托珠单抗联合改善病情抗风湿药治疗类风湿关节炎的多中心、随机、双盲、安慰剂对照临床研究

  目的 评价托珠单抗联合改善病情抗风湿药（DMARDs）治疗DMARDs疗效不佳的活动性中重度类风湿关节炎（RA）患者的有效性与安全性。方法 随机、双盲、安慰剂对照、多中心临床试验。DMARDs疗效不佳的中重度活动性RA患者按2∶1 的比例随机分入托珠单抗组(托珠单抗+DMARDs) 或安慰剂组(安慰剂+DMARDs),每4 周静脉滴注1次托珠单抗8 mg/kg,同时继续应用稳定剂量的DMARDs。完成双盲期的患者可以选择进入为期24周的开放期,接受每4周静脉滴注1次托珠单抗8 mg/kg。主要观察指标：第24周时达到美国风湿病学会（ACR）制定的RA疗效缓解20%（ACR20）、RA疗效缓解50%（ACR50）、RA疗效缓解70%（ACR70）的受试者比例;达到28个关节疾病活动指数（DAS）≤3.2、DAS28<2.6的受试者比例。结果 （1）托珠单抗组139例、安慰剂组69例患者完成了24周的双盲期临床观察,达到ACR20、ACR50和ACR70的受试者比例托珠单抗组（69.8%、38.8%、12.9%）显著高于安慰剂组（24.6%、10.1%、2.9%,P<0.05)。托珠单抗组患者红细胞沉降率、C反应蛋白、血红蛋白、DAS28≤3.2及DAS28<2.6的受试者比例的改善优于安慰剂组。托珠单抗组患者治疗后Ⅰ型胶原羧基端吡啶并啉交联肽、ⅡA型前胶原氨基端前肽、基质金属蛋白酶-3水平下降。（2）48周开放期共有202例RA患者接受了托珠单抗治疗,达到ACR20、ACR50、ACR70的受试者比例分别为81.2%、60.4%、36.6%。DAS28降至2.760±1.402,50.5%的患者达到DAS28<2.6。（3）托珠单抗组发生59例（42.4%）不良事件,高于安慰剂组（27.9%）。严重不良事件发生率托珠单抗组为0.7%,安慰剂组为5.9%。最常见的不良事件为感染,绝大多数为轻中度。托珠单抗组患者出现丙氨酸转氨酶和天冬氨酸转氨酶显著升高;总胆固醇、低密度脂蛋白、高密度脂蛋白和甘油三酯水平升高,但未观察到心血管事件的增加。治疗48周时未出现新的不良事件。结论托珠单抗联合DMARDs治疗DMARDs疗效不佳的中重度活动性RA患者有显著临床疗效,患者安全性与耐受性良好。        

Interleukin-6 receptor inhibition with tocilizumab reduces disease activity in rheumatoid arthritis with inadequate response to disease-modifying antirheumatic drugs: the tocilizumab in combination with traditional disease-modifying antirheumatic drug therapy study

OBJECTIVE: To examine the efficacy and safety of the humanized anti-interleukin-6 receptor antibody tocilizumab combined with conventional disease-modifying antirheumatic drugs (DMARDs) in patients with active rheumatoid arthritis (RA). METHODS: A total of 1,220 patients were randomized (2:1 ratio) in the phase III, double-blind, placebo-controlled, multicenter TOWARD (Tocilizumab in Combination With Traditional DMARD Therapy) study. Patients remained on stable doses of DMARDs and received tocilizumab 8 mg/kg or placebo (control group) every 4 weeks for 24 weeks. RESULTS: At week 24, the proportion of patients achieving a response according to the American College of Rheumatology criteria for 20% improvement (ACR20) was significantly greater in the tocilizumab plus DMARD group than in the control group (61% versus 25%; P<0.0001). Secondary end points including 50% or 70% improvement (ACR50/70), the Disease Activity Score in 28 joints (DAS28), DAS28 remission responses (DAS28<2.6), European League Against Rheumatism responses, and systemic markers such as the C-reactive protein and hemoglobin levels showed superiority of tocilizumab plus DMARDs over DMARDs alone. Seventy-three percent of patients in the tocilizumab group had >or=1 adverse event (AE), compared with 61% of patients in the control group. AEs leading to withdrawal from the study were infrequent (4% of patients in the tocilizumab group and 2% of those in the control group). Serious AEs occurred in 6.7% and 4.3% of patients in the tocilizumab and control groups, respectively, and serious infections occurred in 2.7% and 1.9%, respectively. Elevations in the alanine aminotransferase level, from normal at baseline to >3-fold the upper limit of normal, occurred in 4% of patients in the tocilizumab group and 1% of those in the control group, and elevated total cholesterol levels were observed in 23% and 6% of patients, respectively. Sixteen patients started lipid-lowering therapy during the study. Grade 3 neutropenia occurred in 3.7% of patients receiving tocilizumab and none of the patients in the control group, and no grade 4 neutropenia was reported. CONCLUSION: Tocilizumab combined with any of the DMARDs evaluated was safe and effective in reducing articular and systemic symptoms in patients with an inadequate response to these agents.     

