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Supplementary Information The online version contains supplementary material available at https://doi.org/10.1007/s40744-024-00673-2.Correction to: Rheumatol Ther (2023) 10:1683–1703https://doi.org/10.1007/s40744-023-00605-6A video abstract is now available for this publication. The video abstract can also be accessed on the article's Figshare page here: https://doi.org/10.6084/m9.figshare.25526137.Graph: Video Abstract (MP4 81029 kb)By Hideto Kameda; Kohei Hagimori; Yoji Morisaki; Thorsten Holzkämper; Ayako Konomi and Hiroaki DobashiReported by Author; Author; Author; Author; Author; Author [Extracted from the article]

Objectives. To explore the effectiveness and safety of tocilizumab (TCZ) with or without methotrexate (MTX) in active rheumatoid arthritis (RA) patients showing inadequate responses to DMARDs and/or TNF inhibitors in clinical practice. Methods. We observed consecutive 115 RA patients initiating TCZ treatment in Keio University Hospital, dividing them into two groups with (TCZ + MTX group) or without MTX (TCZ group), and evaluated clinical, functional and structural outcomes besides safety at week 52. Results. Overall mean age, RA duration, and DAS28-ESR were 55.4, 8.4 years, and 5.0, respectively. Proportions of the prior use of TNF inhibitors and concomitant MTX were 45.5% and 57.4%, respectively. Mean dose of concomitant MTX was 8.4 mg/week. Baseline characteristics were comparable between the groups. TCZ improved disease activity measured by DAS28-ESR to 2.1 at week 52 overall, without significant difference between the groups. Clinical (DAS28-ESR < 2.6), functional (HAQ-DI ≤ 0.5), and structural (ΔTSS ≤ 0.5) remission rates in the TCZ group and the TCZ + MTX group were 79.1%/63.8% ( P = 0.10), 62.8%/54.4% ( P = 0.40), and 70.0%/53.8% ( P = 0.61), respectively. Retention rates were 81.0% in the TCZ + MTX group and 88.5% in the TCZ group ( P = 0.47). The rate of serious adverse events was comparable between the groups. Conclusions. TCZ was clinically, functionally, and radiographically effective and safe either with or without low-dose MTX. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objective: The associations between elevated levels of serum Krebs von den Lungen-6 (KL-6) and treatment of rheumatoid arthritis (RA) with tumor necrosis factor (TNF) inhibitors were investigated in five Japanese clinical trials. Methods: Percentages and incidence rates were calculated for elevated serum KL-6 levels. Adverse events associated with elevated levels of serum KL-6 were investigated. Results: In RISING, a clinical trial for infliximab, 15.6 % of the enrolled patients met criterion B (KL-6 ≥500 U/ml and >1.5-fold increase over the baseline value) by week 54. In HIKARI, 7.8 % of the certolizumab pegol (CZP) group and 0 % of the placebo group met criterion B during the double-blind (DB) period ( p = 0.003). In J-RAPID, 8.4 % of the methotrexate (MTX) + CZP and 3.9 % of the MTX + placebo groups met criterion B during the DB period. In GO-MONO, 1.8 % of the golimumab (GLM) and 1.3 % of the placebo groups met criterion B during the DB period. In GO-FORTH, 7.1 % of the MTX + GLM and 0 % of the MTX + placebo groups met criteron B during the DB period ( p = 0.017). No adverse events accompanied the elevation of serum KL-6 levels in 95.7 % of these patients. Conclusion: Serum KL-6 levels may increase during anti-TNF therapy without significant clinical events. In these patients, continuing treatment with TNF inhibitors under careful observation is a reasonable option. [ABSTRACT FROM AUTHOR]

Objective: We investigated associations between treatment with methotrexate (MTX) or biological disease-modifying antirheumatic drugs (DMARDs) and elevation of serum Krebs von den Lungen-6 (KL-6) levels in Japanese patients with rheumatoid arthritis (RA). Methods: Using a standardized form, data were collected retrospectively from medical records and analyzed descriptively. Results: Of a total of 198 RA patients with KL-6 serum levels measured at initiation of treatment (month 0) and two or more times by month 12, 27 (17.9 %) of 151 RA patients treated with biological DMARDs, including infliximab, etanercept, adalimumab, and tocilizumab (the biological DMARDs group), and 5 (10.6 %) of 47 patients treated without biological DMARDs but with MTX (MTX group), met criterion B (max. KL-6 ≥500 U/ml and >1.5-fold from baseline) by 12 months. The majority of patients ( n = 28) meeting criterion B had no apparent interstitial lung disease or malignancy. Of these 28 patients, 21 had serum KL-6 levels available after reaching their maximum level, and 13 (61.9 %) of the 21 then met criterion R [decrease to less than 500 U/ml or to less than (baseline + 0.5 × (maximum − baseline))] by month 12. Conclusion: Serum KL-6 levels may increase during treatment with MTX or these biological DMARDs without significant clinical events. [ABSTRACT FROM AUTHOR]

