Disease Remission Research Articles

Does Magnesium Provide a Protective Effect in Crohn’s Disease Remission? A Systematic Review of the Literature

This systematic review evaluates the hypothesis that optimal serum magnesium levels may enhance remission rates in Crohn’s disease (CD) and considers whether magnesium supplementation could be beneficial in CD management. This review aims to synthesize available evidence concerning the impact of serum magnesium on disease remission in CD, and to analyze the effectiveness and mechanistic roles of magnesium supplementation. Adhering to the PRISMA guidelines, we searched PubMed, Web of Science, and Scopus up to January 2024 using MeSH terms and free-text queries related to CD and magnesium. The inclusion criteria were studies that investigated serum magnesium levels, effects of supplementation, and the inflammatory mechanisms in CD remission. From the 525 records identified, eight studies met the inclusion criteria after the removal of duplicates and irrelevant records. These studies, conducted between 1998 and 2023, involved a cumulative sample of 453 patients and 292 controls. Key findings include significantly lower serum magnesium levels in CD patients (0.79 ± 0.09 mmol/L) compared to controls (0.82 ± 0.06 mmol/L), with up to 50% prevalence of hypomagnesemia in CD patients observed in one study. Notably, CD patients, particularly men, exhibited lower magnesium intake (men: 276.4 mg/day; women: 198.2 mg/day). Additionally, low magnesium levels correlated with increased sleep latency (95% CI −0.65 to −0.102; p = 0.011) and decreased sleep duration (95% CI −0.613 to −0.041; p = 0.028). Another key finding was the significant association between low serum magnesium levels and elevated CRP levels as an indicator of CD disease activity. The findings support the hypothesis that serum magnesium levels are significantly lower in CD patients compared to healthy controls and suggest that magnesium supplementation could improve CD management by enhancing remission rates and sleep quality. However, more rigorous, evidence-based research is necessary to define specific supplementation protocols and to fully elucidate the role of magnesium in CD pathophysiology.

Clinical remission maintained and improved over time in patients with severe asthma treated with omalizumab

Background Clinical remission has recently been proposed as a possible treatment goal even in severe asthma. In this real-world study, we aimed to assess the achievement rate and predictive factors of clinical remission using omalizumab in patients with severe asthma. Methods This retrospective observational study included patients with severe asthma initiated with omalizumab therapy and recruited from the asthma clinic of the Akdeniz University Hospital, Turkey. Clinical remission was defined as patients who received no oral corticosteroid (OCS) therapy; showed no exacerbations; showed an asthma control questionnaire score of ≤ 1, asthma control test (ACT) of ≥ 20, or both and, FEV1 of ≥ 80% predicted. Results A total of 58 patients were included in the study, with an average age of 56.4 ± 13.6 years. The mean duration of asthma was 23.5 ± 11.8 years and the mean duration of omalizumab treatment was 80.05 ± 35.04 months. Clinical remission rates were 25.9% in the first and second year, 34.0% in the third year, 34.1% in the fourth year and 47.4% in the fifth year. Pre-omalizumab ACT, FEV1 (%) and OCS use were significantly higher in patients with clinical remission at 1 year. Logistic regression analyses showed that none of the factors predicted clinical remission. Conclusion Omalizumab has the potential to induce disease remission in a significant proportion of people with severe asthma, and this is maintained and improved over time.

#314 Systemic lupus erythematous (SLE) and isolated multiple sclerosis: analysis of BAFF—VAR variant on gene TNSF13B