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.     

A multicentre trial of bucillamine in the treatment of early rheumatoid arthritis (SNOW study)

In this study, we enrolled early rheumatoid arthritis (RA) patients at multiple institutes who fulfilled the American Rheumatism Association 1987 revised criteria for the classification of RA, and followed the clinical results of disease-modifying anti-rheumatic drug (DMARD) treatment prospectively. With the aim of developing therapeutic guidelines using the disease activity score 28 (DAS28) as disease indices, we investigated the usefulness of bucillamine (BUC), one of the most widely used DMARDs in Japan. Eighty-one patients with early RA who had not previously been treated with DMARDs were suitable for BUC therapy as first-choice treatment. After 24 months of treatment, at least moderate improvement was seen in 87.5% of patients using the DAS28 erythrocyte sedimentation rate (ESR). After 24 months of BUC therapy, 7 patients (43.8%) met the remission criterion of DAS28 (ESR) <2.6. The 24-month BUC continuation rate was 60.5% (49/81, monotherapy + combination therapy), of which 59.2% (29/49) were on BUC monotherapy. From the efficacy and safety viewpoints alike, BUC was useful as first-choice treatment for early RA.     

Tocilizumab en pacientes con artritis reumatoide activa y respuesta inadecuada a fármacos antirreumáticos modificadores de la enfermedad o antagonistas del factor de necrosis tumoral: subanálisis de los datos españoles de un estudio abierto cercano a la práctica clínica habitual

ObjectivesTo analyze the Spanish experience in an international study which evaluated tocilizumab in patients with rheumatoid arthritis (RA) and an inadequate response to conventional disease-modifying antirheumatic drugs (DMARDs) or tumor necrosis factor inhibitors (TNFis) in a clinical practice setting.Material and methodsSubanalysis of 170 patients with RA from Spain who participated in a phase IIIb, open-label, international clinical trial. Patients presented inadequate response to DMARDs or TNFis. They received 8 mg/kg of tocilizumab every 4 weeks in combination with a DMARD or as monotherapy during 20 weeks. Safety and efficacy of tocilizumab were analyzed. Special emphasis was placed on differences between failure to a DMARD or to a TNFi and the need to switch to tocilizumab with or without a washout period in patients who had previously received TNFi.ResultsThe most common adverse events were infections (25%), increased total cholesterol (38%) and transaminases (15%). Five patients discontinued the study due to an adverse event. After six months of tocilizumab treatment, 71/50/30% of patients had ACR 20/50/70 responses, respectively. A higher proportion of TNFi-naive patients presented an ACR20 response: 76% compared to 64% in the TNFi group with previous washout and 66% in the TNFi group without previous washout.ConclusionsSafety results were consistent with previous results in patients with RA and an inadequate response to DMARDs or TNFis. Tocilizumab is more effective in patients who did not respond to conventional DMARDs than in patients who did not respond to TNFis.     

