Low-dose IL-2 mitigates glucocorticoid-induced Treg impairment and promotes improvement of SLE

Dear Editor,Previous studies have proved that regulatory T cell(Treg)insufficiency contributed to the development of autoimmune conditions including systemic lupus erythematosus(SLE).Conventional immunosuppressive treatment was reported to downregulate beneficial Tregs together with pathogenic effector immune cells,which may impede a rapid achievement of optimal therapeutic effects.

Increased human neutrophil lipocalin and its clinical relevance in adult-onset Still’s disease

Background:Human neutrophil lipocalin(HNL)has been used extensively to differentiate acute bacterial infection from febrile diseases as a biomarker to reflect the activation of the neutrophil.The serum HNL levels in the adult-onset Still’s disease(AOSD)patients with and without infection,as well as the healthy controls(HCs),were analyzed statistically in this study to evaluate the value of HNL for the diagnosis of AOSD.Methods:A total of 129 AOSD patients were enrolled,from whom blood samples were drawn and the AOSD diagnosis was confirmed through the review of the medical records,where the systemic score,demographic characteristics,clinical manifestations,and laboratory parameters were also collected for the patients;in addition,a total of 40 HCs were recruited among the blood donors from the healthcare center with the relevant information collected.The HNL test was done for the blood samples with the enzyme-linked immunosorbent assay and the analyses were done for the correlations of HNL with clinical manifestations and diagnostic effectiveness.Results:The serum HNL increased significantly in the patients with only AOSD as compared with that in the HCs(139.76±8.99 ng/mL vs.55.92±6.12 ng/mL;P<0.001).The serum HNL level was correlated with the white blood cell(WBC)count(r=0.335,P<0.001),neutrophil count(r=0.334,P<0.001),erythrocyte sedimentation rate(r=0.241,P=0.022),C-reactive protein(r=0.442,P<0.0001),and systemic score(r=0.343,P<0.0001)in the AOSD patients significantly.Patients with fever,leukocytosis≥15,000/mm^(3),and myalgia in the HNL-positive group were observed relatively more than those in the HNL-negative group(P=0.009,P=0.023,and P=0.007,respectively).HNL was a more sensitive indicator than ferritin and C-reactive protein(CRP)to differentiate the AOSD patients with bacterial infection from AOSD-only patients,and the Youden index was 0.6 for HNL and 0.29 for CRP.Conclusion:Serum HNL can be used as a biomarker for the diagnosis of the AOSD,and HNL is also observed to be associated with the disease activity.

Clinical deep remission and related factors in a large cohort of patients with rheumatoid arthritis

Background:Clinical remission is the treatment target in rheumatoid arthritis (RA).This study aimed to investigate clinical remission and related factors in a large cohort of patients with RA.Methods:This study composed of 342 patients with RA.Data were collected by face-to-face interview of 1049 patients with RA who visited the Department of Rheumatology of three teaching hospitals from September 2015 to May 2016.The patients with RA were clinically assessed by rheumatologists and a four-page questionnaire was completed on site.Subsequently,patients fulfilled remission criteria were further analyzed.The practicability of different definitions of remission of RA was rated by a panel of rheumatologists.Sustained intensive disease modifying anti-rheumatic drug (DMARD) treatment was defined as a combination treatment with two or more DMARDs for at least 6 months.Results:In this cohort of 342 patients with RA,the proportions of patients achieving remission were 38.0%,29.5%,24.9%,21.1%,19.0%,18.1%,and 17.0%,based on criteria of disease activity score in 28 joints (DAS28) using CRP (DAS28-CRP),DAS28 using ESR (DAS28-ESR),routine assessment of patient index data 3 (RAPID-3),Boolean,simplified disease activity index (SDAI),clinical disease activity index,and the newly described clinical deep remission (CliDR),respectively.Boolean and CliDR are the best in practicability scored by rheumatologists (7.5 and 8.0,respectively).Compared with the non-sustained intensive group,sustained intensive treatment with DMARDs yielded higher remission rates of 25.6%,23.8%,and 21.3% in patients with RA based on Boolean (χ^2=3.937,P=0.047),SDAI (χ^2=4.666,P=0.031),and CliDR criteria (χ^2=4.297,P=0.038).The most commonly prescribed conventional synthesized DMARDs (csDMARDs) in patients with RA was leflunomide,followed by methotrexate,and hydroxychloroquine.Compared with the non-remission group,patients achieving remission had a longer median duration of DMARDs (45.0 [22.8–72.3] months,Z=-2.295,P=0.022).Conclusions:The findings in this study indicated that clinical deep remission is achievable in patients with RA.Sustained intensive DMARD treatment is needed to achieve a better outcome in RA.

