Disease Remission In Patients Research Articles

Effectiveness of Biologic Therapy in Controlling Inflammation and Achieving Disease Remission in Patients with Rheumatoid Arthritis: A Systematic Review

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disorder characterized by joint pain, swelling, and potential systemic complications. The usefulness of biological treatments in reducing inflammation and helping RA patients achieve clinical remission is assessed in this systematic narrative review. Using PubMed, Scopus, and Google Scholar, a thorough literature search was carried out with an emphasis on research published in the last five years. The inclusion criteria were English-language human subject research that contributed significantly to our understanding of biological therapies for RA. Despite concerns over long-term drug withdrawal, TNF-alpha inhibitors, including certolizumab, adalimumab, and infliximab, have shown considerable effectiveness in lowering disease activity and inducing remission. Tocilizumab and other IL inhibitors have shown strong anti-inflammatory properties and increased rates of medication retention. Certain patient profiles have shown success with other biologics, such as rituximab and abatacept, especially those who have not responded to previous therapies. Empirical evidence demonstrates that tofacitinib, a JAK inhibitor, is just as effective as conventional biologics. The study emphasizes how important it is to create individualized treatment programs depending on the medical history and response to the condition. Even with encouraging findings, improving RA care requires ongoing observation of safety profiles and long-term effects. This study offers a thorough synthesis of the available data to help physicians choose the best biologic therapy for patients with RA.

#2748 Combined rituximab and daratumumab treatment in difficult to treat nephrotic syndrome cases

Abstract Background and Aims Common treatments for multidrug-resistant and multidrug-dependent nephrotic syndrome (NS) are inconsistently effective and burdened by long-term toxicities. Moreover, affected patients are at high risk of progression to end-stage kidney failure. Objective To test the safety/efficacy profile of combined single infusion of rituximab and daratumumab in inducing proteinuria remission in multidrug resistant nephrotic syndrome and maintaining drug free disease remission in patients with multidrug-dependent nephrotic syndrome after removal of oral immunosuppression. Method We here present a Phase 2 Proof-of-Concept single-arm clinical trial, that enrolled consecutive participants at the Nephrology Unit of the IRCCS Giannina Gaslini Children's Hospital in Genoa, Italy, between September 2021 and March 2023. Enrolled patients, aged between 3 and 24 years, were multidrug-dependent or multidrug-resistant nephrotic syndrome for at least 12 months before enrolment. Multidrug-dependency was defined by the need of at least 2 oral immunosuppressive drugs (prednisone and/or calcineurin inhibitors and/or mycophenolate mofetil) and by the occurrence of at least two consecutive relapses on two immunosuppressive drugs. Multidrug-resistance nephrotic syndrome was defined by the lack of antiproteinuric effect of a double immunosuppressive therapy. Exclusion criteria included genetic forms of NS and administration of monoclonal therapies in the last 9 months before enrolment. Interventions: Rituximab and daratumumab were administered as single doses at 375 mg/m2 and 16 mg/kg, respectively, 15 days apart. Main Outcomes and Measures:Proteinuria, serum albumin, Immunoglobulin M and G, B and T lymphocyte subsets, safety, Quality of Life. Results A total of 7 consecutive multidrug-resistant and 16 multidrug-dependent NS, respectively, were enrolled. In multidrug-resistant NS, combined rituximab and daratumumab promoted complete or partial remission in 6 patients (Fig. 1A). Five subjects experienced proteinuria relapse, that was effectively treated with a second course of combined treatment. Decreased of I'm, but not IgG, correlated with improvement of proteinuria (Fig. 1B).These treatment allowed to reduce the chronic immunosuppressive treatment daily administered (Fig. 1C). In multidrug-dependent NS, combined rituximab and daratumumab extended the relapse-free time, allowing us to remove oral immunosuppressant (Fig. 1D). Disease relapse was invariably anticipated by a recovery of circulating IgM:patients with IgM levels below median values measured at 3 mo post-treatment had a significantly lower rate of relapse at 9 mo than patients with higher IgM levels at 3 mo (Fig. 1E). Combined treatment induced significative reduction of CD38+ plasma cells (Fig. 1F) and IgM, but not IgG. Treatment was well tolerated and significantly increased quality of life. Conclusion Combined rituximab and daratumumab was safe and effective in the treatment of complicated forms of NS, offering a new therapeutic option for this severe condition.

A retrospective cohort study of Epstein-Barr virus infection status and systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) and the Epstein-Barr virus (EBV) are very closely related. This study estimated the impact of EBV infection status on clinical manifestations and disease remission in patients with SLE. A retrospective study was performed using electronic health records of patients with SLE. The SLE disease activity index (SLEDAI-2K) was used to assess disease activity. VCAIgM or EAIgM positive or EBVDNA copies ≥ 50IU/mL were defined as lytic infection group, EBNA-IgG or VCAIgG-positive and who were negative for both VCAIgM and EAIgM with EBVDNA copies < 50IU/mL were defined as the latent infection group. The endpoint (disease remission) was defined as a decrease in SLEDAI-2K score of ≥ 1 grade or ≥ 4 points from baseline. The association between EBV infection status and disease remission was assessed using propensity score weighting and multivariable Cox regression models. There were 75 patients with SLE in the EBV lytic infection group and 142 patients in the latent infection group. The SLEDAI-2K score was higher in the lytic infection group (10.00 (6.25, 16.00) vs. 8.00 (5.00, 10.00), Z = 3.96, P < 0.001). There was a significant difference in the effect of EBV lytic infection on disease remission compared to latent infection (HR 0.30, 95% CI 0.19-0.49, P < 0.001). Patients with SLE with lytic EBV infection have higher disease activity and take longer to achieve remission. Our study furthers our understanding of the relationship between SLE and EBV infection and may inform better treatment practices in the future.

