Immune-mediated Pathogenesis Research Articles

Treatment of Post-COVID-19 POTS by inhibiting FcRn: a phase 2 randomized, placebo controlled, double-blind, proof of concept study with efgartigimod

Abstract Background While the underlying pathophysiology is unknown, post–COVID-19 postural orthostatic tachycardia syndrome (POTS) may be related to immune dysfunction and autoimmunity precipitated by SARS-CoV-2 infection. Various autoantibodies, including those targeting G-protein coupled receptors (GPCRs), have been observed in patients with POTS. Binding of these autoantibodies to adrenergic receptors, which are prototypical GPCRs, has been hypothesized to modulate receptor activity, increase sympathetic tone, and cause tachycardia. Moreover, IgG anti-GPCR autoantibodies, acting as partial agonists, are thought to decrease the effect of peripheral vasomotor control, leading to an increased sympathetic response to upright posture that can result in postural tachycardia in the absence of hypotension. Purpose We hypothesize that a reduction in autoantibody levels by efgartigimod, a FcRn-antagonist, will ameliorate the underlying immune-mediated pathogenesis and lead to clinical improvements in patients who developed POTS following COVID-19 infection. We propose a phase II multicenter, randomized, placebo-controlled, double-blind, proof-of-mechanism study initiated to evaluate the safety and efficacy of efgartigimod in adults with post–COVID-19 POTS. Methods Adult patients diagnosed with new-onset of POTS following SARS-CoV-2 infection are eligible for participation in the study. Prior COVID-19 must be confirmed by documentation of historical PCR test, and POTS diagnosis must meet consensus criteria. Study subjects must have moderate to severe autonomic symptoms (COMPASS-31 score ≥ 35 points at screening). Approximately 42 patients will be randomly allocated (2:1) to receive weekly intravenous efgartigimod or placebo for 24 weeks. At the end of the treatment period, participants who complete the study may roll over into an open-label extension (OLE). The co-primary endpoints are change from baseline to week 24 in the COMPASS-31 and Malmo POTS Symptom Score as well as safety and tolerability outcomes. Key secondary endpoints include assessments of disease activity, fatigue, cognitive function, walking capacity and quantitative autonomic testing. Additional exploratory endpoints include intraepidermal small fiber densities (optional), sudomotor innervation (optional) and peripheral blood biomarkers to define histopathological and immune determinants associated with treatment response. Conclusions This phase II study of efgartigimod will evaluate the effect of FcRn inhibition on disease pathology and the potential for therapeutic benefit in patients with post–COVID-19 POTS.

Apremilast as a Potential Targeted Therapy for Metabolic Syndrome in Patients with Psoriasis: An Observational Analysis.

Psoriasis (PsO) is a chronic inflammatory dermatosis that often presents with erythematous, sharply demarcated lesions. Although psoriasis is primarily a dermatological disease, its immune-mediated pathogenesis produces systemic effects and is closely associated with various comorbid conditions such as cardiovascular disease (CVD), metabolic syndrome (MetS), and diabetes mellitus type II (DMII). Apremilast, an oral phosphodiesterase 4 (PDE-4) inhibitor, has shown promise in treating moderate-to-severe psoriasis and is associated with potential cardiometabolic benefits. In a 12-month prospective observational study involving 137 patients with moderate-to-severe psoriasis, we assessed changes in psoriasis clinimetric scores and metabolic profiles from baseline (T0) to 52 weeks (T1) to evaluate the efficacy of apremilast. After 52 weeks of apremilast treatment, we documented a statistically significant decrease in low-density lipoprotein (LDL) and total cholesterol, triglycerides, and glucose levels. Our findings even suggest a potential synergistic effect among patients treated with apremilast, alongside concomitant statin and/or insulin therapy. Although the results of our study must be validated on a larger scale, the use of apremilast in the treatment of psoriatic patients with cardio-metabolic comorbidities yields promising results.

