Autoimmunity Reviews[JOURNAL]
Sun
200 papers
Subtype-specific mortality in idiopathic inflammatory myopathies: A hospital-based cohort.
Larrauffie A, Bost C, Barrier C … +21 more , Villeneuve T, Acket B, Alric L, Bonnet D, Cintas P, Constantin A, Cougoul P, Chaves SA, Uro-Coste E, Guille M, Maquet J, Moulis G, Mourguet M, Delpuech A, Piel-Julian ML, Prévot G, Sailler L, Biteau M, Zordan J, Faruch M, Pugnet G
Autoimmun Rev · 2026 May · PMID 42178003 · Publisher ↗
INTRODUCTION: The aim of our study is to compare mortality rates, causes of death and associated risk factors for idiopathic inflammatory myopathies (IIM) and their various subtypes in a hospital-based cohort, specially...
INTRODUCTION: The aim of our study is to compare mortality rates, causes of death and associated risk factors for idiopathic inflammatory myopathies (IIM) and their various subtypes in a hospital-based cohort, specially IMNM (immune-mediated necrotizing myopathy). MATERIALS AND METHODS: This retrospective study was conducted using the MIIRTALITY cohort, including patients followed for IIM from 2010 to 2022. They were then categorized into five subtypes: dermatomyositis (DM), polymyositis (PM), antisynthetase syndrome (ASS), immune-mediated necrotizing myopathy (IMNM) and overlap myositis (OM). Survival analysis based on IIM subtypes was performed using the Kaplan-Meier method. Cox proportional hazards models were used to determine baseline variables associated with mortality. RESULTS: During the study period, 33 of the 225 patients enrolled in this study died. IMNM have a mortality rate of 1.7 per 100 person-year. The poorest rate of survival was found in patients with DM (HR 3.32; 95% CI 1.61-6.86; p = 0.001), and the lowest mortality rate, when compared to the rest of IIM, was found in patients with ASS (HR 0.41; 95% CI 0.19-0.88). The presence of malignancy was associated with a markedly increased risk of death (HR 12.2; 95% CI 3.09-48.13; p < 0.001). Joint involvement and classification as a non-DM IIM subtype were associated with a reduced risk of death (HR 0.37; 95% CI 0.18-0.76; p = 0.006 and HR 0.06; 95% CI 0.01-0.36; p = 0.002), respectively. CONCLUSION: Dermatomyositis had the highest mortality among IIM subtypes in our hospital-based cohort, ASS was associated with better survival, highlighting the importance of differentiating IIM subtypes so as to personalize treatment and follow-up strategies. In our hospital-based cohort, IMNM mortality was not higher than that of others subtypes. These findings underscore the importance of distinguishing IIM subtypes to personalize treatment and follow-up strategies.
Iron, autoimmunity, and thrombosis: Exploring sex-specific interactions.
Gualtierotti R, Valenti L
Autoimmun Rev · 2026 Jul · PMID 42178002 · Publisher ↗
Iron is essential for oxygen delivery, energy production and several metabolic processes, but it also plays a crucial role in modulating immunity and coagulation. Impaired iron availability can contribute to both immune...
Iron is essential for oxygen delivery, energy production and several metabolic processes, but it also plays a crucial role in modulating immunity and coagulation. Impaired iron availability can contribute to both immune dysregulation and a prothrombotic state, resulting in tissue damage. This pathophysiological triad of iron deficiency, autoimmunity and hypercoagulability is particularly relevant in women, who are predisposed to lower iron stores due to hormonal and reproductive reasons, as well as to most autoimmune and some thrombotic conditions. This hypothesis-generating, narrative review article explores the intricate connections between iron status, immune response, and thrombosis, with a specific focus on sex-based differences. Here, we hypothesize that iron deficiency provides a common ground for the development of immune thrombotic conditions in predisposed women in response to environmental triggers. Evidence is discussed on how iron deficiency can specifically affect the function of different immune cells, resulting in unbalanced immune responses, and influence the synthesis of coagulation factors and platelets, increasing the risk of thrombotic events. The impact of gender-affirming hormone therapy on iron metabolism in transgender individuals is also addressed, emphasizing the importance of interpreting iron status based on hormonal exposure rather than sex assigned at birth. The aim is to provide a framework for testing the hypothesis that absolute iron deficiency and its compartmentalization into myeloid cells during inflammation can promote immune dysregulation and hypercoagulability. Understanding these complex interactions is essential for advancing precision medicine approaches in immune-mediated diseases. The manuscript advocates for considering sex-based differences and hormonal influences in the assessment and management of iron status, immune function, and thrombotic risk.
The Interleukin-17-T helper 17 axis in primary sclerosing cholangitis: A narrative review of an emerging pathogenic frontier.
Elzubeir A, Patel M, Rushbrook S
Autoimmun Rev · 2026 May · PMID 42176828 · Publisher ↗
Interleukin-17 (IL-17) and IL-17+ secretory cells, including T helper 17 (Th17) cells play pivotal roles in autoimmune diseases such as psoriasis. Emerging evidence implicates the IL-17 pathway in primary sclerosing chol...
