aTNF Therapy Research Articles

Management and outcomes of histoplasmosis in youth with inflammatory bowel disease in an endemic area.

Patients with inflammatory bowel disease (IBD) prescribed immunosuppressive therapies including antitumor necrosis factor (aTNF) therapies are at increased risk of histoplasmosis. We aim to evaluate the presentation, management, and outcomes of youth with IBD and concurrent histoplasmosis. Single center, retrospective review of youth with IBD diagnosed with histoplasmosis from January 12, 2007 to January 1, 2022. Management and outcomes were followed for up to 2 years after diagnosis. Nineteen patients (10 male, median age 16 years, range 8-22) with IBD were diagnosed with histoplasmosis: disseminated (N = 15/19; 79%), pulmonary (N = 3/19; 16%), lymph node (N = 1/19; 5%). At the time of histoplasmosis diagnosis, patients were predominantly receiving aTNF therapy (N = 17/19; 89%, median duration 21.9 months (interquartile range 8.5-52.0). Thirteen (13/19, 68%) patients required hospitalization and 2/19 (11%) required intensive care. All achieved antigen clearance with no recurrences. At the time of histoplasmosis diagnosis, aTNF was stopped in 15/17 (88%) patients and the following IBD therapies were initiated: 5-aminosalicylates (N = 4/19; 21%), 6-mercaptopurine (N = 3/19; 16%), enteral therapy (N = 2/19; 11%), and vedolizumab (N = 2/19; 11%); 6 of 19 (32%) received no IBD therapy and 2 of 19 (11%) patients continued aTNF. During follow-up, 6 of 19 (32%) patients had an emergency department (ED) visit and/or hospitalization for symptoms attributed to active IBD, all of whom had discontinued aTNF; one patient required colectomy. Severe histoplasmosis infection in youth with IBD was rare. IBD treatment was modified by reducing immunosuppression. Histoplasmosis outcomes were favorable, but multiple patients required hospitalization or ED visits for IBD symptoms. The optimal approach to managing IBD during histoplasmosis treatment is challenging and requires further study.

Progression of Pediatric Crohn’s Disease Is Associated With Anti–Tumor Necrosis Factor Timing and Body Mass Index Z-Score Normalization

The evolution of complicated pediatric Crohn's disease (CD) in the era of anti-tumor necrosis factor (aTNF) therapy continues to be described. Because CD progresses from inflammatory to stricturing (B2) and penetrating (B3) disease behaviors in a subset of patients, we aimed to understand the risk of developing complicated disease behavior or undergoing surgery in relation to aTNF timing and body mass index z-score (BMIz) normalization. Multicenter, 5-year longitudinal data from 1075 newly diagnosed CD patients were analyzed. Descriptive statistics, univariate and stepwise multivariate Cox proportional hazard regression (CPHR), and log-rank analyses were performed for risk of surgery and complicated disease behaviors. Differential gene expression from ileal bulk RNA sequencing was correlated with outcomes. Stricturing complications had the largest increase: from 2.98% to 10.60% over 5 years. Multivariate CPHR showed aTNF exposure within 3 months from diagnosis (hazard ratio [HR], 0.33; 95% CI, 0.15-0.71) and baseline L2 disease (HR, 0.29; 95% CI, 0.09-0.92) to be associated with reduced B1 to B2 progression. For children with a low BMIz at diagnosis (n= 294), multivariate CPHR showed BMIz normalization within 6 months of diagnosis (HR, 0.47; 95% CI, 0.26-0.85) and 5-aminosalicyclic acid exposure (HR, 0.32; 95% CI, 0.13-0.81) were associated with a decreased risk for surgery while B2 (HR, 4.20; 95% CI, 1.66-10.65) and B2+B3 (HR, 8.24; 95% CI, 1.08-62.83) at diagnosis increased surgery risk. Patients without BMIz normalization were enriched for genes in cytokine production and inflammation. aTNF exposure up to 3 months from diagnosis may reduce B2 progression. In addition, lack of BMIz normalization within 6 months of diagnosis is associated with increased surgery risk and a proinflammatory transcriptomic profile.

