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To assess the incidence of anti-drug antibodies (ADA) in patients with rheumatoid arthritis (RA) treated with the TNF inhibitors etanercept (ETN), adalimumab (ADL), or infliximab (IFX), and determine the potential relationship with trough drug concentration, efficacy, and patient-reported outcomes. This multi-national, non-interventional, cross-sectional study (NCT01981473) enrolled adult patients with RA treated continuously for 6-24 months with ETN, ADL, or IFX. ADA and trough drug concentrations were measured by independent assays ≤2 days before the next scheduled dose. Efficacy measurements included Disease Activity Score 28-joint count (DAS28), low disease activity (LDA), remission, and erythrocyte sedimentation rate (ESR). Targeted medical histories of injection site/infusion reactions, serum sickness, and thromboembolic events were collected. Baseline demographics of the 595 patients (ETN: n = 200; ADL: n = 199; IFX: n = 196) were similar across groups. The mean duration of treatment was 14.6, 13.5, and 13.1 months for ETN, ADL, and IFX, respectively. All ETN-treated patients tested negative for ADA, whereas 31.2% and 17.4% patients treated with ADL and IFX, respectively, tested positive. In ADL- or IFX-treated patients, those with ADA had significantly lower trough drug concentrations. There were negative correlations between trough drug levels and both CRP and ESR in ADL- and IFX-treated patients. DAS28-ESR LDA and remission rates were higher in patients without ADA. The rate of targeted medical events reported was low. ADA were detected in ADL- and IFX-treated but not ETN-treated patients. Patients without ADA generally showed numerically better clinical outcomes than those with ADA. This study was registered on www.ClinicalTrials.gov (NCT01981473).

Ankylosing spondylitis (AS) is a type of axial inflammation. Over time, some patients develop spinal ankylosis and permanent disability; however, current treatment strategies cannot arrest syndesmophyte formation completely. Here, we used mesenchymal stem cells (MSCs) from AS patients (AS MSCs) within the enthesis involved in spinal ankylosis to delineate that the HLA-B27-mediated spliced X-box-binding protein 1 (sXBP1)/retinoic acid receptor-β (RARB)/tissue-nonspecific alkaline phosphatase (TNAP) axis accelerated the mineralization of AS MSCs, which was independent of Runt-related transcription factor 2 (Runx2). An animal model mimicking AS pathological bony appositions was established by implantation of AS MSCs into the lumbar spine of NOD-SCID mice. We found that TNAP inhibitors, including levamisole and pamidronate, inhibited AS MSC mineralization in vitro and blocked bony appositions in vivo. Furthermore, we demonstrated that the serum bone-specific TNAP (BAP) level was a potential prognostic biomarker to predict AS patients with a high risk for radiographic progression. Our study highlights the importance of the HLA-B27-mediated activation of the sXBP1/RARB/TNAP axis in AS syndesmophyte pathogenesis and provides a new strategy for the diagnosis and prevention of radiographic progression of AS.

The objective of this case-control study was to investigate the risk of cardiovascular disease (CVD) following non-steroidal anti-inflammatory drug (NSAID) use in patients with ankylosing spondylitis (AS). A total of 10,763 new AS patients were identified from the National Taiwan Health Insurance claims database during the period from 1997 to 2008. In all, 421 AS patients with CVD were recruited as cases, and up to 2-fold as many sex- and age-matched controls were selected. Logistic regression models were used to estimate the odds ratio (OR) between NSAID use and CVD incidence. The medication possession rate (MPR) was used to evaluate NSAID exposure during the study period. AS patients had increased risk of CVD (OR, 1.68; 95% confidence interval (CI), 1.57 to 1.80). Among frequent (MPR≥80%) COX II users, the risks for all types of CVD were ten times lower than those among non-users at 24 months (OR, 0.08; 95% CI, 0.01 to 0.92). Among frequent NSAID users, the risks of major adverse cardiac event (MACE) were significantly lower at 12 months (OR, 0.23; 95% CI, 0.07 to 0.76)--a trend showing that longer exposure correlated with lower risk. Regarding non-frequent NSAID users (MPR<80%), short-term exposure did carry higher risk (for 6 months: OR, 1.41; 95% CI, 1.07 to 1.86), but after 12 months, the risk no longer existed. We conclude that long-term frequent use of NSAIDs might protect AS patients from CVD; however, NSAIDs still carried higher short-term risk in the non-frequent users.

