Phase Angle as a Marker of Physical Function in Non-Sarcopenic Rheumatoid Arthritis.

Background: Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease. Most patients with RA face a barrier to participation in social activities or exercise due to joint pain, despite the beneficial effects of exercise and physical activity. Thus, RA may be a risk factor for sarcopenia in the clinical field. Bioelectrical impedance analysis-derived phase angle (PhA) reflects cellular health and is correlated with the prognosis of various diseases. However, its association with physical function in non-sarcopenic RA female patients remains unclear. We evaluated the association between PhA values and various physical function measures in female patients with non-sarcopenic RA. Methods: Thirty-five participants with RA were screened. One met the criteria for sarcopenia. Finally, 34 patients with non-sarcopenic RA were enrolled. This cross-sectional retrospective study evaluated upper- and lower-extremity strengths, cross-sectional area of rectus femoris, 6 min walking test, Borg scale score, sit-to-stand test, and physical function and mental health from 36-Item Short Form Health Survey scores. Results: In total, 34 female participants (mean age = 49.74 ± 8.15 years) were enrolled. In non-sarcopenic RA patients, PhA was significantly correlated with BMI and ASM/(height)2. Multicollinearity was not detected among the independent variables (VIF < 5). The final multivariable regression model identified ASM/height2 as a significant predictor of PhA among non-sarcopenic RA patients. Conclusion: Multivariable linear regression analyses identified appendicular skeletal muscle mass as a significant predictor of PhA. Bioelectrical impedance analysis-derived PhA is a valuable guidance tool for RA management. PhA can be a useful clinical biomarker of muscle status in non-sarcopenic RA patients.

The acute phase reactant orosomucoid-2 directly promotes rheumatoid inflammation.

Acute phase proteins involved in chronic inflammatory diseases have not been systematically analyzed. Here, global proteome profiling of serum and urine revealed that orosomucoid-2 (ORM2), an acute phase reactant, was differentially expressed in rheumatoid arthritis (RA) patients and showed the highest fold change. Therefore, we questioned the extent to which ORM2, which is produced mainly in the liver, actively participates in rheumatoid inflammation. Surprisingly, ORM2 expression was upregulated in the synovial fluids and synovial membranes of RA patients. The major cell types producing ORM2 were synovial macrophages and fibroblast-like synoviocytes (FLSs) from RA patients. Recombinant ORM2 robustly increased IL-6, TNF-α, CXCL8 (IL-8), and CCL2 production by RA macrophages and FLSs via the NF-κB and p38 MAPK pathways. Interestingly, glycophorin C, a membrane protein for determining erythrocyte shape, was the receptor for ORM2. Intra-articular injection of ORM2 increased the severity of arthritis in mice and accelerated the infiltration of macrophages into the affected joints. Moreover, circulating ORM2 levels correlated with RA activity and radiographic progression. In conclusion, the acute phase protein ORM2 can directly increase the production of proinflammatory mediators and promote chronic arthritis in mice, suggesting that ORM2 could be a new therapeutic target for RA.

Effectiveness and safety of adalimumab in patients with intestinal Behçet's disease: a real-world prospective observational study in South Korea.

BACKGROUND: Intestinal Behçet's disease (BD) is characterized by typical gastrointestinal ulcers in patients with BD followed by complications such as bleeding, perforation and fistula. Biologic agents are currently under active investigation to delay the disease course. Various data regarding infliximab are available, but there is relatively lack of data regarding adalimumab. METHODS: This was a multicenter, real-world prospective observational study to evaluate the effectiveness and safety of adalimumab in intestinal BD. The primary endpoint was disease activity at each follow up, including disease activity index for intestinal Behçet's disease (DAIBD), serum C-reactive protein (CRP) level, and endoscopic findings. The secondary endpoint was the incidence of adverse drug reactions (ADRs). RESULTS: A total of 58 patients were enrolled and 8 of them were excluded. Adverse events were reported in 72.0% of patients with 122 events. ADRs were reported in 24.0% with 28 events. For adverse events, arthralgia was most commonly reported (13.1%: 16/122) and only one experienced critical adverse event (0.82%, 1/122: death due to stroke). On multivariable regression analysis, a longer disease duration was significantly associated with decreased ADRs [Odds ratio 0.976 (0.953-0.999, 95% CI); p = 0.042]. Clinical response rates as assessed by DAIBD were 90.9% at Week 12 and 89.7% at Week 56, respectively. The mean serum CRP level at baseline was significantly decreased after 12 weeks (3.91 ± 4.93 to 1.26 ± 2.03 mg/dL; p = 0.0002). CONCLUSION: Adalimumab was found to be safe and effective in Korean patients with intestinal BD. A longer disease duration was significantly associated with decreased ADRs.