Elevated Levels of Soluble ST2 were Associated with Rheumatoid Arthritis Disease Activity and Ameliorated Inflammation in Synovial Fibroblasts

Background：Much evidence has demonstrated that interleukin （IL）-33 plays an important role in rheumatoid arthritis （RA）.However,there have been limited studies about soluble ST2,a receptor for 1L-33,in RA.The aims of this study were to detect the levels of ST2 in the serum and synovial fluid of RA patients and to reveal the association of these levels with disease activity and the function of ST2 in RA.Methods：A total of 56 RA patients and 38 age-matched healthy controls were enrolled in this study.Synovial fluid samples were collected from another 30 RA patients and 20 osteoartbritis patients.Serum and synovial fluid levels of ST2 were measured by ELISA.In addition,the levels of ST2 in the serum of RA patients before and after therapy were detected.The function of ST2 in RA was revealed by the results of an in vitro cell assay,where recombinant ST2 proteins were used to treat peripheral blood mononuclear cells （PBMCs） and RA synovial fibroblasts （RASFs）.Results：Serum-soluble ST2 levels were significantly higher in RA patients （127.14 ± 61.43 pg/ml） than those in healthy controls （78.37 ± 41.93 pg/ml,P 〈 0.01）.Synovial fluid-soluble ST2 levels （41.90 ± 33.58 pg/ml） were much higher in RA patients than those in osteoarthritis patients （19.71 ± 16.72 pg/ml,P 〈 0.05）.RA patients who received effective therapy for 6 months showed decreased serum-soluble ST2 levels （113.01 ± 53.90 pg/ml） compared to baseline （139.59 ± 68.36 pg/ml） （P =0.01）.RA patients with high disease activity had higher serum-soluble ST2 levels （162.02 ± 56.78 pg/ml） than those with low disease activity （94.67 ± 40.27 pg/ml,P =0.001）.Soluble ST2 did not affect IL-1β,IL-6,IL-8,or tumor necrosis factor-α （TNF-o） expression in PBMCs from RA patients.However,soluble ST2 ameliorated the expressions of IL-33 and IL-1 β but not that of IL-6,IL-8,or TNF-α in resting RASFs.Interestingly,in the RASFs stimulated by TNF-α plus IL-1 β,soluble ST2 showed extensive suppressive effects on the expression of IL-6,IL-8,and TNF-α.Conclusion：Elevated levels of ST2 in the serum and synovial fluid were associated with disease activity and ameliorated IL-33 expression and IL-33-induced inflammation in RASFs,suggesting that soluble ST2 might be a potential therapeutic candidate for RA.

