anti-TNF Therapy Research Articles

TCTAP C-141 Consideration for Coronary Intervention in a Patient Ankylosing Spondylitis With Anti-TNF Monoclonal Antibody Therapy

TCTAP C-141 Consideration for Coronary Intervention in a Patient Ankylosing Spondylitis With Anti-TNF Monoclonal Antibody Therapy

When to start secukinumab treatment in patients with axial spondyloarthropathy: Before or after anti-TNFα treatment?

Introduction and objectivesThis study aimed to evaluate the efficacy of secukinumab (SEC) in axial spondyloarthropathy (axSpA) in anti-TNFα naïve and anti-TNFα experienced patients. It also focused on the duration of SEC treatment and its side effects. Patients and methodsThe patients with axSpA treated with SEC and followed up in our outpatient clinic from May 2018 through October 2021 were included in this study. All patients in the study also fulfilled the ASAS classification criteria for axSpA. Patients were separated into two groups according to whether they received prior anti-TNFα therapy. While anti-TNFα naïve patients comprised group 1, anti-TNFα experienced patients were included in group 2. Pre- and post-treatment BASDAI scores were reported and compared. ResultsEighty-four axSpA patients (42 men; duration of the disease: 86.86±65.35 months in group 1 and 160.65±97.4 months in group 2) were treated with SEC. 45.5% of anti-TNFα naïve patients and 56.5% of anti-TNFα experienced patients were still on SEC therapy in October 2021. Duration of SEC treatment was 12.5±7.9 months in group 1 and 17.19±12 months in group 2 (p=0.098). The differences between pre-and post-treatment BASDAI scores were statistically significant in both groups (p<0.001). While patients in group 1 did not develop any adverse effects, three patients in group 2 experienced alopecia, uveitis, and recurrent pneumonia after SEC treatment. ConclusionOur study's efficacy and safety data on the use of SEC were reassuring in both anti-TNFα naïve and anti-TNFα experienced patients. However, further studies are still needed to determine the appropriate timing to begin SEC treatment.

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

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

ASSOCIATION OF CYCLING BETWEEN ANTI-TNFS VERSUS SWITCHING TO USTEKINUMAB WITH MEDICATION PERSISTENCE IN ANTI-TNF EXPERIENCED PATIENTS WITH CROHN'S DISEASE

Anti-tumor necrosis factor inhibitors (anti-TNFs) are biologics commonly used for the treatment of Crohn’s disease (CD). Over time, patients may require adjustment to anti-TNF therapy, including cycling to a different anti-TNF or switching to a biologic with an alternate mechanism of action. Choice of a treatment strategy could be key to managing symptoms on a sustained basis. This study aimed to compare real-world persistence among patients with CD who cycled to another anti-TNF agent or switched to ustekinumab.

Comparison of Short- and Long-Term Effectiveness between Anti-TNF and Ustekinumab after Vedolizumab Failure as First-Line Therapy in Crohn’s Disease: A Multi-Center Retrospective Cohort Study

The effectiveness of anti-TNF or ustekinumab (UST) as a second-line biologic after vedolizumab (VDZ) failure has not yet been described. In this retrospective multicenter cohort study, We aim to investigate the effectiveness of anti-TNF and UST as second-line therapy in patients with Crohn's disease (CD) who failed VDZ as a first-line treatment. The primary outcome was clinical response at week 16-22. Secondary outcomes included the rates of clinical remission, steroid-free clinical remission, CRP normalization, and adverse events. Fifty-nine patients who failed on VDZ as a first-line treatment for CD were included; 52.8% patients received anti-TNF and 47.2% UST as a second-line therapy. In initial period (Week 16-22), the clinical response and remission rate was similar between both groups: 61.2% vs. 68%, p = 0.8 and 48.3% vs. 56%, p = 0.8 on anti-TNF and UST therapy, respectively. Furthermore, in the maintenance period the rate was similar: 75% vs. 82.3%, p = 0.8 and 62.5% vs. 70.5%, p = 0.8, respectively. Of the patients, 12 out of the 59 stopped the therapy, without a significant difference between the two groups (p = 0.6). Second-line biological therapy after VDZ failure therapy was effective in >60% of the patients with CD. No differences in effectiveness were detected between the use of anti-TNF and UST as a second line.