Quantitative prediction of radiographic progression in patients with axial spondyloarthritis using neural network model in a real-world setting.

BACKGROUND: Predicting radiographic progression in axial spondyloarthritis (axSpA) remains limited because of the complex interaction between multiple associated factors and individual variability in real-world settings. Hence, we tested the feasibility of artificial neural network (ANN) models to predict radiographic progression in axSpA. METHODS: In total, 555 patients with axSpA were split into training and testing datasets at a 3:1 ratio. A generalized linear model (GLM) and ANN models were fitted based on the baseline clinical characteristics and treatment-dependent variables for the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS) of the radiographs at follow-up time points. The mSASSS prediction was evaluated, and explainable machine learning methods were used to provide insights into the model outcome or prediction. RESULTS: The R2 values of the fitted models were in the range of 0.90-0.95 and ANN with an input of mSASSS as the number of each score performed better (root mean squared error (RMSE) = 2.83) than GLM or input of mSASSS as a total score (RMSE = 2.99-3.57). The ANN also effectively captured complex interactions among variables and their contributions to the transition of mSASSS over time in the fitted models. Structural changes constituting the mSASSS scoring systems were the most important contributing factors, and no detectable structural abnormalities at baseline were the most significant factors suppressing mSASSS change. CONCLUSIONS: Clinical and radiographic data-driven ANN allows precise mSASSS prediction in real-world settings. Correct evaluation and prediction of spinal structural changes could be beneficial for monitoring patients with axSpA and developing a treatment plan.

Pyoderma Gangrenosum Triggered by COVID-19 Vaccination in a Patient with Ulcerative Colitis: A Case Report.

Pyoderma gangrenosum (PG) is a rare inflammatory skin disease that is difficult to diagnose. PG may be an extra-intestinal manifestation of ulcerative colitis (UC). In recent times, coronavirus disease (COVID-19) vaccines have caused various adverse cutaneous reactions. However, to the best our knowledge, combinations thereof have not been reported. We encountered a case of PG triggered by COVID-19 vaccination in a patient with UC. A 40-year-old woman developed severe pain and an abscess in the dorsum of the left foot after receiving the first dose of the messenger RNA (mRNA)-based Pfizer/BioNTech BNT162b2 COVID-19 vaccine. Severe painful ulcers with purulent necrosis and gaseous gangrene progressed rapidly along the extensor tendons and muscles to the toes and ankle. Although surgical debridement can worsen PG by triggering pathergy, we nonetheless performed wide debridement including partial extensor tenotomy with abscess drainage to prevent progression to pyogenic ankle arthritis and to rescue the toes. Antibiotics, corticosteroids, and anticoagulants were prescribed during surgical wound management via negative pressure therapy. After the lesion improved, the skin and soft tissue defect were covered using a superficial circumflex iliac artery perforator free flap and a split-thickness skin graft. The patient was satisfied with the foot salvage, and could walk unaided (without a brace or cane) from 8 weeks after the final surgery. PG may be rare even in UC patients, but mRNA-based COVID-19 vaccines may find an immunosuppressive niche. A high level of caution and suspicion of skin manifestations after vaccination is essential.

Intervention with methotrexate in patients with arthralgia at risk of rheumatoid arthritis to reduce the development of persistent arthritis and its disease burden (TREAT EARLIER): a randomised, double-blind, placebo-controlled, proof-of-concept trial.