Effect of Spesolimab on Achieving Sustained Disease Remission in Patients with Generalized Pustular Psoriasis: Results from the Effisayil 2 Study

Introduction: Generalized pustular psoriasis (GPP) is a chronic, rare disease characterized by flares of widespread skin pustulation. Intravenous (IV) spesolimab, an anti-interleukin-36 receptor monoclonal antibody, is approved for GPP flare treatment; however, the optimal dosing and long-term efficacy of subcutaneous (SC) spesolimab treatment in patients with GPP has not yet been reported. We report the effect of SC spesolimab on achieving sustained disease remission in Effisayil 2 (NCT04399837), a 48-week trial that evaluated the efficacy and safety of SC spesolimab in preventing GPP flares.&#x0D; Methods: Patients with a history of GPP were randomized (1:1:1:1) to receive placebo (n=31), low- (n=31, 300 mg loading dose [LD]; 150 mg every 12 weeks [q12w]), medium- (n=31, 600 mg LD; 300 mg q12w) or high-dose (n=30, 600 mg LD; 300 mg every 4 weeks [q4w]) SC spesolimab over 48 weeks. Sustained remission was defined as GPP Physician Global Assessment (GPPGA) total score of 0 or 1 at all visits up to Week 48, or GPPGA total score of 0 or 1 and all GPPGA subscores ≤2 at all visits up to Week 48. Sustained pustular clearance was defined as GPPGA pustulation subscore of 0 at all visits from Week 4 to Week 48. Any use of IV spesolimab or another standard of care for GPP worsening was considered a failure of remission. Missing data were imputed by a sequential logistic regression multiple imputation method. Adjusted risk differences (RD) were calculated by the Mantel−Haenszel type-weighted average of differences.&#x0D; Results: 31 patients received placebo, and 30 patients received high-dose spesolimab. Compared to placebo, more patients had sustained remission in the high-dose arm using both GPPGA total score 0 or 1 (63.3% vs 29.0%; RD [95% CI] 0.35 [0.10–0.59]), and GPPGA total score 0 or 1 and all GPPGA subscores ≤2 (60.4% vs 29.0%; RD [95% CI] 0.32 [0.07–0.56]). Compared to placebo, more patients in the high-dose arm had sustained pustular clearance over 48 weeks (63.6% vs 25.8%; RD [95% CI] 0.38 [0.14–0.62]).&#x0D; Conclusion: Overall, high-dose SC spesolimab q4w is effective for the long-term management of GPP skin symptoms.

A single cell atlas of frozen shoulder capsule identifies features associated with inflammatory fibrosis resolution

Frozen shoulder is a spontaneously self-resolving chronic inflammatory fibrotic human disease, which distinguishes the condition from most fibrotic diseases that are progressive and irreversible. Using single-cell analysis, we identify pro-inflammatory MERTKlowCD48+ macrophages and MERTK + LYVE1 + MRC1+ macrophages enriched for negative regulators of inflammation which co-exist in frozen shoulder capsule tissues. Micro-cultures of patient-derived cells identify integrin-mediated cell-matrix interactions between MERTK+ macrophages and pro-resolving DKK3+ and POSTN+ fibroblasts, suggesting that matrix remodelling plays a role in frozen shoulder resolution. Cross-tissue analysis reveals a shared gene expression cassette between shoulder capsule MERTK+ macrophages and a respective population enriched in synovial tissues of rheumatoid arthritis patients in disease remission, supporting the concept that MERTK+ macrophages mediate resolution of inflammation and fibrosis. Single-cell transcriptomic profiling and spatial analysis of human foetal shoulder tissues identify MERTK + LYVE1 + MRC1+ macrophages and DKK3+ and POSTN+ fibroblast populations analogous to those in frozen shoulder, suggesting that the template to resolve fibrosis is established during shoulder development. Crosstalk between MerTK+ macrophages and pro-resolving DKK3+ and POSTN+ fibroblasts could facilitate resolution of frozen shoulder, providing a basis for potential therapeutic resolution of persistent fibrotic diseases.

P948 Hand Grip Strength is a useful objective measure associated with fatigue and impaired quality of life in patients with inflammatory bowel disease

Abstract Background Hand grip strength (HGS) is a recognised tool for diagnosis / screening of muscle impairment and sarcopenia, however it remains underutilised in IBD cohorts. The aim of the study was to measure the prevalence of muscle impairment by HGS and association with quality of life in a cohort of UC patients in disease remission. Methods Potential subjects were prospectively identified for selection from the Gastroenterology Department in St. Vincent’s University Hospital Outpatient Department. All patients had a confirmed diagnosis of UC for &amp;gt;3 month with stable, quiescent disease (no escalation of medical therapy in the previous 3 months with a documented Faecal Calprotectin (FCP) &amp;lt;100 μg/g). Along with anthropometry data, HGS measurements were performed using the Jamar®Plus+Dynamometer. Quality of life scores were measured using 36-item Short Form Survey (SF-36), Short Inflammatory Bowel Disease Questionnaire (SIBDQ), and Short Health Scale questionnaires were measured. Linear regression was used to calculate standardised β-coefficients for correlation analysis. Non-parametric data was analysed using algorithms including Kruskal-Wallis and Wilcoxon rank-sum test. Results 60% (n=18) of subjects had a HGS outside the lower limit of the 95% confidence interval of age and sex matched normative values, indicative of impaired grip strength. This was significantly more prevalent in subjects with normal BMI than BMI&amp;gt;30 (p=0.035). Prevalence of fatigue was 43.3% according to SIBDQ question 2a and ’Energy/Fatigue’ scores of SF-36 were significantly lower compared to normal Irish population data (51.0 v 64.8, p = 0.0002). Composite scores of fatigue in both SIBDQ (question 2a) and SF-36 were compared, resulting in a standardized β-coefficient of 0.52 of statistical significance (p value = 0.003).Significant correlation was demonstrated between predicted HGS and ’Energy/Fatigue’ SF-36 scores (standardised β-coefficient = 0.4, p value = 0.027). Conclusion HGS is a convenient means of measuring muscle function in an IBD population and correlates significantly with ’Energy/fatigue’ SF-36 scores. These results suggest sarcopenia as a potentially important contributor to fatigue in patients with IBD and suggest HGS is an objective, easily applied objective measure which merits validation as an outcome measure for intervention studies to improve fatigue in patients with IBD.