Relation between Selected Sleep Parameters, Depression, Anti-Tumor Necrosis Factor Therapy, and the Brain-Derived Neurotrophic Factor Pathway in Inflammatory Bowel Disease.

Inflammatory bowel disease (IBD) patients often have sleep and mood disorders. Brain-derived neurotrophic factor (BDNF) and proBDNF were shown to modulate interactions between the central nervous system and the gastrointestinal tract, possibly contributing to psychological issues. Anti-tumor necrosis factor (TNF) therapy in IBD can alter BDNF expression and further affect the brain-gut axis. Eighty IBD patients and 44 healthy controls (HCs) were enrolled and divided into subsets based on disease activity and condition (ulcerative colitis (UC)/Crohn's disease (CD)). Questionnaires evaluating sleep parameters and depression as well as venous blood were collected. The IBD group had a lower expression of BDNF mRNA, but higher proBDNF and BDNF protein concentration than HCs. The UC group had a higher BDNF protein concentration than the CD. BDNF protein was positively correlated to sleep efficiency in the IBD group. Depression severity was associated positively with BDNF mRNA and negatively with BDNF protein in the remission group. Anti-TNF therapy enhanced BDNF mRNA expression. The BDNF pathway might be disturbed in IBD, linking it to sleep disorders and depression. Systemic inflammation could be the main cause of this disruption. BDNF mRNA is a more reliable parameter than protein due to numerous post-translational modifications.

Ustekinumab Versus Anti-tumour Necrosis Factor Alpha Agents as Second-Line Biologics in Crohn's Disease

BackgroundThere are little data on positioning biologics in Crohn's disease (CD).AimsWe aimed to assess the comparative effectiveness and safety of ustekinumab vs tumour necrosis factor-alpha (anti-TNF) agents after first-line treatment with anti-TNF in CD.MethodsWe used Swedish nationwide registers to identify patients with CD, exposed to anti-TNF who initiated second-line biologic treatment with ustekinumab or second-line anti-TNF therapy. Nearest neighbour 1:1 propensity score matching (PSM) was used to balance the groups. The primary outcome was 3-year drug survival used as a proxy for effectiveness. Secondary outcomes included drug survival without hospital admission, CD-related surgery, antibiotics, hospitalization due to infection and exposure to corticosteroids.ResultsSome 312 patients remained after PSM. Drug survival at 3 years was 35% (95% CI 26–44%) in ustekinumab compared to 36% (95% CI 28–44%) in anti-TNF-treated patients (p = 0.72). No statistically significant differences were observed between the groups in 3-year survival without hospital admission (72% vs 70%, p = 0.99), surgery (87% vs 92%, p = 0.17), hospital admission due to infection (92% vs 92%, p = 0.31) or prescription of antibiotics (49% vs 50%, p = 0.56). The proportion of patients continuing second-line biologic therapy did not differ by reason for ending first-line anti-TNF (lack of response vs intolerance) or by type of first-line anti-TNF (adalimumab vs infliximab).ConclusionBased on data from Swedish routine care, no clinically relevant differences in effectiveness or safety of second-line ustekinumab vs anti-TNF treatment were observed in patients with CD with prior exposure to anti-TNF.

Children with Localized Crohn's Disease Benefit from Early Ileocecal Resection and Perioperative Anti-Tumor Necrosis Factor Therapy.

