Combination Of Azathioprine Research Articles

P1128 Course of patients with Ulcerative colitis who have achieved disease clearance from the moment of diagnosis

Abstract Background In patients with ulcerative colitis, histological healing is associated with better clinical outcomes1. Therefore,histological remission as the treatment target is advocated. observational studies2,3 have shown that patients in endoscopic, histological remission have longer relapse-free survival, reduced hospitalization rates, corticosteroid use rates. Methods Demographic information, laboratory findings, clinical courses of patients with ulcerative colitis who had disease clearance, were evaluated retrospectively for 5 years. The files of 529 patients with ulcerative colitis were scanned, patients who had not achieved disease clearance, had a history of surgery, were not followed regularly, were <5 years old were excluded. 87 patients were included in this study. The validated Nancy histological index was used to assess histological disease activity. Results A total of 87 patients with Ulcerative Colitis, 51 of whom were male. The mean age was 54.1±13.5 years. The mean age of the patients at diagnosis was 38.9±13.6 years. The mean follow-up period was 14.5±7.7 years. The mean disease age was 15.6±7.8 years. Only 1 patient had a family history. 5 (5.7%) patients had pANCA positivity. 14 (16%) patients had extraintestinal involvement (ankylosing spondylitis, erythema nodosum, sacroiliitis, arthritis, uveitis). Current disease involvement was E1 in 11 (12.6%) patients, E2 in 45 (51.7%) patients, and E3 in 31 (35.7%) patients. Mayo endoscopic subscore was 0 in 45 (51.7%) patients; Mayo endoscopic subscore was 1 in 42 (48.3%) patients. In maintenance treatment, 50 (57.5%) were receiving only oral/topical 5-ASA, 37 (42.5%) were receiving azathioprine and 5-ASA combination. Remission was achieved in 72 (82.8%) patients with conventional treatment, and only 15 (17.2%) were receiving biological treatment. During the course of the disease, 29 (33.3%) patients required ≥1 steroid. No attacks were observed in 69 (79.3%) patients in the last 5 years. The rate of achieving remission was found to be 16% in 529 patients. Conclusion Although the rate of achieving deep remission in ulcerative colitis is low, remission rates are high in patients with rectal or left colon involvement at the time of diagnosis.

Organ Transplant and Challenges

Abstract: In the 1950s, the first attempts at immunosuppression for kidney transplantation involved total irradiation and was met with some degree of success The use of chemical immunosuppression, initially with 6-mercaptopurine and then with combination of azathioprine and steroids, avoided the problems associated with irradiation and improved outcomes significantly. It was the discovery of cyclosporine in 1976, and its introduction in clinical practice in 1984, that dramatically changed the landscape of OT(Organ Transplant) resulting in an increased one-year survival in both kidney and liver transplant recipients (95 and 75% respectively). Modern immunosuppressive agents (tacrolimus, sirolimis, mycophenolic acid, and everolimus), allow us to currently enjoy superior outcomes and a reduction in adverse immunosuppressive effects. The next important milestone in the development of OT was the founding of the United Network of Organ Sharing (UNOS) in 1984. This organization manages all transplant activities in the US including the maintenance of a national transplant list for all types of transplantation, data collection, and coordination of educational activities. There are a number of organizations in Europe and Asia with similar responsibilities.

Granulomatosis with polyangiitis masquerading as disseminated tuberculosis in presence of bilateral lung cavities and hemorrhagic infarct

Lung cavitations with constitutional symptoms are usually associated with pulmonary tuberculosis due to its high prevalence and are the most common infectious cause in India. Granulomatosis with polyangiitis (GPA) with the systemic pulmonary disease will have different radiological presentations such as nodule, mass, and consolidation with or without cavitation. In this case report, we have reported a 40-year-old female presented with cough, fever, and weight loss of 6 months duration with chest imaging suggestive of bilateral cavitary lung disease. She was labeled as a case of disseminated tuberculosis due to involvement of the central nervous system and empirically treated with anti-tuberculosis treatment (ATT) without microbiological evidence of tuberculosis in smear and cartridge-based nucleic acid amplification tests. The absence of clinical response and radiological worsening to empirical ATT gives a clue for an alternate diagnosis. Bronchoscopy workup documented Aspergillus colonization and vasculitis workup in the presence of cavitary lung disease documented abnormally raised proteinase 3 anti-neutrophil cytoplasmic antibodies titers. She was treated with a combination of systemic methylprednisolone and azathioprine with voriconazole. Her clinical response was observed in 4 weeks and radiological response with complete radiological clearance of pulmonary cavitations was documented after 6 months of treatment. We recommend prompt workup and ruling out GPA in all cases with pulmonary cavitations with negative microbiological workup and no empirical ATT should be given in the era of rapid microbiological tests with good sensitivity and specificity.

