P201 Evaluation of the role of anti-TNF in stabilizing the progression of intestinal lesions in Crohn’s disease using the Lemann Index

Background The Lemann Index (LI) was developed to assess cumulative digestive tract damage in patients with Crohn’s disease (CD), independently of clinical and biological activity. Recently, therapeutic goals in CD have focused on achieving mucosal healing and deep remission rather than simple symptom control, thus requiring prevention of progression of intestinal damage. The aim of this study was to assess the influence of different treatments on the progression of structural damage, using the LI. Methods we retrospectively included all patients with CD, followed in our center during the period between January 2016 and January 2020. The LI was calculated from the first (LI1) and the last (LI2) clinical consultations. The evolution of (LI1-LI2) or Delta LI (DLI) was recorded. Results 112 patients with CD were collected, of which 53.6% were female. The mean age at diagnosis was 33.29 years [15–63]. Active smoking was found in 34 patients (30.4%). Regarding the localization of CD, it was ileal (L1 according to the Montreal classification), colonic (L2), and ileocolonic (L3) in respectively 16.1%, 42.9% and 41%. The disease phenotype was inflammatory (B1) in 60.7%, stricturing (B2) in 21.42%, and penetrating (B3) in 17.85%. The initial flare was judged to be severe in 33.9% of cases, moderate in 55.4% of cases and mild in 10.7% of cases, with a mean CDAI of 305.21 [115–493]. Regarding maintenance treatment, 51.8% of patients (n = 58) were on Azathioprine, 23.2% (n = 26) were on aminosalicylates, and 25% (n = 28) were on anti-TNF, including 42, 9% under combination therapy. The median follow-up was 36.82 ± 16.83 months, with no difference between the groups. During follow-up, the mean LI increased significantly from 3.34 [0.58–8.82] to 7.82 [0.62–32.6] in the azathioprine group (p = 0.0001), from 2.0 [0.58–6.52] to 3.91 [0.6–14.03] in the Aminosalicylates group (p = 0.001) and from 3.79 [1.05–8.42] to 10.01 [2.58–33.08] in the Anti-TNF group (p = 0.0001). The mean DLI was -4.48 for the Azathioprine group, -1.9 for the Salicylates group and -6.14 for the Anti-TNF group, with no statistically significant difference (p = 0.16). Conclusion In patients with CD, the LI tends to increase over time. In our series, the use of Anti-TNF α does not appear to be able to reduce the progression of intestinal lesions, compared to other therapies.

LB004A RANDOMIZED, CONTROLLED TRIAL OF RITUXIMAB VERSUS AZATHIOPRINE AFTER INDUCTION OF REMISSION WITH RITUXIMAB FOR PATIENTS WITH ANCA-ASSOCIATED VASCULITIS AND RELAPSING DISEASE

Background and Aims Rituximab is an effective therapy for induction of remission in ANCA-associated vasculitis (AAV). However, the effect of rituximab is not sustained, and subsequent relapse rates are high, especially in patients with a history of relapse. The RITAZAREM trial (ClinicalTrials.gov identifier: NCT01697267) is an international, multi-center, open-labelled, randomized, controlled trial of patients with AAV with relapsing disease comparing the efficacy, after induction of remission with rituximab, of two relapse-prevention strategies: repeat dosing of rituximab or daily oral azathioprine. Method Patients with AAV were recruited at the time of relapse and received induction therapy with rituximab and glucocorticoids. If remission was achieved by month 4, patients were randomized in a 1:1 ratio to receive either rituximab (1000 mg every 4 months for 5 doses) or azathioprine (2 mg/kg/day) as maintenance therapy. Patients were followed for a minimum of 36 months, with the primary outcome being time to disease relapse. The formal hypothesis testing plan initially considers the hazard ratio for relapse across all time periods. If, and only if this global test is significant at a 5% level then the hazard ratios during the treatment period and the follow-up periods are considered separately. Results 190 patients were enrolled and 170 randomized at 4 months (85 to rituximab; 85 to azathioprine). The data are complete on all patients up to at least month 24. Median age was 59 years (range 19-89), with a prior disease duration of 5.3 years (0.4-38.5). 123/170 (72%) patients had a history of testing positive for anti-proteinase 3 ANCA; 47/170 (28%) for myeloperoxidase ANCA; 104/170 (61%) were enrolled having suffered a major relapse, and 48/170 (28%) received a pre-specified higher dose glucocorticoid induction regimen. Rituximab was superior to azathioprine in preventing disease relapse with a preliminary overall hazard ratio (HR) estimate of 0.36 (95% CI 0.23-0.57, p <0.001) and a during-treatment HR estimate of 0.30 (95% CI 0.15-0.60, p<0.001) (Figure 1). After adjustment, none of the randomization stratification covariates (ANCA type, glucocorticoid induction regimen, or relapse severity) had a significant differential effect on the primary outcome. By 24 months after entry, 20 months after randomization, 11/85 (13%) patients in the rituximab group had experienced a relapse compared to 32/85 (38%) patients in the azathioprine group. In the rituximab group 2/11 (18%) relapses were classified as major, compared to 12/32 (38%) in the azathioprine group. 19/85 (22%) patients in the rituximab group and 31/85 (36%) patients in the azathioprine group experienced at least one severe adverse event (SAE). 25/85 (29%) and 42/85 (49%) patients in the rituximab group developed hypogammaglobulinaemia (IgG <5g/l) and non-severe infections respectively, compared to 21/85 (25%) and 41/85 (48%) in the azathioprine group. Conclusion In the RITAZAREM trial, following induction of remission with rituximab, rituximab was superior to azathioprine for preventing disease relapse in patients with AAV with a prior history of relapse. There were no new major safety signals for use of these medications in this population.

