anti-TNF Treatment Research Articles

S863 Impact of Race on ANTI-TNF Immunogenicity in Patients with Inflammatory Bowel Disease

Introduction: Immunogenicity is a major contributor to anti-tumor necrosis factor (anti-TNF) treatment failure in inflammatory bowel disease (IBD). Immunomodulator and anti-TNF combination therapy is associated with a decreased risk of immunogenicity. Anti-TNF immunogenicity was recently linked to HLA-DQA1*05 genotype. This study aims to determine the impact of race on rates of immunogenicity and treatment outcomes of IBD pts on anti-TNF combination therapy. Methods: This was a single-center, retrospective study of IBD pts who have been treated with immunomodulators and anti-TNF combination therapy between 2012 and 2020. Our primary outcomes were the rates of anti-TNF antibody formation and mean anti-TNF drug levels between Caucasian group(CG) and non-Caucasian group(NCG) on combination therapy. Secondary outcomes included steroid-free clinical remission (SFCR), endoscopic remission (ER) (absence of ulcers/erosions in CD and Mayo endoscopic score ≤ 1 for UC), & normal serum C-reactive protein (CRP) (defined as ≤ 5. mg/L). Continuous variables were analyzed using unpaired student’s t-test. Categorical variables were analyzed using a chi-square test. Results: A total of 124 pts were included (CD; 68.5%, UC; 27.4%, indeterminate colitis; 3.2%, pouchitis; 0.9%). The median age was 32 years (range 13-69), and 54.8% were male. A total of 87 pts were on infliximab & 37 pts were on adalimumab. Combination therapy with thiopurine was employed in 87.1% while 12.9% were on methotrexate. A total of 85 pts were self-identified as Caucasian. There were no significant differences between CG vs NCG in terms of baseline and disease characteristics (Table). Anti-TNF antibody formation was observed in 32.9% of pts in the CG, and 20.5% of pts in the NCG (p=0.16). Mean anti-TNF drug levels were lower in the CG at 15.4 ± 14.5 µg/mL vs. the NCG at 22.7 ± 15.1 µg/mL (p=0.01). SFCR was observed in 61.2% vs. 58.9% (p=0.82) in CG vs. NCG, respectively. In CG 42.4% vs. 33.3% in NCG (p=0.34) discontinued anti-TNF treatment during follow-up. ER was observed in 45.9 % vs 51.3% (p=0.44), and normal CRP was observed in 51.8% vs. 58.9% (p=0.28) in CG vs. NCG, respectively. Conclusion: In our cohort, Caucasian pts on anti-TNF combination therapy for IBD had significantly lower anti-TNF drug levels as compared to the non-Caucasian group. However, there was no significant difference between rates of anti-TNF antibody formation and clinical outcomes between the groups. Larger studies are needed to clarify impact of race on anti-TNF therapy. Table 1. - Comparison of Characteristics Between Caucasian vs. Non-Caucasian Race Caucasian (n=85), n (%), mean (SD) Non-Caucasian (n=39), n (%), mean (SD) P-value 34.7 (13.7) 34.7 (11.7) 0.98 47 (55.3) 21 (53.9) 0.88 7 (8.2) 6 (15.4) 0.23 36.4 (27.1) 41.9 (31.8) 0.35 0.07 53 (62.4) 32 (82.1) 29 (34.1) 5 (12.8) 2 (2.3) 2 (5.1) 1 (1.2) 0 21 (24.7) 15 (38.5) 0.12 24 (28.2) 14 (35.9) 0.81 10 (11.8) 6 (15.4) 0.77 61 (71.8) 26 (66.7) 0.56 69 (81.2) 29 (74.4) 0.39 12.5 (21.4) 6.8 (7.6) 0.15 3.9 (0.6) 4.1 (0.4) 0.16 *Data missing for 68 patients.**Data missing for 42 patients.Abbreviations: Anti TNF, anti-tumor necrosis factor; CRP, C reactive protein.

S971 The Prevalence of Vasculitis Is Increased in Inflammatory Bowel Disease, but Decreased After Anti-TNF Treatment: A Population-Based Study

S971 The Prevalence of Vasculitis Is Increased in Inflammatory Bowel Disease, but Decreased After Anti-TNF Treatment: A Population-Based Study

Electrospun patch delivery of anti-TNFα F(ab) for the treatment of inflammatory oral mucosal disease.