Reduction of Fecal Calprotectin Levels Induced by a Short Course of Escherichia Coli Nissle is Associated with a Lower Likelihood of Disease Flares in Patients with Ulcerative Colitis in Clinical Remission.

Fecal calprotectin (FC) is a biomarker of gut inflammation, and Escherichia coli Nissle 1917 (EcN) is a probiotic strain able to reduce gut inflammation and maintain disease remission in patients with inflammatory bowel disease (IBD). The aim is to assess the effects of EcN administration in patients with IBD in clinical remission and altered FC values. We prospectively included 82 patients with ulcerative colitis (UC) (n=49) and Crohn's disease (CD) (n=33) in clinical remission and with FC values above 250 mcg/g (T0) who were treated with EcN alone for 2 months. FC values were assessed at the end of EcN treatment (T1) and clinical disease activity at 3 months (T2). At T1 median FC values were significantly lower compared to T0 both in patients with CD (312 mcg/g vs 626 mcg/g, p<0.0001) and UC (100 mcg/g vs 584 mcg/g; p<0.0001). Patients with UC who experienced disease relapse at T2 had lesser reduction in median FC values at T1 (-229 mcg/g, vs -397 mcg/g, p=0.049), while in patients with CD we observed no statistically significant difference (-358 mcg/g, vs -427; p=0.568). In patients with UC, a reduction of at least 532 mcg/g in FC had an accuracy of 69.7% and a positive predictive value of 65.7% in predicting maintenance of remission. A short course of EcN was associated with a reduction of FC values in patients with IBD in clinical remission and baseline altered FC values, and in patients with UC this decrease was associated with maintenance of clinical remission.

Mitochondrial Stress Links Environmental Triggers with Pro-Inflammatory Signaling in Crohn's Disease.

Inflammatory Bowel Diseases (IBD) are a group of chronic, inflammatory disorders of the gut. The incidence and activity of IBD are determined by both genetic and environmental factors. Among these factors, polymorphisms in genes related to autophagy and the consumption of non-steroidal anti-inflammatory drugs (NSAIDs) have been consistently associated with IBD. We show that NSAIDs induce mitochondrial stress and mitophagy in intestinal epithelial cells. In an altered mitophagy context simulating that observed in IBD patients, NSAID-induced mitochondrial stress leads to the release of mitochondrial components, which act as Danger Associated Molecular Patterns with pro-inflammatory potential. Furthermore, colonic organoids from Crohn's disease patients and healthy donors show activation of the mitochondrial Unfolded Protein Response (UPRmt) upon treatment with ibuprofen. Finally, colon biopsies from Crohn's disease patients in remission or with low-to-moderate activity also show expression of genes involved in UPRmt, while patients with severe activity show no increase compared to healthy donors. Our results suggest the involvement of mitochondria in the mechanisms triggering inflammation in IBD after NSAID use. Moreover, our results highlight the clinical relevance of mitochondrial stress and activation of the UPRmt pathway in the pathophysiology of Crohn's disease.

Effect of Spesolimab on Achieving Sustained Disease Remission in Patients with Generalized Pustular Psoriasis: Results from the Effisayil 2 Study

Introduction: Generalized pustular psoriasis (GPP) is a chronic, rare and potentially life-threatening disease characterized by flares of widespread skin pustulation. Sustained skin clearance is a key treatment objective. Intravenous (IV) spesolimab, an anti-interleukin-36 receptor monoclonal antibody, is approved for GPP flare treatment; however, the optimal dosing and long-term efficacy of subcutaneous (SC) spesolimab treatment in patients with GPP has not yet been reported. We report the effect of SC spesolimab on achieving sustained disease remission over 48 weeks in Effisayil 2 (NCT04399837), a trial that evaluated the efficacy and safety of SC spesolimab in preventing GPP flares.&#x0D; Methods: Patients with a history of GPP were randomized (1:1:1:1) to receive placebo (n=31), low- (n=31, 300 mg loading dose [LD]; 150 mg every 12 weeks [q12w]), medium- (n=31, 600 mg LD; 300 mg q12w) or high-dose (n=30, 600 mg LD; 300 mg every 4 weeks [q4w]) SC spesolimab over 48 weeks. Sustained remission was defined as GPP Physician Global Assessment (GPPGA) total score of 0 or 1 at all visits up to Week 48, or GPPGA total score of 0 or 1 and all GPPGA subscores ≤2 at all visits up to Week 48. Sustained pustular clearance was defined as GPPGA pustulation subscore of 0 at all visits from Week 4 to Week 48. Any use of IV spesolimab or another standard of care for GPP worsening was considered a failure of remission. Missing data were imputed by a sequential logistic regression multiple imputation method. Adjusted risk differences (RD) were calculated by the Mantel−Haenszel type-weighted average of differences.&#x0D; Results: 31 patients received placebo, and 30 patients received high-dose spesolimab. Compared to placebo, more patients had sustained remission in the high-dose arm using both GPPGA total score 0 or 1 (63.3% vs 29.0%; RD [95% CI] 0.35 [0.10–0.59]), and GPPGA total score 0 or 1 and all GPPGA subscores ≤2 (60.4% vs 29.0%; RD [95% CI] 0.32 [0.07–0.56]). Compared to placebo, more patients in the high-dose arm had sustained pustular clearance over 48 weeks (63.6% vs 25.8%; RD [95% CI] 0.38 [0.14–0.62]).&#x0D; Conclusion: Overall, high-dose SC spesolimab q4w is effective for the long-term management of GPP skin symptoms.

