| ObjectiveRefractory rheumatoid arthritis(RRA)refers to those who can not achieve remission(REM)or low disease activity(LDA)by regular treatment with DMARDs for 3-6 months.These patients tend to be DMARD intolerant(NT)or DMARD restistant(NR)and some are inappropriate to use biological DMARDs(bDMARDs)due to some complications.A long-term cohort study was conducted to evaluate the efficacy and safety of tacrolimus(TAC)in the treatment of moderate and severe RRA and to explore factors affecting the efficacy and discontinuation of TAC.MethodsThis longitudinal prospective observational single-center study included 150 consecutive RA patients(according to American College of Rheumatology(ACR)1987 criteria)from the outpatient clinics of the rheumatology department in Qilu Hospital of Shandong University.Patients were enrolled between August 2013 to June 2019.The disease activity score 28 using erythrocyte sedimentation rate(DAS28-ESR)of all RRA patients were higher than 3.2 at baseline.The patients whose DAS28-ESR>3.2 at baseline were classified as M group,others whose DAS28-ESR>5.1 were sorted as S group.They were also stratified in different ways acording to other baseline characteristics:an DMARD intolerance group(NT group)and an DMARD resistance group(NR group);an RA complication group,in which all patients have extraarticular disease,(C group)and an no extraarticular disease group,(NC group).We also divided patients into different groups based on their whole-course treatment regimes:a TAC with(wi)methotrexate(MTX)group(T+M group)and a without(w/o)MTX combination group(T group);a TAC plus prednisone(Pred)group(T+P group)and a w/o Pred combination group(T+0 group);an TAC both wi MTX and hydroxychloroquine(HCQ)group(+MTX+HCQ group),a wi HCQ but w/o MTX group(-MTX+HCQ group),a wi MTX but w/o HCQ group(+MTX-HCQ group),an neither MTX or HCQ combination group(-MTX-HCQ group).Clinical efficacy with disease activity was evaluated by DAS28-ESR,simplified Disease Activity Index(SDAI),Clinical Disease Activity Index(CDAI),C-reactive protein(CRP),modified Health Assessment Questionnaire(HAQ).Clinical response was calculated using the European League Against Rheumatism(EULAR)improvement criteria and ACR definition of 20%improvement(ACR20).To monitor the differences of treatment prescriptions betweens sub-groups,the dose and the duration of TAC and other csDMARDs including MTX,Pred,and HCQ were recorded in each follow-up time point.Safety was evaluated by physical examinations,monitoring of vital signs and routine clinical laboratory testing.85 patients withdrawed from our cohort(Lost group).FU group included fifteen patients who had completed 144 weeks of observation,and 50 patients still going on at different time points.Clinical variables obtained at the date of observation nearest to each of the reference time points(at baseline,3-,12-,24-,36-,48-,72-,96-,120-,144 week).All data were check up with normal test and anova test.Continuous data are presented as Mean±standard deviation.Categorical variables as absolute number and percentages.The baseline demographic data among the groups were analyzed by independent-Samples T Test or Mann-Whitney U Test.Categorical variables were assessed with the chi-squared test or Fisher's exact test.The longitudinal values such as DAS28-ESR,CRP,or others indexes at each time point were compared with the baseline data and compared between groups by generalized estimating equation(GEE),GEE model with an identity link for longitudinal binary logistical regression analysis was used to assess the effect of covariates on disease activity,and clinical response based on EULAR improvement criteria and ACR20 response.Continuation rate was analyzed with the Kaplan-Meier method,and the log-rank test was performed for comparisons across subgroups in analyses.To investigate the potential predictors related to the TAC discontinuation,we used Cox regression analyses with backward model selection of variables that had a p?0.1 in univariable analysis as well as demographic variables such as age,duration of disease at TAC initiation and sex,p values less than 0.05 were considered statistically significant.ResultsDuring 144 weeks follow up,the disease activity,inflammation indexes(CRP)and HAQ of all RRA patients were significantly decreased,compared to the baseline(p<0.001).DAS28-ESR changed from 5.29±1.12 to 3.97±1.33,CRP decreased from 34.61±34.7(mg/L)to 23.07±30.56(mg/L),HAQ also improved from 0.75±0.54 to 0.41±0.46.In this cohort,35.6%patients reached remission or low disease activity acording to their scores of DAS28-ESR.70.4%patients were evaluated as having a good or moderate response.The ACR20 response rate was 49.8%.Among all the time points,all these activity indicators of RA patients came down most significantly in the first 24 weeks,and then maintain stable after 24 weeks.A little aggravationof disease activity was observed in the point of week 48,72 and 144.but there was no statistical difference compared to week 24.The disease activity indexes of all the subgroups were significantly decreased from baseline to their last time point.The clinical response including EULAR improvement criteria and ACR20 response rate of the patients in S group was significantly better than those in M group.But over the whole observation period,the disease acivity indexes such as DAS28-ESR,SDAI,CDAI of the patients in S group was still higher than those in M group.There were no difference on disease activity indexes between NR and NT group from the baseline to week 36.while after week 48,The patients in NR group had lower DAS28-ESR and CDAI than those in NT group.CRP,SDAI,and HAQ in the T+0 subgroup were all lower than those in the T+P group,indicating that the use of Pred in the treatment process was determined according to the indexes of patients' disease activity,especially the level of CRP.No statistical difference was found between the other compared groups.In the T+M group,the proportion of patients with Pred(73.9%vs 90.2%)and HCQ(20.6%vs 35.0%)and the average dose of Pred(8.03±4.54 vs 11.04±7.07mg/day)were lower than those in the T