Tumor Necrosis Factor Alpha Antagonists Research Articles

DOP49 Guselkumab improves health-related quality of life as measured by PROMIS-29 in patients with moderately to severely active Ulcerative Colitis: Phase 3 QUASAR induction study

Abstract Background Patients (pts) with ulcerative colitis (UC) suffer from symptoms that impair health-related quality of life (HRQoL). The Phase 3 QUASAR induction study (NCT04033445) evaluated the efficacy and safety of guselkumab (GUS), an IL-23 p19 subunit antagonist, in pts with moderately to severely active UC who had demonstrated inadequate response, loss of response, or intolerance to conventional and/or advanced therapies (ie, tumor necrosis factor-alpha antagonists, integrin receptor antagonists, and/or Janus kinase inhibitors). Here we report the effect of GUS IV induction on HRQoL at Week (Wk) 12 as measured by the Patient-Reported Outcomes Measurement Information System (PROMIS)-29. Methods Pts were randomized 3:2 to receive GUS 200 mg IV or placebo (PBO) IV at Wks 0/4/8. PROMIS-29 consists of 7 domains (anxiety, depression, fatigue, pain interference, sleep disturbance, physical function, and social participation) and a pain intensity numeric rating scale (NRS, range 0-10). The raw score of each domain was converted into a standardized T-score based on a general population mean of 50 and standard deviation (SD) of 10. Higher scores indicate better outcomes for physical function and social participation and worse outcomes for all other domains. The physical component summary (PCS) and mental component summary (MCS) scores were calculated based on the domain T-scores for physical and mental HRQoL, with higher scores representing better outcomes. Minimum clinically meaningful improvement was defined as a ≥3-point improvement in the pain intensity NRS score, a ≥5-point (one-half SD of the population) improvement in each domain, and a ≥5-point improvement in the PCS/MCS scores. More stringent thresholds (eg, ≥7- or ≥9-point improvements) were also examined and will be presented. Results Among the primary analysis population, baseline mean PROMIS-29 domain scores were similar between treatment groups, with functional domain scores <50 and symptom domain scores >50, indicating impaired HRQoL (Table). GUS-treated pts achieved a greater mean change from baseline at Wk 12 in each domain T-score, the pain intensity NRS score, and the PCS/MCS than PBO-treated pts. Additionally, the percentage of pts achieving minimum clinically meaningful improvement at Wk 12 was greater for GUS vs PBO in each domain, the pain intensity NRS score, and the PCS/MCS scores (Figure). Conclusion Pts with moderately to severely active UC treated with GUS IV induction experienced broad and clinically meaningful improvements in HRQoL as measured by the PROMIS-29 at Wk 12.

Phenotype of Takayasu-like vasculitis and cardiopathy in patients with Blau syndrome.

We aimed to determine the prevalence of cardiovascular involvement in our Blau syndrome (BS) cohort and provide detailed analysis of their cardiovascular manifestations and outcome. We also tried to find out the risk factors for developing cardiovascular involvement. Clinical manifestations, laboratory findings, and treatments were reviewed. Clinical features were compared between children with cardiovascular involvement and those without angiocardiopathy. A total of 38 BS children were eligible for final analysis. Among them, 13 (34.2%) developed Takayasu-like vasculitis and/or cardiopathy. Compared with those without angiocardiopathy, recurrent fever was more frequent in BS patients with cardiovascular involvement (p < 0.001). What is more, tumor necrosis factor alpha antagonists (anti-TNF) were more urgently needed in children with cardiovascular involvement (p = 0.015). BS patients with cardiovascular involvement include 4 with Takayasu-like vasculitis and 9 with cardiopathy. The onset of cardiovascular manifestations ranged from 0.75 to 18.5years of age, with most cases occurring before school period. Symptoms were elusive and lacked specificity, such as dizziness, short of breath, and edema. Some patients were even identified because of the unexpected hypertension during follow-up. Cardiopathy and vasculitis occurred in patients with different genotypes. Imaging changes were discovered before the presentation of the typical triad in 3/4 patients with Takayasu-like vasculitis. Three children developed left ventricular dysfunction with decreased left ventricular ejection fraction. Combination of glucocorticoids and methotrexate with anti-TNF agents is a common treatment option for these BS patients. In the cohort, BS-related cardiovascular involvement was controlled well, with cardiac structural and functional abnormalities completely recovered and slower progression of vasculitis lesions. Cardiovascular manifestations is not rare in BS patients. Because of its insidious onset, a systematic and comprehensive assessment of cardiovascular involvement should be performed in newly diagnosed patients with BS. Aggressive initiation of anti-TNF agents may be beneficial to improve the prognosis. Key Points • About 34.2% patients with Blau syndrome developed Takayasu-like vasculitis and/or cardiopathy. • Compared with those without angiocardiopathy, recurrent fever and application of anti-TNF agents were more frequent in BS patients with cardiovascular involvement (p < 0.001, p = 0.015) • Regular assessment of cardiovascular involvement is extremely necessary because of its insidious onset.