Depression symptoms increase the risk for initiation or switching to biologic therapy in pediatric inflammatory bowel disease patients in remission

Background and aimsAnxiety and depression symptoms are common in IBD population, both adult and pediatric patients. Increased psychological distress might contribute to initiation and switching to biologic therapy in adult patients with IBD or other chronic inflammatory diseases. Aim of the present study are to evaluate anxiety and depression symptoms in IBD pediatric patients with disease remission and investigate their role in initiation or switching to biologic therapy.MethodsWe performed a retrospective analysis on IBD pediatric patients, assessing for anxiety (GAD-7) and depression (PHQ-9) symptoms. Demographic and disease characteristics were obtained from medical records.ResultsEighty-six patients [31 (36%) females - mean age = 15.6 (SD = 2.8) years] were included. Patients scored above cut-off (> 10) on PHQ-9 and GAD-7 were 17 (19.7%) and 18 (20.9%), respectively. No differences were found between UC and CD patients. Baseline clinically relevant depression symptoms were significantly associated with the odds of initiating or switching to biologic therapy within 2 years [OR = 4.5 (1.4–14.3)], even after confounders adjustment [4.2 (1.2–14.9)]. Relationship was not significant with anxiety symptoms.ConclusionAnxiety and depression symptoms is relatively common in pediatric IBD population, even with disease remission. Pediatric IBD patients with high depression symptoms are at increased risk of initiating or switching to biologic therapy. Mental health screening programs should be incorporated in routine clinical practice, especially for depression, regardless of disease activity and disease type. Early diagnosis and proper intervention for mental illness should be part of routine IBD management.

Immunophenotypic correlates of sustained MRD negativity in patients with multiple myeloma

The role of the immune microenvironment in maintaining disease remission in patients with multiple myeloma (MM) is not well understood. In this study, we comprehensively profile the immune system in patients with newly diagnosed MM receiving continuous lenalidomide maintenance therapy with the aim of discovering correlates of long-term treatment response. Leveraging single-cell RNA sequencing and T cell receptor β sequencing of the peripheral blood and CyTOF mass cytometry of the bone marrow, we longitudinally characterize the immune landscape in 23 patients before and one year after lenalidomide exposure. We compare patients achieving sustained minimal residual disease (MRD) negativity to patients who never achieved or were unable to maintain MRD negativity. We observe that the composition of the immune microenvironment in both the blood and the marrow varied substantially according to both MRD negative status and history of autologous stem cell transplant, supporting the hypothesis that the immune microenvironment influences the depth and duration of treatment response.

Experiences of shifts in physiotherapy for rheumatoid arthritis over time – an autoethnography

ABSTRACT Introduction Several shifts in physiotherapy treatment of patients with rheumatoid arthritis (RA) have occurred over time. Objective This paper aims to identify shifts in physiotherapy practice for patients with RA based on the author’s work experiences from the 1980s until today at two Norwegian rheumatism hospitals, and to explore why shifts may have happened. Methods A narrative was developed by describing events making a difference, categorizing, and ordering them with the help of narrative analysis and a sensitizing analytic lens on discourses. Results The storyline from the 1980s to approximately the turn of the millennium is called ‘Shifts determined mainly by clinical context-driven events’ which occurred in response to medical advances and physiotherapists’ clinical experiences. These shifts were later justified by physiotherapists’ research in the clinical context. The other storyline covers mainly the 2000s and is called ‘Shifts increasingly determined by events beyond clinical physiotherapy context.’ They include adjustments to further medical advances and implementation of biopsychosocial understanding of disease at the hospital, and to external research-based recommendations, health reforms, and economy. Conclusion These processes have moved physiotherapy practice at the hospital from mainly providing individualized remedial and rehabilitative physiotherapy for the purpose to normalize physical function to an increasing focus on generic health measures for the purposes of health promotion and cardiovascular disease prevention. However, this shift may not fully match the complex needs presented by patients in disease remission with unrelenting fatigue and work inability and those who have multiple functional challenges and comorbidities.

