Efficacy and safety of infliximab: A comparison with other biological disease-modifying anti-rheumatic drugs

Objectives: The intensification of infliximab (IFX) treatment, involving escalation of the dose and shortening of interval, was approved in Japan in July 2009. We consider IFX intensification therapy to be preferable for patients with treatment-resistant active rheumatoid arthritis (RA). We retrospectively compared the efficacy of IFX with that of other bDMARDs in methotrexate (MTX)-resistant patients.

Methods: Patients who satisfied the following criteria were enrolled: (i) those who started bDMARDs between February 2011 and December 2016, and (ii) those who required bDMARDs after 180 d of MTX treatment. We compared 33 patients who had been treated with IFX (IFX group) and 146 who had received other bDMARDs treatment (non-IFX group).

Results: IFX was administered at a dose of 6.98?mg/kg/8-week equivalent at 52 weeks. Clinical disease activity index clinical remission (CDAI-CR) was achieved in 49 of the 179 patients at 52 weeks and 13 of these 49 patients received IFX. Logistic regression analysis showed that treatment with IFX was an important variable for the achievement of CDAI-CR at 52 weeks (odds ratio 2.69, 95% confidence interval 1.13–6.42). The severity and frequency of adverse events did not differ.

Conclusion: Intensification of IFX was effective and well tolerated for MTX resistant patients.     

Ultrasound disease activity of bilateral wrist and finger joints at three months reflects the clinical response at six months of patients with rheumatoid arthritis treated with biologic disease-modifying anti-rheumatic drugs

Objective: We evaluated whether the early responsiveness of ultrasound synovitis can predict the clinical response in rheumatoid arthritis (RA) patients treated with biologic disease-modifying anti-rheumatic drugs (bDMARDs).

Methods: Articular synovitis was assessed by ultrasound at 22 bilateral wrist and finger joints in 39 RA patients treated with bDMARDs. Each joint was assigned a gray-scale (GS) and power Doppler (PD) score from 0 to 3, and the sum of the GS or PD scores was considered to represent the ultrasound disease activity. We investigated the correlation of the change in ultrasound disease activity at three months with the EULAR response criteria at six months.

Results: GS and PD scores were significantly decreased at three months (p?p?Conclusions: The responsiveness of ultrasound disease activity is considered to predict further clinical response in RA patients treated with bDMARDs.     

Reduction of methotrexate and glucocorticoids use after the introduction of biological disease-modifying anti-rheumatic drugs in patients with rheumatoid arthritis in daily practice based on the IORRA cohort

Objectives: To evaluate usage patterns for methotrexate (MTX) and/or glucocorticoids in rheumatoid arthritis (RA) patients receiving biological disease-modifying antirheumatic drugs (bDMARDs) in daily practice.

Methods: Data from RA patients who commenced treatment with bDMARDs (infliximab [IFX], etanercept [ETN], tocilizumab [TCZ], or adalimumab [ADA]) from 2008 to 2010 were extracted from the Institute of Rheumatology, Rheumatoid Arthritis (IORRA) database. The proportions of patients taking concomitant MTX and glucocorticoids and doses of these medications were evaluated before and 2 years after initiation of each bDMARD.

Results: A total of 470 RA patients who had initiated a bDMARD (IFX: n?=?98, ETN: n?=?181, TCZ: n?=?90, and ADA: n?=?101) were evaluated. The proportion of patients taking MTX decreased over time among ETN and TCZ users, while it increased among ADA users. The MTX dose decreased over time among IFX, ETN, and TCZ users, but not among ADA users. Although the rate of glucocorticoid use and dose decreased after bDMARD initiation in all four bDMARD groups, approximately 50% of patients continued to receive glucocorticoids 2 years after bDMARD initiation.

Conclusion: MTX and glucocorticoid use and doses in daily practice were commonly reduced after the initiation of bDMARDs, with the dose adjustment varied depending on the bDMARD.     