Impact of HLA-DQA1∗05 Genotype in Immunogenicity and Failure to Treatment with Tumor Necrosis Factor-alpha Antagonists in Inflammatory Bowel Disease: A Systematic Review and Meta-analysis.

HLA-DQA1*05 carriage has been associated with an increased risk of immunogenicity in patients with immune-mediated inflammatory diseases treated with tumor necrosis factor-alpha (TNF-a) antagonists. Results have shown an inconsistent association with a loss of response (LOR) in patients with inflammatory bowel disease (IBD), which could be modified when using proactive optimization and association with immunomodulatory drugs. To define the association of HLA-DQA1*05 on anti-drug antibody development and loss of response (LOR) to anti-TNF-a in IBD. We searched MEDLINE, EMBASE and SCOPUS, for the period up to August 2023, to identify studies reporting the risk of immunogenicity and/or LOR in IBD patients with HLA-DQA1*05 genotype. Twenty-four studies comprising 12 papers, 11 abstracts and 1 research letter, with a total of 5,727 IBD patients, were included. In a meta-analysis of 10 studies (2,984 patients; 41.9% with HLA-DQA1*05 genotype), HLA-DQA1*05 carriers had higher risk of immunogenicity compared to non-carriers (risk ratio, 1.54; 95%CI, 1.23-1.94; I2=62%) (low certainty evidence). Lack of therapeutic drug monitoring (TDM) increased immunogenicity in the presence of risk HLA (risk ratio 1.97; 95%CI, 1.35-2.88; I2=66%), while proactive TDM revoked this association (very low certainty of evidence). A meta-analysis of 6 studies (765 patients) found that risk for secondary LOR was higher among HLA-DQA1*05 carriers (hazard ratio 2.21; 95%CI, 1.69-2.88; I2=0%) (very low certainty evidence), although definition and time to assessment varied widely among studies. HLA-DQA1*05 carriage may be associated with an increased risk of immunogenicity and secondary LOR in IBD patients treated with TNF-a antagonists.

Commentary: Behçet's uveitis - Expanding treatment horizons.

Behçet’s disease is a complex multisystem disease. A standalone positive typing for HLA-B51 is not considered diagnostic, and the diagnosis of this uveitic entity is based on a myriad of multisystem clinical signs that make up the diagnostic criteria.[1] The genetic predisposition to this disease afforded by HLA-B51 positivity (along with other non-HLA genes) has been postulated to get along with an altered microbiome in the gut of Behçet patients, with an additional possible contribution from infectious agents such as Streptococcus sanguinis, to trigger and then sustain an immune response, which disrupts a previously intact T-cell homeostatic environment. This recent understanding has expanded treatment horizons beyond standard treatment protocols, to include biologic therapy, especially tumor necrosis factor-alpha (TNF-α) antagonists, to achieve control of repeated disrupted immune response.[1] Progressive sight-threatening Behçet’s disease involving the entire uveal tract blinds up to 25% of patients within a course of 10 years, after which the disease progression tends to stabilize.[1,2] This mandates an excellent control of inflammation within this all-important “window period” to save the eye either from the direct inflammatory manifestations of Behçet’s uveitis or its potentially blinding complications.[1] The consensus in uveitis management in Behçet’s disease (according to the European Alliance of Associations of Rheumatology [EULAR] and the American Academy of Ophthalmologists’ guidelines) recommends limitation of steroid administration for control of acute inflammation and substituting steroids with conventional disease-modifying antirheumatic drugs (DMARDs) or biologic therapy. Furthermore, the American Academy of Ophthalmology goes a step further to recommend bypassing the “classic DMARDs” in favor of anti-TNF-α agents in severe, sight-threatening uveitis.[3] Thus, EULAR updated its guidelines in 2018 to recommend administering steroids in posterior segment ocular Behçet’s disease patients, but only in combination with steroid-sparing therapies such as azathioprine (AZA), cyclosporine A (CsA), interferon alpha, or monoclonal anti-TNF antibodies.[3] In the current study[4] of Behçet’s disease with ocular lesions from India, all patients have received steroids and 80% patients have been treated with immunosuppression along with steroids. Randomized controlled trials have shown that the antimetabolite AZA and T-cell inhibitor CsA are effective in the treatment of posterior uveitis in Behçet’s disease. Hence, the updated 2018 EULAR guidelines recommended the use of these two drugs (as against others) in the initial therapy of posterior uveitis.[3] Further, the combined use of AZA and CsA, whether as first- or second-line therapy, has shown efficacy in controlling ocular Behçet’s disease (with more periodic side effect monitoring).[1] In the current study from India, AZA and CsA have been combined in 24% of the patients.[4] In Behçet’s disease, TNF-α production by macrophages, CD4+ and CD8+ T cells, and natural killer cells is increased. The reduction of circulating TNF-α has been shown to result in dramatic improvement in the inflammatory activity of patients with severe pan or posterior uveitis.[1] These anti-TNF-α drugs used are recombinant monoclonal antibodies directed against TNF-α. Due to their potent and fast effects, these agents are now used alone or in combination therapy in refractory ocular Behçet’s cases, or sometimes even as first-line treatment in severe sight-threatening attacks.[3] Adalimumab (ADA) is a fully human monoclonal antibody directed against TNF-α and has been tested against a placebo in both active and quiescent, noninfectious uveitis (VISUAL I and VISUAL II studies, respectively). Ocular Behçet’s disease represented 7% of the uveitic cases enrolled in them.[1] Further, other uncontrolled studies have shown significant results regarding the efficacy of ADA in Behçet’s uveitis.[5] Early initiation of ADA in two children with Behçet’s uveitis succeeded in control of the disease activity, allowing tapering of topical and systemic steroids.[6] Comparative studies have been conducted between ADA and the other agent infliximab (IFX), notably a multicenter study on 177 patients with refractory Behçet’s disease uveitis, which found that both agents gave significantly better control in terms of disease activity as the first-line treatment, but the ADA group had higher percentage of patients with better best corrected visual acuity and fewer drug-related reactions.[7] One must remember that exclusion of tuberculosis and other infectious diseases as well as occult malignancies is mandatory before starting therapy with these agents. Also, an additional immunosuppressant (like methotrexate) may be advisable to prevent anti-chimeric, or antihuman, antibody production, which decreases the efficacy of these agents leading to secondary failure.[1] In the current study from India, biologic agents have been used in 40% of the patients; of which ADA was used in 28% and IFX in 12% of patients.[4] Finally, studies have recently reported success with Janus kinase (JAK) inhibitors in the treatment of noninfectious autoimmune uveitis refractory to conventional DMARDs and anti-TNF-α agents. Successful results have been reported with the JAK inhibitor tofacitinib in refractory Behçet’s disease uveitis,[8] and moving forward, these agents shall most likely further expand our treatment horizons for Behçet’s disease.