Interleukin-17 (IL-17) and IL-17+ secretory cells, including T helper 17 (Th17) cells play pivotal roles in autoimmune diseases such as psoriasis. Emerging evidence implicates the IL-17 pathway in primary sclerosing cholangitis (PSC), a chronic cholestatic liver disease lacking approved pharmacological therapies, for which liver transplantation remains the only life-extending option. The IL-17 pathway and Th17 biology is increasingly implicated in PSC pathogenesis through its interactions with hepatic parenchymal and non-parenchymal cells, including cholangiocytes, neutrophils and hepatic stellate cells which promote periductal fibro-inflammation, immune cell recruitment and pro-inflammatory cytokine release. Th17 cells and IL-17+ secreting lymphocytes localise to peribiliary regions, exacerbating biliary injury and fibrosis. Preclinical murine models suggest that inhibition of IL-17 signalling mitigates hepatic fibro-inflammatory responses, providing a compelling rationale for its investigation as a potential therapeutic target in PSC. Whilst licensed IL-17 inhibitors have demonstrated efficacy and safety in a number of autoimmune and immune-mediated diseases, IL-17 has context-dependent roles in tissue homeostasis and host defence underscoring the pathway's complexity. This narrative review synthesises the biology of the IL-17 family, integrating preclinical and translational evidence relevant to PSC, and discusses the translational potential of approved anti-IL-17 agents as novel therapeutic candidates in PSC, whilst highlighting key uncertainties and gastrointestinal safety considerations.
Phage ImmunoPrecipitation sequencing (PhIP-Seq) in autoimmunity research: From high-resolution epitope mapping to multi-omics integration.
Yu R, Lu R, Xue C … +3 more , Bai Y, Li M, Hu C
Autoimmun Rev · 2026 May · PMID 42176827 · Publisher ↗
Autoimmune diseases (AIDs) affect 5-10% of the global population, yet effective diagnosis and treatment remain challenging due to their complexity and heterogeneity. Autoantibodies serve as crucial biomarkers for disease...
Autoimmune diseases (AIDs) affect 5-10% of the global population, yet effective diagnosis and treatment remain challenging due to their complexity and heterogeneity. Autoantibodies serve as crucial biomarkers for disease classification and prognosis, making comprehensive autoantigen profiling essential for advancing our understanding of autoimmune pathogenesis. Phage ImmunoPrecipitation sequencing (PhIP-Seq) has emerged as a transformative high-throughput technology that combines phage display with next-generation sequencing to comprehensively profile antibody-antigen interactions. This review systematically examines PhIP-Seq's methodology, comparing it with conventional approaches including protein microarrays, immunoprecipitation-mass spectrometry, and traditional serological assays. We detail the experimental workflow encompassing library design, immunoprecipitation protocols, and computational analysis pipelines, while highlighting recent algorithmic advances including generalized Poisson models, Z-score methods, and machine learning approaches for hit determination. PhIP-Seq's applications in autoimmune diseases span autoantibody discovery; clinical model development for disease stratification; high-resolution epitope mapping enabling resolution at tens of amino acids; and longitudinal studies tracking disease progression. The technology's integration with other omics platforms and investigation of viral-autoimmune disease associations further demonstrates its versatility. While PhIP-Seq excels in linear epitope identification and high-throughput screening, limitations include inability to detect conformational epitopes, challenges with low-abundance antigens, and lack of post-translational modifications. This review discusses ongoing advancements in library design, methodological improvements, and data integration to address these issues and unlock PhIP-Seq's full potential in autoimmune research.
Italian Society of Clinical Pathology and Laboratory Medicine (SIPMeL) guidelines on the use of autoantibody tests in the diagnosis of autoimmune liver diseases.
Sorrentino MC, Villalta D, Carbone T … +12 more , Alessio MG, Infantino M, Cinquanta L, Deleonardi G, Platzgummer S, Trevisan MT, Pesce G, Porcelli B, Tampoia M, Antico A, Brusca I, Bizzaro N
Autoimmun Rev · 2026 Jul · PMID 42176826 · Publisher ↗
Autoimmune liver diseases (AILDs) are considered rare conditions, though the frequency of their diagnosis is increasing thanks to the introduction of new diagnostic tests and improvements in analytical technologies. In c...
Autoimmune liver diseases (AILDs) are considered rare conditions, though the frequency of their diagnosis is increasing thanks to the introduction of new diagnostic tests and improvements in analytical technologies. In clinical practice, in patients with liver disease of unknown etiology, after a differential diagnosis that excludes other possible causes of hepatic damage, a potential autoimmune origin should be investigated through the evaluation of a specific autoantibody panel. In this context, the diagnostic laboratory plays a pivotal role, since the detection of well-defined autoantibody patterns is essential in the diagnosis and classification of autoimmune liver disorders. In 2009, the Study Group on Autoimmunology (GdS-AI) of the Italian Society of Clinical Pathology and Laboratory Medicine (SIPMeL) issued recommendations pertaining to a rational approach to the interpretation and clinical application of autoantibody testing in autoimmune hepatitis and cholestatic diseases. Then, after fourteen years, the GdS-AI deemed it necessary to revise and update the recommendations for the use of autoantibody testing in the diagnosis and monitoring of AILDs. This updated document provides a summary of the current analytical methodologies and autoantibody markers available for the diagnosis and monitoring of autoimmune liver disorders, together with recommendations regarding the appropriate use of tests and the interpretation of results. The guidelines were prepared after a systematic review of the most recent scientific literature and are structured into 19 specific recommendations, subdivided by disease type into autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), and primary sclerosing cholangitis (PSC). The quality of evidence and strength of each recommendation were assessed following the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) approach, ensuring a rigorous and transparent methodology aimed at producing efficient and clinically effective diagnostic recommendations. These guidelines are designed to support laboratory professionals and clinicians in the selection, application, interpretation, and reporting of autoantibody testing in AILDs, improving diagnostic accuracy and clinical outcomes through evidence-based laboratory medicine.
