Tumor Necrosis Factor Alpha Blockers Research Articles

No Correlation between Anti-drug Antibodies and Therapeutic Response in Tunisian Patients with Chronic Inflammatory Diseases Treated by TNF Blockers.

Tumor necrosis factor alpha (TNF alpha) blockers such as infliximab (IFX) and adalimumab (ADA) had significantly changed the course of inflammatory diseases such as rheumatoid arthritis (RA), spondyloarthritis (SpA) and Crohn's disease (CD). However, about 30% of patients do not respond to these treatments. This lack of response may be due to the formation of antibodies against these drugs (anti-drug antibodies: ADAbs). The aim of this study was to determine the prevalence of ADAbs against IFX and ADA, and the trough serum concentration of IFX and ADA in RA, SpA or CD patients and to assess their impact on the therapeutic response. A cross sectional, multi-centric study was conducted, including patients with RA, SpA or CD treated with IFX or ADA as a first biotherapy for at least 6 months. ADAbs and trough levels were measured by an Enzyme Linked Immunosorbent assay (ELISA). 197 patients were included (57 RA, 73 SpA and 67 CD). ADAbs were positive in 40% of cases for IFX and 25% for ADA. They were positive in 40% of SpA, 35% of RA, and 21% of CD. The presence of ADAbs was inversely correlated to the trough levels of IFX and ADA during RA (p = 0.01 and p < 0.0001), SpA (p < 0.01 and p < 0.0001) and CD (p = 0.001 and p = 0.04). For all pathologies, the presence of ADAbs was not correlated with disease activity. Concomitant methotrexate significantly reduced immunogenicity. In our study, the presence of ADAb and low trough levels seem to not affect the therapeutic response in patients on TNF alpha antagonists. Other tracks more than immunogenicity should be investigated to explain the loss of response to these biotherapies.

Uveitis and multiple sclerosis : Clinical aspects, diagnostics, management and treatment

Approximately 0.5-1% of patients with multiple sclerosis (MS) have co-existing uveitis. Both intraocular inflammation and MS mainly affect women in younger adulthood. The MS in patients is most frequently associated with an often bilateral intermediate uveitis with typical concomitant retinal vasculitis. Both diseases share similar characteristics with chronic inflammatory diseases with arelapsing course and an immune-mediated pathogenesis; however, it is still unclear whether the co-occurrence of uveitis and MS in the same patient represents acoincidence of two separate disease entities or whether uveitis is arare clinical manifestation of MS. In the differential diagnostics of intermediate uveitis, clinical symptoms and signs of MS should be considered. As both diseases are considered to be immune-mediated, immunotherapy is the main treatment option. In recent years the range of medications has expanded and includes several disease modifying drugs (biologics). When selecting the active substance it must be taken into account that tumor necrosis factor (TNF) alpha blockers are contraindicated in patients with MS.

Prognostic models of drug-induced neutralizing antibody formation in patients with rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis treated with TNF-α blockersockers.

This study aimed to construct prognostic mathematical models utilizing multifactorial regression analysis to assess the risk of developing drug-induced neutralizing antibodies in patients with rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis treated with tumor necrosis factor alpha blockers.

Efficacy and safety of infliximab in the treatment of Kawasaki disease: A systematic review and meta-analysis.

Infliximab is a monoclonal antibody specifically binding tumor necrosis factor-alpha and has been approved for the treatment of several inflammatory disorders. However, the efficacy of infliximab in primary treatment of Kawasaki disease (KD) or retreatment of intravenous immunoglobulin (IVIG)-resistant KD in children is controversial. Therefore, we conducted a meta-analysis to compare the efficacy of infliximab alone or in combination with IVIG to IVIG. Eligible randomized and non-randomized trials were retrieved by searching literature databases prior to May 31, 2023. Pooled odds ratio (OR) and 95% confidence interval (95% CI) were calculated for dichotomous variables, and mean difference (MD) with 95% CI was estimated for continuous variables. A total of 14 eligible studies comprising 1257 participants were included. In refractory KD, infliximab alone was associated with a higher effectiveness rate (OR = 4.48, 95% CI 2.67-7.52) and defervescence rate (OR = 5.01, 95% CI 2.99-8.37) and resulted in a 1.08-day-shorter duration of fever (95% CI 0.61-1.55, P < 0.001) and 1.36-day-shorter length of hospital stay (95% CI 0.65-2.08) compared with IVIG. Incidences of coronary artery lesions (CALs), newly developing CALs, and CAL regression did not differ between both groups. For initial treatment of KD, infliximab in addition to IVIG led to a nominally significant higher effectiveness rate (OR = 2.26, 95% CI 1.02-5.01) and a larger reduction of right coronary artery Z score (MD = -0.24, 95% CI -0.27 to -0.21) but did not show additional efficacy in improving other outcomes. The safety profile was similar between both groups. Conclusion: The meta-analysis demonstrates that infliximab alone is a well-tolerated and effective treatment for IVIG-resistant KD. The additional efficacy of infliximab to IVIG for initial treatment of KD is limited. More large and high-quality trials are needed to confirm the efficacy of infliximab, especially for intensification of primary treatment for KD. What is Known: • Infliximab is a novel monoclonal antibody specifically blocking tumor necrosis factor-alpha and is approved for treatment of several immune-mediated inflammatory disorders. • The efficacy of infliximab in treating children with Kawasaki disease is controversial. What is New: • Infliximab is an effective and safe treatment for children with refractory Kawasaki disease but adds limited efficacy to intravenous immunoglobulin for initial treatment of Kawasaki disease.