Chronic ulcerative oral mucosal inflammatory diseases, including oral lichen planus and recurrent aphthous stomatitis, are painful and highly prevalent, yet lack effective clinical management. In recent years, systemic biologic therapies, including monoclonal antibodies that block the activity of cytokines, have been increasingly used to treat a range of immune-mediated inflammatory conditions such as rheumatoid arthritis and psoriasis. The ability to deliver similar therapeutic agents locally to the oral epithelium could radically alter treatment options for oral mucosal inflammatory diseases, where pro-inflammatory cytokines, in particular tumour-necrosis factor-α (TNFα), are major drivers of pathogenesis. To address this, an electrospun dual-layer mucoadhesive patch comprising medical-grade polymers was investigated for the delivery of F(ab) biologics to the oral mucosa. A fluorescent-labelled F(ab) was incorporated into mucoadhesive membranes using electrospinning with 97% v/v ethanol as a solvent. The F(ab) was detected within the fibres in aggregates when visualised by confocal microscopy. Biotinylated F(ab) was rapidly eluted from the patch (97±5% released within 3h) without loss of antigen-binding activity. Patches applied to oral epithelium models successfully delivered the F(ab), with fluorescent F(ab) observed within the tissue and 5.1±1.5% cumulative transepithelial permeation reached after 9h. Neutralising anti-TNFα F(ab) fragments were generated from whole IgG by papain cleavage, as confirmed by SDS-PAGE, then incorporated into patches. F(ab)-containing patches had TNFα neutralising activity, as shown by the suppression of TNFα-mediated CXCL8 release from oral keratinocytes cultured as monolayers. Patches were applied to lipopolysaccharide-stimulated immune-competent oral mucosal ulcer equivalents that contained primary macrophages. Anti-TNFα patch treatment led to reduced levels of active TNFα along with a reduction in the levels of disease-implicated T-cell chemokines (CCL3, CCL5, and CXCL10) to baseline concentrations. This is the first report of an effective device for the delivery of antibody-based biologics to the oral mucosa, enabling the future development of new therapeutic strategies to treat painful conditions.

S738 Real World Evidence Comparing Vedolizumab and Ustekinumab in Anti-TNF Experienced Patients With Crohn’s Disease

Introduction: Many patients with Crohn’s disease (CD) lose response or become intolerant to anti-TNF therapy. Newer classes of biologics have demonstrated efficacy in anti-TNF experienced patients, but real-world comparative effectiveness studies are limited and have yielded conflicting results. We sought to compare the effectiveness and safety of ustekinumab to vedolizumab in a large, geographically diverse United States (U.S.) population of adult patients with CD previously treated with TNF inhibitors. Methods: We conducted a retrospective cohort study using longitudinal claims data from a large national U.S. insurance company (Anthem, Inc.). We identified CD patients initiating vedolizumab or ustekinumab with evidence of anti-TNF treatment in the prior 6 months. Our primary outcome was treatment persistence > 52 weeks. Select secondary outcomes included: 1) all-cause hospitalization; 2) hospitalization for CD with surgery; 3) hospitalization for CD without surgery, and 4) hospitalization for infection. Propensity score fine stratification was used to control for confounding by demographic and clinical characteristics and prior treatments at baseline. Results: We identified 885 new users of ustekinumab and 490 new users of vedolizumab who met criteria for our primary analysis. We observed no difference in treatment persistence [adjusted RR 1.09 (95% CI 0.95 -1.25)]; however, ustekinumab was associated with lower all-cause hospitalization (adjusted HR 0.73 [0.59-0.91]) and non-surgical CD hospitalizations (adjusted HR 0.58 [0.40-0.83]) (Figure). Ustekinumab initiators were also less likely to be hospitalized for infection (adjusted HR 0.56 [ 0.34-0.92]). Conclusion: This real-world comparative effectiveness study of anti-TNF experienced CD patients initiating vedolizumab or ustekinumab showed similar treatment persistence rates beyond 52 weeks, although secondary outcomes such as all-cause hospitalization, non-surgical CD hospitalizations, and hospitalizations for infection favored ustekinumab initiation. We therefore advocate for individualized decision making in this medically refractory population, considering patient preference, prior Anti-TNF experience and other factors such as cost and route of administration.Figure 1.: Incidence and Effect Estimates for Primary and Secondary Endpoints in New Users of Ustekinumab vs Vedolizumab

Impact of Anti-TNFα Treatment on the Humoral Response to the BNT162b2 mRNA COVID-19 Vaccine in Pediatric Inflammatory Bowel Disease Patients.