Scarring Alopecia in Tumor Necrosis Factor-α Antagonists-Induced Scalp Psoriasis

Background A broad spectrum of adverse reactions associated with the use of tumor necrosis factor alpha (TNFα) antagonists has been recognized over the past years. Induction of scalp psoriasis is a less known undesirable consequence of the use of these drugs and is not well characterized. Objective To characterize TNFα inhibitors-induced psoriatic alopecia. Methods We studied 6 patients with TNF-inhibitor induced psoriatic alopecia and reviewed 28 patients with this condition reported in the literature to date. Results In addition to severe scalp psoriasis, we report hair follicle pathologies ranging from alopecia areata to scarring alopecia. Prognosis was good, but discontinuation of TNFα inhibitors was required in more than half of the cases in order to achieve a favourable outcome. Conclusion TNFα inhibitors-associated psoriatic alopecia is rarely reported but requires a high index of suspicion and prompt diagnosis, as timely intervention may prevent irreversible damage.

Identification of Drug Compounds for Capsular Contracture Based on Text Mining and Deep Learning.

Capsular contracture is a common and unpredictable complication after breast implant placement. Currently, the pathogenesis of capsular contracture is unclear, and the effectiveness of nonsurgical treatment is still doubtful. The authors' study aimed to investigate new drug therapies for capsular contracture by using computational methods. Genes related to capsular contracture were identified by text mining and GeneCodis. Then, the candidate key genes were selected through protein-protein interaction analysis in Search Tool for the Retrieval of Interacting Genes/Proteins and Cytoscape. Drugs targeting the candidate genes with relation to capsular contracture were screened out in Pharmaprojects. Based on the drug-target interaction analysis by DeepPurpose, candidate drugs with highest predicted binding affinity were obtained eventually. The authors' study identified 55 genes related to capsular contracture. Gene set enrichment analysis and protein-protein interaction analysis generated eight candidate genes. One hundred drugs targeting the candidate genes were selected. The seven candidate drugs with the highest predicted binding affinity were determined by DeepPurpose, including tumor necrosis factor alpha antagonist, estrogen receptor agonist, insulin-like growth factor 1 receptor, tyrosine kinase inhibitor, and matrix metallopeptidase 1 inhibitor. Text mining and DeepPurpose can be used as a promising tool for drug discovery in exploring nonsurgical treatment to capsular contracture. Therapeutic, V.

