Exchanging plasma exchange for a novel approach: The potential of FcRn antagonists in dermatologic autoimmune disease

By Warren R. Heymann, MD, FAAD
Nov. 1, 2023
Vol. 5, No. 44

Pemphigus vulgaris (PV) and pemphigus foliaceus (PF) are potentially life-threatening disorders demanding aggressive therapy with all the finesse and skill that dermatologists can muster. PV is characterized by IgG autoantibodies targeting desmoglein (Dsg)‐3, which is associated with mucosal lesions, and in 50% of cases, also with Dsg‐1, associated with skin lesions. PF lesions are skin-limited and are caused only by anti‐Dsg‐1 IgG. (1) Other autoantibodies against desmocollins, mitochondrial proteins, acetylcholine receptors, and others may be involved in the pathogenesis of PV and PF. (2) 

The current first-line treatments for PV and PF are corticosteroids and rituximab. (3) The litany of adverse reactions to these medications are well-known. Because of the crucial role IgGs play in the pathogenesis of these disorders, reducing the autoantibody levels by plasma exchange, immunoadsorption, and intravenous immunoglobulin (IVIg) have been used adjunctively in recalcitrant disease. IVIg infusion adverse events, including infusion site reactions, neurological and renal complications, and thrombotic events, may be severe. A safer alternative in decreasing pathogenic IgGs would be a major advance in PV and PF management.  

This commentary focuses on antagonizing the neonatal fragment crystallizable (Fc) receptor (FcRn) that has been likened to “plasma exchange in a bottle.” According to Tran, “During fetal life, this receptor participates in transfer of maternal antibodies across the placenta to the developing fetus, thus conferring passive immunity during the early period of neonatal life. In the adult, IgG (and albumin) is salvaged from intracellular degradation by FcRn, thus extending its half-life by 4-fold over that of immunoglobulins (eg, IgM or IgA) not recycled by FcRN.” (5) 

Ultrichts et al recognized that targeting the FcRn is an innovative, potentially more effective, safer, and convenient alternative for clearing pathogenic IgGs. They performed a randomized, double-blind, placebo-controlled first-in-human study in 62 healthy volunteers to explore single and multiple ascending intravenous doses of the FcRn antagonist efgartigimod. In humans, a single administration of efgartigimod reduced IgG levels up to 50%, while multiple dosing further lowered IgGs by an average of 75% of baseline levels. Approximately 8 weeks after the last administration, IgG levels returned to baseline. Efgartigimod did not alter the homeostasis of albumin or Igs other than IgG. No serious adverse events related to efgartigimod infusion were observed. (4) (Please note that I have no conflict of interest — financial or otherwise — with efgartigimod.) 

In December 2021, intravenous efgartigimod (Vyvgart) was approved for treating generalized myasthenia gravis in adults who are anti-acetylcholine receptor antibody positive. (6) Another formulation (efgartigimod alfa/hyaluronidase) is administered subcutaneously. What is the data regarding its use in pemphigus? 

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Goebeler et al enrolled 34 patients with mild-to-moderate PV vulgaris or PF in an open-label phase II adaptive trial. In sequential cohorts, intravenous efgartigimod was dosed at 10 or 25 mg/kg with various dosing frequencies as monotherapy or as add-on therapy to low-dose oral prednisone. Safety endpoints comprised the primary outcome. Adverse events were primarily mild (nasopharyngitis, headache, diarrhea), except for solitary cases of pneumonia and tooth infection. A major decrease in serum total IgG and anti-desmoglein autoantibodies was observed and correlated with improved Pemphigus Disease Area Index (PDAI) scores. Efgartigimod, as monotherapy or combined with prednisone, demonstrated early disease control in 28 of 31 (90%) patients after a median of 17 days. Optimized, prolonged treatment with efgartigimod in combination with a median dose of prednisone 0.26 mg/kg per day led to complete clinical remission in 14 of 22 (64%) patients within 2-41 weeks. The authors concluded that “efgartigimod was well tolerated and exhibited an early effect on disease activity and outcome parameters, providing support for further evaluation as a therapy for pemphigus.” (1) 