Rheumatoid arthritis (RA) is one of the inflammatory joint diseases that display features of articular cartilage destruction. The underlying disturbance results from immune dysregulation that directly and indirectly influence chondrocyte physiology. In the last years, significant evidence inferred from studies in vitro and in the animal model offered a more holistic vision of chondrocytes in RA. Chondrocytes, despite being one of injured cells in RA, also undergo molecular alterations to actively participate in inflammation and matrix destruction in the human rheumatoid joint. This review covers current knowledge about the specific cellular and biochemical mechanisms that account for the chondrocyte signatures of RA and its potential applications for diagnosis and prognosis in RA.

In this study we aimed to identify the predictors of drug survival for biologic and targeted synthetic DMARDs (bDMARDs and tsDMARDs) among patients with rheumatoid arthritis (RA) in a real-world setting. Data from RA patients receiving bDMARDs and tsDMARDs between 2007 and 2019 were extracted from the Taiwan Rheumatology Association Clinical Electronic Registry (TRACER). Patients were categorized into tumor necrosis factor-alpha (TNF-α) inhibitors, non-TNF-α inhibitors, and tofacitinib groups. The primary outcome was 3-year drug retention and the causes of bDMARDs and tsDMARDs discontinuation were recorded. Baseline demographic data before the initiation of bDMARDs and tsDMARDs treatment were analyzed to identify the predictors of 3-year drug survival. A total of 1,270 RA patients were recruited (TNF-α inhibitors: 584; non-TNF-α inhibitors: 535; tofacitinib: 151). The independent protective factors for 3-year drug survival were positive rheumatoid factor (RF) (HR: 0.48, 95% CI: 0.27–0.85, p = 0.013) and biologics-naïve RA (HR: 0.61, 95% CI: 0.39–0.94, p = 0.024). In contrast, positive anti-citrullinated protein antibody (ACPA) (HR: 2.24, 95% CI: 1.32–3.79, p = 0.003) and pre-existing latent tuberculosis (HR: 2.90, 95% CI: 2.06–4.09, p<0.001) were associated with drug discontinuation. RA patients treated with TNF-α inhibitors exhibited better drug retention, especially in the biologics-naïve subgroup ( p = 0.037). TNF-α inhibitors were associated with lower cumulative incidence of discontinuation due to inefficacy and adverse events (both p <0.001). Baseline RF and ACPA positivity in abatacept-treated patients were associated with a better 3-year drug survival. However, negative ACPA levels predicted superior drug survival of TNF-α inhibitors and tofacitinib. In conclusion, bio-naïve status predicted better drug survival in TNF-α inhibitors-treated RA patients. RF and ACPA positivity predicted better abatacept drug survival. In contrast, ACPA negativity was associated with superior TNF-α inhibitors and tofacitinib survival.