P04 How fibroblasts and azathioprine prepare the soil for cutaneous squamous cell carcinoma

Abstract Introduction and aims DNA damage-inducing immunosuppressive drugs such as azathioprine (AZA) act synergistically with ultraviolet (UV)A radiation and photosensitize the skin of immunosuppressed individuals, such as organ transplant recipients. These individuals have an increased risk of developing cutaneous squamous cell carcinoma (cSCC). The specific combination of AZA and UVA causes oxidative DNA damage that leaves behind a characteristic mutational signature in tumour keratinocytes of patients treated with AZA. However, as UVA radiation can penetrate the dermis, the impact of AZA/UVA on cells of the tumour microenvironment, such as fibroblasts, also need to be addressed. Fibroblasts are crucial for cSCC development and progression as they can switch to a protumourigenic phenotype. Methods Cell viability and senescence assays were performed to investigate the impact of AZA in combination with or without UVA on neonatal (nonsun-exposed) and adult (sun-exposed) human dermal fibroblasts. In addition, the impact of AZA/UVA-treated fibroblasts on the clonal growth properties of different cSCC cell models was investigated using three-dimensional (co)culture models. Results We found that AZA and UVA synergistically reduce the viability of both UV-naïve neonatal and sun-exposed adult dermal fibroblasts. In addition, combined AZA and UVA treatments lead to an increased percentage of senescent fibroblasts. We hypothesize that the aberrant secretome of these senescent fibroblasts can impact the growth behaviour of tumour cells. In a soft agar assay, the more malignant cSCC cells (MET-1) formed more and larger clonal spheroids and were less dependent on growth factors compared with spheroids formed by premalignant (PM-1) keratinocytes. Conclusions AZA and UVA act synergistically and potentiate a UVA-induced senescent fibroblast phenotype. The changed characteristics of these fibroblasts can impact the stem cell-like properties from premalignant and malignant keratinocytes. Combining keratinocyte and fibroblast culture models enables us to study how AZA/UVA promote the initiation and progression of cSCC.

A221 AZATHIOPRINE DOSING THRESHOLD IN ANTI-TNF COMBINATION THERAPY FOR MINIMIZING IMMUNOGENICITY AND OPTIMIZING TREATMENT EFFICACY FOR PATIENTS WITH INFLAMMATORY BOWEL DISEASE. A RETROSPECTIVE COHORT STUDY

Abstract Background Reported rates of anti-drug antibody (ADA) formation to tumor necrosis factor-a antagonists (anti-TNF) range from 20-75%. One way to reduce the risk of ADA formation is to combine a second immune-suppressing agent such as azathioprine (AZA) with the anti-TNF agent, known as combination therapy. However, it is unknown if the risk of combination therapy, including the additive risk of AZA and anti-TNF side effects, could be reduced by exposing individuals with inflammatory bowel disease (IBD) to the lowest dose of azathioprine while still maintaining the beneficial effect of ADA prevention. Aims To identify the minimum dose of AZA needed to prevent ADA formation to anti-TNF agents in individuals with IBD receiving combination therapy. We also assessed the occurrence of adverse drug events, treatment loss of response, treatment discontinuation and the need for treatment dose escalation. Methods A retrospective cohort study is ongoing in adult participants with IBDreceiving either infliximab or adalimumab in combination with AZA. Patients are divided based on their AZA dosage (low dose group, AZA ampersand:003C2mg/kg/day versus standard dose group, AZA 2mg/kg/day). All participants will be followed for 1 year and observed for the occurrence of ADA formation, adverse drug events, treatment loss of response, treatment discontinuation and the need for treatment dose escalation. Results To date, 48 participants are currently included (low dose, n=29; standard dose, n=19). 42 are on Infliximab and 6 are on Adalimumab. The occurrence of ADA was 17.4% in the low dose group and 20% in the standard dose group (pampersand:003E0.99). More participants lost response to treatment and discontinued anti-TNF therapy in the standard dose group (n=7/19, 36.8%) versus the low-dose group (n=8/29, 27.6%, p=0.54). More participants in the low-dose group received anti-TNF dose escalation (n= 20/29,68.9%) compared to the standard dose group (n=6/19, 31.6%, p=0.017). Adverse events, to Anti-TNF was seen in (n=3/19, 15.7%) in the standard dose group, in comparison to (n=4/29, 13.79%, pampersand:003E0.99) in the low dose group. Adverse events to AZA were surprisingly higher in the low dose group (n=14/29, 48.3%) while in the standard dose, it was (n=5/19, 26.3%, p=0.14). Conclusions The preliminary result of the study suggests that there is no significant difference in anti-drug antibody formation between standard and low doses of azathioprine in combination with anti-TNF therapy, in addition, data showed significant lower rates of Anti-TNF discontinuation and loss of response to treatment in low Azathioprine dose group. Completion of the study will help further define if low-dose AZA can be used for ADA prevention in anti-TNF combination therapy without compromising important clinical outcomes. Funding Agencies None

P1043 Immunomodulator and advanced therapies for prevention of clinical relapse and loss of response during maintenance phase in Crohn’s disease: A systematic review and network meta-analysis