The efficacy of the COVID-19 mRNA vaccine, including the third vaccination in pediatric inflammatory bowel disease (PIBD) patients is not fully understood. This study aimed to evaluate the humoral immunogenicity of the BNT162b2 vaccine and the changes in durability until 20–28 weeks after the initial vaccine series in PIBD patients on immunosuppressive drugs. The safety of the initial vaccine series and the booster effect of the third vaccination were also evaluated. A single-center, prospective cohort study was conducted, and 63 participants (anti-TNFα: 11; non-anti-TNFα: 31; 5-ASA: 21), with a mean age of 15.2 (range 9.6–17.9) years, were enrolled. All PIBD patients were seroconverted, with no serious short-term AEs. PIBD patients on anti-TNFα had significantly lower antibody titers than those on other medications at all measurement points. Furthermore, antibody titers waned over time with anti-TNFα and were significantly lower at 20–28 weeks than at 3–9 weeks after a two-vaccine series. In all 10 patients (anti-TNFα: 5; non-anti-TNFα including 5-ASA: 5), the third vaccination led to antibody concentrations significantly higher than those at the same time point after the second vaccination. PIBD patients on anti-TNFα need to remain vigilant about COVID-19 even after two vaccinations, and a third vaccination may be considered.

The ileal fungal microbiota is altered in Crohn's disease and is associated with the disease course.

IntroductionFungal microbiota's involvement in the pathogenesis of Crohn's disease (CD) is incompletely understood. The terminal ileum is a predilection site both for primary involvement and recurrences of CD. We, therefore, assessed the mucosa-associated mycobiota in the inflamed and non-inflamed ileum in patients with CD.MethodsThe mucosa-associated mycobiota was assessed by ITS2 sequencing in a total of 168 biopsies sampled 5 and 15 cm proximal of the ileocecal valve or ileocolic anastomosis in 44 CD patients and 40 healthy controls (HC). CD patients with terminal ileitis, with endoscopic inflammation at 5 cm and normal mucosa at 15 cm and no history of upper CD involvement, were analyzed separately. The need for additional CD treatment the year following biopsy collection was recorded.ResultsCD patients had reduced mycobiota evenness, increased Basidiomycota/Ascomycota ratio, and reduced abundance of Chytridiomycota compared to HC. The mycobiota of CD patients were characterized by an expansion of Malassezia and a depletion of Saccharomyces, along with increased abundances of Candida albicans and Malassezia restricta. Malassezia was associated with the need for treatment escalation during follow-up. Current anti-TNF treatment was associated with lower abundances of Basidiomycota. The alpha diversity of the inflamed and proximal non-inflamed mucosa within the same patients was similar. However, the inflamed mucosa had a more dysbiotic composition with increased abundances of Candida sake and reduced abundances of Exophiala equina and Debaryomyces hansenii.ConclusionsThe ileal mucosa-associated mycobiota in CD patients is altered compared to HC. The mycobiota in the inflamed and proximal non-inflamed ileum within the same patients harbor structural differences which may play a role in the CD pathogenesis. Increased abundance of Malassezia was associated with an unfavorable disease course.

Longitudinal multi-omics analysis identifies early blood-based predictors of anti-TNF therapy response in inflammatory bowel disease

Background and aimsTreatment with tumor necrosis factor α (TNFα) antagonists in IBD patients suffers from primary non-response rates of up to 40%. Biomarkers for early prediction of therapy success are missing. We investigated the dynamics of gene expression and DNA methylation in blood samples of IBD patients treated with the TNF antagonist infliximab and analyzed the predictive potential regarding therapy outcome.MethodsWe performed a longitudinal, blood-based multi-omics study in two prospective IBD patient cohorts receiving first-time infliximab therapy (discovery: 14 patients, replication: 23 patients). Samples were collected at up to 7 time points (from baseline to 14 weeks after therapy induction). RNA-sequencing and genome-wide DNA methylation data were analyzed and correlated with clinical remission at week 14 as a primary endpoint.ResultsWe found no consistent ex ante predictive signature across the two cohorts. Longitudinally upregulated transcripts in the non-remitter group comprised TH2- and eosinophil-related genes including ALOX15, FCER1A, and OLIG2. Network construction identified transcript modules that were coherently expressed at baseline and in non-remitting patients but were disrupted at early time points in remitting patients. These modules reflected processes such as interferon signaling, erythropoiesis, and platelet aggregation. DNA methylation analysis identified remission-specific temporal changes, which partially overlapped with transcriptomic signals. Machine learning approaches identified features from differentially expressed genes cis-linked to DNA methylation changes at week 2 as a robust predictor of therapy outcome at week 14, which was validated in a publicly available dataset of 20 infliximab-treated CD patients.ConclusionsIntegrative multi-omics analysis reveals early shifts of gene expression and DNA methylation as predictors for efficient response to anti-TNF treatment. Lack of such signatures might be used to identify patients with IBD unlikely to benefit from TNF antagonists at an early time point.

