Infliximab Combination Therapy Research Articles

Neutralising antibody responses against SARS-CoV-2 Omicron BA.4/5 and wild-type virus in patients with inflammatory bowel disease following three doses of COVID-19 vaccine (VIP): a prospective, multicentre, cohort study

Patients with inflammatory bowel disease (IBD) receiving anti-TNF and JAK-inhibitor therapy have attenuated responses to COVID-19 vaccination. We aimed to determine how IBD treatments affect neutralising antibody responses against the Omicron BA.4/5 variant. In this multicentre cohort study, we prospectively recruited 340 adults (69 healthy controls and 271 IBD) at nine UK hospitals between May 28, 2021 and March 29, 2022. The IBD study population was established (>12 weeks therapy) on either thiopurine (n=63), infliximab (n=45), thiopurine and infliximab combination therapy (n=48), ustekinumab (n=45), vedolizumab (n=46) or tofacitinib (n=24). Patients were excluded if they were being treated with any other immunosuppressive therapies. Participants had two doses of either ChAdOx1 nCoV-19 or BNT162b2 vaccines, followed by a third dose of either BNT162b2 or mRNA1273. Pseudo-neutralisation assays against SARS-CoV-2 wild-type and BA.4/5 were performed. The half maximal inhibitory concentration (NT50) of participant sera was calculated. The primary outcome was anti-SARS-CoV-2 neutralising response against wild-type virus and Omicron BA.4/5 variant after the second and third doses of anti-SARS-CoV-2 vaccine, stratified by immunosuppressive therapy, adjusting for prior infection, vaccine type, age, and interval between vaccination and blood collection. This study is registered with ISRCTN (No. 13495664). Both heterologous (first two doses adenovirus vaccine, third dose mRNA vaccine) and homologous (three doses mRNA vaccine) vaccination strategies significantly increased neutralising titres against both wild-type SARS-CoV-2 virus and the Omicron BA.4/5 variant in healthy participants and patients with IBD. Antibody titres against BA.4/5 were significantly lower than antibodies against wild-type virus in both healthy participants and patients with IBD (p<0.0001). Multivariable models demonstrated that neutralising antibodies against BA.4/5 after three doses of vaccine were significantly lower in patients with IBD on infliximab (Geometric Mean Ratio (GMR) 0.19 [0.10, 0.36], p<0.0001), infliximab and thiopurine combination (GMR 0.25 [0.13, 0.49], p<0.0001) or tofacitinib (GMR 0.43 [0.20, 0.91], p=0.028), but not in patients on thiopurine monotherapy, ustekinumab, or vedolizumab. Breakthrough infection was associated with lower neutralising antibodies against wild-type (p=0.037) and BA.4/5 (p=0.045). A third dose of a COVID-19 mRNA vaccine based on the wild-type spike glycoprotein significantly boosts neutralising antibody titres in patients with IBD. However, responses are lower against the Omicron variant BA.4/5, particularly in patients taking anti-TNF and JAK-inhibitor therapy. Breakthrough infections are associated with lower neutralising antibodies and immunosuppressed patients with IBD may receive additional benefit from bivalent vaccine boosters which target Omicron variants. Pfizer.

Withdrawal of infliximab or concomitant immunosuppressant therapy in patients with Crohn's disease on combination therapy (SPARE): a multicentre, open-label, randomised controlled trial

The combination of infliximab and immunosuppressant therapy is a standard management strategy for patients with Crohn's disease. Concerns regarding the implications of long-term combination therapy provided the rationale for a formal clinical trial of treatment de-escalation. Our aim was to compare the relapse rate and the time spent in remission over 2 years between patients continuing combination therapy and those stopping infliximab or immunosuppressant therapy. This multicentre, open-label, randomised controlled trial was performed in 64 hospitals in seven countries in Europe and Australia. Adult patients with Crohn's disease in steroid-free clinical remission for more than 6 months, on combination therapy of infliximab and immunosuppressant therapy for at least 8 months were randomly assigned (1:1:1) to either continue combination therapy (combination group), discontinue infliximab (infliximab withdrawal group), or discontinue immunosuppressant therapy (immunosuppressant withdrawal group). Randomisation was stratified according to disease duration before start of first anti-TNF treatment (≤2 or >2 years), failure of immunosuppressant therapy before start of infliximab, and presence of ulcers at baseline endoscopy. The patient number and group of each stratum were assigned by a central online randomisation website. Treatment was optimised or resumed in case of relapse in all groups. Participants, those assessing outcomes, and those analysing the data were not masked to group assignment. The coprimary endpoints were the relapse rate (superiority analysis) and time in remission over 2 years (non-inferiority analysis, non-inferiority margin 35 days). Analyses were done on an intention-to-treat basis. This study is registered with ClinicalTrials.gov, NCT02177071, and with EU Clinical Trials Register, EUDRACT 2014-002311-41. The trial was completed in April, 2021. Between Nov 2, 2015, and April 24, 2019, 254 patients were screened. Of these, 211 were randomised and 207 were included in the final analysis (n=67 in the combination group, n=71 in the infliximab withdrawal group, and n=69 in the immunosuppressant withdrawal group). 39 patients had a relapse (eight [12%] of 67 in the combination group, 25 [35%] of 71 in the infliximab withdrawal group, six [9%] of 69 in the immunosuppressant withdrawal group). 2-year relapse rates were 14% (95% CI 4-23) in the combination group, 36% (24-47) in the infliximab withdrawal group, and 10% (2-18) in the immunosuppressant withdrawal group (hazard ratio [HR] 3·45 [95% CI 1·56-7·69], p=0·003, for infliximab withdrawal vs combination, and 4·76 [1·92-11·11], p=0·0004, for infliximab withdrawal vs immunosuppressant withdrawal). Of 28 patients who had a relapse and were retreated or optimised according to protocol, remission was achieved in 25 patients (one of two in the combination group, 22 of 23 in the infliximab withdrawal group, and two of three in the immunosuppressant withdrawal group). The mean time spent in remission over 2 years was 698 days (95% CI 668-727) in the combination group, 684 days (651-717) in the infliximab withdrawal group, and 706 days (682-730) in the immunosuppressant withdrawal group. The difference in restricted mean survival time in remission was -14 days (95% CI -56 to 27) between the infliximab withdrawal group and the combination group and -22 days (-62 to 16) between the infliximab withdrawal group and the immunosuppressant withdrawal group. The 95% CIs contained the non-inferiority threshold (-35 days). We recorded 31 serious adverse events, in 20 patients, with no difference in frequency between groups. The most frequent serious adverse events were infections (four in the combination group, two in the infliximab withdrawal group, and one in the immunosuppressant withdrawal group) and Crohn's disease exacerbation (three in the combination group, four in the infliximab withdrawal group, and one in the immunosuppressant withdrawal group). No death nor malignancy was recorded. In patients with Crohn's disease in sustained steroid-free remission under combination therapy with infliximab and immunosuppressant therapy, withdrawal of infliximab should only be considered after careful assessment of risks and benefits for each patient, whereas withdrawal of immunosuppressant therapy could generally represent a preferable strategy when considering treatment de-escalation. European Union's Horizon 2020.

