Tumor Necrosis Factor Antagonists Research Articles

Ustekinumab in the Treatment of Inflammatory Bowel Diseases: Evolving Paradigms.

Inflammatory bowel diseases, comprising Crohn's disease (CD) and ulcerative colitis (UC), are chronic, relapsing, and remitting immune-mediated inflammatory diseases affecting the gastrointestinal tract. Ustekinumab (UST) is a monoclonal antibody that blocks the p40 subunit of the anti-interleukin (IL) 12/23. Pivotal trials (CERTIFI and UNITI-IM for CD, UNIFI for UC) established the efficacy of UST for the induction and maintenance of remission in both CD and UC, with the most favorable results in naïve patients to biologics. In recent years, a wealth of 'real-world' data has emerged supporting positive clinical, endoscopic, and histological outcomes in patients treated with UST, as well as reassuring safety data. More recently, the results of the first head-to-head trials of UST and tumor necrosis factor (TNF) antagonists were reported. Moreover, a number of studies exploring the role of UST in specific clinical settings, such as perianal CD, postoperative complications and recurrence, extraintestinal manifestations, chronic antibiotic-refractory pouchitis, and pregnancy, were reported. This review explores the results reported to date on UST, including those from pivotal trials, real-world data, and emerging studies regarding therapeutic drug monitoring and immunogenicity. The safety profile of UST was also reviewed.

P1013 Placebo rates in Crohn's disease: An individual patient data meta-analysis from multiple randomised controlled trials

Abstract Background Estimating placebo rates and their determinants is essential for designing efficient randomised clinical trials (RCTs) in inflammatory bowel disease. We conducted an individual patient data (IPD) meta-analysis of placebo data from RCTs in Crohn’s disease (CD). Methods MEDLINE, Embase, and CENTRAL were searched from 01/2010 to 01/2020 for contemporary phase 2 and 3 placebo-controlled RCTs of biologics in moderate-to-severe CD. De-identified IPD from eligible trials that were available through the Vivli and Yale University Open Data Access data-sharing platforms were obtained. Primary outcomes were placebo clinical response and remission. Pooled placebo rates and 95% CIs were estimated using a 2-stage meta-analytical approach. Significant patient-level factors (P<0.05) associated with placebo rates were identified using regression analyses. Results Placebo IPD were available from 8 induction (n=1147) and 4 maintenance trials (n=524). Pooled placebo clinical response and remission rates varied based on outcome definition and prior biologic exposure (Figure). In induction trials, overall placebo response and remission rates were 27% (95% CI 23-32%) and 10% (95% CI 8-14%), respectively. Among bio-exposed patients, placebo response and remission rates were 27% (95% CI 16-40%) and 9% (95% CI 6-15%), respectively, compared with 29% (95% CI 24-34%) and 11% (95% CI 8-15%) for bio-naïve patients. Overall placebo response and remission rates in maintenance trials were 32% (95% CI 23%-42%) and 22% (95% CI 14-33%), respectively. Corresponding placebo response and remission rates for bio-exposed patients were 21% (95% CI 8-46%) and 17% (95% CI 11-25%), and 36% (95% CI 28-44%) and 24% (95% CI 15-36%) for bio-naïve patients. Placebo rates were lowest when response was defined as a ≥100-point decrease from baseline in the Crohn's Disease Activity Index (CDAI) score, and when remission was defined using stool frequency (≤1.5) and abdominal pain (≤1) subscores. Higher baseline C-reactive protein concentrations were associated with lower odds of placebo response and remission, while higher baseline albumin levels increased the odds of these outcomes (Table). Increased baseline CDAI and 2-item patient-reported outcome (PRO2) scores predicted higher odds of placebo response in induction trials, yet this reduced the odds of remission in induction trials and of both outcomes in maintenance trials. Prior failure to tumour necrosis factor (TNF) antagonist therapy was more predictive than prior TNF antagonist/biologic exposure for reducing the odds of placebo response and remission. Conclusion Placebo rates and the patient-level factors influencing them vary according to study design, clinical outcome measure and outcome definitions.

DOP54 Guselkumab and golimumab combination induction therapy in Ulcerative Colitis results in early local tissue healing that is sustained through guselkumab maintenance therapy

Abstract Background Combination induction therapy with guselkumab (GUS), an interleukin (IL)-23p19 subunit antagonist, and golimumab (GOL), a tumor necrosis factor (TNFα) antagonist, induced higher rates of clinical remission, endoscopic, and histologic outcomes than either monotherapy at Week (WK)12 in patients (pts) with ulcerative colitis (VEGA NCT03662542). Data through WK38 suggested the continued benefit of combination induction even after a transition to GUS monotherapy at WK12. We explored early molecular changes in colon tissue in a subset of pts at WK4 to define mechanistic contributions of each monotherapy and combination; these parameters were evaluated again at WK38 to assess potential carry-over of efficacy. Methods Colon biopsies were obtained at baseline (n=195), WK4 (n=42 substudy), and WK38 (n=172). Transcriptional profiles were generated with RNA sequencing (RNAseq). Gene correlation network analysis was applied in conjunction with publicly available single cell RNAseq data to define biologically relevant bulk and cell type-specific transcriptional modules associated with molecular features of disease. Gene set variation analysis (GSVA) was used to quantitatively assess changes in biologic modules with treatment. Results At WK4, combination induction (n=10) showed significant (p<0.05) decreases in molecular features compared to GUS (n=19) and GOL (n=13), including transcriptomic modules representing the IL-23 pathway, interferon response, and inflammatory epithelial and myeloid transcriptional states associated with endoscopic improvement at WK4 (Mayo endoscopy subscore of 0 or 1) (combination 5/11, GOL 1/13; GUS 2/19). Reduction (p<0.05) in inflammatory modules persisted through WK38 with combination vs monotherapy induction. Module changes between treatments at WK4 indicated a stronger correlation between GUS and combination (R=0.8; p=2.2e-16) than GOL and combination (R=0.52; p=4.1e-12), with processes associated with epithelial and stromal biology, and mucosal inflammation. In contrast, the combination effect on specific neutrophil/myeloid biology at WK4 was more similar to GOL than GUS, supporting the early role of GOL in targeting innate inflammation. Conclusion Combination induction with GUS and GOL showed significant reductions in major inflammatory features of disease as early as WK4 which persisted through WK38 with GUS maintenance. Correlative analysis supports the role of GUS as the primary driver of tissue healing, with GOL further contributing to innate inflammatory activity, which demonstrate differential and complementary mechanisms of action of TNFα and IL-23p19 subunit blockade.