Abstract Background and Aims We report a case of young a woman (33 years old) affected by SLE since 2007. In this year, a renal biopsy showed class IV lupus nephritis and the patient received corticosteroids and immunosuppressant for 3 years. The patient remained thereafter in disease remission with normal renal function, no proteinuria and normal complement levels. In 2013 the patient performed brain MRI for sudden hearing loss. The MRI showed a pattern compatible with isolated multiple sclerosis (RIS), confirmed on subsequent radiographic checks. In 2023, due to the initial onset of renal failure, a new re-staging biopsy showed microscopic aspects compatible with class I/II lupus nephritis (INS/RPS Classification 2004, 2018); the activity index calculated with SLEDAI—2K was +4. A new brain MRI carried out without onset of new symptoms showed a new hyperintense region at the level of the head of the right caudate nucleus and enlargement of the intrasellar CSF content as per the condition of a “partially empty” sella. A genetic variant of the TNFSF13B gene was therefore suspected, since it is involved in encoding the cytochine and drug target B-cell activating factor (BAFF), associated with multiple sclerosis as well as SLE. We searched for the genetic variant in order to undertake target therapy early in our patient. Method We performed PCR amplification and direct sequencing of all coding exons plus all the intron-exon junctions of the analyzed gene, by automatic sequencer with SeqStudio Genetic Analyzer (analytical sensitivity and specificity >99%). Results We found the heterozygous presence of the BAFF-var variant in the 3' UTR region of the TNFSF13B gene (Heterozygous genotype for BAFF-var). This variant involves an insertion/deletion (GCTGT>A) at the level of the 3' UTR region with consequent production of an alternative polyadenylation site (APA). This APA leads to the formation of a shorter transcript (BAFF-var mRNA) which causes greater production of the encoded protein compared to the wild-type transcript (BAFF-WT mRNA). Conclusion The molecular analysis conducted highlighted the presence of the BAFF-var variant in heterozygosis which leads to increased levels of soluble BAFF in the serum, with consequent up-regulation of humoral immunity. It is reported in the literature1 that this variant is associated with both Multiple Sclerosis and SLE and may represent a valid therapeutic target being treatable with the monoclonal antibody Belimumab.

#610 Alterations in frequency and function exhausted memory B cells in lupus nephritis and systemic lupus erythematosus

Abstract Background and Aims Various B cell abnormalities have been implicated in the pathogenesis of LN, and our previous studies have demonstrated that memory B cells assume pathogenic relevance in disease relapse. Memory B cell exhaustion is a B lymphocyte aberration initially reported in chronic human immunodeficiency virus (HIV) infection, and was later also observed in chronic graft versus host disease (cGVHD) and autoimmune disorders. The pathogenic roles of exhausted memory B cells in LN and disease relapse remains unclear. We will validate the significance role of exhausted B cell in the pathogenesis of LN. Method Classical memory (CD19 + CD21 + CD27+) and exhausted B cells (CD19 + CD21 – CD27–) were measured in LN patients with multiple relapses (MR) (n=15) or no relapse (NR) (n=15) during disease remission. B cell-related cytokines, homing and inhibitory receptors, proliferation and calcium mobilization in classical and exhausted memory B cells were also assessed. Using single-cell RNA sequencing data from NIH and GEO, we also performed bioinformatics analysis to identify genes and pathways relevant to memory and exhausted B cells in SLE, LN and healthy controls. Results The MR group exhibited higher proportion of circulating exhausted memory B cells compared to NR. Blood levels of IL-6, BAFF and IL-21 in MR patients were higher than the NR group. The MR had higher blood levels of Siglec-6, CXCR3 and CD62L than the NR group. Expression of inhibitory receptors CD22, CD85j, CD183 and FCRL4 in exhausted B cells were increased in the MR group compared to the NR group. Exhausted B cells from MR patients also showed decreased proliferation compared to NR patients and impaired calcium mobilization in response to B-cell receptor triggering. STAT1, XAF1, MX1, IFI44L, EPSTI1, LCP1, OAS1, NEAT1, IFI16, IFI44 in exhausted B cells and XAF1, MX1, IFI44L in memory B cells play a pathogenic role in LN patients (Figs. 1 and 2). SLE patients also show increased proportion of exhausted B cells compared to healthy control and the expression of STAT1, XAF1, MX1, IFI44L correlate positively with the proportion of exhausted B cells. Conclusion Our results suggested that altered numbers and function of exhausted B cells may have pathogenic significance in SLE and LN.

Prebiotics for Induction and Maintenance of Remission in Inflammatory Bowel Disease: Systematic Review and Meta-Analysis.

Prebiotics are nondigestible carbohydrates fermented by gut bacteria into metabolites that confer health benefits. However, evidence on their role for inflammatory bowel disease (IBD) is unclear. This study systematically evaluated the research on prebiotics for treatment of IBD. A search was performed in PubMed, Embase, Cochrane, and Web of Science. Eligible articles included randomized controlled trials or prospective observational studies that compared a prebiotic with a placebo or lower-dose control in patients with IBD. Meta-analyses were performed using random-effects models for the outcomes of clinical remission, clinical relapse, and adverse events. Seventeen studies were included. For induction of clinical remission in ulcerative colitis (UC), the fructooligosaccharide (FOS) kestose was effective (relative risk, 2.75, 95% confidence interval, 1.05-7.20; n = 40), but oligofructose-enriched inulin (OF-IN) and lactulose were not. For maintenance of remission in UC, germinated barley foodstuff trended toward preventing clinical relapse (relative risk, 0.40; 95% confidence interval, 0.15-1.03; n = 59), but OF-IN, oat bran, and Plantago ovata did not. For Crohn's disease, OF-IN and lactulose were no different than controls for induction of remission, and FOS was no different than controls for maintenance of remission. Flatulence and bloating were more common with OF-IN; reported adverse events were otherwise similar to controls for other prebiotics. Prebiotics, particularly FOS and germinated barley foodstuff, show potential as effective and safe dietary supplements for induction and maintenance of remission in UC, respectively. The overall certainty of evidence was very low. There would be benefit in further investigation on the role of prebiotics as treatment adjuncts for IBD.

