Withdrawal Of Immunomodulators Research Articles

P1055 Intravenous to subcutaneous infliximab switch may reduce the risk of immunogenicity related treatment failure and can be used to facilitate immunomodulator withdrawal

Abstract Background Infliximab (IFX) is an effective treatment option for many patients with inflammatory bowel disease. Immunogenicity mediated treatment failure (IMTF) is a common clinical problem usually tackled by addition of an immunomodulator (IMM) and/or IFX dose escalation. Switching stable patients on IV IFX maintenance therapy to SC IFX has been shown to be safe and effective.1 It is hypothesised that SC IFX may reduce the risk of IMTF but there is little data to support this. We aimed to explore whether switching selected patients at risk of IMTF from IV to SC IFX was safe and effective and assess whether this strategy can facilitate treatment de-escalation and IMM withdrawal. Methods The local IBD database was used to identify potentially suitable patients at higher risk of IMTF. This included those on escalated doses of IV IFX, those who had developed low level anti-drug antibodies (ADA), and those on combination therapy in whom it was felt desirable to withdraw IMM. Those who agreed to switch were commenced on SC IFX 120mg fortnightly and followed up clinically and with IFX drug levels (DLs) and ADA at week 8, 24 and 52. Results 29 eligible patients underwent IV to SC IFX switch. Two patients were excluded: one returned to IV IFX and the other stopped IFX completely within 8 weeks of switch. Outcomes for 27 patients were evaluated: 10 with UC, 14 CD, 3 IBD-unclassified. Median age was 38 (IQR 31-49). Median duration of IV IFX was 34 months (IQR 24-54 months). 17 patients were on accelerated IV IFX dosing. All 27 patients remained on SC IFX at one year. Two required a course of steroids for disease flare. Of the 19 patients who had faecal calprotectin (FCP) data available, the mean FCP prior to switch was 66.1 (30-317) and post initiation of SC IFX was 189.6 (30 – 1800), but this did not reach statistical significance (p=0.172). 12/27 patients were on IV IFX plus IMM therapy. 9/12 successfully stopped IMM after switch to SC IFX. Mean DL prior to switch was 7.13 (2.7-12.5) and post switch was 12.07 (1.6-14.5). In those who were on accelerated IV IFX dosing, 15/17 saw an increase in DLs post switch. In the 8 patients who had ADAs prior to switch, all saw a reduction, with 6 having no detectable ADAs post switch. Conclusion Switching from IV to SC IFX in this cohort was safe and effective. Most patients maintained steroid free remission at one year. All those who stopped IMM were successfully maintained on monotherapy at 1 year. 15/17 people treated with escalated IV dosing were successfully switched to standard SC IFX dosing with improvement in mean IFX DLs and without loss of clinical effect.

Exam 1: Withdrawal of Immunomodulators or TNF Antagonists in Patients With Inflammatory Bowel Diseases in Remission on Combination Therapy: A Systematic Review and Meta-analysis

Exam 1: Withdrawal of Immunomodulators or TNF Antagonists in Patients With Inflammatory Bowel Diseases in Remission on Combination Therapy: A Systematic Review and Meta-analysis

Immunomodulator Withdrawal From Anti-TNF Therapy Is Not Associated With Loss of Response in Inflammatory Bowel Disease

The benefit of concomitant immunomodulators (thiopurines or methotrexate) in patients with inflammatory bowel disease (IBD) on anti-tumor necrosis factor α (anti-TNF) (infliximab or adalimumab) maintenance therapy is debated. We compared outcomes after immunomodulator withdrawal vs continuation of combination therapy. This was a retrospective cohort study in a general hospital and a tertiary referral center. We included adult IBD patients, receiving anti-TNF therapy for ≥4 months, plus an immunomodulator at baseline, between January 1, 2011, and January 1, 2019. The primary endpoints were loss of response (LOR) (ie, anti-TNF discontinuation because of disease activity) and anti-drug antibodies. Adjusted hazard ratios (aHRs) were calculated by mixed-effects Cox regression analysis. We included 614 treatment episodes of combination therapy in 543 individuals, yielding 1664 patient-years of follow-up. The immunomodulator was withdrawn in 296 (48.2%) episodes after 0.9 (interquartile range, 0.6-2.1) years, which was not associated with a higher risk of LOR (aHR, 1.08; 95% confidence interval [CI], 0.72-1.61), although anti-drug antibodies were detected more frequently (aHR, 2.14; 95% CI, 1.17-3.94), compared with continuation. Clinical remission at the time of withdrawal reduced the risk of LOR (aHR, 0.48; 95% CI, 0.25-0.93), while longer duration of combination therapy before withdrawal decreased the risk of anti-drug antibodies (HR per year, 0.56; 95% CI, 0.32-0.91). Higher prewithdrawal infliximab trough levels reduced the subsequent risks of anti-drug antibodies and LOR. Infliximab trough levels were lower after immunomodulator withdrawal (P= .01). Patients who withdrew the immunomodulator in this retrospective cohort were not at increased risk of LOR within the following 1-2 years, but an increase in anti-drug antibodies was observed. Our findings require prospective validation, preferably in adequately powered randomized controlled trials.