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.

Esophageal viral and bacterial microbiome unbalances characterize achalasia

Achalasia is a rare neuromuscular disorder of the esophagus whose pathogenesis is poorly understood. It is characterized by the loss of nerve cells in the esophagus, failure of the lower esophageal sphincter to relax, and impaired esophageal peristalsis. In this study, we re-analyzed transcriptomics data from blood and esophageal tissue samples of achalasia patients publicly available. Blood analysis showed hyperactivation of the immune system and dysfunction of the nervous system, consistent with the hypothesis of immune-mediated pathogenesis leading to neuronal loss. Mucosal tissue analysis e showed a remarkable unbalance in virome and bacteriome compositions in achalasia. In particular, bacterial diversity was reduced across the esophagus in achalasia compared to healthy controls, and in the distal esophagus bacteria associated with the healthy state, such as Firmicutes, Tenericutes, and Bacteroidetes, were less represented if not completely absent. Importantly, the only other component of the microbiota that varied significantly between achalasia and controls was the virome. Bacteriophages that parasite Firmicutes were strongly enriched in the esophagus supporting a predator-prey interaction. In conclusion, our study opens new horizons on a circulating signature of achalasia and the role of viral-bacterial interactions in orchestrating mucosal homeostasis and possibly disease pathogenesis. Key summaryAchalasia is a rare swallowing disorder with unknown causes. The role of gut microbiota, especially viruses, in achalasia is unclear. This study investigated the differences in viral and bacterial communities between achalasia patients and healthy people, and how they affect the esophageal mucosa. The findings may help develop new diagnostic tools and therapies based on novel hypotheses about the pathogenesis of achalasia.

Inflammation, Autoimmunity, and Infection in Fibromyalgia: A Narrative Review.

Fibromyalgia (FM) is a chronic disease characterized by widespread musculoskeletal pain of unknown etiology. The condition is commonly associated with other symptoms, including fatigue, sleep disturbances, cognitive impairment, and depression. For this reason, FM is also referred to as FM syndrome. The nature of the pain is defined as nociplastic according to the latest international classification and is characterized by altered nervous sensitization both centrally and peripherally. Psychosocial conditions have traditionally been considered critical in the genesis of FM. However, recent studies in animal models and humans have provided new evidence in favor of an inflammatory and/or autoimmune pathogenesis. In support of this hypothesis are epidemiological data of an increased female prevalence, similar to that of autoimmune diseases, and the frequent association with immune-mediated inflammatory disorders. In addition, the observation of an increased incidence of this condition during long COVID revived the hypothesis of an infectious pathogenesis. This narrative review will, therefore, discuss the evidence supporting the immune-mediated pathogenesis of FM in light of the most current data available in the literature.

Assessment of TNF-α (-857 C/T) gene polymorphism in oral lichen planus disease: A case-control study.

Oral lichen planus (OLP) is an inflammatory mucocutaneous disorder with an immune-mediated pathogenesis. The tumor necrosis factor-α (TNF-α) level in the serum of OLP patients is significantly higher than in the control group. TNF-α-857 C/T polymorphism can be related to the increased TNF-α level in blood circulation. This study investigated the relationship between TNF-α (-857 C/T) polymorphism and OLP patients in an Iranian population. Saliva samples were taken from 200 people, including 100 patients with OLP and 100 healthy people who did not have significant differences in age and sex. Then, DNA was extracted from them and the TNF-α (-857 C/T) genotype was identified using the polymerase chain reaction with confronting two-pair primers method. Statistical Package for the Social Sciences version 16 software analyzed the results. The frequency of C/C, C/T, and T/T genotypes of the TNF-α-857 C/T polymorphism in the patient group were 78%, 18%, and 4%, respectively, and in the control group were 72%, 23%, and 5%, respectively. The differences between the two groups regarding allele (χ 2 = 0.97, p = 0.32) and genotype (χ 2 = 0.96, p = 0.62) frequency among the studied population were insignificant. This study showed that the difference in the frequency ofsingle nucleotide polymorphism TNF-α-857 C/T polymorphism in the patient and control group had no significant relationship with the increased OLP incidence. Also, no significant association was observed between allele and genotype frequency of TNF-α (-857 C/T) with OLP subtypes.

