Pustular Rash in Crohn’s Patient on Ustekinumab Raises Concern for Drug-Induced Paradoxical Psoriasis

We report the case of a 51-year-old male with Crohn’s disease (CD) who developed a reproducible pustular rash after ustekinumab (UST) administration. The patient first presented with a pustular rash on his hands, body, extremities, and scalp starting 5 weeks after his initial weight-based UST induction. The rash resolved spontaneously, then recurred 4 weeks after his first subcutaneous maintenance dose of UST 90 mg. Biopsy of the affected area demonstrated subcorneal pustular dermatosis (SPD). UST was discontinued and the rash resolved. Unfortunately, the patient experienced clinical recurrence of CD, and given prior failure of multiple CD medications, UST was restarted with premedication. Two weeks after UST re-induction, the rash recurred, though less severe. Given improvement in CD symptoms, UST was continued and the rash managed with topical corticosteroids. This is the first case of drug-induced SPD associated with UST. One case report has previously described de novo pustular psoriasis associated with UST in a patient with CD and enteropathic arthritis. Notably, SPD and pustular psoriasis can be histologically indistinguishable. The development of a paradoxical psoriasiform rash is thought to be one of the few dose and duration dependent side effects of TNF-antagonist therapy but has not previously been established as a side effect of UST. This case demonstrates a new potential side effect of UST.

POS0635 COMPARING THE ULTRASONOGRAPHIC EVALUATION IN PATIENTS WITH JAPANESE RHEUMATOID ARTHRITIS BETWEEN BARICITINIB AND TNF ANTAGONIST THERAPY

Background:Baricitinib (BAR) and TNF antagonist are the important therapeutic agent for the treatment of rheumatoid arthritis.However there is still few studies of improvement of ultrasonographic findings in RA treated comparison with BAR and TNF.Objectives:To evaluate the clinical efficacy of BAR and TNF therapy patients with rheumatoid arthritis (RA) using ultrasonography (US).Methods:Participants comprised 16 and 45 Japanese RA patients who had recently received BAR and TNF. All patients with a diagnosis of RA according to the 2010 ACR/EULAR criteria. Patients underwent clinical and laboratory assessments every 4 weeks from baseline to 24 weeks, and US assessments at baseline, 4, 12 and 24 weeks. Gray scale (GS) and power doppler (PD) signals were scored using a semi-quantitative scale from 0 to 3 at 26 (0-78) synovial sites (22 joints) in the following joints: bilateral first to fifth metacarpopharangeal (MCP) joints (dorsal recess); first interphalangeal (IP) and second to fifth proximal interphalangeal (PIP) (dorsal recess) joints; and the wrists (dorsal radial, median and ulnar). We evaluated the improvement of GS and PD score from baseline to week 24.Results:In the patients receiving BAR (n=16) and TNF (n=45), the mean age was 55.9 vs 54.6 years old (p=0.682), disease duration was 10.2 vs 6.1 years (p=0.094), the rate of MTX use was 75% vs 89% (p=346), the mean MTX dose was 9.3 vs 10.2 mg/w (p=0.443), the rate of ACPA positive was 94% vs 82% (p=0.476), DAS28-ESR was 4.25 vs 4.61 (p=0.289), CDAI was 15.8 vs 18.5 (p=0.210), GS score was 21.6 vs 16.3 (p=0.436) and PD score was 15.0 vs 9.5 (p=0.260). The degree of improvement respective changes in GS and PD score after 4, 12 and 24 weeks were as follows: GS: -7.2 vs -3.7 (p=0.268) and PD: -7.6 vs -2.3 (p=0.158) after 4 weeks, GS: -10.9 vs -5.0 (p=0.161) and PD: -9.2 vs -3.8 (p=0.049) after 12 weeks, GS: -12.9 vs -6.1 (p=0.485) and PD: -11.3 vs -5.7 (p=0.062) after 24 weeks between BAR and TNF (Fig.1, 2). Next, The improvement rate of respective changes in GS and PD score after 4, 12 and 24 weeks were as follows: GS: -23.8% vs -11.6% (p=0.580) and PD: -30.3% vs -16.5% (p=0.343) after 4 weeks, GS: -39.6% vs -15.6% (p=0.129) and PD: -47.1% vs -30.8% (p=0.210) after 12 weeks, GS: -52.2% vs -22.2% (p=0.248) and PD: -77.1% vs -50.1% (p=0.048) after 24 weeks between BAR and TNF.Conclusion:The present study provides evidence supporting both the BAR and TNF therapy showed improvement effect over time, but in a comparison between BAR and TNF, the PD score of BAR showed a siginificant improvement effect compared to TNF at 12 and 24 weeks. It was suggeted that BAR may improve inflammatory synovitis earlier compared to TNF.Disclosure of Interests:None declared