Abstract Background Several effective advanced therapies have been approved for the treatment of Crohn’s disease (CD) in the past two decades. Given lack of adequate head-to head clinical trials it is challenging to position these therapies in the management algorithm. Therefore we performed this network meta-analysis to inform therapeutic decisions. Methods We searched MEDLINE, Embase, and Cochrane Central Register of Controlled Trials between inception and October 2023 for randomised controlled trials (RCTs). Outcomes assessed were clinical relapse (loss of clinical remission), loss of clinical response, adverse events (AE), withdrawal due to AE, and serious AE. We performed random-effects meta-analysis and network meta-analysis (using a frequentist approach), and estimated relative risk (RRs), 95%CI values. We used GRADE to ascertain certainty of evidence. Results A total of 32 RCTs comprising 10,924 patients were included in the analysis. On network meta-analysis of 15 interventions based on prevention of clinical relapse, combination of infliximab (IFX) and azathioprine (AZA) (RR 0.31, 95%CI [0.17-0.56]), IFX (RR 0.62, 95%CI [0.5-0.76], moderate certainty), and adalimumab (RR 0.68, 95%CI [0.55-0.84], moderate certainty) were the only agents that were effective compared to placebo (Figure 1). Methotrexate (RR 0.57, 95%CI [0.32-1.03], low certainty) and azathioprine (RR 0.82, 95%CI [0.62-1.1]), very low certainty) were not effective. On analysis based on prevention of clinical response for nine interventions, there was high certainty evidence for ustekinumab (RR 0.73, 95%CI [0.61-0.86]), upadacitinib (RR 0.64, 95%CI [0.57-0.72]), and moderate certainty of evidence for infliximab (RR 0.71, 95%CI [0.59-0.84]), adalimumab (RR 0.68, 95%CI [0.61-0.75]), certolizumab (RR 0.57, 95%CI [0.47-0.7]), CTP13 (RR 0.46, 95%CI [0.38-0.57]), vedolizumab (RR 0.82, 95%CI [0.68-0.99]), natalizumab (RR 0.54, 95%CI [0.43-0.68]). Tofacitinib was not effective and there was no data available for immunomodulators and combination therapies for this outcome. On analysis of serious adverse events advanced therapies were of no difference to placebo (very low certainty). Conclusion On network meta-analysis immunomodulators and advanced therapies for maintenance phase, combination of anti-TNFs and immunomodulators followed by anti-TNF monotherapy had large effect size with moderate certainty for prevention of clinical relapse. There was moderate to high certainty evidence to suggest newer advanced therapies are effective in prevention of loss of clinical response.

P1038 Does combination immunomodulator therapy impact real-world biologic effectiveness in Inflammatory Bowel Diseases?A propensity score analysis in patients treated with anti-TNF and non-anti-TNF biologics in the UK IBD BioResource

Abstract Background Randomised controlled trials have demonstrated that the combination of infliximab and azathioprine is superior to either drug as monotherapy both in patients with Crohn’s Disease (CD) and ulcerative colitis (UC). Data on the combination of other biological agents -including other anti-TNFs, vedolizumab and ustekinumab- and immunomodulators (IMMs) is lacking or shows conflicting results. Given the risks of combination therapy, physicians are often hesitant on whether to combine IMMs with biologic therapies. Methods We measured the effectivenessof biologic therapies [infliximab (IFX), adalimumab (ADA), golimumab (GLM), vedolizumab (VDZ) and ustekinumab (UST)] in patients with UC and CD with and without IMM use enrolled in the UK Inflammatory Bowel Disease (IBD) BioResource over long durations of followup.Demographic, disease, treatment and outcome data were retrieved. Inverse probability of treatment weighting (IPTW) was used to balance groups of those receiving vs those not receiving IMM using a propensity score-weighting approach accounting for baseline patient or disease related clinical characteristics. Effectiveness of treatment was based on persistence free of treatment discontinuation or treatment failure. Failure was defined as occurring if any of the following occurred: (a) clinician-recorded treatment failure (b) start of treatment with a different advanced therapy (c) occurrence of resectional or defunctioning bowel surgery. We compared Kaplan Meier curves for treatment failure-free survival after IPTW and used a log rank test for differences between the groups. Results In UC, we included 2479 patients receiving IFX (1173 on IMM), 1117 ADA (401 on IMM), 188 GLM (77 on IMM) and 1256 VDZ (392 on IMM). In CD, we included 5956 patients receiving IFX (3062 on IMM), 4524 ADA (1898 on IMM), 1067 VDZ (340 on IMM) and 627 UST (198 on IMM).As expected, combination IMM therapy was associated with increased drug effectiveness for IFX in both UC and CD. Combination IMM therapy was also associated with increased effectiveness of ADA in CD. For all other drugs, there was no significant benefit for combination IMM. Hazard ratios(HRs) for the effect of IMM of each drug effectiveness in UC and CD are summarised (Figure 1). Conclusion We confirm prior results indicated that IFX effectiveness is improved by concomitant use of an IMM in both UC and CD.In contrast to RCT data but in accordance to other robust real-world studies, we find evidence that for ADA in CD concomitant IMM can increase drug effectiveness. We find no evidence of benefit for concomitant IMM for other biologics in UC or CD.

