With new insights into damage accrual, new outcome measures and new therapies emerging, treatment for lupus nephritis (LN) has evolved over the last years. Although a greater proportion of patients shows clinical responses, treatment reduction and withdrawal remain challenging. While immunosuppressive therapy has relevant side effects, relapses pose the risk of long-term kidney function impairment. Unlike other autoimmune kidney diseases, LN lacks a unique biomarker or biomarker profile clearly reflecting disease activity. Here, we review definitions of remission, LN immunosuppressant withdrawal studies and new biomarkers correlated with disease activity. These factors can help to identify patients who can be safely withdrawn from immunosuppression reducing risk of infection, cardiovascular side effects, toxicity and damage accrual.

BACKGROUND:Respiratory syncytial virus (RSV) causes severe respiratory illness in vulnerable populations, including kidney transplant recipients (KTRs) and dialysis patients (DPs). Despite the availability of RSV prefusion F protein-based vaccines, immune phenotyping of vaccine-specific B and T cells in KTRs and DPs remains limited. We hypothesized that RSVPreF3OA vaccination induces distinct immune signatures in KTRs and DPs compared with healthy controls (HCs), reflecting the impact of immunosuppression and uraemia on vaccine-induced B and T cell responses. METHODS:In this observational cohort, we analysed humoral and cellular responses following routine vaccination with the adjuvanted prefusion F protein-based RSVPreF3OA vaccine in 23 KTRs, 14 DPs and 24 HCs. Blood and saliva were collected at baseline and on days 30 and 90 post-vaccination. RSV-specific serum immunoglobulin G/immunoglobulin A, salivary antibodies and antigen-specific B and T cells were quantified by enzyme-linked immunosorbent assay and spectral flow cytometry, with tetanus- and severe acute respiratory syndrome coronavirus 2-specific responses assessed in parallel. RESULTS:In KTRs, vaccination induced increases in serum and salivary antibodies, expansion of RSV-specific B cells with enrichment of a switched memory phenotype unique to RSV-specific B cells and induction of RSV-A- and RSV-B-specific T cells with effector cytokine production. These signatures resembled those observed in HCs, whereas responses in DPs were delayed and attenuated. Across cohorts, RSV-specific B and T cells showed comparable phenotypic and functional characteristics. CONCLUSIONS:This study provides detailed immunophenotyping of RSVPreF3OA vaccine responses in KTRs, DPs and HCs over 90 days, showing that RSVPreF3OA vaccination induces protective RSV responses among KTRs comparable to HCs while DPs mount modestly lower cellular and humoral responses.

Chimeric antigen receptor (CAR) T cell-mediated B cell depletion has demonstrated efficacy in several autoimmune diseases. Here we report clinical and molecular data obtained during the nonrandomized phase 1 part of the phase 1/2 COMPARE trial, evaluating safety and efficacy of mivocabtagene autoleucel (miv-cel), an autologous fully human CD19 CAR T cell therapy, in rheumatoid arthritis (RA). Six patients (three men, three women) with severe, treatment-refractory, anti-citrullinated protein antibody (ACPA)-positive RA received a single infusion of miv-cel after stopping all disease-modifying antirheumatic drug treatments and after standard lymphodepletion therapy. Patients were followed for 36-52 weeks for safety and efficacy. Primary endpoints were the incidence and severity of cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS) and adverse events (AEs) within the first 4 weeks after treatment. Secondary and explorative endpoints assessed clinical efficacy and cellular and humoral immune responses. CRS occurred in all patients and was limited to grade 1 and 2 events. No ICANSs or serious AEs occurred; one dose-limiting toxicity was recorded (grade 3 transaminase elevation, resolved without sequelae). The primary endpoint was met with acceptable safety findings, allowing advancement to phase 2. CAR T cell therapy resulted in depletion of CD19+ B cells across blood and tissue, coinciding with a continuous decline of autoantibodies with seroconversion in four of the six patients for ACPAs against mutated citrullinated vimentin and five of six for rheumatoid factor immunoglobulin M. Despite cessation of immunosuppressive treatments, disease activity improved in all patients (median 34% DAS28-CRP reduction at the latest follow-up with DAS28-CRP remission and American College of Rheumatology 70% response in 3 of 6 patients). CD19 CAR T cells showed acceptable short-term tolerability in patients with treatment-refractory RA, justifying further evaluation. ClinicalTrials.gov identifier: NCT06475495 .

