Anti-survival motor neuron complex antibodies as a novel biomarker for pulmonary arterial hypertension and interstitial lung disease in mixed connective tissue disease.

OBJECTIVE: The presence of anti-U1 RNP antibodies (Abs) is critical for diagnosing MCTD. The aim of this study is to evaluate the clinical relevance of anti-survival motor neuron (SMN) complex Abs, which often coexist with anti-U1 RNP Abs. METHODS: A total of 158 newly diagnosed consecutive cases of SLE, SSc or MCTD with anti-U1 RNP Abs were enrolled in this multicentre observational study between April 2014 and August 2022. Serum anti-SMN complex Abs were screened by immunoprecipitation of 35S-methionine-labelled cell extracts, and associations between anti-SMN complex Abs positivity and clinical characteristics were analysed. RESULTS: Anti-SMN complex Abs were detected in 36% of MCTD patients, which was significantly higher than that in SLE (8%) or SSc (12%). Among MCTD patients classified based on the combination of the clinical features of SLE, SSc and idiopathic inflammatory myopathies, anti-SMN complex Abs showed the highest prevalence in a subset with clinical features of all three components. Anti-SMN complex Abs-positive MCTD had a higher prevalence of pulmonary arterial hypertension (PAH) and interstitial lung disease (ILD), which are related to poor prognosis, than negative patients. Moreover, all three cases of death within 1 year of the treatment were positive for anti-SMN complex Abs. CONCLUSIONS: Anti-SMN complex Abs is the first biomarker of a typical subset of MCTD which bears organ damages such as PAH and ILD.

Comparison of anti-IL-6 receptor and JAK inhibitors in patients with rheumatoid arthritis from the real-world practice FIRST study.

OBJECTIVES: A molecular-targeted drug that is suitable as the second choice for patients with rheumatoid arthritis (RA) who show an inadequate response to the first biological disease-modifying antirheumatic drug (bDMARD) is unknown. This study aimed to analyze the efficacy and safety of interleukin-6 receptor (IL-6Ri) and Janus kinase inhibitors (JAKis), often selected as molecular-targeted drugs for second or subsequent treatments. METHODS: The efficacy and safety of JAKis and IL-6Ri were compared using propensity score-based inverse probability of treatment weighting (PS-IPTW) using propensity scores after 26 weeks of therapy in patients with RA. RESULTS: The remission rate at week 26, determined by the clinical disease activity index (CDAI), and the incidence of infection were higher in the JAKis than in the IL-6Ri group. The CDAI trajectories were divided into four according to the growth mixture modeling. IL-6Ri demonstrated greater efficacy in RA patients with ineffective to single bDMARD therapy compared with those with multiple ineffective bDMARDs. In patients who failed to respond to one bDMARD, there was no significant difference in the CDAI remission rate at week 26 between the JAKis (29.1%) and IL-6Ri (21.8%) groups (p= 0.21). However, for patients who did not respond to at least two bDMARDs, the CDAI remission rate at week 26 was higher in the JAKis than in the IL-6Ri group. CONCLUSIONS: IL-6Ri offers a superior balance of efficacy and safety compared with JAKis for RA patients unresponsive to one bDMARD. However, JAKis may suit patients who do not respond to multiple bDMARDs.

Computed tomography for malignancy screening in patients with rheumatoid arthritis before initiation of disease modifying antirheumatic drug.

OBJECTIVES: This study aimed to clarify the usefulness of screening for malignancies using CT before the initiation of biologic and targeted synthetic DMARDs (b/tsDMARDs) in patients with active RA. METHODS: We examined 2192 patients with RA who underwent plain CT scans prior to the initiation of b/tsDMARDs. The sensitivity for detecting malignancy was measured and compared with that of regular screening (physical examination and X-ray). We then evaluated the clinical characteristics, prognosis and treatment of patients with RA with concomitant malignancies. Additionally, we determined the incidence rate of malignancy in patients with RA who were initiated on b/tsDMARDs after CT screening. RESULTS: Of the 2192 patients, 33 (1.5%) were diagnosed with malignancy after CT screening. Whereas regular screening detected only seven malignancies, CT screening further detected 26 (including 19 at the early stage). On the other hand, 86% of the malignancies detectable by regular screening were at an advanced stage. Patients diagnosed with early-stage malignancies received RA treatments that included b/tsDMARDs after curative resection; 80% of these patients achieved low disease activity after 1 year. This rate was comparable to the patients without malignancy detection after screening (70%). The 5 year incidence of malignancy after the initiation of b/tsDMARDs after CT screening was lower than that of the RA cohort without CT screening (standardized incidence ratio: 0.35). CONCLUSION: Screening in patients with RA using CT before the initiation of b/tsDMARDs allows for the early detection and treatment of malignancy, resulting in safer and more stable b/tsDMARD treatments.