Australian recommendations on perioperative use of disease-modifying anti-rheumatic drugs in people with inflammatory arthritis undergoing elective surgery

Disease-modifying anti-rheumatic drugs (DMARDs) are effective treatments for inflammatory arthritis but carry an increased risk of infection. For patients undergoing surgery, there is a need to consider the trade-off between a theoretical increased risk of infection with continuation of DMARDs perioperatively versus an increased risk of disease flare if they are temporarily withheld. We used the Grading of Recommendations Assessment, Development and Evaluation methodology to develop recommendations for perioperative use of DMARDs for people with inflammatory arthritis undergoing elective surgery. The recommendations form part of the National Health and Medical Research Council-endorsed Australian Living Guideline for the Pharmacological Management of Inflammatory Arthritis. Conditional recommendations were made against routinely discontinuing conventional synthetic and biologic (b) DMARDs in the perioperative period but to consider temporary discontinuation of bDMARDs in individuals with a high risk of infection or where the impact of infection would be severe. A conditional recommendation was made in favour of temporary discontinuation of targeted synthetic DMARDs in the perioperative period.     

Health assessment questionnaire-disability index (HAQ-DI) score at the start of biological disease-modifying antirheumatic drug (bDMARD) therapy is associated with radiographic progression of large joint damage in patients with rheumatoid arthritis

Objectives: Radiographic progression of damage (RPD) to large joints in patients with rheumatoid arthritis (RA) has not been fully studied. We previously demonstrated that Larsen grade of the large joints was associated with RPD of large joints in patients treated with biological disease-modifying anti-rheumatic drugs (bDMARDs); however, no factors associated with background characteristics of patients were identified.

Methods: A total of 400 large joints in the upper and lower extremities, including the shoulder, elbow, knee, and ankle, of 88 patients with RA treated with bDMARDs for 1–3 years were investigated. Radiographs of tender and/or swollen large joints were acquired at least twice during the study period (mean, 16.4 months), and the RPD was evaluated.

Results: A multivariate analysis revealed that health assessment questionnaire-disability index (HAQ-DI) score at the start of bDMARD treatment was associated with RPD. The cutoff value that discriminated progression from non-progression, determined by a receiver operating characteristic (ROC) curve, was 1.4375 (sensitivity: 0.778, specificity: 0.894).

Conclusions: HAQ-DI score at the start of bDMARD treatment was associated with RPD to large joints during a therapeutic period of 1–3 years. Progressive damage is expected to increase when functional disability exceeds an HAQ-DI score of 1.5.     

Risk for malignancy in rheumatoid arthritis patients treated with biological disease-modifying antirheumatic drugs compared to the general population: A nationwide cohort study in Japan

Objectives: To investigate and compare the risk for malignancy in rheumatoid arthritis (RA) patients treated with biologics in Japan to the general population.

Methods: Data for 14,440 patients from 335 institutions who were given infliximab, etanercept, adalimumab, golimumab, tocilizumab, or abatacept were retrieved from the SafEty of biologics in Clinical Use in Japanese patients with RhEumatoid arthritis (SECURE) database.

Results: We identified 333 incidents of malignancies in 320 patients during 49,320 patient-years (PY). The age- and sex-standardized incidence rate (ASR) (95% confidence interval [CI]) for overall malignancy of the SECURE cohort was 313.9/10⁵ PY (271.4–361.3), and the standardized incidence rate ratio (SIR) (95% CI) was 0.745 (0.667–0.826). The ASR was decreased compared to the estimated incidence rate of malignancies in the Japanese general population (462.4/10⁵ PY). The SIRs for site-specific nonhematopoietic malignancies of the SECURE cohort were not significantly elevated compared to the Japanese general population. A significant increase of SIR for malignant lymphoma (6.183, 95% CI, 4.809–7.643) was found in the SECURE cohort, similar to or slightly higher than the SIR previously reported from Japanese cohorts for RA patients.

Conclusions: Continued vigilance with larger numbers of patients, longer observation periods, and inclusion of different biologics are recommended.     

Prevalence and factors associated with sarcopenia in patients with rheumatoid arthritis

Abstract

Objectives: Sarcopenia is characterized by loss of muscle strength and mass, leading to falls and adverse health outcomes. Our aim was to determine the prevalence of sarcopenia in patients with rheumatoid arthritis (RA) and to identify factors associated with sarcopenia in these patients.

