Use Of Immunomodulators Research Articles

P257 The clinical decision support tool has low performance in predicting outcome to ustekinumab in Crohn’s disease

Abstract Background Several biologicals and small molecules have been added to the therapeutic arsenal of inflammatory bowel disease, which generated a wide interest in precision medicine. In this context, both clinical features and laboratory tests have shown some correlation with therapy outcome. Recently, an online clinical decision support tool1 (CDST) was built, using clinical and biochemical variables (e.g. disease location, prior anti-TNF exposure), to help physicians predict the outcome of various biological treatments in Crohn’s disease (CD). We sought to evaluate the predictive performance of this tool in patients with CD initiating ustekinumab (UST). Methods Baseline data were collected from consecutive CD patients who started UST IV induction followed by eight weekly UST 90 mg SC maintenance from December 2015 through March 2021 at our referral center. The probability of achieving clinical remission (low, intermediate, or high) was determined using the online CDST using patients’ data. Also, differences in rates of primary non-response and ustekinumab persistence were compared between CDST classifications. Primary non-response was defined as failing to attain endoscopic response (≥50% decrease in SES-CD) nor clinical response (a drop in the physician global assessment score or patients reported outcome), both assessed at month 6 after UST initiation. Finally, we studied the relation between the individual components used to construct the CDST and the three classifications in a univariate analysis. Results A total of 291 CD patients started UST, of whom 237 had objectively-assessed (CRP, fCal, symptoms or endoscopy) baseline disease activity. Using the CDST, the proportion of patients with “low”, “intermediate” or “high” probability to attain clinical remission were 11.8 % (n=28), 55.7 % (n=132) and 32.5 % (n=77), respectively. The CDST could not discriminate patients with primary non-response (p value = 0.18; Figure 1), nor identify trends in drug persistence (p value = 0.44; Figure 2). In the univariate analysis, 3 out of 9 components (active fistulizing disease, disease location and concomitant immunomodulatory use) were not significantly contributing to the CDST classification (Table 1). Conclusion The recently developed clinical decision support tool showed low performance in predicting short-term (primary clinical and endoscopic response) and long-term (drug persistence) real-life outcomes in CD patients starting UST. These findings underscore the necessity of incorporating molecular variables, in addition to clinical ones, to construct reliable and reproducible tools to predict therapeutic outcomes. 1. https://via.juxlyapps.com/pathway/archemedx/ibd-cdst/index.html#/disease-selection

P296 vedolizumab Does Not Increase Risk of Clostridium Difficile Infection in Patients with Inflammatory Bowel Disease Using vedolizumab: a Retrospective Cohort Study

Abstract Background Several studies have demonstrated that there is increased incidence, recurrence, and severity of Clostridium difficile (CDI) infection over the last decade. Patients with inflammatory bowel disease (IBD) who develop CDI are more prone to morbidity and mortality than CDI in patients without IBD. This study seeks to evaluate whether IBD patients who use vedolizumab are at increased risk of CDI compared to IBD patients using other therapies. Methods This was a retrospective cohort study, and 684 patients with confirmed IBD (228 on vedolizumab, 228 on anti-TNF, and 228 on 5-ASA therapy) were enrolled from January 2015 to August 2019 at a tertiary referral IBD center at McMaster University Medical Centre (MUMC) in Hamilton, Ontario, Canada. The primary outcome was time to the development of CDI in IBD patients using the three different classes of therapy. Secondary outcomes included rates of CDI and the association between baseline variables and risk of CDI. A Cox proportional hazards (PH) model was used to evaluate baseline factors and development of CDI. Results There was no difference in time to CDI between the three treatment groups (log rank p-value 0.37). No difference was seen in the number of patients with CDI; CDI occurred in 16 patients (2.3%), specifically four patients (1.75%) in the vedolizumab group, four patients (1.75%) in the anti-TNF group, and eight patients (3.5%) in the 5-ASA group (p=0.36). The Cox PH model revealed current smoking, older age, and concomitant immunomodulator use as risk factors for CDI, after adjustment for other covariates. Vedolizumab was not associated with increased risk of CDI in the model. Conclusion Biologic therapy with vedolizumab or anti-TNF did not impact risk of CDI. Risk factors for CDI in IBD patients included smoking, older age at the onset of medication, and immunomodulator therapy. Clinicians should have a high degree of suspicion for CDI in IBD patients presenting with diarrhea, particularly in those with risk factors identified in this study.

P203 The performance of the Rutgeerts’ score, SES-CD, and MM-SES-CD for prediction of post-operative clinical recurrence in Crohn’s disease