COVID-19 vaccine-induced antibody and T-cell responses in immunosuppressed patients with inflammatory bowel disease after the third vaccine dose (VIP): a multicentre, prospective, case-control study

BackgroundCOVID-19 vaccine-induced antibody responses are reduced in patients with inflammatory bowel disease (IBD) taking anti-TNF or tofacitinib after two vaccine doses. We sought to assess whether immunosuppressive treatments were associated with reduced antibody and T-cell responses in patients with IBD after a third vaccine dose.MethodsVIP was a multicentre, prospective, case-control study done in nine centres in the UK. We recruited immunosuppressed patients with IBD and non-immunosuppressed healthy individuals. All participants were aged 18 years or older. The healthy control group had no diagnosis of IBD and no current treatment with systemic immunosuppressive therapy for any other indication. The immunosuppressed patients with IBD had an established diagnosis of Crohn's disease, ulcerative colitis, or unclassified IBD using standard definitions of IBD, and were receiving established treatment with one of six immunosuppressive regimens for at least 12 weeks at the time of first dose of SARS-CoV-2 vaccination. All participants had to have received three doses of an approved COVID-19 vaccine. SARS-CoV-2 spike antibody binding and T-cell responses were measured in all participant groups. The primary outcome was anti-SARS-CoV-2 spike (S1 receptor binding domain [RBD]) antibody concentration 28–49 days after the third vaccine dose, adjusted by age, homologous versus heterologous vaccine schedule, and previous SARS-CoV-2 infection. The primary outcome was assessed in all participants with available data.FindingsBetween Oct 18, 2021, and March 29, 2022, 352 participants were included in the study (thiopurine n=65, infliximab n=46, thiopurine plus infliximab combination therapy n=49, ustekinumab n=44, vedolizumab n=50, tofacitinib n=26, and healthy controls n=72). Geometric mean anti-SARS-CoV-2 S1 RBD antibody concentrations increased in all groups following a third vaccine dose, but were significantly lower in patients treated with infliximab (2736·8 U/mL [geometric SD 4·3]; p<0·0001), infliximab plus thiopurine (1818·3 U/mL [6·7]; p<0·0001), and tofacitinib (8071·5 U/mL [3·1]; p=0·0018) compared with the healthy control group (16 774·2 U/mL [2·6]). There were no significant differences in anti-SARS-CoV-2 S1 RBD antibody concentrations between the healthy control group and patients treated with thiopurine (12 019·7 U/mL [2·2]; p=0·099), ustekinumab (11 089·3 U/mL [2·8]; p=0·060), or vedolizumab (13 564·9 U/mL [2·4]; p=0·27). In multivariable modelling, lower anti-SARS-CoV-2 S1 RBD antibody concentrations were independently associated with infliximab (geometric mean ratio 0·15 [95% CI 0·11–0·21]; p<0·0001), tofacitinib (0·52 [CI 0·31–0·87]; p=0·012), and thiopurine (0·69 [0·51–0·95]; p=0·021), but not with ustekinumab (0·64 [0·39–1·06]; p=0·083), or vedolizumab (0·84 [0·54–1·30]; p=0·43). Previous SARS-CoV-2 infection (1·58 [1·22–2·05]; p=0·0006) was independently associated with higher anti-SARS-CoV-2 S1 RBD antibody concentrations and older age (0·88 [0·80–0·97]; p=0·0073) was independently associated with lower anti-SARS-CoV-2 S1 RBD antibody concentrations. Antigen-specific T-cell responses were similar in all groups, except for recipients of tofacitinib without evidence of previous infection, where T-cell responses were significantly reduced relative to healthy controls (p=0·021).InterpretationA third dose of COVID-19 vaccine induced a boost in antibody binding in immunosuppressed patients with IBD, but these responses were reduced in patients taking infliximab, infliximab plus thiopurine, and tofacitinib. Tofacitinib was also associated with reduced T-cell responses. These findings support continued prioritisation of immunosuppressed groups for further vaccine booster dosing, particularly patients on anti-TNF and JAK inhibitors.FundingPfizer.