P556 Immunomodulator and advanced therapies for Induction of clinical remission and response in Crohn’s disease: A systematic review and network meta-analysis

Abstract Background Several effective advanced therapies have been approved for the treatment of Crohn’s disease (CD) in the past two decades. Many have used synthesis techniques to study this area, but these rarely consider both advanced and immunomodulator therapy together in the same analysis. Network meta-analysis enables the direct and indirect comparison of these different therapeutic agents, aiding in determining their relative positioning within the treatment algorithm. Methods We searched MEDLINE, Embase, and Cochrane Central Register of Controlled Trials between inception and October 2023 for randomised controlled trials (RCTs). The outcomes included were clinical remission and response, adverse events (AE), withdrawal due to AE, total and serious AE. We performed random-effects meta-analysis and network meta-analysis (frequentist approach), and estimated relative risk (RRs), 95%CI values. We used GRADE to ascertain certainty of evidence. Results A total of 83 RCTs comprising 19214 patients were eligible. A total of 28 interventions were included in the analysis. Combination of anti-tumor necrosis factor (TNF) and immunomodulators, anti-TNF monotherapy (adalimumab [ADA], infliximab [IFX], BI695501), IL-23 antagonists (ustekinumab [UST], guselkumab, risankizumab [RIS], mirikizumab), anti-integrins (vedolizumab, natalizumab) and upadacitinib were effective in inducing clinical remission compared to placebo (Figure 1). There was moderate certainty of evidence for combination of ADA and azathioprine (AZA) (RR 3.1, 95%CI [2.0-4.8]; risk difference [RD]: 40.1%), IFX+AZA (RR 2.5, 95%CI [1.7-3.8]; RD: 28.9%), ADA (RR 2.5, 95%CI [1.8-3.5]; RD:28.5%), and UST (RR 2.0 95%CI, [1.6-2.5]; RD: 19.2%) in induction of clinical remission compared to placebo. For induction of clinical response, there was moderate certainty of evidence for IFX+AZA (RR 2.8, 95%CI [1.6-4.8]), ADA (RR 2.5, 95%CI [1.7-3.9]), IFX (RR 2.8, 95%CI [1.6-4.8]), RIS (RR 1.9, 95%CI [1.3-2.6]). On analysis of serious adverse events all therapies were of no difference to placebo (very low certainty). On sensitivity analysis, the impact of concomitant immunomodulator use and the biological naivety of patients had little effect on these results. Conclusion On network meta-analysis, combination of anti-TNFs and immunomodulators followed by anti-TNF monotherapy had large effect size with moderate certainty for the induction of clinical remission. More novel therapies appear to have examples of similarly important effect sizes, but are currently limited due to the imprecision of the limited evidence base at present and future research should target these therapies in study.

Tacrolimus versus mycophenolate for AutoImmune hepatitis patients with incompLete response On first-line therapy (TAILOR study): a study protocol for a phase III, open-label, multicentre, randomised controlled trial

BackgroundAutoimmune hepatitis (AIH) is a rare, chronic inflammatory disease of the liver. The treatment goal is reaching complete biochemical response (CR), defined as the normalisation of aspartate and alanine aminotransferases and immunoglobulin gamma. Ongoing AIH activity can lead to fibrosis and (decompensated) cirrhosis. Incomplete biochemical response is the most important risk factor for liver transplantation or liver-related mortality. First-line treatment consists of a combination of azathioprine and prednisolone. If CR is not reached, tacrolimus (TAC) or mycophenolate mofetil (MMF) can be used as second-line therapy. Both products are registered for the prevention of graft rejection in solid organ transplant recipients. The aim of this study is to compare the effectiveness and safety of TAC and MMF as second-line treatment for AIH.MethodsThe TAILOR study is a phase IIIB, multicentre, open-label, parallel-group, randomised (1:1) controlled trial performed in large teaching and university hospitals in the Netherlands. We will enrol 86 patients with AIH who have not reached CR after at least 6 months of treatment with first-line therapy. Patients are randomised to TAC (0.07 mg/kg/day initially and adjusted by trough levels) or MMF (max 2000 mg/day), stratified by the presence of cirrhosis at inclusion. The primary endpoint is the difference in the proportion of patients reaching CR after 12 months. Secondary endpoints include the difference in the proportion of patients reaching CR after 6 months, adverse effects, difference in fibrogenesis, quality of life and cost-effectiveness.DiscussionThis is the first randomised controlled trial comparing two second-line therapies for AIH. Currently, second-line treatment is based on retrospective cohort studies. The rarity of AIH is the main issue in clinical research for alternative treatment options. The results of this trial can be implemented in existing international clinical guidelines.Trial registrationClinicalTrials.gov NCT05221411. Retrospectively registered on 3 February 2022; EudraCT number 2021–003420-33. Prospectively registered on 16 June 2021.

Co-administration of 1,25-dihydroxyvitamin D3 and infliximab improves colitis in mice by modulating Treg differentiation.