Idiopathic granulomatous mastitis as an autoimmune disease: A review of immunopathogenesis and therapeutic response.
Bergstrom LK, Jaen DM, Lamelas A … +15 more , Helseth KA, Harwell PA, Millen JC, Renavikar PS, Lele SM, Arthur MR, Lonowski SL, Thiele GM, Mitchell KB, Saunders TE, Stone K, Yang R, Hong J, Medlin JL, Santamaria-Barria JA
Autoimmun Rev · 2026 Jul · PMID 42173230 · Publisher ↗
Idiopathic granulomatous mastitis (IGM) is a chronic inflammatory breast disease that predominantly affects parous women of reproductive age, with higher incidence in women of Latina, Middle Eastern, Asian, and African d...
Idiopathic granulomatous mastitis (IGM) is a chronic inflammatory breast disease that predominantly affects parous women of reproductive age, with higher incidence in women of Latina, Middle Eastern, Asian, and African descent. Although its etiology remains controversial, accumulating clinical and molecular evidence supports classification of IGM as an organ-specific autoimmune disease modulated by hormonal and environmental factors. This review integrates immunologic, hormonal, genetic, molecular, and therapeutic data to evaluate this hypothesis. The review comprised two components: (1) a broad narrative synthesis of autoimmune and immunopathogenic mechanisms based on searches of PubMed, Google Scholar, and ClinicalTrials.gov (January 2000-April 2026), and (2) a prospectively registered (PROSPERO CRD420251106132) systematic analysis of IGM breast laterality. Results reveal consistent immune dysregulation, including elevated IL-6/Th17-axis cytokines, aberrant macrophage polarization, impaired regulatory T-cell function, and frequent polyautoimmunity (erythema nodosum, arthritis, and autoimmune thyroid disease). Genetic associations involve HLA class I/II alleles and variants in macrophage function and prolactin signaling. Single-cell RNA-sequencing studies confirm enrichment of IL-6/JAK/STAT3, TNF-α/NF-κB, and prolactin receptor pathways in lesional tissue. Clinically, IGM shows favorable responses to corticosteroids, methotrexate, azathioprine, anti-TNF agents, and JAK inhibitors. Laterality analysis of 3,973 patients demonstrated 93.9% unilateral disease with modest left-sided predominance (1.15:1 ratio), which remains hypothesis-generating. Collectively, evidence supports IGM as an organ-specific autoimmune disease. Convergence of prolactin and IL-6 signaling on the JAK/STAT3 pathway provides a plausible mechanistic node and rationale for targeted therapies. Future high-resolution immunoprofiling and prospective trials are needed to define disease subtypes and advance treatment modalities.
Autoimmune encephalitis-associated epilepsy with glutamic acid decarboxylase autoantibodies and type 1 diabetes mellitus: A comprehensive systematic scoping review of a clinical syndrome.
Kouhanjani MF, Plautz A, Melzer N … +9 more , Mann C, Strzelczyk A, Siebenbrodt K, Strüber M, Bojunga J, Kahl S, Roden M, Rosenow F, Willems LM
Autoimmun Rev · 2026 Jul · PMID 42173229 · Publisher ↗
BACKGROUND: Type 1 diabetes mellitus (T1DM) and autoimmune neurological syndromes (AINS), including autoimmune encephalitis-associated epilepsy/seizures (AEAE/S), share immune-mediated mechanisms linked to glutamic acid...
BACKGROUND: Type 1 diabetes mellitus (T1DM) and autoimmune neurological syndromes (AINS), including autoimmune encephalitis-associated epilepsy/seizures (AEAE/S), share immune-mediated mechanisms linked to glutamic acid decarboxylase-65 autoantibodies (GAD-AABs). We reviewed features of patients with the syndrome of coexisting GAD-AAB-associated T1DM and AEAE/S. METHODS: According to PRISMA-ScR, English studies from PubMed, Web of Science, and Scopus were reviewed for patients with T1DM, AEAE/S, and GAD-AABs. RESULTS: We included 78 patients (64% female) from 50 studies. Age at first presentation ranged from 1 to 72 years [25.6 (±17.07)]. T1DM preceded AEAE/S in 40% (n = 31), followed it in 29% (n = 23), overlapped in 9% (n = 7), and unknown order in 22% (n = 17). GAD-AABs were detected in serum in 77/78 patients, and in CSF in 41/60 tested (68%). Brain MRI was abnormal in 41/54 cases (76%), mostly temporal T2-FLAIR hyperintensity (n = 25; 46%). EEG showed interictal epileptiform discharges in 42/51 (82%) and ictal patterns in 19 (37%). Autoimmune thyroid disorders (n = 33; 42%) and overlapping AINS (n = 13; 17%) were frequent. Antiseizure medication was reported in 46 cases (59%), and drug resistance in 32/46 (70%). Of 68 cases with data, 50 (73.5%) received immunotherapy, mainly intravenous immunoglobulins and corticosteroids. Follow-up showed variable seizure control, psycho-cognitive symptoms in 22%, and two deaths. CONCLUSION: The syndrome of GAD-AAB-associated AEAE/S + T1DM exhibits age-dependent variations in clinical presentation with predominantly focal temporal seizures. People with T1DM should be screened for AINS, and those with AEAE/S for autoimmune (endocrine) disorders. A comprehensive immunological assessment guides diagnosis and targeted therapy.
Hydroxychloroquine and teratogenic risk in pregnancy in systemic autoimmune diseases: A systematic narrative review.
