Maladies orphelines

Lancet Neurol. 2026 Nov;25(11):983-996. doi: 10.1016/S1474-4422(26)00337-6. ABSTRACT BACKGROUND: There are no approved exon skipping therapies to treat Duchenne muscular dystrophy due to DMD variants amenable to exon 44 skipping (DMD44). Delpacibart zotadirsen (del-zota, also known as AOC 1044) is a first-in-class antibody-oligonucleotide conjugate designed to deliver an exon 44-skipping phosphorodiamidate morpholino oligomer to muscle to restore dystrophin expression for individuals with DMD44. EXPLORE44 was a first-in-human trial to evaluate del-zota's safety, tolerability, pharmacokinetics, pharmacodynamics, and efficacy. METHODS: EXPLORE44 was a two-part randomised, double-blind, placebo-controlled, phase 1/2 study in healthy adult men (aged 18-55 years; part A) and ambulatory and non-ambulatory male participants with DMD44 (aged 7-27 years; part B) at ten clinical research sites in the USA. Dosing in part B was informed by safety, pharmacokinetic, and pharmacodynamic data from part A. In part B, participants with DMD44 were randomised (3:1 del-zota:placebo) within two dose cohorts to receive three intravenous doses of del-zota (5 mg/kg every 6 weeks, or 10 mg/kg every 8 weeks) or matching placebo. A computer-generated permuted-block randomisation schedule was prepared by an independent statistician with no further role in the study. Infusions were prepared by an unmasked pharmacist under supervision of the masked investigator; other site staff, participants, and sponsor team members were masked to allocation. The primary objective was safety and tolerability measured by the incidence of treatment-emergent adverse events. Secondary endpoints assessing target engagement were change from baseline in exon skipping (ie, defined as the percentage of dystrophin mRNA transcripts in which exon 44 is excluded from the mature mRNA relative to total dystrophin mRNA transcripts) and dystrophin level to month 4 (5 mg/kg cohort) or month 5 (10 mg/kg cohort). The trial was registered with ClinicalTrials.gov (NCT05670730) and is complete. FINDINGS: Between Dec 5, 2022, and June 27, 2024, we enrolled and randomly assigned 45 healthy volunteers and 26 men and boys with DMD44. In part A, three (30%) of ten healthy volunteers who received placebo and 21 (62%) of 34 who received del-zota reported at least one adverse event, none of which were severe or serious. In part B, nine participants with DMD44 received del-zota at 5 mg/kg, ten at 10 mg/kg, and seven received…

Kidney Int. 2026 Nov;110(5):1100-1101. doi: 10.1016/j.kint.2026.08.004. ABSTRACT Autosomal dominant polycystic kidney disease risk stratification relies on total kidney volume, a validated marker of cyst burden and progression. Kremer et al.'s pilot study used rapid breath-hold magnetic resonance fingerprinting with radiomics to evaluate noncystic renal parenchyma in children and young adults. Quantitative T1/T2 texture features distinguished autosomal dominant polycystic kidney disease from controls independently of total kidney volume, cyst fraction, age, or body size, suggesting early tissue changes. Small, cross-sectional, unmatched data require longitudinal validation of reproducibility, prognostic value, and clinical utility. PMID: 42901686 | DOI: 10.1016/j.kint.2026.08.004