Mucormycosis in COVID-19 patients: predisposing factors, prevention and management.

India is considered the diabetes capital of the world and has the highest burden of mucormycosis. Bacterial, viral and fungal co-infections are increasingly being reported in severe acute respiratory syndrome virus 2 (SARSCoV-2) infected patients. India is one of the worst affected countries during the second wave of the COVID-19 pandemic. This combination of diabetes mellitus, COVID-19 and mucormycosis has led to the drastic upsurge of COVID-19-associated mucormycosis (CAM) in India. Immunosuppression, iron disequilibrium, endothelial injury, ketoacidosis and hypoxia are some of the other COVID-19-related risk factors for CAM. There has been an increase in the proportion of mucormycosis affecting paranasal sinuses and central nervous system (CNS) in CAM compared to pre-COVID-19 literature due to the SARSCoV-2-related pathophysiological mechanisms, complications and treatment strategies. CAM is a medical and surgical emergency, and it can present with non-specific symptoms and signs initially resulting in diagnostic delay. High index of suspicion and regular screening for features of CAM are of paramount importance to prevent lethal consequences. Rapid action with a tripod approach consisting of withdrawal of immunomodulators, early antifungal therapy and extensive surgical debridement is considered the best possible treatment model. We review the published data to give a detailed account of the predisposing factors and their mechanisms, diagnostic work-up, treatment modalities and prevention strategies of CAM with special emphasis on CNS mucormycosis.

DOP75 Loss-of-response and immunogenicity following immunomodulator withdrawal from anti-tumour necrosis factor alpha combination therapy: Results from a large retrospective cohort study

Abstract Background Combination therapy with anti-TNF compounds and immunomodulators (IMM; thiopurine or methotrexate) is superior to IMM or anti-TNF monotherapy in patients with inflammatory bowel disease (IBD). IMMs are frequently discontinued during the maintenance phase to mitigate the risk of adverse events, but long-term consequences of this practice are not well studied. We explored the real-world outcomes after IMM discontinuation, including loss-of-response (LOR), dose escalations, immunogenicity and trough levels. Methods This was a multicenter, retrospective cohort study in a general hospital and a tertiary referral center. We included adult patients with IBD, treated >4 months with infliximab (IFX) or adalimumab (ADA) and an IMM at baseline between 2011–2019. The IMM had to be started within 30 days of anti-TNF initiation, or continued for >30 days in case of prior IMM monotherapy. LOR was defined as anti-TNF discontinuation due to disease activity. Adjusted hazards rates (aHR) were calculated using mixed-effects Cox regression analysis with time-varying covariates, accounting for follow-up prior to and after IMM cessation. We adjusted for sex, age, BMI, smoking, Crohn’s disease (CD) vs ulcerative colitis (UC), disease duration, primary sclerosing cholangitis, rheumatological comorbidity, ADA vs IFX, and prior anti-TNF exposure. Results We included 615 episodes of combination therapy (543 individual patients; CD, n=382, 70%). The IMM was discontinued in 296 (48%) episodes after a median of 0.9 (IQR: 0.6 – 2.1) years, at which point 252 (85%) patients were in clinical remission. IMM withdrawal was performed as part of a de-escalation strategy (n=158, 53%), for intolerance (n=86, 29%) or for miscellaneous reasons (n=52, 18%). During a median follow-up of 1.7 (IQR 0.8 – 3.5) years after IMM withdrawal, 46 (16%) patients experienced LOR, 79 (32%) required dose-escalation and 31 (10.3%) developed anti-drug antibodies. Compared to IMM continuation, withdrawal did not significantly increase the risk of LOR (aHR 1.10, 95%CI: 0.74 – 1.64), but more patients required dose escalations (aHR 1.42, 95%CI 1.02 – 1.97) or developed anti-drug antibodies (aHR 2.22, 95%CI 1.21 – 4.08). Among patients who stopped the IMM, clinical remission at IMM withdrawal was the only predictor of LOR (aHR 0.48, 95%CI 0.23 – 0.99), while higher BMI (aHR 1.09, 95%CI 1.01 – 1.17) and shorter duration of combination therapy (Figure 1, aHR 0.57 per year, 95%CI 0.33 – 0.96) increased the risk of immunogenicity. IFX, but not ADA, trough levels decreased significantly after IMM withdrawal. Conclusion Withdrawal of immunomodulators is not associated with higher risk of LOR, but does increase the risk of dose-escalation and unfavorable pharmacokinetics.

