Concomitant Immunosuppression Research Articles

P588 Interim results from the randomised VERDICT trial to determine the optimal treatment target in patients with ulcerative colitis

Abstract Background The optimal treatment target for ulcerative colitis (UC) is uncertain. The VERDICT trial in moderate to severe UC aims to determine if a treatment target of corticosteroid (CS)-free symptomatic + endoscopic + histologic remission is superior to CS-free symptomatic remission alone. Trial progress and the study cohort to date are described herein. Methods Our aim is to enrol 660 patients with moderately to severely active UC (Mayo rectal bleeding subscore [RBS] ≥1; Mayo endoscopic score [MES] ≥2). Patients are randomised to 3 treatment targets (2:3:5 ratio): CS-free symptomatic remission (Mayo RBS = 0) (Group 1); CS-free endoscopic remission (MES ≤1) + symptomatic remission (Group 2); or CS-free histologic remission (Geboes score <2B.0) + endoscopic + symptomatic remission (Group 3). Therapy is administered according to a treatment algorithm that is dependent upon each patient’s UC treatment at screening. Early introduction of vedolizumab (VDZ) and dose escalation up to 300 mg every 4 weeks until the target is met are central to each algorithm. Up to 3 opportunities to achieve the assigned target were prespecified in the algorithms (weeks 16, 32, or 48). Patients and central readers for endoscopy/histopathology are blinded to group allocation, and investigators are unblinded. Results As of 2 November 2022, 331 patients were enrolled at 55 sites across 10 North American and European countries. Mean (SD) baseline characteristics (Table) include a UC duration of 8.6 (8.3) years, Mayo Clinic score of 8.7 (1.7), C-reactive protein level of 13.3 (15.6) mg/dL, and a faecal calprotectin level of 1462.3 (1481.3) mg/kg. At baseline, 52% (172/331) and 11% (37/331) of patients were receiving concomitant CS and immunosuppressives, respectively, and 14% (47/331) had current/prior exposure to tumour necrosis factor antagonists. Most patients (85%) were receiving nonbiologic therapy. Of all randomised patients, 43/69 (Group 1), 65/98 (Group 2), and 115/164 patients (Group 3) have reached week 16; and 28 (65%), 25 (39%), and 42 (37%) met their target, respectively. After a median of 35 weeks (IQR 18-53), a total of 30 (Group 1), 32 (Group 2), and 50 patients (Group 3) have met their target and will be followed to relapse or study termination. The serious adverse event rate (8%; 36/483) was similar across groups. Conclusion VERDICT has randomised ~50% of its target enrolment. Enrolled patients represent a typical moderate to severe UC population and are primarily bionaive and receiving early VDZ initiation. Early results suggest the feasibility of achieving each treatment target, specifically histologic remission, and are consistent with expected values. No new VDZ safety signals were identified. Completion of enrolment is anticipated in late 2023.

Withdrawal of infliximab or concomitant immunosuppressant therapy in patients with Crohn's disease on combination therapy (SPARE): a multicentre, open-label, randomised controlled trial