J Am Acad Dermatol. 2026 Oct 20:S0190-9622(26)03610-8. doi: 10.1016/j.jaad.2026.08.125. Online ahead of print. ABSTRACT BACKGROUND: Hidradenitis suppurativa affects 0.7% to 1.5% of the global population and causes substantial disability and meaningfully impairs quality of life. OBJECTIVE: To provide evidence-based recommendations for the management of hidradenitis suppurativa. METHODS: A workgroup conducted a systematic review and applied the Grading of Recommendations, Assessment, Development, and Evaluation approach to assess the certainty of evidence and to develop recommendations. RESULTS: This guideline presents 37 evidence-based recommendations. Strong recommendations are made for adalimumab, bimekizumab, infliximab, secukinumab, and routine pain assessment. Conditional recommendations are made for topical clindamycin, resorcinol, and ruxolitinib; oral doxycycline, tetracycline, and clindamycin with rifampin; intravenous ertapenem; spironolactone; short-term systemic corticosteroids; upadacitinib; specific procedural interventions; tobacco cessation; supportive pain management; and zinc supplementation and vitamin D repletion. LIMITATIONS: Analysis is limited to best evidence available from systematic review. CONCLUSIONS: These guidelines provide evidence-based recommendations for the management of hidradenitis suppurativa. PMID: 42900024 | DOI: 10.1016/j.jaad.2026.08.125

Low Urin Tract Symptoms. 2026 Nov;18(6):e70101. doi: 10.1111/luts.70101. ABSTRACT Interstitial cystitis and bladder pain syndrome are clinically overlapping conditions that should be distinguished according to Hunner lesion status. IC with Hunner lesions is a distinct inflammatory bladder disease characterized by urothelial denudation, lymphoplasmacytic infiltration, adaptive immune activation, and progressive structural impairment. The intensity and distribution of these inflammatory and structural abnormalities may vary among patients with IC, but the underlying pathological pattern is comparatively coherent. BPS without Hunner lesions is substantially more heterogeneous. Urothelial barrier dysfunction, mast cell and sensory nerve signaling, pelvic floor dysfunction, peripheral sensitization, and central or nociplastic pain mechanisms may contribute to symptoms in different combinations. Candidate urine and blood-based biomarkers, including cytokines, chemokines, neurotrophic factors, immune cell indices, and multiomics signatures, may support phenotyping, assessment of disease activity, or prediction of treatment response. However, most remain exploratory because their intended clinical use, analytical standardization, diagnostic thresholds, and external validity have not been established. This narrative review compares the clinical and histopathological features of IC and BPS, evaluates the evidence for proposed immune and neuroregulatory mechanisms, examines the translational status of candidate biomarkers, and discusses disease-specific and phenotype-guided management. These findings support a primary distinction between IC and BPS. Additional phenotyping is useful after this distinction to characterize heterogeneity within BPS and clinically relevant coexisting mechanisms. PMID: 42894375 | DOI: 10.1111/luts.70101

Clin Exp Rheumatol. 2026 Oct 7. doi: 10.55563/clinexprheumatol/ctftt6. Online ahead of print. ABSTRACT OBJECTIVES: To evaluate the incidence, time to aortic aneurysm (AA) diagnosis, and factors associated with AA development in patients admitted with giant cell arteritis (GCA). METHODS: We conducted a nationwide, registry-based study using the Spanish National Hospital Discharge Database. The study included all hospitalised patients aged ≥50 years with a diagnosis of GCA between 2016 and 2024. RESULTS: Among 5,120 patients hospitalised because of GCA without prior AA, 54 (1.1%) were diagnosed with AA during current admission (AAo group) and 41 (0.8%) developed AA during follow-up (AAf group). Median time from first GCA admission and AA diagnosis was 2.7 years. Incidence rate was 1.8 per 100 patient-years. Established heart disease was markedly more frequent in the AAo compared with the other groups (50.0% at onset vs. 19.5% during follow-up and 32.3% in patients without aneurysm; p=0.006). After adjustment, male sex was independently associated with a higher risk of AA at baseline (RRR 2.42, 95% CI 1.40-4.20), whereas smoking at GCA diagnosis was the only factor independently associated with AA development during follow-up (RRR 3.23, 95% CI 1.47-7.08). CONCLUSIONS: Clinically recognised AA was uncommon among hospitalised patients with GCA and was associated mainly with traditional cardiovascular risk factors, particularly male sex and smoking. Because estimates were based on hospital discharge diagnoses, they reflect clinically overt, hospital-recorded AA rather than the overall aneurysm burden in GCA. Follow-up should prioritise individualised vascular surveillance, particularly in smokers. PMID: 42873682 | DOI: 10.55563/clinexprheumatol/ctftt6

