A Case of a Relapsing Remitting Macrophage Activating Syndrome After Covid-19 Vaccine In a Teenager with UNC13D Heterozygous Variant of Uncertain Significance

Introduction: Macrophage activation syndrome (MAS) is a severe hyper inflammatory condition caused by the over-activation and proliferation of T cells, NK cells and macrophages. It is often associated with complications of rheumatic/immune diseases. We present a case of a 15-year-old female who experiences recurrent episodes of MAS without any known definitive underlying etiology. Case Presentation: A 15-year-old previously healthy female developed fatigue, fevers, myalgia, chest pain, splenomegaly and lymphadenopathy 10 days after receiving her first Pfizer COVID-19 vaccine. Her symptoms recurred 10 days after receiving the second dose. Her myocarditis, MIS-C, and infectious work up was negative except for positive EBV IgG. Laboratory studies revealed anemia, hypertriglyceridemia, hypofibrinogenemia, and hyperferritinemia. She initially responded to decadron;however, her symptoms recurred with steroid taper. Bone marrow biopsy revealed hemophagocytosis. Whole exome sequencing (WES) revealed a heterozygous variant of uncertain significance in UNC13D c.962C>A (p.Thr321Asn). She had multiple re-admissions with significantly elevated inflammatory markers, including extremely high IL2-R, IL-18 and CXCL9. Each episode was complicated by an acute viral infection. She responds to high dose steroids, anti-IL-1, and JAK inhibitors. Nonetheless, it has been difficult to wean decadron without triggering a flare. She continues to require increasing doses of baricitinib. Discussion(s): MAS may be seen as a complication of rheumatic diseases, as well as inborn errors of immunity. However, none of these conditions have been diagnosed in this patient despite extensive testing, including WES. The degree of her immune dysregulation has been very severe making her disease process unpredictable and extremely difficult to control. She has frequent flares precipitated by viral infections or attempts at adjusting her immunomodulators. Weaning her medications has been challenging as she continues to require increasing doses of baricitinib and corticosteroids. The UNC13D gene is associated with autosomal recessive familial hemophagocytic lymphohistiocytosis type 3 (FHL3). Our patient is heterozygous for an UNC13D variant of uncertain significance. Additional genetic inquiries with whole genome sequencing to help elucidate the underlying etiology of her severe condition is being conducted. We hypothesize she developed MAS due to a combination of genetic predisposition, prior EBV infection, and immune stress associated with the COVID-19 vaccine. [Formula presented] [Formula presented] [Formula presented]Copyright © 2023 Elsevier Inc.

Safety of Pharmacotherapy in COVID-19 Patients: A Literature Review.

The safety of COVID-19 pharmacotherapy is a relevant issue, first of all, because of the current lack of experience with using particular medicinal products and with off-label prescribing. The aim of the study was to analyse information on potential adverse drug reactions (ADRs) and their predictors in etiology- and pathogenesis-oriented COVID-19 therapy. According to literature data, the main clinically significant risk factors for COVID-19 patients to develop an ADR are the duration of their hospital stay, combined use of antivirals, polypharmacy, and their history of drug allergies. The most common adverse reactions to antivirals, to virus-neutralising antibodies, and to human anti-COVID-19 immunoglobulin and convalescent plasma are, respectively, gastrointestinal and hepatobiliary disorders;gastrointestinal disorders, neurological disorders, and allergic reactions;and transfusion reactions (fever, chills, etc.). For pathogenesis-oriented therapy with systemic glucocorticosteroids, the most characteristic ADR is hyperglycaemia. Janus kinase inhibitors and interleukin inhibitors are most often associated with gastrointestinal disorders and hypertransaminasemia;neutropenia is also characteristic of a number of interleukin inhibitors. Haemostatic adverse reactions to anticoagulants depend on the patient's dosing regimen and condition. Drug-drug interactions are a common problem in COVID-19 treatment, with the combination of nirmatrelvir and ritonavir showing the largest number of significant interactions attributed to their pharmacokinetics. Currently, there is data on the role of pharmacogenetic biomarkers in the safety and clinical outcomes of COVID-19 therapy. Thus, to improve the safety of COVID-19 therapy, an integrated approach is needed that will take into account both the clinical, demographic, and pharmacogenetic predictors of ADRs and the risk of drug-drug interactions.Copyright © 2023 Safety and Risk of Pharmacotherapy. All rights reserved.