ObjectivesThe usefulness of methotrexate-polyglutamates (MTX-PGs) concentration for management of rheumatoid arthritis has been debated. We aimed to clarify the association of MTX-PGs concentration with efficacy and safety in MTX-naïve patients initiating MTX in a prospective interventional clinical trial.MethodsThe MIRACLE trial enrolled 300 MTX-naïve patients. Oral MTX was initiated and increased to the maximum tolerated dose by week 12. Patients who did not achieve remission according to the Simplified Disease Activity Index at week 24 were randomised to either the continued dose or reduced dose group and were started on subcutaneous adalimumab. We measured the concentrations of MTX-PGs in erythrocytes using liquid chromatography-tandem mass spectrometry and analysed the association of these concentrations with efficacy and safety.ResultsThe mean concentration of total MTX-PGs increased with an increasing dose of MTX and continued to elevate for another 12 weeks after the dose was fixed. At week 24, the total MTX-PGs concentration was 110.5 (SD 43.8) nmol/L with MTX dose of 12.6 (3.0) mg/week (0.23 (0.07) mg/kg/week). During MTX monotherapy, the higher MTX-PGs concentration was an independent factor for lower disease activity; however, this association disappeared after adalimumab initiation in patients with continued MTX dose. Hepatotoxicity was related to the higher MTX-PGs concentration regardless of adalimumab use. The total MTX-PGs concentration was significantly elevated by lower estimated glomerular filtration rate, serum albumin and body mass index.ConclusionsThe MIRACLE trial demonstrated that higher total MTX-PGs concentration in erythrocytes is related to the higher efficacy and lower safety of MTX.Trial registration numberNCT03505008.

Connective tissue disease-associated interstitial lung disease (CTD-ILD) is a severe manifestation of CTD that leads to significant morbidity and mortality. Clinically, ILD can occur in diverse CTDs. Pathologically, CTD-ILD is characterized by various histologic patterns, such as nonspecific interstitial pneumonia, organizing pneumonia, and usual interstitial pneumonia. Abnormal immune system responses have traditionally been instrumental in its pathophysiology, and various changes in immune cells have been described, especially in macrophages. This article first briefly overviews the epidemiology, clinical characteristics, impacts, and histopathologic changes associated with CTD-ILD. Next, it summarizes the roles of various signaling pathways in macrophages or products of macrophages in ILD, helped by insights gained from animal models. In the following sections, this review returns to studies of macrophages in CTD-ILD in humans for an overall picture of the current understanding. Finally, we direct attention to potential therapies targeting macrophages in CTD-ILD in investigation or in clinical trials, as well as the future directions regarding macrophages in the context of CTD-ILD. Although the field of macrophages in CTD-ILD is still in its infancy, several lines of evidence suggest the potential of this area.

Background We assessed the external validity of composite indices Ankylosing Spondylitis Disease Activity Score (ASDAS), Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), and Assessment in SpondyloArthritis international Society (ASAS) 40 response (ASAS40) by evaluating the correlations between the changes in some patient reported outcomes (PROs) for patients with non-radiographic axial spondyloarthritis (nr-axSpA) and the changes in the scores of the composite indices. Methods This was a post-hoc analysis of data from the EMBARK study in patients with nr-axSpA treated with etanercept. PROs were grouped according to ASDAS status (inactive [< 1.3], low [≥ 1.3 to < 2.1], high [≥ 2.1 to ≤3.5], and very high [> 3.5]), patient achievement of > 50% improvement in BASDAI (BASDAI50 responders), and > 40% improvement in ASAS (ASAS40 responders) at 104 weeks. Analyses were conducted on observed cases available at Week 104. Changes in PROs from Baseline to Week 104 were assessed using analysis of covariance with adjustment for baseline with linear contrast. Results Higher ASDAS disease activity at 104 weeks was associated with lower long-term improvement from baseline in PROs (e.g., total back pain [visual analog scale, cm (95% confidence interval): − 4.58 (− 4.95, − 4.21), − 3.86 (− 4.28, − 3.43), − 2.15 (− 2.68, − 1.61), and 1.30 (− 0.51, 3.12) for inactive, low, high, and very high ASDAS disease activity, respectively; Multidimensional Fatigue Inventory (MFI) general fatigue: − 4.77 (− 5.70, − 3.84), − 2.96 (− 4.04, − 1.87), − 1.00 (− 2.32, 0.31), and 2.14 (− 2.10, 6.38); all p  < 0.001)]. BASDAI50 non-responders had less improvement in PROs from Baseline to Week 104 vs. responders (e.g., total back pain: − 1.61 (− 2.05, − 1.18) vs. –4.43 (− 4.69, − 4.18); MFI general fatigue: − 0.01 (− 1.12, 1.09) vs. –4.30 (− 4.98, − 3.62); all p  < 0.001). ASAS40 non-responders also had less improvement in PROs from Baseline to Week 104 vs. responders (e.g., total back pain: − 1.91 (− 2.30, − 1.52) vs. –4.75 (− 5.05, − 4.46); MFI general fatigue: − 0.63 (− 1.56, 0.30) vs. –4.64 (− 5.37, − 3.91); all p  < 0.001). Conclusion Composite indices are valid for monitoring treatment response and adequately reflect treatment-related changes experienced by patients with nr-axSpA. Trial registration ClinicalTrials.gov identifier: NCT01258738 . Registered 9 December 2010.