The combination of TNF-α inhibitors and vitamin D in colitis remains to be elucidated. In the present study, we revealed the benefit of infliximab (IFX) and vitamin D in a mouse model of Ulcerative colitis (UC). A dextran sulfate sodium-induced colitis model was used. The therapeutic effect of the combination was evaluated by symptom and histopathology analysis. The synergistic mechanism was explored by detecting the regulatory effect of the combined therapy on Regulatory T cell (Treg) differentiation. IFX and 1,25-dihydroxyvitamin D3 (VitD3) synergistically prevented the development of colitis by improving clinical signs, pathological and hematological manifestation, and inhibiting intestinal inflammation (decreasing TNF-α, IL-1β, and IL-6). Co-administration of IFX (2.5 mg/kg) with VitD3 or IFX (5.0 mg/kg) with VitD3 was more effective than administration of IFX (2.5 mg/kg, 5.0 mg/kg). There was no difference in therapeutic effect between IFX (5.0 mg/kg) and VitD3+ IFX (2.5 mg/kg) groups or between the VitD3+IFX (5.0 mg/kg) and VitD3+ Azathioprine (AZA) groups. VitD3 or combination therapy showed more powerful regulation of splenetic Treg differentiation and IL-10 production than IFX alone. Moreover, VitD3 alone or in combination induced higher levels of Foxp3 and IL-10 than IFX in colon tissue. In ulcerative colitis patients, serum VitD3 levels positively correlated with Treg levels. VitD3 and IFX synergistically inhibit colitis based on their powerful regulation of Treg differentiation. VitD3 combined with IFX is an alternative therapy for patients who are intolerant to standard doses of IFX or combination of IFX and AZA.

Abstract 19163: A Rare Case of Pericarditis as an Initial Manifestation of Rheumatoid Arthritis

Case Presentation: A 69-year-old male with a history of chronic recurrent pericarditis presented with a 3-week episode of chest pain. Despite treatment with ibuprofen, colchicine, prednisone, and anakinra, he experienced multiple flares upon attempting to wean off anakinra. His current workup revealed an elevated C-reactive protein and an echocardiogram showing a small pericardial effusion. Cardiac magnetic resonance imaging showed mild pericardial late gadolinium enhancement and increased pericardial signal on T2 STIR imaging, confirming a flare of recurrent pericarditis. The patient was started on rilonacept while being weaned off anakinra. During a follow-up after 3 months, the patient reported new onset polyarthralgia, prompting a referral to rheumatology. Rheumatoid factor was negative, but anti-citrullinated protein antibodies were positive, leading to a diagnosis of rheumatoid arthritis (RA). Azathioprine was added to the treatment regimen alongside rilonacept. Discussion: The patient's recurrent pericarditis was initially considered idiopathic but, with the subsequent RA diagnosis, it was suspected that RA may have been the underlying cause. While pericarditis is a known cardiac complication of RA, it is uncommon for pericarditis to be the initial manifestation of RA. Anakinra and rilonacept are both interleukin-1 (IL-1) inhibitors, with anakinra being FDA-approved for RA treatment. However, rilonacept has not been extensively studied in patients with RA. The case suggests that the use of certain medications may have masked RA symptoms, and as those medications were tapered, the RA symptoms became more evident. This case highlights the possibility of idiopathic pericarditis evolving into an autoimmune etiology, such as RA, over time. The combination of rilonacept and azathioprine for treating RA has limited evidence, emphasizing the need for further research in this area.

Comparison of Oral Azathioprine and Oral Mini Pulse Steroid in the Treatment of Vitiligo: An Open-Label Randomized Controlled Trial.

Vitiligo is a common acquired depigmentory skin disorder supposed to be of autoimmune aetiology. Different immunosuppressants have been tried with varying success. Azathioprine has been less studied in vitiligo. To study the efficacy of oral azathioprine and compare with systemic steroid in the treatment of vitiligo. It was an interventional study with multi-armed (three), parallel group, an open-label, randomized controlled trial with allocation ratio of 1:1:1. Patients of vitiligo aged between 18 and 60 years having more than 5% body surface involvement were included in the study. Patients were divided into three groups. Group A-patients received oral azathioprine 50 mg OD daily, group B-patients received combination of oral azathioprine 50 mg OD and PUVASOL and group C-patients received combination of betamethasone oral mini pulse (OMP) and PUVASOL. All the groups were treated for 1 year. Repigmentation was evaluated by vitiligo area severity index (VASI), and stabilization was evaluated by vitiligo disease activity (VIDA). Group A, group B and group C showed 24.24%, 53.24% and 47.28% improvement in VASI score, respectively, at the end of 1 year. Group B and group C showed statistically significant superior repigmentation as compared to azathioprine monotherapy. Though azathioprine and betamethasone showed equivalent efficacy, azathioprine has a better safety profile. Side effects were minimal in azathioprine groups, whereas 50% patients developed various side effects in group C. Azathioprine is safe and effective option in the treatment of vitiligo.