OP37 Effect of the HLA-DQA1*05 allele on the efficacy of ustekinumab in patients with Crohn's Disease. Multicenter study based on the ENEIDA registry of GETECCU

Abstract Background HLA-DQA1*05 carriage is associated with the development of anti-drug antibodies and loss of response (LOR) to tumour necrosis factor antagonists (anti-TNF) in patients with inflammatory bowel diseases (IBD)1. Ustekinumab has shown very low rates of immunogenicity and presumably will not be affected by this risk. Identifying patients at high risk of treatment failure would be important when selecting therapy for IBD. The objective of this analysis was to investigate the relationship between the HLA- QA1*05 allele and ustekinumab on development of LOR and drug persistency. Methods This is a retrospective cohort study from a prospectively maintained ENEIDA registry. LOR was defined as recurrence or worsening of IBD related symptoms that required a change or intensification in treatment, hospitalization or surgery. Independent predictors of LOR were identified using univariate and multivariable Cox proportional hazard regression. The HLA-DQA1*05 allele was determined from a saliva sample (kit OGD-600 de DNA Genotek Oragene) and DNA extraction with the Maxwell® RSC-Stabilized Saliva DNA kits. Results 204 patients with Crohn's disease were included. Previous exposure to biological drugs was 96% (61% ≥2 biological drugs). Basal faecal calprotectin levels were 907±970μg/g and PCR levels 16.2±25 mg/dL. The median follow-up was 417±154 days. During this period, 25%, 16% and 13% of the patients required drug intensification, hospitalization or surgery, respectively. 43% of the patients included were carriers of one or two copies of the HLA-DQA1*05 allele. The presence/absence of this allele was not associated with LOR to ustekinumab (20% vs 16%, p = ns) nor with drug withdrawal (11% vs 6%, p = ns). In the multivariate analysis (COX regression), only the number of previous biological drugs was associated with ustekinumab persistency. Conclusion The presence of the HLA-DQA1*05 allele is not related to LOR or persistency of ustekinumab treatment. First-line treatment with ustekinumab rather than anti-TNF agents may be considered in HLA-DQA1*05-positive patients, particularly when the use of a concomitant immunosuppressant is contraindicated. 1. Sazonovs A, Kennedy NA, Moutsianas L, Heap GA, Rice DL, Reppell M, Bewshea CM, et al. PANTS Consortium. HLA-DQA1*05 Carriage Associated With Development of Anti-Drug Antibodies to Infliximab and Adalimumab in Patients With Crohn's Disease. Gastroenterology. 2020 Jan;158(1):189-199.

Recent Insight into Herbal Bioactives-Based Novel Approaches for Chronic Intestinal Inflammatory Disorders Therapy.

Inflammatory bowel disease (IBD) is a life-threatening complex disease. It causes chronic intestinal inflammation in GIT. IBD significantly affects people's lifestyles and carries a high risk of colon cancer. IBD involves the rectum, ileum, and colon, with clinical manifestations of bloody stools, weight loss, diarrhea, and abdominal pain. The prevalence of inflammatory disease is increasing dramatically worldwide. Over 16 million people are affected annually in India, with an economic burden of $6.8- $8.8 billion for treatment. Modern medicine can manage IBD as immunosuppressive agents, corticosteroids, tumor necrosis factor antagonists, integrin blockers, and amino-salicylates. However, these approaches are allied with limitations such as limited efficacy, drug resistance, undesired side effects, and overall cost, which cannot be ignored. Hence, the herbal bioactives derived from various plant resources can be employed in managing IBD. Science Direct, PubMed, Google, and Scopus databases have been searched for conclusively relevant herbal plant-based anti-inflammatory agent compositions. Studies were screened through analysis of previously published review articles. Eminent herbal bioactives, namely curcumin, resveratrol, ellagic acid, silybin, catechin, kaempferol, icariin, glycyrrhizin acid, berberine, quercetin, rutin, and thymol are reported to be effective against IBD. Herbal leads are promising treatment options for IBD; they have been shown to display antiinflammatory and antioxidant properties by targeting enzymes and regulating the expressions of various inflammatory mediators. Natural products have been reported to have anti-inflammatory properties in various clinical and preclinical studies, and some are available as herbal preparations. Herbal medicine would be promising in association with the implication of a novel drug delivery system for managing IBD.

Early Versus Late Use of Vedolizumab in Ulcerative Colitis: Clinical, Endoscopic, and Histological Outcomes.

We explored the potential for differential efficacy of vedolizumab between early and late ulcerative colitis [UC] with evaluation of clinical, endoscopic, and histological endpoints. This was a multicentre, multinational, open-label study in patients with moderately-to-severely active UC, defining early UC by a disease duration <4 years and bio-naïve and late UC by a disease duration > 4 years and additional exposure to tumour necrosis factor antagonists. Patients received standard treatment with intravenous vedolizumab for 52 weeks [300 mg Weeks 0, 2, 6, every 8 weeks thereafter without escalation]. The primary endpoint was corticosteroid-free clinical remission with endoscopic improvement [total Mayo score ≤2 with no subscore >1] at both Weeks 26 and 52. A total of 121 patients were included: in the "early" group, 25/59 [42.4%] achieved the primary endpoint versus 19/62 [30.6%] in the "late" group [p = 0.18]. There were no significant differences between the two groups in endoscopic improvement [Week 26: "early" 32/59 [54.2%] versus "late" 29/62 [46.8%]; p = 0.412; Week 52: 27/59 [45.8%] versus 25/62 [40.3%]; p = 0.546] or in histological remission [Robarts Histopathology Index <3 without neutrophils in the epithelium and lamina propria] [Week 26: 24/59 [40.7%] versus 21/62 [33.9%]; p = 0.439; Week 52: 22/59 [37.3%] versus 22/62 [35.5%]; p = 0.837]. No significant differences in clinical, endoscopic, and histological outcomes were observed between "early" and "late" disease.

