Integrated safety analysis of filgotinib in patients with moderate-to-severe rheumatoid arthritis over a treatment duration of up to 8.3 years.

OBJECTIVES: To update the long-term safety profile of filgotinib, a Janus kinase-1 preferential inhibitor, in patients with moderate-to-severe rheumatoid arthritis. METHODS: Data from seven trials were integrated (NCT01888874, NCT01894516, NCT02889796, NCT02873936, NCT02886728, NCT02065700 and NCT03025308). Patients received once-daily filgotinib 100 mg or 200 mg. Exposure-adjusted incidence rates (EAIRs)/100 patient-years of exposure (PYE) were calculated for treatment-emergent adverse events (TEAEs). Post hoc analyses assessed patients aged <65 and ≥65 years. RESULTS: Patients (N=3691) received filgotinib for a median (maximum) of 3.8 (8.3) years (12 541 PYE). Rates of TEAEs of interest: serious infections, malignancies, major adverse cardiovascular events (MACE) and venous thromboembolism were stable over time and comparable between doses. In the overall population, numerically lower EAIR (95% CI)/100 PYE of herpes zoster was observed for filgotinib 100 mg versus 200 mg (1.1 (0.8 to 1.5) vs 1.5 (1.2 to 1.8)). Incidence of serious infections, herpes zoster, MACE, malignancies and all-cause mortality was higher in patients aged ≥65 versus <65 years. In patients aged ≥65 years, EAIRs (95% CI)/100 PYE for non-melanoma skin cancer (NMSC) (0.4 (0.1 to 1.1) vs 1.4 (0.8 to 2.2)), malignancies excluding NMSC (1.0 (0.5 to 1.9) vs 2.0 (1.3 to 2.9)) and all-cause mortality (1.3 (0.7 to 2.2) vs 1.6 (1.0 to 2.5)) were numerically lower for filgotinib 100 mg versus 200 mg. CONCLUSIONS: In the overall population, TEAEs of interest were stable over time and similar between filgotinib 100 mg and 200 mg dose groups, except for herpes zoster. A dose-dependent relationship between malignancies and all-cause mortality was suggested in patients ≥65 years old.

Risk of flare and damage accrual after tapering glucocorticoids in modified serologically active clinically quiescent patients with systemic lupus erythematosus: a multinational observational cohort study.

OBJECTIVES: To assess the risk of flare and damage accrual after tapering glucocorticoids (GCs) in modified serologically active clinically quiescent (mSACQ) patients with systemic lupus erythematosus (SLE). METHODS: Data from a 12-country longitudinal SLE cohort, collected prospectively between 2013 and 2020, were analysed. SLE patients with mSACQ defined as the state with serological activity (increased anti-dsDNA and/or hypocomplementemia) but without clinical activity, treated with ≤7.5 mg/day of prednisolone-equivalent GCs and not-considering duration, were studied. The risk of subsequent flare or damage accrual per 1 mg decrease of prednisolone was assessed using Cox proportional hazard models while adjusting for confounders. Observation periods were 2 years and censored if each event occurred. RESULTS: Data from 1850 mSACQ patients were analysed: 742, 271 and 180 patients experienced overall flare, severe flare and damage accrual, respectively. Tapering GCs by 1 mg/day of prednisolone was not associated with increased risk of overall or severe flare: adjusted HRs 1.02 (95% CI, 0.99 to 1.05) and 0.98 (95% CI, 0.96 to 1.004), respectively. Antimalarial use was associated with decreased flare risk. Tapering GCs was associated with decreased risk of damage accrual (adjusted HR 0.96, 95% CI, 0.93 to 0.99) in the patients whose initial prednisolone dosages were >5 mg/day. CONCLUSIONS: In mSACQ patients, tapering GCs was not associated with increased flare risk. Antimalarial use was associated with decreased flare risk. Tapering GCs protected mSACQ patients treated with >5 mg/day of prednisolone against damage accrual. These findings suggest that cautious GC tapering is feasible and can reduce GC use in mSACQ patients.

EULAR recommendations for the management of psoriatic arthritis with pharmacological therapies: 2023 update.