Updated results from MOMENTUM: Momelotinib vs. Danazol in JAK inhibitor-experienced, symptomatic, and anaemic myelofibrosis patients

The phase 3 MOMENTUM study (NCT04173494) of the ACVR1/JAK1/JAK2 inhibitor momelotinib (MMB) vs. danazol (DAN) in patients with myelofibrosis (MF) previously treated with a JAK inhibitor (JAKi) met the primary endpoint and all key secondary endpoints at week 24 (W24). We provide updated results from week 48 assessments. Eligible patients had primary or post-ET/ PV MF;DIPSS high, Int-2, or Int-1 risk;Total Symptom Score (TSS) >=10;haemoglobin (Hb) <10 g/dL;platelets >=25 x 109/L;prior JAKi for >=90 days (>=28 days if red blood cell [RBC] transfusions >=4 units in 8 weeks or grade 3/4 thrombocytopenia/anaemia/ hematoma);and palpable spleen >=5 cm. Randomisation was 2:1 to MMB 200 mg/day or DAN 600 mg/day for 24 weeks, followed by open-label (OL) MMB. Week 48 endpoints included durations of response (TSS, transfusion independence [TI], splenic) and overall and leukaemia-free survival (OS, LFS). As of 17 May 2022, 93/130 (72%) MMB -> MMB and 41/65 (63%) DAN -> MMB patients received OL MMB;mean MMB durations were 48 weeks and 24 weeks, respectively. Analyses for W24 responders showed the following: of TSS responders, 31/32 (97%) MMB -> MMB and 6/6 DAN -> MMB patients had TSS < baseline;of TI responders, 36/40 (90%) and 10/13 (77%) had no RBC transfusions or Hb <8 g/dL;and of spleen responders, all patients had splenic volume < baseline. In the OL phase, the most common grade >=3 treatment-emergent adverse events (TEAEs) were thrombocytopenia (MMB -> MMB, 9%;DAN -> MMB, 15%) and anaemia (MMB -> MMB, 9%;DAN -> MMB, 2%). Grade >=3 infections occurred in 19% of MMB -> MMB and 10% of DAN -> MMB patients, including grade >=3 (nonfatal) COVID-19. Peripheral neuropathy (PN) occurred in 2% of patients in each arm, and none discontinued MMB due to PN. TEAEs led to MMB discontinuation in 18% (MMB -> MMB) vs. 10% (DAN -> MMB). A trend towards improved OS up to W24 was previously observed with MMB vs. DAN (hazard ratio [HR], 0.506;p = 0.0719);after all patients crossed over to OL MMB, OS and LFS curves for both arms converged (HR, 0.945, 95% CI, 0.528-1.693;HR, 0.830, 95% CI, 0.473-1.4555). Sixty of 81 (74%) MMB -> MMB and 29 of 43 (67%) DAN -> MMB patients with baseline platelets <=150 x 109/L entered the OL phase. Efficacy and safety results in thrombocytopenic subgroups in the OL period were consistent with the intent-to- treat (ITT) population. OL MMB maintained symptom, TI, and spleen responses with continued good survival and safety in the ITT and low platelet populations. MMB may address an unmet need in anaemic patients with MF.

Long-Term Efficacy and Safety of Upadacitinib in Patients with Psoriatic Arthritis Refractory to Biologic Therapies: 2-Year Results from the Phase 3 Select-Psa 2 Study

Background/Aims Upadacitinib (UPA), an oral Janus kinase (JAK) inhibitor, demonstrated efficacy and safety in patients (pts) with psoriatic arthritis (PsA) and prior inadequate response or intolerance to >=1 biologic disease modifying antirheumatic drug (bDMARD) at week (wk) 56 in the phase 3 SELECT-PsA 2 study. We aimed to evaluate the efficacy and safety of UPA at wk 104 from the ongoing long-term extension of SELECTPsA 2. Methods Pts were randomized to UPA 15mg (UPA15), UPA 30mg (UPA30), or placebo (PBO) for 24 wks;PBO pts were then switched to UPA15 or UPA30. For continuous UPA treatment groups, efficacy endpoints at wk 104 were analyzed using non-responder imputation (NRI) and as observed (AO) (binary endpoints) or mixed-effect model repeated measures (MMRM) and AO (continuous endpoints). Treatmentemergent adverse events (TEAEs) were summarized for pts who received >=1 dose of study drug using visit-based cut-off at wk 104. Results A total of 641 pts received >=1 dose of study drug. At wk 104, 38.4% of all patients had discontinued study drug, with the highest discontinuation observed in patients randomized to PBO at baseline (all PBO: 46.7%). The most common reasons for discontinuation were lack of efficacy (UPA15: 12.3%, UPA30: 8.7%, all PBO: 21.7%) and adverse event (UPA15: 10.9%, UPA30: 13.3%, all PBO: 12.7%). The proportion of UPA pts that achieved ACR20/50/70, MDA, PASI75/90/100, and resolution of dactylitis and enthesitis were generally similar, or further improved, with 104 wks of treatment vs 56 wks. Similarly, mean change from baseline in HAQ-DI, patient's assessment of pain, BASDAI, and ASDAS was improved with UPA treatment. At 104 wks of therapy, clinical responses were largely similar with UPA15 and UPA30. Generally, safety data at wk 104 were consistent with that reported at wk 56. Rates of serious infection, herpes zoster, hepatic disorder, anemia, neutropenia, lymphopenia, and CPK elevation remained numerically higher with UPA30 vs UPA15, while rates of malignancies, MACE, and VTE were similar for both UPA groups. One death was reported with UPA15 (unexplained due to lack of information;however, the patient had recently been diagnosed with ovarian cancer) and two with UPA30 (pancytopenia and COVID-19 pneumonia). Conclusion In PsA pts with prior inadequate response or intolerance to>=1 bDMARD, clinical responses were maintained with UPA15 and UPA30 up to two years of treatment. No new safety signals were identified in this long-term extension.