The combination of infliximab and immunosuppressant therapy is a standard management strategy for patients with Crohn's disease. Concerns regarding the implications of long-term combination therapy provided the rationale for a formal clinical trial of treatment de-escalation. Our aim was to compare the relapse rate and the time spent in remission over 2 years between patients continuing combination therapy and those stopping infliximab or immunosuppressant therapy. This multicentre, open-label, randomised controlled trial was performed in 64 hospitals in seven countries in Europe and Australia. Adult patients with Crohn's disease in steroid-free clinical remission for more than 6 months, on combination therapy of infliximab and immunosuppressant therapy for at least 8 months were randomly assigned (1:1:1) to either continue combination therapy (combination group), discontinue infliximab (infliximab withdrawal group), or discontinue immunosuppressant therapy (immunosuppressant withdrawal group). Randomisation was stratified according to disease duration before start of first anti-TNF treatment (≤2 or >2 years), failure of immunosuppressant therapy before start of infliximab, and presence of ulcers at baseline endoscopy. The patient number and group of each stratum were assigned by a central online randomisation website. Treatment was optimised or resumed in case of relapse in all groups. Participants, those assessing outcomes, and those analysing the data were not masked to group assignment. The coprimary endpoints were the relapse rate (superiority analysis) and time in remission over 2 years (non-inferiority analysis, non-inferiority margin 35 days). Analyses were done on an intention-to-treat basis. This study is registered with ClinicalTrials.gov, NCT02177071, and with EU Clinical Trials Register, EUDRACT 2014-002311-41. The trial was completed in April, 2021. Between Nov 2, 2015, and April 24, 2019, 254 patients were screened. Of these, 211 were randomised and 207 were included in the final analysis (n=67 in the combination group, n=71 in the infliximab withdrawal group, and n=69 in the immunosuppressant withdrawal group). 39 patients had a relapse (eight [12%] of 67 in the combination group, 25 [35%] of 71 in the infliximab withdrawal group, six [9%] of 69 in the immunosuppressant withdrawal group). 2-year relapse rates were 14% (95% CI 4-23) in the combination group, 36% (24-47) in the infliximab withdrawal group, and 10% (2-18) in the immunosuppressant withdrawal group (hazard ratio [HR] 3·45 [95% CI 1·56-7·69], p=0·003, for infliximab withdrawal vs combination, and 4·76 [1·92-11·11], p=0·0004, for infliximab withdrawal vs immunosuppressant withdrawal). Of 28 patients who had a relapse and were retreated or optimised according to protocol, remission was achieved in 25 patients (one of two in the combination group, 22 of 23 in the infliximab withdrawal group, and two of three in the immunosuppressant withdrawal group). The mean time spent in remission over 2 years was 698 days (95% CI 668-727) in the combination group, 684 days (651-717) in the infliximab withdrawal group, and 706 days (682-730) in the immunosuppressant withdrawal group. The difference in restricted mean survival time in remission was -14 days (95% CI -56 to 27) between the infliximab withdrawal group and the combination group and -22 days (-62 to 16) between the infliximab withdrawal group and the immunosuppressant withdrawal group. The 95% CIs contained the non-inferiority threshold (-35 days). We recorded 31 serious adverse events, in 20 patients, with no difference in frequency between groups. The most frequent serious adverse events were infections (four in the combination group, two in the infliximab withdrawal group, and one in the immunosuppressant withdrawal group) and Crohn's disease exacerbation (three in the combination group, four in the infliximab withdrawal group, and one in the immunosuppressant withdrawal group). No death nor malignancy was recorded. In patients with Crohn's disease in sustained steroid-free remission under combination therapy with infliximab and immunosuppressant therapy, withdrawal of infliximab should only be considered after careful assessment of risks and benefits for each patient, whereas withdrawal of immunosuppressant therapy could generally represent a preferable strategy when considering treatment de-escalation. European Union's Horizon 2020.

Single nucleotide polymorphisms in ADAM17, IL23R and SLCO1C1 genes protect against infliximab failure in adults with Crohn’s disease

BackgroundTo predict primary failure of infliximab (IFX) therapy in Crohn’s disease (CD) and to identify patients who maintain long-term effectiveness to IFX is currently not feasible. Some genetic variations are proposed as potential biomarkers. AimWe assessed a set of single nucleotide polymorphisms (SNPs) in genes related to the IFX mechanism of action and the presence of HLA-DQA1 * 05 allele on the primary response and long-term durability in CD patients. MethodsA multi-centre cross-sectional study of IFX-exposed adult patients with CD was undertaken. Treatment persistence and time to failure were co-primary endpoints. DNA from the 131 patients was genotyped. Association between SNPs and clinical variables with IFX persistence was assessed. ResultsFailure to IFX was documented in 65 (49.6%) out of 131 patients. IFX persistence was associated either with carrying the TT genotype in ADAM17 rs10929587 (ORa=0.2; 95%CI=0.1–0.8; p = 0.021), or the CC genotype in SLCO1C1 rs3794271 (ORa=0.2; 95%CI=0.1–0.7; p = 0.008), according to multivariate logistic regression. In contrast, previous bowel resection increased the risk of IFX failure (ORa=2.8; 95%CI=1.1–7.3; p = 0.025). Cox regression analysis confirmed these findings and also identified IL23R rs10489629-TT (HRa 0.41; 95%CI=0.22–0.75; p = 0.004) and concomitant immunosuppressants (HRa 0.46; 95%CI=0.27–0.77; p = 0.003) as protection from IFX failure. However, no association between HLA-DQA1 * 05 allele and persistence of IFX therapy was found, with similar failure rates among carriers and non-carriers (52.8% vs. 47.4%, respectively; p = 0.544). ConclusionsSNPs rs10929587-TT in ADAM17, rs10489629-TT in IL23R and rs3794271-CC in SLCO1C1, together with no previous bowel surgery and concomitant immunosuppression, were identified as protection from failure to IFX.

Optimum timing of antithymocyte globulin in relation to adoptive regulatory T cell therapy

Reducing the recipient’s T cell repertoire is considered to increase the efficacy of regulatory T cell (Treg) therapy. This necessitates timing the administration of antithymocyte globulin (ATG) early enough before adoptive cell therapy (ACT) so that residual serum ATG does not deplete the transferred Tregs. The optimum time point in this regard has not been defined. Herein, we report the effects of residual serum ATG on the viability of an in vitro expanded Treg cell product used in a clinical trial of ACT in kidney transplant recipients (NCT03867617). Patients received ATG monotherapy (either 6 or 3 mg/kg body weight) without concomitant immunosuppression 2 to 3 weeks before transplantation and Treg transfer. An anti-ATG immunoglobulin G (IgG) immune response was elicited in all patients within 14 days. In turn, the elimination of total and Treg-specific ATG was accelerated substantially over control patients receiving the same dose of ATG with concomitant immunosuppression. However, ATG serum concentrations of <1 μg/mL, which had previously been reported as subtherapeutic threshold, triggered apoptosis of Tregs in vitro. Therefore, ATG levels need to decline to lower levels than those previously thought for efficacious Treg transfer. In 5 of 6 patients, such low levels of serum ATG considered safe for Treg transfer were reached within 2 weeks after ATG administration.