OBJECTIVE: New modes of action and more data on the efficacy and safety of existing drugs in psoriatic arthritis (PsA) required an update of the EULAR 2019 recommendations for the pharmacological treatment of PsA. METHODS: Following EULAR standardised operating procedures, the process included a systematic literature review and a consensus meeting of 36 international experts in April 2023. Levels of evidence and grades of recommendations were determined. RESULTS: The updated recommendations comprise 7 overarching principles and 11 recommendations, and provide a treatment strategy for pharmacological therapies. Non-steroidal anti-inflammatory drugs should be used in monotherapy only for mild PsA and in the short term; oral glucocorticoids are not recommended. In patients with peripheral arthritis, rapid initiation of conventional synthetic disease-modifying antirheumatic drugs is recommended and methotrexate preferred. If the treatment target is not achieved with this strategy, a biological disease-modifying antirheumatic drug (bDMARD) should be initiated, without preference among modes of action. Relevant skin psoriasis should orient towards bDMARDs targeting interleukin (IL)-23p40, IL-23p19, IL-17A and IL-17A/F inhibitors. In case of predominant axial or entheseal disease, an algorithm is also proposed. Use of Janus kinase inhibitors is proposed primarily after bDMARD failure, taking relevant risk factors into account, or in case bDMARDs are not an appropriate choice. Inflammatory bowel disease and uveitis, if present, should influence drug choices, with monoclonal tumour necrosis factor inhibitors proposed. Drug switches and tapering in sustained remission are also addressed. CONCLUSION: These updated recommendations integrate all currently available drugs in a practical and progressive approach, which will be helpful in the pharmacological management of PsA.

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.

Comparison of Attainment and Protective Effects of Lupus Low Disease Activity State in Patients With Newly Diagnosed Versus Established Systemic Lupus Erythematosus.

OBJECTIVE: To assess whether Lupus Low Disease Activity State (LLDAS) attainment is associated with favorable outcomes in patients with recent onset systemic lupus erythematosus (SLE). METHODS: Data from a 13-country longitudinal SLE cohort were collected prospectively between 2013 and 2020. An inception cohort was defined based on disease duration < 1 year at enrollment. Patient characteristics between inception and noninception cohorts were compared. Survival analyses were performed to examine the association between LLDAS attainment and damage accrual and flare. RESULTS: Of the total 4106 patients, 680 (16.6%) were recruited within 1 year of SLE diagnosis (inception cohort). Compared to the noninception cohort, inception cohort patients were significantly younger, had higher disease activity, and used more glucocorticoids, but had less organ damage at enrollment. Significantly fewer inception cohort patients were in LLDAS at enrollment than the noninception cohort (29.6% vs 52.3%, P < 0.001), but three-quarters of both groups achieved LLDAS at least once during follow-up. Limiting analysis only to patients not in LLDAS at enrollment, inception cohort patients were 60% more likely to attain LLDAS (hazard ratio 1.37, 95% CI 1.16-1.61, P < 0.001) than noninception cohort patients and attained LLDAS significantly faster. LLDAS attainment was significantly protective against flare in both the inception and noninception cohorts. A total of 88 (13.6%) inception cohort patients accrued organ damage during a median 2.2 years of follow-up. CONCLUSION: LLDAS attainment is protective from flare in recent onset SLE. Significant protection from damage accrual was not observed because of low rates of damage accrual in the first years after SLE diagnosis. (ClinicalTrials.gov: NCT03138941).

Vitamin D efficacy in type 1 and type 2 diabetes.

It is well known that vitamin D has a profound effect on calcium and bone metabolism, but its influence on other organs (extraskeletal effect) has been proposed. Consistently, vitamin D deficiency is associated with an increased incidence of various diseases, including type 1 and type 2 diabetes, as reported by many observational studies. However, there has been no consensus on whether vitamin D deficiency is a causative factor in the incidence of diabetes mellitus. There have been no randomized controlled trials (RCTs) aimed at preventing the onset of type 1 diabetes with vitamin D intake. In addition, the results of RCTs evaluating the preventive effect of vitamin D supplementation on type 2 diabetes development have been inconsistent. The recent observational studies, randomized controlled trials, and meta-analyses are confirming that vitamin D or active vitamin D administration is effective in preventing the incident of type 1 and type 2 diabetes.

