Long-term safety study of iguratimod in patients with rheumatoid arthritis

We conducted a 52-week clinical study of iguratimod in 394 Japanese patients with rheumatoid arthritis to evaluate the long-term safety of the drug. Iguratimod was administered orally at a daily dose of 25 mg for the first 4 weeks and 50 mg for the subsequent 48 weeks. Some of the patients continued the treatment for 100 weeks for their benefit. The cumulative incidence of adverse events for 100 weeks was 97.6%. The cumulative incidence of adverse reactions was 65.3%; unfavorable symptoms and signs (excluding abnormal laboratory data changes) accounted for 33.2% of the reactions, and abnormal laboratory data changes accounted for 50.4%. The continued treatment rate was 66.8% at week 28 and 53.6% at week 52. For reference, the American College of Rheumatology (ACR) 20 response rate was calculated for the patients who had assessable disease activity, who did not violate the study protocol, and who continued the study treatment at weeks 28 and 52. The rate was 46.9% at week 28 and 41.0% at week 52. To use iguratimod safely for a long time, patients should be observed closely for adverse reactions such as increased hepatic enzymes.     

Hepatitis B virus reactivation in patients with rheumatoid arthritis: A single-center study

Objectives: This study aimed to investigate the frequency of hepatitis B virus (HBV) reactivation in patients with rheumatoid arthritis (RA) and to verify the guidelines relating to HBV reactivation in Japan.

Methods: We retrospectively investigated 1351 RA patients who were treated with antirheumatic drugs at our hospital.

Results: Fifty patients (3.7%; 50/1351) were determined to be HBV carriers and 360 patients (26.7%; 360/1351) had resolved infections. HBV reactivation occurred in six cases (1.7%: 6/360) with resolved infections, of whom, two cases (0.6%; 2/360) developed de novo HBV infections. Eleven of the patients who were HBV carriers received a nucleoside analogue (NA) prophylactically. In all of the cases, the HBV-DNA levels became undetectable and the patients’ liver function normalized. Sixteen patients, who had lower titers of the HBV surface antigen and undetectable HBV-DNA levels, did not show HBV reactivation in the absence of NA therapy.

Conclusions: The results from this study suggest that HBV reactivation might not be so frequent among RA patients, and that reliable indicators for prescribing a NA should be clarified for RA patients.     

Long-term safety study of iguratimod in patients with rheumatoid arthritis

Abstract

We conducted a 52-week clinical study of iguratimod in 394 Japanese patients with rheumatoid arthritis to evaluate the long-term safety of the drug. Iguratimod was administered orally at a daily dose of 25?mg for the first 4 weeks and 50?mg for the subsequent 48 weeks. Some of the patients continued the treatment for 100 weeks for their benefit. The cumulative incidence of adverse events for 100 weeks was 97.6%. The cumulative incidence of adverse reactions was 65.3%; unfavorable symptoms and signs (excluding abnormal laboratory data changes) accounted for 33.2% of the reactions, and abnormal laboratory data changes accounted for 50.4%. The continued treatment rate was 66.8% at week 28 and 53.6% at week 52. For reference, the American College of Rheumatology (ACR) 20 response rate was calculated for the patients who had assessable disease activity, who did not violate the study protocol, and who continued the study treatment at weeks 28 and 52. The rate was 46.9% at week 28 and 41.0% at week 52. To use iguratimod safely for a long time, patients should be observed closely for adverse reactions such as increased hepatic enzymes.     

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.     

Efficacy of the clinical use of iguratimod therapy in patients with rheumatoid arthritis

Abstract

Objective. Iguratimod (IGU) is a new synthetic disease-modifying antirheumatic drug intended to treat patients with rheumatoid arthritis (RA). We conducted a 24-week study on the efficacy of IGU in RA patients with daily clinical use.

Methods. Forty-one patients were enrolled in this study, and the improvement in RA was evaluated every 4 weeks during the 24 weeks.