Avatrombopag treatment response in patients with immune thrombocytopenia: the REAL-AVA 1.0 study.

Thrombopoietin-receptor agonists (TPO-RAs) are used to treat immune thrombocytopenia (ITP), a disorder characterized by prolonged low platelet counts (PCs) that pose a risk of serious bleeding episodes. Avatrombopag (AVA) is the most recently approved TPO-RA for the treatment of chronic ITP. A high proportion of patients responded to AVA in clinical trials, and treatment was well-tolerated; however, limited real-world effectiveness data have been reported to date. To describe demographic and clinical characteristics, treatment patterns, and outcomes following the initiation of AVA in patients with ITP in the United States. This is a retrospective study using administrative claims data from the Komodo Healthcare Map (1 February 2017 to 28 February 2022) linked with PC laboratory data. Patients with ⩾1 diagnosis of ITP, ⩾1 paid prescription for AVA (index date), and ⩾1 month of pharmacy coverage after AVA initiation were selected. Baseline characteristics and follow-up steroid, immunosuppressant, and rescue medication use were described. The percentage of patients achieving clinically meaningful PC thresholds (⩾30 × 109/l) were assessed among patients with ⩾1 PC following AVA initiation and prior to AVA discontinuation/switch (effectiveness subgroup). A total of 205 patients met eligibility criteria and 49% reported TPO-RA use in the prior 6 months. Approximately 70% and 93% of patients did not require use of steroid or immunoglobulin rescue medication during follow-up, respectively. Among patients with concomitant steroid (n = 75) or immunosuppressant (n = 7) use at AVA initiation, 35% and 57% discontinued those treatments, respectively. Of the 21 patients in the effectiveness subgroup, 81% achieved clinically meaningful PC thresholds. A high proportion of evaluable patients with ITP in this real-world study achieved clinically meaningful PCs, without requiring rescue medication during AVA treatment, with many able to discontinue baseline concomitant steroid or immunosuppressant utilization. Despite limited availability of PC data, these results are consistent with results from the AVA pivotal clinical trials.

Hydroxychloroquine daily dose, hydroxychloroquine blood levels and the risk of flares in patients with systemic lupus erythematosus

BackgroundRecent guidelines for SLE recommend using a hydroxychloroquine (HCQ) dose less than 5.0 mg/kg/day to reduce the risk of retinopathy. To determine if this dose reduction would have an impact...

Risk of alanine aminotransferase flare in patients with previous hepatitis B virus exposure on biological modifier therapies-A population-based study.

It is uncertain whether biological therapies would increase the risk of hepatitis among patients with past hepatitis B virus (HBV) infection. This study aimed to evaluate the risk of alanine aminotransferase (ALT) flare in patients with past HBV infection while using biological therapies. Patients who received biological therapies for ≥3months from 2000 to 2019 were identified from a population-based database in Hong Kong. Patients with past HBV infection were compared with a control group without prior HBV exposure. The primary endpoint was development of ALT flare within 5 years of starting biological therapies, defined as ALT >80 IU/L. There were 2471 and 2394 patients with and without past HBV infection respectively. There was a non-significant increase in risk of ALT flare among the HBV-exposed group (27.6% vs. 23.7%, p=.055). In multivariable analysis, using prednisolone-equivalent dose of >20 mg daily, male sex and concomitant immunosuppressants were risk factors for ALT flare. The risk of ALT flare was significantly higher with anti-CD20 when compared to other biological agents (36.1% vs. 14.5%, p < .01), but was not significantly different among anti-tumour necrosis factor, anti-cytokine, Janus kinase inhibitors and T cell/B cell inhibitors or anti-integrin (15.2% vs. 14.6% vs. 11.7% vs. 11.1%, p=.82). Among patients with documented hepatitis B surface antigen seroreversion, 96% were on anti-CD20. Our study further supports the current suggestion of prophylactic anti-viral before starting anti-CD20 in HBV-exposed patients. While other biological therapies appear to have a lower risk for ALT flare, this result needs further confirmation.

Glucocorticoid tapering and associated outcome in patients with newly diagnosed systemic lupus erythematosus: the real-world GULP prospective observational study

ObjectiveA subanalysis of the multicentre Early Lupus inception cohort was performed to investigate the real-world Glucocorticoids (GCs) Use in newly diagnosed systemic lupus erythematosus (SLE) Patients (GULP).MethodsPatients starting prednisone (PDN)...

