Sequencing JAK-inhibitors in ulcerative colitis: effectiveness and safety of switching within treatment class.

Biologics have transformed the management of severe psoriasis, yet despite long-term safety data published from the British Association of Dermatologists (BAD) Biologics and Immunomodulators Registry, most institutions continue frequent and costly blood monitoring. The 2014–2020 BAD guidelines for biologic therapy recommend monitoring full blood count, renal function and liver function at 3 months then every 6 months, with tuberculosis and other panels as clinically indicated. Our study aimed to evaluate real-world reasons for biologic switches or discontinuations in our large psoriasis cohort to assess blood abnormalities and inform optimized monitoring strategies. This was a retrospective review of patients with psoriasis requiring intervention in biologic therapy between 2007 and 2024 across multiple dermatology units in our multisite teaching NHS trust. Patients on biologics for ≥ 2 years were included, while those lost to follow-up were excluded. Among 548 patients with psoriasis on biologics, 148 (27%) required intervention (222 episodes: switch n = 196, discontinuation n = 26). Of those requiring intervention, most had at least one comorbidity (73%, n = 108), including psoriatic arthritis (71%, n = 105), type 2 diabetes (16%, n = 23), nonalcoholic fatty liver disease (10%, n = 15) and ulcerative colitis (3%, n = 4). Ethnicities were White (43%, n = 64), South Asian (43%, n = 63), Afro-Caribbean (2%, n = 3) and others (12%, n = 18). Concurrent systemic immunosuppression (methotrexate or ciclosporin) was prescribed in 21% (n = 31). The mean cumulative duration on biologics was 83.3 months (range 24–204), and the mean time to first intervention was 43.0 months (range 2–170). The biologics with most interventions were adalimumab or biosimilars (n = 102: Humira n = 39, Idacio n = 30, Hyrimoz n = 23, Amgevita n = 10), ustekinumab (n = 39), secukinumab (n = 35), guselkumab (n = 13) and certolizumab (n = 11). Of 222 interventions, reasons included secondary failure (44%, n = 97), primary failure (27%, n = 59), side-effects (9%, n = 20) and blood abnormalities (5%, n = 11). The main blood abnormality was positive tuberculosis ELISpot assay (interferon-γ release assay) (n = 6: Humira n = 2; and Idacio, ustekinumab, etanercept and risankizumab n = 1 each). Other abnormalities included leucocytosis in sepsis (n = 2; ustekinumab, secukinumab), neutropenia (n = 1; Hyrimoz), raised alanine aminotransferase (n = 1; Humira) and raised fetal calprotectin (n = 1; Ixekizumab). Side-effects were dermatological (n = 7; urticarial rash, paradoxical eczema, hidradenitis suppurativa), painful injections (n = 4; Idacio n = 3, Hyrimoz n = 1), gastrointestinal (n = 3; secukinumab n = 2; Idacio n = 1) and recurrent infections (n = 2; Hyrimoz, ustekinumab). Adalimumab antibodies were elevated in 8% (8 of 102) of primary or secondary failures in the adalimumab and biosimilars group. In conclusion, this 17-year multisite study highlights primary and secondary failures as main reasons for biologic therapy intervention. Blood abnormalities requiring treatment intervention were infrequent, most commonly positive tuberculosis testing. Our findings support reducing blood monitoring of patients with stable psoriasis on biologics to every 12 months, while considering annual tuberculosis screening, to enhance resource efficiency while maintaining patient safety in management of biologics for psoriasis.