Anti-TNF Therapies Suppress Adipose Tissue Inflammation in Crohn's Disease.

Anti-TNF biologics have been shown to markedly improve the quality of life for patients with Crohn’s disease (CD), yet one-third of patients fail to benefit from this treatment. Patients with CD develop a characteristic wrapping of visceral adipose tissue (VAT) in the inflamed intestinal area, termed creeping fat, and it is known that adipose tissue expansion influences the efficacy of anti-TNF drugs. We questioned whether anti-TNF therapies impact the creeping fat in CD, which might affect the outcome of the disease. Adipose tissue biopsies were obtained from a cohort of 14 patients with CD that received anti-TNF drugs and from 29 non-anti-TNF-treated patients (control group) matched by sex, age, and body mass index undergoing surgical interventions for symptomatic complications. We found that anti-TNF therapies restored adipose tissue morphology and suppressed immune cell infiltration in the creeping fat. Additionally, anti-TNF treatments appeared to markedly improve the pro-inflammatory phenotype of adipose-tissue macrophages and adipose-tissue-derived stem cells. Our study provides evidence that anti-TNF medications influence immune cells and progenitor cells in the creeping of patients with CD, suppressing inflammation. We propose that perilesional VAT should be considered when administering anti-TNF therapy in patients with CD.

Identification of the optimal medical and surgical management for patients with perianal fistulising Crohn's disease.

The aim of our study was to assess the best medical and surgical approaches for perianal Crohn's disease (PCD) in order to identify an optimal combined medical and surgical treatment. Medical records of all patients with PCD treated with TNFα antagonists in two referral centres between 1998 and 2018 were reviewed. Predictors of long-term outcomes were identified using a Cox proportional hazard model. A total of 200 patients were included. Fifty-three patients (26.5%) were treated with adalimumab and 147 (73.5%) with infliximab. A combination of TNFα antagonist with an immunosuppressant and the presence of proctitis were independently associated with fistula closure. Seton was placed in 127 patients (63.5%) before starting biological therapy. Eighty patients (40%) underwent additional perineal surgery. Prior PCD surgery, seton positioning, additional perineal surgery, and additional surgery within 52 weeks of anti-TNFα treatment were associated with an increased rate of fistula closure. Finally, medical combination therapy (anti-TNFα plus immunosuppressant) along with seton placement and additional surgery within 1 year was the best management for PCD patients (p= 0.02). Combined medical and surgical management is required for the treatment of PCD patients. Medical combination therapy associated with seton placement and additional surgery within 1 year is the best management for PCD patients.

Case Report: Susceptibility to viral infections and secondary hemophagocytic lymphohistiocytosis responsive to intravenous immunoglobulin as primary manifestations of adenosine deaminase 2 deficiency

Deficiency of adenosine deaminase 2 (DADA2) is an autosomal recessive disease associated with a highly variable clinical presentation, including systemic vasculitis, immunodeficiency, and cytopenia. We report a case of a 16-year-old girl affected by recurrent viral infections [including cytomegalovirus (CMV)-related hepatitis and measles vaccine virus-associated manifestations] and persistent inflammation, which occurred after Parvovirus infection and complicated by secondary hemophagocytic lymphohistiocytosis (HLH). HLH’s first episode presented at 6 years of age and was preceded by persistent fever and arthralgia with evidence of Parvovirus B19 infection. The episode responded to intravenous steroids but relapsed during steroids tapering. High-dose intravenous immunoglobulin (IVIG) helped manage her clinical symptoms and systemic inflammation. The frequency of IVIG administration and the dosage were progressively reduced. At the age of 9, she experienced varicella zoster virus (VZV) reactivation followed by the recurrence of the inflammatory phenotype complicated by HLH with neurological involvement. Again, high-dose steroids and monthly IVIG resulted in a quick response. Targeted next-generation sequencing (NGS) for autoinflammatory diseases and immunodeficiencies revealed the homozygous Leu183Pro ADA2 mutation, which was confirmed by Sanger analysis. ADA2 enzymatic test showed a complete loss of ADA2 activity. For about 3 years, IVIG alone was completely effective in preventing flares of inflammation and neurological manifestations. Anti-TNF treatment was started at the age of 13 for the appearance of recurrent genital ulcers, with a complete response. This case further expands the clinical spectrum of DADA2 and emphasizes the importance of extensive genetic testing in clinical phenotypes characterized by persistent unspecific inflammatory syndromes. The use of high doses of IVIG might represent a possible effective immune modulator, especially in combination with anti-TNF treatment.

