Is a Functional Cure Possible in Autoimmune Diseases? Evidence from Trigger Eradication, Transplantation, and Cellular Therapies

Autoimmune diseases (AIDs) are a diverse group of conditions characterized by the breakdown of immune tolerance against self-antigens with ensuing chronic inflammation and progressive tissue injury [1, 2]. Traditionally, these diseases are thought to be incurable with treatment designed primarily at controlling the inflammatory activity aside from preventing irreversible damage and securing quality of life [3]. The natural course of many diseases, such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), systemic sclerosis (SSc), and immune thrombocytopenic purpura (ITP), has been well described to be chronic and relapsing, fluctuating between remission and flare-up, rather than resolving completely [4, 5].

There is growing evidence in recent decades that a ‘functional cure’ may be possible under specific conditions. This idea was first introduced in infectious diseases like HIV and is defined as a state of antiretroviral therapy (ART)-free HIV-infected patients who are asymptomatic and clinically stable, with normalization or stabilization of biomarkers for immunological activity [6]. When translated to autoimmunity would be the long-term clinical remission, without any immunosuppressive drugs and normalization of serological features (auto-antibodies and complement) [7]. In this review, we use the term “functional cure” in this operational sense, acknowledging that it does not imply complete eradication of genetic or immunologic susceptibility to disease relapse.

The plausibility of this phenomenon is supported by a number of clinical models. Among the most established models is clearance of infectious triggers like Helicobacter pylori with eradication leading to a complete or durable response in patients with ITP [8, 9]. A similar model applies to paraneoplastic syndromes, where curative treatment of the underlying cancer often causes remission of associated autoimmune findings (e.g., TIF1γ-related dermatomyositis [10, 11]).

Another area of interest is immune reconstitution after intense therapeutic regimens, such as autologous-hematopoietic stem cell transplant (HSCT), and most recently with advanced cellular therapies of chimeric antigen receptor T cells (CAR-T) [12, 13]. Randomized controlled trials in SSc have shown that HSCT may lead to durable remission and reduce the requirement for long-term immunosuppressive medication [14, 15]. Likewise, recent series on the use of CAR-T cells in both SLE and other such B-cell-mediated autoimmune diseases have shown remissions extending over 1 year off intervention [16, 17].

Besides the immunological approach, evidence for the influence of environmental and nutritional factors to modify autoimmunity is increasing. For instance, vitamin D functions as an immune response modulating agent that has been linked to down-regulation of the activity in an autoimmune disease [18]. Similarly, unprocessed vegan diets can contribute to persistent remission in SLE and Sjögren’s syndrome according to research [19].

Extracorporeal photopheresis (ECP) likewise appears as a promising immunomodulatory approach. While clinical trials in systemic sclerosis have failed to show clear-cut superiority over standard treatment, ECP is still a valuable physiologic model of immunologic tolerance induction attempts [20].

The purpose of this review is to describe at length the evidence on sustained remission and functional cure in ADs, breaking it down into five major axes: (1) eradication of infectious triggers, (2) immune reset through chemotherapy or autologous hematopoietic stem cell transplantation (aHSCT), (3) state-of-the-art cellular therapies; (4) Advanced environmental and nutritional approaches; and (5) remissions that happen within a cancer treatment setting as seen in paraneoplastic conditions. We deliberately focused on these five therapeutic axes—infectious trigger eradication, immune reset via HSCT or cytotoxic regimens, advanced cellular therapies, environmental and nutritional strategies, and paraneoplastic contexts—because each provides mechanistic insight into reversal of autoimmunity and sustained drug-free remission. Conventional synthetic and biological disease-modifying antirheumatic drugs (DMARDs) are essential for disease control and can lead to DMARD-free sustained remission in a subset of patients with rheumatoid arthritis and other diseases, but they have been extensively reviewed elsewhere and generally act as long-term suppressive rather than truly resetting interventions.

The present systematic review followed the PRISMA 2020 (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines [21]. The search strategy was conducted in PubMed/Medline, Embase, Scopus, Web of Science, and the Cochrane Library from their inception until September 2025 with no language restrictions applied. MeSH terms and key words were modified for each database but included five major axes: (1) eradication of infectious triggers including Helicobacter pylori, viruses or other bacteria; (2) immunological reset achieved through chemotherapy schemes or autologous HSCT; (3) advanced cell therapies comprising CAR-T, extracorporeal photopheresis so on; (4) environmental and nutritional interventions such as vitamin D supplementation, eating habits modification, microbiota manipulation; and paraneoplastic syndromes in which cancer treatment can led to disappearance of the cause-specific autoimmune artifact.