BACKGROUND:Dapirolizumab pegol is a novel CD40 ligand inhibitor. In this phase 3 trial, we aimed to evaluate the efficacy and safety of dapirolizumab pegol in patients with systemic lupus erythematosus (SLE). METHODS:PHOENYCS GO was a 48-week, randomised, double-blind, placebo-controlled, phase 3 trial conducted in 177 centres (hospitals, private practices, and trial centres) in 25 countries. Patients aged 16 years or older with moderate-to-severe, active SLE despite standard-of-care medication were randomly assigned (2:1), via an interactive web response system, to intravenous dapirolizumab pegol 24 mg/kg or placebo every 4 weeks in addition to standard of care. Patients, investigators, and funders were blinded to treatment assignments. The primary outcome was British Isles Lupus Assessment Group-based Composite Lupus Assessment (BICLA) response at week 48. Efficacy analyses were conducted on a modified intention-to-treat population. Safety analyses included all randomly assigned patients who received at least one study medication dose. This trial is registered with ClinicalTrials.gov (NCT04294667) and is completed. FINDINGS:Between Aug 12, 2020, and June 8, 2023, 643 patients were screened and 321 patients were randomly assigned to dapirolizumab pegol (n=213) or placebo (n=108) plus standard of care. All randomly assigned patients received at least one dose of study medication. Six patients were excluded due to non-compliance of one site with Good Clinical Practice guidelines; therefore, the full-analysis set included 315 patients (293 female, 22 male). A significantly greater proportion of patients receiving dapirolizumab pegol (50% [103/208]) versus placebo (35% [37/107]) had BICLA response at week 48 (p=0·011; difference 14·6; 95% CI 3·3-25·8). Treatment-emergent adverse events occurred in 83% (176/213) of patients receiving dapirolizumab pegol versus 75% (81/108) receiving placebo. Serious treatment-emergent adverse events occurred in 10% (21/213) of patients receiving dapirolizumab pegol versus 15% (16/108) receiving placebo. Hypersensitivity reactions during infusion occurred in 3% (6/213) of patients receiving dapirolizumab pegol. Serious infections occurred in 4% (8/213) and 6% (6/108) of patients receiving dapirolizumab pegol and placebo, respectively. One thromboembolic event (myocardial infarction) occurred in one patient in the dapirolizumab pegol group and one death (gangrene-related sepsis) occurred in another patient in the dapirolizumab pegol group. INTERPRETATION:Dapirolizumab pegol was associated with significant improvement in disease activity in patients with SLE. These findings support the further investigation of dapirolizumab pegol as a treatment option for SLE. FUNDING:UCB and Biogen.

Die primäre Sjögren-Erkrankung (SjD) ist eine chronische Autoimmunerkrankung, die vorwiegend exokrine Drüsen betrifft, aber auch zahlreiche systemische Organmanifestationen aufweisen kann. Darstellung des aktuellen Verständnisses zur Krankheitsentstehung mit Fokus auf genetischer Prädisposition, epithelialer Aktivierung, Interferonsignatur und resultierender B‑T-Zell-Interaktion, welche die Grundlagen für innovative Therapieansätze darstellen. Selektive Literaturrecherche aktueller Primärarbeiten, Reviews und klinischer Studien. Die aktuelle Forschung geht davon aus, dass die SjD durch eine Kombination genetischer und epigenetischer Prädispositionen, hormoneller Einflüsse und möglicher viraler Trigger eine epitheliale Fehlregulation auslöst. Es kommt zur Freisetzung von dsDNA, dsRNA oder ssRNA, was in der Folge zu einer Aktivierung des angeborenen Immunsystems führt. Speicheldrüsenepithelzellen (SGECs), dendritische Zellen (pDCs) und Monozyten produzieren proinflammatorische Zytokine, und weitere Immunzellen werden rekrutiert. Durch pDCs kommt es zu einer massiven Produktion von Typ-I-Interferon. In der Folge bildet sich ein entzündliches Mikromilieu, durch welches SGECs in Apoptose gehen und weitere Antigene freisetzen sowie T‑Zellen rekrutieren. In dem Rahmen produzieren myeloische Zellen und SGECs umfangreiche Mengen des Zytokins BAFF. Dies fördert die weitere Rekrutierung von B‑Zellen. Durch Th1-Zellen und Tfh-Zellen bildet sich eine T‑B Zell-Interaktion, und es kommt zur Entstehung von ektopischen Keimzentren, einschließlich der Induktion autoreaktiver B‑Zellen. Die Pathophysiologie des SjD ist ein mehrstufiger Prozess, in dem die frühe Aktivierung des Speichelepithels und folgende Aktivierung des angeborenen Immunsystems mit Interferon (IFN) eine entscheidende Rolle in der Initiierung spielen. In der Folge kommt es zur Aktivierung des adaptiven Immunsystems mit einem Fokus auf T‑B-Zell-Interaktion und einer pathologischen B‑Zell-Aktivierung. Die chronische Entzündung bei der SjD kann als positive Rückkopplung der Aktivierung des angeborenen und erworbenen Immunsystems verstanden werden, auf deren Unterbrechung innovative Therapieansätze zielen. Diese umfassen TLR- und IFN-Blockade, Inhibition der T‑B-Zell Interaktion durch CD154/CD40-Blockade (z. B. Dazodalibep, Iscalimab) bzw. B‑Zell-Depletionsstrategien, u. a. Anti-BAFF-R- und Anti-CD19 CAR-T-Zellen.