Identification of Novel Loci Involved in Adalimumab Response in Crohn's Disease Patients Using Integration of Genome Profiling and Isoform-Level Immune-Cell Deconvoluted Transcriptome Profiling of Colon Tissue.

Crohn’s disease is a consequence of dysregulated inflammatory response to the host’s microbiota. Although anti-TNF treatment improves the quality of the patient’s life, a large proportion of patients lose response to the treatment. The past decade of research has led to a continuum of studies showcasing the heterogeneity of anti-TNF response; thus, the aim of the present study was to dissect transcriptome-wide findings to transcript isoform specific levels and combine the analyses with refined information of immune cell landscapes in colon tissue, and subsequently select promising candidates using gene ontology and genomic integration. We enrolled Slovenian Crohn’s disease patients who were naïve with respect to adalimumab treatment. We performed colon tissue RNA sequencing and peripheral blood mononuclear cell DNA genotyping with a subsequent contemporary integrative approach to combine immune cell deconvoluted isoform transcript specific transcriptome analysis, gene ontology layering and genomic data. We identified nine genes (MACF1, CTSE, HDLBP, HSPA9, HLA-DMB, TAP2, LGMN, ANAPC11, ACP5) with 15 transcripts and 16 variants involved in the adalimumab response. Our study identified loci, some of which were previously shown to contribute to inflammatory bowel disease susceptibility, as novel loci involved in adalimumab response in Crohn’s disease patients.

Serum and Mucosal CD30 in Pediatric Inflammatory Bowel Diseases: Useful Biomarker for Diagnosis and Disease Activity Monitoring?

Inflammatory bowel diseases (IBD) frequently manifest in pediatric age, but may have atypical clinical, histological and laboratory features. Their underlying immune pathophysiology is incompletely understood, rendering quick diagnosis followed by tailored therapy difficult. The tumor necrosis factor superfamily receptor CD30 has been proposed as a potential marker of ulcerative colitis (UC) and has also been associated with elevated Th2 helper T cells. A cohort of pediatric patients with UC and Crohn's disease (CD) was evaluated for serum soluble CD30 (sCD30) using ELISA and expression of CD30 and subpopulations of Th1/Th2/Th17 lymphocytes in the gastrointestinal mucosa using flow cytometry (FCM). The dataset is supported by endoscopic and microscopic activity of the disease and basic laboratory markers of inflammation. The cohort consisted of 102 observations from 94 patients. sCD30 levels did not differ between patients with CD or UC. However, sCD30 levels correlated with levels of CRP, ESR, fecal calprotectin and albumin and also with clinical activity of the disease in patients with both UC and CD. FCM was not helpful in evaluation of mucosal CD30, which was lowly expressed and not associated with the diagnosis or disease activity. We show augmented Th2 and Th1/17 response in terminal ileum and right-sided colon and decreased Th1/17 response in left-sided colon of UC patients. T lymphocyte subsets were also affected by anti-TNF treatment and patients' age. Neither sCD30 nor mucosal CD30 expression was helpful in differentiating between UC and CD. sCD30 seems to reflect a degree of systemic inflammation and clinical activity in IBD.

Validation and update of a prediction model for risk of relapse after cessation of anti-TNF treatment in Crohn's disease.