In pediatric Crohn's disease ileocecal resection is performed reluctantly as postoperative recurrence is frequent. Anti-tumor necrosis factor (TNF) therapy reduces postoperative recurrence rates but increases the risk for infections. We retrospectively reviewed pediatric Crohn's disease patients who underwent ileocecal resection in our center. We compared disease activity and z-scores for height, weight, and body mass index of patients, who continuously received perioperative anti-TNF therapy (TNF + ), with those who did not (TNF-). Of 29 patients (48% females), 13 and 16 were grouped to TNF+ and TNF-, respectively. Patients' characteristics did not differ between groups, except a longer follow-up time in TNF-. We saw significant postoperative improvement but no normalization in z-scores for weight (1.78 vs. 0.77, p < 0.001), body mass index (1.08 vs. 0.22, p < 0.001), and height (0.88 vs. 0.66, p < 0.001). Disease activity improved significantly more in patients receiving anti-TNF therapy (moderate improvement in 83% vs. 31%, p = 0.02). Endoscopic recurrence was more frequent in patients without anti-TNF therapy (80% vs. 20%; p = 0.023), but endoscopic follow-up was incomplete. There was no increase of infections under perioperative anti-TNF therapy (1 patient each; p = 1.000). In patients with localized Crohn's disease an ileocecal resection leads to short-term postoperative improvement of disease activity, body mass index, weight, and growth. For relevant catch-up growth an earlier intervention is necessary. Continuous perioperative anti-TNF therapy had no increased risk of perioperative infections.

Risk of infection in elderly patients with inflammatory bowel disease under biologics: A prospective, multicenter, observational, one-year follow-up comparative study

The emergence of biologics has improved the course of inflammatory bowel diseases (IBD) in the elderly population despite a potential higher risk of infections. We conducted a one-year, prospective, multicenter, observational study to determine the frequency of occurrence of at least one infectious event in elderly IBD patients under anti-TNF therapy compared with that in elderly patients under vedolizumab or ustekinumab therapies . All IBD patients over 65 years exposed to anti-TNF, vedolizumab or ustekinumab therapies were included. The primary endpoint was the prevalence of at least one infection during the whole one year follow-up. Among the 207 consecutive elderly IBD patients prospectively enrolled, 113 were treated with anti-TNF and 94 with vedolizumab (n=63) or ustekinumab (n=31) (median age 71 years, 112 Crohn's disease). The Charlson index was similar between patients under anti-TNF and those under vedolizumab or ustekinumab as well as the proportion of patients under combination therapy and under concomitant steroid therapy did not differ between both both groups. The prevalence of infections was similar in patients under anti-TNF and in those under vedolizumab or ustekinumab (29% versus 28%, respectively; p=0.81). There was no difference in terms of type and severity of infection and of infection-related hospitalization rate. In multivariate regression analysis, only the Charlson comorbidity index (≥ 1) was identified as a significant and independent risk factor of infection (p=0.03). Around 30 % of elderly patients with IBD under biologics experienced at least one infection during the one-year study follow-up period. The risk of occurrence of infection does not differ between anti-TNF and vedolizumab or ustekinumab therapies, and only the associated comorbidity was linked with the risk of infection.

A212 THE IMPACT OF COMBINED MEDICAL AND SURGICAL TREATMENT FOR PERIANAL CROHN’S DISEASE: A SYSTEMATIC REVIEW AND META-ANALYSIS