Int J Rheum Dis. 2026 Oct;29(10):e70910. doi: 10.1111/1756-185x.70910. ABSTRACT Antineutrophil cytoplasmic antibodies (ANCA) define a distinct group of small-vessel vasculitides collectively termed ANCA-associated vasculitis (AAV). Since their initial recognition as immunofluorescence patterns, ANCA have evolved into well-characterized pathogenic autoantibodies directed primarily against proteinase 3 (PR3) and myeloperoxidase (MPO). This review integrates the historical evolution of ANCA discovery with current understanding of disease pathogenesis and contemporary diagnostic practice. We summarize key biological mechanisms underlying AAV, including genetic susceptibility, epigenetic dysregulation, neutrophil priming, complement activation via the alternative pathway, and neutrophil extracellular trap formation, which together drive endothelial injury and necrotizing vasculitis. Recognition of PR3 ANCA and MPO ANCA as pathogenic entities has reshaped disease classification and supports the concept of biologically distinct disease subsets. In parallel, laboratory diagnostics have undergone a major paradigm shift. We critically review the transition from indirect immunofluorescence-first algorithms to immunoassay-first strategies endorsed by the 2017 revised international consensus, highlighting the improved diagnostic performance of contemporary antigen-specific immunoassays. The roles of automated immunofluorescence, biochip mosaic platforms, and multiparametric testing are discussed within harmonized diagnostic workflows. Emphasis is placed on strict clinical gating, quantitative antibody interpretation, and likelihood ratio-based reporting to enhance diagnostic accuracy and reduce false-positive results. By integrating historical, biological, and diagnostic perspectives, this review provides a practical reference framework for evidence-based ANCA testing and interpretation in clinical practice. PMID: 42858356 | DOI: 10.1111/1756-185x.70910

BMJ Case Rep. 2026 Oct 7;19(10):e271520. doi: 10.1136/bcr-2025-271520. ABSTRACT A previously healthy woman in her early 30s developed rash, fever and arthralgia 3 weeks after SARS-CoV-2 infection, rapidly progressing to multiorgan failure. Laboratory studies revealed severe thrombocytopenia (23×10 9 /L), microangiopathic haemolytic anaemia, acute kidney injury and ferritin >100 000 ng/mL. Kidney biopsy demonstrated thrombotic microangiopathy with negative antinuclear antibody, supporting atypical haemolytic uraemic syndrome (aHUS). Concurrently, low haptoglobin, elevated lactate dehydrogenase (2500 U/L), interleukin-2 receptor (18 644), triglycerides (425 mg/dL) and splenomegaly supported haemophagocytic lymphohistiocytosis (HLH). Despite plasmapheresis, corticosteroids, etoposide, eculizumab and continuous renal replacement therapy, she died 7 weeks after SARS-CoV-2 infection. Autopsy confirmed aHUS with extensive thrombotic microangiopathy and HLH with bone marrow haemophagocytosis. This case underscores the importance of recognising concurrent aHUS and HLH after COVID-19, as complement-mediated injury and hyperinflammation may produce catastrophic outcomes. PMID: 42843919 | DOI: 10.1136/bcr-2025-271520