Effectiveness of vedolizumab and ustekinumab as second biologic agent in achieving target outcomes in tumor necrosis factor antagonists experienced patients with inflammatory bowel disease (enroll-ex study).

Background: About a third of patients with inflammatory bowel disease (IBD) do not respond to anti-tumor necrosis factor (anti-TNF) therapy. In our study, we evaluated the effectiveness of vedolizumab and ustekinumab in achieving clinical and endoscopic outcomes in anti-TNF-experienced patients with IBD. Methods: We conducted a retrospective cohort study. Electronic medical records of patients with moderate to severe IBD, who were previously received anti-TNF therapies, were reviewed and evaluated retrospectively in a gastroenterology center. Outcomes of patients treated with ustekinumab or vedolizumab after failing one anti-TNF agent were evaluated. The primary outcomes were the percentage of hospitalization, surgery, mucosal healing and steroid-free remission. Mucosal healing was defined as a Mayo endoscopic score of 0 or 1 in ulcerative colitis (UC) and an SES-CD score of less than 3 in Crohn's disease (CD). Outcomes were quantified using descriptive analysis. Results: A total of 207 (130 CD: 77 UC) patients with IBD who had previously received one anti-TNF agent were included in the study. Of the total cohort, 62 (30.0%) patients were receiving vedolizumab, and 145 (70.0%) patients were on ustekinumab. 101 (77.6%) patients with CD who failed one anti-TNF therapy were on ustekinumab. Of these patients, 26 (19.7%) patients were hospitalized, and 12 (11.9%) patients had IBD-related surgery. 16 (16.1%) patients had at least one corticosteroid course. 60 (59.0%) patients with CD on ustekinumab achieved mucosal healing. 29 (22.3%) patients with CD who failed one anti-TNF therapy were receiving vedolizumab. Of those, 7 (25%) patients were hospitalized, and 11 (37.9%) patients had IBD-related surgery. 15 (51.0%) patients achieved mucosal healing. 44 (57.1%) patients with UC who failed one anti-TNF therapy were on ustekinumab. Of these 6 (14.1%) patients were hospitalized, 3 (7.0%) patients had IBD-related surgery and 13 (30%) patients had at least 1 corticosteroid course. 25 (57.0%) patients achieved mucosal healing. 33 (42.8%) patients with UC who failed one anti-TNF therapy were receiving vedolizumab. Of those, 6 (18.6%) patients were hospitalized, and 16 (49.6%) patients had at least 1 corticosteroid course. 17 (53.2%) patients achieved mucosal healing. Conclusion: Ustekinumab and vedolizumab were both effective in achieving clinical outcomes in patients with IBD after failing an anti-TNF agent. However, patients receiving ustekinumab had numerically higher percentages of reaching target outcomes than patients receiving vedolizumab. A prospective head-to-head trial is warranted to confirm these findings.

Rapid response to spesolimab in a patient with severe refractory pyoderma gangrenosum.

We report on a patient with severe ulcerative pyoderma gangrenosum that was recalcitrant to systemic corticosteroid, tumour necrosis factor antagonist and ciclosporin treatment and finally controlled when spesolimab was added to the treatment regimen.

Predictors and optimal management of tumor necrosis factor antagonist nonresponse in inflammatory bowel disease: A literature review.

Tumor necrosis factor-α (TNF-α) antagonists, the first biologics approved for treating patients with inflammatory bowel disease (IBD), are effective for the induction and maintenance of remission and significantly improving prognosis. However, up to one-third of treated patients show primary nonresponse (PNR) to anti-TNF-α therapies, and 23%-50% of IBD patients experience loss of response (LOR) to these biologics during subsequent treatment. There is still no recognized predictor for evaluating the efficacy of anti-TNF drugs. This review summarizes the existing predictors of PNR and LOR to anti-TNF in IBD patients. Most predictors remain controversial, and only previous surgical history, disease manifestations, drug concentrations, antidrug antibodies, serum albumin, some biologic markers, and some genetic markers may be potentially predictive. In addition, we also discuss the next steps of treatment for patients with PNR or LOR to TNF antagonists. Therapeutic drug monitoring plays an important role in treatment selection. Dose escalation, combination therapy, switching to a different anti-TNF drug, or switching to a biologic with a different mechanism of action can be selected based on the concentration of the drug and/or antidrug antibodies.