P503 Early TNF-antagonist maintenance therapy results in better outcomes than immunomodulators in paediatric Crohn’s disease: A multi-centre prospective cohort study

Abstract Background Early initiation of TNF-antagonist (aTNF) therapy for Crohn’s disease (CD) is associated with greater clinical and endoscopic improvement but trialing an immunomodulator (IM) first remains common in paediatrics. This study aimed to determine if early aTNF is superior to IM maintenance therapy in paediatric luminal CD. Methods Children 2–17 years old with newly diagnosed CD were enrolled prospectively at one of 12 sites of the Canadian Children IBD Network. Patients with luminal inflammatory disease receiving IM or aTNF-based first maintenance therapy, following induction with steroids, exclusive enteral nutrition (EEN), or aTNF, were included. Those with perianal disease as the sole indication for aTNF were excluded. The primary outcome was sustained steroid-free clinical remission, defined by the short Pediatric CD Activity Index, at 6, 12, and 18 months, while continuing initial maintenance. A secondary outcome was combined sustained steroid-free clinical and endoscopic remission by 18 months, defined as the absence of ulcers at follow-up colonoscopy when ulcers were present at baseline. Multivariable logistic regression modeled the propensity of receiving aTNF maintenance therapy and 1:1 Greedy matching, without replacement, was used to match each of the participants who received aTNF with a participant who received an IM. The primary outcome was analyzed in the whole cohort, and in the subgroup receiving steroids or EEN as induction, using a Chi-square test, as well as in the matched group with a McNemar’s test, generalized estimating equation (GEE), and with a mixed model to account for clustering by centre. Sensitivity analyses with inverse probability treatment weights using GEE were performed. Results Among children with CD enrolled in the inception cohort study between 01/2014 and 12/2018, 464 met inclusion criteria and received IM (n=284) or aTNF (n=180 of whom 88 received steroids or EEN induction) as first maintenance therapy (Table 1). 162 patients were included in the matched cohort. In every analysis, more of the aTNF group achieved sustained 18-month steroid-free clinical remission, despite more severe baseline disease (Figure 1). The result remained significant in sensitivity analyses (Table 2). In patients with ulcers at baseline, 57.1% of the aTNF group versus 4.6% of the IM group achieved sustained steroid-free clinical remission and endoscopic remission by 18 months (p<0.001). Conclusion In this paediatric cohort, aTNF was superior to IM as first maintenance therapy. These results may help advocate for better access and funding for early aTNF therapy in paediatric CD.

Enthesitis Related Arthritis in a Longitudinal Southeast Asian Registry: High Prevalence of HLA-B27, Different Sacroiliitis Risk Factors and Less Common Drug-Free Remission.

Objective. To describe the clinical characteristics, predictors and treatment of children with Enthesitis Related Arthritis (ERA) in a Singapore longitudinal cohort over 11 years. Methods. ERA patients were recruited from our registry (2009–2019). Nonparametric descriptive statistics including median (interquartile range, IQR) were used to describe data. Kaplan–Meier survival and logistic/Cox regression analyses were used to estimate the probabilities and determine predictors of clinical variables, respectively. The significance level was set at <0.05. Results. One hundred and forty-six ERA patients (87% male, 82% Chinese) were included. Median onset age was 11.9 years (IQR 9.4–14.0) and median disease duration was 4.9 years (IQR 2.6–8.3). Family history of Human Leukocyte Antigen (HLA)-B27 associated diseases was positive in 7.5%. Acute uveitis occurred in 3.4%. Oligoarthritis was present in 89.7%. Hip, knee and ankle joints were among the most common joints involved. One-fourth had enthesitis at diagnosis (Achilles tendon entheses, 82.9%). Sacroiliitis occurred in 61%. Probabilities of sacroiliitis development were 0.364, 0.448 and 0.578 at 1, 2 and 5 years after onset, respectively. Negative HLA-B27, female, older age at onset and hip arthritis at diagnosis were associated with shorter time for sacroiliitis development (p = 0.001–0.049). Methotrexate (MTX) remained the most common disease modifying anti-rheumatic drug (DMARD) used (77.4%). However, 77.9% required anti-TNF (aTNF) therapy secondary to MTX failure. Among MTX-treated sacroiliitis patients, 85.3% failed, requiring aTNF, as compared to 63.2%patients without axial disease. Longer duration to diagnosis (p = 0.038) and MTX use (p = 0.007) predicted aTNF therapy. None had joint deformity. Conclusions. This study underscores differences in ERA clinical characteristics, predictors and treatment responses. Our ERA population had many unique findings but good functional outcomes.