Efficacy and safety of low-dose interleukin-2 in combination with methotrexate in patients with active rheumatoid arthritis:a randomized,double-blind,placebo-controlled phase 2 trial

Rheumatoid arthritis(RA)is an aggressive autoimmune arthritis,and current therapies remain unsatisfactory due to low remission rate and substantially adverse effects.Low-dose interleukin-2(Ld-IL2)is potentially a therapeutic approach to further improve the disease.This randomized,double-blind,placebo-controlled trial was undertaken to evaluate the efficacy and safety of Ld-IL2 in patients with active RA.Patients were randomly assigned(1:1)to receive Ld-IL2,defined as a dose of 1 million IU,or placebo in a 12-week trial with a 12-week follow-up.Three cycles of Ld-IL2 or placebo were administered subcutaneously every other day for 2 weeks(a total of 7 doses),followed by a 2-week break.All patients received a stable dose of methotrexate(MTX).The primary outcomes were the proportion of patients achieving the ACR20,DAS28-ESR<2.6,and the change from baseline in CDAI or SDAI at week 24.Secondary endpoints included other clinical responses and safety.The primary outcomes were achieved in the perprotocol population.The improvements from baseline in CDAI and SDAI were significantly greater across time points for the LdIL2+MTX group(n=17)than for the placebo+MTX group(n=23)(P=0.018 and P=0.015,respectively).More patients achieved ACR20 response in the Ld-IL2+MTX group than those in the placebo+MTX group at week 12(70.6%vs 43.5%)and at week 24(76.5%vs 56.5%)(P=0.014).In addition,low Treg and high IL-21 were associated with good responses to Ld-IL2.Ld-IL-2 treatment was well-tolerated in this study.These results suggested that Ld-IL2 was effective and safe in RA.ClinicalTrials.gov number:NCT 02467504.

Glucose-6-phosphate isomerase is associated with disease activity and declines in response to infliximab treatment in rheumatoid arthritis

Background:Rheumatoid arthritis (RA), a systemic autoimmune disease characterized by synovial inflammation, can cause cartilage and bone damage as well as disability. The aim of this study was to explore whether serum glucose-6-phosphate isomerase (GPI) is correlated with disease activity and the value of GPI in the evaluation of infliximab treatment in patients with RA.Methods:Sixty-two patients with RA who had an inadequate response to methotrexate (MTX) were enrolled in Peking University People’s Hospital from July 1, 2016 to July 31, 2018. Infliximab (3 mg/kg, intravenous at weeks 0, 2, and 6 and then every 8 weeks) was administered to patients with stable background MTX therapy. Serum samples were obtained at baseline and week 18. Serum GPI levels were determined using enzyme-linked immunosorbent assay. The associations between serum GPI levels and clinical features were analyzed.Results:Serum GPI was positively correlated with Disease Activity Score in 28 joints (DAS28), swollen joint count, tender joint count and C-reactive protein level ( P < 0.001, P < 0.001, P < 0.001, and P = 0.033, respectively). The change of DAS28 in GPI-positive patients was greater than that in GPI-negative patients ( P < 0.001). Compared with those for patients receiving MTX monotherapy at baseline, the GPI levels were significantly declined when MTX was combined with infliximab ( P < 0.001). Conclusion:Serum GPI is related to disease activity and clinical response to infliximab treatment.

Effect of sustained intensive therapy with disease modifying anti-rheumatic drugs in rheumatoid arthritis:a 5-year real-world consecutive study