The Effect of TNF-Alpha Gene Polymorphisms At -376 G/A, -806 C/T, and -1031 T/C on The Likelihood of Becoming a Non-Responder to Etanercept in A Sample of Iraqi Rheumatoid Arthritis Patients

Tumor necrosis factor-alpha (TNF-α) antagonists’ therapy are expensive and has a non-responsive rate between 30% to 40% in rheumatoid arthritis patients. Genetic variation plays a vital role in the responsiveness to this type of therapy.The aim of this study is to investigate if the presence of genetic polymorphism in the TNF-α gene promoter region at locations -376 G/A (rs1800750), -806 C/T (rs4248158), and -1031 T/C (rs1799964) affects rheumatoid arthritis patient's tendency to be a non-responder to etanercept. Eighty RA patients on etanercept (ETN) for at least six months were recruited from the Rheumatology Unit at Baghdad Teaching Hospital. Based on The European League Against Rheumatism response (EULAR) criteria, patients were divided into two groups: responders and non-responders. After polymerase chain reaction amplification of their DNA, the amplified DNA was sequenced by Sanger method to determine the polymorphisms at the positions -376G/A, -806 C/T, and -1031T/C. The results of this study found that equally Phi correlation and binary logistic regression analysis revealed a non-significant association for all genotypes in the three polymorphic sites with the tendency for being non-responder. Moreover, there was no significant difference in TNF-α mean level or the change in disease activity score for 28 joints (DAS28) after six months of etanercept therapy between all genotypes for each polymorphic site. The present study concludes that there was no correlation between the polymorphisms in the TNF-α promoter region at -376G/A, -806 C/T, and -1031T/C with the tendency for being non-responder to ETN.

Article Topic: Positioning Ulcerative Colitis Therapies in 2022 and Beyond.

Ulcerative colitis (UC) is a chronic disease with an increasing incidence. Recent guidelines emphasize treating toward objective targets, requiring the use of effective, steroid-sparing therapies. This review summarizes the safety and efficacy data of available therapies as well comparative effectiveness studies in order to help the reader make rational treatment decisions. Following the approval of tumor necrosis factor alpha antagonists, we have seen recent regulatory approval of several additional biologic and small molecule agents from several therapeutic classes (integrin antagonists, interleukin 12/23 antagonists, Janus kinase inhibitors, and sphingosine-1-phosphate receptor antagonists) for UC. Randomized, controlled trials, real-world analyses, and network meta-analyses have investigated the comparative safety and efficacy of these therapies in order to help clinicians better position these therapies in clinical practice. Numerous agents are now approved for the treatment of UC. This evidence-based review will help the reader understand the important factors weighing into treatment decisions for patients with UC and enable patient education and discussion with a focus on a shared decision-making approach.

Current Expertise, Opinions, and Attitude toward TNF-⍺ Antagonist Biosimilars among Physicians: A Self-Administered Online Survey in Western Switzerland

Tumor necrosis factor-alpha (TNF-⍺) antagonists are biological drugs with multiple authorized biosimilars. Biosimilars are becoming critical to the financial sustainability of health systems. Recent studies emphasize that physicians' knowledge regarding biosimilars has not yet progressed sufficiently to overcome their concerns regarding biosimilars' safety and efficacy. To assess the current knowledge, opinions, and attitudes toward TNF-⍺ antagonist biosimilars among postgraduate physicians and specialists, an anonymous, self-administered survey was implemented on SurveyMonkey between February and May 2022. The survey was validated through think-aloud interviews with senior and postgraduate physicians in rheumatology, gastroenterology, and immunoallergology, and a senior epidemiologist. Participant recruitment was conducted with the help of the physicians' professional societies and departmental head physicians of two university hospitals in Western Switzerland. Most physicians felt more comfortable initiating a TNF-⍺ antagonist biosimilar in biologic-naive patients (BNPs) than switching patients stabilized on the original biologic (originator). However, most participants agreed that BNPs should start treatment with the biosimilar rather than the originator when available. Postgraduate physicians and specialists in rheumatology, gastroenterology, and immunoallergology who participated in this survey were familiar with TNF-⍺ antagonist biosimilars and were confident in prescribing them. Yet, they still preferred to avoid switching a patient already on the originator.

Decreased Infliximab Concentrations in Patients With Inflammatory Bowel Disease Who Carry a Variable Number Tandem Repeat Polymorphism in the Neonatal Fc Receptor or Variant HLADQA1*05G>A Genotype.