#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.

#1739 Combination rituximab & low-dose IV cyclophosphamide induction therapy for severe multi-system eosinophilic granulomatosis with polyangiitis

Abstract Background and Aims Current guidelines advise rituximab (RTX) or cyclophosphamide treatment for organ-threatening disease in eosinophilic granulomatosis with polyangiitis (EGPA). However, conventional treatment is often limited by partial efficacy, toxicity, high relapse rate and steroid dependency. We investigate the use of a combined RTX, low-dose cyclophosphamide, and steroid regimen for treatment of severe EGPA. Method Single-centre retrospective cohort study of patients treated with a combination induction regimen for severe EGPA (with kidney, cardiac or neurological involvement) between 2012-23. Data reported as median (±IQR) Results Eighteen patients (10 male; age 56 years [52-62]) are included. At treatment, BVAS was 16.3 [14-20], peak eosinophil count 9.3 × 109/L [5-13], C-reactive protein (CRP) 122 mg/L [80-193]. Eleven cases were ANCA positive (10 MPO-, 1 PR3-ANCA.) The proportions of patients affected by active/new respiratory, ENT, neurological, and gastrointestinal disease were 18/18 (100%), 14/18 (78%), 11/18 (61%), and 1/18 (6%), respectively. 11/18 (61%) had cardiac involvement (troponin 10345 ng/L [1240-7621]) and 6/18 (33%) had necrotising glomerulonephritis confirmed by renal biopsy (creatinine 123 µmol/L [83-167]). Cumulative cyclophosphamide dose was 3.5g [3.0-3.5] and total RTX dose was 2g. Initial prednisolone dose was 0.5-1.0 mg/kg/day, and this was rapidly weaned to 5 mg daily at a median time of 6.1 months [3.9-7.2], and 9/18 (50%) had steroids withdrawn completely by 11.7 months [4.6-20.6]. First-line maintenance treatment was azathioprine or MMF. By 6 months, all achieved disease remission as assessed by BVAS (all 0) and improved laboratory parameters: CRP 1 mg/L, eosinophil count 0.1 × 109/L, and ANCA testing negative. In those with renal disease, kidney function improved or stabilised in all (creatinine 95 µmol/L). In those with cardiac disease (11/18), magnetic resonance imaging was performed at baseline and at follow up (median time of 3.7 months) in all patients. Of these, 9/11 (82%) had oedema on initial scan and this improved in all cases; 10/11 (91%) had late gadolinium enhancement at baseline, which persisted in every case, though with significantly lower burden. The median follow-up period was 38 months [14-55]. At 1, 3 and 5 years, 100%, 92% and 76% of patients were in sustained remission (Fig. 1A). Three patients experienced relapse; one patient had major relapse with skin involvement requiring reinduction treatment; two patients had minor ENT relapse requiring retreatment with glucocorticoids. Infection-free survival at 1, 3 and 5 years was 94%, 78%, 62%, respectively (Fig. 1B). There were no deaths. Conclusion This regimen provided rapid disease control in patients with severe multi-system EGPA, including those with life-threatening cardiac manifestations, and enabled rapid glucocorticoid tapering and withdrawal. Disease-free remission was sustained during long-term follow up. Combination induction regimens may have a role in the treatment of organ-threatening disease in EGPA.