S500 Long-Term Follow-Up of Esophageal Strictures in Eosinophilic Esophagitis Using Structured Esophagram Protocol

Introduction: Reversal of transmural fibrostenosis in eosinophilic esophagitis (EoE) is not well studied. Our aim was to determine the effect of medical therapy, dilation and initial diameter on esophageal lumen diameter using serial structured esophagrams over a period of years. Methods: Retrospective study of 78 patients who completed two EoE protocol esophagrams at an academic tertiary referral center 2003 to 2021. Maximum and minimum esophageal diameters were measured on images during rapid swallowing in the RAO recumbent position. EoE was diagnosed by consensus definition and classified as active using ≥15 eosinophils per high power field (hpf). Demographics, medical therapies, and endoscopic data were obtained by chart review. Change in esophageal diameter was analyzed with Wilcoxon signed rank test and reported as median, 25th percentile (Q1), and 75th percentile (Q3) values. Results: Median age at first esophagram was 36.2 and 60.3% were male. Medical therapies during last esophagram were PPI (39.5%), swallowed topical steroids (31.6%), diet elimination (13.2%), biologic therapies (1.3%), and clinical trials (1.3%). Eleven patients had dilation before the first esophagram and 33 between esophagrams without significant effect on results. Median years between esophagrams was 2.6 (Table). Median maximum diameter significantly increased by 1.0 mm (Q1: -1.0 mm, Q3: 3.0 mm) (P=0.034) independent of dilation (P=0.744). Median maximum diameter change per year significantly increased by 0.4 mm (Q1: -0.4 mm, Q3: 1.3 mm, P=0.010). The increase appeared most profound in patients starting in the lowest maximum diameter group (9-15 mm) with median increase of 3.0 mm while the highest starting maximum diameter group ( >21 mm) had further narrowing by 2.0 mm (Figure). There was no difference in maximum diameter change for patients on medical therapy compared to no therapy at second esophagram at 1.0 mm (Q1: -1.0 mm Q3: 3.0 mm) and 1.0 mm (Q1: 0.0 mm Q3: 2.0 mm) respectively (P=0.640); however, for patients in disease remission at second esophagram, there was a significant increase in maximum diameter per year compared to active disease at 0.8 mm (Q1: 0.0 mm Q3: 5.3 mm) and 0.0 mm (Q1: -0.4 mm Q3: 0.6 mm) respectively (P=0.019). Conclusion: Long term medical therapy leads to a small, but significant improvement in esophageal diameter in EoE. Whether this improvement is due to reversal of fibrosis or transmural inflammation is unclear.Figure 1.: Maximum Diameter Change Between Esophagram 1 and 2 based on starting maximum esophageal diameter. Table 1. - Esophagram Characteristics No Dilation (n=43) Dilation (n=34) P-Value Total (n=78) P-Value Median Years Between Esophagrams (Range) 2.7 (0.1-11.6) 2.4 (0.1-12.4) 2.6 (0.1-12.4) Median Maximum Diameter Change, mm 1.0 1.0 0.744 1.0 0.034 Q1, mm -1.0 0.0 -1.0 Q3, mm 2.5 3.0 3.0 Median Maximum Diameter Change Per Year, mm 0.3 0.4 0.961 0.4 0.010 Q1, mm -0.4 0.0 -0.4 Q3, mm 1.5 1.3 1.3 Median Minimum Diameter Change, mm 0.0 1.0 0.317 0.0 0.277 Q1, mm -2.0 -1.0 -1.5 Q3, mm 2.0 3.0 2.0 Median Minimum Diameter Change Per Year, mm 0.0 0.4 0.249 0.0 0.059 Q1, mm -0.7 -0.3 -0.5 Q3, mm 0.9 1.5 1.1 mm, millimeters; Q1, 25th percentile; Q3, 75th percentile

Sequential rituximab therapy sustains remission of nephrotic syndrome but carries high risk of adverse effects.

Sequential rituximab (RTX) administration has emerged as an important strategy to sustain remission of disease in patients with difficult-to-treat nephrotic syndrome. We report the efficacy and safety of sequential therapy with two or more courses of intravenous RTX in 250 patients with difficult-to-treat steroid dependence (n=127) and calcineurin inhibitor (CNI)-dependent or CNI-refractory steroid resistance (n=123) managed at one center during 2015-2021. Subsets of patients were cross-sectionally tested for hypogammaglobulinemia, seroprotection against and hyporesponsiveness to vaccines for hepatitis B and tetanus, BK/JC viruria and human antichimeric antibodies (HACAs). Sequential RTX therapy, initiated at a median of 10years [interquartile range (IQR) 7.3-14.4], was administered for 1.8courses/person-year [95% confidence interval (CI) 1.7-2.0] over 2.0years (95% CI 1.2-3.0). Therapy was associated with postponement of relapses by a median of 3years in patients with steroid-sensitive disease and 2years in those with steroid resistance. Relapses were reduced by a mean of 2.0relapses/person-year (95% CI 1.8-2.2), enabling a reduction in prednisolone dose to 0.04mg/kg/day (95% CI 0.01-0.11) and withdrawal of additional immunosuppression in 154 (62%) patients. RTX-associated adverse events, occurring at 0.20events/person-year (95% CI 0.17-0.23), were chiefly comprised of infusion reactions (n=108) and infections (n=46); serious adverse events were observed in 10.8% patients, at 0.03events/person-year (95% CI 0.02-0.05). Hypogammaglobulinemia was observed in 35% of 177 patients and was moderate to severe in 8.5% of cases. Rates of seroprotection at baseline and response following vaccination were lower for hepatitis B [1.9% and 29.4% (n=52)] than tetanus [65.5% and 34.5% (n=58)]. BK/JC viruria, without viremia, was observed in 7.3% of 109 cases. A total of 19 of 107 patients (17.8%) had HACAs, which were associated with B cell nondepletion and serum sickness. Age at therapy of <9-10years was associated with a risk of early relapse, treatment failure and hypogammaglobulinemia following RTX therapy. Sequential therapy with RTX effectively reduces relapses in patients with difficult-to-treat steroid- and/or CNI-dependent or CNI-refractory nephrotic syndrome. Therapy is associated with high rates of hypogammaglobulinemia and infusion reactions.