Multiple variables contribute to variation in patient exposure and response to tumor necrosis factor alpha antagonist biologics such as infliximab. This study aimed to assess the association between maintenance-phase infliximab concentrations and genetic variation in HLADQA1*05G>A and fragment crystallisable (Fc) fragment of IgG receptor and transporter (FCGRT) among patients with inflammatory bowel disease. A cross-sectional study was carried out in participants with inflammatory bowel disease prescribed infliximab who were in the maintenance phase of treatment. Participants were genotyped for the presence of the FCGRT variable number tandem repeat (VNTR) and HLADQA1*05G>A (rs74291249). A point estimate of the infliximab trough concentration during the maintenance phase was determined using a standard enzyme-linked immunosorbent assay for each patient. Other variables associated with infliximab pharmacokinetics were collected. A total of 156 participants with inflammatory bowel disease were included from 2 tertiary care centers affiliated with Western University, London, Canada. Median infliximab trough concentrations were lower in participants who carried the FCGRT VNTR 2/3 or 2/2 (4.14 µg/mL; interquartile range [IQR], 6.48 µg/mL) vs wild type individuals (7.00 µg/mL; IQR, 7.66; P = .0027). Median infliximab trough concentrations were significantly lower in participants who were HLADQA1*05G>A variant carriers (4.73µg/mL; IQR, 4.79) vs wild type individuals (7.85µg/mL; IQR, 7.44; P = .0006). A significant decrease in infliximab trough concentrations was seen in individuals who were dual carriers of variant polymorphisms in HLADQA1*05G>A and FCGRT VNTR (no variants, 8.96µg/mL; IQR, 6.84 vs one variant, 4.96 µg/mL; IQR, 4.95 vs dual variants, 0.86µg/mL; IQR, 5.82). FCGRT VNTR and HLADQA1*05G>A are associated with lower maintenance-phase infliximab concentrations, particularly among patients who carry both variants.

Tumour necrosis factor-alpha antagonists for treatment of paediatric Crohn’s disease

Tumour necrosis factor-alpha antagonists for treatment of paediatric Crohn’s disease

The Role of Tumor Necrosis Factor Alpha Antagonists (Anti TNF-α) in Personalized Treatment of Patients with Isolated Polymyalgia Rheumatica (PMR): Past and Possible Future Scenarios.

Background: Glucocorticoids (GCs) are the cornerstone of polymyalgia rheumatica (PMR) therapy, but their long-term use (as is usually necessary in PMR patients) can induce many adverse events. Alternatives have long been sought. The primary aim of our narrative review is to provide an overview about the use of anti-tumor necrosis factor alpha (TNF-α) drugs in patients with PMR, and discuss advantages and disadvantages. Materials and methods: we performed a non-systematic literature search (PRISMA protocol not followed) on PubMed and Medline (OVID interface). Results and Conclusions: only two anti TNF-α drugs have been prescribed to PMR patients: infliximab in 62 patients and etanercept in 28 patients. These drugs were normally used in addition to GCs when significant comorbidities and/or relapsing PMR were present; less commonly, they were used as first-line therapy. In general, they have been scarcely successful in patients with PMR. Indeed, randomized controlled trials did not confirm the positive results reported in case reports and/or case series. However, an administration schedule and study design different from those proposed in the past could favour new scenarios in the interest of PMR patients.

A142 IMPACT OF HLADQA1*05G&amp;gt;A GENETIC-SCREENING FOR OPTIMAL ANTI-TNF THERAPY IN INFLAMMATORY BOWEL DISEASE: A PRELIMINARY REPORT

Abstract Background Genetic variation in the human leukocyte antigen ( HLA) gene is strongly associated with the formation of anti-drug antibodies to tumor necrosis factor-alpha antagonists (anti-TNF) in inflammatory bowel disease (IBD). It is also associated anti-TNF loss of response and treatment discontinuation. Aims We aimed to evaluate the utility of preemptive HLADQA1*05G&amp;gt;A screening to reduce the incidence of treatment-related adverse events in an IBD population by lessening the need for combination therapy in those who do not carry the risk allele. We also assessed for the occurrence of anti-TNF anti-drug antibody (ADA) formation, anti-TNF loss of response, treatment discontinuation compared to an unscreened population. Methods A non-randomized open label study is ongoing in IBD patients being considered for anti-TNF therapy. Participants received either pre-treatment HLADQA1*05G&amp;gt;A screening (prospective-screening group, n=25/110 recruited), with the addition of one of azathioprine or methotrexate to anti-TNF therapy (combination therapy) if identified as a high risk variant carrier (G/A or A/A) or received combination therapy without undergoing prospective HLADQA1*05A&amp;gt;G screening (control group, n=25/110 recruited). All participants will be followed for up to 1 year and observed for the occurrence of any adverse drug events, formation of anti-TNF drug antibodies (ADA), anti-TNF loss of response and anti-TNF discontinuation. Results To date, the prevalence of HLADQA1*05 G/A and A/A was 20% in the prospective-screening group and thus 20% (n=5/25) received combination therapy and 80% (n=20) received anti-TNF monotherapy. All participants in the control group (n=25/25) received combination therapy. Considering all groups, 78% (n=39/50) received infliximab, while 22% (n=11/50) received adalimumab. To date, the median follow-up period is 5 (IQR=4) months. Fewer adverse drug events have been reported in the prospective-screening group versus the control group (16.7% vs 33.3%, odds ratio 0.40, 95%CI=0.12–1.56, p=0.18). Anti-TNF ADA formation and treatment discontinuation were similar between groups (prospective-screening, 0% versus control, 4.2%). A higher proportion of controls experienced anti-TNF loss of response (16.7% vs 8.3%, p=0.38). Conclusions Preemptive HLADQA1*05G&amp;gt;A screening appears to reduce the need for combination therapy when using anti-TNF agents in an IBD population. Fewer drug-related adverse events are reported to date in the screened cohort without a concomitant increase in deleterious outcomes such as ADA formation or anti-TNF discontinuation. Completion of this study will help define whether or not HLADQA1*05G&amp;gt;A-screening is a clinically-actionable and relevant tool for guiding the application of combination therapy in IBD. Funding Agencies Lawson Health Research Institute