Abstract Background Multidisciplinary care involving surgical drainage via examinations under anesthesia (EUA) and anti-tumor necrosis factor (TNF) therapy is recommended for perianal Crohn’s disease (PCD). However, the impact of this combined modality approach is not well-established. Purpose To determine the impact of combined modality (surgical and anti-TNF) vs. single modality (either surgical or anti-TNF) therapy on fistula healing in perianal Crohn’s disease. Method MEDLINE, EMBASE, and Cochrane databases were searched systematically from inception through September 15, 2022 independently in duplicate. We included studies that reported on fistula outcomes after treatment with combined modality vs. single modality therapy for PCD. Surgery was defined as EUA ± seton or closure procedure. Weighted summary estimates with 95% CI were estimated by random effects models. Study quality was determined using an adapted version of the Newcastle-Ottawa scale. Result(s) Thirteen studies met inclusion criteria. The total population included 1279 patients: 685 patients treated with single modality therapy with either surgical or anti-TNF therapy and 594 patients treated with combined modality therapy. Patients treated with combined modality therapy were more likely to achieve fistula healing compared to single modality therapy (65.4% vs. 57.7%; OR 1.68; 95% CI 1.03-2.73, p = 0.04) (Figure 1a). In a subgroup analysis, the rates of fistula healing were higher with combined modality therapy than with surgical therapy alone (OR 2.34; 95% CI 0.85-6.46, p = 0.10) but not anti-TNF therapy alone (OR 1.19; 95% CI 0.78-1.81, p = 0.43), although neither comparison was statistically significant (Figures 1b and c). The majority of studies were rated low-quality due to risk of bias from uncontrolled confounding variables. Image Conclusion(s) Limited high-quality evidence suggests that fistula healing occurs more frequently in patients treated with combined modality therapy. However, the benefit of a combined modality approach appears to be driven mainly by anti-TNF therapy. Further prospective randomized trials are needed to confirm these findings. Please acknowledge all funding agencies by checking the applicable boxes below None Disclosure of Interest None Declared

A209 ASSESSMENT OF OUTCOMES OF PATIENTS ADMITTED WITH ACUTE, SEVERE ULCERATIVE COLITIS ON ESTABLISHED BIOLOGIC THERAPY: A SINGLE CENTRE RETROSPECTIVE ANALYSIS

Abstract Background Acute, severe, ulcerative colitis (ASUC) is associated with a high morbidity and mortality. Current guidelines recommend the initiation of high dose intravenous steroids, followed by anti-TNF therapy if a satisfactory therapeutic response is not rapidly achieved. However, guidelines are agnostic on how to manage patients who are admitted for ASUC despite being on established biologic therapy. Furthermore, short-term clinical outcomes in this population are not well characterized. Purpose The aim of this study is to assess the differences in short-term clinical outcomes in patients admitted with ASUC who are on established biologic therapy compared to those not on established biologic therapy. Method We conducted a retrospective chart review of patients admitted with ASUC to Mount Sinai Hospital (MSH) in Toronto, Ontario from January 2018 until December 2021. Patients were included if they were deemed to have a severe flare, defined as having 6 or more loose bowel movements per day with at least one of the following features: temperature of 38.0 Celsius, tachycardia, anemia, or elevated inflammatory markers. Included subjects were considered to be on established biologic therapy if they had a biologic within 56 days prior to admission, all other admitted subjects were included as controls. Our primary outcome was the difference in hospital length of stay (HLOS). We also contrasted duration of intravenous steroids, rates of surgical consultation, rates of in-hospital colectomy, and readmission rates within 90 days of discharge. Result(s) 130 charts were included in our study, 53 of which were patients on established biologic therapy, and 77 of which were patients not on established biologic therapy. The HLOS between the two groups was not significantly different, (7.23 days [established biologic therapy] vs.7.47 days [not on biologic therapy], p value = 0.77). Patients on established biologic therapy were more likely to receive an inpatient surgical consultation (33.96% vs 7.79%, p-value &amp;lt;0.001). However, rates of colectomy prior to discharge were not statistically different (1.89% vs 0%, p-value = 0.23). Patients on established biologic therapy were significantly more likely to be readmitted within 90 days of discharge (30.19% vs 12.99%, p-value = 0.016). Image Conclusion(s) Although there were no differences in HLOS and colectomy rates between the 2 groups, patients with ASUC on established biologic therapy were more likely to be readmitted within 3 months of discharge. Further work is required to define optimal medical management of persons admitted with ASUC who are failing biologic therapies. Please acknowledge all funding agencies by checking the applicable boxes below None Disclosure of Interest None Declared

