Efficacy Of anti-TNF Therapy Research Articles

HLA-DQA1*05 correlates with increased risk of anti-drug antibody development and reduced response to infliximab in Chinese patients with Crohn's disease.

The efficacy of anti-TNF therapy in Crohn's disease (CD), such as infliximab, is often compromised by the development of anti-drug antibodies (ADAs). The genetic variation HLA-DQA1*05 has been linked to the immunogenicity of biologics, influencing ADA formation. This study investigates the correlation between HLA-DQA1*05 and ADA formation in CD patients treated with infliximab in a Chinese Han population and assesses clinical outcomes. In this retrospective cohort study, 345 infliximab-exposed CD patients were genotyped for HLADQ A1*05A G (rs2097432). We evaluated the risk of ADA development, loss of infliximab response, adverse events, and treatment discontinuation among variant and wild-type allele individuals. A higher percentage of patients with ADAs formation was observed in HLA-DQA1*05 G variant carriers compared with HLA-DQA1*05 wild-type carriers (58.5% vs 42.9%, P = 0.004). HLA-DQA1*05 carriage significantly increased the risk of ADAs development (adjusted hazard ratio = 1.65, 95% CI 1.18-2.30, P = 0.003) and was associated with a greater likelihood of infliximab response loss (adjusted HR = 2.55, 95% CI 1.78-3.68, P < 0.0001) and treatment discontinuation (adjusted HR = 2.21, 95% CI 1.59-3.06, P < 0.0001). Interestingly, combined therapy with immunomodulators increased the risk of response loss in HLA-DQA1*05 variant carriers. HLA-DQA1*05 significantly predicts ADAs formation and impacts treatment outcomes in infliximab-treated CD patients. Pre-treatment screening for this genetic factor could therefore be instrumental in personalizing anti-TNF therapy strategies for these patients.

Safety and Efficacy of Anti-TNF Therapy in Older Adults With Ulcerative Colitis: A New Path Forward

Cheng D, Cushing KC, Cai T, et al. Safety and efficacy of tumor necrosis factor antagonists in older patients with ulcerative colitis: patient-level pooled analysis of data from randomized trials. Clin Gastroenterol Hepatol 2021;19:939–946.

IL-33 Gene Polymorphisms as Potential Biomarkers of Disease Susceptibility and Response to TNF Inhibitors in Rheumatoid Arthritis, Ankylosing Spondylitis, and Psoriatic Arthritis Patients.

ObjectiveRheumatoid arthritis (RA), ankylosing spondylitis (AS), and psoriatic arthritis (PsA) belong to inflammatory rheumatic diseases, the group of conditions of unknown etiology. However, a strong genetic component in their pathogenesis has been well established. A dysregulation of cytokine networks plays an important role in the development of inflammatory arthritis. Interleukin 33 (IL-33) is a recently identified member of the IL-1 family. To date, the significance of IL-33 in inflammatory arthritis has been poorly studied. This research aimed to investigate the potential of IL-33 gene polymorphisms to serve as biomarkers for disease susceptibility and TNF inhibitor response in RA, AS, and PsA patients.Materials and MethodsIn total, 735 patients diagnosed with RA, AS, and PsA and 229 healthy individuals were enrolled in the study. Genotyping for three single nucleotide polymorphisms (SNPs) within the IL-33 gene, namely, rs16924159 (A/G), rs10975519 (T/C), and rs7044343 (C/T), was performed using polymerase chain reaction amplification employing LightSNiP assays.ResultsIn the present study, the IL-33 rs10975519 CC genotype was associated with a decreased risk of developing RA in females, while the IL-33 rs16924159 polymorphism was associated with the efficacy of anti-TNF therapy and clinical parameters for RA and AS patients. The IL-33 rs16924159 AA genotype correlated with higher disease activity and worse clinical outcomes in RA patients treated with TNF inhibitors, and AS patients carrying the IL-33 rs16924159 AA genotype had higher disease activity and a worse response to anti-TNF therapy. That indicates a deleterious role of the IL-33 rs16924159 AA genotype in the context of RA, as well as AS.ConclusionsThe obtained results suggest that IL-33 gene polymorphisms might be potential candidate biomarkers of disease susceptibility and anti-TNF treatment response in patients with inflammatory rheumatic diseases.