Immunosuppression Exposure and Risk of Infection-Related Acute Care Events in Patients With Glomerular Disease: An Observational Cohort Study

Infections cause morbidity and mortality in patients with glomerular disease. The relative contributions from immunosuppression exposure and glomerular disease activity to infection risk are not well characterized. To address this unmet need, we characterized the relationship between time-varying combinations of immunosuppressant exposure and infection-related acute care events while controlling for disease activity, among individuals with glomerular disease. Prospective, multicenter, observational cohort study. Adults and children with biopsy-proven minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, or immunoglobulin A nephropathy/vasculitis were enrolled at 71 clinical sites in North America and Europe. A total of 2,388 Cure Glomerulonephropathy Network participants (36% aged<18 years) had at least 1 follow-up visit and were included in the analysis. Immunosuppression exposure modeled on a weekly basis. Infections leading to an emergency department visit or hospitalization. Marginal structural models were used to estimate the effect of time-varying immunosuppression exposure on hazard of first infection-related acute care event while accounting for baseline sociodemographic and clinical factors, and time-varying disease activity. A total of 2,388 participants were followed for a median of 3.2 years (interquartile range, 1.6-4.6), and 15% experienced at least 1 infection-related emergency department visit or hospitalization. Compared to no immunosuppression exposure, steroid exposure, steroid with any other immunosuppressant, and nonsteroid immunosuppressant exposure were associated with a 2.65-fold (95% CI, 1.83-3.86), 2.68-fold (95% CI, 1.95-3.68), and 1.7-fold (95% CI, 1.29-2.24) higher risk of first infection, respectively. Absence of medication dosing data, lack of a control group, and potential bias in ascertainment of outcome events secondary to the coronavirus 2 pandemic. Corticosteroids with or without concomitant additional immunosuppression significantly increased risk of infection leading to acute care utilization in adults and children with glomerular disease.

Advantages of an alternate-day glucocorticoid treatment strategy for the treatment of IgG4-related disease: A preliminary retrospective cohort study.

Alternate-day glucocorticoid (GC) therapy is a treatment option that can reduce GC-associated adverse events. We investigated the safety and efficacy of alternate-day GC therapy in patients with immunoglobulin G4-related disease (IgG4-RD).Medical records of patients with IgG4-RD who were followed for at least one year at St. Luke’s International Hospital, Tokyo, Japan, from 2004 to 2020 were reviewed. Patients who fulfilled comprehensive IgG4-RD diagnostic criteria were divided into alternate-day or daily GC treatment groups based on their treatment protocol. The effect of alternate-day GC therapy on glucocorticoid toxicity index (GTI) score was evaluated using multilinear analysis with adjustments for cumulative GC doses until each assessment point and propensity scores (PS) for alternate-day GC therapy. Kaplan–Meier curves and Cox proportional hazard models were used to assess the efficacy of alternate-day GC therapy for disease control.Among the 67 patients with IgG4-RD, patients with alternate-day (n = 13) and daily (n = 31) GC treatments were analyzed after excluding 23 ineligible patients. The median (interquartile range) age was 64 (60–70) years, 29 (65.9%) were male patients, 26 (59.1%) patients had positive biopsy results, and the median follow-up period was 1643 days. Significantly more patients with alternate-day GC treatment used concomitant immunosuppressants (11 [84.6%] vs 11 [35.5%]; P = .007). The alternate-day strategy significantly lowered the GTI score after adjusting for cumulative GC dose until the assessment and PS (adjusted coefficient: −29.5 [−54.3, −4.8], P = .021 at 12 months; −20.0 [−39.8, −0.1], P = .049 at 24 months). Serious infections were numerically less frequent in the alternate-day group (incidence ratio [95% confidence interval [CI]: 0.45 [0.05, 3.63], P = .45). Most patients (92.3%) in the alternate-day GC treatment group and all patients in the daily GC treatment group showed treatment responses in the remission induction therapy. The PS-adjusted hazard ratio of alternate-day GC treatment for disease flares was not significant (1.55 [0.53, 4.51]; P = .43).The alternate-day treatment strategy significantly reduced GC-related adverse events regardless of the cumulative GC dose. Alternate-day GC treatment is a feasible option for patients with IgG4-RD, without a significant increase in disease flares particularly when combined with immunosuppressants.

SARS-CoV-2 IgG spike protein antibody response in mRNA-1273 Moderna® vaccinated patients on maintenance immunoapheresis - a cohort study.