Methods: A cross-sectional study of 388 consecutive women with RA was conducted, assessing muscle mass and strength, and walking speed. Falls and bone fractures sustained over the prior year were evaluated. The association between sarcopenia and RA characteristics, falls, and bone fractures was evaluated using logistic regression analyses.

Results: The prevalence of sarcopenia was 37.1% (14.7%, severe sarcopenia; 22.4%, sarcopenia), with 49.0% classified as having low muscle mass. The incidence of falls, fractures, and lower bone mineral density was higher in patients with than without sarcopenia. Age, RA duration, Steinbrocker’s stage, the high Mini-Nutritional Assessment-Short Form score and the use of biological disease-modifying anti-rheumatic drugs (bDMARDs) were independent factors associated with sarcopenia.

Conclusion: We confirmed that sarcopenia develops in a significant proportion of patients with RA. Age, longer disease duration, joint destruction and malnutrition were positively associated with sarcopenia, with the use of bDMARDs being negatively associated.     

Joint damage in rheumatoid arthritis: radiological assessments and the effects of anti-rheumatic drugs

Summary Joint damage is a major problem in the long-term course of rheumatoid arthritis. It is usually assessed radiologically. In this review the methods of measuring the radiological changes are outlined, and the effects of anti-rheumatic drugs on radiological progression summarised. Two methods of scoring radiographs have become standard techniques; these are the Sharp index and the Larsen index. They both concentrate on cartilage loss and erosive damage in the hands and wrists. Investigations of the effects of drugs upon the radiological progression of rheumatoid arthritis include: indirect studies evaluating the inter-relationships between clinical, laboratory and radiological variables; placebo-controlled studies of slow-acting drugs and similarly controlled studies without a placebo group; open studies evaluating the long-term effects of treatment of slow-acting drugs. Only slow-acting drugs such as gold have been persistently considered to have a possible effect on reducing radiological progression. Unfortunately the therapeutic studies use a wide range of different radiological assessment techniques, and the incomparability is therefore difficult. None of the studies give a good indication that there is a marked reduction in joint damage by slow-acting drugs. On balance studies do suggest minor effects on the process of progression. Instead of debating how strong the evidence of such minor effect really is, it is concluded that rheumatologists should look towards novel therapeutic approaches to induce a major reduction in the rate of damage.     

A combination of biochemical markers of cartilage and bone turnover, radiographic damage and body mass index to predict the progression of joint destruction in patients with rheumatoid arthritis treated with disease-modifying anti-rheumatic drugs

The aim of this study was to evaluate the predictive value of biological, radiological and clinical parameters for the progression of radiographic joint damage in rheumatoid arthritis (RA) patients treated with conventional disease-modifying anti-rheumatic drugs (DMARDs). We analyzed the 145 patients with active RA for less than 5 years who were participating in the prospective 1-year randomized controlled trial of tocilizumab (SAMURAI trial) as a control arm treated with conventional DMARDs. Progression of joint damage was assessed by sequential radiographs read by two independent blinded X-ray readers and scored for bone erosion and joint space narrowing (JSN) using the van der Heijde-modified Sharp method. Multivariate analysis revealed that increased urinary levels of C-terminal crosslinked telopeptide of type II collagen (U-CTX-II), an increased urinary total pyridinoline/total deoxypyridinoline (U-PYD/DPD) ratio and low body mass index (BMI) at baseline were independently associated with a higher risk for progression of bone erosion. In addition to these three variables, the JSN score at baseline was also significantly associated with an increased risk of progression of the JSN score and total Sharp score. High baseline U-CTX-II levels, U-PYD/DPD ratio and JSN score and a low BMI are independent predictive markers for the radiographically evident joint damage in patients with RA treated with conventional DMARDs.     

Effect of early treatment with disease-modifying anti-rheumatic drugs and treatment adherence on disease outcome in rheumatoid arthritis patients

Aim of the work

To evaluate the effects of early and regular treatment with Disease Modifying Anti-Rheumatic Drugs (DMARDs) on disease outcome in rheumatoid arthritis (RA) patients and factors affecting adherence to treatment.

