Clinical trials have indicated that immunoablation followed by autologous hematopoietic stem cell transplantation (ASCT) has the potential to induce clinical remission in patients with refractory systemic lupus erythematosus (SLE), but the mechanisms have remained unclear. We now report the results of a single-center prospective study of long-term immune reconstitution after ASCT in 7 patients with SLE. The clinical remissions observed in these patients are accompanied by the depletion of autoreactive immunologic memory, reflected by the disappearance of pathogenic anti–double-stranded DNA (dsDNA) antibodies and protective antibodies in serum and a fundamental resetting of the adaptive immune system. The latter comprises recurrence of CD31⁺CD45RA⁺CD4⁺ T cells (recent thymic emigrants) with a doubling in absolute numbers compared with age-matched healthy controls at the 3-year follow-up (P = .016), the regeneration of thymic-derived FoxP3⁺ regulatory T cells, and normalization of peripheral T-cell receptor (TCR) repertoire usage. Likewise, responders exhibited normalization of the previously disturbed B-cell homeostasis with numeric recovery of the naive B-cell compartment within 1 year after ASCT. These data are the first to demonstrate that both depletion of the autoreactive immunologic memory and a profound resetting of the adaptive immune system are required to reestablish self-tolerance in SLE. This trial was registered at www.clinicaltrials.gov as #NCT00742300.

Objectives Recent data debate the suitability of Helios, an Ikaros family member, as a marker for thymic-derived regulatory T cells (Treg). Nevertheless, Foxp3⁺ Helios⁺ Treg may be of particular relevance in mediating immune tolerance in chronic autoimmunity, such as systemic lupus erythematosus (SLE), as they possess enhanced suppressive function, compared to Foxp3⁺ Helios⁻ Treg. Methods Multicolour flow cytometry was performed to analyse Foxp3 and Helios expression in peripheral blood CD4 T cells from SLE patients, compared to healthy controls (HC) and systemic sclerosis (SSc) and rheumatoid arthritis (RA) patients. Cytokine production, chemokine receptor expression for CXCR3 and CCR4, basal signal transducer and activator of transcription 5 (STAT5)a phosphorylation levels and T-cell receptor (TCR) Vβ repertoire were analysed by flow cytometry, and the methylation status of the Foxp3 locus (Treg-specific demethylated region, TSDR) by real-time PCR. Results Frequencies of Foxp3⁺ Helios⁺ Treg, unlike Foxp3⁺ Helios⁻ T cells, were significantly increased in SLE patients and positively correlated with disease activity, whereas they were unaltered in SSc and RA patients. Compared to HC, Foxp3⁺ Helios⁺ Treg in SLE predominantly displayed a CD45RA⁻/CD31⁻/FoxP3^low memory phenotype with increased Ki-67 expression, enhanced basal pSTAT5a levels and a restricted TCR repertoire. Nonetheless, similar to HC, Foxp3⁺ Helios⁺ Treg in SLE lacked effector cytokine production, possessed a highly demethylated TSDR and expressed comparable levels of CXCR3 and CCR4. Conclusions Our data suggest that Helios-expressing Foxp3⁺ Treg with functional suppressive capacity and migratory potential into inflamed tissues are expanded in active SLE, presumably through γ-chain signalling cytokines and TCR stimulation, to compensate for autoreactive effector responses.

Systemic sclerosis (SSc) is an orphan disease characterised by autoimmunity, fibrosis of the skin and internal organs, and vasculopathy. SSc may be associated with high morbidity and mortality. In this narrative review we summarise the results of a systematic literature research, which was performed as part of the European Reference Network on Rare and Complex Connective Tissue and Musculoskeletal Diseases project, aimed at evaluating existing clinical practice guidelines or recommendations. Only in the domains ‘Vascular & Ulcers’ (ie, non-pharmacological approach to digital ulcer), ‘PAH’ (ie, screening and treatment), ‘Treatment’ and ‘Juveniles’ (ie, evaluation of juveniles with Raynaud’s phenomenon) evidence-based and consensus-based guidelines could be included. Hence there is a preponderance of unmet needs in SSc referring to the diagnosis and (non-)pharmacological treatment of several SSc-specific complications. Patients with SSc experience significant uncertainty concerning SSc-related taxonomy, management (both pharmacological and non-pharmacological) and education. Day-to-day impact of the disease (loss of self-esteem, fatigue, sexual dysfunction, and occupational, nutritional and relational problems) is underestimated and needs evaluation.

In 2023, 47,731 HCT (20,485 (42.9%) allogeneic and 27,246 (57.1%) autologous) in 43,902 patients were reported by 696 European centers. 6042 patients received advanced cellular therapies, 4888 of which were CAR-T. Compared to the previous year there was an increase in CAR-T (+52.5%), in allogeneic HCT (+7.8%) but none in autologous HCT (+0.4%). Main indications for allogeneic HCT were myeloid (11,748; 60.7%), lymphoid malignancies (4,850; 25.0%), and non-malignant disorders (2558; 13.2%). Use of allogeneic HCT increased for AML (+12.1%) and for NHL (+11.0%), particularly in T-NHL (+25.6%). Main indications for autologous HCT were lymphomas (7890; 32.2%), PCD (14,271; 58.2%), and solid tumors (1608; 6.6%) with recovering numbers for autoimmune diseases. In patients with allogeneic HCT, the use of sibling donors increased by +1.0%, haploidentical donors by +11.7%, and unrelated donors by +11.1%. Cord blood HCT decreased again by −5.4%. Pediatric HCT activity increased slightly (5455; +0.1%) with differences between allogeneic (4111; −0.5%) and autologous HCT (1344: +1.7%). Use of CAR-T increased to a cumulative total of 13,927 patients including patients treated for autoimmune diseases. Overall, numbers show a complete recovery from the pandemic dip with increased cellular therapy at the expense of autologous HCT. Allogeneic HCT activity focuses on myeloid malignancies.

The introduction of targeted biologic therapies has changed the treatment landscape for autoimmune diseases (ADs) substantially, but although these therapies provide more specificity, they require continuous administration, rarely restore organ function or reverse disability, and are not curative. Over the last 25 years, hematopoietic stem cell transplantation (HSCT) has been increasingly used to treat patients in whom the risk:benefit ratio of HSCT is acceptable. In contrast to chronic suppression of immune function, this intensive one-off procedure aims to provide treatment-free remissions by the reinduction of self-tolerance. The European Society for Blood and Marrow Transplantation (EBMT) Autoimmune Diseases Working Party (ADWP) has been central to development of this approach, with over 3,300 HSCT registrations for ADs. Recent data have improved the evidence base to support autologous HSCT in multiple sclerosis, systemic sclerosis, and Crohn's disease, along with a wide range of rarer disease indications, and autologous HSCT has become an integral part of treatment algorithms in various ADs.