Association between 23 drugs and inflammatory bowel disease: a two-sample Mendelian randomization study

BackgroundInflammatory bowel disease (IBD) is a group of diseases characterized by chronic and recurrent inflammation of the gastrointestinal tract. The etiology of IBD remains multifaceted and poorly understood, resulting in limited treatment options that primarily target disease induction and remission maintenance. Thus, the exploration of novel therapeutic options for IBD among existing medications is advantageous. Mendelian randomization analysis (MR) serves as a valuable tool in investigating the relationship between drugs and diseases. In this study, MR analysis was employed to investigate the potential causal relationship between 23 approved drugs for the treatment of various diseases and IBD.MethodWe performed a two-sample MR analysis using publicly available genome-wide association study (GWAS) statistics. The inverse variance weighting (IVW) method was used as the main analysis method, supplemented by the remaining four methods (weighted median, MR Egger regression, simple and weighted models), and Meta-analysis was performed to expand the sample size to obtain a more reliable composite causal effect. Finally, Cochran’s Q statistic and the MR-Egger test for directed pleiotropy were applied to determine whether significant heterogeneity or directed pleiotropy existed.ResultsIn the main MR analysis (IVW), drugs with a negative causal association with the risk of IBD were immunosuppressant {OR (95% CI) = 0.7389 [0.6311–0.8651], p = 0.0046} and diabetes drugs {OR (95% CI) = 0.9266 [0.8876–0.9674], p = 0.0058}. A positive causal association with the risk of IBD was found for salicylic acid and derivatives {OR (95% CI) = 1.2737 [1.0778–1.5053], p = 0.0345}. Negative causal associations with UC risk were identified for immunosuppressants {OR (95% CI) = 0.6660 [0.5133–0.8640], p = 0.0169} and diabetes medications {OR (95% CI) = 0.9020 [0.8508–0.9551], p = 0.0046}; positive causal associations with UC risk were found for β-receptor blockers {OR (95% CI) = 1.1893 [1.0823–1.3070], p = 0.0046}. A negative causal association with the risk of CD was found for immunosuppressants {OR (95% CI) = 0.6957 [0.5803–0.8341], p = 0.0023}. There was no statistically significant association between the remaining 19 drugs and IBD and subtypes.ConclusionThis MR study provides evidence suggesting that immunosuppressants have a mitigating effect on the risk of IBD and demonstrate consistent efficacy in subtypes of ulcerative colitis (UC) and Crohn’s disease (CD). Additionally, diabetes medications show potential in reducing the risk of IBD, particularly in cases of UC, while β-blockers may elevate the risk of UC. Conversely, salicylic acid and its derivatives may increase the risk of IBD, although this effect is not consistently observed in the subtypes of the disease. These findings offer new insights into the prevention and management of IBD.

Genome-wide DNA methylome and transcriptome profiling reveals key genes involved in the dysregulation of adipose-stem cells in Crohn's disease.

Crohn's disease (CD) is characterised by the expansion of mesenteric adipose tissue (MAT), named creeping fat (CF), which seems to be directly related to disease activity. Adipose-stem cells (ASCs) isolated from the CF of patients with CD are extremely pro-inflammatory, which persists during disease remission. We hypothesised that the dysfunctional ASCs in CD accumulate epigenetic modifications triggered by the inflammatory environment that could serve as molecular markers. Genome-wide DNA methylome and transcriptome profiling were performed in ASCs isolated from MAT adipose-tissue biopsies of patients with active and inactive disease and from non-Crohn's disease patients (non-CD). A validation cohort was used to test the main candidate genes via qPCR in other fat depots and immune cells. We found differences in DNA-methylation and gene expression between ASCs isolated from patients with CD and from non-CD subjects, but we found no differences related to disease activity. Pathway enrichment analysis revealed that oxidative stress and immune response were significantly enriched in active CD and integration analysis identified MAB21L2, a cell fate-determining gene, as the most affected gene in CD. Validation analysis confirmed the elevated gene expression of MAB21L2 in MAT and in adipose tissue macrophages in active CD. We also found a strong association between expression of the calcium channel subunit gene CACNA1H and disease remission, as CACNA1H expression was higher in ASCs and MAT from patients with inactive CD, and correlates negatively with C-reactive protein in peripheral blood mononuclear cells. We identified a potential gene signature of CD in ASCs obtained from MAT. Integration analysis highlighted two novel genes demonstrating a negative correlation between promoter DNA methylation and transcription: one linked to ASCs in CD (MAB21L2) and the other (CACNA1H) related to disease remission.

Conception, pregnancy and inflammatory bowel disease-Current concepts for the practising clinician.