Esteve-Valverde E, Miro-Mur F, Anunciacion-LLunell A … +7 more , Ockova M, Gonçalves BA, Ferrer-Oliveras R, Morales-Perez S, Hoxha A, Cervera R, Alijotas-Reig J
Autoimmun Rev · 2026 May · PMID 42173228 · Publisher ↗
BACKGROUND: Hydroxychloroquine (HCQ) is increasingly prescribed during pregnancy to manage systemic autoimmune diseases (SAD) such as systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS). Its use has be...
BACKGROUND: Hydroxychloroquine (HCQ) is increasingly prescribed during pregnancy to manage systemic autoimmune diseases (SAD) such as systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS). Its use has been consistently associated with improved foetal outcomes and a reduced risk of maternal disease flares. Despite growing and consistent evidence supporting its safety in pregnancy, some clinicians express concerns about potential teratogenicity. This systematic narrative review aims to consolidate the current literature and critically evaluate the evidence regarding the teratogenic safety of HCQ during pregnancy. OBJECTIVE: To systematically review and critically appraise the potential teratogenic risk of HCQ during pregnancy, based on available human data from women with SAD. METHODS: We conducted a systematic narrative review following PRISMA 2020 guidelines. PubMed/MEDLINE and EMBASE were searched up to April 2025 for randomized trials, cohort studies, and case-control studies reporting congenital malformations after in utero exposure to HCQ. Risk of bias was assessed using RoB 2 and ROBINS-I tools. Due to clinical and methodological heterogeneity, findings were synthesized narratively without quantitative pooling. RESULTS: Fourteen studies including 4797 HCQ-exposed pregnancies were identified. Across randomized, prospective, and large population-based observational studies, HCQ exposure was not consistently associated with an increased risk of major congenital malformations, and no specific pattern of anomalies was observed. A single large population-based study reported a modest, dose-dependent increase in risk at daily doses ≥400 mg; however, absolute risk differences were small, no consistent malformation phenotype emerged, and findings were not replicated in other large cohorts. Minor congenital anomalies were inconsistently reported and showed no coherent association with HCQ exposure. CONCLUSIONS: The available evidence does not support an increased teratogenic risk associated with HCQ use during pregnancy in women with systemic autoimmune diseases. When weighed against the established risks of uncontrolled maternal disease, continuation of HCQ at standard doses appears justified. Integration of epidemiological data with current mechanistic evidence further supports the biological plausibility of fetal safety.
Chimeric antigen receptor-based cellular therapy in autoimmune diseases: A systematic review and meta-analysis of clinical, serological and safety outcomes.
Wong HJ, Lee ARYB, Yap QV … +3 more , Chan E, Schett G, Tay SH
Autoimmun Rev · 2026 Jul · PMID 42167622 · Publisher ↗
OBJECTIVE: Chimeric antigen receptor (CAR)-T cell and natural killer cell therapies are emerging as treatments for autoimmune diseases (AIDs), capable of inducing immune reprogramming and drug-free remission. However, th...
OBJECTIVE: Chimeric antigen receptor (CAR)-T cell and natural killer cell therapies are emerging as treatments for autoimmune diseases (AIDs), capable of inducing immune reprogramming and drug-free remission. However, their efficacy, safety, and durability across AIDs remain incompletely defined. METHODS: We performed a systematic review and meta-analysis of proportions to evaluate the efficacy and safety of CAR-based therapies in AIDs. PubMed, Embase, and CENTRAL were searched from January 1, 2010, to October 20, 2025. The primary outcome was medication-free remission (MFR); secondary outcomes included disease-specific remission indices, incidence of adverse events and their severity. Subgroup and meta-regression analyses were conducted. RESULTS: Of 3367 records screened, 56 studies met the inclusion criteria (15 eligible for meta-analysis; 41 synthesized qualitatively). For CAR-T cell therapies, among SLE patients, pooled MFR was 0·76 and DORIS remission 0·75. Subgroup analyses revealed a longer disease duration was associated with lower remission rates. From the qualitative analysis, CAR-T cell therapies demonstrated promising clinical efficacy and seroconversion rates in other AIDs, such as systemic sclerosis, myositis and myasthenia gravis. Across all AIDs, CRS of any grade occurred in 0·63, but grade ≥ 3 CRS and any grade of ICANS were negligible (both 0·00). Hypogammaglobulinaemia of any grade occurred in 0·47, while grade ≥ 3 events were rare. Cytopenias were common: neutropenia and anemia of any grade were most frequent. Severe cytopenias occurred in ≤0·3. Infection within 3 months occurred in 0·29. CONCLUSION: CAR-T cell therapies targeting CD19 or BCMA appear highly effective in inducing remission in refractory autoimmune diseases, with predominantly mild CRS and negligible neurotoxicity.
Fatty acid oxidation and inflammatory bowel disease: Highlighting the roles of pathogenesis and treatment.
Li C, Shen J
Autoimmun Rev · 2026 Jul · PMID 42167621 · Publisher ↗
The increasing prevalence of inflammatory bowel disease (IBD) imposes a substantial economic burden, and its pathogenesis is associated with dietary fat intake. Short-chain fatty acids (SCFAs) regulate intestinal inflamm...
