Early Predictors Of Responses,Clinical Outcomes And Medical Treatments For Refractory Ulcerative Colitis

Background:The overall chance of acute exacerbation in patients with ulcerative colitis(UC) is approximately 50%. Severe ulcerative colitis(SUC) have rapid progression, poor prognosis and a high risk of colectomy or second-line rescure medical treatment. Corticosteroids(CS) are the treatment of choice for SUC. but up to 30%–40% of patients fail to respond. Prompt effective treatment at the point of admission can avoid significant complications morbidity and be potentially life-saving in patients with SUC who are Cs-refractory. It is imperative that physicians are aware of the important principles of management of this condition to achieve successful outcomes. However both clinical outcomes and factors predictive for poor response have not yet been well established in the treatment of SUC.Patients with UC who are CS refractory or dependent are at higher risk of developing disease and treatment related complications, is a severe problem in the management of patients with UC. Further management involves use rescue therapy in the form of ciclosporin(Cs A)or neotype biological infliximab(IFX) in CS-refractory SUC patients and maintenane therapy in the form of azathioprine(AZA) in steriod-dependent UC(SDUC).However, Studies assessing the efficacy of medicine in SUC and SDUC are scarce. Data on short and long-term efficacy and safety of medicine are still controversial and the optimal medicine dosage and duration of therapy is unknown. Especially,Study on IFX, Cs A,AZA therapy in Chinese refractory UC patients is less.Aim:1. To assess Clinical outcomes after the course of CS in SUC patients during one year follow up. To identify early predictors of nonresponse to intravenous CS. To explore the point of admission in resure treatment in CS-refractory SUC. 2. To evaluate the short,long-term outcome,the optimal medicine dosage and duration of Cs A and IFX therapy in CS-refractory moderate and severe UC. 3. To explore the efficacy and safety of AZA in maintaining steroid-free remission in Chinese patients with SDUC.Methods:1. Early predictors of responses and clinical outcomes of CS treatment for SUC1) Consecutive in patients with SUC who had been treated with intravenous CS from January 2007 to december 2012 were enrolled. UC was diagnosed according to Lennard-Jones criteria. Disease activity was measured by Truelove criteria.Patients were monitored by clinical, laboratory and endoscopic examinations, and the data were recorded for 1 y prospective study. 2) Clinical response was assessed at one week, one month, and one year after CS treatment. Seven days outcomes were classified as responders or non-responders. One month outcomes were classified into Complete remission, Partial clinical remission and Nonresponse, one year outcomes were classified into prolonged response, CS dependency, and Nonresponse. 3) Patients treated with intravenous CS equivalent to prednisone 1 mg/kg/day for severe attacks of UC. Clinical and biological parameters at basetime line,3 and 5 days after starting CS were recorded. Univariate and multivariate analysis was performed to identify those independent predictors of response at 7 days. In addition, the area under the receiver operating characteristic curve(AUC) was also performed as measure of the accuracy for predicting rapid response to systemic CS in SUC.2. The efficacy of IFX in patients with active refractory UC1) Patients with refractory moderate- to-severe active UC(defined as a baseline Mayo score of 6 to 12) from January 2010 to december 2013 were enrollmented. Patients received IFX(5mg/kg) intravenously at weeks 0, 2, and 6 and then every eight weeks. Patients were followed for 58 weeks2) Efficacy evaluations included the Mayo score, sigmoidoscopy and biological parameters. To evaluate the primary efficacy of IFX including clinical response rate, clinical remission rate, mucosal healing rate and sustained efficacy rate at 8,26 week.3. The rescue efficacy of Cs A in patients with active CS-refractory SUC1) Patients with SUC from January 2010 to December 2013 were enrollmented. Patients received Cs A(2-4mg/kg/d) intravenously for 14 days. A response to therapy leading to discharge from the hospital and treatment with oral Cs A(4-6mg/kg/d) for 6 months. Patients were followed for 1y and monitored by clinical, laboratory and endoscopic parameters.2) Efficacy was assessed at 7d,14 d,1m,3m,6m and one year after Cs A treatment. 