BACKGROUND: Rheumatoid arthritis is the most common autoimmune disease worldwide and requires long-term treatment to suppress inflammation. Currently, treatment is started when arthritis is clinically apparent. We aimed to evaluate whether earlier intervention, in the preceding phase of arthralgia and subclinical joint inflammation, could prevent the development of clinical arthritis or reduce the disease burden. METHODS: We conducted a randomised, double-blind, placebo-controlled, proof-of-concept-trial at the Leiden University Medical Centre, Leiden, Netherlands. Adults aged 18 years or older with arthralgia clinically suspected of progressing to rheumatoid arthritis and MRI-detected subclinical joint inflammation were eligible for enrolment across 13 rheumatology outpatient clinics in the southwest region of the Netherlands and randomly assigned (1:1) to a single intramuscular glucocorticoid injection (120 mg) and a 1-year course of oral methotrexate (up to 25 mg/week), or placebo (single injection and tablets for 1 year). Participants and investigators were masked to group assignment. Follow-up continued for 1 year after the end of the 1-year treatment period. The primary endpoint was development of clinical arthritis (fulfilling the 2010 rheumatoid arthritis classification criteria or involving two or more joints) that persisted for at least 2 weeks. Patient-reported physical functioning, symptoms, and work productivity were secondary endpoints, which were measured every 4 months. Additionally, the course of MRI-detected inflammation was studied. All participants entered the intention-to-treat analysis. This trial is registered with EudraCT, 2014-004472-35, and the Netherlands Trial Register, NTR4853-trial-NL4599. FINDINGS: Between April 16, 2015, and Sept 11, 2019, 901 patients were assessed for eligibility and 236 were enrolled and randomly assigned to active treatment (n=119) or placebo (n=117). At 2 years, the frequency of the primary endpoint was similar between the groups (23 [19%] of 119 participants in the treatment group vs 21 [18%] of 117 in the placebo group; hazard ratio 0·81, 95% CI 0·45 to 1·48). Physical functioning improved more in the treatment group during the first 4 months and remained better than in the placebo group (mean between-group difference in Health Assessment Questionnaire disability index over 2 years: -0·09, 95% CI -0·16 to -0·03; p=0·0042). Similarly, pain (on scale 0-100, mean between-group difference: -8, 95% CI -12 to -4; p<0·0001), morning stiffness of joints (-12, -16 to -8; p<0·0001), presenteeism (-8%, -13 to -3; p=0·0007), and MRI-detected joint inflammation (-1·4 points, -2·0 to -0·9; p<0·0001) showed sustained improvement in the treatment group compared with the placebo group. The number of serious adverse events was equal in both groups; adverse events were consistent with the known safety profile for methotrexate. INTERPRETATION: Methotrexate, the cornerstone treatment of rheumatoid arthritis, initiated at the pre-arthritis stage of symptoms and subclinical inflammation, did not prevent the development of clinical arthritis, but modified the disease course as shown by sustained improvement in MRI-detected inflammation, related symptoms, and impairments compared with placebo. FUNDING: Dutch Research Council (NWO; Dutch Arthritis Society).

Effect of resistance exercise on serum leptin levels in a prospective longitudinal study of women patients with rheumatoid arthritis.

BACKGROUND: Exercise has an anti-inflammatory effect and reduces fat mass. Leptin has been known to be proinflammatory adipokines mainly produced by adipocytes. However, few studies have investigated the association between exercise and changes in serum leptin levels of patients with RA. This study evaluated the effect of an individualized resistance exercise on inflammatory markers including leptin as well as muscle strength and exercise capacity in patients with rheumatoid arthritis (RA). METHODS: A total of 42 age- and sex-matched participants were assigned to a resistance exercise program (60 min, once a week for 12 weeks, and self-exercise twice a week) or to a control group. Muscle strength, exercise capacities, and inflammatory markers such as cytokines and adipokines were assessed at baseline and at 12 weeks follow-up. Longitudinal changes in muscle strength, exercise capacity, cytokines, and adipokines between groups were tested with repeated measures analysis of variance or using the generalized estimating equation, with adjustment for baseline disease activity score 28-C response protein as a covariate. RESULTS: A total of 37 of 42 female patients with RA completed this prospective intervention study. Grip strength improved significantly in the exercise group (P < 0.05), while no between-group changes were found. Quadriceps contraction power (P for group-time interaction = 0.035 for the right side and P for group-time interaction = 0.012 for the left side) and 6-minute walking distance (P for group-time interaction = 0.021) were all improved significantly in the exercise group compared with the control group. In addition, serum leptin levels were significantly decreased in the exercise group compared with the control group (P for group-time interaction = 5.22 × 10-5), but not the other cytokines or adipokines. The change in serum leptin levels correlated with the changes in fat mass (Rho = 0.491, P= 0.015) and visceral fat area (Rho = 0.501, P= 0.013). CONCLUSION: In addition to muscle strength and exercise capacity, the 12 weeks of individualized resistance exercise reduced serum leptin levels in keeping with body fat mass or visceral fat area, suggesting that serum leptin levels might be a surrogate marker of exercise in RA.