The peak incidence of inflammatory bowel disease (IBD) coincides with a woman's prime reproductive years. The management of IBD during pregnancy can be challenging for healthcare professionals, underpinning the need for a multi-disciplinary approach with shared decision-making with the patient. Pre-conception counselling can address patient concerns, improve pregnancy specific IBD patient knowledge and provide a personalized risk assessment, to ensure optimal maternal and fetal outcomes. Most women with IBD have fertility rates comparable with the general population, although voluntary childlessness is common among women with IBD. IBD disease activity at conception and during pregnancy is a key determinant of the course of IBD during pregnancy. Active IBD during pregnancy is associated with adverse pregnancy-related outcomes, including spontaneous abortion, small for gestational age baby and preterm birth, emphasizing the importance of ensuring disease remission prior to conception. Most IBD medications (5-aminosalicylates, thiopurines if already initiated pre-conception, corticosteroids and biologic medications) are considered safe and low risk during pregnancy and breastfeeding, except for methotrexate, JAK-inhibitors, ozanimod and allopurinol and maintaining remission throughout gestation should be the priority. Most women with IBD can have a vaginal delivery, but cesarean section should be considered in active perianal disease and history of ileal pouch surgery. This narrative review outlines the current evidence for themanagement of IBD in pregnancy, as well as considering the pre-conceptual and post-partum period.

Forecasted infliximab concentrations during induction predict time to remission and sustained disease control of inflammatory bowel disease

BackgroundInfliximab (IFX) exposure is established as a predictive factor of pharmacokinetic (PK) origin in inflammatory bowel disease (IBD), and expert consensus is to achieve adequate exposure during induction to achieve and sustain remission. MethodsWe retrospectively evaluated the performance of a Bayesian PK tool in IBD patients starting IFX. Trough IFX serum levels collected immediately before the third (at week 6) and fourth (at week 14) infusions were evaluated from 307 IBD patients (median age=17 years, 50 % females, 83 % with Crohn's disease). Forecasted IFX concentration at the fourth infusion were estimated using serum IFX, antibodies to IFX, albumin and weight determined immediately before the third infusion using population PK calculator with Bayesian prior. The outcome variable was a clinical & biochemical remission status achieved (CRP levels below 3 mg/L in presence of clinical remission). Statistics consisted of Kaplan Meier analysis with calculation of Hazard ratio (HR), and logistic regression. ResultsIFX concentration above 15 µg/mL immediately before the third infusion associated with shorter time to clinical & biochemical remission than concentration below 15 µg/mL without reaching significance (163±14 days vs 200±16 days, respectively; p=0.052). However, using PK parameters at the third infusion, forecasted IFX concentrations above 10 µg/mL immediately before the fourth infusion were significantly associated with a higher rate (HR=1.6 95 %CI: 1.1 to 2.1 p<0.01) and shorter time to remission (148±18 days vs 200±13 days p<0.01). In the presence of IFX concentration above 15 µg/mL at the third infusion, there was a significant 2.5-fold higher likelihood of sustained clinical & biochemical remission status during maintenance as compared to IFX concentrations below 15 µg/mL (p<0.01). Forecasted IFX level above 10 µg/mL at fourth infusion associated with significantly 3.9-fold higher likelihood of clinical & biochemical remission as compared to forecasted IFX concentrations below 10 µg/mL (p<0.01). ConclusionsThese data further support that optimized IFX concentrations during induction are associated with enhanced disease control in IBD.

Intralesional Kenalog Injections for Recurrent Cutaneous Rosai-Dorfman Disease (RDD) in the Lower Extremity

Rosai-Dorfman disease (RDD) is a rare disorder of histiocytic origin with nodal, extranodal, and cutaneous classifications often presenting as eruptive rashes, most commonly affecting the face, trunk, and thigh. Due to its rarity, no consensus exists regarding standard of care for these lesions, as most knowledge regarding treatment is provided by case reports. To our knowledge, we report the first case of a patient with a recurrent lower extremity mass consistent with cutaneous RDD, despite surgical excision and topical steroids treatment. A 51-year-old female presented with recurrent RDD after failed treatment with clobetasol ointment and surgical excision at an outside practice. Examination revealed violaceous plaques with overlying scale, without lymphadenopathy. With the failure of the previous excision, the patient was prescribed 5 mg/ml intralesional Kenalog (ILK) injections to suppress inflammation of the lesion. She experienced improved clinical response to treatment and remission of active disease with residual post-inflammatory hyperpigmentation at 10 months after two rounds of injections, although the patient reported vast improvement at 5 months as well. Treatment of RDD is difficult due to its rarity, hindering clinical trial development. Therapeutics reported to be efficacious include topical, intralesional, and systemic steroids, retinoids, methotrexate, chemotherapy, cryotherapy, phototherapy, and radiation. Clinical management is variable and often requires multiple forms of treatment on a case-to-case basis, highlighting the need for larger clinical studies to establish a standard of care. Our case poses interest in the use of ILK for RDD and should be considered in recurrent cases after prior surgical excision.