Safety and efficacy of anifrolumab therapy in systemic lupus erythematosus in real-world clinical practice: LOOPS registry.

OBJECTIVES: To determine the safety and efficacy of anifrolumab in patients with systemic lupus erythematosus (SLE) classified based on the Lupus Low Disease Activity State (LLDAS) in real-world clinical practice. METHODS: This retrospective observational study involved SLE patients who started anifrolumab therapy. The primary end point was the retention rate over 26 weeks after initiating anifrolumab therapy; 45 patients followed up for 12 weeks or longer were analyzed in the following groups to determine the safety and efficacy up to week 12 after treatment initiation: 1) non-LLDAS achievement group and 2) minor flare group. Safety and efficacy were compared between the minor flare group and the standard of care (SoC) group (treated by adding glucocorticoids (GCs) or immunosuppressants) after adjustment with inverse probability of treatment weighting using propensity score (PS-IPTW). RESULTS: The retention rate of anifrolumab was 89.7% at week 26.The LLDAS achievement rates at week 12 were 42.9% and 66.7% in the non-LLDAS achievement and minor flare groups, respectively. In both groups, GC doses and SELENA-SLEDAI score significantly decreased. When the anifrolumab group with minor flare was compared with the SoC group or the GC dose increase group, the GC dose and SLEDAI score were significantly lower in the anifrolumab group than in both groups; there was no significant difference in LLDAS achievement. CONCLUSIONS: At week 26 after initiating anifrolumab therapy, ∼90% patients remained on therapy. Anifrolumab might lower disease activity without initiating GCs and reduce GC doses, especially in patients who experience minor flares after LLDAS achievement.

Biological/targeted synthetic DMARDs do not arrest bone loss in patients with rheumatoid arthritis: a multicenter prospective observational study.

OBJECTIVE: To elucidate the differential effects of biological/target synthesized DMARDs (b/tsDMARDs) on bone metabolism in patients with rheumatoid arthritis (RA) in a real-world cohort. METHODS: This was a multicentre prospective observational study of RA patients enrolled at the time of 1st b/tsDMARDs administration. Bone mineral density (BMD) and bone turnover markers (BTMs) were measured during the 52-week observation. The study was designed to enrol all eligible RA patients. The end-points were differences in changes in BMD according to b/tsDMARD type, and the correlation between BMD and BTMs. RESULTS: A total of 1,164 patients were enrolled in this study. b/tsDMARDs improved RA disease activity from mean CDAI 25.5 at baseline to 4.5 at week 26. Patients not receiving anti-osteoporotic agents (anti-OP) at baseline with no history of fracture experienced a significant decrease in both femoral neck (F: mean 0.666-0.655 g/cm3) and radial (R: 0.518-0.514) BMD at week 26. Despite maintaining low CDAI levels during weeks 26-52 (5.3-4.4), there was a continued decline in BMD (F: 0.653, R: 0.509. Weeks 52). None of b/tsDMARDs type preserved BMD. Conversely, patients receiving anti-OP at baseline maintained stable BMD throughout the study (Weeks 0/26/52. F: 0.551/0.551/0.555, R: 0.415/0.416/0.415). Although BTMs were changed by b/tsDMARDs, the changes were unrelated to those in BMD. CONCLUSION: Our study suggested the progression of osteoporosis in RA patients during b/tsDMARDs treatment without anti-OP. BTMs may not reflect BMD change. Regular monitoring of BMD in RA should be considered for early management of osteoporosis.

Efficacy and safety of high-dose of mycophenolate mofetil compared with cyclophosphamide pulse therapy as induction therapy in Japanese patients with proliferative lupus nephritis.