Real world analysis on the efficacy and safety of anti-tumor necrosis factor therapy in patients with stricturing Crohn\u2019s disease

Crohn’s disease (CD) is often complicated by strictures and associated with increased risk for surgery. Inflammatory strictures respond to medical therapy, and anti-tumor necrosis factor (TNF) therapy is often used after the failure of steroids. However, data on efficacy of anti-TNF therapy in stricturing CD is limited. We retrospectively analysed the records of patients with stricturing CD who were treated with anti-TNF therapy and were prospectively followed from January 2005 to July 2020. Treatment success was defined as continuation of anti-TNF without the requirement for steroids or parenteral nutrition, switch to other anti-TNF, endoscopic dilation, surgery and severe adverse events leading to the withdrawal of anti-TNF. Fifty-nine patients were included [50-infliximab, 9-adalimumab; mean age-30.1 ± 15 years; males-69.5%; median disease duration-124 (range 30–396) months; median follow-up duration-42 (range 8–180) months]. Ileum was the most common site of stricture (69.5%), 20.3% of patients had colonic strictures, and 64.4% had multiple strictures. 55.9% of patients were steroid dependent and 37.3% were steroid refractory. The median duration of anti-TNF therapy was 14 (range 2–96) months, and 54.2% (n = 32) patients received concomitant immunomodulators. 88% improved with induction (11.8% primary non-response), secondary loss of response was seen in 52.2%, and the cumulative probability of treatment success at 1, 2 and 5 years was 69%, 51%, and 28% respectively. Anaemia at presentation predicted poor response. Only 30% of patients retained biologics on long-term (lack of response, cost, adverse events). 16.9% had adverse events, the commonest being reactivation of tuberculosis (5.1%). Anti-TNF therapy is associated with good short-term treatment success with modest long-term response in stricturing CD.

P591 Anti-TNF therapy for Ulcerative Colitis in Brazil: a comparative real-world national multicentric study from the Brazilian Study Group of IBD (GEDIIB)

Abstract Background Anti-TNF therapy represented a landmark in medical treatment of ulcerative colitis (UC). There is lack of data on the efficacy and safety of these agents in Brazilian patients, as public reimbursement is relatively recent. The present study aimed to analyze rates of clinical and endoscopic remission comparatively, between adalimumab (ADA) and infliximab (IFX), in Brazilian UC patients, and evaluate possible factors associated with remission after 1 year of treatment. Methods A national retrospective multicenter study (24 centers) was carried out including patients with moderate-to-severe UC treated with anti-TNF therapy. Disease activity was categorized using Mayo score at baseline, weeks 8, 26 and 52. Clinical remission was defined as a partial Mayo score ≤ 2. Endoscopic remission was defined as a Mayo endoscopic subscore ≤ 1. Patients were allocated in 2 groups (ADA and IFX) and a comparative efficacy study was performed. Statistical analysis: logistic regression model was used to study effects of predictor variables on categorical outcomes, such as presence or absence of remission at week 52. Statistical significance was assumed if p &amp;lt;0.05. Results Overall, 393 patients were included (111 ADA and 282 IFX). The mean age was 41.86 ± 13.60 y, 61.58% women, most patients had extensive colitis (62.40%) and 19.39% previous exposure to biological agent. Overall, clinical remission rate was 66.78%, 71.62% and 82.82% at weeks 8, 26 and 52, respectively. Remission rates were higher in the IFX group at weeks 26 (75.12% vs. 62.65 %, p &amp;lt;0.0001) and 52 (65.24% vs. 51.35%, p &amp;lt;0.0001) – figure 1. Overall, endoscopic remission was observed in 50% of patients at week 26 and in 65.98% at week 52, with no difference between the two groups (p = 0.114). Colectomy was performed in 23 patients (5.99%). The variables associated with clinical remission after 1 year of treatment were age, non-prior exposure to biological therapy, use of IFX, endoscopic remission at week 26 and no need for optimization (table 1). The variables associated with endoscopic remission after 1 year were non-prior exposure to biological therapy, clinical and endoscopic remission at week 26 and no need for optimization. Conclusion In this national multicentric study, overall efficacy of anti-TNF therapy was similar to real world data with IFX and ADA. IFX treatment was associated with higher rates of clinical remission after 1 year in comparison to ADA. Patients naive to biological therapy presented higher rates of clinical and endoscopic remission. This is the first real world national study analyzing efficacy of anti-TNF agents in UC in Brazil.