Abstract Background Prevention of post-operative recurrence in Crohn’s disease (CD) is important to avoid further complications requiring additional surgeries. The Rutgeerts’s score is currently the gold standard assessment in clinical trials of post-operative CD. However, the Simplified Endoscopic Score for CD (SES-CD) has not been validated or used clinically in post-operative CD patients. The Modified Multiplier of the SES-CD (MM-SES-CD) is a novel internally validated tool that was developed to account for differences in items of the SES-CD and has not yet been validated in the setting of post-operative CD. The purpose of this study was to compare the SES-CD and MM-SES-CD scores with the Rutgeerts’ score for predicting clinical recurrence (CR) of post-operative CD. Methods This was a post-hoc analysis of data from the phase 3 PREVENT trial (ClinicalTrials.gov identifier: NCT01190839) of 208 participants who received infliximab or placebo. Receiver operating characteristic curve analyses to compare the Rutgeerts’, ileum SES-CD, and ileum MM-SES-CD scores at week 76 with CR at week 104. Multivariate logistic regression models evaluated cut-offs for the odds of achieving week 104 CR, after adjustment for confounders, including treatment allocation, disease duration, prior anti-TNF use, and concomitant immunomodulator use. CR was defined as CDAI score ≥200 and ≥70 point increase from baseline (or development of fistulas, abscesses, or treatment failure) and endoscopic recurrence, defined as Rutgeerts’ score ≥i2. Results The Rutgeerts’ score predicted week 104 CR at with fair accuracy [AUC: 0.74 (95% CI: 0.65–0.83)], which was similar to the SES-CD ileum score [AUC: 0.72 (95% CI: 0.64–0.80)] and the MM-SES-CD ileum score [AUC: 0.72 (95% CI: 0.63–0.80)]. Compared to various cut-offs by the other scores, the MM-SES-CD ileum score ≥26 at week 76 had the best ability to predict week 104 CR. Patients with a week 76 MM-SES-CD ileum score ≥26 were 4.17 times (95% CI: 1.90–9.12, p <0.001) more likely to have CR compared to those with a MM-SES-CD ileum score <26. Conclusion The ileal SES-CD and ileal MM-SES-CD perform similarly to the Rutgeerts’ score for predicting CR of post-operative CD. The MM-SES-CD threshold of ≥26 best predicted post-operative CR. Clinicians and trialists should consider the use of the MM-SES-CD in the assessment of post-operative CD given its performance and ability to capture colonic disease recurrence.

P196 Pre-treatment antibodies to infliximab and adalimumab are common but are not associated with anti-TNF treatment failure

Abstract Background Anti-TNF treatment failure is common. Primary non-response and loss of response are frequently caused by low anti-TNF drug levels mediated, principally, by the formation of anti-drug antibodies which can be mitigated by concomitant immunomodulator use. Previous small studies in patients with IBD suggest that antibodies formed prior to treatment can bind drug and impair the pharmacokinetics, efficacy and safety of the anti-TNF drugs. We sought to determine the prevalence, neutralising capacity and clinical relevance of pre-treatment antibodies to infliximab and adalimumab in in anti-TNF-naïve patients with active luminal Crohn’s disease. Methods The Personalised Anti-TNF Therapy in Crohn’s Disease study (PANTS) is a UK-wide, multicentre, prospective observational cohort reporting treatment failure rates of the anti-TNF drugs infliximab and adalimumab in Crohn’s disease. The prevalence of antibodies to infliximab and adalimumab at baseline in all patients were measured using IDKmonitor ELISA assays and neutralising capacity in positive cases was determined using the iLite™ cell-based assays. Associations between baseline antibody status, subsequent immunogenicity and drug levels, and response status were assessed using Mann-Whitney U tests and chi-squared analyses, respectively. Results In the PANTS cohort, at baseline, pre-treatment anti-TNF antibodies were detected in 7.3% (112/1525) patients. Pre-treatment antibodies to infliximab were more common (6.3% 96/1525 vs 2.4% 36/1525, p<0.01) and of higher levels (median (IQR) infliximab: 23.9 (14.2 – 55.2) AU/ml vs adalimumab: 7.2 (6.3 – 10.4) AU/ml, p<0.0001) than adalimumab. A minority (1.3% (20/1525)) of patients had anti-drug antibody reactivity to both drugs. None of the detected anti-drug antibodies had demonstrable anti-TNF neutralising capacity detected by our iLite™ cell-based assay. No associations were seen between baseline antibody reactivity, subsequent immunogenicity, drug levels or response status at week 14 or week 52. Conclusion Pre-treatment anti-drug antibodies are common. However, they do not neutralise anti-TNF drug activity invitro, promote drug clearance or influence clinical response to anti-TNF drugs. Further work is required to understand this cross-reactivity and to determine the exact nature of the antibodies detected in drug naïve individuals.

P212 The DUBLIN Score is a Useful Tool for Predicting Disease Course in Patients with Ulcerative Colitis

Abstract Background The DUBLIN (Degree of Ulcerative colitis Burden of Luminal Inflammation) is a novel simple clinical score of inflammation in patients with Ulcerative Colitis (UC) which can be used easily in outpatients and at the bedside. Methods We sought to validate the clinical utility of scoring UC inflammatory burden at diagnosis in predicting disease outcomes using the DUBLIN score (DS). We performed a multicentre retrospective study of patients recruited to the Genuity medicine IBD research project at three centres. DS at diagnosis was calculated based on disease extent and endoscopic severity. Study outcomes were need for immunomodulators and/or biologic therapy and need for surgery. We also examined the association between DS and FCP, albumin and C-reactive protein. Results 679 patients with confirmed UC were identified. 291 had data allowing calculation of DS at diagnosis (median age 38.9 years, 53% male). Median DS was 4 [1–9]. 122 patients were treated with biologic therapy during follow-up. Median DS at diagnosis was significantly higher in patients requiring biologic therapy compared to those not requiring biologic therapy [4 versus 3, p = < 0.001]. Of patients requiring biologic therapy patients with a DS > 3 had a significantly shorter time on 1st biologic therapy [2.1 versus 3.9 years, p = 0.005]. There was no difference in median DS dependent on immunomodulator use. Similarly median DS at diagnosis was significantly higher in patients requiring colectomy compared to those not requiring colectomy [6 versus 4, p = 0.001]. There was a weak positive correlation between both DS and faecal calprotectin [correlation coefficient 0.27, p = 0.001] and C-reactive protein [correlation coefficient 0.7, p = 0.01] and a weak negative correlation between DS and albumin level [correlation coefficient -0.22, p = 0.04]. Conclusion Our study validates the clinical utility DS is an accurate clinical tool at diagnosis and during a patients’ disease course for identifying disease burden. A higher DS correlates with an increased need for biologic therapy, need for colectomy and increased biomarkers of disease activity. This is a useful tool for day to day use in clinical practise providing personalised management of patients with UC.