OBJECTIVES: To clarify the effectiveness and safety of induction therapy with mycophenolate mofetil (MMF) in patients with lupus nephritis (LN). METHODS: Patients with LN administered MMF (n = 35) or intravenous cyclophosphamide pulse therapy (IVCY) (n = 25) plus high-dose corticosteroids between July 2015 and June 2020 were included. MMF was increased from 2 to 3 g/day, with no adverse events (AEs). The primary endpoint was the 6 month renal remission rate. Secondary endpoints were retention rate and AEs. RESULTS: There were no significant differences in age, sex, disease duration, renal histological type, SLE disease activity index, and urine protein creatinine ratio between the two groups. Twenty-six patients (74%) continued with MMF therapy, whereas 12 (48%) completed six IVCY courses. The retention rate was significantly higher in the MMF than in the IVCY group (p = 0.048). Twenty-four and 14 patients in MMF and IVCY groups, respectively, achieved renal remission with insignificant differences. Grade 3 or higher AEs were observed in 8 and 14 patients in the MMF and IVCY groups, respectively (p = 0.014). CONCLUSIONS: The efficacy of high-dose MMF was comparable to that of IVCY in Japanese patients with proliferative LN, with fewer AEs and a higher retention rate than IVCY, suggesting the high tolerability of MMF.

5-year remission rate after the discontinuation of adalimumab in patients with rheumatoid arthritis: Long-term follow-up results of the HONOR study.

Objectives: To determine the rate and factors associated with remission (disease activity score (DAS) 28-erythrocyte sedimentation rate (ESR) of <2.6) during a 5-year follow-up after the discontinuation of adalimumab (ADA) in patients with rheumatoid arthritis (RA).Methods: 75 patients who had been treated with ADA + methotrexate (MTX) and maintained DAS28-ESR <2.6 for at least 6 months were enrolled. Among them, 52 patients discontinued ADA, and 46 patients completed a 5-year follow-up.Results: During the 5 years, 11 patients had DAS28-ESR <2.6. In 15 patients with DAS28-ESR <3.2, no significant changes were found in the health assessment questionnaire disability index (HAQ-DI) and modified total Sharp score (mTSS). When comparing patients with DAS28-ESR ≤1.61 versus 1.61 2 years). Among 31 patients who experienced flare, ADA was restarted in 24 patients, and 17 patients of these achieved DAS28-ESR <3.2 within 1-year.Conclusion: During the 5-year ADA-free period, remission rate was persistent in 21% of the patients. ADA-free remission was possible especially in patients with deeper remission (DAS28-ESR ≤1.61) and shorter disease duration (≤2 years).

Abatacept therapy reduces CD28+CXCR5+ follicular helper-like T cells in patients with rheumatoid arthritis.

OBJECTIVES: The characteristics of T cells targeted by abatacept (ABT) in cases of rheumatoid arthritis (RA) are still unknown. The goal of the study was to determine the pathogenicity of T cells and the predictors of therapeutic effects of ABT. METHODS: We analysed the peripheral T cell phenotype of 34 RA patients via flow cytometry. The correlation of the phenotypes of CD4+ T cells with clinical disease activity and change in CD4+ T cell subsets at baseline and 24 weeks after ABT treatment were evaluated. RESULTS: RA patients showed an increase in the proportion of CD28- cells among CD4+ cells, which was significantly high in patients who had not achieved remission after ABT therapy. The proportions of CD4+CXCR5+ T follicular helper-like (Tfh-like) cells increased in RA patients compared to healthy donors. The proportions of Tfh-like cells among CD4+CD28+ cells were significantly higher than those among CD4+CD28- cells. The proportion of Tfh-like cells was higher in anti-cyclic citrullinated peptide antibody (ACPA)-positive patients. By contrast, the proportions of CD4+CXCR3+ T helper 1-like (Th1-like) cells and effector memory phase T cells among CD4+CD28- cells were significantly higher than those among CD4+CD28+ cells, and the proportion of these cells did not correlate with disease activity. After ABT therapy, the proportion of Tfh-like cells among CD4+CD28+ cells was significantly reduced. CONCLUSIONS: These results imply that CD4+ CD28+ Tfh-like cells could possibly be the targets of ABT. Conversely, CD4+ CD28- cells may be a potential predictor of treatment resistance.