Immunogenicity of BNT162b2 Vaccine Booster Dose in Patients With Inflammatory Bowel Disease Receiving Infliximab Combination Therapy: A Prospective Observational Study.

IntroductionFew data exist regarding the immunogenicity of the third dose of BNT162b2 relative to the second dose in patients with inflammatory bowel disease (IBD) on different immunosuppressive therapies. We investigated the immunogenicity of BNT162b2 vaccine booster dose in patients with IBD on infliximab combination therapy.MethodThis is a prospective single-center observational study conducted from January 1, 2022 to February 28, 2022. Patients were recruited at the time of attendance at the infusion center. Eligibility criteria included patients with a confirmed diagnosis of IBD who are receiving infliximab with azathioprine or 6-mercaptopurine. Patients who received two doses of BNT162b2 vaccine (second dose group) were compared to patients who had received three doses of BNT162b2 vaccine [third dose (booster) group]. Patients were excluded if they were infected or had symptoms of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) previously since the start of the pandemic or received other vaccines than the BNT162b2. Our primary outcome was the concentrations of SARS-CoV-2 antibodies Immunoglobulin G (IgG) and neutralizing antibodies 40–45 weeks from the first dose of BNT162b2 vaccine in patients with IBD receiving infliximab combination therapy. Medians with interquartile range (IQR) were calculated.ResultsIn total, 162 patients with IBD and receiving infliximab combination therapy were recruited, and the number of patients in both the second dose group and third dose (booster) group was 81. Mean age was 35 years old in both groups. Median (IQR) SARS-CoV-2 IgG levels were significantly lower after the second dose [125 BAU/ml (43, 192)] compared to patients who received the third booster dose [207 BAU/ml (181, 234)] (P = 0.003). Neutralizing antibody levels were also lower after the second dose [80% (21, 95)] compared to patients who received the third booster dose [96% (93, 99)] (P ≤ 0.001). The percentage of patients who achieved positive SARS-CoV-2 IgG levels in the third (booster) dose group was 96.3%, whereas it was 86.4% in the second dose group. The percentage of participants who received the third (booster) dose and achieved a positive SARS-CoV-2-neutralizing antibody level was 100%, whereas it was 88.9% in the participants who received the second dose only.ConclusionMost patients with IBD on infliximab combination therapy had positive SARS-CoV-2 IgG and neutralizing antibody concentrations 40–45 weeks post BNT162b2 vaccination. However, SARS-CoV-2 IgG and neutralizing antibody concentrations were lower in patients who received two doses only compared to patients who received a third dose. A longer follow-up study is needed to evaluate decay in antibodies over time.

OP21 COVID-19 vaccine-induced antibody responses are impaired in Inflammatory Bowel Disease patients treated with infliximab, ustekinumab or tofacitinib, but not thiopurines or vedolizumab

BackgroundRobust COVID-19 vaccine-induced antibody (Ab) responses are important for protective anti-viral immunity. Data are urgently needed to determine whether vaccine-induced immunity is impacted by commonly used immunosuppressive drug regimens in IBD.MethodsWe prospectively recruited 447 adults (90 healthy controls and 357 IBD) at nine UK centres. The IBD study population was established (>12 weeks therapy) on either thiopurine monotherapy (n=78), infliximab (IFX) monotherapy (n=61), thiopurine & IFX combination therapy (n=70), ustekinumab (uste) monotherapy (n=56), vedolizumab (vedo) monotherapy (n=62) or tofacitinib (tofa) monotherapy (n=30). Participants had two doses of either ChAdOx1 nCoV-19, BNT162b2 or mRNA1273 vaccines. The primary outcome was anti-SARS-CoV-2 spike (S1 RBD) Ab concentrations, measured using the Elecsys anti-SARS-CoV-2 spike (S) Ab assay, 53–92 days after second vaccine dose, in participants without prior infection, adjusted by age & vaccine type. Secondary outcomes included proportions failing to generate protective Ab responses (defined cut-off anti-S concentration 15U/mL, which correlated with 20% viral neutralization).ResultsGeometric mean S Ab concentrations (figure 1) were lower in patients treated with IFX (153U/mL;p<0.0001), IFX and thiopurine combination (109U/mL;p<0.0001), tofa (430U/mL;p<0.0001) and uste (561U/mL;p=0.013) compared to controls (1596U/ml). No differences in S Ab concentrations were found between controls and thiopurine monotherapy-treated patients (1020U/mL;p=0.62), nor between controls and vedo-treated patients (944 U/mL;p=0.69). In multivariable modelling (figure 2), lower S Ab concentrations were independently associated with IFX (FC 0.10 [95% CI 0.07–0.14], p<0.0001), tofa (0.36 [95% CI 0.19–0.69],p=0.002) and uste (0.56 [95% CI 0.31–1.00],p=0.049), but not with thiopurine (0.77 [95% CI 0.54–1.11],p=0.17) or vedo (1.01 [95% CI 0.61–1.68],p=0.96). mRNA vaccines (3.67 [95% CI 2.72–4.96],p<0.0001) and older age (0.82 [95% CI 0.73–0.91],p=0.0003) were independently associated with higher & lower S Ab concentrations respectively. Protective Ab responses were generated by all thiopurine monotherapy, vedo, tofa and healthy control participants, but not by 11% of patients on IFX monotherapy, 13% on thiopurine & IFX combination therapy and 4% on uste. ConclusionCOVID-19 vaccine-induced Ab responses are significantly reduced in patients treated with IFX, or tofa, and to a lesser extent with uste. No significant reduction was seen in vedo or thiopurine monotherapy-treated patients. Our data suggest that 3rd primary or booster vaccine doses for IBD patients might be tailored to an individual’s immunosuppressive treatment.Financial support was provided as a Research Grant by Pfizer Ltd.