P535 Association of anti-Infliximab antibodies and HLADQA1*05 variant in ulcerative colitis: a retrospective single centre study

Abstract Background The genetic variation HLADQA1*05 has been reported to be associated with anti-Infliximab antibody in CD. The relevance in UC patients receiving infliximab is uncertain. We aimed to evaluate the association of HLADQA1*05 and infliximab antibody formation, treatment changes and infliximab persistence in a real world setting of single centre cohort Methods Infliximab treated UC patients (n=94) were retrospectively screened for HLDqA1*05. The risk of anti-infliximab antibody formation, absent drug levels in presence of antibody, change in therapy from infliximab were assessed in variant carrying patients in comparison to those without the variants. The proportion of patients needing dose optimisation of infliximab also evaluated Results Anti-infliximab antibodies were detected in 41.5% of patients in a median follow up of 14.75 (IQR 9–29) months. HLA DQAI*05 was positive in 39.13% of patients. 52.2 % of patients were on concomitant immunomodulators. Higher proportion of patients with HLADQA1*05 developed anti-Infliximab antibodies (59% Vs 24%, p=0.002). Eighty percent of patients who had anti Infliximab antibodies with absent drug levels were positive for HLADQA1*05 with Hazzard Ratio (HR) for development of anti-Infliximab antibodies of 4.54 (95% CI 1.73–11.89) and for antibodies with absent infliximab drug levels 9.86 (95% CI 2.43 -40.01). Higher proportion of HLADQA1*05 patients required dose escalation (78% vs 31%, p=0.001). After adjusting for age, initial infliximab dose and concomitant immunomodulator use, there was no difference anti TNF persistence in patients with HLADQA1*05 variant (HR 2.36, 95% CI 0.89–6.25, p=0.06) Conclusion Determination of HLADQA1*05 status may identify patients at higher risk of anti-infliximab antibodies in ulcerative colitis. Early intervention with dose optimisation and concomitant immunomodulation may avoid loss of response and facilitate treatment persistence

P619 Patterns of Anti-TNF Prescribing & Therapy Outcome in a Large Multicentre Cohort of Inflammatory Bowel Disease Patients

Abstract Background Anti-TNF agents are effective therapies for Inflammatory Bowel Disease (IBD), however, a significant proportion of patients lose response over time. Real world data on prescribing practices and outcome of anti-TNF therapy are of utility to practicing clinicians Methods To evaluate Anti-TNF prescribing practice and durability of Anti-TNF response in a large multicentre IBD cohort. IBD patients commencing an anti-TNF agent, as first biologic therapy, at participating academic centres were identified from institutional databases. Baseline demographic data, concomitant medication and biologic therapy history were collected. Adalimumab(ADA) and Golimumab(GOL) were consider subcutaneous(SC) anti-TNF agents. Date of commencement and discontinuation of first and second line anti-TNF therapy was documented. Kaplan-Meier survival curves were constructed for time based analyses. P values less than 0.05 were considered significant in all analyses. Results N=991 patients with IBD were included in the study. 29%, 69% and 2% had UC, CD and IBD-U respectively; median [IQR] age 27 [19–37] years; 50% female. 31%, 63% and 4% received infliximab(IFX), ADA and GOL respectively as first-line anti-TNF therapy. 35% of patients received an immunomodulator in combination with first-line anti-TNF agent. Median [95% CI] survival free of therapy discontinuation for first and second-line anti-TNF agents was 4.6 [3.7 – 5.3] years and 3.0 [2.1 – 3.9] years respectively. Survival free of anti-TNF discontinuation was significantly shorter for IFX monotherapy group compared with IFX combination therapy, SC anti-TNF monotherapy and SC anti-TNF combination therapy groups, p=0.005. Conclusion While anti-TNF therapies are effective a significant proportion of patients discontinue therapy over time. Second line anti-TNF therapy results in a less durable response with a shorter time to drug discontinuation compared with first line anti-TNF therapy. The use of a combination immunomodulator is particularly important with infliximab therapy, however, does not influence durability of response for subcutaneous anti-TNF agents.