Efficacy and safety of dual therapy - biological and small molecules in patients with ulcerative colitis

Сombination of two or more biological or immunosuppressive drugs in order to achieve a synergistic effect in patients with refractory inflammatory bowel disease (IBD) has been in the spotlight for many years. Combination therapy may include various medications, most often biological and immunosuppressants. Despite the fact that biological therapy of IBD has traditionally focused on drugs that block tumor necrosis factor-alpha, the development of new drugs that act on different targets, such as vedolizumab, ustekinumab, tofacitinib or ozanimod, has made it possible to use combined immunosuppressive therapy. The treatment algorithm suggests various combinations of dual biological therapy for 2 categories of patients with IBD: patients with well-controlled luminal IBD and uncontrolled extra-intestinal symptoms (indications such as arthritis or psoriasis) and patients with refractory, uncontrolled IBD. Thus, data on the efficacy and safety of dual biological therapy as a method of treating Crohn’s disease (CD) or ulcerative colitis (UC) remain very limited. In fact, the vast majority of literature consists of individual cases and a series of cases. Given the lack of studies with a high level of evidence, gastroenterologists have turned to larger studies of dual biological therapy in other areas of medicine, such as rheumatology and dermatology. The aim of this article is to demonstrate clinical experience of combination therapy with genetically engineered biological drugs and selective immunosuppressors in UC, to analyze potential adverse effects or risks associated with combination therapy, and to determine future directions in the use of this treatment.

ОПЫТ ПРИМЕНЕНИЯ ИНФЛИКСИМАБА В ЛЕЧЕНИИ ИММУНОГЛОБУЛИН-РЕЗИСТЕНТНОЙ БОЛЕЗНИ КАВАСАКИ

Kawasaki disease (KD) is an acute systemic disease characterized by predominant damage to small and medium-sized arteries with the development of destructive-proliferative vasculitis, damage to the coronary arteries (CA) and other visceral arteries manifested by fever, changes in the mucous membranes, skin, and lymph nodes. The initial KD therapy is intravenous immunoglobulin (IVIG) at a dose of 2 g/kg coupled with acetylsalicylic acid. However, 10% to 38% may be resistant to standard therapy. There are no uniform recommendations for the management of patients with immunoglobulin-resistant KD. Possible therapies include repeated IVIG, high-dose glucocorticoids, genetically engineered biological drugs and other cytostatic drugs. Authors represent a clinical case of a 4-month-old boy with a complete form of KD, giant CA aneurysms and a resistance to the previous 4 courses of immunomodulatory therapy (2 courses of IVIG, etanercept, pulse therapy with methylprednisolone) with the effective use of the tumor necrosis factor alpha blocker, infliximab.

Frequency of latent tuberculosis in patients receiving Anti-TNF-Alpha therapy.

In this study, it was aimed to reveal the incidence of tuberculosis development in patients receiving tumor necrosis factor-alpha (TNF-α) blocker therapy, despite tuberculosis chemoprophylaxis. 520 patients who were receiving anti TNF-α treatment in the last 3 years were evaluated retrospectively. Radiological imaging tuberculin skin test (TST), history of tuberculosis, BCG vaccine, chemoprophylaxis administration, used anti TNF-α drugs were recorded. There were 265(51.0%) of the patients with ankylosing spondylitis (AS), 175(33.7%) with rheumatoid arthritis, 35(6.7%) with Crohn's, 10(1.9%) with ulcerative colitis (UC), 21(4.0%) with psoriatic arthritis, 14(2.7%) with psoriasis vulgaris. In total, 455 (79.6%) patients were given INH prophylaxis. Active tuberculosis development was observed in five patients (4: pulmonary,1: extrapulmonary; 3: UC, 2:AS) who all received anti TNF-α treatment (0.96%), infliximab. Three patients had tuberculosis disease in the 6th month, and the other 2 patients in the 5th and 24th month of their anti TNF-α treatments, and two had 9-month, and 1 had 6-month chemoprophylaxis history. The incidence of tuberculosis development in patients treated with anti TNF-α was found to be higher than the general population. In our country, where tuberculosis is still prevalent, patients receiving Anti TNF-α treatment (especially infliximab) should be carefully questioned and examined about tuberculosis.