DOP58 Non-white race is associated with decreased efficacy of tumor necrosis factor antagonist therapy in Ulcerative Colitis: A post-hoc analysis of individual level data from golimumab clinical trials

Background Observational studies suggest non-white patients with inflammatory bowel disease (IBD) have worse clinical outcomes.1 There are limited data on whether race impacts response to biologic therapy. We therefore aimed to evaluate the efficacy of the tumor necrosis factor (TNF) antagonist golimumab comparing white to non-white participants, using individual participant level data from phase 2/3 randomized clinical trials of TNF antagonist therapy in ulcerative colitis (UC). Methods We conducted a pooled analysis of individual-level data from the induction and maintenance trials of golimumab in UC accessible through Yale University Open Data Access Project (YODA). There were insufficient non-white participants in infliximab studies accessible through YODA, precluding meaningful analysis. We analyzed patients in the placebo and treatment arms separately. Our primary outcome was clinical response and secondary outcomes were clinical remission and endoscopic healing according to clinical trial definitions. We compared white and non-white (defined as Black, Asian, or Other race) participants using multivariable logistic regression a priori adjusting for age, sex, treatment group, baseline Mayo score, immunomodulator and corticosteroid use. Effect estimates were expressed as adjusted odds ratios (aOR) and 95% confidence intervals (95% CI). Results A total of 1,006 participants were included in the induction trial (PURSUIT-SC; 18% non-white) and 783 participants in the maintenance trial (PURSUIT-M; 17% non-white). Non-white participants had significantly lower odds of week 6 clinical response (aOR 0.43, 95%CI 0.28–0.66), clinical remission (aOR 0.41, 95%CI 0.22–0.77) and endoscopic remission (aOR 0.48, 95%CI 0.30–0.74) compared to white participants (Figure). Non-white participants also had a lower adjusted odds of week 30 clinical response (aOR 0.64, 95%CI 0.40–1.01), clinical remission (aOR 0.45, 95%CI 0.28–0.74), and endoscopic remission (aOR 0.62, 95%CI 0.41–0.96). By week 54, the lower odds of these outcomes among non-whites were no longer statistically significant (Figure). Conclusion Non-white UC patients were less likely to achieve clinical response, clinical remission, and endoscopic healing with golimumab compared to white patients in these clinical trials. Further studies are needed to understand these differences and whether they are observed with other drugs or outside the context of clinical trials. Reference

OP06 5-aminosalicylates are not associated with adverse outcomes in Inflammatory Bowel Disease patients with COVID-19: Analysis from an international registry