Hepatotoxicity Induced by Biological Agents: Clinical Features and Current Controversies.

Novel biological agents including cytokines and recombinant fusion proteins are increasingly prescribed for cancer, rheumatologic, autoimmune, and inflammatory diseases, and are currently being evaluated in hepatocellular carcinoma (HCC). They are classified by their mechanism of action and include tumor necrosis factor-alpha (TNF-α) antagonists, T cell mediated antitumor inhibitors, interleukin receptor antagonists, and immune checkpoint inhibitors (ICIs). Some ICIs cause frequent hepatotoxicity with a variable clinical, biochemical, and serological presentation, especially in patients receiving another immunomodulatory agent. Half of the cases of liver damage induced by biological agents spontaneously regress after drug withdrawal, but the others require steroid therapy. Unfortunately, there are no widely accepted recommendation for the use of corticosteroids in these patients, even though international cancer societies have their own guidelines. Differentiating drug-induced autoimmune hepatitis (DIAIH) from classic AIH is challenging for pathologists, but liver biopsy is valuable, particularly in cases with unclear clinical presentation. Interesting, novel histological patterns have been described in liver damage induced by these agents (i.e., endothelitis, ring granuloma and secundary sclerosing cholangitis associated with lymphocytic infiltration of cytotoxic CD8+T cells). Here, we describe the clinical and biochemical characteristics of patients with hepatotoxicity induced by TNF-α antagonists and ICIs. Controversial issues involved in the administration of corticosteroid therapy, and hepatitis B virus (HBV) reactivation induced by immunosuppressive therapy are also discussed.

OP23 The efficacy and safety of guselkumab induction therapy in patients with moderately to severely active Ulcerative Colitis: Phase 2b QUASAR Study results through week 12

Abstract Background The QUASAR Induction Study 1 (NCT04033445) is a phase 2b randomized, double-blind, placebo-controlled, dose-ranging study to evaluate the efficacy and safety of guselkumab (GUS), an interleukin-23 p19 subunit antagonist, as induction therapy in patients with moderately to severely active ulcerative colitis (UC) who had an inadequate response or intolerance to conventional (ie, thiopurines or corticosteroids) or advanced therapy (ie, tumor necrosis factor alpha antagonists, vedolizumab, or tofacitinib). Methods Patients included in these analyses had moderately to severely active UC (defined as a modified Mayo score of 5 to 9, inclusive) with a Mayo rectal bleeding subscore ≥ 1 and a Mayo endoscopy subscore ≥ 2 obtained during central review of video endoscopy at baseline. Patients were randomized 1:1:1 to receive IV GUS 200 mg, 400 mg, or placebo at Weeks 0, 4, and 8. The primary endpoint was clinical response at Week 12, and major secondary endpoints included clinical remission, symptomatic remission, endoscopic improvement, histo-endoscopic mucosal improvement, and endoscopic normalization at Week 12. Type 1 error was controlled at the 0.05 significance level for the primary endpoint; no other endpoints were controlled for multiplicity. Safety was assessed through Week 12. Results Three hundred thirteen patients were randomized in the primary analysis population (mean age, 41.6 yrs; male 59.1%, mean UC duration, 7.55 yrs; mean Mayo score, 9.2; endoscopy subscore of 3 indicating severe disease, 70%; baseline oral corticosteroid use, 39.6%). Approximately 50% had a prior inadequate response or intolerance to advanced therapy for UC. The baseline demographics and disease characteristics were generally similar among treatment groups (Table 1). At Week 12, a significantly greater proportion of patients treated with GUS 200 mg and 400 mg achieved clinical response compared with placebo (61.4% and 60.7% vs 27.6%, respectively, both p&amp;lt;0.001). A greater proportion of GUS-treated patients compared with placebo-treated patients achieved the major secondary endpoints at Week 12 (Figure 1). The proportions of patients reporting adverse events, serious adverse events, and adverse events leading to discontinuation in the GUS groups were not greater compared with placebo (Table 2). No serious infections were reported for GUS. No cases of malignancy or death were reported. Conclusion In patients with moderately to severely active UC, GUS induction treatment demonstrated superior efficacy compared with placebo treatment. Overall, safety results through Week 12 were consistent with the known safety profile of GUS in approved indications. The efficacy and safety of GUS 200 mg and 400 mg were comparable.