Effect of Immunosuppression on the Immune Response to SARS-CoV-2 Infection and Vaccination.

Immunosuppressive treatment in patients with rheumatic diseases can maintain disease remission but also increase risk of infection. Their response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination is frequently blunted. In this study we evaluated the effect of immunosuppression exposure on humoral and T cell immune responses to SARS-CoV-2 infection and vaccination in two distinct cohorts of patients; one during acute SARS-CoV-2 infection and 3 months later during convalescence, and another prior to SARS-CoV-2 vaccination, with follow up sampling 6 weeks after vaccination. Results were compared between rituximab-exposed (in previous 6 months), immunosuppression-exposed (in previous 3 months), and non-immunosuppressed groups. The immune cell phenotype was defined by flow cytometry and ELISA. Antigen specific T cell responses were estimated using a whole blood stimulation interferon-γ release assay. A focused post-vaccine assessment of rituximab-treated patients using high dimensional spectral cytometry was conducted. Acute SARS-CoV-2 infection was characterised by T cell lymphopenia, and a reduction in NK cells and naïve CD4 and CD8 cells, without any significant differences between immunosuppressed and non-immunosuppressed patient groups. Conversely, activated CD4 and CD8 cell counts increased in non-immunosuppressed patients with acute SARS-CoV-2 infection but this response was blunted in the presence of immunosuppression. In rituximab-treated patients, antigen-specific T cell responses were preserved in SARS-CoV-2 vaccination, but patients were unable to mount an appropriate humoral response.

Remission of HPV-Related Diseases by Antivirals for Herpesvirus: Clinical Cases and a Literature Review.

Epidemiological studies have shown that HPV-related diseases are the most prevalent sexually transmitted infections. In this context, this report will present various clinical cases demonstrating the effectiveness of Acyclovir (ACV) or its prodrug Valaciclovir (VCV), both acyclic guanosine analogs commonly used for the treatment of HHV-1 and HHV-2, for the treatment of HPV-related diseases. The report shows the remission of five cases of penile condyloma and a case of remission in a woman affected by cervical and vaginal condylomas and a vulvar giant condyloma acuminate of Buschke and Lowenstein. The literature review shows that ACV is effective in treating skin warts when administered orally, topically, and intralesionally, suggesting its therapeutic potential in other diseases associated with HPV. ACV was also used successfully as an adjuvant therapy for juvenile and adult forms of laryngeal papillomatosis, also known as recurrent respiratory papillomatosis, prolonging the patient's symptom-free periods. Although the prevention of HPV infections is certainly achieved with the HPV vaccine, ACV and VCV have shown to be effective even against genotypes not included in the current vaccine and can be helpful for those problematic clinical cases involving unvaccinated individuals, immunocompromised patients, people who live with HIV, or non-responders to the vaccine. We and others concluded that randomized clinical trials are necessary to determine the efficacy of ACV and VCV for HPV-related diseases.

Association of Preterm Birth with Adverse Glomerular Disease Outcomes in Children and Adults.

While some studies of children with nephrotic syndrome have demonstrated worse outcomes in those born preterm compared with term, little data exists on associations of preterm birth with outcomes in adult-onset glomerular disease. Cardiovascular outcomes in those born preterm with glomerular disease are unknown. We performed a cross-sectional and longitudinal analysis of participants in the Cure Glomerulonephropathy (CureGN) cohort. Preterm (<37 weeks' gestation) was compared to term (≥37 weeks' gestation). A survival analysis and adjusted Cox proportional hazards model were used to examine a composite outcome of 40% decline in estimated glomerular filtration rate (eGFR) or progression to kidney failure. An adjusted logistic regression model was used to examine remission of proteinuria. There were 2,205 term and 235 preterm participants. APOL1 risk alleles were more common in those born preterm. More pediatric than adult participants in CureGN were born preterm: 12.8% vs. 7.69% (P<0.001). Adults born preterm as compared to term had a higher prevalence of Focal Segmental Glomerulosclerosis (FSGS) (35% vs. 25%, P=0.01) and APOL1 high-risk genotype (9.4% vs 4.2%, P=0.01). Participants born preterm had a shorter time interval to a 40% eGFR decline/kidney failure after biopsy (P=0.001). In adjusted analysis, preterm participants were 28% more likely to develop 40% eGFR decline/kidney failure (Hazard Ratio: 1.28 [1.07, 1.54], P=0.008) and 38% less likely to attain complete remission of proteinuria (Odds Ratio: 0.62 [0.45, 0.87], P=0.006). There was no significant difference in cardiovascular events. Preterm birth was a risk factor for adverse outcomes in this heterogenous cohort of children and adults with glomerular disease. Adults born preterm were more likely to have an APOL1 high-risk genotype and FSGS. In analyses adjusted for FSGS and APOL1 risk status, there was less remission and faster progression of kidney disease in those born preterm.