Comparison of the efficacies of abatacept and tocilizumab in patients with rheumatoid arthritis by propensity score matching.

OBJECTIVE: To compare the clinical outcomes at 1 year after the treatment with either abatacept or tocilizumab in patients with rheumatoid arthritis in routine clinical practice. METHODS: To overcome potential bias in allocation to treatment with abatacept or tocilizumab, a propensity score based on multiple baseline characteristics variables was calculated and 102 of 194 patients treated with abatacept and 102 of 273 patients treated with tocilizumab were statistically extracted. Clinical outcomes were assessed. RESULTS: The baseline characteristics were statistically comparable. At week 52, 72%/69% of patients (abatacept/tocilizumab) were still receiving treatment. The Simplified Disease Activity Index (SDAI) decreased from 28.7/27.7 at baseline to 14.0/12.5 at week 52 with abatacept/tocilizumab, respectively. At week 52, the remission rates for abatacept/tocilizumab were 18%/20%, respectively. No statistical difference in clinical efficacy between abatacept and tocilizumab was seen. Moreover, a subanalysis showed that abatacept and tocilizumab had similar effectiveness with or without methotrexate. However, prognostic factors at baseline contributing to the Clinical Disease Activity Index at week 52 were different between the two groups by multiple regression analysis. A higher rheumatoid factor (RF) titre and lower SDAI at baseline were associated with lower SDAI at week 52 in patients treated with abatacept, whereas patients receiving tocilizumab with a lower Health Assessment Questionnaire Disability Index and who were biologics-naïve at baseline had a lower SDAI at week 52. CONCLUSIONS: We compared patients treated with abatacept or tocilizumab after statistical adjustment by propensity score matching. Clinical efficacies, including SDAI, were comparable in both treatment groups. However, the predictive factors were different: abatacept appears to benefit patients with higher RF titres, and early induction of tocilizumab is an important factor for good clinical efficacy.

Clinical, radiographic and functional efficacy of abatacept in routine care for rheumatoid arthritis patients: Abatacept Leading Trial for RA on Imaging Remission (ALTAIR) study.

OBJECTIVES: To investigate the efficacy and safety of abatacept for treating patients with rheumatoid arthritis (RA) in routine clinical practice and to determine the prognostic factors affecting clinical outcomes. METHODS: We performed a retrospective study of 194 RA patients treated with abatacept. Clinical outcomes at 1 year after the treatment were assessed. Joint damage was assessed by the van der Heijde-modified total Sharp score (mTSS). RESULTS: Of the 194 patients, abatacept was discontinued in 51 patients, resulting in a retention rate at week 52 of 73.7%. At week 52, 23.7% of patients achieved clinical remission (SDAI ≤3.3). Lower SDAI and higher RF titre at baseline were the prognostic factor for SDAI at 52 weeks. Structural remission (ΔmTSS ≤0.5) was achieved in 73.4% of patients. However, clinical relevant radiographic progression which was defined as an increase in ΔmTSS >3 in a year, occurred in 7.6% of patients. Likewise, rapid radiological progression, which was defined as an increase in ΔmTSS >5 in a year, was observed in 6.4% of patients. 16.5% of patients achieved comprehensive disease remission, which was defined as SDAI ≤3.3, HAQ-DI ≤0.5, ΔmTSS ≤0.5, while 22.4% of patients achieved comprehensive disease control (CDC), which was defined as SDAI ≤11.0, HAQ-DI ≤0.5, ΔmTSS ≤0.5. CONCLUSIONS: The present results confirm that abatacept is effective and safe in routine clinical practice. It is possible that abatacept is more effective in seropositive RA patients with significant immunological abnormality.

Clinically relevant radiographic progression in joint destruction in RA patients with abnormal MMP-3 or high levels of CRP despite 1-year treatment with infliximab.