Ann Intensive Care. 2026 Oct 5;16:100180. doi: 10.1016/j.aicoj.2026.100180. eCollection 2026. ABSTRACT BACKGROUND: Severe diffuse alveolar hemorrhage (DAH) is a potentially fatal complication of ANCA-associated vasculitides (AAV). This study aimed to identify distinct clinical phenotypes among patients to the ICU, and to examine their association with mortality. METHODS: We conducted an ancillary analysis of the national multicenter retrospective PLEXHIA cohort, including 197 patients with severe AAV-related DAH, defined by respiratory symptoms with new infiltrates consistent with alveolar hemorrhage, along with oxygen saturation ≤85%, high-flow oxygen or mechanical ventilation requirement. Kohonen self-organizing maps were applied to predefined clinical variables at ICU admission, excluding treatment and outcomes. Clusters were interpreted and compared regarding organ involvement, severity, management, and mortality at 30 and 90 days. RESULTS: Between 2012 and 2024, 197 patients (66 years old, 52% female) were included, revealing marked clinical heterogeneity. Three phenotypes emerged: The MPO pulmonary-renal (MPO-PR) cluster included patients with anti-MPO ANCA, renal involvement and high oxygen requirements. The mild-respiratory (Mild-R) cluster included predominantly female patients with less severe respiratory compromise and mild renal involvement. The PR3 multi-organ (PR3-MO) cluster involved younger patients with anti-PR3 ANCA, severe acute respiratory failure and multiorgan failure. Renal replacement therapy was most frequent in the MPO-PR group (73%), while invasive mechanical ventilation was most common in the MPO-PR and PR3-MO groups (71% and 68%). Thirty-day mortality differed significantly: 23% (MPO-PR), 4% (mild-R cluster), and 14% (PR3-MO cluster). CONCLUSION: This large ICU cohort highlights three clinically relevant phenotypes of AAV-related DAH, which could inform the development of phenotype-driven immunosuppressive strategies. PMID: 42898067 | PMC: PMC13677274 | DOI: 10.1016/j.aicoj.2026.100180

J Eur Acad Dermatol Venereol. 2026 Oct 3. doi: 10.1111/jdv.70749. Online ahead of print. ABSTRACT Recent developments in hidradenitis suppurativa (HS) have focused on targeting key inflammatory pathways implicated in the pathogenesis of the disease, including interleukin (IL)-17, IL-1, tumour necrosis factor (TNF), Janus kinase (JAK) and tyrosine kinase 2 (TYK2) signalling as well as innate immune mechanisms such as neutrophil activation and complement pathways. Novel biologics, dual cytokine-inhibition strategies and bispecific agents represent an emerging therapeutic paradigm. Small-molecule inhibitors, including JAK1 and TYK2 inhibitors, offer the potential advantage of oral administration and broader immunomodulatory effects. Therapies targeting alternative mechanisms, including B-cell modulation, complement inhibition, chemokine signalling and intracellular pathways, are also being actively investigated. While some agents have shown encouraging results in selected HS trials, including responses at higher thresholds, such as IHS4-75 or IHS4-90, findings remain heterogeneous. Some trials have not met their primary endpoints, highlighting the challenges of translating mechanistic rationale into consistent clinical benefit. Overall, the expanding therapeutic pipeline in HS reflects a shift towards precision medicine and pathway-specific interventions. This review aims to summarize the upcoming treatments in hidradenitis suppurativa and to outline the future therapeutic landscape of the disease. PMID: 42828451 | DOI: 10.1111/jdv.70749

Skin Therapy Lett. 2026 Sep;31(5):5-7. ABSTRACT Hidradenitis suppurativa (HS) is a painful, chronic inflammatory condition that forms recurring nodules and abscesses in skin folds, leading to severe scarring. While the exact pathogenesis is still being determined, it is thought to involve follicular occlusion and rupture, driven by multifactorial influences such as genetics, environment, hormones, microbiome, and immune dysregulation. The complex nature of this disease entails complicated management and has led to the development of various therapies targeting these different factors. While moderate-to-severe HS has seen growing therapeutic options in recent years, mild early-stage forms of the disease lack any approved treatments. This review examines the most recent developments in topical therapies specifically for mild HS, along with advancements in daily HS skin care and post de-roofing wound management. These emerging therapies offer the potential for more effective, personalized care to reduce the disease burden for patients living with HS. PMID: 42805594

