Background We have reported previously the insufficient absolute number or functional defects of regulatory T cells (Tregs) in patients with rheumatoid arthritis (RA), challenging conventional unspecific immunosuppressive therapy. Sirolimus, a mTOR inhibitor, is reported to allow growth of functional Tregs; here, we investigated the efficacy of low-dose sirolimus combined with conventional immunosuppressants (sirolimus immunoregulation therapy) for RA treatment with lower side effects and better tolerance. Methods In this nonblinded and parallel-group trial, we randomly assigned 62 patients to receive conventional glucocorticoids and immunosuppressants with or without sirolimus at a dosage of 0.5 mg on alternate days for 24 weeks in a 2 : 1 ratio. The demographic features, clinical manifestations, and laboratory indicators including peripheral blood lymphocyte subgroups and CD4+T subsets were compared before and after the treatment. Results Finally, 37 patients in the sirolimus group and 18 in the conventional treated group completed the 6-month study. By 24 weeks, the patients with sirolimus experienced significant reduction in disease activity indicators including DAS28, ESR, and the number of tender joints and swollen joints (p < 0.001). Notably, they had a higher level of Tregs as compared with those with conventional therapy alone (p < 0.05), indicating that sirolimus could partly restore the reduced Tregs. Concomitantly, their usage of immunosuppressants for controlling disease activity was decreased as compared with the conventional group with no difference in blood routine, and liver and renal functions both before and after the treatment of sirolimus and between the two groups (p > 0.05). Conclusions Low-dose sirolimus immunoregulatory therapy selectively upregulated Tregs and partly replaced the usage of immunosuppressants to control disease activity without overtreatment and evaluable side effect. Further study is required using a large sample of RA patients treated with sirolimus for a longer period. This trial is registered at the Chinese Clinical Trial Registry (http://www.chictr.org.cn/showproj.aspx?proj=17245).

Aim: Caregivers of patients with rheumatoid arthritis (RA) often experience a sense of burden and depression. This study aimed to determine the degree of burden and depression on caregivers of RA patients and identify characteristics of both patients and caregivers that may contribute to that distress. Methods:A convenience sample of 195 patients with RA and their caregivers completed a demographic questionnaire, Zarit Care Burden Scale, Center Depression Self Rating Scale, Health Assessment Questionnaire Disability Index, and the Short Form Health Survey. Univariate and multivariate regression analysis were used to evaluate contributing factors. Results: Overall, caregivers' feelings of burden and depression were moderate, with 52 (26.7%) feeling depression and 156 (80%) feeling burdened. Caregivers with poorer health (OR = 4.393; 95% CI = 1.155-16.708; P = 0.030) and less education (OR = 6.458; 95% CI = 1.675-24.895; P = 0.007) experienced greater burdens than those with better health and more education. The greatest degree of stress occurred during the first 6 months of providing care and after 5 years of caregiving.Conclusions: Overall occurrence of depression among caregivers is low. Caregivers with poorer health, less education and closer relationship with the patient bear a heavier burden. Healthcare professionals should be aware of these potential problems and provide information and support to ensure the best quality of life for both RA patients and their caregivers. K E Y W O R D Scaregiver burden, China, depression, rheumatoid arthritis

Aims: CD4+ T cells play crucial roles as both mediators and regulators of the pathogenesis of rheumatoid arthritis (RA). However, the characteristics of CD4+ T cell subpopulations in the earliest stage of RA development remain unclear. Hence, we determined the proportions and absolute counts of circulating CD4+ T cell subsets in patients with seropositive undifferentiated arthritis (SUA), the early and preclinical stage of RA. Methods: Peripheral blood samples and clinical information were collected from 177 patients with SUA, 104 patients with RA, and 120 healthy controls. All patients were newly diagnosed and untreated. Proportions and absolute counts of CD4+ T cell subpopulations were determined by flow cytometric analysis. Results: In patients with SUA, percentages and absolute counts of circulating regulatory T (Treg) cells were decreased significantly and Th17/Treg cell ratios were abnormally increased, whereas Th17 cell numbers were similar to those in healthy controls. In addition, sex-based differences in circulating Treg cells were observed, with female SUA patients having lower proportions and absolute counts of Treg cells than those in males. Moreover, female patients with SUA had higher erythrocyte sedimentation rates and 28-joint Disease Activity Scores than those in males. Conclusion: Immune tolerance deficiency resulting from an abnormal reduction in circulating Treg cells might be the most crucial immunological event in the earliest stage of RA. The sex-specific disparity in Treg cells should also be considered for immunoregulatory and preventive strategies targeting early RA.