Articular damage in late rheumatoid arthritis

This study aims to examine the long-term articular damage in rheumatoid arthritis (RA) patients according to rheumatoid arthritis articular damage (RAAD) score and to evaluate the parameters correlated with this score. The RAAD score was assessed in 85 RA patients who had the disease for more than 10 years. Patients were divided into three groups according to duration of the disease: group 1, 10–14 years; group 2, 15–19 years; and group 3, more than 20 years. Patients were also divided into three groups according to the time of initiation of treatment with disease-modifying antirheumatic drugs: group A, within the first 2 years, group B, between 2 and 5 years; and group C, after 5 years. We investigated the RAAD score relationship between groups 1, 2, 3; groups A, B, C; sex; drug compliance; age of onset of the disease; and Health Assessment Questionnaire (HAQ). We observed significant differences in RAAD scores according to groups 1, 2, 3 (p<0.01), but not to groups A, B, C; sex; or drug compliance (p>0.05). While the RAAD score correlated well with the HAQ (r=0.560, p<0.001), it did not correlate with the age at onset of the disease (p>0.05). As RA is not a benign disease and articular damage progresses over time, the goal of RA therapy must be to maintain a response before the onset of irreversible damage and loss of function.     

Radiographic repair in three Japanese patients with rheumatoid arthritis treated with bucillamine

Abstract

Bucillamine (Bc) is a cysteine derivative with two SH groups, and a homolog of d-penicillamine, a disease-modifying antirheumatic drug (DMARD) widely used in Japan. However, it remains unclear whether Bc repairs bone erosion in patients with RA. Here, we treated three RA patients with Bc who subsequently showed radiographic repair of erosions and cysts.     

Discontinuation of adalimumab treatment in rheumatoid arthritis patients after achieving low disease activity

Abstract

Objective We implemented a retrospective study to explore discontinuation of therapy with adalimumab (ADA) without exacerbation in rheumatoid arthritis (RA) patients who had achieved low disease activity (LDA) with the biological agent.

Methods We enrolled 46 RA patients who had completed open extension of a double-blind, placebo-controlled trial of ADA monotherapy in Japan and who had LDA (DAS28-CRP <2.7) at the last administration of ADA in the extension trials; this date was defined as week 0 in the present study. Treatment of RA was at the discretion of the attending physician after week 0. The primary endpoint of this study was the percentage of patients who maintained discontinuation of biological agents and LDA for 52 weeks.

Results Twenty-four of the enrolled patients continued ADA while the rest discontinued ADA after the administration of the drug at week 0. Fourteen of the 22 patients did not restart biological agents, and 4 (18.2%) of these maintained LDA through week 52. All 4 of these patients had received ADA monotherapy before week 0.

Conclusion Some RA patients who have achieved LDA with ADA monotherapy can discontinue the biologic without incurring increased disease activity. A prospective randomized study is required to confirm the results of our study.     

A survey of United States rheumatologists concerning effectiveness of disease-modifying antirheumatic drugs and prednisone in the treatment of rheumatoid arthritis

Objective . To collect the ratings of American rheumatologists regarding relative short-term and long-term effectiveness of disease-modifying anti-rheumatic drug (DMARD) therapy in the treatment of rheumatoid arthritis and to compare these data with results of a meta-analysis of randomized, controlled clinical trials (RCTs) of these drugs. Methods . A survey was mailed to 3,200 United States rheumatologists who were members of the American College of Rheumatology during the summer of 1996. The survey was completed by 645 rheumatologists. Results . Methotrexate (MTX) was rated as substantially more effective than any other DMARD after both 1 year and 4 years of therapy. At 1 year, more than 90% of rheumatologists rated MTX as “good or excellent,” compared with 35% giving a similar rating to intramuscular (IM) gold, the second-ranked DMARD. At 4 years, MTX was rated as “good or excellent” by 65%, compared with 53% for combinations, 30% for prednisone, and 11% for hydroxychloroquine, the second-ranked single DMARD. These ratings reflect results of long-term observational studies, but differ considerably from a meta-analysis of results of short-term RCTs, in which the efficacy of MTX, sulfasalazine, penicillamine, and IM gold were indistinguishable. Conclusion . The ratings of US rheumatologists regarding effectiveness of DMARD therapies are in agreement with observational data, but differ substantially from results of RCTs. These findings suggest that observational studies may yield useful and important information about treatment results, which are complementary to, but not available from, the RCT model. Regulatory agencies should consider long-term observational studies as a part of the evaluation of drugs.     