Disease control and anti-TNF (aTNF) therapy use during peripregnancy psoriasis patients

Disease control and anti-TNF (aTNF) therapy use during peripregnancy psoriasis patients

20 ETROLIZUMAB IMPROVED ENDOSCOPIC SCORE, PATIENT-REPORTED OUTCOMES, AND INFLAMMATORY BIOMARKERS IN PATIENTS WITH MODERATE TO SEVERE UC WHO HAD FAILED TNF ANTAGONIST THERAPY: THE HICKORY OPEN-LABEL INDUCTION (OLI) COHORT

Patients with ulcerative colitis (UC) who have experienced failure of TNF antagonist (aTNF) therapy are a difficult-to-treat population with a notable unmet medical need. Centrally read endoscopy demonstrates reduced placebo remission rates as low as 0%–8% in this population (1,2). HICKORY OLI evaluates etrolizumab in patients intolerant/refractory to aTNFs. Patients received etrolizumab 105 mg every 4 weeks in a 14-week induction period. Endoscopic subscore (ES) and patient-reported rectal bleeding (RB) and stool frequency (SF) were assessed at baseline (BL) and week 14. Assessed outcomes were clinical response: ≥ 3-point and 30% reduction of Mayo Clinic score (MCS) from BL and ≥ 1-point decrease in RB or RB ≤ 1; remission: MCS ≤ 2, with individual subscores ≤ 1 and RB = 0; endoscopic improvement: ES ≤ 1; RB remission: RB = 0; SF remission: SF ≤ 1 with ≥ 1-point reduction from BL. HICKORY OLI enrolled 130 patients with aTNF failure; 45% with failure of > 1 aTNF. BL scores were mean MCS of 9.4 and median fecal calprotectin (FC) of 1778 mg/kg. At week 14, SF remission was achieved in 35.4% of patients, RB remission in 52.3%, clinical response in 50.8%, remission in 12.3%, and ES ≤ 1 in 23.9%. In the 43.9% of patients with ≥ 1-point improvement in ES, there was an association with higher rates of SF and RB remission. Among those with ES = 0, 90% reported SF ≤ 1, and 100% reported RB ≤ 1 (Fig 1). Patients achieving SF remission, RB remission, or ES ≤ 1 demonstrated > 70% geometric mean reduction in FC. In aTNF-failed patients with high disease burden, etrolizumab achieved clinically meaningful response, remission, and endoscopic improvement. Patients who had improved ES achieved higher rates of RB and SF remission and greater reductions in inflammatory biomarkers. Recruitment is ongoing. 1. Vermeire S, et al. Lancet. 2014;384:309–318. 2. Sandborn W, et al. N Engl J Med. 2017;376:1723–1736.

Impact of thiopurines and anti-tumour necrosis factor therapy on hospitalisation and long-term surgical outcomes in ulcerative colitis.