Werth et al performed a multicenter, open-label safety and tolerability phase 1b/2 trial using ALXN1830 (a humanized IgG4 antibody that blocks neonatal FcRn interactions with IgG) in patients aged ≥18 years with confirmed, active PV or PF. Dosing included 5 weekly intravenous doses of ALXN1830 (10 mg/kg) and follow-up through day 112 (study termination). Pharmacokinetics, pharmacodynamics, safety, and efficacy were evaluated by determining the change in the median PDAI. In this pilot study of 8 patients, 5 weekly infusions produced a rapid improvement in the PDAI score within 14 days of the first dose. PADI improvement increased further with reductions in IgG, circulating immune complexes of IgG, and anti-desmoglein antibodies without affecting albumin, IgM, IgA, or C-reactive protein levels. ALXN1830 was well-tolerated, with headache as the most common adverse event. One patient had an urticarial infusion reaction. Another patient experienced herpes simplex and MRSA infections complicated by acute kidney injury due to antibiotics; these were deemed to be serious adverse events unrelated to the study drug. The authors concluded that the FcRn is important in pemphigus biology, noting a potential for use of ALXN1830 in pemphigus treatment. (7) 

Mechanistically, efgartigimod may do more than decrease pathogenic IgG levels. Zakrewicz et al analyzed the role of FcRn in human keratinocytes treated with antibodies isolated from a PV patient or with recombinant anti-desmoglein-3 antibodies that induce pathogenic changes in desmosomes, such as loss of monolayer integrity, aberrant desmoglein-3 localization, and degradation of desmoglein-3. The authors demonstrated that efgartigimod stabilizes the keratinocyte monolayer, although the loss of desmoglein-3 is not prevented. Their data suggest that FcRn may also play a direct role in the pathogenesis of pemphigus at the level of the autoantibody target cells, the epidermal keratinocytes. (8) 

One of the joys of academic practice is receiving questions/comments/observations from former residents. Zoe Smith, currently at UCLA, sent me a text informing me that her attending dermatologist used efgartigimod successfully in a patient with granulomatosis and polyangiitis, wanting to know my thoughts. I had none but was motivated to learn more. Aside from pemphigus, efgartigimod is currently being investigated for other autoimmune disorders including bullous pemphigoid, chronic inflammatory demyelinating polyradiculoneuropathy, immune thrombocytopenia, and autoimmune myositis. (6) This is an active area of inquiry — justifiably so. The FcRn receptor antagonist rozanolixizumab (Rystiggo) is approved for patients with generalized myasthenia gravis who are acetylcholine receptor antibody positive or muscle-specific tyrosine kinase (anti-MuSK) antibody positive. Trials of novel FcRn antagonists such as nipocalimab and batoclimab are underway. (9) 

Tran is correct in stating “Long-term experience with efgartigimod [and newer FcRn antagonists] remains lacking and studies are needed to establish the role of efgartigimod in the acute setting. (5). Despite that sobering reality, I am optimistic about the vast therapeutic potential for these agents in dermatologic disorders due to IgG autoimmunity.  

Point to Remember: FcRn antagonists, currently approved for treating myasthenia gravis, show potential for treating pemphigus and other autoimmune diseases.  

Our experts’ viewpoints

Christoph T. Ellebrecht, MD, FAAD
Assistant Professor of Dermatology
University of Pennsylvania Perelman School of Medicine 

Dr. Heymann invited me to contribute my insights to his article focusing on the rapidly evolving realm of FcRn targeting therapies in autoimmune bullous diseases. 

The cornerstone hypothesis — from theory to therapeutic promise. 

The scientific community’s understanding of IgG catabolism has been substantially shaped by Brambell’s hypothesis. In 1964, Brambell, Hemmings, and Morris postulated that specific “protection receptors” for IgG, termed FcRp, played a crucial role in prolonging the survival of IgG compared to other plasma proteins. (10) According to their model, these receptors bind IgG and guide its transport back into the circulation. Only when these receptors reach their saturation point does excess IgG proceed to unrestricted lysosomal catabolism. Expanding on this, Brambell also theorized the existence of the neonatal gut transport receptor (FcRn), emphasizing its similar saturable attributes. 

Both FcRp and FcRn turned out to be same protein whose cloning in 1996 showcased an amazing trajectory of scientific discovery — from experimental observation to the development of a theoretical framework, culminating in the unveiling of a molecular mechanism that allowed the development of a rational and targeted therapeutic approach. This journey underscores the importance of basic research in the development of innovative treatment avenues for chronic, incurable diseases. 