Clinical Features and Therapeutic Outcomes of Post-colectomy Enteritis with Ulcerative Colitis.

Objectives: Few reports are available on post-colectomy enteritis (PCE) with ulcerative colitis (UC), which can be severe and sometimes fatal. The clinical characteristics are unclear, and treatment and diagnosis protocols have not been established. We aimed to investigate the incidence, clinical characteristics, diagnostic criteria, and therapeutic outcomes of PCE in this study. Methods: Patients with UC who underwent colectomy between April 2010 and December 2019 were included in this study. We retrospectively analyzed patients who developed PCE and excluded patients with other forms of enteritis. Results: We performed 829 colectomies because of a preoperative diagnosis of UC. Eleven and four patients were diagnosed with Crohn's disease and indeterminate colitis after surgery, respectively; 22 patients developed enteritis in the perioperative period. We excluded six patients with backwash ileitis, five with prepouch ileitis, three with infectious enteritis, and one with ischemic enteritis. In total, 7/814 (0.8%) patients developed PCE. All patients with PCE had pancolitis. PCE was observed a median of 33 (12-248) days after surgery. Endoscopy showed friable and granular mucosa. The extent of disease included various types such as pan-enteritis with diffuse type, pan-enteritis and mild inflammation in the middle ileum, and only ileitis. Gastroduodenitis-associated UC developed in 6/7 cases. All patients improved with tumor necrosis factor alpha (TNFα) antagonists even if TNFα antagonists had not been effective for colitis. Conclusions: PCE was rare. The mucosal endoscopic findings were similar to those of UC, and the extent of disease varied. TNFα antagonist administration for PCE was effective.

Monitoring the efficacy of tumor necrosis factor alpha antagonists in the treatment of Ankylosing spondylarthritis: a pilot study based on MR relaxometry technique

BackgroundSpA is a disease that seriously affects the quality of life and working ability of patients. At present, there is a lack of scientific and effective quantitative indicators to evaluate the activity of sacroilitis and the efficacy of tumor necrosis factor-α antagonists in the treatment of active sacroilitis. MRI STIR sequence is the most commonly used method for the diagnosis of sacroiliac joint inflammation, but its response to the disease still lags behind the pathological changes and cannot provide quantitative indicators. This study aimed to evaluate the feasibility of using MRI Relaxometry technique to monitor the efficacy of TNF-α antagonists in the treatment of SpA, so as to provide an effective quantitative index for monitoring the efficacy.MethodsThis is a prospective study, 114 patients with sacroiliac joint were enrolled, including 15 patients as a control group, 99 patients as the case group, and 20 patients in the case group as the treatment group. The differences of T1 mapping, T2 mapping, T2* mapping of subchondral bone marrow of sacroiliac joint were compared among different groups. The diagnostic efficacy was analyzed by ROC, and the best quantitative index of diagnostic efficiency was used to monitor curative effects of different treatment cycles in the treatment group.Results1. Compared with the control group, values of three different relaxation times in the subchondral bone marrow region of the sacroiliac joint in the case group increased in varying degrees, and T1 mapping showed the best diagnostic efficacy. 2. The decreasing rate of T1 mapping in different treatment periods benefits the monitoring of curative effects.ConclusionThis study indicates that T1 mapping technique is preferred in quantitative diagnosis. T1 mapping is superior to T2* mapping and T2 mapping in the diagnosis of subchondral BME of SpA. It can quantitatively monitor edema changes during treatment, benefiting clinical individualized treatment and timely adjustment of the treatment plan.

An Update Review of Biosimilars of Adalimumab in Psoriasis – Bioequivalence and Interchangeability

Biologic drugs have revolutionized the treatment of psoriasis and other rheumatological diseases. In recent years, many biosimilar agents that are highly similar in structure and function to their originator products have been developed, including the tumor necrosis factor-alpha antagonist adalimumab. The considerably lower cost of these products has greatly cut the economic burden of the patients and increased the accessibility of biologic therapies worldwide. The US Food and Drug Administration and/or the European Medicines Agency have approved eight biosimilars of adalimumab (ABP 501/BI 695501/SB5/GP2017/FKB327/MSB11022/PF-06410293/CT-P17) for the treatment of psoriasis, and others are under review. Given that these agents showed pharmacokinetic, efficacy, safety, and immunogenicity profiles comparable to those of the originator, adalimumab biosimilars were licensed for all indications approved for reference adalimumab based on extrapolation; however, some of the equivalence studies were only conducted in one or two disease populations. This review discusses the bioequivalence of adalimumab biosimilars as demonstrated by various clinical trials, the extrapolation of indications, guidance and policies of the EU and US on interchangeability (nonmedical switching/automatic substitution) between biosimilars and originators, and the real-life practices of switching from reference adalimumab to the respective biosimilars. Further data from real-world studies and post-marketing analyses are needed better to address the efficacy and safety of the transition strategy.