A205 EVALUATING THE ASSOCIATION BETWEEN PERIPHERAL BLOOD EOSINOPHILS AND DRUG RESPONSE IN CROHN'S DISEASE: CONTINUING ANALYSIS

Abstract Background Th2 cytokines, IL-5 and IL-13 enhance peripheral and mucosal eosinophil survival, recruitment and degranulation, facilitating inflammation in Crohn's Disease. In a preliminary analysis, peripheral eosinophilia (PBE) is seen to have an association with rates of steroid response and anti-TNF response in CD patients. Participants with high PBE (&amp;gt; 200 cells/μL) appear to be more steroid-responsive but less responsive to Th1-targeting anti-TNF therapies. We hypothesize the pattern of PBE at CD diagnosis can help identify distinct subsets within a larger CD population and correlate with response to treatments such as prednisone or anti-TNFs. Purpose We aim to evaluate the pattern of PBE of CD patients at time of diagnosis (prior to drug exposure) and with each subsequent treatment; and if baseline PBE or any changes seen with drug exposures are predictive of treatment response. Method A retrospective cohort study is ongoing with CD patients exposed to glucocorticoids and an anti-TNF seen at 3 hospitals affiliated with University of Western Ontario. Patients were identified using administrative databases and reviewed for biochemical data (complete blood count) and disease activity (Harvey Bradshaw Index) at baseline, before and after each drug exposure. Participants were classified as having high PBE (eosinophils&amp;gt;200 cells/μL) versus low PBE (eosinophils &amp;lt;200 cells/μL). To date, 350 patients have been screened. Subgroup analyses of PBE &amp;gt; 300 cells/μL, and differences between female and male patients will be carried out. Result(s) 46 of 200 CD patients are included in the continuing analysis with a mean age of 45 years. 26 had PBE &amp;gt;200 cells/μL at baseline and 20 did not. The median number therapies used was 4 (IQR=0.75). All received glucocorticoids followed by an anti-TNF. There was no difference in the occurrence of hospitalization or surgery between the two groups. Overall 50% participants with high PBE &amp;gt;200 and &amp;gt;300 cells/μL had clinical response to glucocorticoid exposure, seen as a 3-point decrease in HBI compared to 45%, 47% in the low PBE cohort (n=13/26 vs. n=9/20 p=0.77; n=6/12 vs. n=16/34 p=1.0 respectively). With subsequent anti-TNF exposure, PBE rebounded in 7 participants. 36% patients in the high PBE group required anti-TNF dose escalation versus 24% in the low PBE group (n=9/25 vs. n=5/21, p=0.52). The proportion of patients with anti-TNF discontinuation was similar in both groups (high PBE 19.2%, n=5/26 vs. low PBE 15%, n=3/20, p=1.0). Men had higher steroid response rates compared to women in both high and low PBE groups (n=6/8 vs. n=8/18 p=0.21; n=4/9 vs. 4/11 p=1.0 respectively). Conclusion(s) Peripheral eosinophilia is seen in varying degrees in CD patients. Participants with high PBE are more steroid-responsive. High PBE patients overall were less responsive to anti-TNF therapies, requiring more dose-escalation and discontinued anti-TNF treatment. Completion of this study will help clarify the association between PBE in CD and treatment response. Please acknowledge all funding agencies by checking the applicable boxes below None Disclosure of Interest None Declared

A210 THE BURDEN OF IBD HOSPITALIZATION IN CANADA: AN ASSESSMENT OF THE CURRENT AND FUTURE BURDEN IN A NATION-WIDE ANALYSIS

A210 THE BURDEN OF IBD HOSPITALIZATION IN CANADA: AN ASSESSMENT OF THE CURRENT AND FUTURE BURDEN IN A NATION-WIDE ANALYSIS

Clinicopathologic Spectrum of Renal Lesions Following Anti-TNF- α Inhibitor Therapy: A Single Center Experience.