OP01 Withdrawal of infliximab or anti-metabolite therapy in Crohn’s Disease patients in sustained remission on combination therapy: A randomized unblinded controlled trial (SPARE)

Abstract Background Combination therapy with infliximab and anti-metabolites is a standard option for patients with Crohn’s disease (CD). The implications of long term use of combination therapy may lead patients and clinicians to contemplate treatment de-escalation once steroid-free remission has been achieved. The aim of our study was to assess the relapse rates and time spent in remission over 2 years, after withdrawal of infliximab or anti-metabolite compared to continuation of combination therapy. Methods CD patients treated with a combination therapy of infliximab (IFX) and anti-metabolite &amp;gt; 8 months and in sustained steroid-free remission &amp;gt; 6 months were recruited in 64 centers in France, United Kingdom, Belgium, Sweden, Australia, Germany and The Netherlands. Patients were randomized into 3 arms - continuing combination therapy (arm A); stopping IFX (arm B); or stopping anti-metabolite (arm C). In case of a relapse [defined by CDAI and an objective marker of inflammation (CRP or fecal calprotectin)], patients were retreated by resuming infliximab in arm B or the anti-metabolite in arm C, according to a pre-defined scheme, including optimization of IFX up to 10 mg/Kg if necessary in all arms. The two co-primary endpoints were the relapse rate and mean survival time spent in remission over 2 years. A major secondary endpoint was treatment failure (complications or not recapturing remission). Results 254 patients were screened, 211 randomized, 5 withdrew consent and 1 was lost to follow-up, leaving 205 patients for the analysis - 67 randomized to arm A, 71 to arm B and 67 to arm C. Demographic and clinical characteristics are shown in Table 1. The two-year relapse rates were 14% (IC95%: 4–23%) in arm A, 40% (IC95%: 28–51%) in arm B, and 10% (IC95%: 2–18%) in arm C (p=0.0003 arm B vs arm A and &amp;lt;0.0001 arm B vs arm C) (figure 1). The time spent in remission was 1.91 yrs (IC95%: 1.83–1.99), 1.89 yrs (IC95%: 1.82–1.96) and 1.93 yrs (IC95%: 1.86–2.00) in arm A, B and C, respectively. Out of the 39 relapsers, 28 were retreated/optimized. Remission was achieved in 1/2 retreated patients in arm A, 22/23 in arm B and 2/3 in arm C. Treatment failure was observed in 4/67, 4/71 and 3/67 patients, in these three arms, respectively. No malignancy was observed, one tuberculosis in arm C and two severe infections (pneumonia and viral pericarditis) in arm B. Conclusion Infliximab withdrawal, but not antimetabolite withdrawal, was associated with a significantly higher risk of relapse than continuation of combination therapy. Almost all patients who stopped IFX achieved rapid remission when resuming treatment. The time spent in remission over 2 years was similar across groups.

P494 A serum metabolite panel predicts Crohn’s disease relapse in patients discontinuing infliximab and continuing antimetabolite therapy: sub-analysis of the SPARE Trial

Abstract Background Combination therapy with infliximab and anti-metabolites is an effective strategy for maintaining remission in patients with Crohn’s disease (CD); however, the implications of long-term combination therapy has led clinicians to consider discontinuing one of the two agents after sustained remission has been achieved. The SPARE investigators have addressed this in an unblinded clinical trial in which 211 patients were randomised to either continuation of combination therapy, withdrawal of infliximab, or withdrawal of antimetabolite therapy. Here, we aimed to determine whether nuclear magnetic resonance (NMR)-based metabolomics analysis of patient sera at baseline could determine which patients randomised to infliximab withdrawal would relapse over 2-years on anti-metabolite monotherapy. Methods The study cohort comprised patients randomised to infliximab cessation who had a serum aliquot available for analysis (n=63). All patients had been treated with a combination therapy of infliximab (IFX) and anti-metabolite &amp;gt;8 months and had been in sustained steroid-free remission &amp;gt;6 months. Disease relapse was defined by CDAI&amp;gt;250 (or between 150–250 with 70 points increase over two consecutive weeks) alongside serum CRP and faecal calprotectin levels. Untargeted metabolomic profiling was carried out using NMR spectroscopy. Key metabolites were identified by their variable importance in projection (VIP) score using orthogonal partial least squares discriminant analysis (OPLS-DA) with 10-fold cross-validation on independent data. Multiple logistic regression on the metabolites with highest VIP score was used to report a receiver operator characteristic (ROC) curve integral (AUC) value after collinear variables were removed. Results Of 63 patients, 21 (33%) relapsed. The mean time to relapse after infliximab discontinuation was 7.9 months. Four independent (multicollinearity R2&amp;lt;0.4) serum metabolites (alanine, glutamine, acetoacetate, glucose) identified relapse with an AUC of 0.84 (95% confidence interval 0.74–0.94, p&amp;lt;0.0001). The positive predictive value was 66.7%, and the negative predictive value was 77.1%. All serum metabolites identified were independent of baseline CRP level (p&amp;gt;0.05, Pearson correlation). Patients who relapsed following infliximab discontinuation had significantly elevated serum acetoacetate and decreased alanine and glutamine levels (post-hoc students t-test, p&amp;lt;0.05) at baseline. Conclusion Here, we identify a panel of serum metabolites independent of baseline serum CRP, which predict high risk of disease relapse after infliximab discontinuation. These data may help in stratifying patients suitable for drug withdrawal, together with other clinical and multi-omic parameters.