Efficacy of Second Line Agents Dapsone & Azathioprine in Children & Adults with Immune Thrombocytopenia: Single Centre Experience from India

There are approximately 10 therapeutic agents listed as second line therapy for steroid refractory or relapsed ITP but there are no clear guidelines for timing & order of their use or that of splenectomy. At our center, we have used dapsone or azathioprine as second line therapy prior to splenectomy in such patients who do not have critical bleeding. This study describes the outcome of that approach. Three hundred patients fulfilling ITP International Working Group definition of steroid non-response & relapse ITP (Rodeghiero et al Blood 2009) were included. Response to treatment was assessed using American Society of Hematology 2011 guidelines (Neunert et al Blood 2011). This analysis was approved by the institutional ethics committee. Patients received either dapsone (n = 170) at 1-2 mg/kg/day or azathioprine (n = 130) at 1-3 mg/kg/day in escalating doses based on physician preferences. Additional intermittent corticosteroids were given in 36 patients. Data was retrieved from individual medical records and electronic database. Statistical analysis was performed using SPSS version 16.0 Results: Baseline characteristics of the patients & outcome are described in Table 1. After 3 months of therapy, overall response was 58.6% while it was 58.8% for the dapsone group and 58.5% for azathioprine group. The number of patients achieving complete & partial response was 46% & 12.7% for overall group, 45.9% & 13% for dapsone group & 46.2% & 12.3% for azathioprine group. The median duration of response was 35 months (2-74 months) and was significantly longer with azathioprine - 60 months (2-60 months) compared to 27 months (5-74 months) with dapsone (p=0.015). Therapy was well tolerated with 4 patients discontinuing dapsone (methemoglobinemia, dapsone syndrome) and 2 discontinuing azathioprine (cytopenia). There were no deaths. At a median follow up of 33 months (24-42 months), 67 (38%) of the 176 responders have relapsed. These included 49 patients that relapsed while on therapy and 18 that relapsed after cessation of therapy. Relapses were significantly more common with dapsone (40.3%) than azathioprine (20.4%) (p=0.002). The median time to relapse while on therapy was 14 months for both agents. Any response to second line therapy less than complete response (p=0.030) & steroid nonresponsive ITP (p=0.042) were significantly associated with increased risk of relapse on therapy. Overall, 59.6% patients responding to dapsone and & 79.5% of patients responding to azathioprine continue to remain in remission both on & off therapy. Patients who switched to dapsone at the time of relapse showed significantly better response rate - 54% than azathioprine - 22.2% (p<0.001). Forty one patients who failed second line therapy eventually underwent splenectomy, with a response rate of 70.7%. In conclusion, the use of dapsone & azathioprine appears to be a safe approach, with need for splenectomy only in a few patients. The optimal dose & duration of therapy for these agents needs further evaluation in prospective studies. Table 1. Patient Characteristics Characteristics Total (%) N = 300 Dapsone (%) n = 170 Azathioprine (%) n = 130 P value Children 104 (34.7) 64(37.7) 40(30.7) ns Adults 196 (65.3) 106(62.3) 90(69.3) ns Male:Female Ratio 0.56:1 0.68:1 0.42:1 0.069 Median ITP Duration (months) 5 (1-262) 4 (1-262) 6 (1-146) ns Steroid Non-responsive 144 90 (52.9) 54 (41.5) 0.062 Relapsed ITP 156 80 (47.1) 76 (58.5) 0.062 Overall Response 176 (58.6) 100 (58.8) 76 (58.5) ns Complete Response 138 (46) 78 (45.9) 60 (46.2) ns Relapse rates 67/176 (38) 40.3% 20.4% 0.002 ns = not significant Disclosures No relevant conflicts of interest to declare.

Randomized study with cyclosporine in kidney transplantation: 10-year follow-up.

This study presents the 10-yr follow-up results of a multicenter controlled trial on 108 recipients of cadaveric renal transplantation, randomized to receive cyclosporine (N = 55) or azathioprine (N = 53), both in combination with steroids. The 10-yr patient survival rate was 89% in the cyclosporine group and 83% in the azathioprine group (P = not significant [NS]); the 10-yr graft survival was 56% and 35%, respectively (log-rank test, P = 0.009). The half-life of grafts functioning after 1 yr was 15.4 +/- 3.9 versus 10.6 +/- 3.6, P = NS). The rate of early rejection in the cyclosporine group was significantly lower than that in the azathioprine group (0.30 versus 1.4, P < 0.01). Although the mean creatinine clearance rate was always higher in the azathioprine group, the decline in graft function from the first to the tenth yr was not significantly different between the two groups (-13.0 +/- 16.4 versus -12.3 +/- 19 mL/min, P = NS). In cadaveric renal transplantation, cyclosporine allows better graft survival than azathioprine, not only in the short term but also in the long term, with similar attrition of graft function for up to 10 yr.

A Comparison of Cyclosporin versus Azathioprine Treatment in Renal Transplants in Edinburgh

Three year graft survival rates were calculated for 66 patients on cyclosporin and prednisolone immunosuppression and compared to survival rates for 73 patients on azathioprine and prednisolone. There was a temporary early advantage for the cyclosporin treatment group up to four months post transplant. There was no further significant difference between the two treatment groups with graft survival rate of 81.4% in cyclosporin and 76.7% in azathioprine group at three years post transplant. Fewer of the patients on cyclosporin had acute episodes of rejection. There was no significant difference in serum creatinine or urea at one year, but the haemoglobin level was higher in cyclosporin treated patients. Cyclosporin does not appear to have increased the survival rate significantly in our centre where there is already a high graft survival with azathioprine.