7 and 14 days outcomes(Short-term efficacy)were classified as responders or non-responders. 1,3,6 months and 1y outcomes(long-term efficacy)were assessed clinical response rate and mucosal healing rate. Cs A serum drug concentrations were detected at 4,7,14 d and once a month after oral administration.4. Efficacy and safety of AZA in SDUC1) Patients with SDUC(defined as have been unable to successfully reduce CS below the equivalent of prednisone 10 mg per day within 3 months of starting CS, without experiencing a recurrence in colitis symptoms or had a relapse within 3 months of stopping CS) from January 2007 to december 2012 were enrollmented. In this observational cohort study, 28 patientss with SDUC were recruited for AZA therapy during a 2-year period. 2) AZA was adjusted for a target dose of 2–3 mg/kg/day. CS therapy was tapered off following a standardized regimen. Clinical,endoscopic,inflammation marker improvement after AZA administration were performed at 3 m,6m,1y and 2y. 3)The primary efficacy were clinical response rate, clinical remission rate, mucosal healing rate.. Secondary efficacy included clinical recurrence, yearly steroid dose, and safety of treatment. 4) AZA safety evaluation included TPMT(Thiopurine S-methyltransferase)gene through PCR( polymerase chain reaction) methods, 6-TGNs(6-thioguanine nucleotides) concentration and white blood count were monitored at regular intervals.Result:1. Early predictors of responses and clinical outcomes of CS treatment for SUC1) Our study included a total of 62 SUC patients. 14(22.6%)patients failed intravenous CS at 7 days. At one month, complete remission was documented in 23(47.9%) patients and partial remission in 18(37.5%). seven patients(14.6%) were refractory to the treatment. At one year, we found 21(51.2%)patients in prolonged response, fifteen(36.6%) patients in CS dependency, five(12.2%)patients with no response. Total 12(19.4%) patients were underwent colectomy within 1 year. and 14(22.6%) patients received medical conversion therapy including Cs A and IFX. 2) Several predictors were associated with non-response to intravenous CS at 7 days. These included the full Mayo Score at baseline(p=0.007), partial Mayo Score, number of bowel movements, the presence of blood in stool, abdominal pain, and levels of CRP, Hgb, PLT and ESR on day 3(p<0.05), partial Mayo Score, number of bowel movements, the presence of blood in stool, abdominal pain, and levels of pulse,CRP, Hgb, PLT,ESR and ALB on day 5(p<0.05). Multiple logistic regression analysis identified the partial Mayo Score at day 3 and at day 5 as an independent predictor of outcome(p = 0.012, p =0.009). 3) ROC curve analysis showed that Mayo score at baseline time,Partial Mayo score, the levels of CRP, PLT and ESR on day 3 and day 5 have predictive value. AUC for Mayo score at baseline time was 0.728. AUC for Partial Mayo score, CRP, PLT and ESR on day 3 were 0.883,0.832,0.746 and 0.746,respectively. AUC for Partial Mayo score, CRP, PLT and ESR on day 5 were 0.964,0.894,0.831,0.766, respectively. The accuracy of other indicators was poor with AUCs lower than 0.7.2. The efficacy of IFX in patients with active refractory UC1) At week 8, 72.7%(8/11)patients achieved clinical response, 36.4%(4/11)achieved clinical remission and 45.6%(5/11)patients achieved mucosal healing.2) At week 26, 63.6.%(7/11)patients achieved clinical response, 36.4%(4/11)achieved clinical remission and 36.4%(4/11)patients achieved mucosal healing. 45.5%(5/11) patients had sustained response(clinical response at both week 8 and week 26).3) A notable decrease in Mayo score,partial Mayo score and Baron endoscope score was observed from baseline to week 8 and week 26(p<0.05). At week 8, CRP, PLT and ALB concentration were significantly difference from baseline time(p=0.018,p=0.027,p=0.008,respectively), At week 26, CRP and ALB concentration were significantly difference from baseline time(p=0.032,p =0.007,respectively). 