P619 Patterns of Anti-TNF Prescribing &amp; Therapy Outcome in a Large Multicentre Cohort of Inflammatory Bowel Disease Patients

Abstract Background Anti-TNF agents are effective therapies for Inflammatory Bowel Disease (IBD), however, a significant proportion of patients lose response over time. Real world data on prescribing practices and outcome of anti-TNF therapy are of utility to practicing clinicians Methods To evaluate Anti-TNF prescribing practice and durability of Anti-TNF response in a large multicentre IBD cohort. IBD patients commencing an anti-TNF agent, as first biologic therapy, at participating academic centres were identified from institutional databases. Baseline demographic data, concomitant medication and biologic therapy history were collected. Adalimumab(ADA) and Golimumab(GOL) were consider subcutaneous(SC) anti-TNF agents. Date of commencement and discontinuation of first and second line anti-TNF therapy was documented. Kaplan-Meier survival curves were constructed for time based analyses. P values less than 0.05 were considered significant in all analyses. Results N=991 patients with IBD were included in the study. 29%, 69% and 2% had UC, CD and IBD-U respectively; median [IQR] age 27 [19–37] years; 50% female. 31%, 63% and 4% received infliximab(IFX), ADA and GOL respectively as first-line anti-TNF therapy. 35% of patients received an immunomodulator in combination with first-line anti-TNF agent. Median [95% CI] survival free of therapy discontinuation for first and second-line anti-TNF agents was 4.6 [3.7 – 5.3] years and 3.0 [2.1 – 3.9] years respectively. Survival free of anti-TNF discontinuation was significantly shorter for IFX monotherapy group compared with IFX combination therapy, SC anti-TNF monotherapy and SC anti-TNF combination therapy groups, p=0.005. Conclusion While anti-TNF therapies are effective a significant proportion of patients discontinue therapy over time. Second line anti-TNF therapy results in a less durable response with a shorter time to drug discontinuation compared with first line anti-TNF therapy. The use of a combination immunomodulator is particularly important with infliximab therapy, however, does not influence durability of response for subcutaneous anti-TNF agents.

NUDT15 intermediate metabolisers are associated with lower loss of response in paediatric Crohn's disease patients treated by combination treatment with infliximab and azathioprine.

NUDT15 polymorphisms are associated with leukopenia during treatment with thiopurines. However, data regarding its effect on treatment outcomes are scarce. To investigate the outcomes between NUDT15 normal and intermediate metabolisers in paediatric patients with Crohn's disease (CD) treated with a combination therapy of infliximab (IFX) and azathioprine (AZA). In this retrospective observational study, 143 patients categorised into the NUDT15 normal and intermediate metaboliser groups were compared based on clinical remission (CR), biochemical remission (BR), mucosal healing (MH) at 1year treatment, IFX trough levels (TLs), antibodies to IFX (ATIs), 6-thioguanine nucleotide (6-TGN) levels, loss of response (LOR) and IFX durability. No significant differences were observed between the groups in CR, BR, MH at 1year, whereas IFX TLs and ATIs and 6-TGN levels were comparable. However, LOR (6.5% vs 27.7%, P=0.025) was significantly lower and IFX durability significantly higher (96.8% vs 80.4% P=0.027) in the intermediate group. Multivariable Cox proportional hazard regression analysis showed that ATI positivity (hazard ratio (HR): 4.76, 95% CI: 2.25-10.07, P<0.001) and the NUDT15 metaboliser group was associated with LOR (HR: 0.18, 95% CI: 0.04-0.76, P=0.019). The Kaplan-Meier survival curves showed that the LOR-free survival rate was significantly lower in normal metabolisers (log-rank test P=0.009). NUDT15 intermediate metabolisers were associated with lower LOR in paediatric patients with CD treated with IFX and AZA combination therapy. This finding may partially explain the longer durability of IFX in Korean children than their counterparts in Western countries.

Immunogenicity of BNT162b2 Vaccine in Patients with Inflammatory Bowel Disease on Infliximab Combination Therapy: A Multicenter Prospective Study.

Background: Vaccination is a promising strategy to protect vulnerable groups like inflammatory bowel disease (IBD) patients against COVID-19 and associated severe outcomes. COVID-19 vaccine clinical trials excluded IBD patients taking infliximab with azathioprine or 6-mercaptopurine (infliximab combination). Therefore, we sought to evaluate serologic responses to COVID-19 vaccination with the mRNA vaccine, BNT162b2, in patients with IBD receiving infliximab combination therapy compared with healthy participants. Method: This was a multicenter prospective study. Patients with IBD were recruited at the time of attendance at infusion center between 1 August 2021, and 15 September 2021. Our primary outcome were the concentrations of SARS-CoV-2 antibodies 4–10 weeks after vaccination with two doses of BNT162b2 vaccine in patients with IBD taking infliximab combination therapy (study group) compared with a healthy participants group (control group). Both study and control groups were matched for age, sex, and time-since-last-vaccine-dose using optimal pair-matching method. Results: In total, 116 participants were recruited in the study, 58 patients in the study group and 58 in the control group. Median (IQR) IgG concentrations were lower in the study group (99 BAU/mL (40, 177)) than the control group (139 BAU/mL (120, 188)) following vaccination (p = 0.0032). Neutralizing antibodies were also lower in the study group compared with the control group (64% (23, 94) vs. 91% (85, 94), p < 0.001). The median IgA levels in the study group were also significantly lower when compared with the control group (6 U/mL (3, 34) vs. 13 U/mL (7, 30), p = 0.0097). In the study group, the percentages of patients who achieved positive IgG, neutralizing antibody and IgA levels were 81%, 75%, and 40%, respectively. In the control group, all participants (100%) had positive IgG and neutralizing antibody levels while 62% had positive IgA levels. Conclusion: In patients with IBD receiving infliximab combination therapy, SARS-CoV2 IgG, IgA, and neutralizing antibody levels after BNT162b2 vaccination were lower compared with healthy participants. However, most patients treated with infliximab combination therapy seroconverted after two doses of the vaccine.