An Overview of Emerging Trends and Technologies in Ulcerative Colitis

&#x0D; This report provides an overview of the evolving therapeutic landscape for moderate to severe ulcerative colitis (UC), including recent changes to clinical practice guidelines, key trends in therapeutic strategies, and new or emerging treatment options, with a focus on biologics and small-molecule therapies.&#x0D; Recent guidelines on the medical management of patients with UC include those of the American Gastroenterological Association (AGA), American College of Gastroenterology (ACG), and European Crohn’s and Colitis Organisation (ECCO), which were published in 2019, 2020, and 2022, respectively. These guidelines provide an accurate reflection of how clinical practice has changed to incorporate newer therapies that have entered the market and newer evidence that has been published since the release of the Canadian guidelines in 2015. The ACG, AGA, and ECCO guidelines all recommend use of a tumour necrosis factor (TNF) antagonist, vedolizumab, or tofacitinib for induction of remission in patients with moderate to severe UC; the AGA and ECCO guidelines also recommend ustekinumab as an option and recommend vedolizumab over adalimumab, whereas the AGA guidelines recommend early use of biologic drugs over a step-up approach after failure of 5-aminosalicylates.&#x0D; Two important trends in therapeutic strategies for UC include changes in the use and definition of treatment targets and recommendations regarding therapeutic drug monitoring (TDM).&#x0D; &#x0D; The 2021 Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE-II) guidelines provide contemporary consensus recommendations for using new and updated targets throughout an individualized treatment timeline in patients with inflammatory bowel disease (IBD). Although histologic remission is not considered a formal UC treatment target in STRIDE-II, it is acknowledged as an adjunctive measure to endoscopic remission to represent a deeper level of healing and is the focus of many current studies.&#x0D; The use of TDM emerged from challenges associated with the use of older biologics (primarily TNF antagonists), which posed difficulties related to immunogenicity and dosing. The relevance of TDM for newer biologics with different mechanisms of action, reduced immunogenicity, and fixed dosing (e.g., vedolizumab and ustekinumab) is a topic of ongoing debate. Although AGA guidelines on TDM in IBD and expert consensus statements support the use of reactive TDM for patients with UC who lose response to a TNF antagonist, evidence gaps remain regarding appropriate use of proactive TDM, utility of TDM for small molecules and biologics outside of the TNF antagonist class, and consistent target concentration thresholds to guide dose changes.&#x0D; &#x0D; &#x0D; There is a substantial pipeline of new and emerging drugs for the treatment of adults with moderate to severe UC, with many in phase IIb or III of clinical development; several notable trends of emerging pharmacotherapies exist, including an increasing number of Janus kinase inhibitors, several therapies with biologic targets that are new in UC (e.g., interleukin-23 antibodies, TNF-like ligand 1A inhibitors), an increasing number of oral therapies, and the first combination of 2 biologic therapies in UC.&#x0D; The Canadian health care system should be prepared to adapt to the rapidly evolving treatment landscape and potential clinical practice changes in moderate to severe UC. Drugs with new mechanisms of action in the treatment area and the new paradigm of combination therapy with multiple biologics of different classes may lead to improved patient outcomes but can also further complicate the treatment decision-making process. Therefore, it is important for health care providers to stay up to date on new and upcoming treatment options, which may require educational initiatives for both providers and patients as well as updates to the Canadian treatment guidelines. Overall, potential changes on the horizon may have substantial implications for the health care system given the prevalence of UC in Canada, the costs of advanced therapies, and the increasing number of available treatment options.&#x0D;

Validation of a rapid HLA-DQA1*05 pharmacogenomics assay to identify at-risk resistance to anti-tumor necrosis factor therapy among patients with inflammatory bowel disease.

The HLA-DQA1*05 variant (rs2097432) is associated with increased risk of immunogenicity to tumor necrosis factor antagonists, with subsequent resistance to therapy in patients with inflammatory bowel disease. Identification of these patients would optimize personalized therapeutic selection. Genomic DNA was extracted from 80 deidentified samples in an unselected patient population with an unknown rs2097432 genotype. Split sample analysis was performed using a reference laboratory. Primer probes for a TaqMan quantitative polymerase chain reaction (qPCR) assay (Thermo Fisher Scientific) were custom designed. Synthesized genomic-block fragments were used as controls. All qPCR reactions were performed using a TaqMan GTXpress Master Mix (Thermo Fisher Scientific) on the Applied Biosystems 7500 system under fast cycling conditions. Of 80 samples, 50% were wild-type reference genotypes, 22.5% were heterozygous, and 27.5% were homozygous variant calls, comparable to population data. Split analysis samples between 2 independent laboratories were 100% concordant. The detection limit tested across genomic-block controls processed in duplicate was reproducible on sample input from 10 ng titrated down to 1.25 ng across 2 independent runs. Further, analytical specificity assessed with previous wild-type reference and homozygous variant DNA spiked into genomic-block controls produced appropriate heterozygous genotypes. Here we present validation of a lab-developed test for a rapid HLA-DQA1*05 (rs2097432) pharmacogenomics assay targeting a hotspot identified by genome-wide association studies. Targeted genotyping employed here will allow for expeditious personalized therapeutic selection.

Suboptimal response to tumor necrosis factor antagonists in inflammatory bowel disease in Latin America: EXPLORE LATAM study

ObjectiveData on anti-tumor necrosis factor (anti-TNF) treatment and suboptimal response (SOR) among patients with inflammatory bowel diseases (IBD) in Latin America (LATAM) are scarce. This study evaluated the incidence and indicators of SOR to anti-TNF therapy in patients with ulcerative colitis (UC) and Crohn's disease (CD) from Argentina, Colombia and Mexico. Patients and methodsWe performed retrospective analysis of data from LATAM patients of the EXPLORE study (NCT03090139) including adult patients with IBD who initiated anti-TNF therapy between March 2010 to March 2015. The cumulative incidence of SOR to first-line anti-TNF therapy was assessed. A physician survey to assess barriers to anti-TNF therapies was also carried out. ResultsWe included 185 IBD patients (UC/CD: 99/86) treated with first-line anti-TNF from Argentina (38 UC; 40 CD), Colombia (21 UC; 25 CD) and Mexico (40 UC; 21 CD). 36.4% of patients with UC and 46.5% of patients with CD experienced SOR to anti-TNF therapy during the median (interquartile range) observational period: 49.0 months (37.2–60.1) in UC, and 50.0 months (40.9–60.1) in CD. The most common indicator of SOR among patients was augmentation of non-biologic therapy (UC: 41.7%; CD: 35.0%). Affordability and late referral to IBD specialist care centers were the most common barriers to anti-TNF therapies. ConclusionsSOR to anti-TNF therapy was common in LATAM IBD patients, where augmentation with non-biologic therapy represented the most frequent indicator of SOR across indications. Our findings contribute to the current evidence on the unmet needs associated with anti-TNF in LATAM.

Guilt by Association: Inflammation and Shared Genetic Risk Between Stress-Related and Immune Disorders