Anti-tumor necrosis factor (TNF) therapy is effective for the treatment of Crohn's disease. Cessation may be considered in patients with a low risk of relapse. We aimed to externally validate and update our previously developed prediction model to estimate the risk of relapse after cessation of anti-TNF therapy. We performed a retrospective cohort study in 17 Dutch hospitals. Crohn's disease patients in clinical, biochemical or endoscopic remission were included after anti-TNF cessation. Primary outcome was a relapse necessitating treatment. Discrimination and calibration of the previously developed model were assessed. After external validation, the model was updated. The performance of the updated prediction model was assessed in internal-external validation and by using decision curve analysis. 486 patients were included with a median follow-up of 1.7 years. Relapse rates were 35 and 54% after 1 and 2 years. At external validation, the discriminative ability of the prediction model was equal to that found at the development of the model [c-statistic 0.58 (95% confidence interval (CI) 0.54-0.62)], though the model was not well-calibrated on our cohort [calibration slope: 0.52 (0.28-0.76)]. After an update, a c-statistic of 0.60 (0.58-0.63) and calibration slope of 0.89 (0.69-1.09) were reported in internal-external validation. Our previously developed and updated prediction model for the risk of relapse after cessation of anti-TNF in Crohn's disease shows reasonable performance. The use of the model may support clinical decision-making to optimize patient selection in whom anti-TNF can be withdrawn. Clinical validation is ongoing in a prospective randomized trial.

Critical roles of RGS16 in the mucosal inflammation of ulcerative colitis.

BackgroundUlcerative colitis is a chronic and progressive inflammatory disorder. The regulator of the G-protein signaling (RGS) is involved in the pathogenesis of several immune system disorders. RGS16, a member of the RGS protein superfamily, has been shown to play critical roles in several immune system-related diseases. However, the roles of RGS16 in ulcerative colitis remain to be elucidated.MethodsWe analyzed the expression of RGS16 in peripheral blood mononuclear cells (PBMCs) and inflamed mucosa of ulcerative colitis patients using quantitative reverse transcription-PCR, western blotting and immunohistochemistry. We performed Spearman’s correlation to analyze the correlation between RGS16 expression and the ulcerative colitis endoscopic index of severity (UCEIS), Mayo index, erythrocyte sedimentation rate (ESR) and serum tumor necrosis factor alpha (TNF-a) and IL-17A levels. Further, PBMCs were stimulated with inflammatory cytokines in vitro.ResultsRGS16 expression significantly increased in the colonic mucosa and PBMCs from patients with ulcerative colitis and significantly correlated with the Mayo index, UCEIS, ESR and serum TNF-α and IL-17A levels. TNF-α upregulated RGS16 expression in PBMCs in a dose- and time-dependent manner via the nuclear factor kappa beta (NF-kB) signaling pathway. Moreover, anti-TNF treatment with infliximab significantly decreased RGS16 expression in PBMCs and intestinal mucosa of patients with ulcerative colitis.ConclusionOur study revealed a novel mechanism by which RGS16 expression in ulcerative colitis is positively correlated with disease activity. Thus, RGS16 might serve as a potential therapeutic marker for the treatment of ulcerative colitis.

Tuberculosis Infection Under Anti-TNF Alpha Treatment.

Anti-tumor necrosis factor-α (TNF-α) is a life-changing treatment leading to quality-of-life improvement. Nonetheless, this treatment is associated with a high risk of infection, especially tuberculosis. Our study aimed to determine the frequency of active tuberculosis in our patients with chronic rheumatic disease and treated with TNF-α. We conducted a retrospective study including patients with Rheumatoid Arthritis and Spondylarthritis diagnosed according to ACR/EULAR 2009 criteria and ASAS 2010, respectively, and treated with biological agents for at least 6 months. We collected data regarding tuberculosis screening and the occurrence of active tuberculosis during follow-up. 82 patients were included (37 men and 45 women). The mean age was 42 ± 3.4 years. At inclusion, no patient had a medical history of tuberculosis. The diagnosis of latent tuberculosis infection was established in 17 patients (20.7%). Prophylactic treatment was prescribed in all these cases for three months. Two cases (2.4%) of active tuberculosis occurred under biologic (infliximab). It was two severe forms of tuberculosis. The first case had miliary tuberculosis associated with hepatic and peritoneal involvement. The second one had pleural tuberculosis. These two patients received anti-tuberculosis therapy, and the biological treatment was interrupted. Given the high disease activity, the anti-TNF-α was restarted after 3 and 4 months. There was no recurrence of tuberculosis after 7 years of follow-up. The use of TNF-α blockers is associated with a risk of disseminated forms of tuberculosis. Tuberculosis screening, which is recommended before the biological onset, is also necessary under this treatment. Restarting the anti-TNF-α after appropriate treatment of tuberculosis seemed to be safe.