Transfus Med. 2026 Oct 1. doi: 10.1111/tme.70122. Online ahead of print. ABSTRACT Sickle cell disease (SCD) is one of the most common inherited haemoglobin disorders worldwide and is associated with substantial morbidity, premature mortality and lifelong healthcare utilisation. Red blood cell (RBC) transfusion remains a cornerstone of SCD management and is indispensable for the treatment and prevention of life-threatening complications, including acute chest syndrome, ischaemic stroke, severe anaemia and perioperative complications. Despite its undeniable therapeutic benefits, repeated transfusions are accompanied by important adverse consequences, including alloimmunisation, iron overload, delayed haemolytic transfusion reactions and transfusion-transmitted infections. Beyond haemoglobin S dilution, transfusion therapy interacts with the chronic inflammatory and immune-activated milieu characteristic of SCD. Persistent haemolysis, endothelial dysfunction, nitric oxide depletion, leukocyte and platelet activation collectively influence both disease severity and transfusion-related immune responses, thereby contributing to alloantibody formation and other immunological complications. This review provides a comprehensive overview of the clinical indications, transfusion strategies, immunological mechanisms and transfusion-related complications in patients with SCD. Particular emphasis is placed on the cellular and molecular mechanisms underlying alloimmunisation, including the roles of antigen-presenting cells, CD4 + T lymphocytes, B cells and regulatory T cells. Contemporary approaches to minimising transfusion-related complications-including extended antigen matching, molecular RBC genotyping, routine alloantibody screening, iron chelation therapy and emerging immunomodulatory strategies-are critically discussed. In addition, the review highlights regional challenges and evolving transfusion practices in Saudi Arabia, including newborn screening programmes, comprehensive care initiatives, donor-recipient antigen mismatch and implementation of national transfusion strategies. By integrating current evidence from clinical medicine, immunology and transfusion science, this review provides clinicians with an updated framework for optimising transfusion therapy while minimising preventable complications and improving long-term outcomes in patients with SCD. PMID: 42817913 | DOI: 10.1111/tme.70122

Hemoglobin. 2026 Sep 24:1-12. doi: 10.1080/03630269.2026.2736312. Online ahead of print. ABSTRACT Sickle cell disease (SCD) is characterized by recurrent vaso-occlusive crises (VOCs), which are the primary contributors to morbidity and mortality globally. Conventional clinical markers, including fetal hemoglobin (HbF), reticulocyte count, and lactate dehydrogenase (LDH), offer limited predictive value because of interpatient variability and an inability to capture the complex, multifactorial pathophysiology of VOCs. Recent advances in metabolomics and proteomics have enhanced understanding of VOC biology. Metabolomic profiling has identified perturbations in glycolysis, amino acid metabolism, oxidative stress pathways, and lipid metabolism, while proteomic studies have revealed dysregulation of inflammatory mediators, adhesion molecules, coagulation factors, and endothelial markers. Although significant progress has been made, most reported metabolomic and proteomic signatures remain insufficiently reproducible and are not yet clinically applicable. This limitation is primarily attributed to biological heterogeneity, limited cohort sizes, and methodological inconsistencies across studies. Recent evidence indicates that pathway-level markers, longitudinal sampling strategies, and integrated multi-omics approaches are more likely to yield clinically relevant biomarkers than isolated single-molecule candidates. Significant challenges remain, including limited validation across diverse populations and barriers to implementation in resource-limited settings. Addressing these challenges will require collaborative, multicenter studies, improved analytical harmonization, and the development of accessible diagnostic platforms. This narrative review synthesizes current evidence on metabolomic and proteomic profiling of VOCs, highlights implications for equity and global health, and outlines priorities for translational research to advance personalized care and improve clinical outcomes in SCD. PMID: 42786727 | DOI: 10.1080/03630269.2026.2736312