Inclusion criteria: Eligible studies were RCTs, meta-analysis, systematic reviews, observational (cohort and case–control), case series, and individual case reports reporting sustained remission or functional cure in autoimmune diseases. Only studies with a clear definition of sustained clinical remission, typically ≥ 6 months, were included and preferably trial discontinuation of immunosuppressive therapy (IST), with or without laboratory evidence for remission. Papers reporting partial improvement of disease activity without meeting remission criteria, follow-up less than 6 months, or those that did not report objective clinical and laboratory data were excluded.

One pivotal aspect of this review was to standardize the conceptual definitions being used: “Clinical remission” was determined as the absence of clinical signs and symptoms of disease activity by internationally established criteria for each disorder, including Disease Activity Score Calculator for Rheumatoid Arthritis (DAS28) < 2.6 for rheumatoid arthritis [22]. The Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2 K) = 0 for systemic lupus erythematosus [23], and stability of modified Rodnan skin score (mRSS) in systemic sclerosis [24]. “Complete remission” was defined as resolution of clinical symptoms and normality of all laboratory tests, including either negativity or stable values for autoantibodies, complement, and inflammatory markers. “Sustained remission” was defined as the persistence of these criteria for a minimum of 12 months. “Drug-free remission” referred to the maintenance of sustained remission off immunosuppressive agents and corticosteroids. Finally, “functional cure” was defined as the same condition as complete clinical remission for at least 12 months without immunosuppressive therapy, but also normal immunological biomarkers or stabilization of them and no new appearance of progressive damage during follow-up. These definitions were adopted from the respective international consensus papers: DORIS, for lupus [23], EULAR/ACR recommendations, for RA [22], and EUSTAR guidelines, for SSc [24] and applied transversally to all AD to make comparison across them viable. We recognize that not all primary studies used exactly these criteria; when different remission definitions were reported, we mapped their endpoints onto this framework (clinical, complete, sustained, drug-free remission or functional cure) as closely as possible and clarified these details in the corresponding tables.

Results were synthesized in a narrative and thematic structure along the five axes we had established. The CDS to foster an interpretation by which data collected in separate fields (infectious, immunological, cellular, environmental, and oncologic) were once again seen under one concept: the reversibility of autoimmunity and the restoration of self-tolerance.

This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.

Additional methodological details and extended content are available in the Supplementary Material.

The possibility of a functional cure in autoimmune diseases has ceased to be merely theoretical as different interventions have demonstrated the capacity to re-establish immunological tolerance and interrupt the cycle of self-aggression. Historically, autoimmunity was considered irreversible because it involves disruption of central and peripheral tolerance, with expansion of autoreactive T- and B-cell clones and cumulative tissue damage [1, 2]. However, advances in immunology, cell biology, and targeted therapies have shown that, under certain conditions, the immune system can be “rebooted” and return to a functional equilibrium similar to that observed in healthy individuals [3, 4].

The first line of evidence comes from the eradication of infectious triggers, especially Helicobacter pylori. The most established paradigm is immune thrombocytopenic purpura (ITP), in which the microorganism appears to act as a cofactor in triggering and perpetuating the autoreactive response against platelets. Meta-analyses show response rates exceeding 50% after eradication, often with sustained normalization of platelet counts and discontinuation of immunosuppressants [8, 9, 25]. The response is particularly marked in Asian and European countries, suggesting that genetic differences in the recognition of bacterial antigens and Fcγ receptor polymorphisms may modulate outcomes [8].

The most accepted pathophysiological mechanism is molecular mimicry, whereby H. pylori epitopes share structural homology with platelet glycoproteins (such as GPIIb/IIIa), leading to the production of autoantibodies. Bacterial elimination halts the antigenic stimulus and allows regulatory mechanisms—particularly regulatory T cells (Tregs) and IL-10 production—to restore peripheral tolerance [26‐28]. This phenomenon also applies to other diseases, such as psoriasis and lichen planus, in which the pathogen acts as a perpetuator of chronic inflammation [26‐28].

In Behçet’s disease, clinical improvement after H. pylori eradication reinforces the hypothesis that infectious agents maintain an abnormal immune response through continuous activation of Th1 and Th17 T cells [29]. Reports of remission in autoimmune thyroiditis after antibacterial therapy, although rare, suggest that the microbiota–mucosa axis may be crucial for systemic immune balance [31]. Although fragmented, these findings point to a fundamental principle: autoimmunity can be reversible when the antigenic trigger is removed early. This model underscores the role of chronic exposure to environmental antigens in maintaining the autoreactive state, offering a conceptual analogy to remission observed after viral eradication (such as chronic hepatitis) in other autoimmune conditions [6, 62].