Study of active controlled monotherapy used for rheumatoid arthritis, an IL-6 inhibitor (SAMURAI): evidence of clinical and radiographic benefit from an x ray reader-blinded randomised controlled trial of tocilizumab

OBJECTIVE: To evaluate the ability of tocilizumab (a humanised anti-IL-6 receptor antibody) monotherapy to inhibit progression of structural joint damage in patients with RA. METHODS: In a multi-centre, x ray reader-blinded, randomised, controlled trial, 306 patients with active RA of <5 years' duration were allocated to receive either tocilizumab monotherapy at 8 mg/kg intravenously every 4 weeks or conventional disease-modifying antirheumatic drugs (DMARDs) for 52 weeks. Radiographs of hands and forefeet were scored by the van der Heijde modified Sharp method. RESULTS: Patients had a mean disease duration of 2.3 years and a disease activity score in 28 joints of 6.5 at baseline. Mean total modified Sharp score (TSS) was 29.4, which was very high despite the relatively short disease duration. At week 52, the tocilizumab group showed statistically significantly less radiographic change in TSS (mean 2.3; 95% CI 1.5 to 3.2) than the DMARD group (mean 6.1; 95% CI 4.2 to 8.0; p<0.01). Tocilizumab monotherapy also improved signs and symptoms. The overall incidences of AEs were 89% and 82% (serious AEs: 18% and 13%; serious infections: 7.6% and 4.1%) in the tocilizumab and DMARD groups, respectively. CONCLUSION: Tocilizumab monotherapy was generally well tolerated and provided radiographic benefit in patients with RA.     

Retreatment efficacy and safety of tocilizumab in patients with rheumatoid arthritis in recurrence (RESTORE) study

Abstract

Objectives To evaluate the safety and efficacy of retreatment with tocilizumab (TCZ) in patients who had participated in the DREAM study (Drug free remission/low disease activity after cessation of tocilizumab [Actemar] monotherapy study) and had experienced loss of efficacy.

Methods Patients were retreated with TCZ or other disease modifying antirheumatic drugs (DMARDs). Disease activity was measured using the 28-joint disease activity score (DAS28) for 12 weeks.

Results A total of 164 eligible patients, including 161 who experienced loss of efficacy within 52 weeks of the DREAM study, resumed treatment: 157 with TCZ and 7 with DMARDs and/or infliximab. Of TCZ-treated patients, 88.5 % (139 patients) achieved DAS28 <2.6 within 12 weeks, whereas among patients treated with DMARDs and/or infliximab only 14.3 % (1 patient) achieved DAS28 <2.6. Adverse events were observed in 70 TCZ-treated patients (44.0 %), but no serious infusion reactions were observed.

Conclusions Retreatment with TCZ was well-tolerated and effective in patients who had responded to the preceding TCZ monotherapy but had experienced loss of efficacy after cessation of TCZ.     

The usefulness of a new triple combination treatment utilizing methotrexate,salazosulfapyridine, and bucillamine in rheumatoid arthritis

Objectives. Combination treatment with methotrexate, salazosulfapyridine and bucillamine as an alternative to treatment with TNF-inhibiting biologics in rheumatoid arthritis was investigated.

Methods. Twenty-six facilities allied with the Japan Association of Rheumatologists in Private Practice participated in this study. One hundred and twelve patients enrolled in this study, all of whom were within 3 years of diagnosis with rheumatoid arthritis for whom treatment with one DMARD or a combination of two DMARDs had failed (DAS28 > 3.2). Patients chose their own treatment. The triple DMARDs combination group was comprised of 72 patients; the TNF-inhibiting biologics treatment group was comprised of 40 patients.

Results. DAS28 scores for the triple DMARDs combination group and the TNF-inhibiting biologics treatment groups were 4.84 ± 0.96 and 5.23 ± 1.26, and there was no significant difference between the two groups. From the 6th month, average disease activities of both groups were reduced, and there was no difference between the two groups at 12 months (DAS28, 3.39 ± 1.43 and 3.05 ± 1.43, p = 0.39). Furthermore, there was no significant difference in the degree of bone destruction between the two groups at 12 months.

Conclusions. The triple DMARD combination therapy provided a new treatment option for those patients for whom treatment with biologics is difficult.     