Comparison of the outcomes between early and late anti-tumor necrosis factor therapy in patients with enthesitis-related subcategory of juvenile idiopathic arthritis: a multi-center study in Southeast Asia

ABSTRACT Background Little is known about the impact of delayed initiation of anti-tumor necrosis factor (TNF) therapy in patients with enthesitis-related arthritis (ERA). Here, we compared the impact of delayed treatment on disease outcomes of ERA patients in Southeast Asia. Research design and methods This retrospective study enrolled 149 ERA patients from Thailand and Singapore. Early (e-aTNF) and late (l-aTNF) treatment groups received anti-TNF therapy starting at ≤6 months and >6 months, respectively, after diagnosis. Outcomes included mean differences in disease activity parameters, Juvenile Spondyloarthritis Disease Activity (JSpADA) score, Juvenile Arthritis Diseases Activity (JADAS)-10 score, and American College of Rheumatology Pediatric (ACR Pedi) criteria, and the frequency of clinically inactive disease and first flare event. Results The mean changes in JSpADA (p = 0.002) and JADAS-10 (p < 0.001) scores over time were significantly higher in the e-aTNF group than in the l-aTNF group. A significantly higher proportion of patients in the e-aTNF group than l-aTNF group satisfied ACR Pedi 100 criteria at 2 years (p = 0.042). All other long-term outcomes were not significantly different between the groups. Conclusions Although early anti-TNF treatment improved disease activity parameters somewhat better than delayed anti-TNF therapy, there was no significant difference in long-term outcomes.

Effects of Anti-Tumor Necrosis Factor Therapy on Osteoblastic Activity at Sites of Inflammatory and Structural Lesions in Radiographic Axial Spondyloarthritis: A Prospective Proof-of-Concept Study Using Positron Emission Tomography/Magnetic Resonance Imaging of the Sacroiliac Joints and Spine.

Proof-of-concept trial to determine the effects of tumor necrosis factor inhibitor (TNFi) therapy on osteoblastic activity at sites of inflammatory and structural lesions in patients with radiographic axial spondyloarthritis (SpA), using fluorine 18-labeled NaF (18 F-NaF) positron emission tomography/magnetic resonance imaging (PET/MRI). Sixteen patients with clinically active radiographic axial SpA were prospectively enrolled to receive TNFi treatment and undergo 18 F-NaF PET/MRI of the sacroiliac (SI) joints and spine at baseline and at a follow-up visit 3-6 months after treatment initiation. Three readers (1 for PET/MRI and 2 for conventional MRI) evaluated all images, blinded to time point. Bone marrow edema, structural lesions (i.e., fat lesions, sclerosis, erosions, and ankylosis), and 18 F-NaF uptake at SI joint quadrants and vertebral corners (VCs) were recorded. Overall, 11 male and 5 female patients (mean age ± SD 38.6 ± 12.0 years) were followed up for a mean duration of 4.6 months (range 3-6). 18 F-NaF PET/MRI was conducted on SI joints for 16 patients and the spine for 10; 128 SI joint quadrants and 920 VCs were analyzed at each time point. At baseline, 18 F-NaF uptake was demonstrated in 96.0% of SI joint quadrants with bone marrow edema, 94.2% with sclerosis, and 88.3% with fat lesions. At follow-up, 65.3% of SI joint quadrants with bone marrow edema (P < 0.001), 33.8% with sclerosis (P = 0.23), and 24.5% with fat lesions (P = 0.01) had less 18 F-NaF uptake, compared with baseline. For VCs, 18 F-NaF uptake at baseline was found in 81.5% of edges with sclerosis, 41.9% with fat lesions, and 33.7% with bone marrow edema. At follow-up, 73.5% of VCs with bone marrow edema (P = 0.01), 53.3% with fat lesions (P = 0.03), and 55.6% with sclerosis (P = 0.16) showed less 18 F-NaF uptake, compared with baseline. Anti-TNF antibody treatment led to a significant decrease in osteoblastic activity within 3-6 months, especially, but not solely, at sites of inflammation. Larger data sets are needed for confirmation of the antiosteoblastic effects of TNFi for the prevention of radiographic progression in axial SpA.

Anti-TNFα Treatment Impairs Long-Term Immune Responses to COVID-19 mRNA Vaccine in Patients with Inflammatory Bowel Diseases.