Systemic juvenile idiopathic arthritis (sJIA) is a complex and difficult to cure condition with high disability and mortality rates. Herein, we report the case of a patient with sJIA who was treated with sequential tocilizumab (TCZ) and tofacitinib treatment. The patient was a 4-yearold girl hospitalised with fever accompanied by multiple joint swelling and pain in June 2020. Laboratory tests revealed a white blood cell count of 15.3 9 10 9 /L, platelet count of 676.8 9 10 9 /L, haemoglobin of 91.8 g/L, serum ferritin level of 1103.8 U/L, erythrocyte sedimentation rate of 85.0 mm/h, C-reactive protein level of 146.0 g/L and interleukin (IL)-6 level of 288.0 pg/ml. Rheumatoid factor and autoantibodies test results were negative, and she was diagnosed with sJIA. The patient was started on a combination of ibuprofen, methotrexate and TCZ, and her fever decreased to the normal range without any recurrence.Painful joint swelling had resolved significantly at 3-month follow-up. Janus kinase (JAK) inhibitors inhibit the effects of several cytokines, particularly IL-6, and are economical and convenient. Therefore, we selected tofacitinib to replace TCZ in this case, while the other drugs remained unchanged. Arthritis symptoms disappeared gradually after 9-month follow-up. In May 2021, the patient was hospitalised owing to a slight recurrence of the upper respiratory tract infection. She was administered one intravenous infusion of TCZ along with a switch to oral tofacitinib, which quickly relieved the symptoms. In March 2022, the patient's condition was stable. The curative effect of sequential TCZ and tofacitinib treatment was remarkable. IL-6 inhibitors sequential to JAK inhibitors could be a new option in the treatment of systemic juvenile idiopathic joints.

Background: Juvenile-onset systemic lupus erythematosus (JSLE) has a higher mortality risk compared to adultonset SLE. We compared the diagnostic value of anti-cmDNA antibodies with that of antinucleosome antibodies (AnuA), anti-Sm antibodies, and anti-dsDNA antibodies and human B lymphocyte Raji cells with that of human promyelocytic leukemia HL60 cells as substrates in an indirect immunofluorescence assay to detect anti-cmDNA antibodies in JSLE patients. Methods: We recruited 92 JSLE patients and 71 patients with other juvenile-onset rheumatic diseases. Anti-cmDNA antibodies and antinuclear antibodies (ANA) were detected in patient sera using indirect immunofluorescence assays. Anti-dsDNA antibodies were detected by combining ELISA and indirect immunofluorescence. Anti-Sm antibodies were detected by double immunodiffusion assay and immunoblotting, while AnuA were detected by ELISA. results: The JSLE group had a significantly higher percentage of patients positive for anti-cmDNA compared to patients with other rheumatoid diseases. Using one antibody for diagnosis, anti-cm DNA antibodies had the highest accuracy at 84.0%; using two antibodies, the combination of anti-cm DNA and anti-dsDNA antibodies had 90.8% accuracy. Raji cells used as substrate demonstrated a stronger intensity of fluorescent patterns compared to HL60 cells. conclusion: The high sensitivity, specificity, and accuracy of detection of anti-cmDNA antibodies make it a valuable diagnostic tool for JSLE. s ystemic lupus erythematosus (SLE) is an autoimmune disease characterized by the presence of autoimmune antibodies against a number of nuclear and nonnuclear antigens, resulting in immune complex-mediated inflammation and systemic, multiple organ failure (1). Almost 15-20% of all SLE patients are below the age of 18 (ref. 2). Juvenile SLE (JSLE) is characterized by an exaggerated immune response with highly activated autoreactive B lymphocytes, dysregulated immune regulatory pathways, and frequent involvement of the renal, hematological and central nervous systems (3)(4)(5). Children with JSLE also have a higher disease severity and a significantly higher mortality risk compared to patients with adult onset disease (6,7). Timely diagnosis and treatment have been shown to significantly improve the prognosis and the clinical management of JSLE (8).Disease activity in SLE patients is currently evaluated using the SLE activity index (SLEDAI), the systemic lupus activity measure, and the British Isles Lupus Assessment Group (9). Recently, the anti-Smith (Sm) antibodies, anticell membrane DNA (cmDNA) antibodies, antidouble strand DNA (dsDNA) antibodies, antinuclear antigen (ANA) antibodies, antinucleosome (AnuA) antibodies, anti-C1q antibodies, and antiphospholipid antibodies have been proposed as useful biomarkers of JSLE (10-16). Anti-dsDNA antibodies, anti-Sm antibodies and antiphospholipid antibodies are included in the diagnostic criteria outlined by the American College of Rheumatology (10). JSLE patients were shown to be more frequently positive ...