The 2023 Guidelines for the management and treatment of glucocorticoid-induced osteoporosis.

INTRODUCTION: Although synthetic glucocorticoids (GCs) are commonly used to treat autoimmune and other diseases, GC induced osteoporosis (GIOP) which accounts for 25% of the adverse reactions, causes fractures in 30-50% of patients, and markedly decreases their quality of life. In 2014, the Japanese Society for Bone and Mineral Research (JSBMR) published the revised guidelines for the management and treatment of steroid-induced osteoporosis, providing the treatment criteria based on scores of risk factors, including previous fractures, age, GC doses, and bone mineral density, for patients aged ≥18 years who are receiving GC therapy or scheduled to receive GC therapy for ≥3 months. MATERIALS AND METHODS: The Committee on the revision of the guidelines for the management and treatment of GIOP of the JSBMR prepared 17 clinical questions (CQs) according to the GRADE approach and revised the guidelines for the management and treatment of GIOP through systematic reviews and consensus conferences using the Delphi method. RESULTS: Bisphosphonates (oral and injectable formulations), anti-RANKL antibody teriparatide, eldecalcitol, or selective estrogen receptor modulators are recommended for patients who has received or scheduled for GC therapy with risk factor scores of ≥3. It is recommended that osteoporosis medication is started concomitantly with the GC therapy for the prevention of fragility fractures in elderly patients. CONCLUSION: The 2023 guidelines for the management and treatment of GIOP was developed through systematic reviews and consensus conferences using the Delphi method.

Occupational Medicine, Go Above and Beyond.

The population of people in Japan over 65 years old is expected to exceed 30% by 2025. As the society ages, there are not only healthy workers and employers, but also an increasing number of diseased or injured workers. Falls, the most common occupational hazard, increase in incidence with age. The management of osteoporosis and prevention of bone fractures from falls are emerging in elderly female workers, to reduce the loss of work productivity. Rheumatoid arthritis is a representative musculoskeletal disease that causes functional decline because of joint damage mainly in working women, but appropriate treatment improves disease activity and work productivity in workers with rheumatoid arthritis. It is also important not only to digitize subjective information by converting it into digital form (digitization), but also to digitalize the physiological information related to health, labor and disease (digitalization). In the future, artificial intelligence (AI) will be able to analyze vast amounts of physiological information (big data) obtained from workers and patients via the Internet of things (IoT), which will improve the information value linked to health promotion and optimal treatment practices, and contribute to the Digital transformation (DX).

Safety and effectiveness of peficitinib 100 mg/day in patients achieving clinical remission from a long-term open-label extension study in Japan, Korea, and Taiwan (RAJ2).

OBJECTIVES: This post hoc analysis of the RAJ2 study assessed long-term safety and effectiveness of peficitinib 100 mg/day for treatment of rheumatoid arthritis. METHODS: Eligible patients previously completed two Phase 3 (RAJ3 and RAJ4) studies of peficitinib in Asia. All patients received peficitinib 100 mg/day at RAJ2 Week (W)0; dose change to 50 mg/day or 150 mg/day was permitted. Safety endpoints included treatment-emergent adverse events and laboratory test results. Effectiveness endpoints included peficitinib exposure pattern, achievement of Clinical Disease Activity Index (CDAI) remission by peficitinib exposure pattern at W0 and W48, and association of demographics/characteristics with CDAI remission at W0 and W48. RESULTS: Overall, no new safety findings were reported at W48, and renal function was unaffected. Of patients included in effectiveness analyses at W48, 70.9% (451/636) had maintained peficitinib 100 mg/day since W0. Of patients who achieved CDAI remission at W0 and maintained peficitinib 100 mg/day to W48, 50.3% (79/157) maintained CDAI remission to W48. Low disease activity and a lower number of prior disease-modifying antirheumatic drugs were significantly associated with CDAI remission at W48. CONCLUSIONS: Long-term peficitinib treatment at a dose of 100 mg/day was generally well tolerated and, following induction therapy, maintained effectiveness through to W48.