Real-World Single-Centre Experience of Jak Inhibitor Use in Ra

Background/Aims The use of Janus Kinase Inhibitors (JAKi) has been gradually increasing overtime in the management of rheumatoid arthritis (RA) and other inflammatory arthritis and these appeal to patients. being oral agents. Nevertheless, rheumatologists have become cautious about their use since recent trials have shown safety concerns about VTEs, MACE and malignancies. Methods We decided to study use of JAKi at our centre in Princess of Wales Hospital Bridgend. The aim was to assess whether appropriate patients were selected (considering cautions about MACE, VTEs and malignancies). We also wanted to see whether all patients had required pretreatment safety testing and post-treatment monitoring performed. Results These were 70 patients;59 were females and 11 were males. All of them were diagnosed as RA. Average age was 61.1 years (20-85), average duration of disease 129.9 months (16-340) and average duration of treatment was 58.1 weeks. The most common JAKi being used was baricitinib (84%) followed by tofacitinib (12%) and upadacitinib (4%). 50% patient were on concomitant csDMARDs among whom two-thirds were on methotrexate. Looking at previous biologic use, 9 patients were biologic naive, 22 had one biologic, 15 had two biologics used in the past. All patients were appropriately selected (severe RA and no significant risk factors for MACE, VTEs and malignancies). All patients had pre-treatment Hepatitis B, Hepatitis C, latent TB, FBC and LFTs checked. All patients had FBC and LFTs monitored post treatment. No patient developed VTE, MACE or cancer on treatment. 84.2% patients had lipids tested before starting JAKi. 22.8% patients had abnormal lipids before Rx initiation and 62.5% of these were on lipid lowering Rx. All patients had lipids tested post treatment, but the timing was quite variable and only 62.5% of patients had lipids tested on the recommended time. There were 2 deaths recorded in this cohort. One of those was an 80-year-old RA patient on baricitinib 2mg OD, who died due to chest infection on the background of ILD. He was not on steroids or csDMARDs. The second patient was 63 years' old (on baricitinib 4mg OD), and died due to respiratory sepsis, and was also on azathioprine. She had RA with advanced ILD. The reasons for discontinuing JAKi were inefficacy (46%), side effects (39%) and both inefficacy and side effects (15%). 41.4%of patient experienced side effects due to JAKi. These included infection 28%, deranged lipids 17%, cytopenia 14%, deranged LFTs 14%, GI side effects 10%, skin rash 7% and varicella zoster 3%. Conclusion There has been steady increase in the use of tsDMARDs for RA and other rheumatic conditions. Due to short half-life, these drugs became a popular choice during COVID-19 pandemic but on the other hand safety monitoring became extremely challenging during this time.

Long-Term Outcomes of Treatment With and De-Escalation From a Combination of Vedolizumab and Another Biologic or Tofacitinib for Inflammatory Bowel Disease

Introduction: There are scant data on long-term outcomes of treatment of inflammatory bowel disease (IBD) with a combination of advanced therapies, including after de-escalation. Method(s): We identified patients with IBD at a tertiary center who began therapy with vedolizumab (VDZ) in combination with another advanced therapy (biologic or JAK inhibitor) between 2016 and 2020 and examined their outcomes through 6/1/22. We defined biochemical remission as CRP, 5 mg/L and calprotectin < 150 mcg/g, and endoscopic remission as Mayo endoscopic subscore 0 or simple endoscopic score for Crohn's disease (CD) 0. Short-term outcomes of this cohort were previously reported. Result(s): Fourteen patients with a median of 322 (IQR 251-322) weeks of follow up were identified. 10 had ulcerative colitis, 3 CD, and 1 indeterminate colitis. VDZ was combined with tofacitinib in 9 patients, ustekinumab in 3 and adalimumab in 2. Median time on combination therapy was 94 weeks (IQR 17-133). Eight patients achieved objective remission (3 biochemical, 5 endoscopic), 1 changed combination with subsequent endoscopic remission, 2 had primary non-response, 1 had secondary non-response, 1 stopped within 1 month due to reported adverse effect (paresthesia), and 1 lacked follow-up data. Eight patients de-escalated to a single agent, 4 at physician direction and 4 due to insurance denial. Before de-escalation, 6 had objective remission (2 biochemical, 4 endoscopic). After de-escalation, 3 patients maintained objective remission (2 biochemical, 1 endoscopic), 3 had disease flare, of which 1 required colectomy, and 2 lacked data. All 3 patients with disease flare had de-escalated following an insurance denial. Two patients remained on combination therapy through follow up: 1 has endoscopic remission after changing one drug of their combination and 1 has ongoing moderate endoscopic disease despite combination therapy. There were 2 infections requiring hospitalization (rotavirus, C. difficile), and 8 non-serious infections (5 mild SARS-COV-2, 1 peristomal cellulitis, 1 pneumonia, 1 sinus) while on combination therapy. Conclusion(s): In long-term follow up of this small cohort, there were no new signals on effectiveness or safety of combining advanced agents. De-escalation to a single agent was tolerated in half of patients with follow-up data;all patients who flared following de-escalation had adjusted therapy due to insurance denial. More data is needed to inform de-escalation decisions.