Prednisolone and rapamycin reduce the plasma cell gene signature and may improve AAV gene therapy in cynomolgus macaques

Adeno-associated virus (AAV) vector gene therapy is a promising approach to treat rare genetic diseases; however, an ongoing challenge is how to best modulate host immunity to improve transduction efficiency and therapeutic outcomes. This report presents two studies characterizing multiple prophylactic immunosuppression regimens in male cynomolgus macaques receiving an AAVrh10 gene therapy vector expressing human coagulation factor VIII (hFVIII). In study 1, no immunosuppression was compared with prednisolone, rapamycin (or sirolimus), rapamycin and cyclosporin A in combination, and cyclosporin A and azathioprine in combination. Prednisolone alone demonstrated higher mean peripheral blood hFVIII expression; however, this was not sustained upon taper. Anti-capsid and anti-hFVIII antibody responses were robust, and vector genomes and transgene mRNA levels were similar to no immunosuppression at necropsy. Study 2 compared no immunosuppression with prednisolone alone or in combination with rapamycin or methotrexate. The prednisolone/rapamycin group demonstrated an increase in mean hFVIII expression and a mean delay in anti-capsid IgG development until after rapamycin taper. Additionally, a significant reduction in the plasma cell gene signature was observed with prednisolone/rapamycin, suggesting that rapamycin’s tolerogenic effects may include plasma cell differentiation blockade. Immunosuppression with prednisolone and rapamycin in combination could improve therapeutic outcomes in AAV vector gene therapy.

FRI339 Hypophysitis Secondary To Small Vessel Anca Vasculitistreated With Rituximab

Abstract Disclosure: A. Rivadeneira: None. N. Kumar: None. S. Banerjee: None. M. Gubbiotti: None. D. Yoshor: None. J. Kharlip: None. C.A. White: None. Introduction: Granulomatosis with polyangiitis (GPA) is an autoimmune small-vessel vasculitis associated with anti-neutrophil cytoplasmic antibodies (ANCAs) that rarely involves the pituitary. Conventional treatment of GPA includes high dose glucocorticoids with cyclophosphamide. Rituximab has been used in refractory cases with high rates of remission. We present a case of pituitary GPA treated with and excellent response to rituximab. Case: 51-year-old woman with hypothyroidism, post I-131 treatment for Graves’ disease. Patient presented with 1 year of worsening fatigue, myalgias, frontal headaches, sinus congestion and epistaxis. CT sinus showed pituitary enlargement and chronic mucosal disease. MRI pituitary showed diffusely enlarged pituitary with non-visualized posterior pituitary bright spot and thickened stalk. CT chest showed 18x11 mm nodular opacity and peribronchial fibrosis. Laboratory evaluation showed ACTH 26.7 pg/mL, cortisol 13.4 mcg/dL, TSH 1.1, T4 9.7, prolactin 53 ng/dL, estradiol <20, LH 4, FSH 23. Sodium 140 and urine osm 488. There was positive p-ANCA staining and elevated serum anti-proteinase 3 antibody (PR3), 74 units (0-20). Myeloperoxidase antibody was not elevated. ESR 73 mm/h (0 - 30) and CRP 7.9 (<7.4). Due to atypical ANCA pattern (p ANCA typically is associated with MPO not PR3), pituitary biopsy was performed and showed adenohypophysis with dense lymphoplasmacytic infiltration with nodularity of the inflammatory infiltrates, some arranged peri vascularly, compatible with involvement of the pituitary gland by GPA. She began rituximab 375 mg/m2 weekly for four weeks with plan to continue every 6 months. After treatment, the patient experienced resolution of daily frontal headaches, congestion, cough and epistaxis. CT chest showed improvement of prior lung findings, and ESR/CRP normalized. Repeat pituitary MRI is pending. Discussion: Pituitary involvement is uncommon in GPA, occurring in only 3.9% of cases. It may lead to partial or complete pituitary dysfunction, particularly central diabetes insipidus (87.5%) and hypogonadism (75%). Typical MRI abnormalities include diffusely enlarged pituitary gland, thickened pituitary stalk and absence of posterior bright spot. Treatment of GPA includes a combination of corticosteroids, Cyclophosphamide, Azathioprine and Rituximab. Remission is achieved in up to two thirds of patients. Treatment of lymphocytic hypophysitis, another common cause of diffuse pituitary enlargement, relies on high dose glucocorticoids, leading to many side effects and taper is limited by worsening symptoms. This case highlights the critical role in serologic evaluation and targeted pituitary biopsy to identify the specific etiology of pituitary infiltration to help guide alternate treatment options, and the emerging role of Rituximab as a steroid sparing agent for treatment of pituitary inflammation. Presentation: Friday, June 16, 2023

Case Report: A successful treatment approach of rituximab and azathioprine for pemphigus vulgaris