Back to table of contents Previous article Next article EditorialsFull AccessGuilt by Association: Inflammation and Shared Genetic Risk Between Stress-Related and Immune DisordersAndrew H. Miller, M.D., and Elisabeth B. Binder, M.D., Ph.D.Andrew H. MillerSearch for more papers by this author, M.D., and Elisabeth B. BinderSearch for more papers by this author, M.D., Ph.D.Published Online:1 Apr 2023https://doi.org/10.1176/appi.ajp.20230078AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail “A person is known by the company they keep”—AesopThe significant interrelationship between stress-related disorders, including posttraumatic stress disorder (PTSD), and autoimmune and inflammatory diseases provides compelling evidence that inflammation represents both a mechanism and a target for the treatment of these psychiatric conditions (1–3). Indeed, data indicate that stress-related neuroendocrine alterations can drive inflammatory responses that overlap with those seen in autoimmune and inflammatory disorders. For example, special attention has been paid to the disruptive effects of chronic or traumatic stress on the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system and their effects on the regulation of the inflammatory response. HPA axis hormones, notably cortisol, play an important role in restraining inflammation, while activation of the sympathetic nervous system has been shown to mobilize immune cells from the bone marrow and stimulate intracellular inflammatory signaling pathways, including the nuclear factor kappa B (NF-kB) pathway (1, 2, 4). Increased levels of inflammatory markers have been reliably reported in the peripheral blood of patients with stress-related disorders and PTSD, including increases in the acute-phase reactant C-reactive protein (CRP) and the inflammatory cytokines tumor necrosis factor (TNF), interleukin-1 beta, interleukin-6, and interferon gamma (5). Moreover, increased activation of inflammatory signaling pathways has been found in blood transcriptomic analyses of PTSD patients (2). Childhood trauma, a major risk factor for stress-related disorders and autoimmune diseases (6), has also been linked with inflammation, in part through epigenetic effects on relevant genes, including FKBP5, which not only plays a role in the sensitivity to cortisol through effects on the glucocorticoid receptor but also affects activation of NF-kB signaling pathways (7). Increased inflammation in turn has been shown to engage relevant brain circuits involved in anxiety and depression (4). Interestingly, while it is clear that stress-induced neuroendocrine disturbances can lead to increased inflammation and related behavioral changes, there is also evidence that inflammation prior to trauma can increase the likelihood of developing stress-related pathology (1). In a study of over 2,500 male U.S. marines, predeployment CRP levels significantly predicted postdeployment PTSD (8). These data suggest that an inflammatory bias is a risk factor for stress-related disorders and PTSD, and thus the arrow between stress-related disorders and inflammation points in both directions (1).Providing further support for the notion that stress-related disorders and inflammation are joined at the hip is the article by Zeng et al. (9) in this issue of the Journal. In this study, a variety of complementary analytic strategies were used to examine the genetic relationships between stress-related disorders, including PTSD, and autoimmune and inflammatory diseases, such as rheumatoid arthritis, ulcerative colitis, psoriasis, and insulin-dependent diabetes. In a large database of over 4 million individuals from Swedish nationwide registries, the authors observed not only a significant co-occurrence of these two types of disorders within individuals but also a co-occurrence of these two phenotypes in pairs of relatives. Their co-occurrence significantly increased as a function of ascending kinship, with a 51% greater likelihood of having both a stress-related disorder and an autoimmune disease in monozygotic twin pairs and a 28% and 16% greater likelihood in dizygotic twin pairs and full-sibling pairs, respectively. A similar increased likelihood of having an autoimmune disorder in individuals with a diagnosis of a stress-related disorder was found in the UK Biobank data, with a striking odds ratio of 2.35 (95% CI=1.90–2.91) for an autoimmune disease among individuals with an inpatient diagnosis of PTSD. This correlation on the phenotypic level was also accompanied by shared genetic risk. In fact, polygenic risk scores for stress-related disorders were associated with significantly increased risk for autoimmune diseases and vice versa. A positive genetic correlation (rg) of 0.26 was found between stress-related disorders and autoimmune disorders, and this correlation was even stronger for PTSD specifically (rg=0.39). The extent of this genetic correlation was as large as or larger than the one observed between PTSD and cardiovascular disease (rg=0.24) (10), further substantiating a genetic link between PTSD and diseases associated with inflammation, including both cardiovascular disease and autoimmune disorders. Ten genes and five functional gene modules were found to be shared between stress-related disorders and autoimmune diseases. Of note, the validity of the findings was further supported by the consistency of results when stress-related disorders (primarily adjustment disorders) and PTSD were considered separately and when each autoimmune or inflammatory disorder was analyzed individually. Overall, the findings have the advantage of the study’s having drawn from multiple databases and employing several strategies of genetic analyses, ultimately identifying commonalities at the molecular level as well as specific treatment targets for future studies. Finally, the results of the study confirm and extend other findings of genetic associations between psychiatric phenotypes, including PTSD, and immune-related phenotypes (2).The question then arises as to why these relationships between behavior and the immune system persist in the gene pool despite the detrimental consequences of both stress-related disorders and autoimmune and inflammatory diseases. One possibility is that these relationships derive from evolutionary pressures that required an immune and behavioral preparedness to address an ancestral environment rife with pathogens and predators that challenged survival to reproductive age (4, 11). Aggressive immune responses support fighting infection and wound healing, while hypervigilance can protect against future attack, especially in vulnerable individuals who are infected or wounded. Of note, administration of inflammatory stimuli has been reliably shown to activate