High Baseline Neutrophil-to-Lymphocyte Ratio Could Serve as a Biomarker for Tumor Necrosis Factor-Alpha Blockers and Their Discontinuation in Patients with Ankylosing Spondylitis.

This study explores the association of neutrophil-to-lymphocyte (NLR), monocyte-to-lymphocyte (MLR), and platelet-to-lymphocyte (PLR) ratios with the 3-month treatment response and persistence of tumor necrosis factor-alpha (TNF-α) blockers in patients with ankylosing spondylitis (AS). This retrospective cohort study investigated 279 AS patients who were newly initiated on TNF-α blockers between April 2004 and October 2019 and 171 sex- and age-matched healthy controls. Response to TNF-α blockers was defined as a reduction in the Bath AS Disease Activity Index of ≥50% or 20 mm, and persistence referred to the time interval from the initiation to discontinuation of TNF-α blockers. Patients with AS had significantly increased NLR, MLR, and PLR ratios as compared to controls. The frequency of non-response at 3 months was 3.7%, and TNF-α blockers' discontinuation occurred in 113 (40.5%) patients during the follow-up period. A high baseline NLR but not high baseline MLR and PLR showed an independently significant association with a higher risk of non-response at 3 months (OR = 12.3, p = 0.025) and non-persistence with TNF-α blockers (HR = 1.66, p = 0.01). NLR may be a potential marker for predicting the clinical response and persistence of TNF-α blockers in AS patients.

Defining the course of neurosarcoidosis according to presentation at onset and disease modifying treatment: a cohort study of 84 patients.

Neurosarcoidosis is a rare manifestation of sarcoidosis with heterogeneous presentations. Patient management is challenging due to the current lack of knowledge about the long-term disease course. To identify specific disease courses of neurosarcoidosis according to the clinical and paraclinical presentations at onset. We conducted an observational multicenter cohort study by retrospectively collecting data from the medical records of 84 patients diagnosed with definite, probable, or possible neurosarcoidosis in three tertiary referral centers in France (Nancy, Strasbourg, and Bordeaux). We collected demographic characteristics, clinical and paraclinical data at the beginning of patient management, and during follow-up under the different treatment lines. Two expert neurologists determined disease course profiles. The mean follow-up was 6.6 years. Almost every patient (96.4%) received steroids at some point of their follow-up. Tumor Necrosis Factor-alpha blockers were given in 10.7% as first-line treatment and in 33.3% during follow-up. Every patient presented with a relapsing disease, often monophasic (75%) and sometimes polyphasic with the recurrence of identical manifestations (11.9%). Patients developing new neurological symptoms during follow-up were a minority (13.1%). No patients exhibited a progressive course. Patients with isolated cranial nerves injury or aseptic meningitis always exhibited a monophasic course, and 62.5-75% of them had a full recovery after first-line treatments. This proportion was 15.6% in other forms of the disease. Those with peripheral presentations were more likely to present a polyphasic course than patients with other forms of neurosarcoidosis. Spinal cord presentations were monophasic, but resulted in sequelae and exhibited poor response to first-line treatments despite frequent use of TNF-alpha blockers. Identification of these disease course profiles, based on the initial clinical and paraclinical presentation, could guide the clinician to select the optimal therapeutic approach and follow-up modalities for their patients with neurosarcoidosis.

Protracted fever after infliximab induction therapy in a patient with ulcerative colitis (clinical case)

Inflammatory bowel diseases (ulcerative colitis and Crohn’s disease) tend to increase in frequency and prevalence worldwide and lead to a significant reduction in quality of life with a complicated course. Intravenous administration of corticosteroids in acute severe ulcerative colitis is effective in 60–70 % of cases. Rescue therapy for patients with steroid‐refractory and steroid-dependence attacks is effective for reducing colectomy or colproctectomy and improves long-term treatment outcomes. Despite the proven efficacy of infliximab, limitations to the use of monoclonal antibodies are adverse reactions to the administration of genetically engineered biologic therapy (GEBT), both well-known and studied, and rare.The aim of the study. To analyze a case of an extremely rare and paradoxical incurable hyperergic reaction that occurred after using genetically engineered biological therapy with tumor necrosis factor alpha blockers in a patient suffering from ulcerative colitis.Materials and methods. We carried out the search in the PubMed, Embase, Scopus and Medline databases until November 1, 2022 using the following keywords: inflammatory bowel disease, ulcerative colitis (UC), anti-tumor necrosis factor α (antiTNFα), infliximab, fever, adverse events. In the scientific electronic library eLIBRARY, a search was made for Russian-language publications using similar queries in Russian. We analyzed the patient’s medical records from 03.06.2013 up to the present day; the patient signed an informed consent for the publication and discussion of the presented data.Conclusion. The widespread use of GEBT in the treatment of autoimmune and autoinflammatory diseases leads to the accumulation of both positive and negative experience of clinicians in real clinical practice. The officially described adverse events in the appointment of any drug suggest options for their prevention and treatment. Atypical manifestations or casuistic cases must be systematized for further fundamental pathophysiological studies.