BackgroundThe SARS-CoV-2 pandemic increased mortality and morbidity among immunocompromised populations. Vaccination is the most important preventive measure, however, its effectiveness among patients depending on maintenance immunoglobulin G (IgG) apheresis to control autoimmune disease activity is unknown. We aimed to examine the humoral immune response after mRNA-1273 Moderna® vaccination in immunoapheresis patients.MethodsWe prospectively monitored SARS-CoV-2 IgG spike (S) protein antibody levels before and after each IgG (exposure) or lipid (LDL) apheresis (controls) over 12 weeks and once after 24 weeks. Primary outcome was the difference of change of SARS-CoV-2 IgG S antibody levels from vaccination until week 12, secondary outcome was the difference of change of SARS-CoV-2 IgG S antibody levels by apheresis treatments across groups.ResultsWe included 6 IgG and 18 LDL apheresis patients. After 12 weeks the median SARS-CoV-2 IgG S antibody level was 115 (IQR: 0.74, 258) in the IgG and 1216 (IQR: 788, 2178) in the LDL group (p=0.03). Median SARS-CoV-2 IgG S antibody reduction by apheresis was 76.4 vs. 23.7% in the IgG and LDL group (p=0.04). The average post- vs. pre-treatment SARS-CoV-2 IgG S antibody rebound in the IgG group vs. the LDL group was 46.1 and 6.44%/week from prior until week 12 visit.ConclusionsIgG apheresis patients had lower SARS-CoV-2 IgG S antibody levels compared to LDL apheresis patients, but recovered appropriately between treatment sessions. We believe that IgG apheresis itself probably has less effect on maintaining the immune response compared to concomitant immunosuppressive drugs. Immunization is recommended independent of apheresis treatment.

P2.12-05 Cancer and Atopy: Parallel Drivers? IL-4 Blockade Synergizes with PD-L1 Blockade to Reverse Type-2Mediated Immunosuppression

Type-2 cytokines, such as IL-4, alter macrophage immunogenicity in vitro leading to the M1/M2 paradigm, however, the role of IL-4 in-vivo in cancer remains unclear. Using high dimensional immune profiling of human NSCLC lesions we previously described several functionally distinct populations of macrophages, and a tumor-enriched dendritic cell program of concomitant immunosuppression and activation which we termed the mregDC, and we identified analogous cells in a murine model of lung cancer (Maier et al, Nature 2020, Casanova-Acebes et al, Nature, 2021, Leader et al, Cancer Cell 2021).

Ten-year safety of pluripotent stem cell transplantation in acute thoracic spinal cord injury.

The purpose of this study was to evaluate the safety of oligodendrocyte progenitor cells (LCTOPC1) derived from human pluripotent stem cells administered between 7 and 14 days postinjury to patients with T3 to T11 neurologically complete spinal cord injury (SCI). The rationale for this first-in-human trial was based on evidence that administration of LCTOPC1 supports survival and potential repair of key cellular components and architecture at the SCI site. This study was a multisite, open-label, single-arm interventional clinical trial. Participants (n = 5) received a single intraparenchymal injection of 2 × 106 LCTOPC1 caudal to the epicenter of injury using a syringe positioning device. Immunosuppression with tacrolimus was administered for a total of 60 days. Participants were followed with annual in-person examinations and MRI for 5 years at the time of this report and will be followed with annual telephone questionnaires for 6 to 15 years postinjection. The primary endpoint was safety, as measured by the frequency and severity of adverse events related to the LCTOPC1 injection, the injection procedure, and/or the concomitant immunosuppression administered. The secondary endpoint was neurological function as measured by sensory scores and lower-extremity motor scores as measured by the International Standards for Neurological Classification of Spinal Cord Injury examinations. No unanticipated serious adverse events related to LCTOPC1 have been reported with 98% follow-up of participants (49 of 50 annual visits) through the first 10 years of the clinical trial. There was no evidence of neurological decline, enlarging masses, further spinal cord damage, or syrinx formation. MRI results during the long-term follow-up period in patients administered LCTOPC1 cells showed that 80% of patients demonstrated T2 signal changes consistent with the formation of a tissue matrix at the injury site. This study provides crucial first-in-human safety data supporting the pursuit of future human embryonic stem cell-derived therapies. While we cannot exclude the possibility of future adverse events, the experience in this trial provides evidence that this cell type can be well tolerated by patients, with an event-free period of up to 10 years. Based on the safety profile of LCTOPC1 obtained in this study, a cervical dose escalation trial was initiated (NCT02302157).

Comparative Effectiveness of Ustekinumab and Anti-TNF Agent as First-Line Biological Therapy in Luminal Crohn's Disease: A Retrospective Study From 2 Referral Centers.