Does anti-tumor necrosis factor alpha prevent the recurrence of Crohn's disease? Systematic review and meta-analysis.

Anti-tumor necrosis factor (TNF) α agents are now well known to function as effective treatments for Crohn's disease (CD). Several meta-analyses have revealed the efficacy of anti-TNF therapy for preventing recurrence after surgery; however, the efficacies reported in some prospective studies differed according to the outcomes. Moreover, adverse events (AEs) were not well evaluated. We conducted this systematic review and meta-analysis to evaluate both the efficacy of anti-TNF therapy after stratification by the outcome of interest and the AEs. We performed a systematic literature review of studies investigating anti-TNF therapy, CD, and postoperative recurrence. Meta-analyses were performed for endoscopic and clinical recurrence and AEs. A total of 570 participants, including 254 patients in the intervention group and 316 patients in the control group, in eight studies, were analyzed for recurrence. Based on the results of the meta-analysis, the efficacies of anti-TNF therapy at preventing endoscopic and clinical recurrence were as follows: relative risk (RR) 0.34, 95% confidence interval (CI) 0.22-0.53 and RR 0.60, 95% CI 0.36-1.02, respectively. The RR of AEs with anti-TNF therapy was 1.75 (95% CI 0.81-3.79). Anti-TNF therapy after surgery for CD displays efficacy at preventing endoscopic recurrence for 1-2years, without increasing the incidence of AEs. However, clinical recurrence was not significantly reduced. The efficacy of postoperative anti-TNF therapy may differ in terms of the outcomes, which include long-term prevention, the avoidance of further surgery, and cost-effectiveness.

Safety and Efficacy of Tumor Necrosis Factor Antagonists in Older Patients With Ulcerative Colitis: Patient-Level Pooled Analysis of Data From Randomized Trials

Treatment of older patients (more than 60 years) with ulcerative colitis (UC) can be a challenge, because they might be more vulnerable to adverse events (AEs). We determined the effects of age on the safety and efficacy of anti-tumor necrosis factor (TNF) therapy in a pooled analysis of data from randomized trials. We obtained individual patient-level data from 4 trials of anti-TNF therapy for patients with UC from the Yale Open Data Access Project. Participants were assigned to groups of older age (60 years or older) and younger age (younger than 60 years). The primary outcome was difference in serious AEs (SAEs), defined as death, life-threatening event, hospitalization, and/or significant disability. Secondary outcomes were severe infections, non-severe infections, neoplasms, and achievement of clinical remission, defined by trial investigators as Mayo score ≤ 2 with no sub-score >1 at the end of induction or maintenance therapy. A random effects logistic regression model was fitted to estimate the effect of anti-TNF therapy on safety and efficacy by age, adjusting for confounders and trial-level effects. The study cohort included 2257 patients (231 60 years or older). Higher proportions of older patients receiving anti-TNF therapy had SAEs (20%) and hospitalizations (14.4%), compared with younger patients (10.2% had SAEs and 5.2% were hospitalized); there were no significant differences between groups in proportions with severe or non-severe infections. Compared with placebo, there was no significant difference in safety risks associated with anti-TNF therapy (SAEs reduced by 5.4% in older patients vs reduction of 2.4% in younger patients; hospitalizations reduced by 6.7% in older patients vs reduction of 2.5% in younger patients; severe infections reduced by 3.1% vs increase of 0.7% in younger patients). There was no significant difference in between older vs younger patients in efficacy of anti-TNF therapy in inducing remission (odds risk ratio, 1.05, 95% CI, 0.33-3.39) or in maintaining remission (odds risk ratio, 0.49; 95% CI, 0.18-1.33). In a pooled analysis of data from randomized trials, we found that older patients with UC have an increased baseline increased risk of SAEs, but no increase in risk can be attributed to anti-TNF therapy in older vs younger patients.