Immune pathogenesis of idiopathic granulomatous mastitis: from etiology toward therapeutic approaches.

Idiopathic granulomatous mastitis (IGM) is a noncancerous, chronic inflammatory disorder of breast with unknown causes, posing significant challenges to the quality of life due to its high refractoriness and local aggressiveness. The typical symptoms of this disease involve skin redness, a firm and tender breast mass and mastalgia; others may include swelling, fistula, abscess (often without fever), nipple retraction, and peau d'orange appearance. IGM often mimics breast abscesses or malignancies, particularly inflammatory breast cancer, and is characterized by absent standardized treatment options, inconsistent patient response and unknown mechanism. Definite diagnosis of this disease relies on core needle biopsy and histopathological examination. The prevailing etiological theory suggests that IGM is an autoimmune disease, as some patients respond well to steroid treatment. Additionally, the presence of concurrent erythema nodosum or other autoimmune conditions supports the autoimmune nature of the disease. Based on current knowledge, this review aims to elucidate the autoimmune-favored features of IGM and explore its potential etiologies. Furthermore, we discuss the immune-mediated pathogenesis of IGM using existing research and propose immunotherapeutic strategies for managing this condition.

Ischemic heart disease mortality in individuals with inflammatory bowel disease: A nationwide analysis of disparities in the United States

IntroductionInflammatory bowel disease (IBD) is linked to immune-mediated pathogenesis and a pro-inflammatory state, leading to accelerated atherosclerosis. This earlier onset of clinical cardiovascular disease poses significant morbidity and mortality. We sought to identify IHD mortality trends in individuals with IBD in the United States (US). MethodsMortality due to ischemic heart diseases (IHD) as the underlying cause of death with the IBD as a contributor of death were queried from death certificates using the CDC database from 1999 to 2020. Yearly crude mortality rates (CMR) were estimated by dividing the death count by the respective population size, reported per 100,000 persons. Mortality rates were adjusted for age using the Direct method and compared by demographic subpopulations. Log-linear regression models were utilized to assess temporal variation (annual percentage change [APC]) in mortality. ResultsAge-adjusted mortality rates (AAMR) decreased from 0.11 in 1999 to 0.07 in 2020, primarily between 1999 and 2018 (APC -4.41, p < 0.001). AAMR was higher among male (AAMR 0.08) and White (AAMR 0.08) populations compared to female populations (AAMR 0.06) and Black (AAMR 0.04) populations, respectively. No significant differences were seen when comparing mortality between urban (AAMR 0.07) and rural (AAMR 0.08) regions. Southern US regions (AAMR 0.06) had the lowest mortality rates when compared to the other US census regions: Northeastern (AAMR 0.08), Midwestern (AAMR 0.08), and Western (AAMR 0.08). ConclusionDisparities in IHD mortality exist among individuals with IBD in the US based on demographic factors, with an overall decline in mortality during the 22-year period. Further investigation is warranted to confirm these findings and evaluate for contributors to the observed disparities.

Combined immunosuppressive treatment for giant cell myocarditis: a case report

Giant cell myocarditis (GCM) is a rare and often fulminant autoimmune disease. The immune-mediated pathogenesis of GCM is also supported by animal models, association with other immunological diseases and therapeutic efficacy of immunosuppressive drugs. The diagnosis of GCM is based on endomyocardial biopsy. GCM is an orphan disease. Heart transplantation is effective but up to 25% of transplanted patients experience disease recurrence. Immunosuppressive drugs have been shown to be potential therapeutic agents for GCM. In the present case report, the prescription of cyclosporine, azathioprine and prednisone resulted in a rapid and prolonged remission in support of the role of a combined immunosuppressive regimen in improving the long-term prognosis of this cardiac pathology.

