Sequential Application Of Etanercept And Disease Modifying Anti-Rheumatic Drugs(DMARDs)in Treating Ankylosing Spondylitis:A Prospectively Mid-term Follow-up Study

BackgroundAt present the pathogenesis of ankylosing spondylitis(AS)has not been identified.Hence,to date,there is no radical cure for patients with AS.The adhibition of tumor necrosis factor inhibitors(TNFi)is considered as a major advance in the management of patients with AS for its short-term effectivity and the prognosis improvement by long-term application.However,the standard TNFi treatment schemes are too expensive to long-term comply with in many developing countries.Patients shoulder huge economic burden due to the high expenses of biological agents and treatment interruptions exist frequently in daily clinical practices.And once interrupted,disease remission causing by TNFi won’t last for long and patients will experience a relapse soon.That come up with a conclusion that the management of AS should persevere in the long term.Taking into account the treat-to-target management strategy proposed by Josef S Smolen et al.in 2014,the idea of dividing AStreatment into active phase and stable phase proposed by American College of Rheumatology(ACR)in 2015 and the idea of adjustments of biological treatment can be considered if a patient is in sustained remission status proposed by the recommendation of Assessment of Spondyloarthritis International Society and European League Against Rheumatism(ASAS-EULAR)in 2016,this study proposes a new scheme dividing AS treatment into relatively active phase and relatively stable phase,and sequentially introducing TNFi and Disease modifying anti-rheumatic drugs(DMARDs)in each phase relatively.Therapy costs would be reduced because DMARDs,which are cheap,partially replace TNFi in the management of relatively stable phase.Meanwhile,using DMARDs to maintain disease in remission is supposed to avoid the issue of treatment interruptions.PurposeThis study aims to evaluates the mid-term therapeutic effect and safety of this TNFi/DMARDs sequential-applicated scheme through a 12-month,prospectively,self originally controlled clinical research.At the same time,the mean cost of drugs of this scheme is calculated to assess if this scheme,compared to the standard TNFi treatment scheme,could further reduce the economic burden and become an as practical,but more economical alternative scheme for low-income AS patients.Materials and Methods35 patients with active AS,diagnosed based on modified New York diagnostic criteria for AS(1984),treating in our department from January,2017 to July,2017 were enrolled.The CRP,ESR levels and activities of disease were monitored regularly.ETN 25mg twice a week was introduced half a month to the patients who meet low disease activity standard*;one month to patients who meet high disease activity standard*;an d switched to DMARDs combination for one month when they achieved disease remission standard*to maintain this status.Treatment regime was adjusted according to the disease status assessed at the end of last regime,and then repeated to assure continuous maintenance.The clinical response was assessed by Patient Global Assessment,BASFI,BASDAI,SQoL-AS questionnaire and acute-phase reactants(APRs)levels.The primary outcome measures were the percentages of patients achieving the Assessments in Ankylosing Spondylitis 20%and 40%response(ASAS 20,ASAS 40).All outcome measures were assessed at the baseline,3,6 and 12 months.Moreover,the total drug costs of all patients during the follow-up period are calculated to assess to what extent the treatment cost would be reduced through this scheme compared to the standard one.Results35 AS patients who meet the inclusion criteria were enrolled,and finally,23 patients completed all treatments and efficacy assessments during the whole observation period.At the end of 12 months follow-up,95.7%patients achieved ASAS 20 remission and 82.6%patients achieved ASAS 40 remission.The mean BASDAI score was reduced from 5.28 at the baseline to 1.65 at the end of the follow up(P<0.05);the mean BASFI score was reduced from 5.02 to 0.92(P<0.05);the mean Patient Global score was reduced from 7.48 to 1.52(P<0.05);the mean score of the quality of life(SQOL-AS)was improved from 73.61 to 105.26(P<0.05),including 4 dimensions of physiological function,psychological state,social adaptation and self-awareness.As for ARPs,the mean ESR values were 32.70 mm/h at the baseline and 14.26 mm/h(P<0.05),14 mm/h(P<0.05),10.70 mm/h(P<0.05)at 3 months,6 months,12 months follow-ups respectively;the mean CRP values were 16.84 mg/L at the baseline and10.02 mg/L(P<0.05),6.48 mg/L(P<0.05),7.52 mg/L(P<0.05)at 3 months,6 months,12 months follow-ups respectively Comparatively,the reductions of mean ESR values were superior to CRP.4 patients did not meet the ASAS 40 remission at the end of follow-up whose disease duration was 5.5 years,baseline BASDAI,BASFI,Patient Global,SQOL-AS scores and ESR,CRP levels were 6.21、6.50、8.5、58.50、61.25mm/h、44.99 mg/L respectively,all significantly higher than the mean baseline values of other enrolled patients.Their BASDAI,BASFI,Patient Global,SQOL-AS scores and ESR,CRP levels were 4.25、2.83、4.75、85.00、29.25 mm/h、33.70 mg/L at the end of follow-up.All the clinical indexes were improved after 12 months treatment.The mean cost of drugs of this scheme is ￥30 147.62 per year among these 23 patients who completed all treatments and efficacy assessments during the whole observation period.This scheme reduced cost by 60.5%for each patient-year of follow-up,compared to the standard ETN treatment scheme,when achieving the clinical efficacy mentioned above.No tuberculosis,opportunistic infection,tumor,kidney damage,hypocytosis,myelosuppresion,central nervous system toxicity,corneal and retinal damage were found during treatment.Conclusions1.According to the 12-month follow-up outcomes,there are 95.7%and 82.6%patients achieved ASAS 20,ASAS 40 remission respectively which confirming that the TNFi/DMARDs sequential-applicated scheme do have a curative effect on AS.2.According to the outcome of the total drug cost during the 12 months follow-up period,the TNFi/DMARDs sequential-applicated scheme reduced cost by 60.5%for each patient-year of follow-up compared to the standard ETN treatment scheme.3.The main adverse reaction of the TNFi/DMARDs sequential-applicated scheme is gastrointestinal side effects which mainly occur in the DMARDs combination treatment period.No tuberculosis,opportunistic infection,tumor,kidney damage,hypocytosis,myelosuppresion,central nervous system toxicity,corneal and retinal damage were found during 12 months follow-up.This outcome shows great mid-term safety of this scheme.But the safety in longer period still need further follow-up to confirm.4.The TNFi/DMARDs sequential-applicated schememay not as good for patients with long disease durations and high baseline disease activities in the 12-month treatment.However,whether DMARDs combination could exert a more stable and durable effect in maintaining disease remission status for these patients when their disease activities were stabilized in comparatively low levels needs further follow-up to determine.