threat-related neurocircuitry involving the dorsal anterior cingulate cortex, the insula, the hippocampus, and the amygdala (4). Nevertheless, although an aggressive immune response coupled with increased threat sensitivity and hyperarousal might have subserved evolutionary fitness in ancestral times, in the modern world, such evolutionary legacies may be less adaptive, and in conjunction with inflammation-associated lifestyles (characterized by obesogenic diets, sedentary activity, and social isolation) and exposure to trauma, they may contribute to rising rates of autoimmune and inflammatory diseases as well as stress-related disorders and PTSD.An important implication of the shared genetic associations between stress-related disorders and autoimmune disease, especially shared genes and gene modules, is the identification of immune targets for the treatment of PTSD and other stress-related disorders. It has been demonstrated that blocking inflammation with the anti-TNF drug infliximab reduces psychic anxiety and symptoms of anhedonia in otherwise medically healthy depressed patients with high baseline levels of CRP (12). Infliximab, which was one of the early biologic anticytokine drugs used to treat autoimmune diseases, was also found to reduce amygdala activation during an emotional face processing task using functional MRI in patients with inflammatory arthritis (13). Consistent with these findings, anticytokine therapies have also been reported to decrease symptoms of anxiety and depression in patients with a variety of autoimmune and inflammatory disorders (14). These data suggest that drugs used to treat autoimmune and inflammatory diseases may be relevant for the treatment of stress-related disorders such as PTSD. Of particular interest in this regard are drugs that are being developed for autoimmune diseases and target immunometabolism (15, 16). Upon activation, immune cells, especially monocytes, which are the primary mediators of the inflammatory response, shift their metabolism from the energy-efficient oxidative phosphorylation to the relatively energy-inefficient glycolysis. This metabolic shift allows rapid access to ATP that can be used for cellular growth and proliferation and for the production of inflammatory mediators, without the need to create more mitochondria, where oxidative phosphorylation occurs. Immunometabolic shifts toward glycolysis are prominent in autoimmune and inflammatory diseases and have been described recently in stress-related psychiatric disorders, including depression (17). Blocking signaling pathways that support this metabolic shift has become an intriguing new target for drug development for the treatment of autoimmune and inflammatory disorders (15, 16). Interestingly, five of the 10 risk genes shared by stress-related disorders and autoimmune disease identified in the study by Zeng et al. play a role in cellular metabolism; the majority of these genes are linked to glycolysis, including EMP2, MYCBP, RRAGC, and SAMSN1, through their involvement with hypoxia-inducible factor-1 alpha, MYC, mammalian target of rapamycin, and AMP-activated protein kinase signaling pathways (16). These data further highlight the relevance of the genetic associations between these two phenotypes and their implications for drug development, especially those linked to immunometabolism. It should be emphasized, however, that any overlap in behavioral and immune phenotypes will be relevant only in a subset of patients with stress-related disorders or PTSD, and therefore the principles of precision psychiatry should apply to drug development in this space. More specifically, clinical trials should use biomarkers to enrich for patients with the relevant immunopathology and assess outcome variables that are directly related to the impact of any treatment on the immune system and ultimately the impact of inflammation on the brain and behavior. In summary, the shared associations between stress-related and immune disorders, genetic and otherwise, provide important clues regarding the role of inflammation in the pathophysiology of these psychiatric conditions, while also shedding light on a path forward for the development of mechanism-based, targeted treatments for these diseases.Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta (Miller); Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich (Binder).Send correspondence to Dr. Miller ([email protected]).Dr. Miller has served as a consultant for Cerevel Therapeutics and Sirtsei Pharmaceuticals. Dr. Binder reports no financial relationships with commercial interests.REFERENCES1. Sumner JA, Nishimi KM, Koenen KC, et al.: Posttraumatic stress disorder and inflammation: untangling issues of bidirectionality. Biol Psychiatry 2020; 87:885–897Crossref, Medline, Google Scholar2. Katrinli S, Oliveira NCS, Felger JC, et al.: The role of the immune system in posttraumatic stress disorder. Transl Psychiatry 2022; 12:313Crossref, Medline, Google Scholar3. O'Donovan A, Cohen BE, Seal KH, et al.: Elevated risk for autoimmune disorders in Iraq and Afghanistan veterans with posttraumatic stress disorder. Biol Psychiatry 2015; 77:365–374Crossref, Medline, Google Scholar4. Miller AH, Raison CL: The role of inflammation in depression: from evolutionary imperative to modern treatment target. Nat Rev Immunol 2016; 16:22–34Crossref, Medline, Google Scholar5. 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Mol Psychiatry 2021; 26:5150–5160Crossref, Medline, Google Scholar14. Kappelmann N, Lewis G, Dantzer R, et al.: Antidepressant activity of anti-cytokine treatment: a systematic review and meta-analysis of clinical trials of chronic inflammatory conditions. Mol Psychiatry 2018; 23:335–343Crossref, Medline, Google Scholar15. Pålsson-McDermott EM, O’Neill LAJ: Targeting immunometabolism as an anti-inflammatory strategy. Cell Res 2020; 30:300–314Crossref, Medline, Google Scholar16. O’Neill LAJ, Kishton RJ, Rathmell J: A guide to immunometabolism for immunologists. Nat Rev Immunol 2016; 16:553–565Crossref, Medline, Google Scholar17. Bekhbat M, Goldsmith DR, Woolwine BJ, et al.: Transcriptomic signatures of psychomotor slowing in peripheral blood of depressed patients: evidence for immunometabolic reprogramming. Mol Psychiatry 2021; 26:7384–7392Crossref, Medline, Google Scholar FiguresReferencesCited byDetailsCited byInsights From Genetic, Neuroimaging, and Behavioral Neuroscience StudiesNed H. Kalin, M.D.1 April 2023 | American Journal of Psychiatry, Vol. 180, No. 4 Volume 180Issue 4 April 01, 2023Pages 259-261 Metrics KeywordsInflammationStressImmune DisordersImmunotargetPosttraumatic Stress Disorder (PTSD)PDF download History Accepted 13 February 2023 Published online 1 April 2023 Published in print 1 April 2023