Anti-tumor necrosis factor (TNF)-alpha inhibitors, as biological agents, are used in autoimmune inflammatory states, rheumatoid arthritis (RA), psoriatic arthritis (PA), and Crohn's disease. They can induce autoimmune serologic responses and clinical disorders including systemic vasculitis and lupus-like diseases, affecting the kidney. Retrospective analysis of clinicopathologic features of kidney disease following anti-TNF alpha therapy (treatment group) from our renal biopsy files from 2000-2018 is conducted and compared with 106 cases without therapy (control group). Forty-eight patients using anti-TNF-alpha agents had renal biopsies, RA in 30, PA in 6, Crohn's disease 6, RA and PA 1, RA and Crohn's disease 1, and others 4. 20 received etanercept, 15 adalimumab, 8 infliximab and 5 had 2 forms of agents manifesting new onset nephritic syndrome or CKD, 17 with acute kidney injury and 16 nephrotic syndrome, with recent ANCA and/or lupus serology. The renal lesions were crescentic glomerulonephritis in 8, 5 pauci-immune type and 5 ANCA+. Lupus or lupus-like nephritis seen in 6: ISN/RPS 2018 class II-2, class V-2, class III+V-1, class IV+V-1, 3 with concurrent fibrillary GN, scleroderma/TMA and amyloidosis. Renal lesions unrelated to anti-TNF-alpha therapy or underlying autoimmune disease in 23 (eg diabetic nephropathy, interstitial nephritis, acute tubular injury, infection-related GN), IgA nephropathy, renal sarcoidosis and AA amyloidosis were noted in 5 cases. Thrombotic microangiopathy was recognized in 5 cases, 1 associated with scleroderma and 1 antiphospholipid antibodies, and 2 nephrotic syndrome secondary to podocytopathy. The control group was similar with higher immune mediated GN, interstitial nephritis and amyloidosis. The renal lesions during anti-TNF-alpha therapy have an autoimmune basis such as ANCA, lupus or lupus-like disease, correlated with new onset serology, while others were similar to those observed in the control group. Renal biopsy findings integrated with clinical features and therapy can identify the underlying pathophysiologic process for appropriate management.

Associations of Tinnitus Incidence with Use of Tumor Necrosis Factor-Alpha Inhibitors among Patients with Autoimmune Conditions.

Tumor necrosis factor-alpha (TNFα) may promote neuroinflammation prompting tinnitus. This retrospective cohort study evaluated whether anti-TNFα therapy influences incident tinnitus risk among adults with autoimmune disorders and no baseline tinnitus selected from a US electronic health records database (Eversana; 1 January 2010-27 January 2022). Patients with anti-TNFα had ≥90-day history pre-index (first autoimmune disorder diagnosis) and ≥180-day follow-up post-index. Random samples (n = 25,000) of autoimmune patients without anti-TNFα were selected for comparisons. Tinnitus incidence was compared among patients with or without anti-TNFα therapy, overall and among at-risk age groups or by anti-TNFα category. High-dimensionality propensity score (hdPS) matching was used to adjust for baseline confounders. Compared with patients with no anti-TNFα, anti-TNFα was not associated with tinnitus risk overall (hdPS-matched HR [95% CI]: 1.06 [0.85, 1.33]), or between groups stratified by age (30-50 years: 1 [0.68, 1.48]; 51-70 years: 1.18 [0.89, 1.56]) or anti-TNFα category (monoclonal antibody vs. fusion protein: 0.91 [0.59, 1.41]). Anti-TNFα was not associated with tinnitus risk among those treated for ≥6 months (hdPS-matched HR [95% CI]: 0.96 [0.69, 1.32]) or ≥12 (1.03 [0.71, 1.5]), or those with RA (1.16 [0.88, 1.53]). Thus, in this US cohort study, anti-TNFα therapy was not associated with tinnitus incidence among patients with autoimmune disorders.