OBJECTIVE: Identify the independently related factors of joint destruction progression in RA patients despite of infliximab treatment. METHODS: The subjects were cases who underwent infliximab treatment for one year or longer in our department (n = 244). Patients in which modified total sharp score (mTSS), joint erosion (JE), and joint space narrowing (JSN) had advanced to the standard value (3.0) or more for one year were defined as mTSS- Clinically-Relevant-Rapid Progression (CRRP) (n = 20), JE-CRRP (n = 20), and JSN-CRRP (n = 23), and the respective related factors at baseline and week 54 were defined by multiple logistic regression. RESULTS: The median disease duration was 24 months and median mTSS 9.0 at baseline. The median DAS28, CRP, and yearly progression of mTSS improved from 5.8 to 2.6, 1.2 to 0.1 mg/dL, and 4.4 to 0.0 point/year, respectively. The related factor in each of mTSS-CRRP, JE-CRRP, and JSN-CRRP was high CRP levels at baseline. At week 54, the related factor of mTSS-CRRP and JSN-CRRP was high MMP-3 titer; however, the related factor of JE-CRRP was high CRP levels. CONCLUSION: High CRP levels at baseline were an independent predictive factor of joint destruction advancement during infliximab treatment. Moreover, it was believed that abnormal MMP-3 at week 54 was the index for mTSS and JSN advancement, while high CRP levels were the index for JE advancement.

Association of the multi-biomarker disease activity score with joint destruction in patients with rheumatoid arthritis receiving tumor necrosis factor-alpha inhibitor treatment in clinical practice.

OBJECTIVE: Evaluate the association between the multi-biomarker disease activity (MBDA) score and radiographic progression in patients with rheumatoid arthritis (RA) treated with tumor necrosis factor (TNF)-α inhibitors. METHODS: Change (Δ) in modified total Sharp score (mTSS) over 52 weeks and disease activity scores were examined retrospectively by Spearman's rank correlation coefficient in patients (N = 83) with RA initiating TNF-inhibitor treatment. Relative risk (RR) of ΔmTSS >0.5 for low MBDA score and 28-joint count disease activity score (DAS28) categories and associations between ΔmTSS and MBDA score categories conditional on DAS28 categories were assessed. RESULTS: At 52 weeks, 34% of patients had ΔmTSS >0.5 and 12% had ΔmTSS >3. Strongest correlations were observed between ΔmTSS and MBDA score (r = 0.47) or DAS28 (r = 0.42) at Week 24 and for area under the curve at Week 52 (MBDA score: r = 0.44, DAS28: r = 0.41), all p < 0.001. At Week 24, RR of ΔmTSS >0.5 for moderate/high MBDA score (≥30) or DAS28 (>3.2) were 6.6 (p < 0.001) and 2.7 (p = 0.005), respectively. Low DAS28 had greater risk of ΔmTSS >0.5 at 52 weeks when MBDA score was ≥30 (p < 0.05). CONCLUSION: Higher MBDA score or DAS28 at Week 24 was associated with greater radiographic progression over 52 weeks of TNF-inhibitor treatment. MBDA score improved risk discrimination for radiographic progression within DAS28 categories.

Discontinuation of adalimumab after achieving remission in patients with established rheumatoid arthritis: 1-year outcome of the HONOR study.

OBJECTIVES: To investigate the possibility of discontinuing adalimumab (ADA) for 1 year without flaring (DAS28-erythrocyte sedimentation rate (ESR) ≥3.2), and to identify factors enabling established patients with rheumatoid arthritis (RA) to remain ADA-free. METHODS: Of 197 RA patients treated with ADA+methotrexate (MTX), 75 patients who met the ADA-free criteria (steroid-free and sustained DAS28-ESR remission for 6 months with stable MTX doses) were studied for 1 year. RESULTS: The mean disease duration and DAS28-ESR score in 75 patients was 7.5 years and 5.1 at baseline, respectively. The proportion of patients who sustained DAS28-ESR <2.6 (48%) and DAS28-ESR <3.2 (62%) for 1 year were significantly lower in the ADA discontinuation group than in the ADA continuation group; however, in patients with deep remission (DAS28-ESR ≤1.98) identified by receiver operating characteristics analysis following logistic analysis, these rates increased to 68% and 79%, respectively, with no significant difference between both groups. Remarkably, ADA readministration to patients with flare was effective in returning DAS28-ESR to <3.2 within 6 months in 90% and 9 months in 100% patients; among the patients who sustained DAS28-ESR <3.2 during ADA discontinuation, 100% remained in structural remission and 94% in functional remission. CONCLUSIONS: The possibility of remaining ADA-free for 1 year was demonstrated in established patients with RA with outcomes that ADA can be discontinued without flaring in 79% patients with deep remission, with similar rates in the ADA continuation group, and showed no functional or structural damage in patients with DAS28-ESR <3.2. ADA readministration to patients with flare during ADA discontinuation was effective.