S806 Impact of Biologics Therapy on the Prevalence of Pregnancy Complications Among Women With Inflammatory Bowel Disease: A Nationwide Population-Based Study

Introduction: Inflammatory bowel disease (IBD) typically coincides with childbearing years in women. IBD has been established as an independent risk factor for pregnancy complications (PC) and adverse pregnancy outcomes. Biologics have been shown to decrease inflammation among IBD patients however its implications on pregnancy outcomes remain unclear. We sought to compare the prevalence of PC among individuals with or without IBD and to assess whether the risk of PC among patients with IBD is altered by biologics therapy. Methods: We used the IBM Explorys clinical database which includes over 74 million de-identified unique patients across 300 hospitals in the United States. Patient were identified using SNOMED and ICD codes. We included female patients in childbearing age between 18 – 50 years, with history of pregnancy and diagnosis of either Crohn’s disease (CD) or ulcerative colitis (UC). We investigated the prevalence of PC in IBD patients compared to patients with no IBD. PC included pre-eclampsia, pre-term labor and miscarriages. Also, we compared the prevalence of PC in IBD patients who received biologics therapy against other treatment modalities. Odds ratios with 95% confidence intervals were calculated to evaluate the risk of pregnancy complications. Results: Among our cohort of women with history of pregnancy, we identified 23,830 patients with CD and 19,220 patients with UC, of whom 6,550 (27.5%) and 5,520 (28.7%) developed PC, respectively compared to 18.8% in women without IBD, p< 0.0001 to all. Both CD [OR: 1.64; 95% CI: 1.59 – 1.69] and UC [OR: 1.74; 95%CI: 1.69 – 1.80] patients had a significant higher risk of PC compared to patients without IBD. 2,870 (12.0%) patients with CD and 1,520 (7.9%) patients with UC received biologics therapy. Sub-group analysis of the biologics-treated cohort was associated with a significantly lower risk of developing PC in CD [OR: 0.87; 95%CI: 0.79 – 0.95] and UC [OR: 0.81; 95%CI: 0.72 – 0.92], respectively (Figure). Conclusion: In this large retrospective study, we found that the prevalence of pregnancy complications in women with IBD was significantly higher than the general population. Furthermore, we found that IBD patients treated with biologics were significantly less likely to be associated with pregnancy complications. Further studies are required to determine whether biologics therapy may mitigate pregnancy complications risk.Figure 1.: Logistic Regression of pregnancy complications risk in IBD, IBD; inflammatory bowel disease. Immunomodulators included azathioprine, methotrexate and mercaptopurine. Other biologics included natalizumab, ustekinumab and vedolizumab. TNF-a Blockers; tumor necrosis factor-alpha blocker. Table 1. - Demographics of patients with IBD and PC Variable Patients with Pregnancy Complications No Pregnancy ComplicationsN=2,413,580 (%) With IBDN=8,210 (%) Without IBDN=552,000 (%) Age >35 4960 (60.4%) 333,810 (60.5%) 1,322,060 (54.8%) Caucasian 6,460 (78.7%) 337,470 (61.1%) 1,386,960 (57.5%) Smoker 2,180 (26.6%) 72,990 (13.2%) 222,460 (9.2%) Alcohol Abuse 230 (2.8%) 12630 (2.3%) 35,300 (1.5%) T2DM 610 (7.4%) 32,660 (5.9%) 82,280 (3.4%) Hyperlipidemia 1,680 (20.5%) 43,590 (7.9%) 125,010 (5.2%) HTN 280 (3.4%) 13,460 (2.4%) 28,800 (1.2%) CAD 580 (7.1%) 3,870 (0.7%) 13,860 (0.6%) Obesity 4,750 (57.9%) 127,470 (23.1%) 355,890 (14.7%) Intestinal Resection 880 (10.7%) 7,410 (1.3%) 24,130 (1.0%) Colectomy 540 (6.6%) 6,170 (1.1%) 20,350 (0.8%) Pre-eclampsia 1,570 (19.1%) 113,220 (20.5%) NA Pre-term Labor 2,910 (35.4%) 116,860 (21.2%) NA Miscarriage 4,930 (60.0%) 365,420 (66.2%) NA IBD; inflammatory bowel disease, PC; pregnancy complications, T2DM; type 2 diabetes mellitus; HTN; hypertension, CAD; coronary artery disease.