Immunomodulator comedication promotes the reversal of anti-drug antibody-mediated loss of response to anti-TNF therapy in inflammatory bowel disease

PurposeLoss of therapeutic response (LOR) due to anti-drug antibodies (ADA) against tumor necrosis factor (TNF) inhibitors is common in patients with inflammatory bowel disease (IBD). We aimed to investigate whether immunomodulator comedication can reverse the immunogenic LOR to TNF inhibitors in IBD.MethodsIn this real-world retrospective cohort study, 123 IBD patients with neutralizing ADA to infliximab or adalimumab and concomitant subtherapeutic trough levels were screened for clinical LOR. Subsequent ADA and trough level measurements and clinical outcomes were analyzed for patients who received either immunomodulator comedication or dose intensification of infliximab or adalimumab to overcome LOR.ResultsFollowing immunogenic LOR, the initial anti-TNF regimen was optimized in 33 patients. In univariable and multivariable logistic regression analyses, immunomodulator comedication was identified as the crucial factor for regaining clinical remission and ADA clearance. Detectable trough levels (≥ 0.98 or ≥ 1.00 mg/L, respectively) had optimal predictive performance for both endpoints in receiver operating characteristics curves [area under the curve 0.86 (95% confidence interval 0.68–1.00) for regaining clinical remission, 0.87 (0.71–1.00) for ADA clearance]. Furthermore, 11/20 patients (55%) on a comedication with azathioprine or methotrexate and 2/13 patients (15%) receiving anti-TNF dose intensification exclusively (P = 0.032) exhibited ADA elimination, regain of therapeutic trough levels, and clinical remission. Regain of clinical remission alone was achieved in 17/20 (85%) patients receiving comedication and 2/13 (15%) patients receiving anti-TNF dose intensification (P = 1.6 × 10−4).ConclusionImmunogenic LOR to infliximab or adalimumab in IBD can be successfully reversed using immunomodulator comedication.

Past, Present and (Foreseeable) Future of Biological Anti-TNF Alpha Therapy

Due to the key role of tumor necrosis factor-alpha (TNF-α) in the pathogenesis of immunoinflammatory diseases, TNF-α inhibitors have been successfully developed and used in the clinical treatment of autoimmune disorders. Currently, five anti-TNF-α drugs have been approved: infliximab, adalimumab, golimumab, certolizumab pegol and etanercept. Anti-TNF-α biosimilars are also available for clinical use. Here, we will review the historical development as well as the present and potential future applications of anti-TNF-α therapies, which have led to major improvements for patients with several autoimmune diseases, such as rheumatoid arthritis (RA), ankylosing spondylitis (AS), Crohn's disease (CD), ulcerative colitis (UC), psoriasis (PS) and chronic endogenous uveitis. Other therapeutic areas are under evaluation, including viral infections, e.g., COVID-19, as well as chronic neuropsychiatric disorders and certain forms of cancer. The search for biomarkers able to predict responsiveness to anti-TNF-α drugs is also discussed.

Biogenetic Markers for Predicting Response to Immunotherapy in Rheumatoid Arthritis