BACKGROUND:Primary Sjögren's disease (SjD) is a chronic autoimmune disease that predominantly affects exocrine glands but can also show numerous systemic organ manifestations. OBJECTIVE:Presentation of the current understanding of the pathogenesis of the disease, focusing on genetic predisposition, epithelial activation, interferon signature and the resulting B‑T cell interaction, which form the basis for innovative treatment approaches. METHODS:Selective literature review of current original articles, reviews and clinical studies. RESULTS:Current research postulates that SjD triggers epithelial dysregulation through a combination of genetic and epigenetic predispositions, hormonal influences and possible viral triggers. This leads to the release of dsDNA, dsRNA or ssRNA, which in turn activate the innate immune system. Salivary gland epithelial cells (SGECs), plasmacytoid dendritic cells (pDCs), and monocytes produce proinflammatory cytokines and additional immune cells are recruited. The pDCs produce massive amounts of type I interferon. This results in the formation of an inflammatory microenvironment, which causes SGECs to undergo apoptosis, the release of further antigens and the recruitment of T cells. In this context, myeloid cells and SGECs produce large amounts of the cytokine B‑cell activating factor (BAFF). This promotes the further recruitment of B cells. Through Th1 cells and Tfh cells a T-B cell interaction is formed, leading to the development of ectopic germinal centers, including the induction of autoreactive B cells. DISCUSSION:The pathophysiology of SjD is a multistage process in which the early activation of the salivary epithelium and subsequent activation of the innate immune system with IFN play a crucial role in its initiation. This is followed by activation of the adaptive immune system with a focus on T‑B cell interaction and pathological B cell activation. The chronic inflammation in SjD can be understood as positive feedback from the activation of the innate and adaptive immune systems, which innovative therapeutic approaches aim to interrupt. These comprise TLR and IFN blockade, inhibition of T‑B cell interaction via CD154/CD40 blockade (e.g., dazodalibep, iscalimab) or B cell depletion strategies including. anti-BAFF‑R and anti-CD19 CAR-T cells.

IntroductionAntiphospholipid syndrome (APS) is an autoimmune disorder characterized by thrombotic events and/or obstetric complications due to persistent antiphospholipid antibodies. Type I interferon (IFN) upregulation has been identified as a potential contributor to the pathophysiology of APS, however, the relationship between type I IFN and clinical manifestations of APS still needs to be delineated. The objective of this study was the evaluation of the potential role of type I IFN regarding different APS manifestations.MethodsWe conducted a retrospective analysis of APS patients who presented to our clinic between 2017 and 2024, focusing on clinical manifestations, recurring events and serological profiles in relation to Siglec-1 expression on monocytes, as a surrogate marker of type I IFN signature.ResultsOut of the 218 APS patients included in the study, 123 were diagnosed with primary APS (pAPS) and 95 with secondary APS (sAPS), the latter mostly SLE associated, showing a general higher type I IFN signature as the pAPS cohort. While no significant differences in Siglec-1 expression were observed across most APS manifestations (venous, arterial, mixed and obstetric events), significantly higher type I IFN activity was detected in APS patients with thrombocytopenia compared to those without (p = 0.0061). Moreover, we found an inverse correlation between platelet numbers and Siglec-1 values. Interestingly, the difference in type I IFN signature was confirmed in the pAPS cohort with thrombocytopenia (p = 0.0242). In sAPS, Siglec-1 expression did not differ significantly between patients with and without thrombocytopenia (p = 0.4664). With regard to serological and clinical characteristics, patients with thrombocytopenia exhibited a higher prevalence of triple positivity, elevated levels of anti-cardiolipin IgG antibodies and an increased incidence of recurrent and mixed (arterial/venous) thromboembolic events.DiscussionTo conclude, the data indicate that type I IFN may be a relevant factor for the occurrence of thrombocytopenia in pAPS. Moreover, thrombocytopenia in APS was linked to increased prevalence of triple positivity, higher anti-cardiolipin IgG titres, and higher disease severity, underscoring the importance of closer monitoring in this subgroup. These results warrant validation in prospective studies and could support potential therapeutic targeting of type I IFN in a subset of APS patients.