Real-life data on the efficacy of ustekinumab as first-line therapy for the treatment of luminal Crohn's disease (CD) compared with anti-tumor necrosis factor (anti-TNF) agents are lacking. We compared the clinical response rates at 3 months in 2 cohorts of biologic-naïve patients treated by ustekinumab and anti-TNF agents. Biologic-naïve patients starting either ustekinumab or an anti-TNF agent for luminal CD between 2016 and 2019 in 2 tertiary centers were retrospectively included. The primary endpoint was clinical response at 3 months, defined as a Harvey-Bradshaw Index <4 or a 3-point drop in the score without steroids, need for CD-related surgery, or treatment discontinuation owing to failure or intolerance. Patients treated with ustekinumab were matched to patients receiving anti-TNF agents by a propensity score algorithm. We included 156 patients starting anti-TNF agents (95 adalimumab and 61 infliximab) and 50 ustekinumab. After matching, clinical response rates at 3 months were 64% and 86% in the ustekinumab and anti-TNF groups, respectively (P = .01). At 12 months, in multivariate analysis adjusted for disease duration, location, concomitant immunosuppressant and steroids, and symptoms, clinical remission was independently associated with the biological therapy received (odds ratio, 2.6 for anti-TNF agent vs ustekinumab; P = .02). With a median follow-up duration of 40 (interquartile range, 23-52) months, no difference was observed in terms of time to drug withdrawal (P = .29) or safety. This retrospective real-world data suggest that an anti-TNF agent as a first-line biological therapy is associated with higher rates of response at 3 months than ustekinumab in patients with CD.

COVID-19 and Kidney Transplantation: Epidemiology, Histopathological Presentation, Clinical Presentation and Outcomes, and Therapeutic Strategies

Multiple case series of kidney transplant recipients with COVID-19 have shown increased mortality compared to nontransplant patients. To date, we do not have high-level evidence to inform immunosuppression minimization strategies in infected transplant recipients. Most centers, however, have adopted an early antimetabolite withdrawal in addition to other interventions. The epidemiological problem concerns also dialysis patients and waitlisted patients who have a higher COVID-19 infection diffusion with respect to kidney transplant recipients. Several factors influence mortality among kidney transplant recipients. Among these factors are the age, race, and comorbidity factors, such as hypertension, diabetes mellitus, obesity, and previous respiratory problems. Treatment is still limited. The only effective antiviral drug is remdesivir that should be administered before the development of the cytokine storm. Vaccination seems to be useful, but due to the concomitant immunosuppression limiting its efficacy, at least three or four doses should be administered.

Predicting Sustained Clinical Response to Rituximab in Moderate to Severe Systemic Manifestations of Primary Sjögren Syndrome.

ObjectiveTo assess outcomes of repeat rituximab cycles and identify predictors of sustained clinical response in systemic manifestations of primary Sjögren syndrome (pSS).MethodsAn observational study was conducted in 40 rituximab‐treated patients with pSS. Clinical response was defined as a 3‐point or more reduction in the European League Against Rheumatism (EULAR) Sjögren Disease Activity Index (ESSDAI) at 6 months from baseline. Peripheral blood B cells were measured using highly sensitive flow cytometry. Predictors of sustained response (within two rituximab cycles) were analyzed using penalized logistic regression.ResultsThirty‐eight out of 40 patients had moderate to severe systemic disease (ESSDAI >5). Main domains were articular (73%), mucocutaneous (23%), hematological (20%), and nervous system (18%). Twenty‐eight out of 40 (70%) patients were on concomitant immunosuppressants. One hundred sixty‐nine rituximab cycles were administered with a total follow‐up of 165 patient‐years. In cycle 1 (C1), 29/40 (73%) achieved ESSDAI response. Of C1 responders, 23/29 received retreatment on clinical relapse, and 15/23 (65%) responded. Of the 8/23 patients who lost response, these were due to secondary non‐depletion and non‐response (2NDNR; 4/23 [17%] as we previously observed in systemic lupus erythematosus with antirituximab antibodies, inefficacy = 2/23, and other side effects = 2/23). Within two cycles, 13/40 (33%) discontinued therapy. In multivariable analysis, concomitant immunosuppressant (odds ratio 7.16 [95% confidence interval: 1.37–37.35]) and achieving complete B‐cell depletion (9.78 [1.32–72.25]) in C1 increased odds of response to rituximab. At 5 years, 57% of patients continued on rituximab.ConclusionOur data suggest that patients with pSS should be co‐prescribed immunosuppressant with rituximab, and treatment should aim to achieve complete depletion. About one in six patients develop 2NDNR in repeat cycles. Humanized or type 2 anti‐CD20 antibodies may improve clinical response in extra‐glandular pSS.