Pemphigus Vulgaris is an uncommon autoimmune skin disorder that is characterized by persistent and blistering lesions. In approximately 50% of patients, mucous membrane erosions are the initial symptom. The primary presenting symptom is often oral mucosal erosions. Affected individuals frequently experience flaccid blisters and erosions on healthy skin and mucous membranes, and other areas of the body may also be affected. This condition is the result of autoantibodies that target desmosomal antigens. We are presenting a case of a 28-year-old male who presented to the hospital with fluid-filled lesions on his forehead and in his oral cavity. A skin biopsy was performed, and he was diagnosed with pemphigus vulgaris. Initially, he was started on a combination of steroids and azathioprine, but he did not respond to this treatment regimen. However, he was successfully treated with injection rituximab. Rituximab has been found to be an effective treatment approach towards pemphigus vulgaris. It can help prevent further complications and reduce the severity of the disease. By targeting the autoantibodies that cause the disorder, rituximab can help control the patient's symptoms and improve their quality of life. It is important to note that early diagnosis and treatment can play a critical role in the management of pemphigus vulgaris.

The use of oclacitinib compared to azathioprine in the management of canine pemphigus foliaceus: A retrospective analysis.

Oclacitinib (Apoquel; Zoetis) has been reported to be beneficial for treating immune-mediated disorders. This retrospective study evaluates in which group of dogs [oclacitinib (OC) or azathioprine (AZ)] remission of pemphigus foliaceus (PF) was more effectively achieved with matched induction dosing of glucocorticoids; it further evaluates which group had a higher glucocorticoid-sparing effect. Review of 30 medical records of dogs diagnosed with PF presented to a private practice dermatological service. Retrospective analysis of dogs diagnosed with PF and treated with OC or AZ in combination with glucocorticoids. There was no significant difference in the ability to induce remission between AZ and OC groups. In the AZ group, 13 of 15 dogs went into some type of remission (partial or complete), compared with 11 of 15 in the OC group. There was no significant difference between the two groups for the glucocorticoid-sparing effect. The AZ group had an average reduction of 77.9% from the induction glucocorticoid dose, and OC group had an average reduction of 64.4%. One of 15 patients in the AZ group and three of 15 patients in the OC group had a 100% reduction of the glucocorticoid dose. These results indicate that OC can be considered as a treatment option for canine PF.

Clinical and pathogenetic justification of the use of azathioprine in the treatment of progressive non-segmental vitiligo

BACKGROUND: Vitiligo refers to acquired hypomelanosis, characterized by the appearance of depigmented spots on the skin. The search for new vitiligo treatment approaches, which would simultaneously have a pathogenetic focus on the therapy of this disease and at the same time have a safe spectrum of side effects, is relevant today.
 AIM: to evaluate the clinical and laboratory efficacy of azathioprine in progressive non-segmental vitiligo compared with NB-UVB monotherapy.
 MATERIALS AND METHODS: 60 patients with progressive non-segmental vitiligo were divided into 2 equal groups: group 1 received azathioprine in combination with NB-UVB, group 2 received NB-UVB monotherapy. The follow-up period was 6 months. The effectiveness of therapy was evaluated based on the dynamics of the Vitiligo Area Scoring Index (VASI), dermatological quality of life index (DLQI), as well as the titers of proinflammatory cytokines IL-1, IL-2, IL-6, IL-8, IFN-, TNF- and S100 protein in serum blood.
 RESULTS: In the azathioprine + NB-UVB group, compared with the control group, a statistically significant prevalence of VASI and DLQI indices reduction was observed. (Me -61.70%, Q1Q3: -75.14-47.08%, p 0.001; Me -55.83%, Q1Q3: -67.80-40.29%, p 0.001). The dependence of the quality of life of patients on the prevalence of the skin process was noted (p 0.001). There was a statistically significant relationship between the activity of the skin process and the S100 protein in the blood serum of patients with vitiligo. (p 0.05) In addition, the analysis of the dynamics of immunological parameters of the main group compared with the control group showed a more significant decrease in the level of cytokines, as well as S100 protein in blood serum (p 0.001).
 CONCLUSION: The combination of azathioprine and NB-UVB is effective and safe, helps to stabilize the skin process and stimulate the repigmentation of foci, significantly improving the quality of life of patients, contributes to the normalization of immunological parameters, leading to an earlier stop of the progression of the skin process.

Comparative Efficacy and Safety of Mycophenolate Mofetil and Azathioprine in Combination with Corticosteroids in the Treatment of Lymphocytic Myocarditis.