208 – Safety and Efficacy of Anti-TNF Therapy in Older Patients with Ulcerative Colitis: A Patient-Level Pooled Analysis of Rct Data

208 – Safety and Efficacy of Anti-TNF Therapy in Older Patients with Ulcerative Colitis: A Patient-Level Pooled Analysis of Rct Data

Sa1802 - Efficacy of Anti-TNF Therapy in Patients with Complex Perianal Fistulizing Disease with and without Luminal Crohn's Disease: A Comparative Cohort Study

Sa1802 - Efficacy of Anti-TNF Therapy in Patients with Complex Perianal Fistulizing Disease with and without Luminal Crohn's Disease: A Comparative Cohort Study

Previous Exposure to Multiple Anti-TNF Is Associated with Decreased Efficiency in Preventing Postoperative Crohn's Disease Recurrence.

Infliximab and adalimumab are increasingly used to prevent postoperative recurrence in Crohn's disease patients. The impact of previous exposure to one or more anti-tumour necrosis factor [TNF] agents before surgery on the efficacy of anti-TNF therapy on postoperative recurrence is unknown. We performed a retrospective analysis of Crohn's disease patients who underwent surgical bowel resection with anastomosis and prophylactic treatment with anti-TNF therapy between January 2005 and June 2013. A total of 57 consecutive Crohn's disease patients with bowel resection and anastomosis followed by prophylactic treatment with anti-TNF were included; 21 [37%] and 24 [42%] patients had a previous exposure to one and more than one anti-TNF agents, respectively; 39 patients [68%] had a surveillance colonoscopy. Cumulative rates of postoperative endoscopic recurrence at 2 years were 45.5% [26.6-69.6%] in patients exposed to two or more anti-TNFα as compared with 29.1% [11.5-48.1%] in patients exposed to one or to zero anti-TNFα before surgery [p = 0.07]. Cumulative rates of clinical recurrence at 1 year were 21.6% [9.6-44.4%] in patients exposed to two or more anti-TNFα as compared with 6.9% [1.8-25.1%] in patients exposed to zero or one anti-TNFα before surgery [p = 0.02]. Multivariable analysis identified smoking and previous exposure to two or more anti-TNFα as risk factors for Crohn's disease clinical or endoscopic postoperative recurrence (hazard ratio [HR] = 3.17; 95% confidence interval [CI]: 1.3-7.8, p = 0.01 and HR = 4.2; 95% CI: 1.8-10.2, p = 0.001, respectively). Previous exposure to two or more anti-TNF agents was associated with a higher risk of postoperative recurrence in Crohn's disease patients.

Could early anti-tumor necrosis factor therapy change the prognosis of Crohn's disease?

Could early anti-tumor necrosis factor therapy change the prognosis of Crohn's disease?

SAT0136 Predictive factors of efficacy of anti TNF therapy in real practice: Experience from the national registry of biological therapy attra

BackgroundThe efficacy of biological therapy has been proven in a number of randomized clinical trials. The important data are however provided by registries of the biological therapies that reflect the...

Efficacy of anti-TNF therapies in refractory severe microscopic colitis

Background Refractory microscopic colitis is a rare condition with an unknown rate of occurrence. The efficacy of anti-tumor necrosis factor (TNF) therapy for microscopic colitis has never been reported. Aims 1) To report the frequency of refractory microscopic colitis in the database of the participant hospitals. 2) To describe the therapeutic response to anti-TNF therapy among the refractory cases. Methods Patients with a histological diagnosis of collagenous colitis and lymphocytic colitis were identified through the Department of Pathology database and the IBD practice database. Patients refractory to medical treatment and with severe symptoms were offered anti-TNF therapy. Results Five of 372 MC patients (1.3%; 95% CI, 0.6 to 3.1) presented with severe symptoms refractory to standard medical therapies. One patient was denied therapy from her insurance carrier. The other 4 received infliximab therapy. The response was excellent after one dose experiencing a 60–90% decrease in bowel movements. Three patients were switched to adalimumab (2 allergic reactions and 1 early loss of response to infliximab). Long-term clinical remission (more than 1 year) was achieved in three cases (2 with adalimumab and 1 with infliximab). One patient on adalimumab had an early loss of response and was referred for colectomy. Conclusions Microscopic colitis with severe symptoms refractory to standard medical therapy including immunosuppressives is uncommon. In this setting, anti-TNF therapies may be a good option to avoid colectomy.