Unraveling the Immunopathological Landscape of Celiac Disease: A Comprehensive Review.

Celiac disease (CD) presents a complex interplay of both innate and adaptive immune responses that drive a variety of pathological manifestations. Recent studies highlight the role of immune-mediated pathogenesis, pinpointing the involvement of antibodies against tissue transglutaminases (TG2, TG3, TG6), specific HLA molecules (DQ2/8), and the regulatory role of interleukin-15, among other cellular and molecular pathways. These aspects illuminate the systemic nature of CD, reflecting its wide-reaching impact that extends beyond gastrointestinal symptoms to affect other physiological systems and giving rise to a range of pathological landscapes, including refractory CD (RCD) and, in severe cases, enteropathy-associated T cell lymphoma. The existing primary therapeutic strategy, a gluten-free diet (GFD), poses significant challenges, such as low adherence rates, necessitating alternative treatments. Emerging therapies target various stages of the disease pathology, from preventing immunogenic gluten peptide absorption to enhancing intestinal epithelial integrity and modulating the immune response, heralding potential breakthroughs in CD management. As the understanding of CD deepens, novel therapeutic avenues are emerging, paving the way for more effective and sophisticated treatment strategies with the aim of enhancing the quality of life of CD patients. This review aims to delineate the immunopathology of CD and exploring its implications on other systems, its complications and the development of novel treatments.

Idiosyncratic Drug-Induced Liver Injury: From Pathogenesis to Risk Reduction

Idiosyncratic drug-induced liver injury (iDILI) is a rare and poorly predictable adverse drug reaction that may lead to death or liver transplantation in severe cases.The aim of the study was to review contemporary concepts of the immune-mediated pathogenesis of iDILI and possible ways to predict and prevent the risk of developing this condition.The liver is characterised by high immune tolerance due to a complex of mechanisms involving various cells (antigen-presenting cells, T-cells), cytokines, and other molecules, which prevents severe immune responses to xenobiotics entering the body. Previous research has shown that iDILI results from a combination of multiple synergistic unfavourable factors that impair liver immune tolerance at different levels. These factors include the hepatotoxicity-associated chemical properties of medicines and the individual characteristics of the patient, including the genetically determined structure and function of the adaptive immune system components. Since iDILI has a multilevel and multifactor pathogenesis, it is difficult to determine a risk biomarker for a particular medicine. According to the literature review, the risk of hepatotoxicity of a drug candidate and/or a metabolite can be reduced at the preclinical level by assessing the ability to cause mitochondrial damage, form non-covalent bonds, produce reactive oxygen species, and release damage-associated molecular patterns (DAMPs). The association of iDILI with gene polymorphisms in patients receiving certain medicines has a high negative predictive value and can be used in clinical practice to rule out iDILI or identify hepatotoxic medicinal products in polypharmacy. The identification of the allele combinations associated with an increased risk of iDILI seems promising for enhancing the predictive value of genetic studies and may be used in personalised medicine.

Heart involvement in multisystem inflammatory syndrome in children correlated with SARS-CoV-2 infection: a review by ANMCO/SICP

Acute clinical manifestations of COVID-19 are generally less severe in childhood, however a proportion of them can develop a severe systemic hyperinflammatory syndrome after SARS-CoV-2 infection, known as the multisystem inflammatory syndrome (multisystem inflammatory syndrome in children, MIS-C). Cardiovascular manifestations in MIS-C are frequent (34-82%), including myocardial dysfunction, coronary artery dilation or aneurysms, arrhythmias, conduction abnormalities, pericarditis and valvulitis. The most affected cases can develop cardiogenic shock needing intensive care unit admission, inotropic support and sometimes even mechanical circulatory support. The elevation of myocardial necrosis markers, the frequently transient left ventricular systolic dysfunction and the presence of changes on magnetic resonance imaging, support the hypothesis of an immune-mediated post-viral pathogenesis similar to myocarditis. Although MIS-C shows excellent short-term survival, further studies are needed to demonstrate complete reversibility of residual subclinical heart damage.