The aims of this study were to estimate the incidences of herpes zoster (HZ) and postherpetic neuralgia (PHN) in patients after traumatic brain injury (TBI). Furthermore, we aimed to explore the risk factors of the development of HZ and PHN in patients after TBI. This population-based, longitudinal analysis was conducted using the Taiwan National Health Insurance Research Database (consisting of 1,000,000 beneficiaries) from 1996 to 2010. Using the longitudinal National Health Insurance Research Database, we conducted a retrospective population-based cohort study to evaluate the incidence of HZ and PHN in adult TBI patients and controls. Kaplan-Meier analysis and Cox regression were used to compare differences in the development of HZ and PHN. The effects of gender, comorbidity and surgery on the risk of HZ and PHN development were assessed by subgroup analyses. Over a 15-year follow-up, the cumulative incidence of HZ in 28,234 TBI patients (604.00/100,000 person-years) was significantly higher than 34,085 controls (322.21/100,000 person-years) (P<0.0001, by log-rank test). Females showed a significantly higher incidence of HZ than males (p for interaction = 0.0010). The time to HZ development in the follow-up period was 5.9 years in TBI patients compared to 9.9 years in the control set (p <0.0001). TBI patients were 2.93 and 2.11 times likely to develop HZ and PHN, respectively, than the general population. The incidences of HZ and PHN in TBI patients were also significantly greater than for controls in the CCI = 0 subgroup. To our knowledge, this is the first population-based cohort study to reveal that TBI is an independent risk factor for HZ and PHN in TBI patients, especially in females. Physician should pay attention to the possibility of HZ and PHN in TBI patients and be aware that HZ vaccination early after brain trauma may lower the incidence of HZ and PHN.

BackgroundThis retrospective cohort study evaluated the association between gout and the risk of benign prostatic hyperplasia among men by using data from Taiwan’s National Health Insurance Research Database.MethodsPopulation-based representative insurance (outpatient and inpatient) claims data of 29,269 patients with gout and 29,269 matched patients without gout (1:1 ratio) for the period of 1997–2010 in Taiwan were identified. The association between gout and benign prostatic hyperplasia was evaluated using the Cox proportional hazards model. The associations of age by gout and gout phenotypes with benign prostatic hyperplasia risk were estimated.ResultsPatients with gout had a higher incidence rate of benign prostatic hyperplasia than those in the matched gout-free group (19.62 vs. 10.11 events per 1000 person-years). Compared with the gout-free group, the adjusted hazard ratios (HRs) (95% confidence intervals (CIs)) for benign prostatic hyperplasia were 1.30 (1.24–1.36). The gout-to-benign prostatic hyperplasia association was modified by age (Pinteraction < 0.0001) in gout patients the age groups of 20–40 years (adjusted HR 2.74, P < 0.0001) and 41–60 years (adjusted HR 1.39, P < 0.0001) but not in the age group of >60 years (adjusted HR 1.07, P = 0.063). Compared with gouty tophi, a higher risk of benign prostatic hyperplasia was noted in gouty nephropathy (adjusted HR 1.30, 95% CI 1.12–1.50).ConclusionsOur results suggest that male gout is positively related to benign prostatic hyperplasia, particularly in young gout patients and those with gouty nephropathy.