TNF is required for the induction but not the maintenance of compression‐induced BME signals in murine tail vertebrae: Limitations of anti‐TNF therapy for degenerative disc disease

While bone marrow edema (BME) is diagnostic of spondyloarthropathy, its nature remains poorly understood. In contrast, BME in ankylosing spondylitis is caused by tumor necrosis factor (TNF)-induced vascular and cellular changes. To investigate the relationship between chronic compression and TNF signaling in compression-induced BME we utilized a tail vertebrae compression model with WT, TNF-Tg, and TNFR1&2-/- mice to evaluate: (i) healing following release of chronic compression, (ii) induction of BME in the absence of TNFR, and (iii) efficacy of anti-TNF therapy. Compression-induced normalized marrow contrast enhancement (NMCE) in WT was significantly decreased threefold (p < 0.01) within 2 weeks of release, while the NMCE values in TNF-Tg vertebrae remained elevated, but had a significant decrease (p < 0.05) by 6 weeks after the release of compression. TNFR1&2-/- mice were resistant to compression-induced BME. Anti-TNF therapy did not affect NMCE versus placebo. Histological examination revealed that NMCE values significantly correlated with marrow vascularity and cellularity (p < 0.05), which account for 76% of the variability of NMCE. Collectively, these data demonstrate a critical role for TNF in the induction of chronic compression-induced BME, but not in its maintenance. Amelioration of BME is achieved through biomechanical stability, but is not affected by anti-TNF therapy.

Tumour necrosis factor inhibitors in ankylosing spondylitis

Ankylosing spondylitis (AS) is the most common form of spondyloarthropathy. Non-steroidal anti-inflammatory medications and exercise are used to manage the chronic inflammatory spinal pain and stiffness. Up to 20% of patients have a peripheral inflammatory arthritis, which is treated with standard disease-modifying anti-rheumatic drugs especially sulfasalazine and methotrexate. Patients may also have extra-articular manifestations, such as anterior uveitis, psoriasiform skin lesions and inflammatory bowel disease. Anti-tumour necrosis (TNF) therapy has been used with great success in rheumatoid arthritis. There are now good data of the efficacy of anti-TNF therapies in the short and medium terms in AS. Etanercept, infliximab and adalimumab have been shown in randomized placebo-controlled trials of short duration to significantly reduce disease activity, including pain and stiffness as well as improving function, spinal movement and quality of life. It is hoped that long-term therapy will prevent radiologic progression and ankylosis and studies of long-term efficacy are awaited. Anti-TNF therapies are generally well tolerated in AS. It is important to screen for latent tuberculosis before the commencement of anti-TNF therapy. The side-effect profile of anti-TNF therapies in AS does not appear different from that in rheumatoid arthritis. Currently, treatment with anti-TNF therapy in AS is indicated in established disease with radiographic damage. There is evidence that response to therapy is greater in patients with earlier disease and less damage. Future developments may see this therapy extended to patients with pre-radiographic AS.

Diagnostic précoce des spondylarthropathies

Spondyloarthritis (SpA) encompass different diseases with common characteristics, ankylosing spondylitis (AS) being the most typical. Undifferentiated SpA may evolve into AS. In France, SpA and rheumatoid arthritis could have the same prevalence. AS has a profound impact on the quality of live and function of patients as well as social and economic consequences for the society. There is a mean delay of five to eight years between onset of symptoms and diagnosis of AS. This is due to the fact that radiographic sacroiliitis is delayed. The purpose of an earlier diagnosis is emphasized by the need for a better management, the new diagnostic method including magnetic resonance imaging and ultrasonography, and by the efficacy of anti-TNF therapy. The current criteria (New-York, Amor, ESSG) are classification but not diagnostic criteria. Their sensitivity is insufficient for an early diagnosis of SpA. Several groups are studying methods to ensure an early diagnosis. The group of Berlin has proposed, for patients suffering inflammatory chronic back pain, an algorithm using clinical, radiological and biological signs with, if necessary, search of HLA-B27 and MRI of sacroiliac joints. But this system is theoretical and the group of Maastricht found it of little effectiveness. Furthermore, it does not take account patients with symptoms beginning out of the spine. We believe that only the follow-up of cohorts constituted of patients with early SpA will enable us to improve our knowledge regarding diagnostic criteria and new tools for early diagnosis, as well as outcome, prognosis and early management of SpA and AS.