Objectives G protein-coupled receptors (GPCRs) participate in various pathophysiological processes in Sjögren’s disease (SjD); in particular, autoantibodies against muscarinic acetylcholine receptor 3 (M3R) inhibit the secretion of saliva and tears by exocrine glands. We aimed to identify autoantibodies targeting other muscarinic receptors in SjD and assess their potential functional relevance to signalling pathways. Methods Autoantibodies against all muscarinic acetylcholine receptor subtypes were investigated in the serum of patients with SjD (n = 347) using enzyme-linked immunosorbent assays (ELISAs). Healthy controls (HCs; n = 50), patients with non-Sjögren’s sicca syndrome (NSS; n = 44), and patients with other autoimmune diseases (AIDs; n = 67) served as controls. To analyse the functional role of muscarinic receptor autoantibodies against muscarinic acetylcholine receptors 1 to 3 and 5 (M1R, M2R, M3R, and M5R, respectively), purified immunoglobulin (Ig) G fractions from patients with SjD (n = 10) and HCs (n = 10) were examined in Chinese hamster ovary (CHO) cells transfected with the specific receptor using calcium mobilisation and cyclic adenosine monophosphate (cAMP) accumulation assays. Results IgG autoantibodies against M1R to M5R were significantly increased in patients with SjD compared with HCs (p ≤ .05) and detected in up to 30% of patients. A combination of anti-M2R, anti-M3R, and anti-M5R identified up to 31% of Ro/SSA-negative SjD cases, with 96% and 75% specificity for SjD vs HCs and SjD vs NSS, respectively. Functionally, purified IgG from SjD serum reduced calcium flux by up to 30% in M1R-, M3R-, and M5R-expressing CHO cells, whereas its effects on cAMP accumulation in M2R-transfected cells were absent. Conclusions The association between autoantibodies targeting M1R to M5R in patients with SjD and their functional quantification provides strong evidence that autoantibodies against all muscarinic receptor isotypes may have pathogenic relevance in SjD.

International wird das Sjögren-Syndrom jetzt als Sjögren’s disease (abgekürzt SjD) bezeichnet. Es sollte ein Konsensus gefunden werden, wie das Sjögren-Syndrom künftig im deutschsprachigen Raum benannt wird. Von den drei Fachgesellschaften im D‑A-CH-Raum (Deutsche Gesellschaft für Rheumatologie und Immunologie e. V. [DGRh], Österreichische Gesellschaft für Rheumatologie und Rehabilitation [ÖGR], Schweizerische Gesellschaft für Rheumatologie [SGR]) wurden die Autorinnen und Autoren dieses Manuskripts benannt, um die internationalen Empfehlungen für den deutschsprachigen Raum umzusetzen. Der Begriff „Sjögren-Erkrankung“ sollte „Sjögren-Syndrom“ ersetzen. Die englische Abkürzung „SjD“ (Sjögren Disease) sollte auch auf Deutsch als Abkürzung für „Sjögren-Erkrankung“ verwendet werden. Der Begriff „assoziiert“ sollte anstelle von „sekundär“ verwendet werden für eine Sjögren-Erkrankung, die in Verbindung mit einer anderen klassifizierbaren systemischen Autoimmunerkrankung auftritt.

BACKGROUND:Sjögren's syndrome is now referred to internationally as Sjögren's disease (abbreviated SjD). OBJECTIVES:The aim was to reach a consensus on how Sjögren's syndrome should be referred to in German-speaking countries in the future. MATERIAL AND METHODS:The authors of this manuscript were appointed by the three professional associations in the D‑A-CH region, the German Society for Rheumatology and Immunology (DGRh), the Austrian Society for Rheumatology (ÖGR) and the Swiss Society for Rheumatology (SGR) to implement the international recommendations for the German-speaking region. RESULTS:The term "Sjögren-Erkrankung" should replace "Sjögren-Syndrom." The English abbreviation "SjD" (Sjögren's disease) should also be used in German as an abbreviation for "Sjögren-Erkrankung." The term "associated" should be used instead of "secondary" for Sjögren's disease that occurs in conjunction with another classifiable systemic autoimmune disease.