Infliximab plus azathioprine is more effective than azathioprine alone in achieving mucosal healing in pediatric patients with Crohn's disease.

Over the past few years, mucosal healing (MH) has emerged as a promising goal in the treatment of pediatric patients with Crohn's disease (CD). We aimed to assess whether combination therapy with infliximab (IFX) + azathioprine (AZA) was more effective than AZA therapy alone in achieving mucosal healing in pediatric patients with CD. Newly diagnosed pediatric patients with CD at the Department of Pediatrics in University Hospital in Hradec Králové were retrospectively recruited (2000-2014). The patients were divided into two groups according to the therapy: (a) IFX + AZA ± corticosteroids ± 5-aminosalicylic acid (5-ASA) (n = 16); and (b) AZA ± corticosteroids ± 5-ASA (n = 40). The patients were also divided into two groups: "MH" and "no MH," according to their MH status. MH was defined as the complete endoscopic disappearance of all mucosal ulcerations (including aphthous ulcerations) and the absence of any sign of mucosal inflammation in the terminal ileum and the large bowel. Of 56 patients, MH was observed in 56% (9/16) treated with combined therapy in comparison with 15% (6/40) of patients in the AZA group (P = 0.006). The median dose of AZA in both groups was 2.1 mg/kg per day. We observed eight adverse events in seven patients from the IFX + AZA group. Adverse effects were less common in the AZA group (P = 0.002). Combined therapy (IFX + AZA) was more effective in achieving MH in pediatric CD than treatment with AZA alone.

Clinical experience of combination therapy of infliximab and total glucosides of paeony for severe psoriasis with liver disorder history

Severe psoriasis patients are reported to have a higher risk of liver abnormalities. Treatment option for severe psoriasis patients with liver disorder history remains a great challenge. Hepatic toxicity and long-term safety are the major concerns. Hence it is necessary to look for safer and more effective treatment for those patients. This retrospective review evaluated the safety and efficacy of combination therapy of infliximab and total glucosides of paeony (TGP) in treating 13 severe psoriasis patients with liver disorder history. Patients with severe psoriasis, comprising eight men and five women with a mean age of 37.3 ± 12.3, were observed. The patients experienced a mean course of psoriasis of 11.2 ± 7.1 years. The mean psoriasis area and severity index (PASI) score was 29.3 ± 12.9. All patients have the history of liver disorder. In our study, these patients were treated with infliximab at a dose of 5 mg/kg and TGP at a dose of 1.8 g/day. No liver test abnormalities were seen during combination therapy. After treatment, 61.5% patients showed PASI 50 response at week 2, and 81.8% patients have PASI 75 response at week 6. The mean time for achieving PASI 75 and PASI 90 improvement was 4.2 weeks and 9.6 weeks, respectively. Our observation demonstrates that combined therapy of infliximab and TGP is effective and safe in the treatment of severe psoriasis, especially for patients with liver disorder history.

Risk Factors for Rescue Therapy in Crohn's Patients Maintained on Infliximab After Withdrawal of the Immunomodulator: A Long-Term Follow-Up.

Usefulness of thiopurine and scheduled infliximab combination therapy in non-immunomodulator (IM)-naïve Crohn's disease (CD) patients and theoptimal length of dual therapy are still debated. To determine proportion of patients developing disease flare requiring rescue therapy and risk factors associated with disease flare after de-escalation of IM from combination therapy. Adult CD patients in clinical remission on combination therapy were identified from a large single-center database between 2002 and 2009. Patients who had their IM stopped in the absence of adverse events were included. Association between clinical and demographic variables and time until rescue therapy was analyzed using Cox-proportional hazard models. Forty-three CD patients on combination therapy in clinical remission at time of IM de-escalation were identified and followed up for a median duration of 61.6months (range 5.4-129.5). Median duration of remission on combination therapy prior to IM de-escalation was 12.0months (range 4-74). Thirty-one patients (72.1%) required rescue therapy during follow-up. On multivariable analysis, age at diagnosis <16years versus >40years (HR 4.55, 95% CI 1.18-17.62, p=0.028), using methotrexate instead of azathioprine in combination with infliximab (HR 3.37, 95% CI 1.14, 9.96, p=0.028), and duration of combination therapy <6months (HR 5.68, 95% CI 1.58, 20.36, p=0.007) increased risk forrescue therapy. A large proportion of CD patients on combination therapy experienced a flare following IM withdrawal. Young age at diagnosis, short duration of combination therapy, and methotrexate use were independent predictors of the need for rescue therapy.

Rheumatoid arthritis patients with continued low disease activity have similar outcomes over 10 years, regardless of initial therapy.

