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).

Rheumatoid arthritis (RA) is an incurable aggressive chronic inflammatory joint disease with a worldwide prevalence. High levels of autoantibodies and chronic inflammation may be involved in the pathology. Notably, T follicular regulatory (Tfr) cells are critical mediators of T follicular helper (Tfh) cell generation and antibody production in the germinal center (GC) reaction. Changes in the number and function of Tfr cells may lead to dysregulation of the GC reaction and the production of aberrant autoantibodies. Regulation of the function and number of Tfr cells could be an effective strategy for precisely controlling antibody production, reestablishing immune homeostasis, and thereby improving the outcome of RA. This review summarizes advances in our understanding of the biology and functions of Tfr cells. The involvement of Tfr cells and other immune cell subsets in RA is also discussed. Furthermore, we highlight the potential therapeutic targets related to Tfr cells and restoring the Tfr/Tfh balance via cytokines, microRNAs, the mammalian target of rapamycin (mTOR) signaling pathway, and the gut microbiota, which will facilitate further research on RA and other immune-mediated diseases.

Background: Immunophenotyping of blood lymphocytes is an essential tool to evaluate the immune function of patients with immunodeficiency or autoimmunity. Predominately identified CD4 + T cell subsets, Th1, Th2, Th17, as well as regulatory T (Treg) cells, play crucial roles in several immunological and pathological conditions. Considering the variations in cell counts among populations and ethnicities, specific CD4 + T cell subset reference values need to be locally established to enable meaningful comparisons and accurate data interpretation in clinical and research settings. Therefore, the aim of this study was to establish distributions and reference ranges for blood CD4 + T cell subpopulations in age-and sex-balanced healthy adults of a Han Chinese population in Shanxi Province, North China. Methods: Peripheral blood CD4 + T cell subsets were examined in 150 healthy volunteers (75 males, 75 females) aged 20-70 years with a four-color FACSCalibur flow cytometer. Results: Reference value percentages (absolute counts, cells/μl) were defined as 95% of the population for cell types as follows: CD4 +

BackgroundMany immunosuppressants used to treat rheumatoid arthritis (RA) were designed to broadly suppress T cell function, including that of regulatory T cells (Tregs). Patients with inactive RA also show a reduced frequency of peripheral Tregs [1]. Tregs are essential for maintaining effective immune tolerance and a homeostatic balance of Th17/Treg. Accordingly, there has been increasing interest in developing Treg-friendly regimens to minimize or eliminate the immunosuppression of conventional medications for RA. mTOR signaling negatively controls the development and function of Tregs. Rapamycin, an mTOR inhibitor, could expand Tregs (CD4+CD25+FoxP3+) in patients with active systemic lupus erythematosus [2] and active RA [3]; however, the response of Tregs to rapamycin in RA patients with DAS28 ≤ 3.2 is still unclear.ObjectivesTo investigate the effects of rapamycin, under the generic name sirolimus, on Tregs in RA patients with DAS28 ≤ 3.2 who previously received conventional DMARDs.MethodsFifty-five RA patients and 60 healthy controls were enrolled in this study. All patients had previously received conventional DMARDs and had a low DAS28 score (≤ 3.2). Peripheral blood samples and clinical information were obtained at baseline and following 6 and 12 weeks of sirolimus treatment, or after 12 weeks of conventional treatment. The circulating levels of lymphocyte subpopulations were assessed by flow cytometry.ResultsThirty-five patients received sirolimus and 20 patients continued treatment with conventional DMARDs. None of the baseline clinical characteristics differed significantly between the two groups. The absolute counts and proportions of CD4+CD25+FoxP3+ Tregs were significantly lower in all RA patients with DAS28 ≤ 3.2 as compared with those in healthy controls. By contrast, the difference in circulating Th17 cell numbers was not significant. Sirolimus administration resulted in significant elevations in circulating Treg cell numbers and significant reductions in the Th17/Treg cell ratio, whereas the circulating level of Tregs and the Th17/Treg cell ratio in patients under conventional treatment both showed a tendency of reduction (Figure 1). Furthermore, a greater proportion of patients under sirolimus treatment achieved DAS28-based remission at 12 weeks.ConclusionSirolimus can favorably expand Tregs in RA patients with DAS28 ≤ 3.2, consequently restoring a healthy balance of Th17/Treg cells, which might improve the likelihood of long-term and sustained clinical remission and reduce the probability of disease flare-ups in RA. These findings provide valuable insights that might potentially lead to changes in clinical practice for the routine treatment of RA.References[1] Niu Q, Cai B, Huang ZC, Shi YY, Wang LL. Disturbed Th17/Treg balance in patients with rheumatoid arthritis. Rheumatol Int, 2012, 32(9): 2731-2736.[2] Lai ZW, Kelly R, Winans T, et al. Sirolimus in patients with clinically active systemic lupus erythematosus resistant to, or intolerant of, conventional medications: a single-arm, open-lab...

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