 8 mg/kg TCZ treatment every 4 weeks and had withdrawn from the treatment were enrolled. They resumed TCZ treatment after TCZ was authorized for RA treatment in Japan. Disease activity was assessed by the Disease Activity Score 28 using erythrocyte sedimentation rate (DAS28-ESR), and synovitis in the wrists and elbows was measured by ultrasonography at baseline and during follow-up. The mean DAS28-ESR was 6.32 before the first TCZ infusion. After fewer than 20 months of initial TCZ treatment, the mean DAS28-ESR decreased to 1.87. However, after withdrawal of TCZ treatment, the disease activity could not be sufficiently controlled with conventional disease-modifying antirheumatic drugs or biologic agents. The maximum interval between TCZ treatments was approximately 34 months. Following reinstatement of the TCZ treatment, within 12 months the mean DAS28-ESR improved from 5.21 to 2.87, with the synovitis in the wrists and elbow joints also showing great improvement. These findings demonstrate that TCZ retreatment in active RA patients who had relapsed after long-term discontinuation of TCZ treatment led to an improvement in the signs and symptoms of RA and in synovitis without any severe adverse events.     

Effectiveness of golimumab for rheumatoid arthritis in patients with an inadequate response to tocilizumab

Objectives: Several biological disease–modifying antirheumatic drugs (bDMARDs) are currently available for the treatment of rheumatoid arthritis (RA). Increasing evidence indicates that second-line bDMARDs are effective for inadequate responders to first-line bDMARDs. However, all previous studies investigated the use of tumor necrosis factor inhibitors (TNFi) as a first-line bDMARD, while investigated the efficacy of second-line bDMARDs after the use of tocilizumab (TCZ), a non-TNFi, as a first-line bDMARD. Thus, we investigated the efficacy of golimumab (GLM) as a second-line bDMARD after treatment with TCZ as a first-line bDMARD.

Methods: The final study population consisted of 26 patients (inadequate responders to TCZ; TCZ group) with moderate or high disease activity (DAS28-ESR ≥3.2) at week 24 of treatment with TCZ as a first-line bDMARD or whose DAS28-ESR score worsened after starting TCZ treatment. These patients could be followed for another 52 weeks or more after the subsequent switch to GLM treatment. For comparison, 19 patients treated with TNFi as a first-line bDMARD and inadequate response to TNFi (TNFi group) were included.

Results: The DAS28-ESR score at week 52 after the start of treatment with GLM improved significantly compared with baseline in the TCZ and TNFi groups. However, the TCZ group showed significantly better improvement. Patients in both groups had significantly improved treatment outcomes according to European League Against Rheumatism response criteria, but there was no statistically significant difference among them. The retention rate at week 52 after the start of treatment with GLM was significantly higher in the TCZ group than in the TNFi group (81% vs. 68%, respectively). In addition, no difference was found in the progression of bone destruction determined by the change in van der Heijde modified total Sharp scoring system scores between groups.

Conclusions: GLM was an effective therapeutic option for inadequate responders to TCZ.     

Switching to the anti-interleukin-6 receptor antibody tocilizumab in rheumatoid arthritis patients refractory to antitumor necrosis factor biologics

Abstract

We evaluated the short-term effects of the anti-interleukin-6 (IL-6) receptor antibody tocilizumab (TCZ) in six patients with rheumatoid arthritis (RA) who had been refractory to tumor necrosis factor (TNF) antagonist therapy. All subjects were considered to be secondary nonresponders to TNF antagonists as decided by each physician. The Disease Activity Score of 28 Joints (DAS28) appeared to improve slowly by TCZ compared with TNF antagonist therapy, but significantly decreased at 24 weeks. One patient achieved DAS28 remission [DAS28–erythrocyte sedimentation rate (ESR) <2.60, and 5 of 6 patients showed good or moderate clinical response. The change in the clinical Disease Activity Index was similar to that of the DAS28–ESR. The serum level of matrix metalloproteinase-3 (MMP-3), a marker for synovial overgrowth, also significantly decreased after the treatment (518 ± 567 at baseline, 141 ± 90 ng/ml at 24 weeks, p < 0.05). One patient discontinued TCZ because of tuberculous peritonitis. Although physicians need to watch for infectious adverse events, these data indicate that TCZ is effective for treating RA patients refractory to TNF antagonists.     