To compare 10-year disease outcomes of RA patients who have continuous low disease activity and are on MTX with or without initial combination therapy with infliximab or prednisone and SSZ. Recent-onset RA patients from the Behandel Strategieen (BeSt) (Dutch acronym for Treatment Strategies) study with 10 years of follow-up were analysed. Treatment was tightly controlled, targeted at DAS ⩽ 2.4. The selected patients had low disease activity from 6 months until 10 years and therefore did not intensify treatment. Patients were grouped into those receiving MTX monotherapy and those receiving initial combination therapy. Between-group differences over time were compared, using (generalized) linear mixed model analyses, for the outcomes DAS, HAQ, ESR, visual analogue scale patient global health, percentage of patients in (drug-free) remission and percentage of patients with Sharp/van der Heijde score progression ⩾5. At 10 years, 28/247 (11%) patients on MTX monotherapy (some tapered to drug free) had continued DAS ⩽ 2.4 compared with 68/261 (26%) patients on combination therapy (all tapered to monotherapy or drug free). No between-group differences in continuous responders were found over time, except for a higher percentage of patients in drug-free remission after MTX monotherapy. Significant group-time interactions were found for DAS, ESR and visual analogue scale patient global health, but the results seem clinically negligible. More patients achieved continuous low disease activity on initial prednisone or infliximab combination therapy than on initial MTX monotherapy, but there appeared to be no additional benefits. Regardless of induction therapy, patients with continuous low disease activity have similar long-term outcomes, with only a higher proportion of patients in drug-free remission after MTX monotherapy.

Clinical experience of combination therapy of infliximab and total glucosides of paeony for severe psoriasis with liver disorder history

Severe psoriasis patients are reported to have a higher risk of liver abnormalities. Treatment option for severe psoriasis patients with liver disorder history remains a great challenge. Hepatic toxicity and long-term safety are the major concerns. Hence it is necessary to look for safer and more effective treatment for those patients. This retrospective review evaluated safety and efficacy of combination therapy of infliximab and TGP in treating 13 severe psoriasis patients with liver disorder history.Thirteen patients with severe psoriasis, including 8 men and 5 women, with a mean age of 37.3 ± 12.3 were observed. The patients experienced a mean course of psoriasis of 11.2 ± 7.1 years. The mean PASI score was 29.3 ± 12.9. All patients have the history of liver disorder. In our study, these patients were treated with infliximab at a dose of 5mg/kg and TGP at a dose of 1.8g/day. No liver test abnormalities were seen during combination therapy. After treatment, 61.5% patients showed PASI 50 response at week 2, and 81.8% patients have PASI 75 response at week 6. The mean time for achieving PASI 75 and PASI 90 improvement was 4.2 week and 9.6 week, respectively. Conclusion: Our observation demonstrates that combined therapy of infliximab and TGP is effective and safe in the treatment of severe psoriasis, especially for the patients with liver disorder history.

Positioning Therapy for Ulcerative Colitis.

Ulcerative colitis (UC) is a chronic inflammatory condition of the colon, characterized by diffuse mucosal inflammation, bloody diarrhea, and urgency. The mainstay of treatment has been mesalamine agents, steroids, thiopurines, and anti-tumor necrosis factor alpha (TNF-α) antibodies. Over the past several years, new therapies have emerged which have provided clinicians new treatment options as well as new challenges in deciding which treatment is best for their patient at given points in their disease course. These agents include budesonide-Multi-Matrix System (MMX), adalimumab, golimumab, and vedolizumab. In addition, randomized controlled trials have investigated a combination therapy of infliximab and azathioprine and a controlled trial of infliximab versus cyclosporine for intravenous steroid refractory UC. This review will focus on where these agents may be optimally positioned in treatment algorithms for UC.

Long-term combination therapy with infliximab plus azathioprine predicts sustained steroid-free clinical benefit in steroid-dependent ulcerative colitis.

Infliximab (IFX) has demonstrated effectiveness for inducing 12-month steroid-free clinical remission in patients with steroid-dependent ulcerative colitis (UC), but long-term data are lacking. The aim of the study was to describe the long-term outcome of IFX treatment in steroid-dependent UC and investigate if predictors of sustained clinical response and colectomy could be identified. Consecutive patients with steroid-dependent UC treated with IFX were studied. The coprimary prespecified outcomes were sustained clinical response in patients who achieved clinical remission or response after IFX induction and colectomy-free survival. Secondary analyses were addressed to look for predictors of sustained clinical response and colectomy. After induction, 76% (96/126) of patients achieved clinical benefit. The median duration of follow-up on IFX maintenance therapy was 41.5 months (interquartile range, 26-45). Sixty-four percent (46/96) of patients had sustained clinical response at median follow-up. Colectomy-free survival was 77% at median follow-up. Combination therapy of IFX with thiopurines was an independent predictor of sustained clinical response (P < 0.0001; hazard ratio [HR], 3.98; 95% confidence interval [CI], 1.73-9.14). Independent predictors of colectomy were Mayo endoscopic subscore of 3 at baseline (P = 0.04; HR, 2.77; 95% CI, 1.09-7.05) and high C-reactive protein after induction (P = 0.001; HR, 5.65; 95% CI, 2.03-15.7). Thiopurine naive status (P = 0.025; HR, 0.34; 95% CI, 0.13-0.87) was protective from colectomy. Long-term IFX treatment is effective in inducing sustained clinical response in patients with steroid-dependent UC. Combination therapy is predictive of sustained clinical response in the long-term. Patients with more severe endoscopic lesions at baseline and high C-reactive protein after induction are at higher risk of colectomy. Conversely, thiopurine naive status is protective from colectomy.