IL-6-accelerated calcification by induction of ROR2 in human adipose tissue-derived mesenchymal stem cells is STAT3 dependent.

OBJECTIVE: The mechanisms of ectopic calcification in inflammatory diseases are poorly understood. We investigated the effects of inflammatory cytokines on the mechanisms of calcification in human adipose tissue-derived mesenchymal stem cells (hADSCs). METHODS: The effects of inflammatory cytokines were evaluated using hADSCs cultured in osteoblast induction medium. mRNA expression was measured by real-time PCR and protein levels were measured by western blotting. Cell mineralization was evaluated by Alizarin Red S staining. RESULTS: In hADSCs, administration of IL-6/soluble IL-6 receptor (sIL-6R), TNF or IL-1ß accelerated calcification through enhanced expression of an osteoblast differentiation marker, runt-related transcription factor 2 (RUNX2). IL-6/sIL-6R had the greatest effect. The transcription of mRNA for receptor tyrosine kinase-like orphan receptor 2 (ROR2), involved in the non-canonical wingless-type (WNT) MMTV integration site pathway, was increased, while ß-catenin expression, an essential factor in the canonical WNT signalling pathway for osteoblast differentiation, did not change. Suppression of signal transducer and activator of transcription 3 (STAT3), but not STAT1, by small interfering RNA (siRNA) exerted a strong inhibitory effect on RUNX2 and ROR2 expression, and inhibited accelerated calcification. CONCLUSION: IL-6/sIL-6R stimulation accelerated the ROR2/WNT5A pathway in hADSCs in a STAT3-dependent manner, resulting in augmented calcification. These results suggest that the mechanisms of ectopic calcification accelerated by IL-6 in hADSCs may be involved in chronic inflammatory tissues and that IL-6 inhibitors may be beneficial in the treatment of ectopic calcification in inflammatory diseases.

Effects of tofacitinib on lymphocytes in rheumatoid arthritis: relation to efficacy and infectious adverse events.

OBJECTIVES: To assess the effects of tofacitinib on T lymphocytes in RA patients with a special focus on efficacy and infectious adverse events (iAEs). METHODS: Forty-four RA patients participated in 12-month phase II/III randomized clinical trials and an open-label extension trial. Peripheral lymphocyte subsets and in vitro CD4(+) T lymphocyte proliferation were measured in 23 patients of 44 at baseline and at the end of the 12-month trial. RESULTS: Forty-four patients [35 females, age 54.3 years, disease duration 84.3 months, simplified disease activity index (SDAI) 36.5, CRP 24.9 mg/l, ESR 53 mm/h, MMP-3 284 pg/ml, RF 172.6 IU/ml, neutrophil count 4842 per µl, lymphocyte count 1410 per µl] were treated with tofacitinib. At the end of the study, the SDAI improved to 6.2, but the peripheral lymphocyte count and absolute numbers of CD4(+) and CD8(+) subpopulations did not change during this period. However, CD4(+) T lymphocyte proliferation was suppressed, which correlated with the improvement in SDAI, but not with iAEs (n = 19) during the 12-month treatment. Receiver operating characteristic analysis identified a CD8(+) T lymphocyte count ≤ 211 per µl at baseline as a significant predictor of clinically significant iAEs. CONCLUSION: The efficacy of tofacitinib is mediated through the suppression of CD4(+) T lymphocyte proliferation without affecting the absolute number of these cells in the periphery. A low CD8(+) T cell count at baseline correlated with the development of iAEs during the treatment of RA patients.

Efficacy and safety of reducing duration of infliximab infusion.