P245 Identifying predictors of short-term response to rituximab in extra-glandular primary Sjogren’s Syndrome

Abstract Background/Aims Randomised controlled trials (RCTs) of rituximab (RTX) in primary Sjogren’s syndrome (pSS) have failed to alleviate glandular symptoms and fatigue. The question remains as to whether B-cell depleting therapies have a place for the treatment of pSS. Post-hoc analyses from RCTs showed greater improvement in objective measures such as salivary flow rate, salivary gland ultrasound and histology scores in RTX-treated group vs placebo. Moreover, there are limited data on efficacy of the initial and repeat cycles of RTX on extra-glandular pSS. Here, our objectives were to assess the effectiveness of RTX on extra-glandular symptoms and identify predictors of short-term response with a view to personalised B-cell depleting therapy in pSS. Methods A retrospective longitudinal cohort study was conducted in 40 consecutive RTX-treated pSS patients in a single-centre for over 15 years. All patients fulfilled the 2002 AEG criteria and were CCP negative. Clinical response at 6 months was defined as ≥ 3 point reduction of ESSDAI from baseline. B-cell subsets were measured using highly sensitive flow cytometry. Predictors of short-term response were analysed using penalised logistic regression. Results 38/40 (95%) patients were female, mean (SD) age 54 (13.7) years, median (IQR) disease duration 5 (2-9) years, 39/40 (98%) had positive ANA and 28/40 (70%) were on concomitant immunosuppressant (IS). Mean (SD) ESSDAI at RTX initiation was 11.5 (6.7) and main domains for RTX were articular (73%), skin (23%), haematological (18%), PNS (15%) and lungs (10%). 169 RTX cycles were administered with a total follow-up of 165PY. In Cycle 1 (C1) RTX, the proportion of patient achieving ESSDAI response from baseline was 29/40 (73%; 95% CI 58-87). There were significant reductions in ESSDAI, daily prednisolone dose and IgG levels at 6 months (all p &amp;lt; 0.05). Of C1 responders, 23/29 received retreatment on clinical relapse; of which 8/23 (35%) lost response [secondary non-depletion non-response (2NDNR) associated with anti-RTX antibodies as we previously observed in SLE=4 (17%)]; side effects=1; ineffective=3. Of C1 non-responders, 9/11 were retreated but only 2/9 responded in C2. Overall, 13/40 (33%) discontinued RTX within two cycles. In multivariable analysis, concomitant immunosuppressant [OR 0.07 (95% CI 0.01-0.52); p = 0.010] and achieving compete B-cell depletion in C1 [0.04 (0.02-0.82); 0.036] reduced non-response to RTX. Conclusion All patients with pSS should be co-prescribed immunosuppressant with RTX and future therapeutics should aim to achieve complete depletion. About one in six pSS patients lose response in repeat cycles which is associated with 2NDNR phenomenon. The use of humanised or next-generation type 2 anti-CD20 antibodies should overcome these issues and improve the clinical response of extra-glandular pSS. Disclosure S. Pepple: None. J. Arnold: None. E. M Vital: Consultancies; Dr Vital has received consulting fees from Roche. Grants/research support; Dr Vital has received funding for research from Roche. A. C Rawstron: None. C. Pease: None. S. Dass: None. P. Emery: Consultancies; Prof Emery has received consulting fees from Roche. Grants/research support; Prof Emery has received funding for research from Roche. M. Md Yusof: None.

P241 Efficacy of obinutuzumab in systemic lupus erythematosus patients with secondary non response to rituximab

Abstract Background/Aims Rituximab is a chimeric type-1 anti-CD20 monoclonal antibody approved by NHS England for refractory SLE. Secondary inefficacy with infusion reactions and anti-rituximab-antibodies occurs in 14% of re-treated patients. Obinutuzumab is a next-generation humanised type-2 anti-CD20 antibody licensed for the treatment of haematological malignancies. Methods We collated data from nine SLE patients receiving off-label obinutuzumab for secondary non-response to rituximab with infusion reactions across six centres (Leeds, Bradford, York, UCL, Birmingham and Nottingham). Disease activity was assessed using BILAG-2004 and SLEDAI-2K and serology in local diagnostic laboratories before, and 6 months after, obinutuzumab 2x1000mg infusions 2 weeks apart alongside methylprednisolone 100mg. Results All patients received concomitant oral immunosuppression and prednisolone. 6/9 received hydroxychloroquine. The median number of rituximab cycles before obinutuzumab therapy was 2.5. Before obinutuzumab 6/9 patients had BILAG A/B mucocutaneous, 6/9 had BILAG A/B musculoskeletal and 4/9 had BILAG A/B renal. 6 months after obinutuzumab 1/9 patients had BILAG B mucocutaneous, no patients had BILAG A/B musculoskeletal and 2/9 patients had BILAG A/B renal. Median dsDNA reduced from 118 to 83 IU/mL, C3 increased from 0.53 to 1.02g/L and C4 increased from 0.095 to 0.23g/L. Prednisolone dose was reduced in 5/9 patients; before obinutuzumab all patients received 10mg or more. After obinutuzumab, 4/9 patients received 5mg and were in Lupus Low Disease Activity State (LLDAS). Patient 5 did not respond and required further methylprednisolone and cyclophosphamide at 4 months. Patient 6 had a partial renal response but required renal transplantation, which was successful. Patient 8 responded well to obinutuzumab but died from severe COVID-19 infection (unvaccinated). After obinutuzumab 6 patients with B-cell data all achieved complete depletion including 4/4 assessed with highly sensitive assays. Conclusion These results demonstrate obinutuzumab’s efficacy in patients with secondary non-response to rituximab. These patients have severe disease with few treatment options, but previous responsiveness to B-cell depletion. Therefore, switching to another therapy in this class is mechanistically logical. Obinutuzumab appeared effective in renal and non-renal SLE as well as steroid-sparing. Immunological markers also improved. Obinutuzumab was generally well tolerated and will be further investigated for treatment-refractory lupus in the REGENCY and ALLEGORY trials. Disclosure J.E. Arnold: None. S. Dass: Consultancies; Received consultancy fees from Roche, Abbvie, UCB &amp; Chugai. Honoraria; Received honoraria from Roche, Abbvie, UCB &amp; Chugai. S. Twigg: None. C.H. Jones: None. B. Rhodes: None. P. Hewins: None. M. Chakravorty: None. P. Courtney: None. M. Ehrenstein: Honoraria; Received honoraria from GSK. Grants/research support; Received funding from GSK. M. Md Yusof: None. E. Vital: Consultancies; Received consulting fees from Roche, GSK, Eli Lilly and AstraZeneca. Honoraria; Received honoraria from Roche, GSK, Eli Lilly and AstraZenec. Grants/research support; Received research support from Roche and AstraZeneca (Paid to the University of Leeds).