Mechanism-based target therapy in primary biliary cholangitis: opportunities before liver cirrhosis?

Primary biliary cholangitis (PBC) is an immune-mediated liver disease characterized by cholestasis, biliary injuries, liver fibrosis, and chronic non-suppurative cholangitis. The pathogenesis of PBC is multifactorial and involves immune dysregulation, abnormal bile metabolism, and progressive fibrosis, ultimately leading to cirrhosis and liver failure. Ursodeoxycholic acid (UDCA) and obeticholic acid (OCA) are currently used as first- and second-line treatments, respectively. However, many patients do not respond adequately to UDCA, and the long-term effects of these drugs are limited. Recent research has advanced our understanding the mechanisms of pathogenesis in PBC and greatly facilitated development of novel drugs to target mechanistic checkpoints. Animal studies and clinical trials of pipeline drugs have yielded promising results in slowing disease progression. Targeting immune mediated pathogenesis and anti-inflammatory therapies are focused on the early stage, while anti-cholestatic and anti-fibrotic therapies are emphasized in the late stage of disease, which is characterized by fibrosis and cirrhosis development. Nonetheless, it is worth noting that currently, there exists a dearth of therapeutic options that can effectively impede the progression of the disease to its terminal stages. Hence, there is an urgent need for further research aimed at investigating the underlying pathophysiology mechanisms with potential therapeutic effects. This review highlights our current knowledge of the underlying immunological and cellular mechanisms of pathogenesis in PBC. Further, we also address current mechanism-based target therapies for PBC and potential therapeutic strategies to improve the efficacy of existing treatments.

Acute Vulvar Aphthous (Lipschütz) Ulcer After COVID-19 Vaccine: Two Cases [ID: 1337743

INTRODUCTION: Vulvar aphthous ulcers are uncommon, non-sexually transmitted genital lesions that typically arise in adolescents and young women after viral infection. The pathogenesis of this condition is poorly understood but is thought to arise from an immune-mediated process. More recently, there have been several reports of vulvar aphthosis after COVID-19 infection, and to date, we have identified five case reports describing the development of this condition within days of receiving one of the existing U.S. Food and Drug Administration-approved mRNA COVID-19 vaccines. METHODS: We present the cases of two adolescents, aged 13 and 16 years, who both developed acute genital aphthous ulcers within days of their second Pfizer-BioNTech COVID-19 vaccinations with no other apparent triggers. CONCLUSION: These two cases represent a growing number of patients who have developed acute genital ulceration (AGU) in close temporal proximity to COVID-19 vaccination, which represents a potential novel etiology for this uncommon condition. If vaccination is indeed a trigger for AGU, this may support an immune-mediated pathogenesis, although future studies are needed to explore this further. The continued publication of high-quality case reports describing AGU will allow us to gather enough data to make statistical inferences and to raise awareness for this condition, which is underrecognized and often misdiagnosed by providers.

Unusual Presentation of COVID-19 Associated Acute Myelitis with Predominant Corticospinal Tract Involvement: A Case Report (P4-10.006)

