Autoimmune diseases (AID) are driven by pathogenic IgG autoantibodies that sustain inflammation and tissue damage. Eliminating these autoantibodies can mitigate disease progression and improve outcomes. The neonatal Fc receptor (FcRn) prolongs IgG half-life by preventing lysosomal degradation and contributes to antigen presentation via immune complex internalization. FcRn inhibition (FcRni) accelerates IgG catabolism, reduces T cell activation, and has emerged as a transformative therapeutic strategy. While FcRni have already reshaped the treatment landscape for neurological and hematological disorders, their role in rheumatology remains under active investigation. This study aims to map the global FcRni clinical trial landscape and highlight their promise in rheumatic diseases.

We systematically searched Trialtrove database and ClinicalTrials.gov (2014–2024) using the keywords “FcRn inhibitors” and “target/FcRn”. Trials were included if they involved autoimmune indications with sufficient protocol details. Extracted variables included trial phase, status, therapeutic indication, region, sponsor, and outcomes. Descriptive statistics were summarized and visualized (Figure 1).

1. Global Clinical Trial Landscape of FcRni in AID

    Between 2014 and 2024, a total of 137 eligible trials were identified across 62 countries. Among them, 66 (48.2%) have been completed, while 52 (38.0%) remain ongoing or planned. Over the past decade, FcRni trials have expanded rapidly, particularly since 2018, with a pronounced surge from 2020 onward (Figure 1A-B). Early-phase studies dominate: 74 phase I–II trials (54%), reflecting the novelty and exploratory momentum of FcRni. Nine phase IV trials (6.5%)—all with efgartigimod—have been completed, mostly for generalized myasthenia gravis (gMG) and CIDP, with five conducted in China, highlighting China’s growing influence in late-stage validation.

    Geographic distribution (Figure 1C) reveals concentration in North America, Northern Europe, and East Asia, consistent with regions reporting higher autoimmune disease burdens and advanced clinical research capacity. China has emerged as a major contributor, launching 12 new trials in 2024 alone, reflecting both epidemiologic demand and strategic investment.

2. Therapeutic Areas and Indications

    FcRni trials span multiple specialties: neurology, hematology, dermatology, nephrology, endocrinology, and rheumatology (Figure 1D-E). Neurologic disorders represent the largest share (58%), followed by hematologic conditions such as immune thrombocytopenia (ITP) and warm autoimmune hemolytic anemia (wAIHA). Importantly, rheumatology is an expanding frontier, with 12 phase II–III trials underway in Sjögren’s syndrome (SS), systemic lupus erythematosus (SLE), systemic sclerosis (SSc), idiopathic inflammatory myopathies (IIM), rheumatoid arthritis (RA), and fibromyalgia syndrome (FMS). The leading agents are efgartigimod, nipocalimab, and rozanolixizumab, developed by argenx, Johnson & Johnson, and UCB, respectively.

3. Breakthroughs in Autoimmune Rheumatic Diseases (AIRD)

    Recent trial results underscore FcRni’s transformative potential in rheumatology. As for Sjögren’s syndrome (SS): The Phase 2 DHLIAS study (NCT04969812) of nipocalimab demonstrated significant improvements in ClinESSDAI and ESSDAI scores, alongside marked IgG and autoantibody reduction. Patients with high baseline anti-Ro/La titers benefited most. In 2024, these results led to FDA breakthrough designation for moderate-to-severe SS, a field with no approved systemic therapy. 

    As for idiopathic inflammatory myopathies (IIM): Preclinical and clinical data support FcRni efficacy. Efgartigimod reduced IgG-mediated pathology in murine models and improved refractory immune-mediated necrotizing myopathy in case reports. The Phase 2 proof-of-concept trial (NCT05523167) met its primary endpoint with significant gains in total improvement scores and safety. Subsequently, a Phase 3 trial was initiated in late 2024 across IIM subtypes, aiming to position FcRni as the first targeted therapy in this domain.

    Collectively, these findings illustrate FcRni’s ability to attenuate autoantibody-mediated pathology, restore organ function, and expand therapeutic options in diseases traditionally reliant on steroids and nonspecific immunosuppression.

The FcRn pathway has emerged as a critical immunologic checkpoint in IgG-driven autoimmunity. Our global clinical trial landscape analysis demonstrates rapid expansion of FcRni development across multiple specialties, with growing emphasis on rheumatology. Breakthrough results in SS and IIM highlight FcRni’s capacity to redefine treatment paradigms, offering precision immunomodulation with durable efficacy and manageable safety. With several Phase II–III studies underway, FcRn inhibitors are poised to become cornerstone therapies in rheumatology, addressing long-standing unmet needs and improving patient quality of life. Continued multinational collaboration and mechanistic exploration will be essential to fully harness their therapeutic promise.