S964 Impact of Biologics Therapy on the Prevalence of Erectile Dysfunction Among Patients With Inflammatory Bowel Disease: A Nationwide Population-Based Study

Introduction: Erectile dysfunction (ED) is a well-established comorbidity of Inflammatory bowel disease (IBD). However, the connection between the two diseases remains unclear. Previous studies have suggested that chronic inflammation resulting in endothelial dysfunction maybe a contributing factor in the pathology of ED. Biologics have been shown to decrease inflammation among IBD patients. Therefore, we sought to investigate the prevalence of ED among individuals with IBD in a large national claims database and assess if biologics therapy may affect the risk of ED in patients with IBD. Methods: We used the IBM Explorys clinical database which includes over 74 million de-identified unique patients across 300 hospitals in the United States. Patients were identified using SNOMED and ICD codes. We identified all male patients (age >18 years) who were diagnosed with either Crohn’s disease (CD) or ulcerative colitis (UC). We investigated the prevalence of ED in IBD patients compared to patients with no IBD. Also, we compared the prevalence of ED between IBD patients with and without biologics therapy. Odds ratios with 95% confidence intervals were calculated to evaluate the risk of ED. Results: In this male-only cohort, we identified 100,020 patients with CD and 86,340 patients with UC, of whom 7,060 (7.06%) and 7,430 (8.61%) developed ED, respectively compared to 2.89% in individuals without IBD, p< 0.0001 to all. Both CD [OR: 2.54; 95% CI: 2.48-2.61] and UC [OR: 3.16; 95%CI: 3.08-3.23] patients had a significant higher risk of ED compared to patients without IBD. 20,040 (20.0%) patients with CD and 10,980 (12.7%) patients with UC received biologics therapy. The biologics-treated cohort was not significantly associated with a lower risk of developing ED in both CD [OR: 1.02; 95%CI: 0.96-1.09] and UC [OR: 0.99; 95%CI: 0.92-1.07], respectively (Figure). Conclusion: In this large retrospective study, we found that the prevalence of ED in patients with IBD was significantly higher than the general population. Overall, treatment with biologics was not associated with a significant decline in ED among IBD patients. These findings suggest that ED among patients with IBD may be driven by a different pathology besides chronic inflammation. Further studies are needed to determine the etiology behind ED among IBD patients.Figure 1.: Logistic Regression of Erectile Dysfunction Risk in IBD, IBD; inflammatory bowel disease. Immunomodulators included Azathioprine, Methotrexate and Mercaptopurine. Other biologics included Natalizumab, Ustekinumab and Vedolizumab. TNF-a Blockers; tumor necrosis factor-alpha blocker. Table 1. - Demographics of patients with IBD and ED Variable Patients with ED With IBD Without IBD No ED N 12,780 % 903,480 % 30532290 % Age 18 - 64 5,760 45.1% 434,850 48.1% 21,038,710 68.9% Age >65 7,070 55.3% 472,220 52.3% 9,126,770 29.9% Caucasian 10,640 83.3% 663,680 73.5% 16,599,190 54.4% Smoker 2,810 22.0% 151,670 16.8% 1,791,870 5.9% Alcohol abuse 980 7.7% 52,640 5.8% 674,360 2.2% T2DM 4,150 32.5% 270,010 29.9% 2,627,640 8.6% Hyperlipidemia 9,350 73.2% 639,150 70.7% 5,077,870 16.6% HTN 4,330 33.9% 255,660 28.3% 1,366,290 4.5% CAD 3,780 29.6% 196,350 21.7% 2,027,450 6.6% Depressive disorder 4,590 35.9% 213,260 23.6% 2,010,190 6.6% Colectomy 3,190 25.0% 89,640 9.9% 488,020 1.6% Small intestinal repair/resection 1,880 14.7% 16,560 1.8% 473,250 1.6% PDE5 inhibitor use 4,620 36.2% 337,800 37.4% 342,420 1.1% IBD; inflammatory bowel disease, ED; erectile dysfunction, T2DM; type 2 diabetes mellitus, HTN; essential hypertension, CAD; coronary artery disease, PDE5; phosphodiesterase type 5 inhibitor.