Time-integrated Cumulative Parameters Predictive of Radiographic Progression of Rheumatoid Arthritis: Real-world Data From a Prospective Single-center Cohort.

Objective: With many chronic inflammatory diseases, outcomes are determined by assessing both disease activity at presentation and cumulative activity over time. Here, we investigated whether cumulative activity better reflects the radiographic progression (RP) of rheumatoid arthritis (RA) than measurement of activity at a single time point. Methods: From a prospective cohort of RA patients, most of whom were treated with anti-rheumatic drugs, we selected 117 subjects for whom laboratory, clinical, and radiographic parameters potentially influencing RP were monitored serially for more than 1 year. X-ray images of both hands and both feet were scored using the van der Heijde modified total Sharp score (mTSS). In addition to cross-sectional values at baseline, longitudinal and cumulative values for each parameter were calculated in a time-integrated and averaged manner. Results: Among the values measured at baseline, mTSS, but not the baseline erythrocyte sedimentation rate (ESR) or C-reactive protein level, was associated with RP. By contrast, multivariate analyses identified cumulative values such as the cumulative ESR, cumulative tender joint count, cumulative swollen joint count (SJC), and cumulative Disease Activity Score 28-ESR as major determinants of RP. In particular, the cumulative SJC showed the best predictive performance for RP. Conclusion: This study highlights the importance of cumulative indices for predicting progression of RA. Specifically, dynamic and cumulative values of RA activity-related factors, particularly the cumulative SJC, may be the major determinants of RP in the current practice.

Clinical Implications of Shared Epitope and Anti-citrullinated Peptide Antibody in Patients With Rheumatoid Arthritis.

Objective: The shared epitope (SE) and anti-citrullinated peptide antibody (ACPA) are involved in the pathogenesis of rheumatoid arthritis (RA). This study evaluated the clinical implications of SE and ACPA in terms of disease manifestation and response to biologic disease modifying anti-rheumatic drugs (DMARDs). Methods: Patients with identified human leukocyte antigen (HLA)-DRB1 alleles were included to compare the clinical characteristics and drug survival rate of tumor necrosis factor (TNF) inhibitors or abatacept based on the presence of SE and ACPA. Results: Of the 533 patients with identified HLA-DRB1 alleles, 329 patients (61.7%) with SE alleles showed higher disease activity and erosive changes compared to patients without SE alleles. SE-positive patients were more likely to start biologic (b-) or targeted synthetic DMARDs (tsDMARDs) within the first 5 years (p=0.020). The presence of SE, smoking, dyslipidemia, and higher erythrocyte sedimentation rate were independently associated with the initiation of b- or tsDMARDs (p=0.016, 0.028, 0.031, and 0.001, respectively). The presence of SE and ACPA did not affect the drug survival rate of TNF inhibitors, whereas the abatacept retention rate was higher in ACPA-positive patients (p=0.024). Conclusion: The presence of SE affected disease characteristics and prognosis in Korean patients with RA without a significant impact on drug survival rate of TNF inhibitors and abatacept. ACPA positivity was associated with abatacept drug retention, suggesting that abatacept may be helpful in ACPA-positive patients than in ACPA-negative patients.

Use of Disease-modifying Antirheumatic Drugs After Cancer Diagnosis in Rheumatoid Arthritis Patients.

Objective: There is no recommendation for the use of disease-modifying antirheumatic drugs (DMARDs) in patients with rheumatoid arthritis (RA) who developed cancer. We examined changes in the DMARDs prescription patterns associated with cancer diagnosis in RA patients. Methods: We reviewed the medical records of 2,161 RA patients who visited rheumatology clinic between January 2008 and February 2017 and found 40 patients who developed cancer during RA treatment. In these patients, we examined DMARDs prescription patterns before and right after cancer diagnosis and at recent outpatient clinic visits. Results: Before cancer diagnosis, methotrexate (MTX)-combined conventional synthetic DMARDs (csDMARDs) were most commonly prescribed (22, 55.0%) and biological DMARDs (biologics) in nine patients (22.5%). For cancer treatment, 19 patients received chemotherapy (including adjuvant chemotherapy) and 21 patients had surgery only. Right after cancer diagnosis, changes in the DMARDs prescription patterns were similar in discontinuation (13, 32.5%), switching (14, 35.0%), and maintenance (13, 32.5%). DMARDs were discontinued more frequently in the chemotherapy group (9/19, 47.4%) than the surgery only group (4/2, 19.0%) (p<0.05). Among the 13 patients who discontinued DMARDs, nine (69.2%) resumed DMARDs after a median of 5.5 months (interquartile range [IQR] 2.9, 18.3) due to arthritis flare. At a median of 4.6 years (IQR 3.3, 6.7) after cancer diagnosis, 25 patients were evaluated at recent outpatient clinic visits. Four patients received no DMARD, three MTX monotherapies, 11 csDMARDs combination therapies, and seven biologics. Conclusion: A significant number of RA patients who developed cancer during RA treatment were still receiving DMARDs including biologics after cancer diagnosis.