Experience of Baricitinib in a Real-World Population with Efficacy and Side Effects: A South London Regional Analysis

Background/Aims Baricitinib is the most common Janus Kinase inhibitor (JAKi) used in the treatment of rheumatological conditions. Whilst randomised controlled trials have demonstrated the efficacy and safety profile of baricitinib, real-world data on the experience of JAKi use in clinical practice is lacking. The aim of this analysis was to evaluate baricitinib use in a real-world patient population in South London. Methods We looked at two rheumatology departments in South London (St George's Hospital;a tertiary teaching centre and Kingston Hospital;a district general hospital). All patients prescribed baricitinib between January 2017 to June 2022 were included. A retrospective assessment of electronic patient notes was performed to evaluate disease activity (determined by DAS-28 scores at baseline, 3-6 months and presently);adverse effects including side effects, rates of and reasons for discontinuation;and prescribing practice, including previous use of other biological disease modifying anti-rheumatic drugs (bDMARDs). Baseline data including age, gender, co-morbidities and rheumatological diagnoses were also included. Results 233 patients were included in this evaluation, with seropositive rheumatoid arthritis being the most common diagnosis (58%) and with a significant female population (87%). Baricitinib improved average DAS-28 scores from 5.75 (range 3.57-8.3) at baseline to 3.23 (range 0.28-7.49) at 3-6 months post-baricitinib, with the most recent DAS-28 score of 2.90 (range 0.56-6.77). Rates of adverse effects were low as shown in Table 1. Baricitinib was discontinued in 60/233 patients, with average duration to discontinuation of 9.5 months. The most common reasons for discontinuation were: ineffective disease control (28/60), recurrent bacterial infection (5/60), deranged liver function (3/60) and venous thromboembolism (2/60). Eight patients died whilst taking baricitinib. Where documented, the causes of death were Covid-19 (4/8) and malignancy (1/8). 110 out of 233 patients had received other bDMARDs before starting baricitinib. Documented reasons for baricitinib choice over tumour necrosis factor inhibitors (TNFi) included: previous lack of response to TNFi (89/233), contra-indication to TNFi (11/233) and preference of oral route (10/ 233). Conclusion Our real-world study of JAKi use shows that baricitinib is efficacious in the treatment of rheumatological conditions. Moreover, baricitinib is well tolerated, with low rates of adverse effects and subsequent discontinuation. (Table Presented).

Janus Kinase Inhibitors in Rheumatoid Arthritis Patients: Real-World Experience from a Regional Centre in Uk

Background/Aims Tofacitinib and baricitinib were the first orally available, targeted synthetic Janus kinase (JAK) inhibitors approved for the treatment of rheumatoid arthritis (RA) in the UK. Evidence suggests that JAK inhibitors are as efficacious as biological DMARDs in the treatment of RA. Their safety profile has been demonstrated in long term extension studies and RCTs. However, real-world, long-term data remains as important in bridging the gap between controlled studies and routine practice. We report our initial real-world experience of a cohort of RA patients commenced on JAKi before the SARS-CoV-2 pandemic within a regional centre in the UK. Methods All patients commenced on JAKi for the treatment of RA between February 2018 and March 2020 were identified from our in-house database. Data was retrospectively collected from clinical notes and electronic health records from February 2018 up until April 2022. This included patient demographics, disease duration, serological status, concurrent csDMARD usage, history of bDMARD exposure, duration of use and reason for discontinuation of the drug if appropriate. DAS- 28 scores were recorded at baseline and quarterly. SPSS (version 22.0) was used for data analysis. Results One hundred thirty patients were treated with JAK inhibitors (Tofacitinib 22%, Baricitinib 78%);80% female, mean (S.D.) age 61.5 (12.3) years. 92 (70.8%) patients were seropositive. 70 (53.8%) patients were on concurrent csDMARDs and 23 (17.7%) on concurrent steroids. The mean number of previous bDMARDs was 1.8 +/- 1.7;41 (31.5%) were bDMARD naive. The mean baseline DAS-28 ESR (S.D.) score was 5.96 (0.96). There were significant differences in mean DAS- 28 ESR scores (compared with baseline) of 1.54, 1.96, 2.41, 2.33 and 1.80 at 3, 6, 12, 18 and 24 months respectively (p<0.0001). Mean DAS-28 ESR scores were not statistically significant between bDMARD naive patients and those that had previously received bDMARDs. Overall JAKi retention rate was 66.9% with a mean follow up duration of 27.4+/-13.1 months. Persistence was 88.5%, 76.9%, 73.2% and 68.5% at 6, 12, 18, and 24 months, respectively. Of the 38 patients who stopped JAK inhibitors, 11 stopped due to inefficacy (6, primary inefficacy). 3 patients were lost to follow-up and 6 deceased. Cause of death was sepsis (2), venous thromboembolism (1) and unknown (3). 18 patients stopped because of adverse events (AEs). The most common AEs were recurrent infections (11), gastrointestinal side effects (9), lymphopenia (7), thromboembolic events (6) and herpes zoster (5). In total 6 (4.1%) patients had thromboembolic events which included pulmonary embolism (4) and deep vein thrombosis (1) and central retinal artery thrombosis (1). Conclusion JAK inhibitors in this real-world population of RA patients were effective in reducing disease activity and patients had high persistence rates. Recurrent infections, herpes zoster and thrombo-embolism remain adverse events of concern.