S809 Impact of Biologics Therapy on the Prevalence of Parkinson’s Disease Among Patients With Inflammatory Bowel Disease: A Nationwide Population-Based Study

Introduction: Inflammatory bowel disease (IBD) and Parkinson’s disease (PD) are chronic progressive disorders that mainly affect different organs: the gut and brain, respectively. Increasing evidence supports reciprocal communication between the enteric and the central nervous system in disease, termed the 'gut-brain axis'. Biologics have been shown to decrease inflammation among IBD patients however the long-term neurological implications remain unclear. We sought to compare the prevalence of PD among individuals with or without IBD and to assess whether PD risk among patients with IBD is altered by biologics therapy. Methods: We used the IBM Explorys clinical database which includes over 74 million de-identified unique patients across 300 hospitals in the United States. Patient were identified using SNOMED and ICD codes. We identified all patients (age >18 years) who were diagnosed with either Crohn’s disease (CD) or ulcerative colitis (UC). We investigated the prevalence of PD in IBD patients compared to patients with no IBD. Also, we compared the prevalence of PD between IBD patients with and without anti-TNF therapy. Odds ratios with 95% confidence intervals were calculated to evaluate the risk of PD. Results: We identified 249,480 patients with CD and 209,030 patients with UC, of whom 7,180 (2.88%) and 2,700 (1.29%) developed PD, respectively compared to 0.37% in individuals without IBD, (Table) p< 0.0001 to all. Both CD [OR: 7.91; 95% CI: 7.73-8.10] and UC [OR: 3.44; 95%CI: 3.31-3.57] patients had a significantly higher risk of PD compared to patients without IBD. 45,030 (18.0%) patients with CD and 23,110 (11.1%) patients with UC received biologics therapy. Sub-group analysis of the biologics-treated cohort was associated with a significantly lower risk of developing PD in CD [OR: 0.13; 95%CI: 0.11-0.13] and UC [OR: 0.40; 95%CI: 0.34-0.49], respectively (Figure). Conclusion: In this large retrospective study, we found that the prevalence of PD in patients with IBD was significantly higher than the general population. Furthermore, we found that IBD patients treated with biologics were significantly less likely to be diagnosed with PD. These findings may support a role of systemic inflammation in the pathogenesis of both diseases. Further studies are required to determine whether biologics therapy may mitigate PD risk.Figure 1.: Logistic Regression of Parkinson’s disease Risk in IBD, IBD; inflammatory bowel disease. Immunomodulators included Azathioprine, Methotrexate and Mercaptopurine. Other biologics included Natalizumab, Ustekinumab and Vedolizumab. TNF-a Blockers; tumor necrosis factor-alpha blocker. Table 1. - Demographics of patients with IBD and PD Variable Patients with PD No PD With IBD Without IBD N 9050 259900 70129700 18-65 3310 (36.6%) 26610 (10.2%) 47,919,160 (68.3%) >65 5600 (61.9%) 226030 (87.0%) 21,034,720 (30.0%) Female 5210 (57.6%) 112100 (43.1%) 38,353,970 (54.7%) Caucasian 7710 (85.2%) 200420 (77.1%) 37,649,020 (53.7%) T2DM 3160 (34.9%) 74510 (28.7%) 5,575,570 (8.0%) Primary HTN 6200 (68.5%) 174330 (67.1%) 14,014,310 (20.0%) Hyperlipidemia 7700 (85.1%) 144590 (55.6%) 11,635,480 (16.6%) Obesity 2700 (29.8%) 36170 (13.9%) 5,404,010 (7.7%) Tobacco Abuse 3710 (41.0%) 22280 (8.6%) 3,789,760 (5.4%) Cannabis Abuse 280 (3.1%) 1540 (0.6%) 528,780 (0.75%) Alcohol Abuse 670 (7.4%) 6530 (2.5%) 1,083,540 (1.55%) Carbidopa-levodopa 2030 (22.4%) 130470 (50.2%) NA Dopamine agonists 2470 (27.3%) 145230 (55.9%) NA MAO-B inhibitors 310 (3.4%) 22630 (8.7%) NA IBD; inflammatory bowel disease, PD; Parkinson’s disease, T2DM; type 2 diabetes mellitus; HTN; hypertension, MAO-B inhibitors; mono-amine oxidase B inhibitors.

P647 Idiopathic Thrombocytopenic Purpura associated with Inflammatory Bowel Disease: a multi-centre ECCO CONFER case series