P395 Proactive Therapeutic Drug Monitoring May Reduce the Need for Combination Therapy in Inflammatory Bowel Disease Patients Treated with Infliximab

Abstract Background Combination therapy with an immunomodulator [IM] is recommended by ECCO guidelines for patients with moderate-to-severe inflammatory bowel disease (IBD) treated with infliximab [IFX]. Combination therapy reduce anti-drug antibody (ATI) formation. Maintenance of adequate trough IFX levels is also known to reduce ATI formation. Methods We hypothesised that the use of proactive TDM in patients receiving IFX monotherapy would result in equivalent therapy outcomes compared with patients receiving IFX in combination with an immunomodulator. A pilot study using proactive TDM was undertaken at our unit with IFX and ATI levels, assessed at trough, in all IBD patients receiving IFX. We retrospectively evaluated the outcome of proactive IFX TDM on IFX therapy outcome. Baseline demographics, IFX dosing schedules and use of concomitant immunomodulators were documented. The study primary endpoint was time to infliximab discontinuation in IFX monotherapy and combination therapy groups. Results 109 IBD patients receiving IFX with proactive TDM assessment were included. Median age, 36 years, 46% were female and, 36% UC., 37% and, 67% of patients were receiving IFX combination and monotherapy respectively. There was no significant difference in mean time to drug discontinuation between IFX combination and monotherapy groups, 2.33 [95% CI, 2.2–2.5] versus, 2.32 [95% CI, 2.0 –, 2.6] years respectively, p = 0.63. ATI concentrations [median] did not differ significantly between IFX combination and monotherapy groups, 2.9 AU/mL versus, 11.6 AU/mL, p = 0.54. In a multivariate analysis disease activity [p=0.005], low IFX levels [p=0.01] and elevated ATIs [p=0.001] were all independently associated with IFX discontinuation. There was no association between the use of IFX combination therapy and rates of IFX discontinuation, p=0.42. Conclusion Infliximab persistence, which is a proxy for successful therapy outcome, was similar in IFX monotherapy and combination therapy groups when proactive TDM was utilised. In the absence of concomitant immunomodulatory therapy, proactive TDM may improve IFX monotherapy outcomes, by maintaining higher IFX concentrations.

A Patient with Juvenile Recurrent Respiratory Papillomatosis Complicated by Laryngeal Stenosis after Laryngeal Microsurgery: A Clinical Case

BACKGROUND: The relevance of the problem of juvenile respiratory papillomatosis lies in the recurrent course of the disease in young children. This can lead to the development of respiratory stenosis, requiring repeated, in some cases, monthly surgical treatments for endolaryngeal removal of papillomas, which sometimes leads to persistent scar stenosis of the larynx. We present clinical case of achieving remission of recurrent juvenile papillomatosis of the larynx. CLINICAL CASE: Patient, 5 years old, who applied in February 2016, was hospitalized in the ENT department with severe dyspnea, laryngoscopy revealed laryngeal papillomatosis with 3–4 grade stenosis. Over the past 10 months, the patient has undergone laryngeal surgery 6 times using cold instruments and a CO2 laser due to papillomatosis. Taking into account the recurrent nature of the course of the disease, the patient is administered to consult an allergist-immunologist. Based on the anamnesis and the results of the tests, the immunologist-allergist diagnosed: Primary immunodeficiency, unspecified (insufficiency in the production of specific antibodies), persistent allergic rhinitis, in the stage of incomplete remission and prescribed treatment. The patient was operated twice from 2017 to 2018 for a developed post-operative complication – cicatricial stenosis of the larynx. With these surgical repairs, no recurrence of laryngeal papillomatosis was detected. Furthermore, in 2021, according to endovideolaryngoscopy, remission was confirmed. R In this clinical case, we managed to achieve remission of laryngeal papillomatosis in a patient after surgery and treatment by an immunologist. Allergen elimination and immunocorrection helped us achieve deep remission. Surgical treatment eliminated laryngeal stenosis, recovering breathing and voice quality. Furthermore, this clinical case demonstrates the importance of studying the immune status in patients with laryngeal papillomatosis. CONCLUSION: The results obtained by us show the need for the use of immunomodulators in these patients. All children with prolonged hoarseness should undergo laryngoscopy, which will allow diagnosing laryngeal papillomatosis at earlier uncomplicated stages of the disease. Treatment of laryngeal papillomatosis should be comprehensive and in addition to surgical treatment should include differential immune correction. RESULTS AND DISCUSSION: In the above clinical case, we managed to achieve remission of laryngeal papillomatosis in a patient after surgery and treatment by an immunologist. Allergen elimination and immunocorrection helped us achieve deep remission. Surgical treatment eliminated laryngeal stenosis, recovering breathing and voice quality. Furthermore, this clinical case demonstrates the importance of studying the immune status in patients with laryngeal papillomatosis. The results obtained by us show the need for the use of immunomodulators in these patients. All children with prolonged hoarseness should undergo laryngoscopy, which will allow diagnosing laryngeal papillomatosis at earlier uncomplicated stages of the disease. Treatment of laryngeal papillomatosis should be comprehensive and in addition to surgical treatment should include differential immune correction.