Pediatr Blood Cancer. 2026 Aug 3:e70607. doi: 10.1002/1545-5017.70607. Online ahead of print. ABSTRACT BACKGROUND: Sickle cell disease (SCD) has undergone major changes in the last decades. Its prevalence has been steadily increasing and numerous advances have been made in the management of the disease. However, the effect in real-life setting of these major changes is unknown, particularly in a Canadian environment. PROCEDURE: We aimed to assess the impact of these changes on the evolution in the healthcare utilization (HCU) of children with SCD in a Canadian pediatric tertiary center from 2009 to 2024. RESULTS: The number of children with SCD followed at our center more than doubled (221 to 499 patients). Practice changes reduced mean time to hydroxyurea introduction, resulting in a steady annual increase in mean fetal hemoglobin across the patients with HbSS. Reflecting the number of patients followed, the absolute number of annual outpatient and ED visits increased significantly (1207 to 1769 and 192 to 526, respectively). However, there was a significant decrease in the mean number of outpatient visits (5.46 to 3.55 [p = 0.03]) and hospitalizations (1.18 to 0.58 [p<0.0001]) by patient annually. There was also a reduction in the percentage of admissions after an ED visit (62.5% to 42.6% [p<0.0001]). CONCLUSION: Although the number of patients with SCD followed at our institution drastically increased in 15 years, the practice changes were effective and likely mitigated the impact on admissions. It illustrates the significant impact of improved management in the care of patients with SCD. Allocated resources need to reflect the overall increase in HCU to allow for continuous optimal care of this vulnerable population. PMID: 42544872 | DOI: 10.1002/1545-5017.70607

Chest. 2026 Jul 30:S0012-3692(26)00952-9. doi: 10.1016/j.chest.2026.05.051. Online ahead of print. ABSTRACT BACKGROUND: Combined pulmonary fibrosis and emphysema (CPFE) is an important phenotype in patients with fibrotic interstitial lung disease (ILD). RESEARCH QUESTION: What is the prevalence of CPFE? What is the predictive performance of the CPFE index and of physiologic airflow obstruction for CT imaging emphysema extents? Is the extent of emphysema on CT imaging associated with outcomes in patients with fibrotic ILD? STUDY DESIGN AND METHODS: Consecutive patients with idiopathic pulmonary fibrosis (IPF) and non-IPF fibrotic ILD who underwent a standardized visual assessment of the baseline high-resolution CT imaging of the chest from a prospective registry were included. CPFE was defined as emphysema extent of ≥ 15% on CT imaging, with sensitivity analyses using different thresholds: ≥ 5%, ≥ 10%, and ≥ 20%. Emphysema subtypes were categorized based on their predominant distribution: centrilobular, paraseptal, or panlobular. The CPFE index was derived using measurements of spirometry and diffusion capacity of the lungs for CO 2 . RESULTS: The prevalence of CPFE at baseline was 20% for IPF (92/455) and 7% in non-IPF fibrotic ILD (84/1121). Both FEV 1 to FVC ratio less than the lower limit of normal and < 0.70 showed poor sensitivity (IPF, 11.1%-18.9%; non-IPF fibrotic ILD, 13.1%-23.7%) for detecting emphysema on CT imaging, although high specificity (IPF, 96.2%-98.8%; non-IPF fibrotic ILD, 92.8%-95.8%). The CPFE index was correlated moderately with extent of emphysema on CT imaging in both IPF (r = 0.48) and non-IPF fibrotic ILD (r = 0.41), but with poor agreement and wide limits of agreement on Bland-Altman analysis. Extent of emphysema on CT imaging of ≥ 20% was associated consistently with differences in lung function trajectories and worse transplant-free survival in IPF and non-IPF fibrotic ILD. No significant relationships were noted between emphysema subtypes and health outcomes. INTERPRETATION: Our results show that coexisting emphysema is important in both IPF and non-IPF fibrotic ILD, with extent of emphysema on CT imaging of ≥ 20% being associated with worse health outcomes. Both physiologic and radiologic assessments are needed to identify coexistent emphysema in patients with fibrotic ILD. PMID: 42413722 | DOI: 10.1016/j.chest.2026.05.051