Use of Upadacitinib in 11 Tofacitinib-Refractory Ulcerative Colitis Patients at a Single Tertiary Care Center

INTRODUCTION: Ulcerative colitis (UC) is a chronic inflammatory condition characterized by diarrhea, abdominal pain, rectal bleeding, and weight loss. Upadacitinib is an oral, selective, small molecule Janus Kinase (JAK) inhibitor that was recently approved in the United States for moderate to severe UC. Clinical trials evaluating the efficacy of upadacitinib excluded patients with a previous exposure to tofacitinib, a nonselective JAK inhibitor;therefore, the efficacy of upadacitinib in patients with previous exposure to tofacitinib remains largely unknown. METHOD(S): We present a small retrospective case series of all patients with a diagnosis of ulcerative colitis seen at our institution between with a prior exposure to tofacitinib who were initiated on upadacitinib between May and August of 2022. Demographic data was collected as well as outcome data on clinical improvement, steroid-free remission, biochemical improvement, colectomy status, and adverse events. RESULT(S): Eleven tofacitinib-refractory patients with ulcerative colitis were initiated on upadacitinib. Mean age was 38.1 years, five (45.5%) patients were female, nine (81.8%) patients were white, seven (63.6%) patients had pancolitis, and mean duration of UC was 7.4 years (Table 1). In this group, there were high rates of prior targeted therapy failures. These patients were followed for a mean of 121 days. The clinical course of each patient is presented in Table 2. Of the 11 patients included in our study, nine (81.8%) patients reported symptomatic improvement, six (54.5%) patients were able to successfully taper corticosteroids, and two (18.2%) patients underwent colectomy, one of which was elective and planned prior to initiating upadacitinib. The mean fecal calprotectin improvement was 1430mg/kg of patients with both baseline and follow-up testing. Three (27.3%) patients experienced an adverse event;two (18.2%) patients with mild COVID-19 not requiring hospitalization and one (9.1%) patient with Enteropathogenic E. Coli. DISCUSSION: This real-world single-center case series of 11 patients, suggests that upadacitinib may be an effective option for patients with a previous tofacitinib exposure. Larger prospective studies are needed to confirm these findings. [Formula presented] [Formula presented]Copyright © 2023

COVID-19 vaccine-induced neutralising antibody responses against SARS-CoV-2 Omicron BA.4/5 are diminished in patients with inflammatory bowel disease on anti-TNF or JAK-inhibitor therapy

Background: Patients with Inflammatory bowel disease (IBD) receiving anti-TNF or JAK-inhibitor therapy have attenuated responses to COVID-19 vaccination. We aimed to determine how IBD treatments affect neutralising antibody responses against the currently dominant Omicron BA.4/5 variants. Method(s): We prospectively recruited 329 adults (68 healthy controls (HC) and 261 IBD) who had received three doses of COVID-19 vaccine at nine UK centres. The IBD population was established (>12 weeks therapy) on either thiopurine (n=60), infliximab (IFX) (n=43), thiopurine and IFX combination (n=46), ustekinumab (n=43), vedolizumab (n=46) or tofacitinib (n=23). Pseudoneutralisation assays were performed and the half maximal inhibitory concentration (NT50) of participant sera was calculated. The primary outcome was anti-SARSCoV-2 neutralising response against wild-type (WT) virus and the BA.4/5 variant after the second and third doses of anti-SARS-CoV-2 vaccine, stratified by immunosuppressive therapy, adjusting for prior infection, ethnicity, vaccine type and age. Result(s): Heterologous (two doses adenovirus vaccine, third dose mRNA vaccine) and homologous (three doses mRNA vaccine) vaccination strategies significantly increased neutralising titres against both WT SARS-CoV-2 virus and the BA.4/5 variants in HCs and IBD (fig 1). Antibody titres against BA.4/5 were significantly lower than antibodies against WT virus in both groups (Geometric Mean Ratio (GMR) [95% CI], 0.11 [0.09, 0.15], P<0.0001 in healthy participants;GMR 0.07 [0.06, 0.08], P<0.0001 in IBD patients). Multivariable models showed that neutralising antibodies against BA.4/5 after three doses of vaccine were significantly lower in IBD patients on IFX (GMR 0.44 [0.20, 0.97], P=0.042), IFX and thiopurine combination (GMR 0.34 [0.15, 0.77], P=0.0098) or tofacitinib (GMR 0.37 [0.15, 0.92], P=0.032), but not in patients on thiopurine monotherapy, ustekinumab or vedolizumab. Breakthrough infection was associated with lower neutralising antibodies against WT and BA.4/5 (P<0.05). Conclusion(s): A third dose of COVID-19 vaccine based on the WT spike glycoprotein boosts neutralising antibody titres in patients with IBD. However, responses are lower against the currently dominant variant BA.4/5, particularly in patients taking anti-TNF or JAK-inhibitor therapy. Breakthrough infections are associated with lower neutralising antibodies and immunosuppressed IBD patients may receive additional benefit from bivalent vaccine boosters which target Omicron variants. .