Background:Intensive therapy with disease modifying anti-rheumatic drugs(DMARDs)has been reported to improve the outcomes of rheumatoid arthritis(RA).However,real-world study on the effect of intensive therapy on RA sustained remission is still lacking.This study aimed to investigate the outcome of sustained intensive DMARD therapy(SUIT)for RA in a real-world 5-year consecutive cohort.Methods:Based on a consecutive cohort of 610 out-patients with RA,remission of RA was assessed in 541 patients from 2012 to 2017,by dividing into SUIT,non-SUIT,and intermittent SUIT(Int-SUIT)groups.Changes in the disease activity scores were evaluated by 28-joint disease activity score based on erythrocyte sedimentation rate(DAS28-ESR),28-joint disease activity score based on C-reactive protein(DAS28-CRP),and clinical deep remission criteria(CliDR).Cumulative remission rates between different groups were compared using Kaplan-Meier curves and predictive factors of sustained remission were identified by univariate and multivariate logistic regression analysis.Results:The remission rates of the SUIT group decreased from 12.0%(65/541)to 5.6%(20/359)based on DAS28-ESR,from 14.0%(76/541)to 7.2%(26/359)based on DAS28-CRP,and from 8.5%(46/541)to 3.1%(11/359)based on CliDR,respectively,with a gradually decreasing trend during the 5 years.The SUIT regimen led to a significantly higher cumulative remission rate than non-SUIT regimen based on DAS28-ESR(39.7%vs.19.5%,P=0.001),DAS28-CRP(42.0%vs.19.6%,P=0.001),and CliDR(24.5%vs.8.7%,P=0.001).The cumulative remission rates of patients treated with SUIT regimen were significantly higher than those treated with Int-SUIT regimen based on DAS28-ESR(39.7%vs.25.7%,P=0.043)and CliDR(24.5%vs.14.2%,P=0.047),but there was no significant difference between the two groups based on DAS28-CRP(42.0%vs.27.4%,P=0.066).Multivariate logistic regression analysis showed that the use of SUIT regimen was an independent favorable predictor according to different remission definitions(for DAS28-ESR:odds ratio[OR],2.215,95%confidence interval[CI]:1.271–3.861,P=0.005;for DAS28-CRP:OR,1.520,95%CI:1.345–1.783,P=0.002;for CliDR:OR,1.525,95%CI:1.314–1.875,P=0.013).Conclusion:Sustained intensive treatment of RA is an optimal strategy in daily practice and will lead to an increased remission rate.

Clinical Relevance of Autoantibodies against Interleukin-2 in Patients with Systemic Lupus Erythematosus

Background： Increased serurn autoantibodies against interleukin-2 （anti-IL-2 autoantibodies） were reported in patients with systemic lupus crythematosus （SLE） and in patients receiving IL-2 therapy. This study aimed to explore the clinical relevance of serum anti-IL-2 autoantibodies and the interactions between low-dose IL-2 therapy and serum anti-IL-2 autoantibodies. Methods： Serum samples were collected from 152 SLE patients and 100 age- and gender-matched healthy controls （HCs）. Among them, 75 SLE patients were followed tip for 10 weeks, and all of them were treated with corticosteroids, antimalarials, and/or immunosuppressants. Forty-six out of the 75 SLE patients received low-dose IL-2 therapy additionally. Clinical and laboratory parameters were collected at baseline and week 10. Serum anti-lL-2 autoantibodies were determined by enzyme-linked immunosorbent assay. Results： Compared with HCs, median levels and positive rates of sernm anti-IL-2 autoantibodics were higher in SLE patients （32.58 [23.63, 45.23] arbitrary unit [AU] vs. 37.54 [27.88, 60.74] AU, P- 0.006, and 5.0% vs. 18.4%, P = 0.002, respectively）. Compared to those without the corresponding disorders, serum anti-IL-2 autoantibody was increased in patients with alopecia （49.79 [36.06, 64.95] AU vs. 35.06 [25.40, 58.46] AU, P = 0.033）, but it was decreased in those with lupus nephritis （31.71 [22.60, 43.25] AU vs. 44.15 [31.43, 68.52] AU, P= 0.001 ）. Moreover, serum anti-I L-2 autoantibody was positively correlated with serum IgA （r= 0.229, P = 0.005）, total lgG （r= 0.327, P 〈 0.001 ）, and total lgM （r=0.164, P = 0.050）. Treatment with exogenous IL-2 was not significantly associated with serum anti-IL-2 autoantibody. In addition, no significant difference was found in serum anti-lL-2 autoantibody between responders and nonresponders to low-dose I L-2 therapy. Conclusions： Serum anti-lL-2 autoantibody was increased and associated with disease severity in SLE. Exogenous low-dose IL-2 did not significantly induce anti-IL-2 autoantibody production.