P282 High plasma oncostatin-M predicts non-response to tumour necrosis factor-alpha antagonists in inflammatory bowel disease

Abstract Background The interleukin-6 family cytokine, oncostatin-M (OSM) has been associated with a lack of remission to tumor necrosis factor-α antagonists (anti-TNFs) in small cohorts of patients with inflammatory bowel disease (IBD). We aimed to further evaluate the association between plasma OSM concentrations and response to anti-TNFs (infliximab and adalimumab) in addition to other clinical outcomes in both ulcerative colitis (UC) and Crohn’s disease (CD). Methods A retrospective cohort study was carried out in patients with IBD with a history of anti-TNF exposure. Blood samples, collected prior to anti-TNF exposure, were analyzed by enzyme-linked immunosorbent assay for the presence and quantity of OSM. The primary outcome evaluated was clinical remission at 1-year based on the Harvey Bradshaw Index (HBI, remission, HBI&amp;lt;5) for CD and the Partial Mayo Score for UC (remission, Partial Mayo Score&amp;lt;2). Data pertaining to the occurrence of surgery, hospitalization, corticosteroid use, and adverse drug events during the 1-year follow-up period were also collected. Lastly the threshold OSM plasma concentration associated with anti-TNF non-response was assessed by receiver operator characteristic (ROC) curve analysis. Results One hundred and fourteen patients with IBD (CD, n=73; UC, n=40) seen at a tertiary care centre in London, Ontario Canada, were included in the analyses. Patients received one of infliximab (n=61) or adalimumab (n=53). For those with UC achieving clinical remission at 1-year (n=24), the mean OSM concentration was 84.5±119.7pg/ml versus those not achieving clinical remission (n=16) where the mean OSM concentration was 1064.0±958.8pg/ml (p&amp;lt;0.0001). For those with CD, the mean OSM concentration was 116.3 ± 222.3pg/ml in those achieving clinical remission (n=52) versus those did not (n=22) where the mean OSM concentration was 1220.0 ± 1274.0pg/ml (p&amp;lt;0.0001). A threshold OSM concentration of 168.7pg/ml in CD and 233.6pg/ml in UC separated those who achieved clinical remission at 1-year on an anti-TNF from those who did not (CD: area under the receiver operator characteristic curve, AUROC=0.880, 95%CI=0.79-0.96, p&amp;lt;0.0001; UC: AUROC=0.938, 95%CI=0.87-1.00, p&amp;lt;0.0001). In CD, participants with a plasma OSM concentration above the threshold concentration of 168.7pg/ml, were more likely to discontinue their anti-TNF at 1-year (p&amp;lt;0.0001), require hospitalization (p=0.0019) and/or corticosteroid rescue therapy (p&amp;lt;0.0001), require a surgical intervention (p=0.0087) or experience a drug-related adverse event (p=0.009). Conclusion OSM plasma concentrations were associated with response to anti-TNFs at 1-year in IBD. A threshold OSM concentration of 168.7pg/ml distinguished patients with CD at-risk of poor clinical outcomes.

Association between arthritis treatments and ovarian reserve: a prospective study

Research questionHow do anti-Müllerian hormone (AMH) concentrations in women with and without arthritis compare? Is there an association between AMH and arthritis drug regimen? DesignIn this prospective cohort study, AMH was measured at two time points (T0 and T1) in 129 premenopausal women with arthritis. AMH at T0 was compared with that from a bank of serum samples from 198 premenopausal women without arthritis. Primary outcomes were: (i) diminished ovarian reserve (DOR) (AMH <1.1 ng/ml) and (ii) annual rate of AMH decrease. Univariate, multivariable and Firth logistic regression identified variables associated with annual AMH decrease in excess of the 75th percentile. ResultsMedian time between T0 and T1 was 1.72 years. At time T0, median age-adjusted AMH in women with arthritis was significantly lower than that of women without arthritis (median 2.21 ng/ml versus 2.78 ng/ml; P = 0.009). Women with arthritis at highest risk for DOR had a history of tubal sterilization or were over the age of 35. Those with highest odds of having an annual AMH decrease in excess of the 75th percentile (over 28% decrease per year) were those: over the age of 35 or who sought care for infertility. Women with arthritis taking methotrexate alone (OR 0.08, 95% CI 0.01–0.67) or methotrexate plus tumour necrosis factor-alpha antagonists (OR 0.13, 95% CI 0.02–0.89) were less likely to be in the highest quartile of annual AMH decrease than women with arthritis not taking medication. ConclusionsWomen with arthritis had lower AMH than healthy controls. Long-term methotrexate use was not associated with an annual AMH decrease.