Rheumatologists' judgements about the efficacy of anti-TNF therapy in two neighbouring regions

The requirement in Northern Ireland to prescribe biological agents according to National Institute for Clinical Excellence/British Society for Rheumatology (NICE/BSR) guidelines and within a fixed budget has created a waiting list for treatment that has no parallel in the Republic of Ireland. The study investigated the bearing this situation may have had on consultants' judgements in the respective areas. Seventy-eight case vignettes created from the data on real patients with RA treated with biologicals in the north and south of Ireland were appraised by nine southern and eight northern consultants, who judged the clinical benefit and significance of the patients' condition after a trial of therapy. Quantitative (clinical judgement analysis) and qualitative (focus groups) techniques were used. Northern consultants perceived a slightly greater degree of clinical benefit after a trial of therapy than southern consultants. Judgement models of northern and southern consultants were broadly comparable. The latter tended to be more uniform in their judgements than the southern group. Focus group discussions with consultants largely validated the findings of the quantitative analysis but revealed how clinical judgement analysis might be misled by gaming strategies. Despite the absence of overt rationing in the south of Ireland, as far as the judgement of therapeutic benefit from biologicals was concerned, the clinical judgement policies of practitioners were very similar to those in the north. The adoption of NICE/BSR guidelines in the north may have improved the uniformity of clinical practice in Northern Ireland.

The role of pharmacogenomics in the prediction of efficacy of anti-TNF therapy in patients with Crohn's disease.

TNF-alpha plays a central role in the pathophysiology of Crohn's disease. Infliximab, a chimeric monoclonal antibody against TNF-alpha, has been shown to be effective and well-tolerated in several large placebo-controlled trials and has become a common treatment for Crohn's disease. The blockade of TNF through the infusion of infliximab is characterized by high clinical efficacy and rapid onset of action. A single infusion of infliximab results in a remission rate of 30-40%. Lack of response appears to be a stable trait even after repeated infusions, suggesting that it might be genetically determined. Mutations in the TNF-alpha gene have been extensively studied as predictors of response with various results. Polymorphisms in the TNF-alpha receptors TNF-R1 and TNF-R2 have been found not to be associated with treatment response. Similarly, the three mutations in the CARD15 gene, which are independently associated with susceptibility to Crohn's disease, have also been found not to be associated with treatment response.

Systemic tumor necrosis factor alpha mediates an increase in peripheral CD11bhigh osteoclast precursors in tumor necrosis factor alpha-transgenic mice.

To investigate the mechanisms whereby tumor necrosis factor alpha (TNFalpha) increases osteoclastogenesis in vivo. TNFalpha-transgenic (TNF-Tg) and wild-type mice injected with TNFalpha were studied. In vitro osteoclastogenesis assays, monocyte colony-forming assays, and fluorescence-activated cell sorting were performed using splenocytes, peripheral blood mononuclear cells (PBMCs), and bone marrow cells to quantify and characterize osteoclast precursors (OCPs). Etanercept, a TNFalpha antagonist, was used to block TNFalpha activity in vivo. The effects of TNFalpha on proliferation, apoptosis, and differentiation of OCPs were assessed using 5-bromo-2'-deoxyuridine labeling, annexin V staining, and reverse transcriptase-polymerase chain reaction. OCP numbers were increased 4-7-fold in PBMCs and spleen, but not in bone marrow of TNF-Tg mice. The OCPs in spleen were in the CD11b(high) population and contained both c-Fms- and c-Fms+ cells. The increased number of OCPs correlated with the initiation of detectable TNFalpha in serum and the onset of inflammatory arthritis in TNF-Tg mice. Etanercept eliminated the increase in peripheral OCPs. TNFalpha did not affect proliferation, survival, or differentiation of CD11b(high) splenocytes in vivo or in vitro, but caused a rapid increase in CD11b+ cells in blood within 4 hours of a single injection and an accumulation of CD11b(high) OCPs in spleen after 3 days of multiple injections. Systemic TNFalpha induces a marked increase in circulating OCPs that is reversible by anti-TNF therapy and may result from their mobilization from bone marrow. Our findings provide a new mechanism whereby TNFalpha stimulates osteoclastogenesis in patients with inflammatory arthritis, suggesting that CD11b+ PBMCs could be used to evaluate a patient's potential for erosive disease and the efficacy of anti-TNF therapy.