COVID-19 INFECTIONS IN VACCINATED PATIENTS WITH INFLAMMATORY BOWEL DISEASE: OUTCOMES AND RISK FACTORS FOR SEVERE DISEASE

There are limited data on coronavirus disease 2019 (COVID-19) in vaccinated patients with inflammatory bowel disease (IBD). We aimed to describe outcomes and identify risk factors for hospitalization, severe COVID-19, and death in this population. Data from the Surveillance Epidemiology of Coronavirus Under Research Exclusion in Inflammatory Bowel Disease (SECURE-IBD) database were analyzed. Patients with IBD who received at least one vaccine dose prior to diagnosis of COVID-19 were included. Patients received mRNA (Pfizer and Moderna), adenovirus vector (CanSino, AstraZeneca, Sputnik, and Janssen), or inactivated SARS-CoV-2 (Sinovac) vaccines. Partial vaccination was defined as having not received the full complement of doses for the vaccine received. Outcomes were hospitalization, death, and severe COVID-19, a composite of intensive care unit admission, mechanical ventilation, and/or death. Among 141 cases, 12 (8.5%) were hospitalized, 4 (2.8%) had severe COVID-19, and 1 (0.7%) died. During the same period, proportions in the unvaccinated were 9.3%, 1.9%, and 1.2%, respectively. Nearly three-quarters of patients with COVID-19 after vaccination were on biologics and one-third were taking immunomodulators. Fewer hospitalizations occurred in those with completed vaccine series than partially complete series (5.7% vs 13.2%, p = 0.13), and in those receiving mRNA vaccines than adenovirus vector (4.7% vs 22.7%, p = 0.01) or inactivated SARS-CoV-2 (4.7% vs 16.7%, p=0.15) vaccines. Only 2.9% of those with completed mRNA series were hospitalized. Patients on biologic monotherapy were less frequently hospitalized than patients on immunomodulator monotherapy (4.2% vs 27.3%, p=0.03) or combination therapy (4.2% vs 10.0%, p = 0.36). Overall, hospitalized patients were older (mean age 50 years vs 40 years, p = 0.03). Severe COVID-19 was less common in those receiving mRNA vaccines than adenovirus vector (0.9% vs 4.6%; p = 0.31) or inactivated SARS-CoV-2 (0.9% vs 16.7%; p = 0.02) vaccines. Of the four patients with severe COVID-19, two were taking tumor necrosis factor antagonists, three were taking azathioprine, and one had chronic lung disease. The only death was in a patient on triple immunosuppression with adalimumab, azathioprine, and systemic steroids. In patients with IBD, incomplete vaccination, non-mRNA vaccines, and immunomodulator use are associated with increased risk of adverse events during COVID-19 infections.

Chronic Granulomatous Disease With Inflammatory Bowel Disease: Clinical Presentation, Treatment, and Outcomes From the USIDNET Registry

Chronic granulomatous disease (CGD) is an inborn error of immunity caused by defects in the phagocytic nicotinamide adenine dinucleotide phosphate oxidase complex, leading to increased susceptibility to infection and inflammatory autoimmune diseases. Up to 50% of patients have gastrointestinal (GI) involvement and meet diagnostic criteria for inflammatory bowel disease (CGD-IBD). We analyzed patients with CGD from the US Immunodeficiency Network (USIDNET) registry to determine whether IBD changes the presentation, treatment, and outcomes of patients with CGD. A retrospective evaluation of CGD cases from the USIDNET registry was completed. CGD-IBD was defined as the presence of any major physician-reported inflammatory, noninfectious GI disease manifestation. Demographic information, conditions, infections, antimicrobial therapies, immunomodulator use, and hematopoietic stem cell transplantation data were analyzed. Of 194 patients with a diagnosis of CGD, 96 met criteria for IBD and 98 were categorized in the non-IBD group. Patients with CGD-IBD had an increased rate of infection compared with the non-IBD group (0.66 vs 0.36 infections/patient/year). Enteric organism infections were more common in patients with IBD. Immunomodulators were used at a significantly higher percentage in patients with IBD compared with patients without IBD (80% vs 56%, P < .001). Of the entire CGD cohort, 17 patients died (8.8%), with no significant difference between patients with IBD and patients without IBD (P= 1.00). Infectious events, enteric organism infections, and use of immunomodulatory drugs were higher in patients with IBD than patients without IBD; however, mortality was not increased. Patients with CGD and concurrent IBD are at increased risk for disease complications, supporting the importance of early recognition, diagnosis, and treatment.