Immune Checkpoint Inhibitor Use in Solid Organ Transplant Recipients: A Systematic Review.

Chronic immunosuppression in solid organ transplant recipients (SOTRs) leads to an increased risk of a wide variety of cancers. Immune checkpoint inhibitor (ICI) therapy is indicated for many of these; however, the risks and benefits of ICI use in the SOTR population have not been well characterized. We performed a systematic literature review identifying 119 reported cases of ICI use among SOTRs. Treatments used included PD-1 inhibition (75.6%), CTLA-4 inhibition (12.6%), PD-L1 inhibition (1.7%), and combination and/or sequential ICI therapy (10.1%). The most common cancers included cutaneous melanoma (35.3%), hepatocellular carcinoma (22.7%), and cutaneous squamous cell carcinoma (18.5%). The overall objective response rate (ORR) was 34.5%, with a median duration of response of 8.0 months. Ongoing response was seen in 21.0%. Cutaneous squamous cell carcinoma had significantly better ORR compared with other cancer types (68.2% vs 26.8%; odds ratio [OR], 5.85; P =.0006). Factors associated with improved ORR included increasing time from transplant to ICI (OR, 1.09; P =.008) and preemptive reduction in intensity of the graft maintenance immunosuppressive regimen (50.0% vs 18.5%; OR, 4.40; P =.0088). Rejection occurred in 41.2%, graft failure in 23.5%, and immune-related adverse events in 18.5%. Factors significantly associated with allograft rejection included allograft PD-L1 positivity (100% vs 0%; P<.0001) and absence of tacrolimus in the immunosuppressive regimen (48.7% vs 25.6%; OR, 0.36; P =.019). The most common cause of death was progressive malignancy (64.0%), followed by graft failure (24.0%). Our analysis provides current benchmark data to help inform management of SOTRs with advanced cancers that are reflected by our patient cohort. Biomarker development, more robust datasets, and prospective study of concomitant immunosuppression management may help refine decision-making in this complex scenario in the future. Close coordination of care between the medical oncologist and transplant specialist is encouraged to help optimize treatment outcomes.

Severe Acute Respiratory Syndrome Coronavirus 2 Cross-Reactive B and T Cell Responses in Kidney Transplant Patients

BackgroundImmune responses to seasonal endemic coronaviruses might have a pivotal role in protection against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Those SARS-CoV-2-crossreactive T cells were recently described in immunocompetent individuals. Still, data on cross-reactive humoral and cellular immunity in kidney transplant recipients is currently lacking. MethodsThe pre-existing, cross-reactive antibody B and T cell immune responses against SARS-CoV-2 in unexposed adults with kidney transplantation (Tx, n = 14) and without (non-Tx, n = 12) sampled before the pandemic were compared with 22 convalescent patients with COVID-19 (Cp) applying enzyme-linked immunosorbent assay and flow cytometry. ResultsIn both unexposed groups, SARS-CoV-2 IgG antibodies were not detectable. Memory B cells binding spike (S) protein SARS-CoV-2 were detected in unexposed individuals (64% among Tx; 50% among non-Tx) and higher frequencies after infection (80% Cp). The numbers of SARS-CoV-2-reactive T cells were comparable between patients who had undergone Tx and those who had not. SARS-CoV-2-reactive follicular T helper cells were present in 61% of the unexposed cohort in both patients who had undergone Tx and those who had not. ConclusionsCross-reactive memory B and T cells against SARS-CoV-2 exist also in transplanted adults, suggesting a primed adaptive immunity. The effect on the disease course may depend on the concomitant immunosuppressive drugs.