Background Prior data have suggested that 5-aminosalicylates (5-ASA) may be associated with an increased risk of severe COVID-19 among inflammatory bowel disease (IBD) patients. We aimed to evaluate the association of 5-ASA with severe COVID-19 in a large cohort of IBD patients. Methods We analyzed data from the Surveillance Epidemiology of Coronavirus Under Research Exclusion for Inflammatory Bowel Disease (SECURE-IBD) registry, a large, international database of IBD patients with confirmed COVID-19. The primary outcome was severe COVID-19, defined as intensive care unit admission, ventilator use, and/or death. Hospitalization due to COVID-19 was a secondary outcome. We performed multivariable regression modeling with a generalized estimating equation accounting for country as a random effect to analyze the association of 5-ASA with severe COVID-19. Models a priori included age, sex, race, disease phenotype (CD or UC/IBD-U), corticosteroid use, azathioprine/6-mercaptopurine use, TNF antagonist use, disease activity by physician global assessment, number of comorbidities, and days from SECURE-IBD inception to reporting. We constructed three models examining 5-ASA use as binary covariate using 1) all patients, 2) only patients on any biologic, and 3) only patients on TNF antagonists. Results 5,174 patients were included with 212 (4.1%) severe COVID-19 events. At the time of COVID-19 infection, 1,504 patients were taking 5-ASA. 5-ASA patients were older (mean age 44 vs. 38.3 years, p<0.001), more likely to have UC (70.7% vs. 27.7%, p<0.001), less likely to be in remission (49.6% vs. 57.2%, p<0.001), and more likely to have at least one comorbidity (33.6% vs. 26.7%, p<0.001) compared to patients not on 5-ASA. 3,325 patients were on any biologic and 2,216 were on a TNF antagonist. Among all patients, 5-ASA was not associated with severe COVID-19 (adjusted OR [aOR] 1.14, 95% confidence interval [CI] 0.86–1.52) (Table 1). Prior associations of age, comorbidities, TNF antagonists, and corticosteroids with severe COVID-19 were similar to prior analyses (Table 1). In analyses restricting to those on any biologic or only TNF antagonists, there was also no significant association between 5-ASA and severe COVID-19 (aOR 0.76, 95% CI 0.38–1.50 and aOR 0.99, 95% CI 0.43–2.32, respectively). Use of 5-ASA was not associated with risk of COVID-19 related hospitalization in any analysis. Conclusion In an analysis of updated data from the SECURE-IBD registry, 5-ASA use was not associated with worse outcomes among IBD patients with COVID-19.

Serological response to COVID-19 vaccination in IBD patients receiving biologics

Objective The impact of medications on COVID-19 vaccine efficacy in IBD patients is unknown, as patients with immunosuppressed states and/or treated with immunosuppressants were excluded from vaccine trials. To address this, we evaluated serological responses to COVID-19 vaccination with the SARS-CoV-2 spike (S) mRNA BNT162b2 (Pfizer-BioNTech) and mRNA-1273 (NIH-Moderna) vaccines in IBD patients enrolled in an ongoing SARS-CoV-2 sero-survey at the Icahn School of Medicine at Mount Sinai in New York City. Design We obtained sera from 48 patients who had undergone vaccination with one or two vaccine doses. Sera were tested for SARS-CoV-2 anti-RBD total immunoglobulins and IgG (Siemens COV2T and sCOVG assays), anti-Spike IgG (in-house ELISA), and anti-nucleocapsid antibodies (Roche). Results All IBD patients (15/15) who completed two-dose vaccine schedules achieved seroconversion to high levels. Two IBD patients with history of COVID-19 infections and who were seropositive at baseline seroconverted to high levels after the first dose. Concurrent biologic use was 85% (41/48), including 33% of patients (16) on TNF antagonist monotherapy, 42% (17) on vedolizumab monotherapy, 6% (3) on vedolizumab combination therapy with thiopurine, and 8% (4) ustekinumab; 1 patient was receiving guselkumab for psoriasis. Three patients (6%) were on oral steroids at the time of vaccination. Conclusion IBD patients receiving biologics can seroconvert with robust serological responses after complete Pfizer-BioNTech and NIH-Moderna COVID-19 vaccination. In IBD-patients with previous SARS-CoV-2 seroconversion, a single dose of either vaccine can induce high index values, mirroring findings from the general population.

TREM-1+ Macrophages Define a Pathogenic Cell Subset in the Intestine of Crohn’s Disease Patients

Background and Aims Uncontrolled activation of intestinal mononuclear phagocytes (MNPs) drives chronic inflammation in inflammatory bowel disease (IBD). Triggering receptor expressed on myeloid cells 1 (TREM-1) has been implicated in IBD pathogenesis. However, the role of TREM-1 + cell subsets in driving IBD pathology, and the link with clinical parameters, are not understood. We investigated TREM-1 expression in human intestinal MNP subsets and examined blocking TREM-1 as a potential IBD therapy. Methods TREM-1 gene expression was analysed in intestinal mucosa, enriched epithelial and lamina propria (LP) layers and purified cells from controls and IBD patients. TREM-1 protein on immune cells was assessed by flow cytometry and immunofluorescence microscopy. Blood monocyte activation was examined by large-scale gene expression using a TREM-1 agonist or LP conditioned media (LP-CM) from patients in the presence or absence of TREM-1 and TNF antagonist antibodies. Results TREM-1 gene expression increases in intestinal mucosa from IBD patients and correlates with the disease score. TREM-1 + cells, which are mainly immature macrophages and CD11b + granulocytes, increase among LP cells from Crohn’s patients and their frequency correlates with inflammatory molecules in LP-CM. LP-CM from Crohn’s patients induces an inflammatory transcriptome in blood monocytes, including increased IL-6 expression, which is reduced by simultaneous blocking of TREM-1 and TNF. Conclusions High intestinal TREM-1 expression, reflecting a high frequency of TREM-1 + immature macrophages and TREM-1 +CD11b + granulocytes, is linked to the deleterious inflammatory microenvironment in IBD patients. Therefore, blocking the TREM-1 pathway, especially simultaneously with anti-TNF therapy, has potential as a new IBD therapy.