Background Very few data exist on the use of a second JAK inhibitor (JAKi) in patients with ulcerative colitis (UC), already exposed to a first line of JAKi. The aim of this study was to evaluate the efficacy and safety of a second line of JAKi in UC. Methods We conducted an ambispective observational multicenter study in 28 Belgian and French centers. All patients with refractory UC, previously exposed to a first-line JAKi and subsequently receiving another JAKi, were included between July 2019 and September 2024. The primary endpoint was corticosteroid-free clinical remission at the end of the induction period (weeks 8-14), defined by a partial Mayo score ≤ 2 without any subscore > 1. Results A total of 153 patients, 61% men, with a median age at diagnosis of 23 years (IQR [18.1-34.7]), were included and followed up for a median of 3 months (IQR [2- 10.9]). The median duration of disease was 7 years (IQR [4.2- 11.9]) and 90% of patients had been exposed to at least two biologics (excluding JAKi). The first-line JAKi was tofacitinib for 107 patients (70%), filgotinib for 38 (25%) and upadacitinib for 8 patients (5%). At baseline, the median partial mayo score was 6 (IQR [5-8]), the median CRP was 4.6 mg/L (IQR [1.5-14]) and the median fecal calprotectin was 611 μg/g (IQR [325-1488]). In second-line treatment, 96 patients (63%) received upadacitinib, 48 (31%) filgotinib and 9 (6%) tofacitinib. Follow-up data for the induction period were available for 125 patients. At week 8-14, 57/125 patients (46%) were in corticosteroid-free remission, including 40/78 on upadacitinib (51%), 15/40 (38%) on filgotinib and 2/7 (29%) on tofacitinib. No significant difference was found in steroid-free remission rates between upadacitinib and filgotinib at induction (p=0.19). Clinical response was achieved in 57 patients (73%) on upadacitinib, 23 patients (58%) on filgotinib and 5 patients (71%) on tofacitinib. The median partial Mayo score, CRP and calprotectin were 2 (IQR [0 ;3]), 1 (IQR [1 ;6.7]) and 385 μg/g (IQR [90 ;855]) respectively, for the overall population. Among the 23 patients (18%) who discontinued treatment before weeks 8-14, the reason was primary failure for 16 patients (70%) and an adverse event for 6 (26%). During the induction period, 14 patients (18%) on upadacitinib experienced AEs, the most frequent being acne; 8 (19%) on filgotinib; and 2 (29%) on tofacitinib. No cases of herpes zoster, cancer or vascular accident were observed. Seven (5%) patients underwent colectomy during follow-up. Conclusion In refractory UC, 46% of patients treated with a second JAKi were in corticosteroid-free remission at the end of the induction phase, with no significant difference based on the molecule used.

BACKGROUND Tofactinib is a JAK inhibitor that targets mainly JAK 1 and JAK3 approved to treat Ulcerative Colitis (UC) in 2018. The JAK inhibitor Upadacitinib (upa) was recently approved to treat UC in March 2022 and has increased selectivity for JAK1. The relative efficacy and safety of these two JAK inhibitors is not presently clear. An important clinical question is whether patients who have not responded or lost response to tofacitinib will have a reasonable likelihood of response with upadacitinib. AIM To determine whether patients previously exposed to tofacitinib would benefit from treatment with upa. METHODS We identified adult patients at our center with active UC who had previously been treated with tofacitinib who were started on upa in the spring of 2022. Pre- and post- upa characteristics were recorded including demographic information, prior treatments, hemoglobin (hgb), albumin (alb), C-reactive protein (CRP), and partial Mayo score (pMS). Primary end points evaluated were clinical response (decrease in pMS >2), and clinical remission (pMS < 2). Secondary endpoints included serious adverse events, steroid use at time of follow up, and normalization of CRP, hgb and alb. IRB approval was obtained for the study. RESULTS A total of 3 patients were identified. All patients were given upa 45 mg daily for 8 weeks followed by 30 mg daily for maintenance. Median follow up time was 10 weeks (range 10-11 weeks). All three patients achieved the primary endpoints of clinical response and remission with pMS values of 0 at time of follow up. Patients 1 and 2 were concurrently started on a prednisone taper when initiating upa and were no longer on prednisone at time of follow up. Patients 1 and 2 had normalization of their CRP values, patient 3 only had a pre-upa CRP value available and that was 0. See table 1 for data on hgb and alb levels. Patient 1 had a pre-upa endoscopic mayo score of 3, while patients 2 and 3 had pre-upa endoscopic mayo scores of 2. No patient had post-upa endoscopic evaluation at time of follow up. No patient had any serious adverse events. CONCLUSIONS In this small case-series, use of upadacitinib in patients previously treated with tofacitinib was safe and effective in achieving clinical remission.

Inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn's disease (CD), often results in significant morbidity among patients with moderate to severe forms. While biologics and small molecules are effective in inducing remission, many patients experience refractory disease or extraintestinal manifestations. This study assesses the safety and efficacy of dual-targeted therapy in IBD patients treated at the Inflammatory Bowel Disease Center. This retrospective cohort study examined 79 patients with UC or CD who received dual-targeted therapy at the University from October 2018 to August 2023. Data collected included demographics, disease characteristics, previous treatments, and clinical outcomes. Primary outcomes were endoscopic, radiographic, and patient-reported clinical improvements, with secondary outcomes focusing on safety profiles. Among the 79 patients (42 UC, 37 CD), 97 dual-targeted therapy cases were analyzed, primarily involving a biologic combined with a JAK inhibitor (90.7%). The median therapy duration was 39.1 weeks. Endoscopic improvement occurred in 69% of matched samples, with significant differences between pre- and postdual-targeted therapy Mayo scores for UC (P = .002) and Simple Endoscopic Score for CD (SES-CD) scores for CD (P = .018). The median pre- and postdual-targeted therapy Mayo scores across matched samples were 3 (range 1-3) and 1 (range 0-3), respectively, and for SES-CD scores were 12 (range 0-36) and 4 (range 0-20), respectively. Clinical improvement was reported by 73.2% of patients, with notable reductions in ESR (median 19 [range 2-124] mm/h to 9 [range 0-116] mm/h, P = .006), CRP (median 8.0 [range 0.2-78.5] mg/L to 3.0 [range 0.2-68.2] mg/L, P < .001), and albumin levels (4.0 [range 2.2-4.9] mg/dL to 4.2 [range 3.4-5.2], P < .001). Non-obesity was associated with both more endoscopic improvement (P = .002) and clinical improvement (P = .007). Adverse events occurred in 37 cases, predominantly upper respiratory tract infections and dermatologic issues, with no thromboembolic events reported. Dual-targeted therapy demonstrated efficacy in improving clinical and endoscopic outcomes in patients with severe, refractory IBD and exhibited an acceptable safety profile. Despite the promising results, further research is needed to confirm these findings and determine optimal therapy combinations.

Background:VEXAS (Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic) syndrome is an autoinflammatory disease of adults associated with somatic mutations in the UBA1 gene. The prognosis is poor with a 5-year survival...

Background No clinical trial has previously assessed the best therapeutic strategy between switching to another anti-TNF or swapping to another class of biologic class after the failure of a first anti-TNF in ulcerative colitis (UC). The aim of the EFFICACI trial was to compare the efficacy of vedolizumab with infliximab in patients who had failed a first sub-cutaneous anti-TNF (golimumab and/or adalimumab). Methods EFFICACI was a French double-blind multicenter randomized controlled trial (1:1) comparing intravenous vedolizumab 300 mg at weeks 0-2-6 to intravenous infliximab 5 mg/kg at weeks 0-2-6. Eligible patients had moderate-to-severe UC, defined by a total Mayo score ≥ 6, despite at least 12 weeks (W) of treatment with adalimumab or golimumab as first line of advanced therapy. The primary endpoint was steroid free clinical remission at W14. The number of patients (N=150) was estimated for a 20% difference in favor of vedolizumab with a type 1 risk of 5% and a power of 80%. Patients were subsequently followed in an open-label fashion until week 54. The analysis was performed on an intention-to-treat basis. Only results at W14 will be presented. (CPP: 2018-002673-21; ClinicalTrial: 35RC17_8841_EFFICACI) Results From January 2018 to December 2023, 151 patients were randomized among 19 centers: 78 in the vedolizumab arm and 73 in the infliximab arm. Characteristics and demographics at inclusion were similar between groups, with 102/151 (67.5%) patients failing adalimumab and 49/151 (32.5%) failing golimumab. Concomitant immunosuppressive treatment with thiopurine or methotrexate was associated with infliximab and vedolizumab for 37/72 (51.4%) patients and 43/78 (55.1%) patients, respectively. At W14, proportions of patients in clinical remission (primary endpoint) were 34.6% (27/78) with vedolizumab and 19.2% (14/73) with infliximab (p=0.033). The clinical response rates were 46/78 (59.0%) with vedolizumab and 36/72 (50.0%) with infliximab (p=0.27). Proportions of patients in clinical response at W2, W6 and W14 are shown in Figure 1. At W14, endoscopic improvement (Mayo endoscopic subscore 0 or 1) was observed in 36/77 (46.8%) patients in the vedolizumab arm and 21/72 (29.2%) in the infliximab arm (p=0.027). No factor at inclusion was predictive of remission at week 14, including pharmacokinetic data for the first-line anti-TNF. Adverse event rates were similar in both groups - 46 (63.9%) infliximab arm, 55/78 (70.51%) vedolizumab arm. Eight patients were hospitalized for a severe flare (5 in the infliximab arm and 3 in the vedolizumab arm). Conclusion After failure of a first subcutaneous anti-TNF, induction therapy with vedolizumab was superior to infliximab in achieving steroid free clinical remission at week 14 in patients with UC.