Monitoring C-reactive protein levels to predict favourable clinical outcomes from tocilizumab treatment in patients with rheumatoid arthritis

Objectives

The inflammatory cytokine interleukin-6 (IL-6) directly stimulates C-reactive protein (CRP) expression. The present study aimed to examine how clinical treatment outcomes of rheumatoid arthritis (RA) with tocilizumab (TCZ), a humanised monoclonal anti-IL-6 receptor antibody, are related to CRP levels monitored for 52 weeks.

Methods

One hundred and twenty-two RA patients who underwent TCZ treatment between May 2008 and September 2009 were registered in the Tsurumai Biologics Communication Registry. Data were collected at initiation of treatment (baseline) and over 52 weeks for Disease Activity Score 28-ESR (DAS28-ESR), Boolean core measurements, serum CRP levels and matrix metalloproteinase-3 levels. To compare clinical results, patients were divided into three groups based on treatment time required to achieve normal CRP levels.

Results

Multivariate analysis using the Cox proportional-hazards regression model found that higher CRP levels at baseline was a significant and independent factor in predicting normal CRP levels over 52 weeks (hazard ratio 0.86 per 1 mg/dL). In contrast, disease duration, concomitant methotrexate use and previous tumour necrosis factor inhibitor failure were not significant factors. Patients with normal CRP levels at 12 weeks of TCZ treatment achieved better clinical outcomes, including remission based on DAS28-ESR criteria, compared to patients with elevated CRP levels at 12 weeks.

Conclusions

Adequate suppression of pathological IL-6 signalling during TCZ treatment improves clinical outcomes and can be monitored with serum CRP levels, a readily available biomarker in clinical practice.     

Evaluation of switching from intravenous to subcutaneous formulation of tocilizumab in patients with rheumatoid arthritis

Objective: To evaluate the efficacy of switching the route from intravenous tocilizumab (TCZ) infusion (TCZ-IV) to subcutaneous TCZ injection (TCZ-SC) in a real-world setting through a comparison of the clinical response.

Methods: Fifty-eight rheumatoid arthritis (RA) patients, for whom TCZ-SC was initiated following TCZ-IV between June 2013 and August 2014, were consecutively enrolled. Disease activity score (DAS)28-ESR, simplified disease activity index (SDAI), and clinical disease activity index (CDAI) were examined at baseline and after switching from TCZ-IV to TCZ-SC for 3 months. We investigated whether body weight and body mass index (BMI) affected the efficacy of TCZ-SC.

Results: Most of the patients had achieved remission or low disease activity at baseline (77.6% examined by DAS28). Fifty-seven patients (98%) continued the TCZ-SC treatment, and the disease activity was well controlled after 3 months. ΔDAS28 tended to be worsened after switching to TCZ-SC in the high-body-weight groups (≥60?kg) as compared with the groups with body weight?<60?kg, although no statistical significance was found. BMI did not affect the efficacy of TCZ-SC.

Conclusions: Caution should be exercised in the high-body-weight subjects, but these data indicate that TCZ-SC maintains the favorable RA disease activity established using TCZ-IV.     

Differential effects of IL-6 blockade tocilizumab and TNF inhibitors on angiogenesis in synovial tissues from patients with rheumatoid arthritis

Objective: To compare the influences of tocilizumab (TCZ) and TNF inhibitors (TNFi) on the angiogenesis in synovial tissues of rheumatoid arthritis (RA).

Methods: Synovial tissues were obtained during joint operations from 13 RA patients treated with TCZ for at least 4 months with or without previous use of TNFi, from 13 RA patients with TNFi alone and from 10 RA patients with only conventional synthetic DMARDs (csDMARDs). Synovial tissues were evaluated by hematoxylin and eosin stain as well as by immunohistological staining with anti-CD31 in which the microvessel densities (MVD) were quantitated. Synovial histopathology was scored for various components.