Pseudopterygium in a Rabbit - Treatment with Tracolinus

Background: Pseudopterygium, also known as aberrant conjunctival growth, is poorly described in the literature, although it is known that this abnormality is uncommon and affects dwarf rabbits and their crossbreeds. The etiology of this disease is unknown, but there are hypotheses that the conjunctival growth cause may have its origins in immunological factors, inflammation, traumatic conditions, or cartilage dysplasias. Thus, this study reports the treatment efficacy applied in a rabbit, through the continuous use of tracolimus eye drops, after surgical procedure of conjunctival fold resection, as a way of controlling the pseudopterygium in rabbits.Case: This case report discusses the positive results from the surgical and therapeutic conduct of a clinical case attended by the Ophthalmology and Microsurgical Veterinary Service at the Hospital Veterinário Universitário (HVU) of the UFSM. The patient was a male rabbit, sterilized cunicle, approximately 2-year-old, crossed with a dwarf rabbit. The owner's main complaint was the change in the aspect of the left eye, with progressive worsening in the previous four weeks. In the ophthalmological examination, the animal did not present impaired vision or discomfort, however, a vascularized pink membrane was noted, which consisted of a fold of the bulbar conjunctiva, that grew centripetally and covered 90% of the cornea in 360 degrees. The diagnosis was confirmed through visual inspection and the patient's history. The eye alteration had a characteristic aspect, described as proliferation of the bulbar conjunctiva over the cornea, in a centripetal manner and without signs of inflammation. In addition, other ophthalmological alterations were ruled out during the patient's physical and specific examination. The patient was referred for anesthetic evaluation and, in addition, pre-surgical blood tests were performed, which were normal, according to the expected ranges for the species. Subsequently, the animal was submitted to surgical treatment, which consisted of dividing the exuberant conjunctiva, followed by three radial incisions in equal portions. Next, the conjunctival fold was completely incised to the edge of the limbus, without the need of sutures. Anterior lamellar keratectomy was performed on the portion where the membrane was attached to the cornea. For home care, tobramycin-based eye drops (QID, for 7 days) and 0.02% aqueous tacrolimus eye drops (BID - continuous use) were prescribed. The animal was reevaluated 7, 14, 30, 60, 120 and 180 days after surgical correction, and no recurrence of pseudopterygium was observed during the follow-up period. The prognosis of patients with pseudopterygium is reserved, as it is known that the disease may recur after surgical treatment. Therefore, the continuous use of the chosen immunomodulating eye drops was recommended as well as periodic follow-up of the patient.Discussion: In the current study, it was not possible to increase knowledge regarding about the pseudopterygium etiology. Although the condition is not serious, it can cause partial impairment of vision and chronic discomfort. However, the vision field described in the rabbit in this current case remained unchanged, in accordance with other cases described in the literature. Furthermore, no signs of patient discomfort were detected. Some surgical techniques described in the literature for correction of pseudopterygium, shows membrane’s growth recurrence. The use of immunomodulatory drugs is suggested for relapses controlling. In this study, the tracolimus eye drops efficacy was tested, and presented good results in the patient's evaluations for a long period after surgery. The use of immunomodulators is an option for adjuvant topical treatment for controlling pseudopterygium growth, which, associated with corrective surgical treatment, has shown positive results.Keywords: conjunctiva, aberrant, immunomodulator, treatment, bunny.Título: Pseudopterígio em coelho - tratamento com tracolimusDescritores: conjuntiva, aberrante, imunomodulador, tratamento, coelho.

Влияние системной энзимотерапии и иммуномодуляторов на уровень цитокинов в секретах урогенитального тракта

Objective. To evaluate cytokine levels (interleukin-1β and interferon-γ) in male and female genitourinary secretions before and after systemic enzyme therapy and immunomodulatory therapy. Patients and methods. The levels of interleukin-1β and interferon-γ in the genitourinary secretions of men and women before and after systemic enzyme therapy and immunomodulatory therapy were assessed. Patients were divided into two groups: group 1 (31 couples) received a combination of enzymes (Wobenzym) in addition to standard pregravid preparation; group 2 (32 couples) received meglumine acridonacetate (Cycloferon). Results. Initial examination of the levels of anti-inflammatory cytokines in both groups of patients showed elevated values compared with those in healthy individuals: the concentrations of interleukin-1β in men were 2.7 times higher and that of interferon-γ were by 2.9 pg/mL higher; the concentrations of interleukin-1β in women were 2.8 times higher and interferon-γ – by 3.0 pg/mL higher. After treatment with Cycloferon (by the 21st day of therapy), the levels of proinflammatory cytokines in the secretion decreased to the values of healthy individuals. Conclusion. The use of systemic enzyme therapy in the complex of pregravid preparation has no effect on the local cytokine status in patients. Additional use of immunomodulator in the cycle of pregravid preparation leads to normalization of proinflammatory cytokines in men and women, which can be used for effective pregravid preparation. Key words: infertility, immunomodulators, systemic enzyme therapy, cytokines

Mortality analysis of COVID-19 cases during the second wave and its comparison with the first wave: A hospital-based study.

This study was undertaken to determine the characteristics of COVID-19 deaths during the second wave and to compare these characteristics with the mortality during the first wave in a dedicated COVID hospital (DCH). It was a hospital record-based descriptive study. The study was conducted in a tertiary care COVID hospital, using a standard death audit proforma. The data were analyzed to know various demographic characteristics and factors related to mortality during the second wave from March to June 2021. The findings were compared with the mortality data during the first wave from April to July 2020 at the same hospital. A total of 264 deaths occurred at the center during the study period with a mortality rate of 22.8%. Male cases were more in number, the age group was 21-70 years, the highest number of mortality was seen in the mid of the study period, duration of stay was five days on average and common causes of death were pneumonia alone or with acute respiratory distress syndrome with sepsis. In comparison to the first wave, the mortality rate was four times higher, the age group was younger and opportunistic infections viz. mucormycosis and aspergillosis were present during the second wave. The mortality rate was significantly higher and the younger age groups were involved during the second wave, with opportunistic fungal infections due to the use of immunomodulators.

Risk of consecutive immunogenic failure in switchers of anti-tumor necrosis factor alpha among patients with inflammatory bowel diseases.

Background:Evidence regarding the risk of immunogenicity in patients with inflammatory bowel disease (IBD) who switched anti-tumor necrosis factor alpha (anti-TNFα) therapies to a subsequent anti-TNFα (either infliximab or adalimumab) is conflicting. We aimed to assess the risk of consecutive immunogenicity to anti-TNFα in a large cohort of patients.Methods:This was a multicenter retrospective study. Medical records of adult and pediatric IBD switchers who had pharmacokinetic data for both agents between 2014 and 2020 were retrieved. Data including age, sex, disease type, duration of therapies, and concomitant use of immunomodulators (IMMs) were recorded.Results:Overall, 164 patients were included [52% female; 88% Crohn’s disease; mean age = 24.4 ± 14.6 years; 108 (66%) switched from infliximab to adalimumab and 56 (34%) vice versa]; 120 (73.1%) patients switched due to an immunogenic failure. Among patients switching therapy from infliximab to adalimumab due to an immunogenic failure immunogenicity to infliximab was significantly associated with consecutive immunogenicity to adalimumab (p = 0.026). Forthy four out of 120 patients (36.6%) with an immunogenic failure to the first anti-TNFα started an IMM with the second anti-TNFα. This combination with IMM was not associated with reduction of consecutive immunogenicity (p = 0.31), but it was associated with longer drug retention (p = 0.007). Multivariate analysis demonstrated that older age at second anti-TNFα, adjusted to the chronology of therapy and sex, was associated with increased immunogenicity to the second anti-TNFα.Conclusion:Patients with IBD who switch from infliximab to adalimumab following an immunogenic failure are at increased risk for consecutive immunogenicity to adalimumab. IMM use after a switch prolongs drug retention.