BackgroundVedolizumab has proven efficiency in adults but data in paediatric inflammatory bowel disease (pIBD) is limited. We present the outcome of treatment with vedolizumab in refractory pIBD cohort.Study DesignRetrospective and...

BackgroundFew studies have addressed what is the optimal therapeutic option in patients with rheumatoid arthritis (RA) who failed treatment with JAK inhibitors (JAKi).ObjectivesThe aim of this study was to evaluate...

Background Vedolizumab (VDZ) is an α4β7 integrin antibody used to treat moderate-to-severe ulcerative colitis (UC) and Crohn’s disease (CD). We aimed to assess the real-life long-term effectiveness and safety of VDZ as a first- or second-line biological therapy and identify predictors of efficacy in a large cohort of patients with refractory or difficult-to-treat UC. Methods This was a multicenter, retrospective observational cohort study including patients with moderately-to-severely active UC who received VDZ for at least 12 weeks. Primary endpoints were clinical remission (partial Mayo score ≤ 2), endoscopic remission (endoscopic Mayo subscore of 1 or 0), and steroid-free clinical remission at week 52. Secondary endpoints included clinical response at weeks 12, 26, and 52; endoscopic response at week 52; primary and secondary loss of response; drug discontinuation; need for dose optimization; adverse events (AEs); need for hospitalization; and colectomy. Clinical predictors of VDZ treatment success were evaluated. Univariable and multivariable analyses as well as Kaplan–Meier analyses of treatment persistence were performed. Results We included 206 UC patients (mean age 44.9 ± 16.2 years, 56.8% female, 56% pancolitis, 76.8% biologic-naïve, and 22.7% with previous anti-TNF failure). Clinical remission was observed in 69.2% of biologic-naïve patients and 63.8% of anti-TNF failure patients at week 52. Steroid-free clinical remission was achieved in 70.3% and 58.8% of biologic-naïve and anti-TNF failure patients, respectively. Endoscopic remission at one year was achieved in 48.9% and 42.9% of biologic-naïve and anti-TNF failure patients, respectively. Biochemical remission at one year was achieved in 77.8% and 73.9% of biologic-naïve and anti-TNF failure patients, respectively. Primary and secondary loss of response occurred in 7.5% and 13.8% of biologic-naïve patients and in 18.2% and 21.3% of anti-TNF failure patients, respectively. Treatment persistence was higher among biologic-naïve UC patients (84.9% vs. 72.3%, p = 0.048). Three patients (1.4%) required colectomy, and 14 patients (6.8%) needed hospitalization while on VDZ treatment. Clinical response at week 12 (p = 0.001) and biologic-naïve status (p = 0.006) were predictors of better VDZ response, whereas BMI &amp;gt; 30 kg/m² (p = 0.04) and serum albumin ≤ 3.5 g/dL (p = 0.03) were predictors of poorer response. Conclusion In this real-world study of patients with severe UC, VDZ demonstrated effectiveness in inducing clinical remission and endoscopic improvement, even in cases of previous anti-TNF failure, with a favorable safety profile. Biologic-naïve status and early clinical response were associated with higher likelihood of one-year clinical and endoscopic remission.