Abstract Background Idiopathic Thrombocytopenic Purpura (ITP) is an acquired haematological disorder with an incidence of 1 to 6 per 100.000, with reported comorbidity in patients with Inflammatory Bowel Disease (IBD). The current study aimed to evaluate the clinical presentation and outcome of ITP in IBD patients. Methods This multicenter retrospective case series was performed as part of the ECCO Collaborative Network of Exceptionally Rare case reports (CONFER) project. Cases of patients with ITP and IBD were collected by participating investigators. Clinical data were recorded in a standardised collection form. Results This report includes 20 patients with concurrent ITP and IBD: 15 were males, median age was 34 [Interquartile range (IQR) 25–56]. 12 subjects had a diagnosis of ulcerative colitis and 8 of Crohn’s disease. The diagnosis of IBD preceded the ITP diagnosis in 17 patients (median time between diagnosis was 7 years [IQR 1–14 years]). Among those, 10 patients were in IBD clinical remission at ITP diagnosis. Nine were treated with mesalamine, one with thiopurine, 4 with tumor necrosis factor-alpha (TNF) blockers, and 3 with no treatment. The mean platelet count at the presentation of ITP was 41.7±38.6 ×109/L. 6 patients had rectal bleeding, 8 had purpura, 6 had mucosal petechia, 2 had epistaxis, and 6 patients were asymptomatic. Regarding ITP treatment, 11 were treated with corticosteroids, 1 with Anti-RhD immunoglobulin, 7 with intravenous immunoglobulins (IVIG), 2 with rituximab and 2 patients eventually required splenectomy. All patients whose first presentation of ITP was rectal bleeding were treated medically with successful control of the ITP and IBD, None of them required splenectomy. 3 patients required colectomy with long-term follow-up, indicated by the IBD and not due to massive bleeding as a complication of ITP. With long-term follow-up, all patients had thrombocytes count above 50 ×109/L, and 18 were in IBD clinical remission. Conclusion Most ITP cases in this case series occurred after the IBD diagnosis and responded well to regular ITP treatment. The course of the ITP in the IBD patients follows a regular course, including response to medical therapy and low rates of splenectomy.

Delayed treatment with a tumor necrosis factor alpha blocker associated with worse outcomes in patients with spondyloarthritis: data from the Czech National Registry ATTRA.

Introduction:The administration of biologic disease-modifying antirheumatic drugs, including tumor necrosis factor (TNF)-α inhibitors, is observed to interfere with the disease activity and progression. In this study, we aimed to assess the effectiveness and response predictors of adalimumab (ADA), a TNF-α blocker, in patients with axial spondyloarthritis (AxSpA).Methods:This study was a historical prospective, registry-based observational study on patients with AxSpA treated with first-line ADA after conventional drug failure. For evaluation and comparison, patients were divided into three groups according to the number of years from AxSpA diagnosis to initiation of ADA treatment: (A) <5 years, (B) 5–10 years, and (C) >10 years. The assessment instruments ankylosing spondylitis disease activity score (ASDAS), Bath ankylosing spondylitis activity index (BASDAI), Bath ankylosing spondylitis functional index (BASFI), health assessment questionnaire (HAQ), Short Form 36 questionnaire (SF-36), and EuroQoL 5 dimension questionnaire (EQ-5D) were regularly administered for up to 24 months of follow-up.Results:This study included 1043 patients with AxSpA (9.2% with non-radiographic AxSpA, 68.9% men). By month 6, a significantly higher proportion of patients with ASDAS remission (<1.3) was achieved upon earlier intervention in group A (30.1%) and B (32.9%) than in the late intervention group C (22.6%) (p ⩽ 0.05). At month 6, lower age and better BASFI at treatment initiation were identified as the strongest predictors of ASDAS remission in both univariable [odds ratio (OR): 0.956, p ⩽ 0.001; OR: 0.834, p ⩽ 0.001, respectively] and multivariable analyses (OR: 0.963, p ⩽ 0.001; OR: 0.859, p ⩽ 0.001, respectively). Earlier intervention also led to improvement in most patient-reported outcomes (PROs) based on HAQ, SF-36, and EQ-5D.Conclusion:Results from the ATTRA registry concur with previous clinical trials that supported efficacy of TNF-α blockers and showed better treatment outcomes with early interventions, including reduction of disease activity and improvement in PROs. We identified age and BASFI as the main factors influencing treatment effectiveness.

Tumor Necrosis Factor Alpha Blockade and Multiple Sclerosis: Exploring New Avenues.

Multiple sclerosis (MS) is the most common disabling disease of the central nervous system (CNS) with a progressive neurodegenerative pattern. It is characterized by demyelination of white matter in CNS and apoptosis of oligodendrocytes. Tumor necrosis factor (TNF) alpha is a major cytokine in the pathogenesis of MS. However, the failure of TNF alpha inhibitors in preclinical and clinical trials disapproved of their use in MS patients. Nevertheless, failures and misses sometimes open avenues for new hits. In the later years, it was discovered that TNF signaling is mediated via two different receptors, TNFR1 and TNFR2, both of which have paradoxical effects. TNFR1 mediates demyelination and apoptosis, while TNFR2 promotes remyelination and neuroprotection. This explained the cause of the failure of non-selective TNF alpha-blockers in MS. It also enlightened researchers that repurposing the previously formulated non-selective TNF alpha-blockers using a receptor-selective approach could lead to discovering novel biologic agents with a broader spectrum of indications and better safety profiles. This review focuses on a novel premier TNFR1 blocker, atrosab, which has been tested in animal models of MS, experimental autoimmune encephalomyelitis (EAE), where it demonstrated a reduction in symptom severity. The early promise shown by atrosab in preclinical studies has given us hope to find another revolutionary drug for MS in the future. Clinical trials, which will finally decide whether this drug can be used as a better therapeutic agent for MS or not, are still going on, but currently, there is no approved evidence regarding efficacy of these agents in treating MS.