Accelerated diastolic dysfunction in premenopausal women with rheumatoid arthritis.

BACKGROUND: Disturbances of diastolic function precede systolic heart failure and, although clinically silent, represent the earliest sign of cardiac involvement. Diastolic dysfunction (DD) is associated with age, gender (female), and hypertension. However, little is known about the age-specific incidence rates and risk factors for DD in patients with rheumatoid arthritis (RA). METHODS: We used standard two-dimensional/Doppler echocardiography to screen for the presence of diastolic dysfunction in 61 patients with RA and 107 healthy subjects. All participants were premenopausal women with no history of hypertension. DD includes an impaired relaxation with or without increased left ventricular (LV) filling pressures, pseudonormal filling, and restrictive filling based on parameters measured using echocardiography. RESULTS: The two groups were similar with respect to age (P=0.269). Patients with RA had significantly higher LV mass index, LV filling pressure, and lower E/A velocity than controls. All patients had preserved ejection fraction (EF ≥50%). DD was more common in patients with RA at 47% compared to 26% in the controls (P=0.004). Women with RA in the 30- to 49-year age range were over 3.5 times more likely to have DD than those of similar age in the control group (OR=3.54; 95% CI 1.27 to 9.85). Among patients with RA, high CRP levels were independently associated with DD even after adjustment for cardiovascular risk factors (P=0.009). CONCLUSIONS: In premenopausal women with RA, DD is much more common and the age of onset is reduced. Early screening of myocardial function may provide an opportunity for preventing future cardiovascular disease.

Influenza infection as a trigger for systemic lupus erythematosus flares resulting in hospitalization.

In patients with systemic lupus erythematosus (SLE), there are concerns that infections may increase the risk of flares. We evaluated the association between influenza infection and SLE flares resulting in hospitalization. SLE flares resulting in hospitalization and influenza cases were ascertained from the Korean national healthcare insurance database (2014-2018). We used a self-controlled case series design. We defined the risk interval as the first 7 days after the influenza index date and the control interval was defined as all other times during the observation period of each year. We estimated the incidence rates of SLE flares resulting in hospitalization during the risk interval and control interval and compared them using a Poisson regression model. We identified 1624 influenza infections among the 1455 patients with SLE. Among those, there were 98 flares in 79 patients with SLE. The incidence ratio (IR) for flares during the risk interval as compared with the control interval was 25.75 (95% confidence interval 17.63-37.59). This significantly increased the IRs for flares during the risk interval in both women (IR 27.65) and men (IR 15.30), all age groups (IR 17.00-37.84), with and without immunosuppressive agent (IR 24.29 and 28.45, respectively), and with and without prior respiratory diseases (IR 21.86 and 26.82, respectively). We found significant association between influenza infection and SLE flares resulting in hospitalization. Influenza infection has to be considered as a risk factor for flares in all SLE patients regardless of age, sex, medications, and comorbidities.

Association of influenza infection with hospitalisation-related systemic lupus erythematosus flares: a time series analysis.