OBJECTIVES:This study aims to provide an update of the European Alliance of Associations for Rheumatology (EULAR) rheumatoid arthritis (RA) management recommendations addressing the most recent insights. METHODS:An International Task Force was formed with a wide expertise and solicited 2 systemic literature research activities on the safety and efficacy of disease-modifying antirheumatic drugs (DMARDs). New evidence was discussed, considering the update from 2022. A voting process was applied to each item. Levels of evidence and strengths of recommendation were assigned, and participants voted on the levels of agreement. RESULTS:The task force agreed on 5 overarching principles and reduced the number of recommendations to 9 concerning use of conventional synthetic DMARDs (methotrexate [MTX], leflunomide, sulfasalazine); glucocorticoids (GCs); biological (b)DMARDs (tumour necrosis factor inhibitors [adalimumab, certolizumab pegol, etanercept, golimumab, infliximab], abatacept, rituximab, tocilizumab, sarilumab, including biosimilars) and targeted synthetic [ts]DMARDs (namely the Janus kinase inhibitors [JAKi] tofacitinib, baricitinib, filgotinib, upadacitinib). Guidance on monotherapy, combination therapy, treatment strategies (treat-to-target), and tapering following clinical remission is provided. Safety aspects, including risk of major cardiovascular events (MACEs) and malignancies, costs and sequencing of b/tsDMARDs were considered. Initially, MTX ideally in combination with short-term GCs is recommended; upon insufficient response after 3 to 6 months, a bDMARD should be added; after careful consideration of risks, including MACEs, malignancies and/or thrombo-embolic events, JAKi may also be considered. If the first bDMARD (or JAKi) fails, any other bDMARD (from another or the same class) or JAKi (considering risks) is recommended. With sustained remission, DMARDs may be tapered, but caution is required as stopping often leads to a flare. Levels of evidence and levels of agreement were high for most recommendations. CONCLUSIONS:These updated EULAR recommendations provide consensus on RA management based on currently available evidence regarding efficacy, safety, and cost.

IntroductionThe diagnosis of Sjögren’s disease (SjD) in patients without autoantibodies against Ro/SSA is a major challenge. We aimed to identify novel autoantibodies in SjD that may facilitate the diagnostic procedure for Ro/SSA negative SjD.MethodsIgG and IgA autoantibody reactivity of 94 potential candidate autoantigens for SjD, selected from a discovery screen of 1,629 human antigens coupled to Luminex beads and prior knowledge about potential biological relevance, were examined in serum of SjD patients (n=347) using Luminex and ELISA technology. Healthy (HC, n=118) and non-Sjögren’s sicca syndrome (NSS, n=44) individuals served as controls. To assess disease specificity, the novel autoantibodies were also measured in serum of patients with Rheumatoid Arthritis (RA, n=50), Systemic Lupus Erythematosus (SLE, n=49), and Systemic Sclerosis (SSc, n=37). Results45 novel autoantibodies were significantly (p ≤ 0.05) more prevalent in SjD than in HC and were detected in up to 19% of the SjD cohort. The most common autoantibodies were against CCL4, M5, TMPO and OAS3. Some of the novel autoantibodies were associated with extraglandular disease manifestations, such as anti-TONSL or anti-IL6 with pulmonary involvement. We have developed a three and five marker panel for the detection of Ro/SSA negative patients, consisting of anti-FNBP4, anti-SNRPC, anti-CCL4, anti-M3 and anti-KDM6B, which had a sensitivity of up to 46% with a specificity of 95% (SjD vs. HC). Both panels discriminate these patients from HC, whereas the three-marker more effectively differentiates between Ro/SSA negative patients and NSS.DiscussionNovel autoantibodies will facilitate the diagnosis of Ro/SSA negative patients with SjD, in particular our predictive panel will be useful in the diagnosis and differentiation of these patients from healthy and NSS individuals in a clinical context. In addition, the autoantibodies may also be useful for risk stratification of extraglandular manifestations.