HLA-DQA1*05 ASSOCIATES WITH IMMUNOGENICITY AND LOSS OF RESPONSE TO ANTI-TNF THERAPY IN THE IBD POPULATION: A META-ANALYSIS

The human leukocyte antigen (HLA) allele group HLA-DQA1*05 has been associated with the development of antidrug antibodies (ADA) to tumor necrosis factor antagonists (anti-TNF)1 in the inflammatory bowel disease (IBD) population, except in the setting of proactive optimization2. We performed a meta-analysis to determine the prevalence of HLADQA1*05 carriage, to define the association of HLA-DQA1*05 on immunogenicity and loss of response (LOR) to anti-TNF, and to explore the impact of therapeutic drug monitoring (TDM) on this association.

Second–Line Biologic Therapy Following Tumor Necrosis Factor Antagonist Failure: A Real–World Propensity Score–Weighted Analysis

Tumor necrosis factor (TNF) antagonists often are used as first-line medications to treat moderate to severe inflammatory bowel disease (IBD), but many patients do not achieve or maintain response. Our aim was to compare the effectiveness of second-line treatments (ustekinumab, vedolizumab, or a second TNF antagonist) after TNF antagonist exposure in patients with Crohn's disease (CD) and ulcerative colitis (UC) from 2 electronic health records-based cohorts. We identified patients with prior TNF antagonist exposure who switched to a different biologic in the Mount Sinai Health System (MSHS) electronic health records (CD, n= 527; UC, n= 165) and the Study of a Prospective Adult Research Cohort (SPARC) from the Inflammatory Bowel Disease Plexus Program of the Crohn's & Colitis Foundation (CD, n= 412; UC, n= 129). Treatment failure was defined as the composite of any IBD-related surgery, IBD-related hospitalization, new prescription of oral/intravenous corticosteroids, or need to switch to a third biologic agent. Time-to-event analysis was conducted with inverse probability of treatment-weighted data. Overall, treatment failure occurred in 85% of MSHS and 72% of SPARC CD patients. In SPARC, the likelihood of treatment failure was significantly lower with ustekinumab compared withvedolizumab as second-line treatment (adjusted hazard ratio, 0.66; 95% CI, 0.54-0.82; P<.001), a trend confirmed in MSHS (adjusted hazard ratio, 0.89; 95% CI, 0.77-1.04; P= .15). In both cohorts, the superiority of ustekinumab compared with vedolizumab was shown when considering treatment failure as prescription of steroids or a third biologic agent. In UC, no differences between second-line treatment groups were identified. In 2 independent real-world cohort settings, second-line therapy in CD with ustekinumab after TNF antagonist treatment failure was associated with a lower likelihood of treatment failure than second-line vedolizumab.

DOP72 HLA-DQA1*05 associates with immunogenicity and loss of response to anti-TNF therapy in the IBD population: A meta-analysis

Abstract Background The human leukocyte antigen (HLA) allele group HLA-DQA1*05 has been associated with the development of antidrug antibodies (ADA) to tumor necrosis factor antagonists (anti-TNF)1 in the inflammatory bowel disease (IBD) population, except in the setting of proactive optimization2. We performed a meta-analysis to determine the prevalence of HLADQA1*05 carriage, to define the association of HLA-DQA1*05 on immunogenicity and loss of response (LOR) to anti-TNF, and to explore the impact of therapeutic drug monitoring (TDM) on this association. Methods A systematic search of EMBASE, MEDLINE, Web of Science, and SCOPUS was conducted and identified 49 studies. Fourteen studies were included in the meta-analysis according to our inclusion and exclusion criteria. Two reviewers independently assessed eligibility and extracted data. Data extraction focused on the prevalence of HLADQA1*05 carriage, management style of the subjects (proactive TDM vs not), use of combination therapy with immunomodulators (IMM), and association of the variant with ADA and LOR. To examine the potential mitigating effect of management style, three forest plots were generated for each outcome including: 1. all studies, 2. studies using solely proactive TDM, and 3. studies where TDM was either not defined or not performed. Results The prevalence of HLADQA1*05 carriage was 43.3% across the 14 manuscripts (Table 1). Ten studies used data from adult populations, 2 reported on pediatrics only, and 2 reported on a mix of pediatrics and adults. Nine studies took place in Europe, and 5 occurred in North America. A little over half (57%) were abstracts. All studies included some patients on combination therapy with IMM. Data analysis confirmed that possessing the HLADQA1*05 variant leads to an increased ADA risk (OR 1.63 [95% CI: 1.35 - 1.98]). When focusing on the studies that used proactive optimization of anti-TNF therapy, the variant was no longer a risk factor for developing ADA (OR 0.37 [95% CI: 0.19 - 0.70]). Without proactive optimization, the carriage of HLADQA1*05 appears to consistently be associated with a higher risk of immunogenicity (OR 1.93 [95% CI: 1.58 - 2.36]) (Figure 1). HLADQA1*05 was also found to be a risk factor for LOR (HR 1.84 [95% CI: 1.53 - 2.22]) (Figure 2); insufficient data were available for the studies with proactive TDM on LOR. Conclusion Prevalence of HLADQA1*05 carriage is consistent across studies from both North America and Europe. This variant increases the risk of ADA and LOR to anti-TNF. However, in studies that used solely proactive TDM, variant carriage no longer conferred a risk for ADA. 1. Sazonovs A, et al. Gastro. 2020;158(1):189-199. 2. Spencer EA, et al. Gastro. 2022;162(6):1746-1748.e1743.

P588 Interim results from the randomised VERDICT trial to determine the optimal treatment target in patients with ulcerative colitis

Abstract Background The optimal treatment target for ulcerative colitis (UC) is uncertain. The VERDICT trial in moderate to severe UC aims to determine if a treatment target of corticosteroid (CS)-free symptomatic + endoscopic + histologic remission is superior to CS-free symptomatic remission alone. Trial progress and the study cohort to date are described herein. Methods Our aim is to enrol 660 patients with moderately to severely active UC (Mayo rectal bleeding subscore [RBS] ≥1; Mayo endoscopic score [MES] ≥2). Patients are randomised to 3 treatment targets (2:3:5 ratio): CS-free symptomatic remission (Mayo RBS = 0) (Group 1); CS-free endoscopic remission (MES ≤1) + symptomatic remission (Group 2); or CS-free histologic remission (Geboes score &amp;lt;2B.0) + endoscopic + symptomatic remission (Group 3). Therapy is administered according to a treatment algorithm that is dependent upon each patient’s UC treatment at screening. Early introduction of vedolizumab (VDZ) and dose escalation up to 300 mg every 4 weeks until the target is met are central to each algorithm. Up to 3 opportunities to achieve the assigned target were prespecified in the algorithms (weeks 16, 32, or 48). Patients and central readers for endoscopy/histopathology are blinded to group allocation, and investigators are unblinded. Results As of 2 November 2022, 331 patients were enrolled at 55 sites across 10 North American and European countries. Mean (SD) baseline characteristics (Table) include a UC duration of 8.6 (8.3) years, Mayo Clinic score of 8.7 (1.7), C-reactive protein level of 13.3 (15.6) mg/dL, and a faecal calprotectin level of 1462.3 (1481.3) mg/kg. At baseline, 52% (172/331) and 11% (37/331) of patients were receiving concomitant CS and immunosuppressives, respectively, and 14% (47/331) had current/prior exposure to tumour necrosis factor antagonists. Most patients (85%) were receiving nonbiologic therapy. Of all randomised patients, 43/69 (Group 1), 65/98 (Group 2), and 115/164 patients (Group 3) have reached week 16; and 28 (65%), 25 (39%), and 42 (37%) met their target, respectively. After a median of 35 weeks (IQR 18-53), a total of 30 (Group 1), 32 (Group 2), and 50 patients (Group 3) have met their target and will be followed to relapse or study termination. The serious adverse event rate (8%; 36/483) was similar across groups. Conclusion VERDICT has randomised ~50% of its target enrolment. Enrolled patients represent a typical moderate to severe UC population and are primarily bionaive and receiving early VDZ initiation. Early results suggest the feasibility of achieving each treatment target, specifically histologic remission, and are consistent with expected values. No new VDZ safety signals were identified. Completion of enrolment is anticipated in late 2023.