The increasing prevalence of inflammatory bowel disease (IBD) imposes a substantial economic burden, and its pathogenesis is associated with dietary fat intake. Short-chain fatty acids (SCFAs) regulate intestinal inflammation and immunity by inhibiting histone deacetylases (HDACs) or binding to G protein-coupled receptors (GPCRs). Specialized pro-resolving mediators (SPMs) derived from polyunsaturated fatty acids (PUFAs) contribute to inflammation resolution. Fatty acid oxidation (FAO) is a primary energy source for intestinal epithelial cells. Previous studies indicate that patients with IBD exhibit decreased levels of SCFAs and reduced intermediates of the tricarboxylic acid (TCA) cycle, suggesting impaired FAO. These alterations may exacerbate intestinal inflammation through energy deficiency in intestinal epithelial cells, barrier disruption, and dysregulated immune cell polarization. This review aims to broaden therapeutic options by identifying underlying targets and proposing potential strategies.
Mepolizumab for eosinophilic granulomatosis with polyangiitis (EGPA): A scoping review of effectiveness and safety data derived from real-world evidence.
Rúa-Figueroa Í, Velasco B, Cid MC
Autoimmun Rev · 2026 May · PMID 42167620 · Publisher ↗
BACKGROUND: Management of eosinophilic granulomatosis with polyangiitis (EGPA) is challenging due to inconsistent responses and frequent relapses with classic treatments. Mepolizumab (MPZ), an anti-interleukin-5 monoclon...
BACKGROUND: Management of eosinophilic granulomatosis with polyangiitis (EGPA) is challenging due to inconsistent responses and frequent relapses with classic treatments. Mepolizumab (MPZ), an anti-interleukin-5 monoclonal antibody, has emerged as an effective treatment for patients with EGPA. This review assessed evidence of clinical outcomes and safety among patients with EGPA receiving MPZ in real-world settings. METHODS: A scoping review was conducted to identify real-world evidence on MPZ use in patients with EGPA. Relevant articles were identified in searches of OVID Medline and EMBASE databases alongside manual searches. RESULTS: Seventy-one references involving 51 original studies were selected for review. MPZ was administered at different dosages (predominantly 100 mg or 300 mg subcutaneously every 4 weeks) with a cumulative sample size of 2312 MPZ-treated patients. The mean duration of follow-up was 16.3 ± 9.7 months. Reported remission rates (mostly defined as a Birmingham Vasculitis Activity Score of 0 without or with low doses of glucocorticoids [GC]) ranged from 30.4% to 94.4% at 12-24 months. The overall reduction in relapse rates with MPZ ranged from 42% to 90.6%. The GC dose was significantly reduced after MPZ treatment (up to 87.2% at 16-18 months and 79.1% at 24-26 months). Approximately 50% of patients successfully discontinued GC usage at 12 months or more. No new safety signals were reported in real-world studies compared with the randomized controlled trials. CONCLUSIONS: In a real-world setting, MPZ treatment supported clinically significant benefits in patients with EGPA, with a very good safety profile.
Long-term outcomes and prognostic factors in juvenile dermatomyositis: A systematic review of studies with more than 12 months of follow-up.
Scagnellato L, Kostopoulou C, Roberta R … +1 more , Ciurtin C
Autoimmun Rev · 2026 Jul · PMID 42167619 · Publisher ↗
BACKGROUND: Juvenile dermatomyositis (JDM) is a rare autoimmune myopathy in children and young people (CYP), with long-term outcomes that remain poorly defined. We systematically reviewed long-term studies to summarise o...
BACKGROUND: Juvenile dermatomyositis (JDM) is a rare autoimmune myopathy in children and young people (CYP), with long-term outcomes that remain poorly defined. We systematically reviewed long-term studies to summarise outcomes and prognostic factors associated with remission or persistent disease. METHODS: This review was registered in PROSPERO (ID 1085849). A PubMed search (November 2025) identified eligible studies based on predefined PICO criteria. Inclusion required >10 CYP with JDM, ≥12 months follow-up, outcome reporting, and English full text. Studies with mixed cohorts or < 12 months follow-up were excluded. Data were independently extracted by two assessors, and study quality was evaluated using the Newcastle-Ottawa Scale. RESULTS: Of 341 records screened, 42 studies (2000-2025) including 6194 CYP met criteria. Study quality ranged 4-9/9, with 38.1% rated high quality. Most were retrospective or prospective cohorts. Follow-up ranged 1-21.7 years - only 8 studies had >10 years follow-up. Nine studies using PRINTO remission criteria reported remission rates of 21.6-73.0%, with pre-PRINTO studies showing monocyclic remission rates of 24.5-70.3%. PROM-based analyses identified persistent disease in 11-12% of cases, and one study found 59% patient-reported active disease at 12 years. The most frequent complication was calcinosis (10-40%). Mortality occurred mainly in the acute phase due to pulmonary or infectious complications. Poorer outcomes were associated with younger onset, African ancestry, socioeconomic disadvantage, diagnostic delay, and high baseline skin and muscle involvement. CONCLUSION: Long-term follow-up data in JDM remain limited, but remission is achievable. Early diagnosis, timely treatment, and validated outcome measures are for improving prognosis.
Annexin A1 and its membrane receptor complex: Implications for immune regulation and autoimmune disease mechanisms.
Ambrish T, Jayaswamy PK, Haridas V … +3 more , Kellarai A, Shetty S, Shetty P
Autoimmun Rev · 2026 Jun · PMID 42162635 · Publisher ↗
Annexin A1 (AnxA1) is a key anti-inflammatory mediator that regulates both innate and adaptive immunity, promoting resolution of inflammation and tissue repair. It is highly expressed in neutrophils, macrophages, dendrit...