Reliability of the rheumatoid arthritis articular damage score in Tunisian patients

The clinical rheumatoid arthritis articular damage (RAAD) score is easy to perform and showed good intraobserver reliability. It correlates well with the Larsen score and disease duration and can be recommended for rheumatoid arthritis patients follow-up in developing countries.     

Efficacy and safety of sirukumab in Japanese patients with moderate to severe rheumatoid arthritis inadequately controlled by disease modifying anti-rheumatic drugs: Subgroup analysis of a phase 3 study

Abstract

Objective: To evaluate the efficacy and safety of sirukumab in Japanese patients with active rheumatoid arthritis (RA) uncontrolled by disease-modifying antirheumatic drugs.

Methods: This subgroup analysis based on a double-blind, placebo-controlled, 52-week phase 3 study (SIRROUND-D) assessed American College of Rheumatology (ACR) 20 response at week 16 and van der Heijde-modified Sharp score (vdH-S) at week 52 (coprimary endpoints).

Results: A total of 168 (Japanese)/1670 patients received sirukumab 50?mg/4 weeks (q4w, n?=?58), 100?mg/every 2 weeks (q2w, n?=?54), or placebo (n?=?56) subcutaneously. Significantly more patients achieved ACR20 response at week 16 with sirukumab (50?mg q4w: 69.0%; 100mg q2w: 66.7%) vs. placebo (21.4%; p?<?.001). Median change from baseline in total vdH-S score at week 52 was significantly lower with sirukumab (50?mg q4w: 0.3, p?=?.024; 100?mg q2w: 0.0, p?=?.002) vs. placebo (1.3). Sirukumab consistently showed greater improvements in secondary endpoints at weeks 24 and 52. Nasopharyngitis, elevated liver enzymes, injection site erythema and upper respiratory tract infections were the common treatment-emergent adverse events (TEAEs). Incidences of TEAEs and serious AEs were consistent between sirukumab groups through week 52.

Conclusion: Sirukumab showed clinically meaningful improvements consistent with significant improvements in the global study. No new safety signals were observed.     

Radiographic progression in weight-bearing joints of patients with rheumatoid arthritis after TNF-blocking therapies

The aim of the present study was to assess the influence of tumor necrosis factor (TNF)-blocking therapies on weight-bearing joints in patients with rheumatoid arthritis. Changes in clinical variables and radiological findings in 213 weight-bearing joints (69 hip joints, 63 knee joints, and 81 ankle joints) of 42 consecutive patients were investigated at baseline and at 1 year of TNF-blocking therapies. Structural damage to the weight-bearing joints was assessed using the Larsen scoring method. Detailed comparisons of the sizes and locations of erosions were performed for each set of radiographs of the respective joints. Assessment of radiographs of the 213 weight-bearing joints indicated progression of the Larsen grade in eight joints. Another five joints without Larsen grade progression showed apparent radiographic progression of joint damage based on increases in bony erosions. Overall, 13 joints (6%) of eight patients (19%) showed progression of joint damage after 1 year of TNF-blocking therapies. Analysis of each baseline grade indicated that radiographic progression of joint damage was inhibited in most grade 0–II joints. On the other hand, all hip and knee joints with pre-existing damage of grade III/IV showed apparent progression even in patients with good response. The results further suggested that radiographic progression may occur in less damaged joints when the patients were non-responders to the therapy. Among the weight-bearing joints, ankle joints showed different radiographic behavior and four ankle joints displayed improvement of radiographic damage. Early initiation of anti-TNF therapy should be necessary especially when the patients are starting to show early structural damage in weight-bearing joints.