The second line of evidence concerns immune reset achieved through chemotherapy regimens and autologous hematopoietic stem cell transplantation (HSCT). The ASTIS and SCOT trials in systemic sclerosis were landmarks in this field, showing that HSCT not only controls inflammation but also modifies the natural history of the disease [12, 13]. Ablative immunosuppression eliminates autoreactive clones, and subsequent regeneration of the lymphocyte repertoire from hematopoietic progenitors rebuilds a tolerogenic immune network [35, 51]. Immunophenotypic studies confirm that, after HSCT, there is an increase in Tregs, a decrease in Th17 cells, and normalization of the memory B-cell repertoire, which correlates with sustained clinical remission [58‐60].

In SLE, this phenomenon is particularly notable. International cohorts show that up to 60% of patients achieve long-term drug-free remission, some for more than 10 years, with the disappearance of anti-DNA autoantibodies and normalization of complement [14‐16]. These results support the hypothesis that, once “restarted,” the immune system can restore mechanisms of self-tolerance. Even so, early mortality related to conditioning regimen toxicity and opportunistic infections remains the main barrier to wider adoption [51].

In diseases such as multiple sclerosis, inflammatory myopathies, and Crohn’s disease, the same principles apply. Immune reset allows reconfiguration of the balance between effector and regulatory cells, reducing autoreactivity and promoting immune re-education [33‐35]. Experimental models of autoimmunity corroborate these findings, suggesting that after selective destruction of pathogenic T-cell clones and thymic regeneration, central tolerance is restored [57].

Advanced cellular therapies represent one of the most significant advances in the quest to restore immune tolerance. The introduction of CAR-T cells) targeting CD19—originally developed for hematologic malignancies—has opened a new perspective in the treatment of severe, refractory autoimmune diseases [16, 17]. The pioneering study by Mougiakakos et al. demonstrated that selective depletion of CD19⁺ B cells by CAR-T can abolish autoantibody production and induce sustained remission in patients with refractory SLE [16]. In 2024, Schett and colleagues expanded this experience to a larger series involving SLE, autoimmune myopathies, and SS, confirming the efficacy and safety of the approach [17]. The pathophysiological explanation involves eradication of autoreactive memory B-cell clones and regeneration of a tolerogenic B-cell repertoire [48].

This reconfiguration of the B-cell compartment is accompanied by restoration of Treg function and reduction of Th17 populations—both central to autoimmune inflammation [58, 60]. The phenomenon is analogous, albeit more selective, to what is observed after HSCT, constituting an immune “reset” without global ablative conditioning [48, 61]. In addition, anti-CD19 CAR-T cells appear to indirectly modulate costimulatory axes such as CD40/CD40L, interfering with T–B interaction and durably reducing autoimmunity [47]. Expansion of this technology includes the development of anti-BCMA and anti-CD20 CAR-T products, in early phases for diseases such as myasthenia gravis and neuromyelitis optica; although still preliminary, there are reports of sustained remission with follow-up of up to 2 years [48].

Another cellular approach, older and with a distinct immunomodulatory profile, is extracorporeal photopheresis (ECP). This procedure—which combines leukocyte collection, exposure to 8-methoxypsoralen and UVA light, and subsequent reinfusion—induces apoptosis of pathogenic lymphocytes and promotes immune tolerance [20, 37]. Trials and series in systemic sclerosis have shown clinical stabilization and microvascular improvement, albeit without robust superiority across all endpoints [20, 37]. Mechanistically, there is evidence of expansion of CD4⁺CD25⁺FoxP3⁺ Tregs and increased IL-10/TGF-β, cytokines associated with peripheral tolerance [58]. Although ECP rarely leads to complete remission, it represents a physiological model of gradual tolerance induction that may be replicated by new cellular and immunomodulatory therapies [61].

In the environmental and nutritional axis, vitamin D deserves emphasis for its multifaceted immunoregulatory role. In addition to promoting Treg differentiation and reducing expression of pro-inflammatory cytokines such as IL-17 and IFN-γ, it acts on the transcription of genes associated with tolerance [18, 38]. Clinical evidence suggests reduced activity in multiple autoimmune diseases and, in some cases, sustained remissions with prolonged supplementation [18]. Beyond vitamin D, dietary factors and the intestinal microbiota also appear to influence remission. Plant-based diets with lower saturated fat content modulate the microbiota and the production of short-chain fatty acids (SCFAs), exerting tolerogenic effects on Tregs and dendritic cells [19, 50, 56]. Studies of fecal microbiota transplantation (FMT) in ulcerative colitis and RA show promising results, with reports of sustained remission in subgroups [39]. Although still incipient, these data support the concept that the microbiota functions as an adaptive immunologic organ whose reprogramming may be equivalent to an immune “reset” [50, 56].