4) IFX was generally well tolerated in this study, and no serious adverse reactions were happened.3. The rescue efficacy of Cs A in patients with active CS-refractory SUC1) Eight patients were included. Day-7 response rates were 62.5%(5/8), Day-14 response rates 75.0%(6/8) after Cs A treatment. At 7 days and 14 days partial Mayo scores were 4.6 ± 1.5 and 4.1 ± 1.6 points. A notable decrease in partial Mayo score was observed from baseline to day 7 and 14(p<0.001). CRP concentration were significantly difference from baseline time to day 7 and 14(P=0.034, P=0.016,respectively). 2) Total colectomy rates were 25.0%(2/8). One patient(40%) required surgery in short time. The other patient was operated on 3 month. Clinical response rate were 75.0%(6/8),50.0%(4/8),62.5%(5/8),62.5%(5/8)respectively at 1m,3m,6m and 1y, mucosal healing rate were 50%(4/8),37.5%(3/8),37.5%(3/8),37.5%(3/8)respectively at 1m,3m,6m and 1y. A notable decrease in Mayo score、partial Mayo score and Baron endoscope score was observed from baseline to 1m,3m,6m and 1y(P< 0.05). 3) Mean Cs A blood levels were174.77±60.55ng/ml in the intravenous Cs A and 190.60±57.07ng/ml in the oral Cs A. The main side-effects during treatment with Cs A were paraesthesia and tremor,nausea and vomiting,hypertrichosis,hypertension. In no case was Cs A discontinued because of an adverse reaction. There were not serious side effects in the moderate to low range of drug concentrations.4. Efficacy and safety of AZA in SDUC1) Clinical response rate were 65.4%,66.7%,71.5%,77.8% at 3m,6m,1y and 2y, respectively. Clinical remission rate were 26.9%,41.7%,52.5%,61.1% at 3m,6m,1y and 2y, respectively. Mucosal healing rate were 39.3%,53.6%,42.8%,70.0% at 3m,6m,1y and 2y, respectively. A notable decrease in Mayo score、partial Mayo score and Baron endoscope score was observed from baseline to 1m,3m,6m and 1y(P< 0.05). 2) Total colectomy rates were 14.3%(4/28).A significant decrease in clinical recurrence frequency and median cumulative yearly steroid dose( MCSD mg/year) were observed during 1 and 2 years on AZA compared with the previous year. MCSD were 4282, 1161 and 1042 before AZA therapy,at 1y and 2y during AZA therapy, respectively. clinical recurrence frequency were 2.28,0.91,0.76,before AZA therapy,at 1y and 2y during AZA therapy, respectively. 3) Only 1 patient had TPMT mutation. But adverse effects did not occur. Mean 6-TGN levels were242.7±79.4pmol/(8×108)RBC, 285.5±125.2 pmol/(8×108)RBC at 1y and 2y, respectively. There was no difference in 6-TGN levels between effcective group and ineffcective group(p>0.05). Adverse effects were observed in 9 patients(32.1%,9/28). Leukopenia(7 patients) was the most common adverse effect. AZA was withdrawn in 2 cases because of serious leucopenia.Conclusion:1. The majority of patients with SUC responded to initial CS treatment. However, a considerable number of patients eventually became refractory to or dependent on CS.The Mayo score and laboratory characteristics were factors useful in predicting short-term outcome of CS treatment. 2. IFX improved the symptoms and partial laboratory parameters of refractory moderate- to-severe active UC. The therapeutic benefit was also demonstrated by achievements in clinical response, clinical remission and mucosal healing at week 8 and week 26. The safey and efficacy data from this study support a favorable profile for IFX in treatment of Chinese patients with active UC. 3. Cs A is a relatively safe and effective treatment for refractory SUC in the moderate to low range of drug concentrations. Cs A is a viable alternative to emergency colectomy in 2 weeks short time. It induced long-term clinical response and mucosal healing of the patients during follow up one year. 4. A dose of 1-2.5mg/ kg/day of AZA is effective in SDUC,especially in Clinical response rate,Clinical remission rate and mucosal healing rate. Meanwhile, reduce MCSD and clinical recurrence frequency. AZA safety is better. Serious adverse events was rare, But need regular monitoring of WBC count. TPMT gene and 6-TGNs concentration may not be value for predicting the appearance of adverse events and efficacy.