Arsenic Trioxide and Venetoclax Synergize against AML Progenitors by ROS Induction and Inhibition of Nrf2 Activation.

Venetoclax (VEN) in combination with hypomethylating agents induces disease remission in patients with de novo AML, however, most patients eventually relapse. AML relapse is attributed to the persistence of drug-resistant leukemia stem cells (LSCs). LSCs need to maintain low intracellular levels of reactive oxygen species (ROS). Arsenic trioxide (ATO) induces apoptosis via upregulation of ROS-induced stress to DNA-repair mechanisms. Elevated ROS levels can trigger the Nrf2 antioxidant pathway to counteract the effects of high ROS levels. We hypothesized that ATO and VEN synergize in targeting LSCs through ROS induction by ATO and the known inhibitory effect of VEN on the Nrf2 antioxidant pathway. Using cell fractionation, immunoprecipitation, RNA-knockdown, and fluorescence assays we found that ATO activated nuclear translocation of Nrf2 and increased transcription of antioxidant enzymes, thereby attenuating the induction of ROS by ATO. VEN disrupted ATO-induced Nrf2 translocation and augmented ATO-induced ROS, thus enhancing apoptosis in LSCs. Using metabolic assays and electron microscopy, we found that the ATO+VEN combination decreased mitochondrial membrane potential, mitochondria size, fatty acid oxidation and oxidative phosphorylation, all of which enhanced apoptosis of LSCs derived from both VEN-sensitive and VEN-resistant AML primary cells. Our results indicate that ATO and VEN cooperate in inducing apoptosis of LSCs through potentiation of ROS induction, suggesting ATO+VEN is a promising regimen for treatment of VEN-sensitive and -resistant AML.

OP0042 LONG-TERM EFFICACY AND SAFETY OF CANAKINUMAB IN PATIENTS WITH FAMILIAL MEDITERRANEAN FEVER (FMF) - INTERIM ANALYSIS OF THE RELIANCE REGISTRY

BackgroundFamilial Mediterranean Fever (FMF) is a chronic disease characterized by recurrent attacks of fever as well as serositis and bears the risk of serious complications (e. g. amyloidosis). Treatment of FMF according to EULAR aims to control acute attacks and subclinical inflammation as well as to improve patient´s quality of life1. Clinical data indicate that the inhibition of interleukin-1β with canakinumab (CAN) is effective in controlling and preventing flares in FMF patients2.ObjectivesThe present study explores the long-term efficacy and safety of canakinumab in routine clinical practice conditions in pediatric (age ≥2 years) and adult FMF patients.MethodsRELIANCE is a prospective, non-interventional, multi-center, observational study based in Germany with a 3-year follow-up period. Patients with clinically confirmed FMF diagnosis who routinely receive canakinumab are enrolled in order to evaluate effectiveness and safety of canakinumab. Disease activity and remission by physicians´ assessment, disease activity, fatigue and impact on social life by patients’ assessment, inflammatory markers and AIDAI (Auto-Inflammatory Diseases Activity Index) score were recorded at baseline and assessed at 6-monthly intervals within the 3-year observation period of the study.ResultsThis interim analysis of FMF patients (N=74) enrolled by December 2021 includes baseline as well as 6- to 24-month data. Mean age in this cohort was 25 years (2−61 years) and the proportion of female patients was 51 % (N=38). At baseline, median duration of prior CAN treatment was 1.0 years (0−6 years).At month 24, physician ratings report around 63% of patients in disease remission and patient-reported disease activity (mean PPA) decreased from moderate (3.0) to low (2.6) during the observation period. Other disease activity parameters also decreased (Table 1). A total of 18 serious adverse events were reported, of which 2 (1 case of tonsillectomy and 1 case of tachycardia) were classified as drug - related.Table 1.Baseline characteristics and 4th interim analysis data of patients with FMFBaseline12 months24 monthsNumber of patients, N744624Number (%) of patients with days absent from work/school during last 6 months6 (8)11 (24)9 (38)Number (%) of patients in disease remission (physician assessment)22 (45)23 (72)12 (63)Patient’s assessment of current disease activity; 0–10, median (min; max)2.0 (0; 10)2.0 (0; 7)2.0 (0; 10)Patient’s assessment of current fatigue; 0–10, median (min; max)5.0 (0; 10)2.0 (0; 10)4.0 (0; 10)Number (%) of patients without impairment of social life by the disease27 (50)28 (80)8 (67)CRP (mg/dl) | SAA (mg/dl) | ESR (mm/h); median0.2 | 0.7 | 8.00.2 | 0.5 | 4.00.2 | 0.7 | 6.0Number (%) of patients with disease-related symptomsprior to inclusion into the study | at baseline12 months24 monthsFever68 (93) | 14 (29)8 (25)3 (16)Abdominal pain67 (92) | 20 (41)10 (31)4 (21)Thoracic pain45 (62) | 5 (10)3 (9)1 (5)Headache34 (47) | 11 (22)7 (22)5 (26)Myalgia23 (32) | 6 (12)4 (13)2 (11)Arthralgia/arthritis39 (54) | 16 (33)9 (28)5 (26)Dermal symptoms (urticarial, maculopapulose)15 (21) | 5 (10)3 (9)0 (0)SAENumber of eventsIncidence rate# per 100 patient yearsAll types of SAE1814.03SADR21.56Incidence rate = number of events * 36,525 / sum of observation days (=46,848).CRP, c-reactive protein; ESR, erythrocyte sedimentation rate; n. a., not annotated; SAA, serum amyloid A; SADR, serious adverse drug reaction; SAE, serious adverse events.ConclusionInterim data of FMF patients from the RELIANCE study, the longest running real-life canakinumab registry confirm efficacy and safety of long-term canakinumab treatment.