Annexin A1 (AnxA1) is a key anti-inflammatory mediator that regulates both innate and adaptive immunity, promoting resolution of inflammation and tissue repair. It is highly expressed in neutrophils, macrophages, dendritic cells, and select lymphocyte subsets, where it limits excessive immune activation and maintains immune homeostasis. Through binding to the G protein-coupled receptor formyl peptide receptor 2 (FPR2/ALX), AnxA1 induces neutrophil apoptosis and promotes macrophage polarization toward an anti-inflammatory M2 phenotype. In adaptive immunity, AnxA1 regulates CD4 T-cell differentiation in a lineage-specific manner, promoting Th1 and Th17 responses while suppressing Th2 polarization; its deficiency skews T cells toward a Th2 phenotype with increased IL-4/IL-13 and reduced IL-17, highlighting its role in maintaining T-cell balance. In autoimmune and inflammatory disorders such as rheumatoid arthritis, lupus, type-1 diabetes, and multiple sclerosis, hyperactivation of toll-like receptor-4 (TLR4) and epidermal growth factor receptor (EGFR) drives STAT1-dependent signaling, sustaining cytokine production and tissue injury. The Annexin A2 (AnxA2)-EGFR complex further amplifies this response by downregulating AnxA1 and reinforcing pro-inflammatory signaling pathways. In contrast, AnxA1 engagement with EGFR and FPR2 redirects signaling toward STAT3, enhancing IL-10 and TGF-β production while suppressing STAT1-driven pathways. This STAT1-STAT3 balance is critical for immune resolution, inflammation control, and tissue homeostasis. Therapeutically, AnxA1-based strategies suppress STAT1 signaling and promote a regulated STAT3/SOCS3 axis associated with immune resolution, while limiting pathogenic Th17-associated STAT3 activity. Overall, AnxA1 acts as a molecular switch integrating receptor-mediated signals to fine-tune immune responses and mitigate tissue damage in chronic inflammatory and autoimmune diseases.
Metabolic signatures in systemic autoimmune diseases: A state-of-the-art overview of systemic lupus erythematosus, primary Sjögren's syndrome, and systemic sclerosis.
Jędreas A, Michorowska S, Le Jan S … +2 more , Servettaz A, Giebułtowicz J
Autoimmun Rev · 2026 Jul · PMID 42162634 · Publisher ↗
Systemic lupus erythematosus (SLE), primary Sjögren's syndrome (pSS), and systemic sclerosis (SSc) are systemic autoimmune diseases characterized by marked heterogeneity in clinical presentation, organ involvement, and d...
Systemic lupus erythematosus (SLE), primary Sjögren's syndrome (pSS), and systemic sclerosis (SSc) are systemic autoimmune diseases characterized by marked heterogeneity in clinical presentation, organ involvement, and disease course. Their management remains challenging, particularly in patients with multi-organ involvement or overlapping autoimmune conditions. Emerging metabolomic studies indicate that distinct molecular signatures are closely linked to disease phenotypes and can reliably distinguish patients from healthy controls, underscoring their potential clinical relevance. This review aims to synthesize current metabolomics research on SLE, pSS, and SSc. We first consolidate knowledge on metabolic alterations by identifying pathways that differentiate patients from controls. We then highlight metabolites associated with organ involvement and disease activity and compare shared and disease-specific metabolic features across the three conditions. Metabolites reported in published metabolomics studies of SLE, pSS, and SSc were systematically mapped to the KEGG database (MetaboAnalyst 6.0) to perform pathway enrichment analysis, providing an integrated overview of disease-associated metabolic pathways. Analysis revealed substantial overlap in metabolic alterations across the three diseases. Amino acid metabolism emerged as a core feature of systemic autoimmunity, whereas lipid-related pathways showed greater disease- and organ-specificity. SLE and pSS are metabolically similar, reflecting their clinical overlap, yet glycerophospholipid metabolism may distinguish pSS. SLE was the most extensively studied disease, with glycine, serine, and threonine metabolism showing particularly pronounced alterations. Altered metabolomic profiles provide insight into shared and disease-specific mechanisms underlying SLE, pSS, and SSc. Systematic integration of metabolomics data may reduce study-specific variability and identify robust metabolic pathways relevant for diagnosis and personalized management. However, further analytical validation and clinical translation are required before these metabolites can be implemented in routine diagnostic and stratification strategies.
The rituximab paradox in rheumatoid arthritis: Re-evaluating B-cell depletion depth and the synovial microenvironment.
Chen C, Luo W
Autoimmun Rev · 2026 May · PMID 42162633 · Publisher ↗
BACKGROUND: Two decades after B-cell depletion altered the therapeutic landscape of rheumatoid arthritis (RA), a clinical paradox persists. Pharmaceutical engineering has yielded advanced anti-CD20 agents (ocrelizumab, o...
BACKGROUND: Two decades after B-cell depletion altered the therapeutic landscape of rheumatoid arthritis (RA), a clinical paradox persists. Pharmaceutical engineering has yielded advanced anti-CD20 agents (ocrelizumab, ofatumumab) exhibiting superior depletion kinetics. These molecules have triumphed in multiple sclerosis but have failed to demonstrate superior clinical benefit in RA. Rituximab, the chimeric prototype, retains clinical dominance through dose optimization and biosimilar economics. MAIN FINDINGS: Optimizing RA treatment does not mandate near-complete systemic B-cell sterilization. Adequate disruption of pathogenic circuits within the synovial niche-specifically the ABC-FLS interaction-suffices for clinical response. Integrating single-cell transcriptomics with longitudinal data from the REDO trial indicates that "incomplete" depletion preserves a critical safety margin of tissue-resident immunity, mitigating infection risks in susceptible populations. CONCLUSIONS: We outline a bifurcated future paradigm: precision tolerance via disease-activity-guided ultra-low dosing for responsive phenotypes and cellular immune resets (CAR-T therapy) targeting deep tissue reservoirs in highly refractory disease.