The effects of sarilumab as monotherapy and in combination with non-methotrexate disease-modifying anti-rheumatic drugs on unacceptable pain in patients with rheumatoid arthritis: a post-hoc analysis of the HARUKA phase 3 study.

OBJECTIVES: To investigate unacceptable pain (UP; visual analogue scale [VAS] >40 mm) and uncontrolled inflammation (C-reactive protein [CRP] ≥1.0 mg/dL) in patients with active rheumatoid arthritis (RA) receiving sarilumab (SAR) as monotherapy or in combination with non-methotrexate conventional synthetic disease-modifying antirheumatic drugs (SAR+csDMARDs). METHODS: In the HARUKA phase 3 study (NCT02373202), Japanese patients received either SAR monotherapy (n=61) or SAR+csDMARDs (n=30). In this post-hoc analysis, changes in the proportions of patients with/without UP and controlled/uncontrolled inflammation were assessed over 52 weeks. RESULTS: At baseline, 80.3% (49/61) of patients receiving SAR monotherapy had UP and this proportion decreased with treatment to 55.9% (33/59) at Week 4 and 15.5% (9/58) at Week 52. The SAR+csDMARDs group achieved a reduction in UP from 73.3% (22/30) at baseline to 34.5% (10/29) at Week 4 and 0% (0/24) by Week 52. At baseline, 34.4% (21/61) and 50% (15/30) of patients had both UP and uncontrolled inflammation in the SAR monotherapy and SAR+csDMARDs groups; by Week 2, the proportions decreased to 6.6% (4/61) and 3.3% (1/30), respectively; and 0% in both groups by Week 52. CONCLUSION: UP and inflammation were reduced in patients with active RA in Japan in both SAR monotherapy and SAR+csDMARDs treatment groups.

Efficacy and safety of sarilumab in patients with rheumatoid arthritis stratified by age (<65 and ≥65 years): A post-hoc analysis of Japanese phase 3 clinical trials.

OBJECTIVES: This study aimed to assess the efficacy and safety of sarilumab in older patients with active rheumatoid arthritis (RA). METHODS: This is a post-hoc analysis of KAKEHASI (NCT02293902) and HARUKA (NCT02373202) trials with stratification by age (<65 and ≥65 years). Patients with moderately-to-severely active RA were treated with sarilumab in combination with methotrexate (MTX) or with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) or as monotherapy. The primary endpoints in KAKEHASI and HARUKA trials were the American College of Rheumatology 20% improvement criteria (ACR20) responses at Week 24 and safety, respectively. Secondary endpoints were other RA disease activity measures, including Clinical Disease Activity Index (CDAI). RESULTS: Approximately 20% of patients were aged ≥65 years in treatment arms across both trials, except the sarilumab+csDMARDs arm (40%, 12/30). ACR20 response rates were similar between age groups across sarilumab treatment arms and similar results were obtained for CDAI scores. Safety profiles were similar between age groups except for a higher incidence of serious adverse events in patients aged ≥65 years in the sarilumab+MTX arm. CONCLUSIONS: In Japanese patients with RA enrolled in phase 3 studies for sarilumab, no clear difference in efficacy or safety was observed between patients aged <65 and ≥65 years.

Safety of sarilumab in a Japanese population with rheumatoid arthritis by age group: Data from an interim analysis of a post-marketing surveillance study.