Sa1105 Ursodiol As a Chemoprotective Agent for Colorectal Cancer in Inflammatory Bowel Disease and Primary Sclerosing Cholangitis: A Meta-Analysis

response rate to infliximab. We conducted a meta-analysis to assess the effect of variations of this unique enteral nutrition therapy with infliximab for clinical remission in patients with Crohn's disease. METHODS: Multiple databases were search (October 2013). Studies on adult patients with Crohn's disease were included that compared enteral nutrition therapy (elemental or polymeric formula, with or without low-fat diet restriction) with infliximab versus infliximab alone with no dietary manipulation. Meta-analysis was performed using the Mantel-Haenszel (fixed effects) model with odds ratio (OR) to assess clinical remission based upon Crohn's disease activity index (remission defined as < 150 or a reduction in score by 70), resolution of clinical symptoms, or reduction in C-reactive protein levels. Publication bias and heterogeneity were assessed. RESULTS: Five studies (n=403) met the inclusion criteria. Specialized enteral nutrition therapy with infliximab resulted in 60% (124/ 206) of patients achieving initial clinical remission compared to 45% (88/197) with infliximab alone. Similarly, 75% (79/106) of patients receiving enteral nutrition therapy and infliximab remained in long-term clinical remission after one year, compared to 49% (62/126) of patients receiving infliximab monotherapy alone. The use of combination therapy of infliximab with specialized enteral nutrition therapy resulted in a statistically significant increase in achieving an initial clinical response (OR 2.43; 95% CI: 1.58-3.74, p<0.01) followed by long-term clinical remission after one year (OR 2.93; 95% CI: 1.66-5.17, p<0.01) as compared to infliximab alone with no dietary manipulation. After adjusting for two trials (Sazuka and Matsumoto) that included use of an elemental or polymeric formula and no diet restrictions, the results were similar for initial clinical remission (p<0.01) and long-term clinical remission (p<0.01). No publication bias or heterogeneity was noted for either outcome. CONCLUSION: Use of a specialized enteral nutrition therapy consisting primarily of an elemental formula combined with or without a low-fat diet restriction appears to enhance the response rate to infliximab, better achieving and maintaining clinical remission among patients with Crohn's disease than drug therapy alone with no dietary manipulation.

Combination therapy of infliximab and thalidomide for refractory entero-Behcet's disease: a case report

BackgroundBehcet's disease (BD) is a systemic inflammatory disease with the histopathological features of leukocytoclastic vasculitis that affects nearly all organs and systems. When it involves the intestine, it is called entero-Behcet's disease (entero-BD).Case presentationHere we described a 23-year-old man with entero-BD refractory to conventional therapies who responded well to the combination therapy of infliximab, an anti-tumor-necrosis-factor (TNF)-alpha antibody, and thalidomide. After combination treatment, the patient’s symptoms improved greatly and his Crohn's Disease Activity Index (CDAI) score decreased from 344 to 52 points, accompanied by a body weight increase from 53 kg to 64 kg. A follow-up endoscopy performed 10 weeks after the treatment showed significant improvement and the patient's multiple ulcers had healed well.ConclusionThe combination therapy of infliximab and thalidomide appears to be clinically effective in a patient with refractory entero-BD. However, further studies need to be performed to evaluate the efficacy of this combination therapy.

Unmanipulated HLA Haploidentical Bone Marrow Transplantation Combined With PBSC With The Options Of Donor Virus Specific CTLs and Mesenchymal Stem Cells Infusion

IntroductionHLA haploidentical relatives could be useful alternative donor option for patients without HLA matched family donor who need relatively urgent stem cell transplantation. However, steroid refractory GVHD and virus infections were critical issues in this setting due to HLA mismatched barrier. Donor derived cellular therapies could be suitable options to improve the outcome of this strategy. Patients and methodsTwenty three children (9 male, 14 female) underwent HLA haploidentical stem cell transplantation in Nagoya University hospital from 2004 to 2013. The median age was 8 years [range 1 – 15years] with 7 AML, 6 ALL, 5 aplastic anemia, 2 JMML, 1 CMML, 1 CAEBV and 1 LCH. All the patients received both bone marrow combined with G-CSF mobilized peripheral blood stem cells to increase the number of infused donor stem cells. Total 15mg /kg of rabbit antithymocyte globulin (ATG) were given as in vivo T cell depletion in preconditioning regimen. Taclolimus and short term MTX were used for GVHD prophylaxis. CMV and EBV specific cytotoxic T cells were tried to expand from donor peripheral blood mononuclear cells if the patient and the donor shared either HLA A2402 or A0201/A0206 as treatment options for drug resistant virus infections since 2008. Mesenchymal stem cells were also expanded from donor bone marrow for the option of treatment for steroid refractory GVHD since 2009. All the donors were one of parents of patient's except for one brother. HLA disparity between patient and donor at HLA A, B, and DR loci were three loci in 12 patients and two loci were in other 11 patients. ResultsAll the patients achieved engraftment with median 18 days [range 14 – 29 days]. Acute GVHD grade II or more were seen in nine patients. Six of them developed steroid refractory GVHD and received Infliximab. Four of them received Daclizumab as well. Among them, two patients developed uncontrolled grade IV GVHD (One patient developed diarrhea more than three litters with blood and another patient developed Grade IV liver GVHD) even after combination therapy of Infliximab and Daclizumab. Two infusions of donor bone marrow derived MSC were given in these two patients and GVHD were diminished. CMV reactivations were seen in 16 and 3 of them developed both GCV and Foscanet resistant CMV infection and donor derived CMV specific CTL infusions were effective to eradicate CMV-DNA in their blood without inducing GVHD. EBV reactivations were seen in 12 and empiric rituximab infusion was effective in 11. One patient developed CD20 negative EBV associated lymphoproliferative disorder and 5 course of donor derived EBV specific T cell infusions eradicate EBV-DNA in his blood and PET positive lymphadenopathy was diminished. BK virus cystitis were seen in four. Cause of death were 8 leukemia relapses, one adenovirus fluminant hepatitis on day 123, one CMV ventriculitis on day 378 and one sepsis on day 509. ConclusionsDonor virus specific CTLs and mesenchymal stem cells were useful options for HLA haploidentical stem cell transplantation to reduce early transplantation related mortality.▪ Disclosures:No relevant conflicts of interest to declare.