group.The same conclusion could be drawn when the treatment regimen was divided into four groups according to whether combined with MTX and/or HCQ,indicating that the dose of Pred and the proportion of patients taking Pred could be reduced by concomitant MTX.We analyzed several significant predictors for disease activity and clinical response in patients with RA using GEE.After adjusting for confounding factors,CRP and TAC dose at baseline were found to be positive factors for maintaining HDA and MDA in patients.DAS28 at baseline and received Pred before TAC initiation were the positive factors for ACR20 response.DAS28 at baseline was the negative factor for poor response by EULAR criteria.This is consistent with the efficacy conclusion reached when we compared the S and M groups.Among the 150 patients,there are 177(23.07%)adverse events(AEs)occurred in 69 patients(46.0%)(AE group).Only one patient had a severe adverse event(SAE),the rest AE were mild or moderate and reversible or resolved after adjusting treatment regimes.The most common AE was infection(45 cases),of which 11(24.44%)were discontinued due to infection.The rest of the patients recovered after anti-infection treatment.The frequencies of renal impairment,glucose tolerance impaired,hypertension,liver impairment,gastrointestinal disorder and alopecia were 15(8.47%),23(12.99%),25(14.12%),22(12.43%),28(15.82%),1(0.56%),respectively.In subgroup analysis,we found that patients in C group proned to get infection(10.2%vs 5.6%),abnormal glucose tolerance(5.4%vs 0.7%),abnormal liver function(3.5%vs 0.5%)and renal abnormalities(4.3%vs 1.4%)than NC group..Patients in NT group had tendency to be stomach upset(5.5%vs2.5%)than NR group.Combined with MTX can reduce the ratio of infection(5.3%vs 11.8%),abnormal glucose tolerance(0.2%vs7.4%)and hypertension(2.0%vs5.1%)when compared with those without MTX.However combined with Pred can induce higher ratio of hypertension(3.6%vs0.0%)than without Pred.Among the 150 enrolled patients,the levels of TAC were monitored in 81(54.0%)RA patients at week 3 or 12,in which the median date was 4.1ng/ml and the quartile spacing of 25%and 75%was 2.6,5.8ng/ml,respectively.The relationship between TAC concentration and adverse events was analyzed by mann-whitney U statistical method:TAC concentration was higher in the AE group than in the No AE group.Patients who suffered from an abnormal glucose tolerance and a hypertension had a higher levels of TAC than that of the patients without.In patients with adverse events,the mean dose of TAC before AE happening(1.59±0.56 mg/d)was not different from that of patients who did not experience AEs(No AE group)(1.62±0.60mg/d).However,the TAC dose of these patients was reduced after AE happening(1.22±0.71 mg/d),which was significantly lower than that before AE(P<0.0001).Additionally,In AE group,the proportion of patients with MTX(44.0%vs 56.8%)was lower than No AE group,which indicated that the dose of TAC was not related to the incidence of AE.TAC combined with MTX could reduce the incidence of adverse events.There were 85 cases(56.67%)discontinued TAC treatment among 150 patients.At week 48,week 96,week 144,the overall TAC continuation rates were 50.70%,37.20%,32.30%,respectively.The median follow-up period of TAC was 73 weeks.The highest discontinuation rate appeared in the first 24 weeks and 72-96 weeks.There was no difference in baseline disease activities of patients in the Lost and FU group,but the DAS28,CRP,HAQ was higher in the Lost group throughout the treatment.Patients in the FU group has lower dose of Pred(8.19 ± 6.17 vs 10.58 ±5.33mg/d)and higher ratio of people on HCQ treatment(34.6%vs 15.1%)compared with Lost group,which showed that increasing the dose of Pred related to the discontinued rate.TAC combined with HCQ reduced the TAC discontinuation rate.Among the 6 reasons causing TAC discontinuation,the common causes were the cost of the medicine(33,22.0%),and lack of efficacy(LOE)(28,18.67%).14(9.33%)patients withdrawed because of AEs.The drug survival rates of patients who were concomitant MTX and/or concomitant HCQ were significantly higher than those who were not.In addition,the drug survival rate of the people who was concomitant MTX plus HCQ was also higher than people who was only concomitant MTX.Furthermore,the Patients who have good clinical response and clinical remission after treatment have a higher drug survival rates.We analyzed several significant predictors for TAC discontinuation in patients with RA using Cox-proportional regression models.After adjusting for confounding factors,concomitant MTX,concomitant HCQ and concomitant MTX plus HCQ were negative factors.PGA>4cm at baseline,less previous drugs(?2)were positive factors for TAC withdrawal due to any cause.We also investigated predictors for cause-specific TAC discontinuation.Concomitant MTX was a negative factor.Received Pred before TAC initiation was a positive factor for TAC withdrawal due to AEs,which coincidenced with the conclusion reached from subgroup comparison using long-rank test.ConclusionThis long-term real world observation indicated that when the traditional DMARDs treatment was inadequate response or intolerance,and biological agents are not appropriate or available,TAC could be used to treat RRA patients.The data showed that TAC monotherapy or combined with MTX,HCQ has a significant clinical efficacy on RRA,can quickly and permanently decrease the disease activity of RRA,especially in patients who has high disease activity at baseline or are not tolerant other DMARDs.This research said that the dose of TAC which varied from lmg/d to 3mg/d was safe for long-term use.Having extraarticular disease is a risk factor for adverse events in patients.Combined with MTX can reduced the incidence of adverse reactions There were no positive relation between TAC dose and the incidence of AE.Combined with MTX and HCQ can reduced the TAC discontinuation.While increasing the dose of Pred could increase the discontinued rate.Therefore,the best concomitant drugs are MTX or HCQ. |
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