Triple therapy in early active rheumatoid arthritis: a randomized, single-blind, controlled trial comparing step-up and parallel treatment strategies

OBJECTIVE: The Tight Control of Rheumatoid Arthritis study previously demonstrated that an intensive step-up disease-modifying antirheumatic drug (DMARD) treatment strategy targeting persistent disease activity was superior to routine care in the management of early rheumatoid arthritis (RA). We undertook this study to test the hypothesis that early parallel triple therapy achieves better outcomes than step-up therapy within an intensive disease management regimen. METHODS: Ninety-six patients with early RA (mean disease duration 11.5 months) were randomized to receive step-up therapy (sulfasalazine [SSZ] monotherapy, then after 3 months, methotrexate [MTX] was added, and when the maximum tolerated dosage of MTX was reached, hydroxychloroquine [HCQ] was added) or parallel triple therapy (SSZ/MTX/HCQ). All patients were assessed monthly for 12 months. If their disease activity score in 28 joints (DAS28) was > or =3.2, the dosage of DMARDs was increased according to protocol, and swollen joints were injected with triamcinolone acetonide (maximum dosage 80 mg per month). A metrologist who was blinded to the treatment allocation performed assessments every 3 months. The primary outcome measure was the mean decrease in the DAS28 score at 12 months. RESULTS: Both groups showed substantial improvements in disease activity and functional outcome. At 12 months, the mean decrease in the DAS28 score was -4.0 (step-up therapy group) versus -3.3 (parallel therapy group) (P = 0.163). No significant differences in the percentages of patients with DAS28 remission (step-up therapy group 45% versus parallel triple therapy group 33%), DAS28 good response (60% versus 41%, respectively), or American College of Rheumatology criteria for 20% improvement (ACR20) (77% versus 76%, respectively), ACR50 (60% versus 51%, respectively), or ACR70 (30% versus 20%, respectively) responses were seen. Radiologic progression was similar in both groups. CONCLUSION: This study confirms that highly effective control of disease activity can be achieved using conventional DMARDs as part of an intensive disease management strategy. Within this setting, step-up therapy is at least as effective as parallel triple therapy.     

Etanercept in combination with conventional disease-modifying antirheumatic drugs (DMARDs) in the treatment of rheumatoid arthritis patients intolerant to methotrexate

Although etanercept (ETN) is effective when used in monotherapy for the treatment of rheumatoid arthritis (RA), ETN/methotrexate (MTX) combination therapy is more efficacious. However, some patients show MTX intolerance; these patients may develop adverse events (AEs) or have risk factors for AEs. There is limited published information regarding the efficacy of combination therapy involving ETN and disease-modifying antirheumatic drugs other than MTX. Therefore, we evaluated the effects of combination therapy with ETN and salazosulfapyridine (SASP) and/or bucillamine (Bc), a d-penicillamine analogue, in MTX-intolerant RA patients. Indices of RA activity, including disease activity score in 28 joints (DAS28), were retrospectively analyzed over a 48-week period in 66 patients treated with ETN. Treatment efficacy was compared in the following 4 major treatment groups: ETN monotherapy, ETN + MTX, ETN + SASP, and ETN + SASP + Bc. Although intergroup differences in the percent change of DAS were not statistically significant, ETN + SASP + Bc seemed to be more effective than ETN monotherapy, and the efficacy of ETN + SASP + Bc was comparable to that of ETN + MTX according to the European League Against Rheumatism (EULAR) improvement ratings. These results suggest that ETN + SASP + Bc combination therapy may be a viable option for RA treatment in patients in whom MTX cannot be used.     

Chronological changes in baseline disease activity of patients with rheumatoid arthritis who received biologic DMARDs between 2003 and 2012

Abstract

Background/Purpose. The use of biologic disease-modifying anti-rheumatic drugs (DMARDs) for rheumatoid arthritis (RA) has been increasing since 2003. In this study, we evaluated changes in the characteristics of patients receiving biologic DMARDs daily, in Japan.