Adaptive immunity relies on antibodies and memory B and T cells, with memory T cells providing "reactive memory". These cells either circulate in the blood or remain as tissue-resident memory T cells, yet the epigenetic mechanisms underlying their recall function and maintenance are not well understood. Here, we present a comprehensive analysis of 56 reduced representation bisulfite sequencing (RRBS) datasets from 22 memory CD4 and CD8 T-cell populations isolated from human bone marrow, intestine, spleen, lung, skin, and peripheral blood, including surface CD69-positive and CD69-negative cells. Our study reveals unique DNA hypomethylation patterns in tissue-resident memory T cells, particularly in regions associated with genes involved in tissue homing, residency, and transcription factors regulating recall effector memory. The methylomes and differential methylation signatures identified here serve as a valuable resource for understanding the epigenetic program of memory T lymphocytes, their roles in immunological recall, and their maintenance within specific tissues.

OBJECTIVES:This study aims to analyse potential relationships between European Alliance of Associations for Rheumatology (EULAR)/American College for Rheumatology (ACR) classification criteria domains and individual criteria items in a large systemic lupus erythematosus (SLE) patient cohort. Previous findings showed meaningful associations only within organ systems, but not across them. We seek to validate these findings and expand on them. METHODS:Cluster analysis was performed on the EULAR/ACR criteria domains in a cohort of 1196 patients with SLE. Criteria items were analysed as binary variables (ever present = 1, always absent = 0) and tested for associations using network analysis. RESULTS:The cluster analysis resulted in 10 clusters, but with no convincing patterns beyond antibody-organ relationships. Relevant correlations between items were found within the domains, but some associations between items of different domains still showed significant, if mostly weak associations with r values of 0.10 to 0.26. These included correlations between antibodies to double-stranded DNA and Sm, low complements and lupus nephritis, and between antiphospholipid antibodies and thrombocytopenia. Anti-Sm antibodies were also associated with alopecia and leukopenia, autoimmune haemolysis with seizures, and serositis with fever. Joint involvement was negatively correlated with lupus nephritis and thrombocytopenia. The network analysis showed fever and serositis detached from the other items, with items within organ domains grouped. CONCLUSIONS:This comprehensive analysis of relationships between the domains and items of the EULAR/ACR SLE classification criteria underlines the relevance of the domain structure. Overall, the data are more compatible with chance distribution than with fixed subsets of SLE.

Sjögren's disease (SjD) is a chronic autoimmune disorder in which sustained B-cell activation drives glandular injury and systemic complications. Epithelial stress and interferon tone amplify B-cell activating factor (BAFF)-dependent survival, skewing selection toward autoreactive clones in both glands and blood. In addition, single-cell B-cell receptor analyses have uncovered interferon-high endotypes with tissue-imprinted oligoclonality and biased isotype and light-chain usage. Within salivary glands, ectopic germinal centers and FcRL4⁺ B cells act as local 'training sites,' integrating Tfh/Tph help, CXCL13 cues, and BAFF/APRIL-NF-κB signaling to sustain plasmablast differentiation. Extrafollicular trajectories - double-negative and age-associated B cells - expand in IFN/TLR7 and IL-21 milieus, while regulatory B-cell restraint is diminished. Emerging data also implicate glycolysis and mTORC1-GLUT1 metabolism in sustaining B-cell hyperactivation. Chronic B-cell receptor signaling and clonal evolution provide a bridge to lymphoma risk. In this review, we outline how these converging pathways define molecular endotypes and propose a precision framework linking them to targeted therapy in SjD.

Personalized cell therapies for autoimmune diseases — such as autologous haematopoietic stem cell transplantation and chimeric antigen receptor-expressing T cells — have the potential to achieve sustained remission in patients with certain autoimmune diseases. The effective elimination of pathogenic lymphocytes and their subsequent repopulation with naive cells has been termed ‘immune reset’. In this Perspective, we trace the origins of the immune reset concept and its clinical, cellular and molecular definitions, and we review current attempts to identify biomarkers for long-term clinical remission in autoimmune diseases. Emerging data from clinical trials support the concept that higher probabilities of long-term remission can be achieved with therapies that can more deeply and broadly deplete B cells than the anti-CD20 antibody rituximab. A better understanding of the cellular and molecular basis for immune reset and the biomarkers associated with this state should accelerate progress towards the goal of restoring a non-autoimmune state and sustaining remission, while reducing the need for chronic immunosuppression. New immunotherapies have the potential to mediate a sustained remission from certain autoimmune diseases. This has been referred to as achieving an ‘immune reset’ in patients. Here, Junt and colleagues discuss how we can most accurately define the term immune reset and explain the challenges in identifying suitable biomarkers of long-term disease remission.