From immune equilibrium to tumor ecodynamics.

There is no theory to quantitatively describe the complex tumor ecosystem. At the same time, cancer immunotherapy is considered a revolution in oncology, but the methods used to describe tumors and the criteria used to evaluate efficacy are not keeping pace. The purpose of this study is to establish a new theory for quantitatively describing the tumor ecosystem, innovating the methods of tumor characterization, and establishing new efficacy evaluation criteria for cancer immunotherapy. Based on the mathematization of immune equilibrium theory and the establishment of immunodynamics in a previous study, the method of reverse immunodynamics was used, namely, the immune braking force was regarded as the tumor ecological force and the immune force was regarded as the tumor ecological braking force, and the concept of momentum in physics was applied to the tumor ecosystem to establish a series of tumor ecodynamic equations. These equations were used to solve the fundamental and applied problems of the complex tumor ecosystem. A series of tumor ecodynamic equations were established. The tumor ecological momentum equations and their component factors could be used to distinguish disease progression, pseudoprogression, and hyperprogression in cancer immunotherapy. On this basis, the adjusted tumor momentum equations were established to achieve the equivalence of tumor activity (including immunosuppressive activity and metabolic activity) and tumor volume, which could be used to calculate individual disease remission rate and establish new efficacy evaluation criteria (ieRECIST) for immunotherapy of solid tumor based on tumor ecodynamics. At the same time, the concept of moving cube-to-force square ratio and its expression were proposed to calculate the area under the curve of tumor ecological braking force of blood required to achieve an individual disease remission rate when the adjusted tumor ecological momentum was known. A new theory termed tumor ecodynamics emphasizing both tumor activity and tumor volume is established to solve a series of basic and applied problems in the complex tumor ecosystem. It can be predicted that the future will be the era of cancer immune ecotherapy that targets the entire tumor ecosystem.

Extent to which weight loss contributes to improving metabolic dysfunction-associated and metabolic and alcohol related/associated steatotic liver disease: a study on Japanese participants undergoing health checkups.

The incidence of steatotic liver disease has increased in recent years. Thus, steatotic liver disease is a major public health issue in Japan. This study investigated the association between weight reduction and the remission of metabolic dysfunction-associated steatotic liver disease (MASLD)/Metabolic and alcohol related/associated liver disease (MetALD) in Japanese individuals undergoing health checkups. This retrospective observational study included 8,707 Japanese patients with MASLD/MetALD who underwent health checkups from May 2015 to March 2023. The participants were monitored for its remission at their subsequent visit. MASLD was diagnosed on abdominal ultrasonography and based on the presence of at least one of five metabolic abnormalities. The impact of body mass index (BMI) reduction on MASLD/MetALD remission was assessed via logistic regression analysis and using receiver operating characteristic curves. Logistic regression analysis revealed that weight loss was significantly associated with MASLD/MetALD remission. Other factors including exercise habits and reduced alcohol consumption were significant predictors of MASLD/MetALD remission in the overall cohort and in male patients. The optimal BMI reduction cutoff values for MASLD/MetALD remission were 0.9 kg/m2 and 4.0% decrease in the overall cohort, 0.85 kg/m2 and 3.9% decrease in males, and 1.2 kg/m2 and 4.5% decrease in females. In participants with a BMI of 23 kg/m2, the cutoff values were 0.75 kg/m2 and 2.7% BMI reduction. Weight reduction plays an important role in both MASLD and MetALD remission among Japanese individuals. That is, targeting specific BMI reduction is effective. This underscores the importance of targeted weight management strategies in preventing and managing MASLD/MetALD in the Japanese population.

Infliximab Tissue Concentrations in Patients With Stable Ulcerative Colitis Are Correlated With More Durable Infliximab-associated Disease Remission.