Methods. The characteristics of all RA patients who received any biologic DMARD at the Institute of Rheumatology, Tokyo Women's Medical University, within 1 year after its approval in Japan, were retrospectively evaluated. The periods of patient enrollment for each biologic agent were: infliximab (IFX), 2003–2004; etanercept (ETN), 2005–2006; tocilizumab (TCZ), 2008–2009; adalimumab (ADA), 2008–2009; abatacept (ABT), 2010–2011; and golimumab (GLM), 2011–2012. We retrospectively collected individual patient characteristics, concomitant medication usage, and disease activity assessed by disease activity score 28 (DAS28) at the time of administration, from the medical records. The retention rate for each agent at 6 months after treatment initiation was also assessed.

Results. The numbers of patients who received each biologic DMARD at our institute within 1 year after its approval were: IFX, 49; ETN, 50; TCZ, 62; ADA, 52; ABT, 40; and GLM, 77. From 2003 to 2012, the proportion of patients with prior use of any biologic DMARD increased, as did concomitant use and dose of methotrexate (MTX); however, corticosteroid use and doses decreased. DAS28, at the time of treatment initiation, gradually decreased. At the time of IFX administration, 75% and 25% of patients had high and moderate disease activity respectively, compared to 25% and 58% respectively, of patients who received GLM. No significant difference was observed in the retention rate of biologic DMARDs at 6 months (range, 75.0% to 89.6%).

Conclusion. Baseline disease activity of RA patients who received biologic DMARDs between 2003 and 2012 has changed from high to moderate in daily practice in Japan.     

Clinical and ultrasound evaluation of the response to tocilizumab treatment in patients with rheumatoid arthritis: a case series

This case series evaluates the clinical and ultrasound response to tocilizumab treatment in patients with rheumatoid arthritis (RA). Six patients with active RA (DAS28 ≥ 3.2) for ≥6 months, refractory to conventional DMARDs or anti-TNF agents, received tocilizumab 8 mg/kg every 4 weeks, as monotherapy or in combination with DMARDs, for 6 months. The following clinical parameters were assessed monthly: number of tender joints (28 and 44 joints), number of swollen joints (28 and 44 joints), DAS28-ESR, DAS28-CRP, VAS score, global health status, health assessment questionnaire, patient global assessment of disease activity, physician global assessment of disease activity, functional assessment of chronic illness therapy (FACIT), erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP). All patients also underwent a gray-scale ultrasonography (US) assessment with power Doppler evaluation at each visit. All clinical parameters improved during the study, versus baseline. This improvement was statistically significant for most parameters 2 months following tocilizumab initiation and was sustained to the end of the observation period. The number of tender joints (44-joint evaluation), the FACIT score, and ESR and CRP concentrations were significantly improved versus baseline values after the first month of tocilizumab treatment. The course of US evaluations mirrored that of clinical parameters; a faster and more evident response was observed for foot joints, with respect to hand joints. This case series suggested the rapid clinical benefit of tocilizumab. Ultrasound assessment showed that the onset of this effect was faster in the foot joints than in the hand joints.     

A multicenter study of leukocytapheresis in rheumatoid arthritis

OBJECTIVE:To evaluate the efficacy and safety of leukocytapheresis (LCAP) in patients with rheumatoid arthritis (RA) that is refractory to disease modifying antirheumatic drugs (DMARDs), we conducted a prospective, multicenter, open-label clinical trial.METHODS:We enrolled 38 active RA patients, including 32 patients who showed an inadequate response to > or = 2 DMARDs and 6 patients with rapidly progressive RA. All patients continued drug therapy and were treated with 5 LCAP sessions conducted at 1-week intervals. The clinical response was evaluated at baseline before starting LCAP and at 4 weeks after the completion of all the LCAP sessions using the American College of Rheumatology (ACR) criteria and the 28-joint disease activity score (DAS28) of the European League Against Rheumatism (EULAR).RESULTS:Of the 35 patients who fulfilled the study's eligibility criteria, 24 (69%), 10 (29%), and 23 (66%) patients achieved 20% (ACR20), 50% (ACR50), and DAS28-C-reactive protein (CRP) EULAR improvement, respectively. The mean DAS28-CRP score of the 35 patients decreased significantly from 5.99 +/- 0.92 at baseline to 4.54 +/- 1.39 after treatment. Comparison analysis of the ACR20 responders and non-responders to LCAP revealed that 22 of 24 responders (92%) concomitantly received methotrexate, whereas significantly fewer, that is, 6 of 11 non-responders (55%) received methotrexate. Less frequent and transient mild-to-moderate adverse events, including nausea and headache, were seen in 12 of 189 LCAP sessions (6.3%).CONCLUSION:These results demonstrate the usefulness of LCAP in combination with DMARDs, particularly methotrexate, as an effective and safe treatment for refractory RA.     