Results. The patient's global assessment of the disease activity with a scale (Pt VAS) was significantly decreased beginning at week 4. The disease activity score (DAS) 28-erythrocyte sedimentation rate, DAS28-C-reactive protein (CRP), simplified disease activity index and clinical disease activity index all significantly decreased at week 24. The matrix metalloproteinase-3 level was significantly decreased by the combination treatment with methotrexate at week 24. According to a logistic regression analysis, the factor which was most associated with the achievement of low disease activity (DAS28-CRP < 2.7) at week 24 was the DAS28-CRP at week 0.

Conclusions. IGU had significant clinical effects on the RA patients within 24 weeks. IGU might therefore represent a new practical choice to treat RA patients.     

A comparative study of the efficacy of Chinese herbal medicine Duhuo Jisheng decoction combined with DMARDs vs isolated DMARDs for rheumatoid arthritis: A protocol for systematic review and meta analysis

Background:Rheumatoid arthritis (RA) is a chronic autoimmune system disease that mainly affects joints throughout the body, causing joint pain, deformity, and even disability. The use of Chinese herbal medicine (CHM) to treat RA has achieved certain effects, and Duohuo Jisheng decoction (DHJSD) is one of them. But there is no high-level evidence to support this result. The purpose of this work is to evaluate the effectiveness of DHJSD combined with DMARDs compared with isolated DMARDs for RA.Methods:We will search articles in 7 electronic databases including Chinese National Knowledge Infrastructure (CNKI), Wanfang Data (WF), Chinese Scientific Journals Database (VIP), Chinese databases SinoMed (CBM), PubMed, Embase, and Cochrane Library databases. All the publications, with no time restrictions, will be searched without any restriction of language and status, the time from the establishment of the database to October 2020. Two reviewers will independently assess the quality of the selected studies, NoteExpress and Excel software will be used to extract data, and the content will be stored in an electronic chart. Different researchers will separately screen the titles and abstracts of records acquired potential eligibility which comes from the electronic databases. Full-text screening and data extraction will be conducted afterward independently. Statistical analysis will be conducted using RevMan 5.4 software.Results:This study will evaluate the efficacy and safety of DHJSD combined with DMARDs compared with isolated DMARDs in the treatment of Rheumatoid arthritis, to provide high-quality, evidence-based clinical recommendations.Conclusion:This study will provide reliable evidence on whether Duhuo Jisheng decoction combined with DMARDs compared with isolated DMARDs is more effective in treating RA.Trial registration number:INPLASY2020100089.     

Comparison of the efficacy and safety indicators of DMARDs for rheumatoid arthritis: A network meta-analysis

Objective:To compare efficacy and safety indicators of disease-modifying antirheumatic drugs, Sarilumab, Sirukumab, Baricitinib, Tocilizumab and Adalimumab in rheumatoid arthritis treatment by a network meta-analysis.Methods:Medline, Embase, Web of Science, The Food and Drug Administration web site, and Cochrane library were searched from build to June 1, 2020. Clinical randomized controlled trails of these 5 drugs for rheumatoid arthritis were collected for network meta-analysis.Results:A total of 4 randomized controlled trails with 2070 patients were obtained. The results of the network meta-analysis showed that:

• (1)There was no significant difference between the 4 drugs (Sarilumab, Sirukumab, Adalimumab, and Tocilizumab) (P > .05) in terms of American College of Rheumatology 20.
• (2)There was no significant difference between the 5 drugs in the aspect of the America College of Rheumatology 50% and 70% (American College of Rheumatology 50, American College of Rheumatology 70) (P > .05).
• (3)There was no significant difference between the 3 drugs (Sarilumab, Sirukumab, Adalimumab) in terms of reducing disease activity score 28-erythrocyte sedimentation rate in patients (P > .05).
• (4)No significant difference was observed among the 5 drugs in terms of incidence of adverse reactions, serious adverse reactions and withdrawal adverse reactions (P > .05).