OBJECTIVES: Using data from a post-marketing surveillance, this interim subgroup analysis investigated the safety of sarilumab in younger (<65 years) and older patients (≥65 and ≥75 years) with rheumatoid arthritis. METHODS: During this interim analysis, patients who were treated with sarilumab in Japan were enrolled between June 2018-2021. Data collected by 12 January 2022 were analysed, with adverse drug events monitored over 52 weeks. RESULTS: Of 972 patients with available data, proportion of patients aged <65 years, ≥65 years and ≥75 years were 40.8%, 59.2% and 27.8%, respectively. Most patients (95.5%) received the standard 200 mg dose of sarilumab as the initial dose. Adverse drug reactions were reported in 24.6% of patients, with serious events accounting for 6.4% of cases. No malignancy and low incidences of adverse drug reactions of special interest were reported across all age groups (<65 years, 7.8%; ≥65 years, 8.2%; ≥75 years, 8.5%). When stratified by absolute neutrophil count above and below the lower limit of normal, there were no numerical differences in incidences of serious and non-serious infections between age groups. CONCLUSIONS: Regardless of age, sarilumab therapy was well tolerated by patients with rheumatoid arthritis, with no new safety signals reported in this study.

Relationship between lymphocyte count and risk of infection in Japanese rheumatoid arthritis patients treated with tofacitinib.

OBJECTIVES: We characterised changes in absolute lymphocyte counts (ALCs) and lymphocyte subset counts (LSCs), and their relationship to incidence of serious infection events (SIEs) and herpes zoster (HZ) events in Japanese patients with moderate to severe rheumatoid arthritis enrolled in the tofacitinib clinical programme. METHODS: Data included 765 patients receiving tofacitinib in Phase 2, Phase 3, and long-term extension studies. ALCs/LSCs and incidence rates (patients with events/100 patient-years) of SIEs and HZ were analysed over 75 months. RESULTS: Median ALCs were generally stable over 75 months of treatment. Transient numerical increases from baseline in median LSCs were observed at Month 3; LSCs were generally lower than baseline for Months 36-75. SIE/HZ incidence rates were higher in patients with ALC <0.5 × 103 cells/mm3 versus those with ALC ≥0.5 × 103 cells/mm3 during tofacitinib treatment. Baseline LSCs were similar in patients with/without SIEs or HZ events. CONCLUSIONS: SIE/HZ risk was highest in patients with ALC <0.5 × 103 cells/mm3, supporting this threshold as clinically relevant for defining increased SIE/HZ risk in Japanese patients with rheumatoid arthritis receiving tofacitinib. However, SIEs and HZ events did not necessarily occur simultaneously with confirmed lymphopenia, preventing conclusions on possible causal relationships being drawn.

Development of quality indicators for pregnancy and childbirth in patients with systemic lupus erythematosus.

OBJECTIVES: A quality indicator for the treatment of systemic lupus erythematosus during pregnancy and childbirth that is useful for sharing standard treatment policies has not yet been developed. This study aimed to develop a quality indicator for systemic lupus erythematosus associated with pregnancy and childbirth. METHODS: To identify candidate quality indicators, we conducted a systematic literature review on the development of quality indicators for systemic lupus erythematosus related to pregnancy and childbirth and on clinical practice guidelines. Candidate quality indicator items were extracted from the final selected articles, and a first evaluation, panel meeting, and second evaluation were conducted to determine whether the candidate items were appropriate as quality indicators. Items for which all panel members reached a consensus were designated pregnancy and childbirth-related systemic lupus erythematosus quality indicators. RESULTS: Four articles on systemic lupus erythematosus-quality indicator development and 28 practice guidelines were listed through abstract/text screening. Based on these studies, 52 candidate quality indicators were extracted that were limited to items related to pregnancy and childbirth, and 41 items were selected on which all panel members agreed. CONCLUSION: We developed pregnancy-related systemic lupus erythematosus quality indicators using the RAND/UCLA method and selected 41 items, which could be used clinically.

Safety of baricitinib in Japanese patients with rheumatoid arthritis in clinical use: 3-year data of all-case post-marketing surveillance study.