Endoscopic score vs blood cell indices for determining timing of immunomodulator withdrawal in quiescent ulcerative colitis

While immunomodulators (IMs) are used as key drugs in remission maintenance treatment for ulcerative colitis (UC), there has been no evidence to date for determining monitoring methods and drug withdrawal. Therefore, we examined if a decrease in white blood cell count (WBC) and an elevation in mean cell volume (MCV) could be used as optimization indices and if mucosal healing (MH) could be a rationale for determining the time of IM withdrawal. Subjects were 89 UC patients who were using IMs and for whom clinical remission had been maintained. Those with a Rachmilewitz Clinical Activity Index score of 4 or lower and those with a Mayo endoscopic subscore (MES) of 0 or 1 were defined as MH. The remission maintenance rates of the following comparative groups were examined: an IM continuation group and an IM withdrawal group; an IM continuation group with a WBC of less than 3000 or a MCV of 100 or greater and an IM continuation group with a WBC of 3000 or greater and a MCV of 99 or lower; an IM continuation group of patients for whom MH had been achieved and an IM continuation group of patients for whom MH had not been achieved; and an IM withdrawal group with a MES of 0 and an IM withdrawal group with a MES of 1. A significantly higher remission maintenance rate was observed in the IM continuation group compared to the withdrawal group (p < 0.01). No significant difference was observed between the IM continuation group with a WBC of less than 3000 or a MCV of 100 or greater and the IM continuation group with a WBC of 3000 or greater and a MCV of 99 or lower (p = 0.08). Higher remission maintenance rates were observed in the IM continuation group of patients for whom MH had been achieved compared to the IM continuation group of patients for whom MH had not been achieved (p = 0.03). No significant difference was observed between the IM withdrawal group with MES 0 and the IM withdrawal group with MES 1. (p = 0.48). This retrospective study showed that remission maintenance could be firmly obtained by continuing IM administration in case of endoscopic MH; however, MH was not an indicator of IM withdrawal.

PTU-049 Concurrent Immunomodulator Therapy does not Influence Infliximab or Adalimumab Trough Levels During Maintenance Therapy