Patients with inflammatory bowel disease (IBD) treated with anti-tumor-necrosis factor-alpha (TNFα) exhibited lower serologic responses one-month following the second dose of the COVID-19 BNT162b2 vaccine compared to those not treated with anti-TNFα (non-anti-TNFα) or to healthy controls (HCs). We comprehensively analyzed long-term humoral responses, including anti-spike (S) antibodies, serum inhibition, neutralization, cross-reactivity and circulating B cell six months post BNT162b2, in patients with IBD stratified by therapy compared to HCs. Subjects enrolled in a prospective, controlled, multi-center Israeli study received two BNT162b2 doses. Anti-S levels, functional activity, specific B cells, antigen cross-reactivity, anti-nucleocapsid levels, adverse events and IBD disease score were detected longitudinally. In total, 240 subjects, 151 with IBD (94 not treated with anti-TNFα and 57 treated with anti-TNFα) and 89 HCs participated. Six months after vaccination, patients with IBD treated with anti-TNFα had significantly impaired BNT162b2 responses, specifically, more seronegativity, decreased specific circulating B cells and cross-reactivity compared to patients untreated with anti-TNFα. Importantly, all seronegative subjects were patients with IBD; of those, >90% were treated with anti-TNFα. Finally, IBD activity was unaffected by BNT162b2. Altogether these data support the earlier booster dose administration in these patients.

Transmural healing evaluated by magnetic resonance enterography in paediatric patients with Crohn's disease receiving maintenance treatment with biologics.

The optimal treatment goal in Crohn's disease (CD) is endoscopic healing (EH). However, transmural healing (TH) facilitated by the development and increasing performance of magnetic resonance enterography (MRE) is emerging as a potential treatment goal. To assess TH rates after 1year of treatment by MRE and its relationship with EH in paediatric patients with CD receiving anti-tumour necrosis factor (TNF) agents, and to investigate factors associated with TH after 1year of treatment. This multi-centre, prospective, observational study included Korean paediatric patients with luminal CD diagnosed at age < 19 years who were naïve to anti-TNF treatment. They simultaneously underwent ileocolonoscopy and MRE at baseline and after 1year of treatment with biologics. We included 116 patients. At 1year, EH and TH were achieved in 59.5% (69/116) and 38.8% (45/116) of the patients, respectively. Both EH and TH was observed in 35.3% (41/116), EH without TH in 24.1% (28/116), TH without EH in 3.4% (4/116), and neither EH nor TH in 37.1% (43/116). Moreover, 59.4% (41/69) of patients who achieved EH at 1year exhibited TH,and 91.1% (41/45) of patients who achieved TH exhibited EH. Baseline MaRIA score was associated with TH according to a multivariate analysis (OR 0.97, 95% CI 0.95-0.99, p=0.023). TH is a more stringent goal than EH. Regular follow-up evaluation of transmural status, and efforts to achieve TH, may alter the natural course of CD in the era of treat-to-target.

Progression to Anti-TNF Treatment in Very Early Onset Inflammatory Bowel Disease Patients.

Limited data are currently available regarding anti-tumor necrosis factor (TNF) use and outcomes in very early onset inflammatory bowel disease (VEOIBD) patients. We aimed to assess the long-term outcomes and time to progression to anti-TNF treatment in VEOIBD patients. We retrospectively reviewed IBD patients diagnosed under 6 years of age, between January 2005 and December 2019, from the British-Columbia (BC) Pediatric IBD database. Demographic data, disease characteristics, disease location and severity were documented. Data on anti-TNF treatment at initiation and during follow up including type of biologic, dosing, and response were collected. Kaplan-Meier curves were used to assess the number of years to progression to anti-TNF treatment and the parameters influencing commencement. Eighty-nine patients with VEOIBD were diagnosed during the study period. Median age at diagnosis was 3.8 years [interquartile range (IQR) 2.6-5.1], 45.3% had Crohn disease (CD) and 62.8% were males. Median duration of follow up was 6.39 years (IQR 3.71-10.55). Anti-TNF treatment was started on 39.5% of patients and 7.0% underwent surgery. Rapid progression to biologic treatment was associated with Perianal fistulizing disease or stricturing disease in CD patients ( P = 0.026, P = 0.033, respectively), and disease severity ( P = 0.017) in ulcerative colitis(UC) patients. The median dose of infliximab at 1 year was 10 mg/kg (IQR 7.5-11) and a median dose interval of 4.5 weeks (IQR 4-6). Clinical remission was reported in 61.8% of patients on their first biologic agent. The response rate was higher than previously reported and might be due to higher infliximab dosing with shorter infusion intervals than standard dosing.