<h3>Objective:</h3> To describe the clinical characteristics and treatment response of a patient with coronavirus disease (COVID-19) associated myelitis with predominant corticospinal tract involvement. <h3>Background:</h3> Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection-related neurological manifestations have been described. Evidence of individuals with COVID-19 associated acute myelitis continue to grow. Various mechanisms have been proposed by which COVID-19 could lead to spinal cord manifestations; an immune-mediated pathogenesis has been considered. However, there is still not a clear distinction between para- and post- infectious presentation of COVID-19 associated myelitis and there are still no specific evidence-based management strategies. For these reasons, it is important to identify and report unusual presentations. <h3>Design/Methods:</h3> We identified a male with few risk factors for severe COVID-19 complications, with sudden onset impaired gait particularly while walking downstairs nine days after the initial presentation of SARS-CoV-2 respiratory symptoms and after receiving a course of nirmatrelvir/ritonavir plus oral steroids. Gait impairment rapidly progressed to leg stiffness and pain of thighs. A second FDA approved COVID-19 booster had been administered months prior to onset. <h3>Results:</h3> Neurologic examination showed lower limbs spasticity, clonus, and corticospinal signs with myalgia of thighs muscles in the absence of weakness, sensory loss, or abnormal sphincter control. CSF showed lymphocytic pleocytosis with elevated proteins; serum inflammatory markers were elevated; viral serology positive for SARS-CoV-2 antigen. Thoraco-lumbar gadolinium MRI was normal. High dose IV steroids were administered with near full recovery. <h3>Conclusions:</h3> SARS-CoV-2 has been associated to several neurological complications. We report a case of pure motor acute-onset rapidly progressing, MRI-negative myelitis, nine days after COVID-19 onset in a vaccinated patient who responded to immunotherapy. To the best of our knowledge, this is the first report of COVID-19 associated myelitis with predominant corticospinal tract involvement without weakness. These findings suggest an immune-mediated pathogenesis and support a combined treatment strategy that needs further investigation. <b>Disclosure:</b> Dr. Reyes Rivera has nothing to disclose. Dr. Tait has nothing to disclose. The institution of Dr. Serrano has received research support from Eli Lilly. The institution of Dr. Serrano has received research support from Abbvie.

Association of Alopecia Areata with Sensorineural Hearing Loss: A Systematic Review and Meta-analysis

Background: Immune-mediated melanocyte-related pathogenesis in alopecia areata (AA) may cause sensorineural hearing loss (SNHL). However, the relation between AA and SNHL has been unclear. Therefore, we aimed to investigate this association between AA and SNHL. Methods: We performed a systematic review and searched MEDLINE and Embase on July 25, 2022, for cross-sectional, case-control, or cohort studies that examined the association of AA with SNHL. The Newcastle-Ottawa Scale was used to evaluate their risk of bias. A random-effects model meta-analysis was performed to obtain the mean differences in frequency-specific hearing thresholds between AA patients and age-matched healthy controls and the pooled odds ratio for SNHL in relation to AA. Results: We included 5 case-control studies and 1 cohort study, with none of them rated with high risk of biases. The meta-analysis showed AA patients had significantly higher mean differences in pure-tone hearing thresholds at 4,000 Hz and 12,000–12,500 Hz. The meta-analysis also found increased odds for SNHL among patients with AA (OR: 3.18; 95% CI: 2.06–4.89; I² = 0%). Conclusions: AA is associated with an increase of SNHL, especially at high frequencies. Otologic consultation may be indicated if AA patients present with hearing loss or tinnitus.

VEDOLIZUMAB, USTEKINUMAB AND TOFACITINIB AS TRIPLE THERAPY FOR ULCERATIVE COLITIS

Therapies for ulcerative colitis include mesalamine, immunomodulators, biologics, and small molecules. Unfortunately, patient response is not universal, and efficacy can diminish with time, postulated to be from increased drug clearance, anti-drug antibodies with biologics, and immune mediated pathogenesis changes. Biologic combinations have been investigated for producing synergistic drug effects and extending targeted therapy in patients lacking monotherapy response, with promise shown in two drug combinations (1), but not investigated using three.

Evaluation of CD137 and CD137L Transcript Levels and the Serum sCD137 in Immune-mediated Polyneuropathy.