Introduction Combination therapy with infliximab (IFX) and immunomodulators (IM) is superior to monotherapy showing better outcomes at 1 year for Crohn’s disease 1 and UC. 2 Withdrawal of IM after 6 months of combination therapy has been shown not to adversely affect clinical outcomes though patients on concurrent thiopurine have higher trough levels and lower CRP. 3 The role of concomitant IM therapy is unclear for patients treated with adalimumab (ADA). We aimed to evaluate the impact of concomitant IM therapy on trough levels of IFX and ADA. Methods We conducted a retrospective observational study of all IBD patients on maintenance therapy who had had IFX and ADA trough levels measured between Jan13-Jan16. Testing was undertaken at the discretion of the treating clinician. Clinical information including duration of disease, site of disease, duration of anti-TNF therapy, IM therapy, smoking status, prior anti-TNF exposure, and disease activity was recorded. Drug level and anti-drug antibody measurements were performed on sera using the Lisa-Tracker IFX and ADA ELISA kit (Theradiag, France). Pairwise comparison of means was used to compare trough levels in patients with and without concomitant IM therapy. A multivariate logistic regression was used to correct for confounders and the impact on antibody formation assessed with Fishers exact test. Results 200 patients (120 IFX and 80 ADA) were included. 65.8% of IFX and 55% of ADA patients were on concurrent IM therapy. Mean ADA trough levels among patients on concurrent IM was 6.72±1.91µg/ml whilst patients not on concurrent IM had levels of 5.16±2.88 µg/ml(p = 0.005). This difference was not significant after adjustment for dose escalation. 23 patients (28.7%) were on weekly dosing whereas 57 (71.2%) were on alternate weeks. The mean trough level in patients on IM was 4.01±3.52 and not on IM was 3.96±2.83(p = 0.9). Thirty patients had positive antibodies and trough levels were 1.25±2.1µg/ml compared to 4.91±3.1µg/ml(p Conclusion Trough levels of IFX and ADA were not significantly different among maintenance patients with and without concomitant IM therapy. Surprisingly, the immunogenicity of IFX was not impacted by concurrent IM. References 1 Ruffolo C, et al . Infliximab, azathioprine, or combination therapy for Crohn’s disease. N Engl J Med 2010; 363 :1086–8. 2 Panaccione R, et al . Combination therapy with infliximab and azathioprine is superior to monotherapy with either agent in ulcerative colitis. Gastroenterology 2014; 146 :392–400. 3 Drobne D, et al . Withdrawal of immunomodulators after co-treatment does not reduce trough level of infliximab in patients with crohn’s disease. Clin Gastroenterol Hepatol 2015; 13 :514–21. Disclosure of Interest None Declared

Withdrawal of Immunomodulators After Co-treatment Does Not Reduce Trough Level of Infliximab in Patients With Crohn’s Disease

The addition of immunomodulators increases the efficacy of maintenance therapy with infliximab for up to 1 year in patients with Crohn's disease who have not been previously treated with immunomodulators. However, there are questions about the effect of withdrawing immunomodulator therapy from these patients. We studied the effects of treatment with infliximab and immunomodulators (co-treatment) and then immunomodulator withdrawal on long-term outcomes of patients, as well as trough levels of infliximab and formation of anti-infliximab antibodies (ATI). In a retrospective study with the median follow-up period of 34 months (interquartile range, 19-58 months), we analyzed data from 223 patients treated for Crohn's disease between May 1999 and December 2010 at the University Hospitals, Leuven, Belgium (65 received infliximab monotherapy, 158 received infliximab and an immunomodulator). Trough levels of infliximab and levels of ATI were measured in blood samples collected from 117 patients throughout co-treatment, as well as the time of immunomodulator withdrawal and after withdrawal. Patients receiving co-treatment had higher trough levels of infliximab (adjusted mean increase, 1.44-fold) than those receiving infliximab monotherapy (95% confidence interval [CI], 1.07-1.92; P= .02). A smaller percentage of patients receiving co-treatment developed ATI (35 of 158, 22%) than those receiving infliximab monotherapy (25 of 65, 38%; P= .01). Among co-treated patients, levels of infliximab remained stable after immunomodulators were withdrawn (before: 3.2 μg/mL; 95% CI, 1.6-5.8 μg/mL and after: 3.7 μg/mL; 95% CI, 1.3-6.3 μg/mL; P= .70). After withdrawal of immunomodulators, 45 of 117 patients (38%) required increasing doses of infliximab, and 21 of 117 (18%) discontinued infliximab. At the time of immunomodulator withdrawal, trough levels of infliximab and C-reactive protein were most strongly associated with response to infliximab thereafter. In a retrospective analysis, we confirmed that withdrawal of immunomodulators after at least 6months (median, 13 months) of co-treatment with infliximab does not reduce the trough levels of infliximab in patients with Crohn's disease. Detectable trough levels of infliximab at the time of immunomodulator withdrawal are associated with long-term response.

Crohn's Disease: Infliximab Trough Levels and CRP During Infliximab-Immunomodulator Combination Treatment Are Associated With Clinical Outcome After Immunomodulator Withdrawal

Crohn's Disease: Infliximab Trough Levels and CRP During Infliximab-Immunomodulator Combination Treatment Are Associated With Clinical Outcome After Immunomodulator Withdrawal

Withdrawal of Immunomodulators During Maintenance Therapy for Crohn Disease

For Crohn disease patients who achieve remission with infliximab, the advantages of cotherapy with an immunomodulator include lower risk for developing