COVID-19 Pandemic and Vitiligo: Changing Paradigms.

Dear editor, The COVID-19 pandemic has now grown to colossal proportions, affecting nearly 233 million cases, with 4.7 million deaths (WHO dashboard 1-10-2021). How vitiligo management has changed during the pandemic has not been explored.[12] A cross-sectional Google form (Google LLC) based questionnaire was developed by a group of 4 consultants of our institutional pigmentary clinic (later updated by Delphi group of 15 members) [Annexure 1] and disseminated, via email to a few national and international experts who had five or more years in managing vitiligo and had been the first or corresponding authors of articles published on the same. Totally 103 participants responded to the survey. Most worked in private clinics (35; 33.9%), followed by university hospitals (30; 29.1%), public hospitals (21; 20.4%), and corporate hospitals’ centers of excellence (17; 16.5%). All questions were answered by the participants. The approximate number of both stable (80.2 ± 26.4/month to 10.4 ± 8.6/month, P < 0.05) and unstable vitiligo cases (60.4 ± 32.8/month to 7.5 ± 7.2/month, P < 0.05) seen by study participants decreased during the lockdown [Figure 1]. A gross decrease in number of face-to-face consultations during the lockdown (74.7% to 13.5%; P < 0.05) was noted [Figure 1].Figure 1: Consultation trends by physiciansThose who presented during the pandemic phase predominantly had unstable disease and nearly 10% presented with an unstable disease for the first time during the pandemic. There was a gross reduction in the usage of almost all scoring systems [Table 1].Table 1: Use of scoring systemsThirty-five percent of respondents had been posted in care of COVID-19 patients, of them 14 (40%) agreed that these assignments had negatively impacted the care of their vitiligo patients due to unavailability and less time. A few (1.9%) of the participants had vitiligo patients who were COVID-19 positive [Table 2].Table 2: Characterization of the vitiligo patients with COVID-19 positiveThe majority of participants (65; 63.1%) felt pandemic had a negative impact on the quality of life of vitiligo patients (VITIQoL and by physician perception). Twenty participants (19.4%) advocated switch over from previous systemic treatment to topical therapies, and disfavored the use of systemic immunosuppressants, phototherapy, and immunomodulators [Table 3].Table 3: Comparison of the initiation of systemic immunosuppressants and immunomodulators during the COVID-19 lockdownFor patients affected with COVID-19, 60 (58.25%) wished to continue only oral mini pulse with dexamethasone at the same dose, whereas 70 (67.9%) felt that the dose of agents like oral cyclosporine, azathioprine, and mycophenolate mofetil should be reduced by 25%–50%. The majority (78; 75.7%) felt that phototherapy can be continued at the same dose and frequency, if feasible. There was hesitation in the initiation of systemic immunosuppressive therapy. The highest level of safety so far appears to be with low dose mini pulse of dexamethasone and with apremilast. The risk is moderate with methotrexate, and high with mycophenolate mofetil and JAK inhibitors.[2] Xu et al.[3] had found that delay in initiation of systemic immunosuppressants was the most significant risk factor for recurrence of vitiligo during the pandemic. Now even though there is a lesser number of cases, the unstable cases constitute a higher proportion. We had observed a trend of hesitancy in the initiation of immunosuppression. Steps need to be taken by the vitiligo task force to regularize the role of adequate immunosuppressive treatment, especially in patients with unstable vitiligo. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.

Subconjunctival use of allogeneic mesenchymal stem cells to treat chronic superficial keratitis in German shepherd dogs: Pilot study.

Chronic superficial keratitis (CSK) is an ocular condition in dogs characterized by corneal opacification leading to visual function impairment. Control of this chronic condition requires the use of topical immunomodulators or corticosteroids daily. Regenerative medicine has shown promising results in several fields of medicine. The aim of this study was to evaluate the clinical effect of allogeneic mesenchymal stem cells (MSCs) of adipose tissue applied via subconjunctival in dogs with CSK. A series of cases of eight dogs diagnosed with CSK were divided into two groups, four dogs each; the conventional treatment group received prednisolone 1% as topical eye drops and the experimental group (EG) received allogeneic MSCs transplantation. The dogs had not previously been treated for CSK. Systemic and ophthalmologic examinations were performed to exclude other abnormalities. An administered amount of MSC (1 × 106 cells each time) was injected via subconjunctival in the peri-limbal region at 0 and 30 days. The animals were followed for 110 days for clinical evaluation, and, at the same time, the images of the corneal abnormalities were obtained and analyzed in the ImageJ software. The statistical analysis was performed in the GrandPrism 7.0 software. Initial and final images revealed that areas with neovascularization, inflammatory infiltrate, and opacity regressed in most eyes in both groups (7/8 eyes in each group) at the end of the 110 days, p = 0.0391 and p = 0.0078 respectively, but this response was minor in the EG comparing to conventional group (CG) (p = 0.026). No local or systemic side effects were observed. Despite the small melioration, MSCs treatment suggests clinical improvement in patients with CSK after 110 days without any local or systemic side effects. However, the improvement achieved was significantly less than the observed within CG. Further studies still are needed to evaluate the use and benefits of stem cells as an adjunct treatment for CSK.