Use of Upadacitinib in 11 Tofacitinib-Refractory Ulcerative Colitis Patients at a Single Tertiary Care Center

INTRODUCTION: Ulcerative colitis (UC) is a chronic inflammatory condition characterized by diarrhea, abdominal pain, rectal bleeding, and weight loss. Upadacitinib is an oral, selective, small molecule Janus Kinase (JAK) inhibitor that was recently approved in the United States for moderate to severe UC. Clinical trials evaluating the efficacy of upadacitinib excluded patients with a previous exposure to tofacitinib, a nonselective JAK inhibitor;therefore, the efficacy of upadacitinib in patients with previous exposure to tofacitinib remains largely unknown. METHOD(S): We present a small retrospective case series of all patients with a diagnosis of ulcerative colitis seen at our institution between with a prior exposure to tofacitinib who were initiated on upadacitinib between May and August of 2022. Demographic data was collected as well as outcome data on clinical improvement, steroid-free remission, biochemical improvement, colectomy status, and adverse events. RESULT(S): Eleven tofacitinib-refractory patients with ulcerative colitis were initiated on upadacitinib. Mean age was 38.1 years, five (45.5%) patients were female, nine (81.8%) patients were white, seven (63.6%) patients had pancolitis, and mean duration of UC was 7.4 years (Table 1). In this group, there were high rates of prior targeted therapy failures. These patients were followed for a mean of 121 days. The clinical course of each patient is presented in Table 2. Of the 11 patients included in our study, nine (81.8%) patients reported symptomatic improvement, six (54.5%) patients were able to successfully taper corticosteroids, and two (18.2%) patients underwent colectomy, one of which was elective and planned prior to initiating upadacitinib. The mean fecal calprotectin improvement was 1430mg/kg of patients with both baseline and follow-up testing. Three (27.3%) patients experienced an adverse event;two (18.2%) patients with mild COVID-19 not requiring hospitalization and one (9.1%) patient with Enteropathogenic E. Coli. DISCUSSION: This real-world single-center case series of 11 patients, suggests that upadacitinib may be an effective option for patients with a previous tofacitinib exposure. Larger prospective studies are needed to confirm these findings. (Table Presented).

Safety of Pharmacotherapy in COVID-19 Patients: A Literature Review.

The safety of COVID-19 pharmacotherapy is a relevant issue, first of all, because of the current lack of experience with using particular medicinal products and with off-label prescribing. The aim of the study was to analyse information on potential adverse drug reactions (ADRs) and their predictors in etiology- and pathogenesis-oriented COVID-19 therapy. According to literature data, the main clinically significant risk factors for COVID-19 patients to develop an ADR are the duration of their hospital stay, combined use of antivirals, polypharmacy, and their history of drug allergies. The most common adverse reactions to antivirals, to virus-neutralising antibodies, and to human anti-COVID-19 immunoglobulin and convalescent plasma are, respectively, gastrointestinal and hepatobiliary disorders;gastrointestinal disorders, neurological disorders, and allergic reactions;and transfusion reactions (fever, chills, etc.). For pathogenesis-oriented therapy with systemic glucocorticosteroids, the most characteristic ADR is hyperglycaemia. Janus kinase inhibitors and interleukin inhibitors are most often associated with gastrointestinal disorders and hypertransaminasemia;neutropenia is also characteristic of a number of interleukin inhibitors. Haemostatic adverse reactions to anticoagulants depend on the patient's dosing regimen and condition. Drug-drug interactions are a common problem in COVID-19 treatment, with the combination of nirmatrelvir and ritonavir showing the largest number of significant interactions attributed to their pharmacokinetics. Currently, there is data on the role of pharmacogenetic biomarkers in the safety and clinical outcomes of COVID-19 therapy. Thus, to improve the safety of COVID-19 therapy, an integrated approach is needed that will take into account both the clinical, demographic, and pharmacogenetic predictors of ADRs and the risk of drug-drug interactions.Copyright © 2023 Safety and Risk of Pharmacotherapy. All rights reserved.