Background: TNF-α plays a critical role in the pathogenesis of RA. Gene polymorphisms occurring in this pro-inflammatory cytokine or their receptors may influence responses to biological therapy. Objectives: This study aimed to evaluate the impact of -238G/A(rs361525), -308G/A(rs1800629), -376G/A(rs1800750), +489G/A(rs80267059) SNPs in TNF-α and +587T/G(rs1061622), +884A/G(rs5746032) SNPs in TNFRII genes on responsiveness to TNF inhibitors as well as their effect on serum levels of TNF-α and TNFRII. Subjects and methods: Sixty patients with RA treated with anti-TNF therapy (30 responders and 30 non-responders) were allocated to this study. SNPs in the TNF-α and TNFRII genes were studied by three different techniques: PCR-sequencing, PCR-RFLP, and q-PCR-TaqMan assay. TNF-α and TNFRII serum levels were determined using the ELISA technique. Results: TNF-α -308 (GA), +489 (GA), and TNFRII +587 (TG) genotypes were found to be more associated with non-responsiveness to TNF than homozygous genotypes (OR: 1.3, 2.5, and 2.0, respectively). On other hand, TNF-α -238 and -376 (GA) genotypes, were found to be more associated with TNFi responsiveness than homozygous genotypes (OR: 0.172 and 0.22, respectively). However, none of them reached a significant level. Furthermore, the studied SNPs were found to be unrelated to serum levels of TNF-α and TNFRII. Conclusion: According to our findings, the TNF-α -238G/A, -308G/A, -376G/A, +489G/A, and TNFRII +587T/G, +884A/G SNPs were not significantly associated with the responsiveness of RA patients to biological therapy and had no effect on the serum levels of TNF-α and TNFR.

MIF Variant rs755622 Is Associated with Severe Crohn’s Disease and Better Response to Anti-TNF Adalimumab Therapy

Crohn's disease (CD), rheumatoid arthritis, psoriatic arthritis and other inflammatory diseases comprise a group of chronic diseases with immune-mediated pathogenesis which share common pathological pathways, as well as treatment strategies including anti-TNF biologic therapy. However, the response rate to anti-TNF therapy among those diseases varies, and approximately one third of patients do not respond. Since pharmacogenetic studies for anti-TNF therapy have been more frequent for other related diseases and are rare in CD, the aim of our study was to further explore markers associated with anti-TNF response in other inflammatory diseases in Slovenian CD patients treated with the anti-TNF drug adalimumab (ADA). We enrolled 102 CD patients on ADA, for which the response was defined after 4, 12, 20 and 30 weeks of treatment, using an IBDQ questionnaire and blood CRP value. We genotyped 41 SNPs significantly associated with response to anti-TNF treatment in other diseases. We found novel pharmacogenetic association between SNP rs755622 in the gene MIF (macrophage migration inhibitory factor) and SNP rs3740691 in the gene ARFGAP2 in CD patients treated with ADA. The strongest and most consistent association with treatment response was found for the variant rs2275913 in gene IL17A (p = 9.73 × 10-3).

Pharmacogenetic Analysis of the MIR146A rs2910164 and MIR155 rs767649 Polymorphisms and Response to Anti-TNF Treatment in Patients with Crohn's Disease and Psoriasis.

The clinical heterogeneity regarding the response profile of the antitumor necrosis factor (anti-TNF) in patients with Crohn's disease (CD) and psoriasis (PsO) is attributed, amongst others, to genetic factors that influence the regulatory mechanisms which orchestrate the inflammatory response. Here, we investigated the possible associations between the MIR146A rs2910164 and MIR155 rs767649 variants and the response to anti-TNF therapy in a Greek cohort of 103 CD and 100 PsO patients. We genotyped 103 CD patients and 100 PsO patients via the PCR-RFLP method, utilizing the de novo formation of a restriction site for the SacI enzyme considering the MIR146A rs2910164, while Tsp45I was employed for the MIR155 rs767649 variant. Additionally, we investigated the potential functional role of the rs767649 variant, exploring in silico the alteration of transcription factor binding sites (TFBSs) mapped on its genomic location. Our single-SNP analysis displayed a significant association between the rare rs767649 A allele and response to therapy (Bonferroni-corrected p value = 0.012) in patients with PsO, a result further enhanced by the alteration in the IRF2 TFBS caused by the above allele. Our results highlight the protective role of the rare rs767649 A allele in the clinical remission of PsO, implying its utilization as a pharmacogenetic biomarker.