This paper aimed to study the efficacy and safety of mycophenolate mofetil (MM) in combination with corticosteroids in the treatment of lymphocytic myocarditis (LM) when compared to the standard combination of corticosteroids and azathioprine. The study included 50 adult patients (47.8 ± 10.8 y.o.) in a NYHA III functional class due to LM who were verified using endomyocardial biopsy. The main group included 29 patients who received MM at 2 g/day. The comparison group comprised 21 patients who received azathioprine at 150 [50; 150] mg/day. Both groups were administered with methylprednisolone. The average follow-up period was 30 [22; 35] months, but no less than 6 months. The groups were comparable in the baseline parameters and standard drug therapy. In both groups, there was a comparable significant increase in the ejection fraction (from 30.6 ± 7.7% to 44.0 ± 9.4% vs. 29.2 ± 7.7% to 46.2 ± 11.8%, p < 0.001), and a decrease in systolic pressure in the pulmonary artery and the dimensions of the left ventricle and atrium. The frequency of death was two (6.9%) and two (9.5%), transplantation was one (3.4%) and one (4.8%) patient and the "death + transplantation" endpoint was three (10.3%) and three (14.3%) without differences between the groups. The presence of the parvovirus B19 in the myocardium in 6/5 patients did not affect the results. The incidence of infectious complications was comparable. The most severe infectious complications were pneumonia and fatal purulent encephalitis (both cases in the azathioprine group), leptospirosis meningitis (in the mycophenolate mofetil group). In the patients with LM, the combination of corticosteroids with MM at a dose of 2 g/day was at least no less effective than with azathioprine. There was a tendency toward a better tolerance using MM.

Interleukin-17A-Correlated Myocarditis in Patients with Psoriasis: Cardiac Recovery following Secukinumab Administration.

(1) Background: Psoriasis (PS) is a common immune-mediated disease of the skin with possible extension to joints, aorta and eye. Myocardial inflammation has rarely been suggested. (2) Aims: Report of PS-related myocarditis. (3) Methods and Results: One hundred consecutive patients with PS were screened for cardiac involvement. Among them, five male patients (aged 56 ± 9.5 years) with a moderate-severe form of PS showed dilated cardiomyopathy (LVEF < 35%) with normal coronary arteries and valves. They underwent a left-ventricular endomyocardial biopsy for evaluation of myocardial substrate. Endomyocardial samples were processed for histology and immunohistochemistry, including myocardial expression of Toll-Like Receptor 4 (TLR4) and interleukin-17A (IL-17A), which play a major role in PS pathogenesis. Real-time PCRs were carried out for cardiotropic viruses, and Western blot analysis was conducted for myocardial expression of IL-17A. Patients' sera were tested for anti-heart autoantibodies. Active lymphocytic myocarditis was revealed in all five patients, characterized by an absence of viral genomes with PCR, positive anti-heart autoantibodies, overexpression of TLR-4 and enhancement of IL-17-A during western blot analysis, showing a 2.48-fold increase in psoriatic myocarditis compared with no psoriatic myocarditis and a six-fold increase compared to myocardial controls. Treatment included combination of prednisone (1 mg/kg daily for 4 weeks, tapered to 0.33 mg/kg) and azathioprine (2 mg/kg, daily) in 3 pts or secukinumab (SK, 150 mg/weekly for 4 weeks followed by 150 mg/monthly) in 2 pts for 6 months. LVEDD and LVEF improved in the first 3 pts (-14% and + 118%, respectively), while they completely recovered (LVEF > 50%) in the last 2 pts on SK. (4) Conclusions: IL-17A-related myocarditis can occur in up to 5% of patients with PS. It manifests as progressive dilated cardiomyopathy. It may completely recover following SK administration.

Evaluation of the mTORC activity in the presence of Toxoplasma gondii and azathioprine in human monocyte cell line

BackgroundAutophagy is an important part of pathogenesis of IBD. Thiopurines such as azathioprine (AZA) are approved drugs for clinical practices in IBD patients. Besides, as an escape strategy, Toxoplasma gondii can use the mTORC1 complex to inactivate autophagy.MethodsIn this study, we investigated whether T. gondii tachyzoites may modulate autophagy and interfere the effects of azathioprine in IBD treatment. PMA-activated human monocyte cell line (THP-1) was infected with fresh T. gondii RH tachyzoites. After 5 h of infection, the cells were treated with AZA for 6 h. The expression of atg5, atg7, atg12, lc3b, and β-actin (BACT) genes was evaluated using quantitative real-time PCR. To analyze the phosphorylation of ribosomal protein S6 (rpS6), western blot using specific primary antibodies was performed.ResultsThe results of real-time PCR revealed that AZA, T. gondii tachyzoites, and a combination of AZA and T. gondii tachyzoites upregulated atg5 gene for 4.297-fold (P-value = 0.014), 2.49-fold (P-value = 0.006), and 4.76-fold (P-value = 0.001), respectively. The atg7 gene showed significant upregulation (2.272-fold; P-value = 0.014) and (1.51-fold; P-value = 0.020) in AZA and AZA / T. gondii, respectively. The expression of atg12 gene was significantly downregulated in AZA and T. gondii tachyzoites for (8.85-fold; P-value = 0.004) and (2.005-fold; P-value = 0.038), respectively, but upregulated in T. gondii/AZA (1.52-fold; P-value = 0.037). In addition, the lc3b gene was only significantly changed in AZA / T. gondii (3.028-fold; P-value = 0.001). Western blot analysis showed that T. gondii tachyzoites significantly phosphorylated rpS6, and tachyzoites did not interfere the effects of AZA to phosphorylate the rpS6.ConclusionTaken together, although AZA and T. gondii similarly affects the expression levels of atg5, atg7, and atg12, but T. gondii does not seem to modulate the effects of AZA via mTORC functions.