Results: The most remarkable change in the synovium with TCZ was reduced angiogenesis as well as degeneration of lining layers irrespective of the previous use of TNFi. Thus, MVD in patients treated with TCZ with or without previous TNFi were significantly decreased compared with those in patients with TNFi alone or with csDMARDs. Moreover, MVD was significantly correlated with lining layer proliferation, but not with synovial stromal proliferation or inflammatory changes.

Conclusions: These results demonstrated that inhibition of angiogenesis is a unique action of TCZ. Moreover, the data also suggest that lining layers proliferation might be closely associated with angiogenesis.     

Effect of interleukin-6 receptor inhibitor,tocilizumab, in preventing joint destruction in patients with rheumatoid arthritis showing inadequate response to TNF inhibitors

Abstract

Objectives. To examine the effectiveness of tocilizumab (TCZ) in preventing joint destruction in patients with inadequate response to tumor necrosis factor inhibitors (TNF-IR) by assessing X-rays.

Methods. RA patients were extracted from the Retrospective actemra investigation for optimal needs of RA patients (REACTION) study. Parameters and components of disease activity were evaluated during anti-TNF treatment and during TCZ treatment. X-ray images of hands and feet at the beginning of this study during anti-TNF treatment (Pre), at the start point of TCZ treatment (Baseline) and after TCZ treatment (Post) were collected for assessing joint destruction.

Results. Forty-five patients from the REACTION study fulfilled the criteria of clinical TNF-IR. During anti-TNF treatment, mean DAS28-ESR rose from 5.35 to 5.87 (mean observation duration, 16 months) but improved significantly to 2.94 (P < 0.0001) at 52 weeks after switching to TCZ. Mean change in van der Heijde-modified Sharp score (TSS) during anti-TNF treatment was 3.17 in this TNF-IR population. After switching to TCZ, mean change in TSS was 1.20 (P < 0.05). Rate of radiographic non-progression improved to 66.7% during TCZ treatment from 40.0% during anti-TNF treatment. The predictive factor for no radiographic progression after switching to TCZ was a HAQ disability index (HAQ-DI) score of ≤ 1.88 at switching to TCZ.

Conclusion. TCZ was a good treatment option for improving signs and symptoms and inhibiting progression of joint damage in patients with clinical and structural TNF-IR.     

Incidence of serious respiratory infections in patients with rheumatoid arthritis treated with tocilizumab

Abstract

We aimed to demonstrate the incidence of serious respiratory infections in patients with rheumatoid arthritis (RA) treated with tocilizumab (TCZ) monotherapy. We analyzed the incidence of serious respiratory infections in 601 RA patients enrolled in TCZ clinical trials and their extension studies (TCZ cohort) and in 601 age- and sex-standardized RA patients treated in daily clinical practice at Tokyo Women’s Medical University (IORRA subsample cohort). The rates of serious respiratory infections were 1.77 per 100 patient-years from 1999 to 2008 in the TCZ cohort and 0.53 per 100 patient-years from 2000 to 2009 in the IORRA subsample cohort. With the IORRA subsample cohort regarded as a standard population, the standardized incidence ratio (SIR) of serious respiratory infection in the TCZ cohort was 3.64 [95% confidence interval (CI) 2.56–5.01], standardized for age and sex; 2.35 (95% CI 1.66–3.24), standardized for age sex, and corticosteroid use; 1.85 (95% CI 1.30–2.55), standardized for age sex, and pre-existing pulmonary involvement; and 2.41 (95% CI 1.68–3.34) standardized for age sex, and disease activity. The risk of serious respiratory infection in the TCZ cohort was approximately double that in the IORRA subsample cohort after standardizing for corticosteroid use, pre-existing pulmonary involvement, or disease activity. This is comparable to the risk reported when tumor necrosis factor (TNF) inhibitors are used.     