OBJECTIVE: To assess safety of baricitinib in Japanese patients with rheumatoid arthritis in real-world clinical practice. METHODS: This all-case post-marketing surveillance study included patients initiating baricitinib for rheumatoid arthritis from September 2017 to April 2019. Treatment duration was recorded. Safety data were collected for up to 3 years from baricitinib initiation (up to 4 weeks post discontinuation in discontinuing patients). RESULTS: Safety analyses included 4720 patients; 2580 (54.7%) were ≥65 years old. Baricitinib persistence rate was 45.4% (3 year Kaplan-Meier analysis); the most common discontinuation reason was insufficient effectiveness (n = 1005, 21.3%). Serious adverse events occurred in 600 patients (incidence rate 10.42/100 patient-years; 95% confidence interval, 9.76-11.09). There were 39 deaths (incidence rate 0.43 [0.30-0.57]/100 patient-years). Incidence rate per 100 patient-years for adverse events of special interest were herpes zoster 4.68 (4.22-5.14), serious infection 3.05 (2.68-3.41), malignancy 1.09 (0.87-1.30), major adverse cardiovascular events 0.35 (0.23-0.48) and venous thromboembolism 0.25 (0.15-0.36). Incidence rates did not increase with prolonged exposure. CONCLUSIONS: No new safety concerns were identified during this 3 year post-marketing surveillance study of baricitinib in Japanese patients with rheumatoid arthritis. Patients and clinicians should be cognizant of herpes zoster and other serious infection risks during baricitinib treatment, especially in the first 6 months.

Evolution of diagnostic criteria and new insights into clinical testing in mixed connective tissue disease; anti-survival motor neuron complex antibody as a novel marker of severity of the disease.

Mixed connective tissue disease (MCTD) is an autoimmune disorder characterized by a combination of clinical features from systemic lupus erythematosus, systemic sclerosis, and inflammatory muscle disease, along with the presence of positive anti-U1-ribonucleoprotein (U1-RNP) antibodies. The exact etiology of the disease remains unclear, but it is believed to involve vascular damage within the context of heightened autoimmune responses. Consequently, Raynaud's phenomenon and pulmonary arterial hypertension are observed in patients with MCTD. While specific biomarkers for MCTD have not yet been identified, the recent study of the utility of anti-survival motor neuron complex (SMN) antibodies in MCTD suggests a promising avenue for further research and the accumulation of additional evidence.

Associations between time in range and insulin secretory capacity in Japanese patients with type 2 diabetes.

Impaired insulin secretory capacity is associated with high glycemic variability in patients with type 2 diabetes (T2DM). However, there are no existing reports on the association between insulin secretory capacity and time in range (TIR). This retrospective study involved 330 T2DM admitted for diabetes education who underwent intermittently scanned continuous glucose monitoring (isCGM) and had their fasting serum C-peptide immunoreactivity (S-CPR) measured within 5 days of admission. The baseline characteristics were as follows: age, 60.2 years; glycated hemoglobin (HbA1c), 9.2%; S-CPR, 2.2 ng/mL; S-CPR index (S-CPR [ng/mL]/fasting plasma glucose [mg/dL] × 100), 1.6; and TIR, 60.3%. TIR correlated significantly with the S-CPR index, which was confirmed by multivariate analysis that included various factors such as HbA1c. Receiver operating characteristic (ROC) analysis showed that 1.88 was the optimal S-CPR index level to predict TIR ≥ 70%. In addition to HbA1c and biguanide use, the S-CPR index was a significant factor associated with TIR > 70%. S-CPR index values of ≥ 1.88 also correlated significantly with TIR > 70%. In conclusion, insulin secretory capacity is associated with TIR in Japanese T2DM, suggesting that the S-CPR index might be a potentially useful biomarker insulin secretory capacity, in association with TIR.Trial registration UMIN0000254333.

Predictors of functional improvement and pain reduction in rheumatoid arthritis patients who achieved low disease activity with disease-modifying antirheumatic drugs: a retrospective study of the FIRST Registry.