Effect of IBD medications on COVID-19 outcomes: results from an international registry

ObjectiveWe sought to evaluate COVID-19 clinical course in patients with IBD treated with different medication classes and combinations.DesignSurveillance Epidemiology of Coronavirus Under Research Exclusion for Inflammatory Bowel Disease (SECURE-IBD) is a large, international registry created to monitor outcomes of IBD patients with confirmed COVID-19. We used multivariable regression with a generalised estimating equation accounting for country as a random effect to analyse the association of different medication classes with severe COVID-19, defined as intensive care unit admission, ventilator use and/or death.Results1439 cases from 47 countries were included (mean age 44.1 years, 51.4% men) of whom 112 patients (7.8%) had severe COVID-19. Compared with tumour necrosis factor (TNF) antagonist monotherapy, thiopurine monotherapy (adjusted OR (aOR) 4.08, 95% CI 1.73 to 9.61) and combination therapy with TNF antagonist and thiopurine (aOR 4.01, 95% CI 1.65 to 9.78) were associated with an increased risk of severe COVID-19. Any mesalamine/sulfasalazine compared with no mesalamine/sulfasalazine use was associated with an increased risk (aOR 1.70, 95% CI 1.26 to 2.29). This risk estimate increased when using TNF antagonist monotherapy as a reference group (aOR 3.52, 95% CI 1.93 to 6.45). Interleukin-12/23 and integrin antagonists were not associated with significantly different risk than TNF antagonist monotherapy (aOR 0.98, 95% CI 0.12 to 8.06 and aOR 2.42, 95% CI 0.59 to 9.96, respectively).ConclusionCombination therapy and thiopurines may be associated with an increased risk of severe COVID-19. No significant differences were observed when comparing classes of biologicals. These findings warrant confirmation in large population-based cohorts.MKH should be changed to MDK for co-last author line

Therapeutic Drug Monitoring of Tumor Necrosis Factor Antagonists in Crohn Disease: A Theoretical Construct to Apply Pharmacokinetics and Guidelines to Clinical Practice

Therapeutic drug monitoring (TDM) is the measurement of drug and antidrug antibody concentrations in individuals to guide treatment decisions. In patients with Crohn disease (CD), TDM, used either reactively or proactively, is emerging as a valuable tool for optimization of tumor necrosis factor (TNF) antagonist therapy. Reactive TDM is carried out in response to treatment failure, whereas proactive TDM involves the periodic monitoring of patients responding to TNF antagonist therapy to allow treatment optimization. In patients with CD, most of the available data for TDM relate to the first-to-market TNF antagonist infliximab and, to a lesser extent, to adalimumab and certolizumab pegol. Several gastroenterology associations, including the American Gastroenterology Association, have endorsed the use of reactive TDM in patients with active CD. However, fewer recommendations currently exist for the use of proactive TDM, although several new prospective randomized controlled trials evaluating proactive TDM strategies have been published. In this review, the current evidence for reactive and proactive TDM is discussed, and a proactive treatment algorithm for certolizumab pegol based on previously published threshold concentrations is proposed.