Finally, behavioral factors such as regular physical activity also modulate immunity; meta-analyses in autoimmune rheumatic diseases indicate reductions in systemic inflammation and potentially increased immunologic plasticity, favoring prolonged periods of remission [40].

Paraneoplastic syndromes constitute one of the most eloquent examples of the interconnection between antitumor immune responses and autoimmunity. In these settings, autoreactive activity arises as a consequence of a vigorous immune response against tumor antigens that mimic self-proteins. Thus, elimination of the tumor—via surgical resection, chemotherapy, or transplantation—often leads to resolution of the associated autoimmune manifestations [10, 11]. Dermatomyositis associated with solid tumors is the most studied model. Aberrant expression of antigens such as TIF1γ and NXP2 in tumors triggers cross-reactive immune responses; studies and clinical series show dermatomyositis remission after oncologic treatment, especially when the tumor is addressed early [10, 11, 41]. Thymoma-associated myasthenia gravis shares similar mechanisms, and thymectomy can result in sustained clinical remission [42].

These observations suggest that, in certain contexts, autoimmunity is an epiphenomenon of an antitumor response directed against shared antigens. When the tumoral stimulus disappears, the autoreactive response ceases—a principle analogous to that observed with eradication of chronic infections such as H. pylori [6, 25]. Cases of autoimmune hemolytic anemia and thrombocytopenic purpura secondary to lymphoma that enter remission after chemotherapy or allogeneic transplantation reinforce the notion that elimination of the neoplastic clone reduces chronic stimulation of autoreactive B cells [32]. Strikingly, there are reports of patients with concomitant SLE and lymphoma who achieved remission of both conditions after chemotherapy [30]. These findings reaffirm that the mechanisms shared between antitumor surveillance and loss of tolerance involve type I interferon pathways, immune checkpoints (CTLA-4/PD-1), and remodeling of the immune microenvironment [43, 44].

Study of these phenomena provides valuable insights into the balance between protective immunity and autoimmunity. Oncologic immunotherapies, such as checkpoint inhibitors, show that hyper-stimulation of antitumor immunity can induce de novo autoimmune diseases (immune-related adverse events, irAEs), highlighting how tenuous the boundaries are between cure and self-aggression [45, 52]. Interestingly, the reverse is also true: interventions that restore tolerance (such as anti-CD19 CAR-T cells or, in certain contexts, HSCT) may, in some cases, eliminate residual tumor clones—a bidirectional axis between autoimmunity and oncogenesis [17, 51].

This review has methodological limitations. First, most available evidence derives from case series and retrospective cohorts, which restricts generalizability. In addition, the definition of functional cure is not yet universally accepted, varying by disease and by the remission parameters used [22, 23]. Moreover, remission outcomes reported in the original trials and cohorts were heterogeneous; wherever possible we reclassified them according to current consensus definitions (DAS28, DORIS, EUSTAR), but this introduces some unavoidable imprecision when comparing across studies and therapeutic axes [66]. Heterogeneous follow-up among studies and the absence of biomarker standardization also hinder comparisons across different therapeutic axes [67].

Nevertheless, the strengths of this work lie in its breadth and conceptual integration: distinct approaches—infection-related, immunologic, cellular, and environmental—were analyzed within a single theoretical framework, that of autoimmunity reversibility [68]. This cross-cutting perspective allows us to understand that, regardless of the therapeutic method, functional cure depends on restoration of immunological tolerance, whether through elimination of antigenic triggers, reconfiguration of the lymphocyte repertoire, or environmental and metabolic modulation [67].

Prospects for the future of functional cure in autoimmune diseases are promising. Next-generation trials are already exploring combinations of cellular and biological strategies aimed at sustained remission with low toxicity [48]. The use of engineered regulatory T cells (CAR-Tregs) shows potential to induce antigen-specific tolerance in diseases such as type 1 diabetes and multiple sclerosis [58]. In parallel, epigenetic and metabolomic approaches are beginning to elucidate how environmental and nutritional factors shape the immune response and can be manipulated therapeutically [49]. Reprogramming of the intestinal microbiota, combined with immunologic interventions, is emerging as an integrative pillar between immunotherapy and preventive medicine [50, 56].

In the long term, redefining functional cure in autoimmune diseases will require objective, consensus parameters integrating clinical, serologic, immunologic, and molecular aspects. Thus, cure will cease to be a binary concept and will come to represent a continuum of functional restoration of the immune system.

The findings of this review show that functional cure in autoimmune diseases, though rare, is a biologically plausible phenomenon documented across multiple clinical contexts. Evidence indicates that autoimmunity can be reversed when its sustaining mechanisms—infection-related, cellular, metabolic, or neoplastic—are interrupted. Future studies are necessary with standardized definitions, predictive biomarkers, and long-term trials to expand the clinical application of this emerging paradigm.