OBJECTIVES: This study aimed to investigate whether the influenza annual outbreak in Korea is related to hospitalisation-related flares in systemic lupus erythematosus (SLE) patients. METHODS: The weekly frequency of hospitalisation-related SLE flares (2012-2015) was collected from the Korean National Health Insurance claim database. The weekly laboratory-confirmed detection rate of influenza infection was obtained from the Korea Centers for Disease Control and Prevention database. A generalised linear model was used to examine the relative risks (RRs) of hospitalisation-related SLE flares associated with influenza infection, after adjusting for time trends and meteorological data. RESULTS: A total of 2,223 hospitalisation-related SLE flares were analysed. An interquartile range (24.5%) increase in influenza infection was associated with a 14.0% increase in hospitalisation-related SLE flares (RR, 1.14; 95% confidence interval [CI]: 1.04-1.25; p=0.006). In addition, influenza infections at lag 0-1 (over 2 weeks including concurrent and 1 previous week) and lag 0-2 (over 3 weeks including concurrent and 2 previous weeks) were associated with increase in hospitalisation-related SLE flares (RR, 1.14; 95% confidence interval [CI]: 1.03-1.26; p=0.014 and RR, 1.13; 95% CI: 1.02-1.26; p=0.023). Significant associations were especially observed in women (RR, 1.15; 95% CI: 1.15-1.16; p=0.006) and immunosuppressant (RR, 1.26; 95% CI: 1.26-1.27; p<0.001) or glucocorticoid recipients (RR, 1.17, 95% CI: 1.16-1.17; p=0.004). CONCLUSIONS: This study shows a significant association between seasonal influenza infection and flares in SLE patients, which suggests influenza can be a novel environmental risk factor for SLE flares.

Pregnancy rates and perinatal outcomes in women with systemic lupus erythematosus: data from the Korean national health claims database.

INTRODUCTION/OBJECTIVES: The pregnancy rate in systemic lupus erythematosus (SLE) is not fully understood and comparisons of adverse pregnancy outcomes (APOs) with SLE versus the general population are limited. This study aimed to estimate the pregnancy rate and APOs in Korean SLE compared to those without SLE. METHOD: Pregnant women were identified using the ICD-10 codes for delivery and abortion in the Korean national health claims database (2013-2015). APOs were classified as fetal loss, intrauterine growth retardation (IUGR), pre-eclampsia/eclampsia, and gestational diabetes. Annual incidence rates (IRs) of pregnancy and APOs were calculated in women with SLE and the general population without SLE and the two groups were compared using age-adjusted incidence rate ratios (IRRs). Age-stratified IRRs were further analyzed. RESULTS: The annual IRs of pregnancy in SLE were 29.54-30.70 per 1000 persons. The IRRs were lower in women with SLE than in the general population: 0.68 (0.61-0.76), 0.66 (0.60-0.74), and 0.74 (0.66-0.82) in each respective year. The IRRs of fetal loss, IUGR, and pre-eclampsia/eclampsia were 1.30 (1.14-1.49), 4.65 (3.55-6.09), and 3.43 (2.70-4.36), respectively. However, the IRR of gestational diabetes in SLE did not significantly differ from that of women without SLE. Among the APOs, fetal loss, IUGR, and pre-eclampsia/eclampsia showed decreasing tendencies as age increased. CONCLUSIONS: Pregnancy rates in SLE were approximately 30% lower than those in the general population. Except for gestational diabetes, fetal loss, IUGR, and pre-eclampsia/eclampsia were higher in SLE and showed a decreasing tendency with age. Key Points • This population-based cohort study showed that pregnancy rates in SLE were approximately 30% lower than those in the general population. • SLE had a 1.3-fold higher rate of fetal loss, more than 4-fold higher IUGR rate, and more than 3-fold pre-eclampsia or eclampsia rate compared with the general population. • Adverse pregnancy outcomes in SLE showed a decreasing tendency with age.

Twelve Weeks of Strengthening Exercise for Patients with Rheumatoid Arthritis: A Prospective Intervention Study.

Rheumatoid arthritis (RA) patients may benefit from exercise for several reasons. However, whole-limb strengthening exercises for such patients remain poorly studied. We hypothesized that systemic strength training that includes the upper and lower extremities would improve strength per se and enhance the quality of life. Here, we investigated the effects of 12 weeks of upper- and lower-limb strengthening exercise on the strength and quality of life of RA patients using the International Classification of Functioning, Disability, and Health model. This was a prospective, interventional controlled trial. Forty female RA patients were recruited and assigned to two groups not based on willingness to exercise, with 20 patients in the exercise group and 20 in the control group. All patients in the exercise group received once-weekly training sessions of 60 min over 12 weeks. All participants were assessed before and after the 12-week intervention period. We measured the hand grip strength and isometric quadriceps contraction, the cross-sectional area of the rectus femoris (CSA-RF) (via ultrasonography), and performed the 30 s sit-to-stand test and the 6 min walk test (6MWT). We derived the Borg scale score after the 6MWT and assessed the extent of social participation and quality of life using a Korean version of the 36-Item Short Form Health Survey (SF-36). A total of 35 subjects completed the experiment (18 in the exercise group, 17 in the control group). After the 12-week intervention period, the lower-limb strength and the CSA-RF were significantly increased in the exercise group. The activity level did not change significantly in either group. The exercise group exhibited significant improvements in the SF-36 mental health domain scores. Thus, strengthening exercise is useful for patients with RA.