Patient-Preferences Favoring Treatment Discontinuation Are Reduced With Vedolizumab and Ustekinumab Compared With TNF Antagonists in Inflammatory Bowel Disease

Background Nonadherence to biologic therapy in inflammatory bowel disease (IBD) is associated with risk of relapse, immunogenicity, and disease complications. Significant nonadherence prevalence is reported with tumor necrosis factor (TNF) antagonists but the risk of nonadherence with newer biologics with better safety profiles is unknown. This study aimed to investigate if IBD patient-preferences favoring biologic discontinuation vary by biologic class and analyze factors associated with such preferences. Methods A convenience sample of 200 adults with IBD on biologic therapy treated at an academic outpatient center was surveyed using a 22-point questionnaire. Patient-preference favoring treatment discontinuation between TNF-antagonist and non-TNF-antagonist biologics [vedolizumab (VDZ)/ustekinumab (UST)] was compared using χ 2 test. Risk factors associated with a preference to discontinue biologic therapy were evaluated using univariable and multivariable logistic regression, and Spearman rank correlation analyses. Results A total of 190 questionnaires were analyzed that contained data on preferences regarding biologic discontinuation (median age 36 years, 62% were females; 63% had Crohn disease; 56% were receiving a TNF antagonist, 31% VDZ, and 14% UST). Overall, 32% patients reported a preference to discontinue biologic treatment with a higher proportion among those receiving a TNF antagonist compared with VDZ/UST (39.6% vs 21.4%; P < 0.01). Current VDZ/UST use was independently associated with a reduced odds of patient-preference favoring biologic discontinuation [adjusted odds ratio: 2.67 (1.42–5.01); P < 0.01]. The most concerning factor to patients was the perceived risk of side effects. Patients on VDZ/UST perceived their therapy to be safer than those receiving a TNF antagonist (r = 0.2, P = 0.04). Conclusions Patient-preference favoring treatment discontinuation is improved with VDZ/UST compared with TNF-antagonist biologic therapy.

A systematic review and meta-analysis: Female smokers,even former smokers lead higher incidence of psoriasis in the treatment of inflammatory bowel disease with biological agents.

Background: At present, infliximab(IFX) and adalimumab(ADA) are the classic drugs for the treatment of moderate-severe inflammatory bowel disease(IBD), which prove effective for the disease control. However, the side effects need to be monitored during the therapy process, especially the paradoxical reaction of the skin system such as psoriasis, which could greatly benefit quality of patients’ life.Aim: In order to describe and analyze TNF-antagonist-induced psoriasis in patients with inflammatory bowel disease from the aspects of incidence, pathogenesis, distribution and type of lesions, prognosis and treatment, the incidence of psoriasis induced by Infliximab (IBD) and Adalimumab (ADA) in the treatment of Inflammatory Bowel Disease Disease (IBD) as well as the relationship between sex, smoking and the incidence of psoriasis were investigated.Methods: Literatures in English language meeting the qualifications on Pubmeb, Embase, Web of Science, Google, and Geenmedical databases were searched . More than two co-authors evaluated the quality of the article and extracted the data respectively. The data obtained were statistically analyzed by statistical software of Revman and Stata.Results: 1) The incidence of psoriasis was higher in ADA Group (OR 0.66, P<0.05, 95% CI (0.52-0.84) ; 2) The incidence of psoriasis was higher in females than in males (OR 1.54, P<0.05, 95% CI (1.27-1.86)) ; 3) Smoking increased the incidence of psoriasis (OR 1.79, P<0.01, 95% CI (1.42-2.24); 4) Psoriasis is mainly distributed in the Scalp, Palmoplantar, skin folds and limbs, and often occurs in the genital organs, the pathogenesis of which is not completely clear; the interval of medication is more than one year, and the interval of medication using IFX is longer than that of ADA Group; most cases can be relieved by local hormone, phototherapy or systemic hormone therapy without changing the strategy of biological agents.Conclusion: The incidence of psoriasis induced by TNF-antagonists is higher in many autoimmune diseases. The frequency of reported in inflammatory bowel disease is higher than other autoimmune diseases, and the safety of ADA Treatment for IBD is higher than that of IFX The incidence of psoriasis is higher in women than in men; the incidence of psoriasis is significantly higher in smokers / ex-smokers than in non-smokers. The interval of drug use of TNF-antagonists may be a predictive factor for the prevention and treatment of psoriasis, and there are differences among different kinds of TNF-antagonists. Change of therapeutic strategy of TNF-antagonists is not recommended in the event of psoriasis.