Enteropathy in STAT3 GOF syndrome: Insights into the role of the JAK-STAT pathway.
Caranfil C, Crepaldi M, Marzollo A … +12 more , Vogel TP, Schumann M, Palo M, Bertin L, Savarino EV, Pizzi M, Dei Tos A, Bresolin S, Fassan M, Scarpa R, Cinetto F, Zingone F
Autoimmun Rev · 2026 Jul · PMID 42162632 · Publisher ↗
The term enteropathy refers to any disease affecting the small intestine. In the past, celiac disease (CeD) was the only well-established atrophic enteropathy, but the spectrum of non-celiac enteropathies with villous at...
The term enteropathy refers to any disease affecting the small intestine. In the past, celiac disease (CeD) was the only well-established atrophic enteropathy, but the spectrum of non-celiac enteropathies with villous atrophy has been expanded, as has knowledge about the underlying pathogenic mechanisms. Kinases within the JAK-STAT3 pathway are essential in transducing signals from various pro-inflammatory cytokines. Uncontrolled activation of these pathways promotes the development and progression of different diseases such as inflammatory and autoimmune diseases, lymphomas, and solid tumors. Therefore, inhibition of JAK-STAT3 represents a promising therapeutic option for patients with these disorders. Gain-of-function mutations in the STAT3 gene cause a rare syndrome characterized by enteropathy and a wide range of immune-mediated manifestations, including lymphoproliferation, autoimmune cytopenias and growth delay. In this narrative review we introduce signalling via the JAK-STAT3 pathway, focusing on potential mechanisms contributing to immune deficiencies in the constellation of a STAT3 gain of function. Furthermore, through an emblematic clinical case on the efficacy of anti-JAK therapy in STAT3 enteropathy, we review different enteropathies which recognize alterations in the JAK-STAT pathway and discuss the role of JAK inhibitors in this setting.
B cells in systemic lupus erythematosus: from pathogenic mechanisms to targeted therapies.
Su X, Lei Q, Chen X … +6 more , Tong Y, Liu S, Guo Y, Yang W, Yu H, Lin L
Autoimmun Rev · 2026 Jun · PMID 42162631 · Publisher ↗
Systemic lupus erythematosus (SLE) is a multisystem autoimmune condition characterized by a pronounced female predilection, particularly during reproductive age, and poses a significant threat to health and survival. A d...
Systemic lupus erythematosus (SLE) is a multisystem autoimmune condition characterized by a pronounced female predilection, particularly during reproductive age, and poses a significant threat to health and survival. A defining pathological feature is the production of autoantibodies by B lymphocytes, leading to the formation of immune complexes that deposit in various tissues and drive inflammation, thereby establishing the pivotal role of B cells in disease pathogenesis. Consistent observational and mechanistic studies have documented significant alterations in peripheral B cell subsets in SLE patients. These cells exhibit a state of hyperactivity and undergo aberrant differentiation, processes modulated by a complex interplay of pro-inflammatory cytokines, dysregulated transcription factor activity, and intracellular signaling pathway dysfunction. Multiple B cell-directed biological agents have undergone rigorous evaluation in both preclinical models and clinical trials. While some of these treatments have demonstrated promising efficacy, many others have often shown suboptimal therapeutic outcomes, highlighting an unmet need for more effective B cell-targeted interventions. This review synthesizes contemporary insights into the fundamental biology of B cells in SLE, integrating recent advances to refine the mechanistic understanding of their contribution to the disease. Furthermore, it critically appraises current and emerging B cell-targeted therapeutic strategies, assessing their translational potential and future directions in the management of SLE.
Nintedanib combined with dual immunosuppression for interstitial lung disease in systemic sclerosis and rheumatoid arthritis: A systematic review and pooled multicentre real-world cohort study.
Chioni A, Campochiaro C, Keret S … +10 more , Panopoulos S, Barešić M, Varelas G, Radić M, Sebastiani M, Tektonidou MG, Sfikakis PP, Rimar D, Matucci-Cerinic M, Daoussis D
Autoimmun Rev · 2026 Jul · PMID 42162630 · Publisher ↗
Interstitial lung disease (ILD) in patients with systemic sclerosis (SSc) or rheumatoid arthritis (RA) carries substantial mortality, and treatment options remain limited. We investigated the effectiveness, safety, and t...