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

The unique genetic, environmental and medical backgrounds of people in Japan might influence the effectiveness and safety of biologic agents in patients with rheumatoid arthritis (RA). Indeed, clinical trials revealed higher response rates to some biologic agents (including infliximab, etanercept and tocilizumab) in patients with RA in Japan than patients treated with the same agents in Western countries, although response rates to adalimumab were comparable in both populations. The reasons why response rates to some biologic agents differ in Japanese individuals is currently under investigation. Post-marketing surveillance data have been collected for all patients with RA who were treated with biologic agents in Japan to monitor drug safety. These data clearly demonstrated that only ∼5% of these patients experienced adverse drug reactions to biologic agents, which were well tolerated. Pneumonia, tuberculosis, Pneumocystis jirovecii pneumonia and interstitial pneumonitis are considered important severe adverse reactions and risk factors for these adverse effects have been identified. Adverse drug reactions could exaggerate the risks associated with biologic therapy in Japanese patients with RA. Attempts have, therefore, been made to predict clinical response and adverse effects to enable personalized therapy with biologic agents and to optimize the outcomes of these patients. [ABSTRACT FROM AUTHOR]

We evaluated the efficacy and safety of low-dose cyclosporine A (CsA) in patients with refractory lupus nephritis. Nine patients with systemic lupus erythematosus who had lupus nephritis resistant to previous treatment with glucocorticoids and immunosuppressants other than CsA were enrolled in a prospective, open-label study. All patients initially received 2.5 mg/kg per day of CsA; the dosage was adjusted to reach a blood trough level of 80–150 ng/ml. The urinary protein concentration decreased significantly 2 weeks after the initiation of treatment. After 30 weeks of CsA treatment, the mean urinary protein concentration was more than 50% lower than the baseline value, and urinary casts had decreased significantly. There were no significant changes in the levels of serum creatinine, serum anti-double-stranded DNA antibodies, or CH50 during any part of the study. The dose of glucocorticoids was significantly tapered by approximately 50%, without any disease flare. Hypertension developed in one patient, but was controlled with antihypertensive agents. Our results suggest that low-dose CsA therapy is an effective and less toxic alternative to conventional cyclophosphamide therapy for the management of refractory lupus nephritis. [ABSTRACT FROM AUTHOR]

The parameters involved in the Disease Activity Score of 28 joints (DAS28) are not mutually independent, and the evaluation excludes ankle and foot joints. We developed a new quantitative and comprehensive assessment of the activity of rheumatoid arthritis (RA), called the handy rheumatoid activity score, with 38 joints (HRAS38), to overcome these disadvantages of DAS28. Forty-six RA patients who recently completed a 1-year infliximab therapy were evaluated for DAS28 (C-reactive protein; CRP) and HRAS38 at 0, 2, 6, 14, 22, 30, 38, 46, and 54 weeks. The 38-joint evaluation in HRAS38 includes 28 joints of DAS28 except for the shoulder joints, with the addition of ankle and metatarsophalangeal joints. The extent of joint swelling was rated on a scale of 0–3. The HRAS38 score is the cumulative sum of three parameters including: (1) a global assessment of disease activity [visual analog scale (VAS) 0–100 mm] by the patient, (2) swollen joint score based on a 38-joint assessment by a physician (0–114), and (3) serum concentration of CRP (mg/l). Scatter plots of HRAS38 and DAS28(CRP), and subsequent linear regression analysis demonstrated a statistically significant correlation between methodologies ( r = 0.846, P < 0.0001). Infliximab treatment resulted in a statistically significant ( P < 0.001) decrease in the mean HRAS38 score from 130.5 to 56.5 within 2 weeks of treatment and at 52 weeks of therapy scores were still reduced at 52.5. The mean DAS28(CRP) was also significantly ( P < 0.001) reduced from a baseline value of 5.8 to 3.7 after 2 weeks treatment with a final value of 3.2 after 52 weeks of therapy. Infliximab reduced the progression of joint destruction by 85%, for terms before infliximab as determined by radiographic analyses. The degree of progression appeared to be associated with the mean HRAS38, although this observation was not shown to be statistically significant by regression analysis ( r = 0.307). The HRAS38 score comprises minimal and independently acquired parameters and is an effective and comprehensive measure of disease activity in RA patients. [ABSTRACT FROM AUTHOR]

Methotrexate (MTX) is the most commonly used disease-modifying antirheumatic drug (DMARD) throughout the world. In Japan, MTX is recommended by the Japanese Ministry of Health, Labour, and Welfare to be given as the second or third DMARD and at a dosage of no more than 8?mg/week. We analyzed the efficacy of MTX in Japanese patients with RA in order to determine whether it is comparable to that in Western countries, where 15-20?mg/week of MTX is used, as well as to elucidate the factors associated with the favorable response to MTX. Around 8?mg/week of MTX was effective in half of the RA patients in the current study, and male sex was the only factor associated with a good response to MTX from a multivariate regression model analysis. Some of the patients who had a poor response to MTX showed an improvement with the addition of bucillamine or prednisolone. For the remaining patients, an increase in the MTX dosage to more than 8?mg/week or the use of biologics such as the anti-tumor necrosis factor (TNF)-a monoclonal antibody may be required. [ABSTRACT FROM AUTHOR]

Abstract: Introduction of biologics, such as infliximab, to the therapy of rheumatoid arthritis (RA) patients has revolutionized the treatment of this disease. However, biomarkers for predicting the efficacy of the drug at an early phase of treatment for selecting real responders have not been found. We here present predictive markers based on a thorough transcriptome analysis of white blood cells from RA patients. RNA from whole blood cells of consecutive 42 patients before the first infusion was analyzed with microarrays for training studies. Samples from the subsequent 26 consecutive patients were used for a prospective study. We categorized the results into no inflammation and residual inflammation groups using the serum C-reactive protein (CRP) level at 14weeks after the first infusion. The accuracy of prediction in our study was 65.4%. [Copyright &y& Elsevier]