OBJECTIVE: To evaluate the safety and efficacy of reducing the duration of infliximab infusion for rheumatoid arthritis (RA) treatment. METHODS: The first 6 infliximab infusions were each administered over a 2-h period. If no adverse reaction was observed, infusion times were shortened to 1 h starting with the seventh infusion with further shortening to 30 min starting with the thirteenth infusion. Subjects were divided into two groups: shortened infusion time group, in which infusion times were shortened as above; and constant infusion time group, in which infusion time was 2 h. Incidence of infusion reactions and improvement in disease activity score for 28 joints (DAS-28) erythrocyte sedimentation rate (ESR) for total infusions were compared for the seventh to twelfth and thirteenth to eighteenth infusions. RESULTS: The incidences of infusion reactions after the seventh to twelfth and thirteenth to eighteenth infusions in the shortened infusion time group were 0.53% and 0.58%, respectively. In the constant infusion time group, these were 0.70% and 0.67%, respectively. Furthermore, shortening the infusion duration did not affect the DAS-28 (ESR) improvement rate. CONCLUSIONS: We established that this stage-wise shortening of infusion duration, first to 1 h and then to 30 min, did not compromise the safety or efficacy of treatment.

Abatacept inhibits radiographic progression in patients with rheumatoid arthritis: a retrospective analysis of 6 months of abatacept treatment in routine clinical practice. The ALTAIR study.

OBJECTIVES: Our objectives in this study were to determine the inhibitory effects of abatacept on joint damage and its clinical efficacy and safety in patients with rheumatoid arthritis (RA). METHODS: Fifty Japanese patients with RA were treated with abatacept for 24 weeks in routine clinical practice. RESULTS: At week 24, 20 % of patients achieved clinical remission [Simplified Disease Activity Index (SDAI) ≤3.3], whereas 50 % were in remission or had a low disease activity. Structural remission [progression of modified total Sharp score (ΔmTSS) ≤0.5] was achieved in 76 % of patients. The ΔmTSS decreased significantly from 7.1 ± 7.3 at baseline to 1.8 ± 5.7 at week 24. C-reactive protein (CRP) was the only independent prognostic factor for joint damage progression at week 24, whereas SDAI and matrix metalloproteinase-3 levels were not. A very high proportion of patients with CRP levels <1.5 mg/dl (88 %) achieved structural remission. In terms of safety, the retention rate for all patients was favorable (80 %), and stomatitis was the only adverse event observed. No patient withdrew from the study because of infections. CONCLUSIONS: Abatacept has favorable clinical and structural effects, inhibits radiographic progression, and has a good safety profile in routine clinical practice.

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

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.

Interleukin-1ß induces differentiation of human mesenchymal stem cells into osteoblasts via the Wnt-5a/receptor tyrosine kinase-like orphan receptor 2 pathway.

OBJECTIVE: Mesenchymal stem cells (MSCs) are considered to be a novel tool for the treatment of rheumatoid arthritis (RA) because of their multipotency to differentiate into osteoblasts and chondrocytes, their immunosuppressive effects, and availability. The aim of this study was to assess the mechanisms of human MSC differentiation into osteoblasts under inflammatory conditions. METHODS: Human MSCs were cultured in commercialized osteogenic induction medium with inflammatory cytokines for up to 10 days. Osteoblast differentiation was detected by alkaline phosphatase staining and messenger RNA (mRNA) expression of multiple osteoblast markers. Mineralization was assessed by alizarin red S staining. RESULTS: Among the various cytokines tested, interleukin-1ß (IL-1ß) induced differentiation of human MSCs into osteoblasts, which was confirmed by alkaline phosphatase activity, expression of RUNX2 mRNA, and strong alizarin red S staining. Among various molecules of the Wnt family, Wnt-5a and receptor tyrosine kinase-like orphan receptor 2 (Ror2), a major receptor of Wnt-5a, were significantly induced in human MSCs by IL-1ß. Silencing of either WNT5A or ROR2 by small interfering RNA with 2 different sequences reduced alkaline phosphatase activity, RUNX2 expression, and alizarin red S staining of human MSCs induced by IL-1ß. CONCLUSION: IL-1ß effectively and rapidly induced human MSC differentiation into osteoblasts and mineralization, mainly through the noncanonical Wnt-5a/Ror2 pathway. These results suggest potential benefits of IL-1ß-treated human MSCs in the treatment of damaged bone as well as in the induction of self-renewal and self-repair of damaged tissue, including osseous tissue.

An elderly man with mild encephalitis/encephalopathy with a reversible splenial lesion (MERS) without neuropsychiatric sequelae.

Mild encephalitis/encephalopathy with a reversible splenial lesion (MERS) is less common in the elderly, and most have some sequelae. However, even in the elderly, MERS may have a good prognosis, and a specific treatment is not always required.