OP0185 TOCILIZUMAB IN COMBINATION WITH 8 WEEKS OF PREDNISONE FOR GIANT CELL ARTERITIS

BackgroundEven with the use of tocilizumab (TCZ), significant glucocorticoid exposure (usually ≥ 6 months) continues to be an important problem in giant cell arteritis (GCA).ObjectivesWe aimed to evaluate the efficacy and safety of tocilizumab (TCZ) in combination with 2 months of prednisone in a group of patients with GCA.MethodsWe conducted a prospective, single arm, open-label study of TCZ in combination with 2 months of prednisone for new-onset and relapsing GCA patients with active disease (ClinicalTrials.gov Identifier NCT03726749). GCA diagnosis required confirmation by temporal artery biopsy or vascular imaging. Active disease was defined as presence of cranial or polymyalgia rheumatica symptoms necessitating treatment within 6 weeks of baseline. All patients received TCZ 162 mg subcutaneously every week for 12 months and an 8-week prednisone taper starting between 20 mg and 60 mg daily (Figure 1). The primary endpoint, sustained prednisone-free remission, was defined as absence of relapse from induction of remission up to week 52 while adhering to the prednisone taper. Relapse was defined as the recurrence of symptoms of GCA requiring treatment intensification regardless of erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels. Safety was also evaluated.Figure 1.Clinical Trial SchemaResultsBetween 11/2018 and 11/2020 we enrolled 30 patients (mean age 74 years, 60% females, 50% new-onset disease, 77% temporal artery biopsy-proven, 47% imaging-proven). The mean ESR and CRP at screening were 45 mm/hour and 48 mg/L, respectively. The initial prednisone dose was 60 mg (n = 7), 50 mg (n = 1), 40 mg (n = 7), 30 mg (n = 6) and 20 mg (n = 9). All patients entered remission within 4 weeks of baseline. The primary endpoint was achieved by 23 (77%) patients (Table 1). The mean (SD) cumulative prednisone dose in these 23 patients was 1052 (390) mg. After a mean period of 16 weeks, 7 (23%) patients relapsed (Table 1). All relapses but one occurred after the completion of the study prednisone taper. Overall, 6 of the 7 patients with relapse received a second prednisone taper over 8 weeks. Of these 6 patients, 4 achieved and maintained remission for the remainder of the trial period, and 2 withdrew from the study after having a second relapse. One patient with relapse received a second prednisone taper over 26 weeks and stayed in remission until the end of the study. The mean (SD) cumulative prednisone dose in the 7 patients with relapse was 1883 (699) mg (Table 1). Overall, 4 (13%) participants developed a serious adverse event (Table 1). No cases of ischemia-related visual symptoms including permanent vision loss occurred during the study.Table 1.Efficacy and Safety OutcomesGCA patients(n = 30)Efficacy Sustained, prednisone-free remission by week 5223.0 (76.7) Cumulative prednisone dose (mg) at week 52, mean (SD)1051.5 (390.3) Relapse7.0 (23.3) Time to relapse, weeks: mean (SD)15.8 (14.7) Prednisone dose (mg/day) at relapse, mean (SD)2.1 (5.2) Cumulative prednisone dose (mg), mean (SD)1883.1 (699.2) Clinical manifestations at relapse Cranial symptoms4 out of 7 patients Ischemic visual symptoms0 out of 7 patients PMR symptoms4 out of 7 patientsSafety Serious adverse events4.0 (13.3) Cellulitis1 COVID-191 Fragility fracture1 Cholecystitis1Values represent number and (%) unless otherwise specified. SD, standard deviation; PMR, polymyalgia rheumaticaConclusionThese results suggest that 12 months of TCZ in combination with 8 weeks of prednisone could be efficacious for inducing and maintaining disease remission in patients with GCA. Confirmation of these findings in a randomized controlled trial is required.Disclosure of InterestsSebastian Unizony Consultant of: Kiniksa, Sanofi, Janssen, GSK, Grant/research support from: Janssen, Genentech, Mark Matza: None declared, Adam Jarvie: None declared, Ana Fernandes: None declared, John H. Stone Consultant of: Roche/Genentech, Grant/research support from: Roche/Genentech

Tyrosine kinase inhibitors for the treatment of indolent systemic mastocytosis: Are we there yet?

Indolent systemic mastocytosis (ISM) is the most prevalent form of systemic mastocytosis. Many patients with ISM suffer from mast cell (MC) mediator-related symptoms. In a small number of patients, hematologic progression is seen in the follow-up. In some patients with ISM, symptoms arising from MC-derived mediators including gastrointestinal symptoms, anaphylaxis, and neuropsychiatric symptoms are kept under control with conventional mediator-targeting drugs or MC-stabilizing agents. However, in a substantial number of patients, the symptoms are refractory to such conventional therapy. For these patients, novel drugs and targeted approaches are considered. One reasonable approach may be to apply tyrosine kinase inhibitors directed against KIT and other key kinase targets expressed in neoplastic MCs in ISM. Because MCs in more than 90% of all patients with typical ISM display the KIT D816V mutant receptor, clinically effective KIT-targeting drugs have to be active against this mutant form of KIT. The 2 such most effective and well-studied agents currently available are midostaurin and avapritinib. Other KIT-targeting drugs, such as imatinib or masitinib, are less effective or even noneffective against KIT D816V and are thus recommended for use only in patients with other KIT mutant forms (noncodon 816 mutations) or with wild-type KIT. In the present article, we review the current state in the treatment of ISM with tyrosine kinase inhibitors, with special emphasis on treatment responses and potential adverse effects. In fact, all of these agents also have unique and common adverse effects, and their use to treat patients with ISM should be balanced against their toxicity and short- and long-term safety.