The results of the ranked probability plot indicated that Tocilizumab and Sarilumab outperform other drugs in terms of efficacy and safety.Conclusion:The results of the ranking of the 5 drugs showed that Tocilizumab and Sarilumab had the best efficacy and safety.     

Efficacy at 52 weeks of daily clinical use of iguratimod in patients with rheumatoid arthritis

Abstract

Objective. In recent years, the use of one or more conventional synthetic disease-modifying antirheumatic drugs has been recommended for the treatment of rheumatoid arthritis (RA). We performed a 52-week study on the efficacy and safety of iguratimod (IGU) against patients with RA in daily clinical use.

Methods. Forty-one patients were enrolled in this study, and the clinical course of RA was regularly evaluated during the 52 weeks of treatment.

Results. The survival rate at week 52 was 53.7%. The disease activity score (DAS) 28-erythrocyte sedimentation rate, DAS28-C-reactive protein, simplified disease activity index, and clinical disease activity index were all significantly decreased at week 52. The matrix metalloproteinase-3 level was significantly decreased at week 52 by combination therapy of IGU and methotrexate. There were one case of the onset of interstitial pneumonia (IP), one exacerbation of IP, and one case of the onset of Pneumocystis jiroveci pneumonia.

Conclusions. IGU is effective for RA patients when used for daily clinical treatment for 52 weeks.     

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.     

Predictors of biologic discontinuation due to insufficient response in patients with rheumatoid arthritis who achieved clinical remission with biologic treatment: A multicenter observational cohort study

Objective: This study aimed to investigate predictors of biologic discontinuation due to insufficient response as a surrogate for relapse in patients with rheumatoid arthritis (RA) who achieved clinical remission with biologic treatment.

Methods: This study was performed based on data from a multicenter registry, and included 404 patients who achieved clinical remission within the first year of treatment with their first biologic. Cumulative retention rate of the first biologic was estimated using Kaplan–Meier curves, and the impact of patient characteristics on biologic discontinuation was assessed with Cox proportional hazards models.

Results: During follow-up, 50 patients discontinued their first biologic due to insufficient response. Overall discontinuation rates due to insufficient response after achieving remission were 6%, 11%, and 19% at 1, 2, and 5 years, respectively. Multivariate analysis revealed that concomitant glucocorticoids at achieving remission [hazard ratio (HR): 3.80, 95% confidence interval (CI): 1.89–7.64)] and a higher level of C-reactive protein (CRP) at achieving remission (HR: 1.47 per 1?mg/dL, 95% CI: 1.09–1.99) independently predict discontinuation due to insufficient response after achieving remission.

Conclusion: Patients with RA who achieved remission with concomitant glucocorticoid treatment and a higher level of CRP are at high risk of subsequent biologic discontinuation due to insufficient response.     

Radiographic progression of large joint damage in patients with rheumatoid arthritis treated with biological disease-modifying anti-rheumatic drugs

Objectives: Radiographic progression of damage to the small joints in patients with rheumatoid arthritis (RA) is well known; however, it has not been studied fully in the large joints. In this study, we looked at the prevalence of radiographic progression of large joint damage in patients with RA treated with biological disease-modifying anti-rheumatic drugs (bDMARDs).

Methods: A total of 273 large joints in the upper and lower extremities of 67 patients with RA treated with bDMARDs were investigated. Radiographs for tender and/or swollen large joints were taken at least twice during the study period (mean 18.6 months), and the progression of damage was evaluated.

Results: Progressive damage was found in 20.9% of patients and 6.2% of joints. A multivariate analysis revealed that the Larsen grade (LG) alone was a risk factor for progressive damage. The LG cutoff value was determined to be 2.5 (sensitivity: 0.529, specificity: 0.805).

Conclusions: The only factor to predict progressive damage was the LG of the joints with symptoms, and the damage must be stopped within LG II. Regular radiographic examinations for large joints should be performed in addition to routine examinations for small joints, such as the hand and foot.     