Combination therapy with sulfasalazine and methotrexate is more effective than either drug alone in patients with rheumatoid arthritis with a suboptimal response to sulfasalazine: results from the double-blind placebo-controlled MASCOT study

BACKGROUND: Optimal use of disease-modifying antirheumatic drugs (DMARDs) in rheumatoid arthritis is vital if progression of disease is to be reduced. Methotrexate (MTX) and sulfasalazine (SASP) are widely used inexpensive DMARDs, recently often combined despite no firm evidence of benefit from previous studies. Aim: To establish whether a combination of SASP and MTX is superior to either drug alone in patients with rheumatoid arthritis with a suboptimal response to 6 months of SASP. METHODS: A randomised controlled study of step-up DMARD treatment in early rheumatoid arthritis. In phase I, 687 patients received SASP for 6 months. Those with a disease activity score (DAS) > or =2.4 were offered additional treatment in phase II (SASP alone, MTX alone or a combination of the two). The primary outcome measure was change in DAS. RESULTS: At 6 months, 191 (28%) patients had a DAS <2.4, 123 (18%) were eligible but did not wish to enter phase II, 130 (19%) stopped SASP because of reversible adverse events and 165 (24%) entered phase II. DAS at 18 months was significantly lower in those who received combination treatment compared with those who received either SASP or MTX: monotherapy arms did not differ. Improvement in European League Against Rheumatism and American College of Rheumatology 20, 50 and 70 scores favoured combination therapy. CONCLUSIONS: In this "true-to-life" study, an inexpensive combination of DMARDs proved more effective than monotherapy in patients with rheumatoid arthritis with a suboptimal response to SASP. There was no increase in toxicity. These results provide an evidence base for the use of this combination as a component of tight control strategies.     

Assessment of adenosine deaminase levels in rheumatoid arthritis patients receiving anti-TNF-α therapy

Anti-TNF-α agents are increasingly used in rheumatoid arthritis (RA) treatment and that is known to increase the risk of tuberculosis (TB) reactivation. Adenosine deaminase (ADA) levels are shown to increase to high levels in TB patients. Our aim is to investigate the serum ADA levels in RA patients being treated with anti-TNF-α and to compare the results with the patients on DMARD therapy. The study groups comprised of 56 RA patients (45 female, mean age 49) who were treated either with two or three DMARDs, 32 RA patients with anti-TNF-α treatment (26 female, mean age 46) and 20 healthy controls (10 female, mean age 48). All patients fulfilled the 1987 ACR criteria for RA. DAS28 score was calculated for all subjects. When compared to healthy controls, ADA levels were measured statistically higher both in patient groups (P = 0.046, 0.002). ADA levels in anti-TNF-α group were similar to conventional therapy (11.3 ± 2.7, 10.9 ± 4.01; P = 0.76). PPD was positive in 17 RA patients in the anti-TNF-α treatment group (%53). The ADA levels were found to be similar in the anti-TNF-α group when compared according to the PPD positivity (positive, 12.4 ± 3.7; negative, 10.5 ± 2.1; P = 0.02). No correlation was found between the ADA levels and age, disease duration, ESR, CRP, DAS 28 and HAQ score. In this study, we observed that RA patients at remission taking DMARD or anti-TNF-α therapy have similar levels of serum ADA. Although serum ADA levels during TB infection increase much higher, in our study, ADA levels of all RA patients were lower than 15 IU/L. Elevated ADA levels may be a clue for diagnosis of TB in patients who were on anti-TNF-α therapy.     