Synergy of Venetoclax and 8-Chloro-Adenosine in AML: The Interplay of rRNA Inhibition and Fatty Acid Metabolism.

Simple SummaryTreatment failures of acute myeloid leukemia (AML) have been attributed to the persistence of leukemia stem cells (LSCs), which are refractory to conventional treatments. Venetoclax (VEN), currently FDA-approved in combination with low-dose cytarabine or hypomethylating agents, is highly effective in inducing disease remission in patients with de novo AML; however, most of these patients eventually relapse; thus, novel VEN combinations are urgently needed. In this regard, 8-chloro-adenosine (8-Cl-Ado) is a novel RNA-directed nucleoside analog that targets AML cells, including LSCs. We demonstrate that VEN and 8-Cl-Ado cooperate in targeting ribosomal RNA synthesis and mitochondrial metabolism in LSCs, thereby decreasing LSC survival. Given the emerging concept that LSC behavior is strongly associated with protein synthesis regulation and mitochondrial metabolism, our results suggest that the VEN/8-Cl-Ado combination is a promising regimen for the treatment of patients with relapsed AML.It is known that 8-chloro-adenosine (8-Cl-Ado) is a novel RNA-directed nucleoside analog that targets leukemic stem cells (LSCs). In a phase I clinical trial with 8-Cl-Ado in patients with refractory or relapsed (R/R) AML, we observed encouraging but short-lived clinical responses, likely due to intrinsic mechanisms of LSC resistance. LSC homeostasis depends on amino acid-driven and/or fatty acid oxidation (FAO)-driven oxidative phosphorylation (OXPHOS) for survival. We recently reported that 8-Cl-Ado and the BCL-2-selective inhibitor venetoclax (VEN) synergistically inhibit FAO and OXPHOS in LSCs, thereby suppressing acute myeloid leukemia (AML) growth in vitro and in vivo. Herein, we report that 8-Cl-Ado inhibits ribosomal RNA (rRNA) synthesis through the downregulation of transcription initiation factor TIF-IA that is associated with increasing levels of p53. Paradoxically, 8-Cl-Ado-induced p53 increased FAO and OXPHOS, thereby self-limiting the activity of 8-Cl-Ado on LSCs. Since VEN inhibits amino acid-driven OXPHOS, the addition of VEN significantly enhanced the activity of 8-Cl-Ado by counteracting the self-limiting effect of p53 on FAO and OXPHOS. Overall, our results indicate that VEN and 8-Cl-Ado can cooperate in targeting rRNA synthesis and OXPHOS and in decreasing the survival of the LSC-enriched cell population, suggesting the VEN/8-Cl-Ado regimen as a promising therapeutic approach for patients with R/R AML.

P561 Clinical utility of therapeutic drug monitoring of adalimumab using a point of care test

Abstract Background Adalimumab (ADL) is a fully human monoclonal antibody against tumor necrosis factor that is approved for the management of inflammatory bowel disease (IBD). Therapeutic drug monitoring (TDM) of ADL is widely used to ensure adequate blood levels for maintenance of the clinical benefit. This study examined the clinical utility of a point of care (POC) ADL assay to facilitate TDM. Methods A fast (&amp;lt;3 min), time-resolved fluorescence resonance energy transfer (FRET) based immunoassay (Procise ADL™) was developed for measuring of ADL and its biosimilars for TDM using 20 µL of finger prick capillary whole blood or serum. To assess its clinical performance we conducted an observational study using stored frozen serum specimens from a nested cohort in a registry population collected over 24 months. Serum samples were thawed and ADL concentrations were measured with Procise ADL™. Adult patients with an established diagnosis of Crohn’s disease (CD) or ulcerative colitis (UC) who received maintenance ADL treatment were included. Primary endpoint was loss of response (LOR) defined as any of the following: (i) disease flare defined by documented worsening symptoms and abnormal endoscopy/imaging/biomarker findings leading to discontinuation of ADL; (ii) disease activity leading to change in IBD medication; (iii) increase in fecal calprotectin ≥150 mg/Gr; (iv) IBD surgery or (v) new or recurring actively draining fistula. To be evaluable LOR patients were required to have a study specimen &amp;lt; 60 days prior to the LOR event. Receiver-operating characteristic (ROC) curves were generated to identify optimal cut-off values to discriminate between patients with maintained response vs. LOR. Results A total of 84 IBD patients (LOR=37, No LOR= 47) were included in this study. Median ADL trough levels were lower in patients who experienced loss of response compared to patients who did not (median ADL 6.0 μg/mL vs 13. μg/mL, P &amp;lt; 0.001, figure 1). Area-Under-the-ROC Curve (AUC) value for loss of response was 0.822 (figure 2). Optimal ADL trough cut-off value was 8 μg/mL (Table 1). Figure 1. shows patients losing response to ADL had serum levels significantly lower than those maintaining response Figure 2. shows ROC curve analysis of the Procise ADL test for the detection of LOR Table 1. Showsclinical performance of Procise ADL for the detection of LOR at various ADL concentration Conclusion IBD patients in disease remission on maintenance ADL therapy with ADL levels below a cut-off 8.0 μg/mL had a 5.34 fold increased risk of LOR compared to those above 8.0 μg/mL. Identifying patients at high risk of LOR with a convenient POC format test enhances the clinical utility of TDM by enabling faster treatment adjustment.