Abnormal humoral and cellular immune responses have been reported in immune-mediated polyneuropathies. CD137, as a costimulatory molecule and a TNF receptor superfamily member, has been demonstrated to have a key role in the pathogenesis of many autoimmune as well as inflammatory disorders. To evaluate the transcripts levels of CD137, its ligand (CD137L), and the serum levels of soluble CD137 (sCD137) in patients with immune-mediated polyneuropathy. A total of 45 patients and 46 sex and age-matched healthy individuals were enrolled in the study. CD137 and CD137L transcript levels were assessed by the Real-Time PCR, and the serum level of sCD137 was measured using the ELISA technique. The Bayesian regression model was used for statistical analysis at the 0.05 significance level in R 4.1.0 statistical environment. Transcript levels of the CD137 and CD137L were higher in polyneuropathy patients in comparison with the healthy subjects (P=0.006 for both). Conversely, the mean level of sCD137 was significantly lower in the sera of patients compared to the controls (P<0.001). Our findings point to the possible role of CD137 and CD137L in immune-mediated polyneuropathy pathogenesis. More investigations are required to clarify the exact contributions of the mentioned molecules to the pathogenesis of immune-mediated polyneuropathies.

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).

VEDOLIZUMAB, USTEKINUMAB AND TOFACITINIB AS TRIPLE THERAPY FOR ULCERATIVE COLITIS

Abstract BACKGROUND Therapies for ulcerative colitis include mesalamine, immunomodulators, biologics, and small molecules. Unfortunately, patient response is not universal, and efficacy can diminish with time, postulated to be from increased drug clearance, anti-drug antibodies with biologics, and immune mediated pathogenesis changes. Biologic combinations have been investigated for producing synergistic drug effects and extending targeted therapy in patients lacking monotherapy response, with promise shown in two drug combinations (1), but not investigated using three. CASE A 20-year-old Caucasian male with UC presented in August 2015 following 1 month hospitalization for Clostridium difficile infection. He had 2 infusions of infliximab 10 mg/kg continued post-discharge, and started mesalamine 4.8gm qd, 6-mercaptopurpine (6MP) 100mg qd, and prednisone taper. By November 2015, colonoscopy showed severe Mayo 3 pancolitis. Due to insufficient response 6MP and infliximab were discontinued and he started vedolizumab. August 2016 colonoscopy had chronic colitis with Mayo 2 inflammation of the ascending, transverse, descending and rectosigmoid colon so prednisone 40mg was initiated and vedolizumab increased to vedolizumab q4 weeks. He responded well clinically and was tapered off prednisone by October 2016. November 2016 colonoscopy had right sided colitis resolution with residual proctosigmoiditis (Mayo 2); May 2017 colonoscopy still had rectosigmoid inflammation (Mayo 2) with chronic active colitis, so ustekinumab q8 weeks was added. December 2017 colonoscopy was unimproved so ustekinumab increased to q4 weeks, prednisone was increased, and he requested addition of budesonide and mesalamine. With clinical improvement, prednisone was tapered by February 2020. However, December 2020 colonoscopy showed severe (Mayo 3) recto-sigmoiditis with mild colitis in the descending to transverse colon, so tofacitinib XR 22 mg qd was added. He improved clinically, so budesonide was discontinued in February 2021. November 2021 colonoscopy showed complete endoscopic remission (Mayo 0) so he initiated de-escalation with initially discontinuing mesalamine and increasing ustekinumab initially to q8 week intervals and later vedolizumab to q8 weeks with maintenance of clinical remission. Given marginal effect, ustekinumab was discontinued initially and later, tofacitinib was discontinued. He remains in remission on vedolizumab q8 weeks monotherapy. CONCLUSION Combination therapies may be considered for suitable patients experiencing severe, refractory disease. Although patients with multiple comorbidities, frailty, immunosuppression or certain contraindications may not be well suited, this patient presents as an ideal candidate with no comorbidities and few other therapeutic options. REFERENCES (1) Privitera G et al. Combination therapy in IBD. Autoimmunity Reviews. 2021 Jun 1;20(6):102832.