BACKGROUNDIt is a crucial issue for patients with refractory ulcerative colitis (UC), including steroid-dependent and steroid-refractory patients, to achieve and maintain steroid-free remission. However, clinical studies focused on the achievement of steroid-free remission in refractory UC patients are insufficient. Cytapheresis (CAP) is a non-pharmacological extracorporeal therapy that is effective for active UC with fewer adverse effects. This study comprised UC patients treated with CAP and suggested the efficacy of CAP for refractory UC patients.AIMTo clarify the efficacy of CAP in achieving steroid-free remission in refractory UC patients.METHODSWe retrospectively reviewed the collected data from 55 patients with refractory UC treated with CAP. We analyzed the following points: (1) Efficacy of the first course of CAP; (2) Efficacy of the second, third, and fourth courses of CAP in patients who experienced relapses during the observation period; (3) Efficacy of CAP in colonic mucosa; and (4) Long-term efficacy of CAP. Clinical efficacy was evaluated using Lichtiger’s clinical activity index or Sutherland index (disease activity index). Mucosal healing was evaluated using Mayo endoscopic subscore. The primary and secondary endpoints were the rate of achievement of steroid-free remission and the rate of sustained steroid-free remission, respectively. Statistical analysis was performed using the paired t-test and chi-squared test.RESULTSThe rates of clinical remission, steroid-free remission, and poor effectiveness after CAP were 69.1%, 45.5%, and 30.9%, respectively. There were no significant differences in rate of steroid-free remission between patients with steroid-dependent and steroid-refractory UC. The mean disease activity index and Lichtiger’s clinical activity index scores were significantly decreased after CAP (P < 0.0001). The rates of steroid-free remission after the second, third, and fourth courses of CAP in patients who achieved steroid-free remission after the first course of CAP were 83.3%, 83.3%, and 60%, respectively. Mucosal healing was observed in all patients who achieved steroid-free remission after the first course of CAP. The rates of sustained steroid-free remission were 68.0%, 60.0%, and 56.0% at 12, 24, and 36 mo after the CAP. Nine patients (36%) had maintained steroid-free remission throughout the observation period.CONCLUSIONOur results suggest that CAP effectively induces and maintains steroid-free remission in refractory UC and re-induces steroid-free remission in patients achieving steroid-free remission after the first course of CAP.

Background Efficacy and safety of ustekinumab for the treatment of ulcerative colitis (UC) has been demonstrated in clinical trials, but few real-world data are available so far. The aim of this study was to assess effectiveness and safety of ustekinumab in a cohort of refractory UC patients. Methods Data of patients with moderate to severe UC treated with ustekinumab were retrospectively collected. Primary endpoint was steroid-free clinical remission at weeks 24 and 52 of therapy. Secondary endpoints were treatment response, endoscopic remission, treatment persistence at 12 months and safety. Results A total of 68 patients [males 63%; median (range) age 42 (16–72) years] were included. Almost all patients (97%) were biologics experienced. At weeks 24 and 52, 31% and 50% of patients achieved steroid-free clinical remission, 84% and 82% had clinical response, respectively. At the end of follow-up, there was a significant reduction of pMS from baseline (p < 0.001) and of steroid use (p < 0.001). At week 52, 22% of the available endoscopies (18/38) showed mucosal healing. The probability to persist in therapy at week 52 was 87%. Only one adverse event occurred. Conclusions Data from our real-life cohort of refractory UC patients suggest satisfactory effectiveness and a good safety of ustekinumab.