A Comprehensive Mini-review on COVID-19 Pathogenesis on Perspectives of Cytokine Storm and Recent Developments in Anti-Covid Nucleotide Analogues

The world has been rocked by the 2019 coronavirus disease (COVID-19), which has significantly changed our way of life. Despite the unusual measures taken, COVID-19 still exists and affects people all over the world. A remarkable amount of study has been done to find ways to combat the infection's unsurpassed level. No ground-breaking antiviral agent has yet been introduced to remove COVID-19 and bring about a return to normalcy, even though numerous pharmaceuticals and therapeutic technologies have been reused and discovered. The cytokine storm phenomenon is of utmost importance since fatality is strongly connected with the severity of the disease. This severe inflammatory phenomenon marked by increased amounts of inflammatory mediators can be targeted for saving patients' life. Our analysis demonstrates that SARS-CoV-2 specifically generates a lot of interleukin-6 (IL-6) and results in lymphocyte exhaustion. Tocilizumab is an IL-6 inhibitor that is currently thought to be both generally safe and effective. Additionally, corticosteroids, tumor necrosis factor (TNF)-blockers and Janus kinase (JAK) inhibitors could be effective and dependable methods to reduce cytokine-mediated storm in SARS-CoV-2 patients.Copyright © The Author(s) 2023.

Effect of upadacitinib on inflammatory markers and clinical outcomes in patients with Crohn's disease in the phase 3, U-EXCEL, U-EXCEED, and U-ENDURE studies

Background: Improvement in clinical outcomes and normalisation of objective markers of inflammation, high-sensitivity C-reactive protein (hs-CRP) and faecal calprotectin (FCP), are considered treatment targets per STRIDE-II guidelines.1 We evaluated the effect of the oral selective Janus kinase inhibitor upadacitinib (UPA) on changes in hs-CRP, FCP, and clinical outcomes in patients with Crohn's disease (CD). Method(s): In 2 phase 3, randomized, double-blind, placebo-controlled induction studies (U-EXCEL, NCT03345849;U-EXCEED, NCT03345836), patients with moderate-to-severe CD received 12-week treatment with UPA 45 mg (UPA45) once daily (QD) or placebo (PBO). Patients with clinical response to UPA45 were rerandomised in U-ENDURE (NCT03345823) to receive 52-week maintenance treatment with UPA 30 mg QD (UPA30), UPA 15 mg QD (UPA15), or PBO. Endpoints included marker normalisation (hs-CRP <= 5 mg/L, FCP <= 250 mug/g) in patients with elevated baseline marker levels, normal marker and clinical remission by Crohn's Disease Activity Index (CDAI < 150) or very soft/liquid stool frequency (SF)/abdominal pain score (APS) (average daily SF <= 2.8 and average daily APS <= 1, neither greater than baseline), and >= 50% reduction from baseline in marker values with a decrease of at least 100 points in CDAI from baseline. Median changes from baseline in marker levels were also evaluated. Non-responder imputation with no special data handling for missing data due to COVID-19 was used. Result(s): Of 1021 enrolled patients, 645 (63.2%) had elevated hs-CRP (> 5 mg/L) and 750 (73.5%) had elevated FCP (> 250 mug/g) levels at baseline. Significantly greater proportions of patients with elevated baseline marker levels achieved normalisation with UPA compared with PBO at week 12 (Fig 1A/B) and week 52 (Fig 2A/B;nominal P < .001 for all). Decreases in marker levels from baseline with UPA were observed as early as week 2 and were significantly greater than with PBO through week 12 (Fig 1C) and week 52 (Fig 2C;nominal P < .001 for all). Patients achieved clinical endpoints and improvements in markers at significantly higher rates with UPA45 vs PBO at week 12 (Fig 1D-F) and with UPA15 and UPA30 vs PBO at week 52 (Fig 2D-F;P < .001 for all). The safety profile of UPA in CD was previously reported and no new safety concerns were identified. Conclusion(s): Improvements in clinical endpoints and normalisation of objective markers of inflammation were achieved as early as week 2 with UPA45 induction and sustained with UPA15 and UPA30 maintenance therapy in patients with CD. Median changes in hs-CRP and FCP with UPA support continued improvement of inflammation up to week 52 .

Ulcerative Colitis: Rapid Evidence Review

Ulcerative colitis is a relapsing and remitting inflammatory bowel disease of the large intestine. Risk factors include recent Salmonella or Campylobacter infection and a family history of ulcerative colitis. Diagnosis is suspected based on symptoms of urgency, tenesmus, and hematochezia and is confirmed with endoscopic findings of continuous inflammation from the rectum to more proximal colon, depending on the extent of disease. Fecal calprotectin may be used to assess disease activity and relapse. Medications available to treat the inflammation include 5-aminosalicylic acid, corticosteroids, tumor necrosis factor-alpha antibodies, anti-integrin antibodies, anti-interleukin-12 and -23 antibodies, and Janus kinase inhibitors. Choice of medication and method of delivery depend on the location and severity of mucosal inflammation. Other treatments such as fecal microbiota transplantation are considered experimental, and complementary therapies such as probiotics and curcumin have mixed data. Surgical treatment may be needed for fulminant or refractory disease. Increased risk of colorectal cancer and use of immunosuppressive therapies affect the preventive care needs for these patients. (Am Fam Physician. 2022;105(4):406-411. Copyright © 2022 American Academy of Family Physicians.)Copyright © 2022 American Academy of Family Physicians. All rights reserved.