Ulcerative colitis (UC) is a chronic inflammatory condition affecting the large bowel and is associated with a significant risk of both requirement for surgery and the need for hospitalisation. Thiopurines, and more recently, anti-tumour necrosis factor (aTNF) therapy have been used successfully to induce clinical remission. However, there is less data available on whether these agents prevent long-term colectomy rates or the need for hospitalisation. The focus of this article is to review the recent and pertinent literature on the long-term impact of thiopurines and aTNF on long-term surgical and hospitalisation rates in UC. Data from population based longitudinal research indicates that thiopurine therapy probably has a protective role against colectomy, if used in appropriate patients for a sufficient duration. aTNF agents appear to have a short term protective effect against colectomy, but data is limited for longer periods. Whereas there is insufficient evidence that thiopurines affect hospitalisation, evidence favours that aTNF therapy probably reduces the risk of hospitalisation within the first year of use, but it is less clear on whether this effect continues beyond this period. More structured research needs to be conducted to answer these clinically important questions.

PTU-086 Ulcerative Colitis (uc) And Anti-tumour Necrosis Factor (a-tnf) Therapy; A Single Unit’s Real World Experience

IntroductionPrescription of a-TNF therapy in UC in the UK is limited to acute severe colitis by NICE. Increasingly physicians are under pressure from patients to offer an alternative to the...

A prospective study of anti‐tumor necrosis factor therapy in South African rheumatoid arthritis patients

To quantify primary and secondary anti-tumour necrosis factor inadequate response (aTNF-IR) and intolerance in South Africans with rheumatoid arthritis (RA) over 1year. Rheumatologists from nine independent private practices monitored RA patients commencing on aTNF therapy (incident cases) or already on aTNF therapy (prevalent cases). Observations at baseline and quarterly intervals recorded discontinuation of therapy for either lack of response or adverse effects. Of the 98 patients screened, 86 were eligible to participate. Mean time from onset of symptoms of RA to start of aTNF treatment was 9.7years (range: 0.5-32years). Only 58 (67.4%) continued on aTNF therapy at 12months, including five judged to have an aTNF-IR. Overall 12 patients had a secondary aTNF-IR with seven discontinuing for this reason. Seven patients discontinued due to adverse events, four due to funding problems and 10 were lost to follow-up. Infections were the most common adverse events, but only two stopped treatment as a result. No cases of active tuberculosis (TB) were recorded, despite nine patients having a positive tuberculin skin test and one, a past history of pulmonary TB. Almost a third of patients discontinued aTNF therapy over the 1-year period, with infections and inadequate response to treatment being the main reasons for discontinuation. The study highlights the need for biologics with alternative modes of action for patients with moderate to severe RA in South Africa.

PReS-FINAL-2032: Changes in immunogenic profile in patients with juvenile idiopathic arthritis exposed to anti tumoral necrosis factor therapy

In a previous study conducted by our group we observed an unusual prevalence of tittles of antinuclear (ANA) and anti-DNA (aDNA) antibodies in children who were previously negative for both antibodies and who received any biologic therapy due to a childhood rheumatic systemic disease (CRSD). This observation has been reported in adulthood previously, mainly in patients exposed to anti tumoral necrosis factor (aTNF) therapy however its clinical impact is not well established.

Leishmaniasis during anti-tumor necrosis factor therapy: Report of 4 cases and review of the literature (additional 28 cases)

ObjectiveTo describe the development of 4 new cases of leishmaniasis in patients receiving anti-tumor necrosis factor-α (anti-TNF) agents and review the pertinent literature. MethodsChart review of the 4 cases and MEDLINE search for additional reported cases. ResultsAll reported cases, including ours, came from endemic areas. The infection was detected on an average of 23.5 months after the initiation of anti-TNF therapy. The majority of cases had the classical clinical presentation. The biological therapy was suspended in 21 cases. The results were successful for leishmaniasis therapy in all cases. In 10 cases it was possible to reintroduce anti-TNF agents. On follow-up it was observed that there was an infection relapse in 3 cases. ConclusionsThe present study shows that leishmaniasis, in its several clinical forms, should be included in the differential diagnosis of possible infections involving patients under use of aTNF therapy. Endemic disease under geographic expansion, easy international displacement and intense human migratory flows certainly represents a risk of this infection in an increasing universe of people which includes the immunosuppressed patients. Cutaneous lesions, prolonged fever, splenomegaly, and pancytopenias, the main clinical-laboratory findings of leishmaniasis, can also be present in autoimmune rheumatic disease, thus leading to delayed diagnosis and treatment of the parasitic disease. The diagnosis depends basically on a high suspicion index, being confirmed with the identification of the protozoan. The classic treatment of the infection when instituted is associated with complete recovery. It is important to point out that all cases reported so far had either originated from or been recently in regions regarded as endemic of leishmaniasis.