Single-center, retrospective analysis of efficacy and safety of tacrolimus as a second-line DMARD in combination therapy and the risk factors contributing to adverse events in 115 patients with rheumatoid arthritis

To retrospectively evaluate the efficacy and safety of combination therapy with tacrolimus (TAC) and other disease-modifying antirheumatic drugs (DMARDs). One hundred fifteen rheumatoid arthritis (RA) patients treated with tacrolimus were enrolled in this retrospective analysis. We collected clinical information, including patient background, treatment efficacy (evaluated using the DAS score), and adverse events observed. Multiple logistic regression analysis was conducted to analyze factors contributing to clinical response and adverse effects. The disease activity score of 28 joints (DAS28) improved significantly at 24?weeks, and continuation rate at 1?year was 57.9%. There was no difference in continuation rate between different DMARD combinations, and not only methotrexate (MTX) but also bucillamine (BUC) and salazosulfapyridine (SSZ) were effective combination partners with TAC. No serious adverse events were observed, and no different inefficacy or safety was observed between non-elderly (<65?years old) and elderly (≥65?years old) RA patients. By conducting multiple logistic regression analysis, combination therapy with MTX and TAC, the number of baseline DMARDs (specifically, ≥3), and old age were identified as risk factors for adverse events. Our findings indicate that TAC is a valuable DMARD for second-line combination therapy in RA.     

Monotherapy with tocilizumab or TNF-alpha inhibitors in patients with rheumatoid arthritis: efficacy, treatment satisfaction, and persistence in routine clinical practice

This study aims to investigate the use of biological disease-modifying antirheumatic drugs (bDMARDs) as monotherapy in patients with rheumatoid arthritis (RA) in “real world” clinical settings and to compare tumor necrosis factor (TNF) inhibitors and tocilizumab monotherapy in terms of efficacy and patient and clinician satisfaction with treatment. This study made use of a retrospective, cohort-19 based study including included data from 254 patients (TNF inhibitors n?=?128; tocilizumab n?=?126) managed in 30 centers throughout Germany. Efficacy of monotherapy and patient and physician overall satisfaction with treatment were assessed at baseline, 3, and 6 months of monotherapy using a range of measures including Disease Activity Score 28 joint (DAS28), swollen joint count (SJC) and tender joint count (TJC), and visual analogue scales (VAS). Between 18 and 41 % of patients treated with bDMARDs received the agent as monotherapy. Intolerance to DMARDs, contraindications for combination therapy, and comorbidities were the most common reasons for introduction of bDMARD monotherapy. Mean DAS28 (erythrocyte sedimentation rate, ESR) was significantly lower at 3 and 6 months following tocilizumab vs. TNF inhibitors (p?≤?0.001). Joint counts improved from baseline to month 6 in both groups (SJC ?5.1 vs. ?3.7 and TJC ?5.6 vs. ?5.1, for tocilizumab and TNF inhibitors, respectively). Patient as well as physician satisfaction (VAS 100 mm scale) was significantly higher for tocilizumab vs. TNF inhibitors (75.3 vs. 66.8; p?=?0.001 and 74.9 vs. 67.1, p?=?0.003, respectively). Significantly more patients remained on tocilizumab monotherapy vs. TNF-inhibitor monotherapy (89.7 vs. 75.8 %; p?<?0.01). Monotherapy with bDMARDs is common in routine clinical practice. Tocilizumab monotherapy appeared to be superior over TNF-inhibitor monotherapy with respect to DAS28 and drug adherence.     

Therapeutic effects of the combination of methotrexate and bucillamine in early rheumatoid arthritis: a multicenter, double-blind, randomized controlled study