Interstitial lung disease (ILD) in patients with systemic sclerosis (SSc) or rheumatoid arthritis (RA) carries substantial mortality, and treatment options remain limited. We investigated the effectiveness, safety, and tolerability of triple therapy combining nintedanib with two immunomodulatory drugs in SSc- and RA-associated ILD. We carried out a systematic search of studies reporting triple combination in SSc-ILD and RA-ILD. Published and unpublished investigator-provided data were pooled into a multicentre cohort. Longitudinal variations in % predicted forced vital capacity (FVC), % predicted diffusing capacity of the lungs for carbon monoxide (DLCO), and modified Rodnan Skin Score (mRSS) in SSc-ILD were analysed at 6 and 12 months using linear mixed-effects models. The cohort comprised 64 patients (36 SSc-ILD, 28 RA-ILD). Longitudinal pulmonary function data were not available for the RA-ILD subgroup; longitudinal analyses were therefore limited to 35 SSc-ILD patients. In SSc-ILD, FVC and DLCO remained overall stable at 6 and 12 months. mRSS remained stable at 6 months, while the mixed-effects model estimated a reduction in mRSS at 12 months (-2.1 points, 95% CI -3.5 to -0.7; p = 0.002). Across the whole cohort, serious adverse events occurred in 3 patients (4.7%), including 1 death, and infections were reported in 5 patients (7.8%). Most patients (75%) continued therapy, following nintedanib dose reduction. Triple therapy was generally well tolerated in SSc- and RA-ILD. Longitudinal lung function stability and a model-based reduction in skin score were observed in the SSc-ILD subgroup. These descriptive findings support further prospective studies.
Double-negative T cells in systemic lupus erythematosus: From immunopathology to therapeutic target.
Zhao Y, Liu X, Li N … +3 more , Liu J, Gao C, Wang C
Autoimmun Rev · 2026 Jul · PMID 42155696 · Publisher ↗
Systemic lupus erythematosus (SLE) is an autoimmune disease marked by diverse clinical manifestations and profound immune dysregulation. Among the immune cells implicated in SLE pathogenesis, double-negative T (DNT) cell...
Systemic lupus erythematosus (SLE) is an autoimmune disease marked by diverse clinical manifestations and profound immune dysregulation. Among the immune cells implicated in SLE pathogenesis, double-negative T (DNT) cells, a unique subset of CD3 T lymphocytes that lack both CD4 and CD8 co-receptors, have emerged as important and context-dependent contributors to disease progression. Pathogenic DNT cells are markedly expanded in SLE patients and disrupt immune tolerance by promoting the production of pathogenic autoantibodies, sustaining chronic inflammation, and directly contributing to tissue injury, particularly in severe manifestations such as lupus nephritis. SLE-associated DNT cells are frequently shaped by inflammatory cytokine milieus and convergent signaling-metabolic hubs (including mechanistic target of rapamycin, mTOR), which help stabilize pathogenic states. Current SLE management, heavily reliant on broad immunosuppression, remains challenged by heterogeneity and limited efficacy. Recent insights into DNT cell biology suggest that targeting pathogenic DNT phenotypes while preserving immunoregulatory subsets may enable a shift from non-specific immunosuppression toward the restoration of immune tolerance. Consequently, DNT cells represent not only key pathogenic effectors in specific inflammatory contexts but also promising biomarkers and therapeutic targets. Because no single surface marker reliably discriminates pathogenic from regulatory DNT states, translational efforts should prioritize multi-parameter phenotyping (e.g., checkpoint and activation markers with differentiation and proliferation states) coupled to functional readouts (IL-17 versus IL-10). Future investigations should focus on developing DNT-targeted strategies, identifying predictive biomarkers, and rigorously assessing long-term safety, thereby paving the way for precision medicine in systemic autoimmunity.
Diagnosis, treatment and monitoring of chronic nonbacterial osteomyelitis (CNO) and chronic recurrent multifocal osteomyelitis (CRMO) - Evidence, practice and consensus-based recommendations from the German pediatric rheumatology society (GKJR).
Schnabel A, Reiser C, Beer M … +16 more , Brück N, Förster C, Grote V, Hahn G, Hofmann C, Hofmann SR, Hospach T, Jansson AF, Kohlmann F, Morbach H, Raab P, Skrabl-Baumgartner A, Tenbrock K, Winterling S, Girschick HJ, Hedrich CM
Autoimmun Rev · 2026 Jul · PMID 42155695 · Publisher ↗
BACKGROUND: Chronic nonbacterial osteomyelitis (CNO), sometimes also referred to as chronic recurrent multifocal osteomyelitis (CRMO), is a rare autoinflammatory bone disease primarily affecting children and adolescents....
BACKGROUND: Chronic nonbacterial osteomyelitis (CNO), sometimes also referred to as chronic recurrent multifocal osteomyelitis (CRMO), is a rare autoinflammatory bone disease primarily affecting children and adolescents. In the absence of diagnostic criteria and biomarkers, CNO remains a diagnosis of exclusion, and treatment is largely empiric. OBJECTIVE: This initiative of the German Society of Pediatric and Adolescent Rheumatology (GKJR) aimed to develop evidence-, practice-, and consensus-based recommendations for the diagnosis and management of CNO, incorporating current knowledge on pathophysiology, therapeutic strategies and disease monitoring. METHODS: Based on a systematic literature review and a subsequent Delphi survey, preliminary statements were developed. This was followed by expert group voting exercises (nominal group exercise) to agree final statements and recommendations. RESULTS: Statements and recommendations were developed for the diagnosis, treatment and disease monitoring of CNO in a multidisciplinary expert group, involving patients/families. Where available, diagnostic workup should include whole-body skeletal imaging (usually MRI). Treatment options include first-line (NSAIDs, short-term corticosteroids) and second-line (conventional and/or biologic DMARDs, bisphosphonates) agents. In patients with vertebral involvement, rapid treatment with bisphosphonates and/or TNF inhibitors is recommended. As CNO is a chronic disease, long-term monitoring is recommended, including follow-up after treatment discontinuation. CONCLUSION: Although evidence levels are low to moderate, consensus statements and recommendations provide structured guidance for clinicians diagnosing and treating CNO. They provide a framework for harmonized care aiming at improved long-term outcomes.
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