Radiographic progression in clinical trials in rheumatoid arthritis: a systemic literature review of trials performed by industry.

OBJECTIVES: To summarise radiographic data in randomised controlled trials (RCTs) as part of the radiographic inhibition claim of disease-modifying antirheumatic drugs (DMARDs) approved for patients with rheumatoid arthritis (RA). METHODS: A systemic literature review was performed using the Medline database from 1994 to February 2020. The results were grouped based on the scoring methods (Sharp, Genant modification, van der Heijde modification) and RA patient populations. RESULTS: One hundred sixty-eight publications were selected. After detailed assessment, 52 RCTs (7 methotrexate (MTX)-naive, 23 MTX inadequate response (IR), 9 DMARDs IR and 3 tumour necrosis factor-alpha inhibitors (TNFi) IR studies) were finally included. Information on patient population, scoring method used, reader reliability, statistical analyses and detailed radiographic data on baseline and change scores over multiple follow-up periods are presented. CONCLUSION: The data gathered in this review serve as a repository for the design of future trials with radiographic damage as an outcome.

Dynamic transcriptome analysis unveils key proresolving factors of chronic inflammatory arthritis.

Despite recent advances in understanding chronic inflammation remission, global analyses have not been explored to systematically discover genes or pathways underlying the resolution dynamics of chronic inflammatory diseases. Here, we performed time-course gene expression profiling of mouse synovial tissues along progression and resolution of collagen-induced arthritis (CIA) and identified genes associated with inflammation resolution. Through network analysis of these genes, we predicted 3 key secretory factors responsible for the resolution of CIA: Itgb1, Rps3, and Ywhaz. These factors were predominantly expressed by Tregs and antiinflammatory M2 macrophages, suppressing production of proinflammatory cytokines. In particular, Ywhaz was elevated in the sera of mice with arthritis resolution and in the urine of rheumatoid arthritis (RA) patients with good therapeutic responses. Moreover, adenovirus-mediated transfer of the Ywhaz gene to the affected joints substantially inhibited arthritis progression in mice with CIA and suppressed expression of proinflammatory cytokines in joint tissues, lymph nodes, and spleens, suggesting Ywhaz is an excellent target for RA therapy. Therefore, our comprehensive analysis of dynamic synovial transcriptomes provides previously unidentified antiarthritic genes, Itgb1, Rps3, and Ywhaz, which can serve as molecular markers to predict disease remission, as well as therapeutic targets for chronic inflammatory arthritis.

The Role of Calcium-Calcineurin-NFAT Signaling Pathway in Health and Autoimmune Diseases.

Calcium (Ca2+) is an essential signaling molecule that controls a wide range of biological functions. In the immune system, calcium signals play a central role in a variety of cellular functions such as proliferation, differentiation, apoptosis, and numerous gene transcriptions. During an immune response, the engagement of T-cell and B-cell antigen receptors induces a decrease in the intracellular Ca2+ store and then activates store-operated Ca2+ entry (SOCE) to raise the intracellular Ca2+ concentration, which is mediated by the Ca2+ release-activated Ca2+ (CRAC) channels. Recently, identification of the two critical regulators of the CRAC channel, stromal interaction molecule (STIM) and Orai1, has broadened our understanding of the regulatory mechanisms of Ca2+ signaling in lymphocytes. Repetitive or prolonged increase in intracellular Ca2+ is required for the calcineurin-mediated dephosphorylation of the nuclear factor of an activated T cell (NFAT). Recent data indicate that Ca2+-calcineurin-NFAT1 to 4 pathways are dysregulated in autoimmune diseases. Therefore, calcineurin inhibitors, cyclosporine and tacrolimus, have been used for the treatment of such autoimmune diseases as systemic lupus erythematosus and rheumatoid arthritis. Here, we review the role of the Ca2+-calcineurin-NFAT signaling pathway in health and diseases, focusing on the STIM and Orai1, and discuss the deregulated calcium-mediated calcineurin-NFAT pathway in autoimmune diseases.