We aimed to determine the correlation between tissue and plasma infliximab concentrations in an outpatient ulcerative colitis (UC) cohort based on histologic disease activity in addition to their relationship with long-term clinical outcomes. We assessed intraparticipant variability in infliximab concentrations between adjacent intestinal samples and the correlation between disease activity and tumor necrosis factor-α (TNF-α). A prospective cohort study was conducted in participants with UC receiving infliximab. Blood and 2 sigmoid colon biopsies were obtained at the index colonoscopy for infliximab and TNF-α quantification. Histological disease activity was assessed. Participants were followed for 2 years for the occurrence of hospitalization, surgery, disease relapse, and infliximab discontinuation. A positive correlation was observed between mean plasma and uninflamed tissue infliximab concentrations only (Rs = 0.75, P = .0071). Lower mean tissue infliximab concentrations correlated with a shorter time to disease relapse vs those with higher mean tissue concentrations (Rs = 0.77, P = .032). This was not seen when using plasma infliximab concentrations. Additionally, no significant intraparticipant variability of infliximab concentrations was observed for all participants independent of disease activity. Neither plasma nor tissue TNF-α correlated with disease activity. These findings support data generated in patients with Crohn's disease: plasma infliximab concentrations are reflective of infliximab exposure in tissue in the UC patient in remission, but not for those with active disease. Increasing tissue concentrations in the noninflamed tissues may improve durability of infliximab. Neither plasma nor tissue TNF-α appear to correlate with UC disease activity. Larger follow-up studies would be of benefit.

Combination immunotherapy with vaccine and oncolytic HSV virotherapy is time dependent.

Oncolytic virotherapy or immunovirotherapy is a strategy that utilizes viruses to selectively infect and kill tumor cells while also stimulating an immune response against the tumor. Early clinical trials in both pediatric and adult patients using oncolytic herpes simplex viruses (oHSVs) have demonstrated safety and promising efficacy; however, combinatorial strategies designed to enhance oncolysis while also promoting durable T cell responses for sustaining disease remission are likely required. We hypothesized that combining the direct tumor cell killing and innate immune stimulation by oHSV with a vaccine that promotes T cell mediated immunity may lead to more durable tumor regression. To this end, we investigated the preclinical efficacy and potential synergy of combining oHSV with a self-assembling nanoparticle vaccine co-delivering peptide antigens and Toll-like receptor-7 and -8 agonists (TLR-7/8a) (referred to as SNAPvax™), that induces robust tumor specific T cell immunity. We then assessed how timing of the treatments (i.e., vaccine before or after oHSV) impacts T cell responses, viral replication, and preclinical efficacy. The sequence of treatments was critical, as survival was significantly enhanced when the SNAPvax™ vaccine was given prior to oHSV. Increased clinical efficacy was associated with reduced tumour volume and increases in virus replication and tumor antigen specific CD8+ T cells. These findings substantiate the criticality of combination immunotherapy timing and provide preclinical support for combining SNAPvax with oHSV as a promising treatment approach for both pediatric and adult tumors.

The efficacy and safety of rituximab with or without glucocorticoid in inducing remission of MCD with different clinical presentations in adults: a retrospective study

Abstract Background To investigate the efficacy and safety of rituximab (RTX) with or without glucocorticoid (GC) in inducing remission of minimal change disease (MCD) in adults. Methods Twenty-one adult MCD patients were included in the study. The patients were assigned to the following three groups according to their background before RTX treatment: an RTX single drug direct induction treatment group (Group A; n = 9), a short-term, low-dose GC combined with RTX induction treatment group (Group B; n = 4) and a short-term, adequate-dose GC-induced remission and RTX maintenance treatment group (Group C; n = 8). The primary endpoints were the time to induction of remission and the rate of clinical remission at 12 months. Results All patients achieved clinical remission, with 19 (90.48%) achieving complete remission (CR), and the median remission time was 4 (2.5, 12) weeks. Eight (88.89%) patients in Group A achieved CR, and the median remission time was 3 (2.25, 14) weeks. In group B, three (75.00%) patients achieved CR, with a median remission time of 4 (4, 10) weeks. In group C, eight (100.00%) patients achieved CR, and the median remission time was 3.5 (2, 4) weeks. Conclusions In MCD patients without acute kidney injury (AKI), adequate RTX alone or short-term combined treatment with low-dose GCs can effectively induce and maintain MCD remission. Adequate short-term GCs combined with RTX maintenance may be an effective alternative for MCD patients in context of AKI. There is a need to investigate different induction therapy regimens for the remission of MCD patients with different backgrounds.