Serum levels of IL-10, IL-6, IL-1ra, and sIL-2R in patients with psoriatic arthritis

Our objective was to evaluate the levels of interleukin-6 (IL-6), soluble receptors of IL-2 (sIL-2R), IL-10, and IL-1 receptor antagonists (IL-1ra) in the serum of patients with psoriatic arthritis (PsA) and to assess the correlation between these levels and parameters of clinical activity of skin and joint disease. In total, 34 patients with PsA and ten healthy volunteers participated in the study. Assessment of joint disease included duration of morning stiffness, number of tender and swollen joints, right and left grip, the presence of inflammatory spinal back pain, and Schober test. Current severity of skin disease was graded according to the psoriasis area and severity index (PASI). Erythrocyte sedimentation rate (ESR) was determined as a marker of disease activity. Serum levels of IL-6, sIL-2R, IL-1ra, and IL-10 were measured by an enzyme immunoassay kit. Significantly higher serum levels of IL-6, sIL-2R, IL-1ra, and IL-10 were found in patients with PsA in comparison with healthy volunteers. A statistically significant correlation was found between levels of sIL-2R and PASI, whereas no association was found with clinical parameters of joint severity. Levels of IL-1ra correlated with the number of tender and swollen joints. No correlation was found between levels of IL-6, IL-10, and clinical parameters of skin and joint severity. In the group of patients with PsA, serum levels of sIL-2R clearly correlated with severity of skin disease, whereas levels of IL-1ra were associated with joint severity. Received: 18 June 1999 / Accepted: 1 October 1999     

Study of active controlled tocilizumab monotherapy for rheumatoid arthritis patients with an inadequate response to methotrexate (SATORI): significant reduction in disease activity and serum vascular endothelial growth factor by IL-6 receptor inhibition therapy

We investigated the clinical efficacy and safety of tocilizumab (a humanized anti-IL-6 receptor antibody) monotherapy in active rheumatoid arthritis (RA) patients with an inadequate response to low dose methotrexate (MTX). In a multicenter, double-blind, randomized, controlled trial, 125 patients were allocated to receive either tocilizumab 8 mg/kg every 4 weeks plus MTX placebo (tocilizumab group) or tocilizumab placebo plus MTX 8 mg/week (control group) for 24 weeks. The clinical responses were measured using the American College of Rheumatology (ACR) criteria and the Disease Activity Score in 28 joints. Serum vascular endothelial growth factor (VEGF) levels were also monitored. At week 24, 25.0% in the control group and 80.3% in the tocilizumab group achieved ACR20 response. The tocilizumab group showed superior ACR response criteria over control at all time points. Additionally, serum VEGF levels were significantly decreased by tocilizumab treatment. The overall incidences of adverse events (AEs) were 72 and 92% (serious AEs: 4.7 and 6.6%; serious infections: 1.6 and 3.3%) in the control and the tocilizumab groups, respectively. All serious adverse events improved by adequate treatment. Tocilizumab monotherapy was well tolerated and provided an excellent clinical benefit in active RA patients with an inadequate response to low dose MTX.     

The efficacy and safety of additional administration of tacrolimus in patients with rheumatoid arthritis who showed an inadequate response to tocilizumab

Objectives: Tocilizumab (TCZ) shows good retention in patients with rheumatoid arthritis (RA), but no previous reports demonstrated hopeful treatment options against inadequate response to TCZ. Tacrolimus (TAC) has proved to show efficacy against inadequate response to tumor necrosis factor alpha inhibitors, yet its add-on effects on TCZ remain unknown.

Methods: Twenty patients with RA (17 women, age 58.6 years, disease duration 12.1 years, prior TCZ duration 2.6 years, 18 intravenous [8?mg/kg/month] and 2 subcutaneous [324?mg/month] TCZ treatments, methotrexate 6.1?mg/week [70.0%]) who showed an inadequate response to TCZ (clinical disease activity index [CDAI]?≥?5.8, 18 secondary non-responders) were additionally treated with TAC (1.1?mg/day), and enrolled in this 24-week, prospective study.

Results: Seventeen patients (85.0%) continued the treatment for 24 weeks. Statistically significant decreases in outcome measures were as follows: disease activity score based on 28 joints with C-reactive protein (DAS28-CRP) from 3.3 at baseline to 2.1 at week 24 (p?p?p?Conclusions: Adding low-dose TAC to inadequate responders to TCZ may be a promising complementary treatment option.