THU0209 Efficacy of anti-TNF therapy in 15 patients with refractory takayasu’s arteritis: Long term unicentric follow-up

BackgroundTakayasu arteritis (TA) is a rare chronic-relapsing granulomatous vasculitis involving primarily the aorta and its major branches1. TA is associated with considerable morbidity and mortality2. Therapy is based on corticosteroids...

THU0177 Structural Differences Between Anti-TNF Agents are Associated with Dissimilar Rates of Secondary Loss of Effectiveness and Drug Adjustments

BackgroundDifferences in drug survival between anti-TNF agents (aTNF) have been attributed to variations in molecular structure leading to increased immunogenicity, in particular between chimeric and fully human monoclonal antibodies (MABs)...

P507 Evolution of osteopenia and osteoporosis over 5 years in patients with inflammatory bowel disease

a first course of endovenous corticosteroids ECT in our tertiary center. Methods: All UC patients admitted to the hospital for an acute flare requiring EC between January 2007 and March 2012 were reviewed. We included only the patients with a first-initial course EC since UC diagnosis time. We defined as “responders” when patients achieved clinical remission in the first seven days of EC and “no responders” when patients needed a rescue therapy because of no clinical response after 7 days of EC. Demographic and clinical features were obtained from the medical records until October 2012. Results: A total of 41 episodes were collected during this period and 14 (34%) completed inclusion criteria. EC “response” was obtained in 9 patients (9/14; 60%, 5F/4M, mean age 36 years). Half of them (5/9), the diagnosis of UC concurred with the hospitalization and EC therapy. After a median follow-up of 24 months (6 56), 4 patients (44%) needed treatment escalation by using IMM for steroid-dependency and 2 (22%) of them used granulocyte aphaeresis before a-TNF therapy. No surgeries were observed in this group. Five patients were EC “no responders” (5/14; 40%, 4F/1M, mean age 30 years). A-TNF therapy was used in 1 patient and 4 received Cyclosporine A (CyA) for steroid-refractoriness and 3 were newly UC diagnose. One patient underwent total colectomy 10 days after EC beginning without further complication or treatment. After 36 months (5 63), 4 patients started IMM (80%) and 1 started a-TNF (20%) but developed a tuberculosis (TBC) infection and after TBC treatment remained with only IMM therapy. Nowadays, 2 more patients (40%) were considered for a-TNF because steroiddependency after acute flare (mean time 6 months). No other surgeries were produced during follow-up. Conclusions: In our center, about half of patients developed a “no responder” to EC flare and most of them will need a-TNF for maintenance therapy even after use of CyA treatment mainly because of steroid-dependence. Even when the UC patients respond to EC, about 40% of them require IMM and even a-TNF for again for steroid-dependence.

PMO-261 Is Crohn's disease in the UK being under treated? Data from the 3rd round UK IBD audit

IntroductionThe British Society Gastroenterology (BSG) guidelines for Inflammatory Bowel Disease (IBD) advise escalating treatment to immunosuppressives (IS) in severe relapsing disease and cases requiring repeated corticosteroids (CS). Anti-TNF (aTNF) therapy...