P495 Vedolizumab trough concentrations and histological remission in Ulcerative Colitis: Results from the LOVE-UC study

Abstract Background To date, the association between vedolizumab (VDZ) serum concentrations and histological remission in ulcerative colitis (UC) has not been studied prospectively. VDZ serum concentrations could potentially offer additional guidance for predicting histological remission. We studied the relationship between VDZ serum concentrations and histological remission in a prospective study. Methods LOVE-UC was a multicentre international (Belgium, the Netherlands, and Hungary) open label prospective study in patients with moderately to severely active UC treated with VDZ. VDZ serum concentrations were measured at trough prior to every infusion. Endoscopy was performed at baseline, week 26 and 52. Biopsies from the most severely affected area and endoscopy videos were scored by blinded central readers. Histological remission was defined as a Robarts Histopathology Index &amp;lt;3 without neutrophils. Patients who did not undergo histological assessment were regarded as not having reached histological remission. Endoscopic remission was defined as a Mayo endoscopic sub-score 0. Results A total of 121 patients (61 male, 62 with prior exposure to tumour necrosis factor antagonists, mean total Mayo score at baseline of 9) received at least one infusion of VDZ. At week 26, 37.2% (45/121) patients were in histological remission, 38.8% (47/121) were in histological remission at week 52. The corresponding rates of combined histological and endoscopic remission were 19.8% (24/121) and 20.7% (25/121), respectively. Median VDZ serum concentrations were numerically higher at all time points in patients who achieved histological remission at week 26 than in those who did not (Table 1). Concentration thresholds (sensitivity, specificity, positive predictive value, negative predictive value, area under the receiver operating characteristic curve) of 32.5 mg/L (66%, 68%, 54%, 74%, 0.681) at week 6 and 12.5 mg/L (76%, 60%, 61%, 70%, 0.724) at week 22 were associated with histological remission at week 26. Higher proportions of patients achieved histological remission at week 26 in higher VDZ serum concentration quartiles (Figure 1). Conclusion VDZ serum concentrations were positively associated with histological remission in UC, although the predictive value of serum concentrations for subsequent histological remission was modest.

Use of Adalimumab, a TNF-Alpha Inhibitor, is Associated with Paradoxical Psoriasis: Two Clinical Case Reports

The use of tumor necrosis factor (anti-TNF) antagonists has become a practice applied in the treatment of various inflammatory diseases, such as psoriasis. However, the use of Anti-TNF can, paradoxically, trigger side effects as a form of psoriasiform or worsening of pre-existing symptoms, in patients with or without previously diagnosed psoriasis. In view of this, two case reports were described. First, we described a 21-year-old female patient who used adalimumab for four months due to extensive suppurative hidradenitis. In the second case, we related a 32-year-old male patient diagnosed with severe Crohn's disease, with Adalimumab for three months developed psoriasis.

HLA-DQA1*05 ASSOCIATES WITH IMMUNOGENICITY AND LOSS OF RESPONSE TO ANTI-TNF THERAPY IN THE IBD POPULATION: A META-ANALYSIS

Abstract BACKGROUND The human leukocyte antigen (HLA) allele group HLA-DQA1*05 has been associated with the development of antidrug antibodies (ADA) to tumor necrosis factor antagonists (anti-TNF)1 in the inflammatory bowel disease (IBD) population, except in the setting of proactive optimization2. We performed a meta-analysis to determine the prevalence of HLADQA1*05 carriage, to define the association of HLA-DQA1*05 on immunogenicity and loss of response (LOR) to anti-TNF, and to explore the impact of therapeutic drug monitoring (TDM) on this association. METHODS A systematic search of EMBASE, MEDLINE, Web of Science, and SCOPUS was conducted and identified 49 studies. Fourteen studies were included in the meta-analysis according to our inclusion and exclusion criteria. Two reviewers independently assessed eligibility and extracted data. Data extraction focused on the prevalence of HLADQA1*05 carriage, management style of the subjects (proactive TDM vs not), use of combination therapy with immunomodulators (IMM), and association of the variant with ADA and LOR. To examine the potential mitigating effect of management style, three forest plots were generated for each outcome including: 1. all studies, 2. studies using solely proactive TDM, and 3. studies where TDM was either not defined or not performed. RESULTS The prevalence of HLADQA1*05 carriage was 43.3% across the 14 manuscripts. Ten studies used data from adult populations, 2 reported on pediatrics only, and 2 reported on a mix of pediatrics and adults. Nine studies took place in Europe, and 5 occurred in North America. A little over half (57%) were abstracts. All studies included some patients on combination therapy with IMM. Data analysis confirmed that possessing the HLADQA1*05 variant leads to an increased ADA risk (OR 1.63 [95% CI: 1.35 - 1.98]). When focusing on the studies that used proactive optimization of anti-TNF therapy, the variant was no longer a risk factor for developing ADA (OR 0.37 [95% CI: 0.19 - 0.70]). Without proactive optimization, the carriage of HLADQA1*05 appears to consistently be associated with a higher risk of immunogenicity (OR 1.93 [95% CI: 1.58 - 2.36]) (Figure 1). HLADQA1*05 was also found to be a risk factor for LOR (HR 1.84 [95% CI: 1.53 - 2.22]) (Figure 2); insufficient data were available for the studies with proactive TDM on LOR. CONCLUSION Prevalence of HLADQA1*05 carriage is consistent across studies from both North America and Europe. This variant increases the risk of ADA and LOR to anti-TNF. However, in studies that used solely proactive TDM, variant carriage no longer conferred a risk for ADA. 1. Sazonovs A, et al. Gastro. 2020;158(1):189-199. 2. Spencer EA, et al. Gastro. 2022;162(6):1746-1748.e1743.