High Body Mass Index is Associated with Shorter Retention of Tumor Necrosis Factor-Alpha Blocker Treatment in Rheumatoid Arthritis.

PurposeTo evaluate the association between body mass index (BMI) and tumor necrosis factor α (TNF-α) blockers retention in patients with rheumatoid arthritis (RA).Patients and MethodsThis prospective cohort study analyzed data about patients with RA who initiated TNF blockers from the Israeli registry of inflammatory diseases from 2011 to 2019. Patients were grouped by BMI: normal (BMI <24.9 kg/m2), overweight (BMI 25–29.9 kg/m2), obese (BMI 30–34.9 kg/m2) and morbid obese (BMI ≥35 kg/m2). Treatment cessation due to inefficacy was defined as an “event” and therapy with a drug above 3 months was defined as a “course.” Kaplan–Meier survival curve was used to describe drug survival. Event-free survival was calculated using Cox regression with a hazard ratio and confidence interval of 95%.ResultsThe final analysis included 521 RA patients (80% females) treated with etanercept, infliximab, adalimumab or golimumab. Eight hundred and eighteen treatment initiations were included in the final analysis, 334 (41%) in the normal weight group, 261 (32%) in the overweight, 144 (17%) in the obese and 79 (10%) in the morbid obesity group. Three hundred and twenty-six (40%) treatment initiations were with etanercept, 215 (26%) with adalimumab 197 (24%) with infliximab, and 80 (10%) with golimumab. BMI was inversely associated with drug survival. Morbid obese patients were more likely to discontinue treatment compared with normal weight patients HR 2.28 (95% CI 1.67–3.10, p<0.01). This association remained significant for each drug type (except for golimumab) in a subgroup analysis. Adalimumab switch rate was higher compared to etanercept with HR =1.51 (95% CI 1.20–1.91, p<0.01), no other significant differences were noted between the other drugs.ConclusionMorbid obese RA patients have lower TNF-α blocker retention compared to normal weight patients.

Effects of alpha-lipoic acid treatment on serum progranulin levels and inflammatory markers in diabetic neuropathy.

ObjectivesProgranulin (PGRN) is a secreted growth factor that helps to regulate neuronal survival by blocking tumor necrosis factor-alpha (TNFα) receptors. The antioxidant alpha-lipoic acid (ALA) is used in diabetic neuropathy to improve nerve conduction and relieve neuropathic pain, but its effects on PGRN levels have not yet been elucidated.MethodsIn this prospective study, 54 patients with type 2 diabetes and peripheral neuropathy received 600 mg of ALA daily for 6 months. Twenty-four patients with diabetes without neuropathy were also included in the study. Serum PGRN and TNFα levels were determined using enzyme-linked immunosorbent assays. In addition, current perception threshold (CPT) testing was used to assess sensory neuropathy.ResultsAfter ALA treatment, serum PGRN levels were significantly increased and CPT values were significantly improved. Furthermore, there were significant positive correlations among TNFα, ICAM-1, and PGRN levels both before and after ALA treatment. A significant negative correlation was observed between the improvements in CPT and the PGRN levels. Furthermore, ICAM-1 levels were an independent predictor of PGRN levels.ConclusionsChanges in serum PGRN levels indicate that ALA treatment may have beneficial effects on endothelial function and neuronal inflammation.

Defining the disease course of TNFα blockers-associated Multiple Sclerosis

Tumour Necrosis Factor alpha (TNFα) blockers are common and effective treatments for several autoimmune diseases but can be associated with neuroinflammatory events. We describe the disease course of ten patients who developed CNS demyelinating events while exposed to TNFα blockers. We divided them into two groups: eight patients with Relapsing Multiple Sclerosis and two isolated optic neuritis. In our cohort, TNFα blockers-associated Multiple Sclerosis does not seem to be associated with a more aggressive course and can be managed with MS-specific DMTs, chosen considering the clinical course and the concomitant autoimmune disease. Our findings need confirmation in larger cohorts to further characterize the disease course of TNFα blockers-associated Multiple Sclerosis.

Резистентность Helicobacter pylori к кларитромицину в Российской Федерации

On specific examples the article demonstrates the clinical efficacy of ustekinumab in severe ulcerative colitis after failure of therapy with tumor necrosis factor alpha blockers, Janus kinase blockers, and alpha-4-beta-7-integrin inhibitors.