Presentation and outcome of histoplasmosis in pediatric inflammatory bowel disease patients treated with antitumor necrosis factor alpha therapy: A case series

Antitumor necrosis factor alpha (aTNF) therapies are commonly used in the treatment of pediatric inflammatory bowel disease (IBD). However, inhibition of the TNF-alpha pathway predisposes to serious infections, including histoplasmosis, which is the most common invasive fungal infection in individuals on aTNF therapy and carries a high mortality rate when associated with delayed diagnosis. Few data exist on the frequency, presentation, and appropriate treatment of pediatric patients with histoplasmosis on aTNF therapy. Following Institutional Review Board approval, cases were identified then reviewed with their primary gastroenterologist and infectious disease specialists. Herein we describe histoplasmosis in five pediatric patients receiving aTNF therapy for IBD in an endemic area. Histoplasmosis is an important complication of treatment with TNF-alpha neutralizing agents. Children with IBD treated with aTNF therapy who develop the infection may present with minimal pulmonary symptoms. While discontinuation of aTNF therapy is important initially, few data exist to determine when and how aTNF therapy can be reinstituted. Recognition of Histoplasma capsulatum is often delayed due to the overlap of symptoms with some of the extraintestinal manifestations of IBD and other more prevalent infectious complications.

El bloqueo terapéutico del factor de necrosis tumoral disminuye la concentración sérica de interleucina 15 en pacientes con artritis reumatoide

Objective To analyze the effect of the TNF blocking agents (aTNF) on the serum levels of interleukin 15 (IL-15). To determine whether baseline IL15 serum levels or their response to aTNF therapy can predict the clinical response to this treatment. Patients and method We studied 75 patients suffering from rheumatoid arthritis that were selected to start aTNF therapy. Serum samples were obtained at baseline visit and after three months of aTNF treatment. Measurement of IL-15 serum concentration was performed through immune-enzyme assay. We collected the clinical and analytical parameters needed to calculate DAS28 both at baseline and final visit, as well as sociodemographic variables and other such as rheumatoid factor, previous disease modifying anti-rheumatic drugs (DMARD), etc. We defined remission as a DAS28 < 2.6 and clinical response when the decrease in DAS28 value was higher than 1.2. Results There was a significant correlation between IL-15 serum level and the number of previous DMARD. We also detected a significant decrease in the concentration of serum IL-15 after three months of treatment with aTNF. However, neither the baseline IL-15 serum level nor the decrease in the concentration of IL-15 were associated with a specific pattern of response to aTNF. Conclusions Our data seem to support previous in vitro findings suggesting that TNF is involved in the regulation of IL-15 expression. Nevertheless, the measurement of IL-15 serum levels does not seem to be a useful tool to select those patients that should be treated with aTNF therapy.

The Therapeutic Blockade of TNF Reduces Serum Levels of Interleukin 15 in Patients With Rheumatoid Arthritis

ObjectiveTo analyze the effect of the TNF blocking agents (aTNF) on the serum levels of interleukin 15 (IL- 15). To determine whether baseline IL-15 serum levels or their response to aTNF therapy can predict the TNF antagonist's clinical response to this treatment. Patients and methodWe studied 75 patients suffering from rheumatoid arthritis that were selected to start aTNF therapy. Serum samples were obtained at baseline visit and after 3 months of aTNF treatment. Measurement of IL-15 serum concentration was performed through immune-enzyme assay. We collected the clinical and analytical parameters needed to calculate DAS28 both at baseline and final visit, as well as sociodemographic variables and other such as rheumatoid factor, previous disease modifying antirheumatic drugs (DMARD), etc. We defined remission as a DAS28 <2.6 and clinical response when the decrease in DAS28 value was higher than 1.2. ResultsThere was a significant correlation between IL-15 serum level and the number of previous DMARD. We also detected a significant decrease in the concentration of serum IL-15 after 3 months of treatment with aTNF. However, neither the baseline IL-15 serum level nor the decrease in the concentration of IL-15 was associated with a specific pattern of response to aTNF. ConclusionsOur data seem to support previous in vitro findings suggesting that TNF is involved in the regulation of IL-15 expression. Nevertheless, the measurement of IL-15 serum levels does not seem to be a useful tool to select those patients that should be treated with aTNF therapy.

Baseline serum RANKL levels may serve to predict remission in rheumatoid arthritis patients treated with TNF antagonists

Aims:The objective of this study was to investigate whether baseline receptor activator for nuclear factor kappaB ligand (RANKL) and osteoprotegerin (OPG) serum (s) levels can predict the therapeutic response to...