Immunomodulation as a tool to reduce antibiotic therapy in intensive poultry production

The aim of the present review is to demonstrate the possibility of limiting antibiotic therapy in intensive poultry production through the use of various immunomodulators. In an era of increasing resistance of microorganisms to antimicrobial agents, it is particularly important to improve the efficiency of the immune system, which is indispensable for birds to survive in an environment where this system is constantly exposed to a number of stimuli that directly or indirectly affect its functioning. This is all the more important as the health of birds kept under intensive systems depends mainly on the functional status of their immune system, which determines the level of postvaccination immunity and the effectiveness of treatment. That is because its proper function is needed for the elimination of pathogenic microorganisms, stimulation of repair processes in damaged tissues and protection against reinfection. This paper focuses on the possibilities of modulating immune mechanisms and correcting the reactivity of the immunological system in poultry by using natural or synthetic immunomodulators. The results presented here suggest that methisoprinol and β-glucans are effective in modulating immune processes in turkeys and may find practical application in mass rearing of these birds: β-glucans mainly in prophylactic programmes, whereas methisoprinol both in prevention and treatment of diseases of viral etiology occurring with immunosuppression. It has also been shown that phytoncides contained in well-composed complementary feeds show immunomodulatory effects in broiler chickens and turkeys and are effective in the prevention and treatment of black head disease in turkeys. Considering the key role of the immune system in fighting pathogens, it should be concluded that synthetic and natural immunomodulators, including phytoncides used in the prevention and treatment of poultry diseases, can effectively reduce and, in some cases, replace or support antibiotic therapy.

IMPROVING THE TACTICS OF TREATMENT OF OBSTRUCTIVE BRONCHITIS IN CHILDREN AGED 1 TO 3 YEARS WITH THE USE OF IMMUNOMODULATORS

Abstract: Introduction. Bronchopulmonary pathology occupies an important place in the structure of childhood morbidity. The issues of prevention, diagnosis and treatment in children with respiratory pathology are currently relevant. Obstructive bronchitis is a common condition in childhood. The significant prevalence of obstructive bronchitis among children is due to disorders in the immune system. Scientists are currently paying much attention to the study of the functioning of the immune system in children with bronchopulmonary pathology. In addition, clinicians are studying the effect of drugs on the activity of immunocompetent cells. The aggressive action of environmental factors, the pathological action of infectious pathogens can contribute to the severe course of the disease, as well as the development of complications. In this work, we studied the effect of immunomodulators on the activity of lysozyme and on the level of circulating immune complexes. Target. Study of the effectiveness of immunomodulators in the complex treatment of obstructive bronchitis in children. Material and methods. Immunomodulators were administered to 26 children aged 1 to 3 years with a diagnosis of obstructive bronchitis. The control group included 11 healthy children. Results. The data obtained reflect the effectiveness of the use of immunomodulators in the treatment of obstructive bronchitis in children. A comparative analysis of treatment with the use of immunomodulators and treatment according to the standard scheme was carried out. There were no side effects when using immunomodulators. Conclusion. Immunological data obtained during the initial examination reflect dysfunction of the immune system. Derinat and polyoxidonium help to optimize the parameters of the immune system. The data obtained in this study made it possible to recommend prescribing the immunomodulators Derinat and Polyoxidonium to children with obstructive bronchitis.

TREATMENT OF OBSTRUCTIVE BRONCHITIS IN CHILDREN AGED 3 TO 6 YEARS USING IMMUNOMODULATORS

In modern conditions, scientists pay great attention to the health of the child population. Respiratory diseases are common and do not tend to decrease. Obstructive bronchitis occupies one of the leading places in the structure of bronchopulmonary pathology in children. It is known that an unfavorable environment can provoke immunological changes in the human body. Despite the vast experience accumulated to improve the quality of treatment of this pathology in children, many questions remain unresolved, their relevance is not decreasing. This problem is increasingly attracting the attention of researchers. Disturbances in the well-coordinated work of the immune system can lead to bronchopulmonary pathology. All this must be taken into account when carrying out therapy. Currently, work is underway to study the effect of drugs on the indicators of immunity in children. It is necessary to pay great attention to improving the quality of treatment for children with obstructive bronchitis. This study includes the results of treatment of inpatient preschool children diagnosed with obstructive bronchitis. Immunological examination of children was carried out. Immunocomplex therapy was performed. Given the risk of chronicity and the development of complications, an integrated approach to the treatment of respiratory pathology in children is required. Treatment of children with bronchopulmonary pathology should be aimed at enhancing the protective properties of the body. Interventions with the immune system must be very selective. Complex therapy did not cause side effects in children. The inclusion of immunomodulators in therapy has a positive effect on the functional state of the immune system. The complex use of immunomodulators can be recommended in the treatment of obstructive bronchitis in children.