A Randomized, Double-Blind, Placebo-Controlled Phase II Study to Evaluate the Efficacy and Safety of Ivarmacitinib (SHR0302) in Adult Patients with Moderate to Severe Alopecia Areata.

BACKGROUND: Alopecia areata (AA) is a CD8+ T cell mediated autoimmune disease characterized by non-scarring hair loss. Ivarmacitinib, a selective oral Janus kinase 1 (JAK1) inhibitor, may interrupt certain cytokine signaling implicated in the pathogenesis of AA. OBJECTIVE: To evaluate the efficacy and safety of ivarmacitinib in adult AA patients who have ≥25% scalp hair loss. METHODS: Eligible patients were randomized 1:1:1:1 to receive ivarmacitinib 2 mg, 4 mg, or 8 mg QD or placebo for 24 weeks. The primary endpoint was percentage change from baseline in Severity of Alopecia Tool (SALT) score at week 24. RESULTS: A total of 94 patients were randomized. At week 24, the least squares mean (LSM) difference in percentage change from baseline in SALT score for ivarmacitinib 2 mg,4 mg, 8 mg, and placebo groups were -30.51% (90% confidence interval [CI]: -45.25, -15.76), -56.11% (90% CI: -70.28, -41.95), -51.01% (90% CI: -65.20, -36.82) and -19.87% (90% CI: -33.99, -5.75), respectively. Two SAEs, follicular lymphoma, and COVID-19 pneumonia were reported. LIMITATIONS: Small sample size limits the generalizability of the results. CONCLUSION: Treatment with ivarmacitinib 4 mg and 8 mg doses in moderate and severe AA patients for 24 weeks was efficacious and generally tolerated.

Safety of Pharmacotherapy in COVID-19 Patients: A Literature Review

The safety of COVID-19 pharmacotherapy is a relevant issue, first of all, because of the current lack of experience with using particular medicinal products and with off-label prescribing. The aim of the study was to analyse information on potential adverse drug reactions (ADRs) and their predictors in etiology- and pathogenesis-oriented COVID-19 therapy. According to literature data, the main clinically significant risk factors for COVID-19 patients to develop an ADR are the duration of their hospital stay, combined use of antivirals, polypharmacy, and their history of drug allergies. The most common adverse reactions to antivirals, to virus-neutralising antibodies, and to human anti-COVID-19 immunoglobulin and convalescent plasma are, respectively, gastrointestinal and hepatobiliary disorders;gastrointestinal disorders, neurological disorders, and allergic reactions;and transfusion reactions (fever, chills, etc.). For pathogenesis-oriented therapy with systemic glucocorticosteroids, the most characteristic ADR is hyperglycaemia. Janus kinase inhibitors and interleukin inhibitors are most often associated with gastrointestinal disorders and hypertransaminasemia;neutropenia is also characteristic of a number of interleukin inhibitors. Haemostatic adverse reactions to anticoagulants depend on the patient's dosing regimen and condition. Drug-drug interactions are a common problem in COVID-19 treatment, with the combination of nirmatrelvir and ritonavir showing the largest number of significant interactions attributed to their pharmacokinetics. Currently, there is data on the role of pharmacogenetic biomarkers in the safety and clinical outcomes of COVID-19 therapy. Thus, to improve the safety of COVID-19 therapy, an integrated approach is needed that will take into account both the clinical, demographic, and pharmacogenetic predictors of ADRs and the risk of drug-drug interactions.

Tofacitinib in the treatment of ulcerative colitis : A position paper issued by the Inflammatory Bowel Disease Working Group of the Austrian Society of Gastroenterology and Hepatology (ÖGGH).

Ulcerative colitis (UC) is one of the main forms of inflammatory bowel disease (IBD). Despite the widening range of drug treatment options, primary nonresponse, secondary loss of response as well as adverse events call for additional treatment alternatives.Tofacitinib is an oral small-molecule drug of the class of Janus kinase inhibitors which, in the European Union, was approved for the treatment of moderate to severe active UC in August 2018. This position paper, drawn up by the IBD Working Group of the Austrian Society of Gastroenterology and Hepatology, summarizes the mechanism of action, clinical development, marketing authorization status, efficacy and safety of tofacitinib. Also, by providing a synopsis of available data from both pivotal and post-marketing studies, clinical aspects of specific interest are highlighted and discussed.The available body of evidence indicates that tofacitinib is an additional effective medication for the treatment of UC that exhibits a good safety profile. This position paper aims at optimizing the safe and effective use of tofacitinib in daily clinical practice.