BACKGROUND: Rheumatoid arthritis (RA) patients sometimes exhibit different levels of improvement in health assessment questionnaire-disability index (HAQ-DI) and subjective pain visual analogue score (VAS) even after achieving low disease activities (LDA). This study aimed to identify factors associated with improvement in HAQ-DI and pain VAS among those who achieved LDA. METHODS: Data of the FIRST registry, a multi-institutional cohort of RA patients treated with biological and targeted-synthetic DMARDs (b/tsDMARDs) were analyzed. Patients who were enrolled from August 2013 to February 2023 and who achieved clinical LDA [clinical disease activity index (CDAI) ≤ 10.0] at 6 months after starting treatment were included. Multiple logistic regression analyses were conducted to identify the factors that associated with achieving HAQ-DI normalization (< 0.5), HAQ-DI improvement (by > 0.22), or pain VAS reduction (≤ 40 mm). RESULTS: Among 1424 patients who achieved LDA at 6 months, 732 patients achieved HAQ-DI normalization and 454 achieved pain VAS reduction. The seropositivity and the use of JAK inhibitor compared with TNF inhibitor were associated with both HAQ-DI < 0.5 and pain VAS reduction at 6 months. On the other hand, older age, past failure in ≥ 2 classes of b/tsDMARDs, higher HAQ-DI at baseline, and use of glucocorticoid were associated with the lower likelihood of HAQ-DI normalization and pain VAS reduction. Longer disease duration, being female, and higher disease activity at baseline was negatively associated HAQ-DI normalization alone. Comorbidities were not associated with the outcomes. CONCLUSIONS: These results suggest some preferable treatment may exist for improvement of HAQ-DI and pain VAS reduction in the early stage of the treatment, which is a clue to prevention of a criteria of difficult-to-treat RA.

Pathological mechanisms and novel drug targets in fibrotic interstitial lung disease.

BACKGROUND: Interstitial lung diseases (ILDs) are a diverse group of conditions characterized by inflammation and fibrosis in the lung. In some patients with ILD, a progressive fibrotic phenotype develops, which is associated with an irreversible decline in lung function and a poor prognosis. MAIN BODY: The pathological mechanisms that underlie this process culminate in fibroblast activation, proliferation, and differentiation into myofibroblasts, which deposit extracellular matrix proteins and result in fibrosis. Upstream of fibroblast activation, epithelial cell injury and immune activation are known initiators of fibrosis progression, with multiple diverse cell types involved. Recent years have seen an increase in our understanding of the complex and interrelated processes that drive fibrosis progression in ILD, in part due to the advent of single-cell RNA sequencing technology and integrative multiomics analyses. Novel pathological mechanisms have been identified, which represent new targets for drugs currently in clinical development. These include phosphodiesterase 4 inhibitors and other molecules that act on intracellular cyclic adenosine monophosphate signaling, as well as inhibitors of the autotaxin-lysophosphatidic acid axis and  α v  integrins. Here, we review current knowledge and recent developments regarding the pathological mechanisms that underlie progressive fibrotic ILD, including potential therapeutic targets. CONCLUSION: Knowledge of the pathological mechanisms that drive progressive fibrosis in patients with ILD has expanded, with the role of alveolar endothelial cells, the immune system, and fibroblasts better elucidated. Drugs that target novel mechanisms hold promise for expanding the future therapeutic armamentarium for progressive fibrotic ILD.

TYK2: an emerging therapeutic target in rheumatic disease.

Tyrosine kinase 2 (TYK2) is a member of the JAK kinase family of intracellular signalling molecules. By participating in signalling pathways downstream of type I interferons, IL-12, IL-23 and IL-10, TYK2 elicits a distinct set of immune events to JAK1, JAK2 and JAK3. TYK2 polymorphisms have been associated with susceptibility to various rheumatic diseases including systemic lupus erythematosus and dermatomyositis. In vitro and animal studies substantiate these findings, highlighting a role for TYK2 in diseases currently managed by antagonists of cytokines that signal through TYK2. Various inhibitors of TYK2 have now been studied in human disease, and one of these inhibitors, deucravacitinib, has now been approved for the treatment of psoriasis. Phase II trials of deucravacitinib have also reported positive results in the treatment of psoriatic arthritis and systemic lupus erythematosus, with a preliminary safety profile that seems to differ from that of the JAK1, JAK2 and JAK3 inhibitors. Two other inhibitors of TYK2, brepocitinib and ropsacitinib, are also in earlier stages of clinical trials. Overall, TYK2 inhibitors hold promise for the treatment of a distinct spectrum of autoimmune diseases and could potentially have a safety profile that differs from other JAK inhibitors.