Selecting a first-line therapy remains challenging in IBD. Adalimumab (ADM) and vedolizumab (VDZ) effectively lead to endoscopic remission in moderate to severe IBD. The VARSITY trial showed superiority of VDZ over ADM in ulcerative colitis (UC) regarding clinical remission and endoscopic improvement at week 52. We explored these results in a real-world setting of UC and Crohn's disease (CD). This retrospective study followed a cohort of biologic-naïve patients starting ADM or VDZ from 2015-2019. Patients had moderate to severe disease (endoscopic Mayo score ≥2 for UC, presence of ulcerations for CD) prior to therapy initiation. For UC, endoscopic remission (endoscopic Mayo score 0) and improvement (endoscopic Mayo score ≤1) at week 52 were assessed. For CD, endoscopic remission (absence of ulcerations) and improvement (markedly better endoscopy despite ulcerations) at weeks 26-52 were studied. Treatment persistence was also evaluated. In total, 195 biologic-naïve patients (109 UC; 86 CD) were included. In UC, VDZ was superior to ADM regarding endoscopic remission (29% vs 11%, P = .03), endoscopic improvement (51% vs 26%, P = .01) at week 52, and treatment persistence (P = .04). In CD, no differences in endoscopic remission (VDZ 48% vs ADM 60%; P=0.37), improvement (VDZ 76% vs ADM 77%; P = 1.00), or treatment persistence (P=0.43) at weeks 26-52 were seen. Safety profiles were similar in UC and CD. This real-world cohort study of biologic-naïve IBD patients found VDZ to be superior to ADM as first-line treatment for patients with UC-but not CD-regarding endoscopic remission at week 52 and treatment persistence.

BackgroundCardiovascular disease (CVD) and CVD risk factors are highly prevalent in rheumatoid arthritis (RA) and associated with morbidity and mortality. We previously reported an association between CVD risk factors and...

Background The IBD community are seeking ways to personalize medication choices for individual patients. Hypoalbumineamia is a poor prognostic marker in ulcerative colitis (UC) as a surrogate marker of disease activity. Biologic molecules are intermittently dosed using albumin binding to maintain plasma concentration, therefore in low albumin states drug clearance is accelerated. This effect is potentially less significant in regularly dosed, JAK inhibitors (JAKi). Methods All patients at our unit taking a JAKi were included. Patients using vedolizumab were selected for inclusion based on the nearest neighbour with respect to medication start date. Vedolizumab was chosen as a second line advanced therapy used regularly in UC. Demographic and disease characteristics were collected. Blood tests immediately prior to starting medication were collected. Outcome measure was response to treatment based based on drug continuation and clinician documentation of treatment success at 6 months. Results 56 patients were included; 28 receiving a JAKi, 28 patients using vedolizumab. The JAKi group consisted of 8 patients receiving Filgotinib, 12 Tofacitinib and 8 Upadacitinib. Patients receiving JAKi were younger (mean age 44 years, SD 14) compared to vedolizumab (56 years, SD 20). Both were predominantly white (JAKi n=16, Vedolizumab n=22). Chronic liver disease was uncommon in both groups; JAKi n=2 (7.1%) and vedolizumab n=3 (10.7%), none of whom had cirrhosis. More hospital admissions were observed in the year prior to starting treatment in patients who received JAKi (n=16, 57.1%) compared to vedolizumab (n=9, 32%). Hypoalbuminaemia (defined as ≤30g/L) was seen in 5 patients in each group. In patients receiving JAKi 16/23 (69.7%) patients without hypoalbuminaemia responded to treatment at 6 months, compared to 3/5 (60%) with low albumin. (p=0.999). In patients receiving Vedolizumab 18/23 (78.3%) patients responded to treatment at 6 months, compared to 1/5 (20%), (p=0.026). Conclusion In patients with hypoalbumineamia, vedolizumab was less effective compared to normal albumin states. A similar effect was not observed in patients receiving JAKi. Numerically the efficacy of both vedolizumab and JAKi was worse in patients with hypoalbuminaemia, as would be expected given the likely reflection of increased disease severity. This data suggests that those patients requiring advanced therapy with hypalbuminaemia might respond better to a JAKi. Further research is needed to investigate this finding.

Outcomes of Non-Myeloablative HLA-Haploidentical Bone Marrow Transplant with Thiotepa and Post-Transplant Cyclophosphamide in Children and Adults with Sickle Cell Disease, a Phase II Trial: Vanderbilt Global Haploidentical Transplant Learning Collaborative (VGC2)