Efficacy and tolerability of six-week extended dosing interval with tocilizumab therapy in a prospective cohort as remission maintenance in patients with rheumatoid arthritis

Objectives: To prospectively evaluate the efficacy and tolerability of a six-week extended dosing interval with tocilizumab (TCZ) in patients with rheumatoid arthritis (RA) in sustained remission.

Methods: Patients who received over six doses of intravenous TCZ in clinical remission (disease activity score [DAS] 28 – erythrocyte sedimentation rate [ESR]?≤?2.6) maintained over 3 months between December 2013 and December 2015 were included. Flare was defined as DAS28-ESR >3.2 at two consecutive visits.

Results: Twenty-five patients were enrolled; 87.5% achieved clinical remission at week 54 after six-week extension and 95.5% achieved a van der Heijde modified total Sharp score (ΔmTSS) ≤0.5. The Health Assessment Questionnaire Disability Index (HAQ-DI) did not increase during 54 weeks. HAQ-DI at baseline and ΔDAS28-ESR at week six positively correlated with increase in DAS28-ESR at week 54. ΔSwollen joint count at week six positively correlated with ΔmTSS at week 54. A total of 12 adverse events occurring in 10 patients did not lead to cessation of TCZ except for one case of recurrent lymphoproliferative disorder at week five.

Conclusion: A six-week extended dosing interval of TCZ for patients with RA in sustained remission is proposed as an acceptable treatment option for maintaining efficacy and tolerability.     

Synovial inflammation analyzed by 3-T magnetic resonance imaging in etanercept-treated patients with rheumatoid arthritis indicates persistent disease activity despite of clinical remission: A pilot study

Abstract

Objectives: To evaluate joint inflammation using 3-T MRI in rheumatoid arthritis (RA) patients treated with conventional disease modifying anti-rheumatic drugs (cDMARDs) as compared to inhibitors for tumor necrosis factor α (TNFi) over 12 months.

Methods: Prospective epidemiologic clinical pilot study using the RA MRI system (RAMRIS), the visual analog scale (VAS, 0–100) and the Disease Activity Score 28-joint count (DAS28) at baseline, 4, and 12 months after initiation of etanercept (ETA). Ten patients with inadequate response to two cDMARDs were treated with ETA and compared to 10 patients responding to cDMARDs.

Results: In cDMARD patients, parameters at baseline and 12 months did not change: VAS: 21.0?±?11.3 and 20.2?±?24.6; DAS28: 2.1?±?0.6 and 2.9?±?1.0; and RAMRIS: 11.0?±?2.3 and 11.8?±?2.8, respectively. In contrast, in the ETA-patients the same parameters were as follows at baseline, 4, and 12 months: VAS: 46.3?±?7.9, 23.9?±?7.1, and 24.0?±?6.3 (each p?=?.04); DAS28: 3.8?±?0.4, 2.8?±?0.3 (ns), and 2.5?±?0.3 (p?=?.01); and RAMRIS: 28.9?±?5.0, 25.8?±?4.7 (ns), and 24.6?±?4.5 (ns). Comparing ETA and cDMARD patients, RAMRIS was significantly different.

Conclusion: The data suggest that synovial inflammation and DAS28 remission are separate entities in RA. MRI scoring before starting a treatment may therefore indicate the requirement for TNFi.     

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.     

Managing comorbidity in patients with rheumatoid arthritis

Rheumatoid arthritis (RA) is a chronic inflammatory disease that decreases physical function and imposes substantial medical costs. Comorbid conditions are common in patients with RA and they adversely affect quality of life and RA‐related outcomes such as work disability and mortality. Rheumatologists have the important responsibility to consider comorbidities and their risks when treating patients and to adapt therapies to the specific situation of individual patients. This paper discusses the common comorbidities in patients with RA and management approaches.