Disease-modifying antirheumatic drug (DMARD) combination therapies are used widely, but there have been few reports clearly demonstrating that combination therapy is more effective than DMARD monotherapy. We conducted a multicenter, double-blind controlled trial in order to clarify that the combination of methotrexate and bucillamine is more effective than either alone. The subjects of this study were 71 patients with active rheumatoid arthritis within 2 years of onset. Dosages were 8 mg methotrexate with 5 mg folic acid per week (MTX group), 200 mg bucillamine per day (BUC group), or both MTX and BUC (combination group). Clinical effects and adverse reactions were observed for 96 weeks. The ACR 20 response rate was 79.2% in the combination group, significantly higher than the rates of 43.5% for the MTX group (P = 0.008) and 45.8% for the BUC group (P = 0.0178). The cumulative survival curve of maintaining the ACR 20 response was significantly higher in the combination group than in the MTX and BUC groups (P = 0.0123 and P = 0.0088, respectively). The mean increase in the total Sharp score over 96 weeks was 12.6 ± 9.0 in the combination group, significantly lower (P = 0.0468) than the value of 28.0 ± 28.3 for the single DMARD (combined MTX and BUC) group. The incidence of adverse reactions did not differ significantly between the three groups. It was concluded that the combination therapy with MTX and BUC showed significantly higher clinical efficacy than either of the single DMARD therapies.     

Efficacy of combination DMARD therapy vs. hydroxychloroquine monotherapy in chronic persistent chikungunya arthritis: a 24-week randomized controlled open label study

In a proportion of patients, chikungunya arthritis (CA) might run into a chronic persistent phase. The treatment for this phase is not very clear. In this randomized parallel group open label study of 24 weeks duration, we evaluated the efficacy of DMARD combination in persistent CA. Consecutive 139 patients with persistent CA (persistent arthritis for >1 year after the chikungunya fever either in 2008 or 2009 fulfilling epidemiological criteria for CA) were screened. Of these patients who were already taking hydroxychloroquine (HCQ) and had active arthritis were randomized to receive either fixed-dose combination therapy (methotrexate 15 mg/day, sulfasalazine 1 g/day, and HCQ 400 mg/day) or continue with HCQ 400 mg/day (dose optimized) monotherapy. Both groups received oral prednisolone up to 6 weeks. Assessments at every 4 weeks were carried out for primary efficacy (disease activity score; DAS ESR 28) and secondary efficacies, HAQ—Indian version and pain VAS100mm. Seventy-two patients were randomized (37 combination therapy, 35 monotherapy). Both groups were well matched in all respects. At 24 weeks, the combination therapy group showed significant improvement in both disease activity (mean ± SD DAS28; 3.39 ± 0.87 vs. 4.74 ± 0.65, p < 0.0001) and disability (mean ± SD HAQ; 1.4 ± 0.31 vs. 1.88 ± 0.47, p < 0.0001). At the study end, pain VAS was significantly less in the combination therapy group (46 ± 6.13 vs. 60.8 ± 11.6, p < 0.0001). Three patients withdrew from the combination group (inefficacy; 2, adverse event; 1) and seven from monotherapy (inefficacy; 7). This study provide evidence that for chronic persistent CA combination DMARD therapy with methotrexate, sulfasalazine and HCQ is superior to monotherapy with HCQ.     

Safety and efficacy profiles of tocilizumab monotherapy in Japanese patients with rheumatoid arthritis: meta-analysis of six initial trials and five long-term extensions

We present safety and efficacy data from Japanese clinical studies on monotherapy with tocilizumab (TCZ), a humanized anti-interleukin 6 receptor monoclonal antibody, in which 601 patients with moderate to severe rheumatoid arthritis, with a total of 2188 patient-years (pt-yr) exposure, were enrolled. The median treatment duration was 3.8 years. The incidence of adverse events (AEs), including abnormal laboratory test results, was calculated as 465.1 per 100 pt-yr. The most common serious adverse events (SAEs) were infections (6.22 per 100 pt-yr). There was no increase in the frequency of AEs or SAEs with long-term treatment. Abnormalities in the laboratory test results, such as increases in lipid parameters or abnormal liver function parameters, were common, but most were mild and there were no SAEs related to them. At baseline, 546 patients (90.8%) were taking corticosteroids; of these, 77.8% were able to decrease their corticosteroid dose during the study period, while 35.2% discontinued corticosteroids altogether. In the patients treated longer than 5 years, 91.3, 73.0, and 51.3% met the ACR20, ACR50, and ACR70 response criteria, respectively, and 59.7% met the DAS remission criterion (DAS28 <2.6) at 5 years. In conclusion, based on these results, TCZ has shown good tolerability and high efficacy during long-term treatment.