Navigating the therapeutic landscape: Promises, concerns, and regulatory hurdles of FcRn-targeting therapies 

FcRn-targeting therapies offer a promising avenue to substantially decrease IgG levels, with reductions spanning 50-75% depending on the dosing regimen. This strategy can be advantageous in autoimmune conditions that respond positively to B cell depletion, such as myasthenia gravis, GPA (granulomatosis with polyangiitis), or multiple sclerosis, as referenced by Dr. Heymann. However, lowering total IgG levels presents a double-edged sword. Such a significant drop mirrors the IgG levels typically observed in patients with primary immunodeficiencies, predisposing them to heightened infection risks. Indeed, this susceptibility has manifested clinically, with infections such pneumonia, other respiratory, and urinary tract infections representing common adverse events of FcRn-targeting therapies. This is in contrast to a traditional FcRn-blocking agent: intravenous immunoglobulins (IVIg). Unlike FcRn-targeting therapies that significantly decrease IgG levels, IVIg provides a supplemental source of IgG. By blocking the FcRn receptor, it helps lower pathogenic antibody levels while simultaneously replacing protective IgG. This dual action can offer a safety net against the increased susceptibility to infections. However, IVIg can also cause side effects, such as headaches, fever and, in rare cases, more severe reactions like thrombosis. Additionally, IVIg treatments can be expensive and might not be easily accessible to all patients. 

As autoimmune bullous diseases are predominantly driven by pathogenic autoantibodies, they naturally represent promising indications for FcRn targeting therapies. Patients diagnosed with autoimmune bullous diseases, alongside their healthcare providers, are often faced with a nuanced choice: balancing the urgent need to alleviate the crippling symptoms of the disease against the potential risks inherent in therapeutic interventions. For instance, many of my pemphigus patients, upon achieving remission through rituximab therapy, find that the lingering side effects of prednisone can overshadow the original manifestations of the disease. In this backdrop, FcRn-targeting agents present themselves as a promising avenue. Their potential to act as a bridge to rituximab, allowing physicians to prescribe reduced prednisone doses in the interim, is indeed enticing. While efgartigimod, ALXN1830, and others offer hope for pemphigus patients, their use in elderly pemphigoid patients necessitates caution, given the potential risk of infections, which might overshadow their benefits. However, the therapy’s non-approval for pemphigus despite promising trials, as opposed to its FDA-approval for myasthenia gravis, underscores a significant debate: The criteria currently used to classify a pemphigus case as clear or almost-clear for assessing the therapeutic benefits appear overly strict, especially when compared to standards set for clinical trials of other autoimmune disorders with similar pathophysiology as pemphigus. Such rigorous guidelines might discourage pharmaceutical companies from furthering research in this direction, potentially delaying or even blocking approval for certain skin conditions.  

Concluding thoughts 

In summary, I perceive FcRn antagonists as a potential bridge to rituximab in pemphigus vulgaris or as an alternative for patients contraindicated for rituximab. By potentially enabling lower doses of prednisone during flares, these antagonists present a promising therapeutic avenue. As with all advancements in medicine, continued research, patient feedback, and regulatory considerations will shape the path forward. 

Matthias Goebeler, MD
Department of Dermatology, Venereology and Allergology
University Hospital Würzburg

Blocking FcRn: a novel approach to treat IgG-mediated bullous autoimmune disorders? 

Pemphigus vulgaris (PV) and pemphigus foliaceus (PF) are severe autoimmune diseases that frequently showed a fatal course in the pre-glucocorticoid era. The introduction of glucocorticoids, immunosuppressants, intravenous immunoglobulins (IvIg) and especially rituximab that depletes CD20-positive B lymphocytes, has led to substantial improvement in disease outcome. Nevertheless, further enhancement of therapeutic modalities for pemphigus disease is urgently needed: higher doses of steroids as well as immunosuppressants show a substantial risk for sometimes severe adverse effects; moreover, rituximab has a comparatively slow onset of action due to its mechanism of action and therefore usually requires bridging with glucocorticoids. In view of the sustained B-cell depletion caused by rituximab, it is also advisable to ensure prior comprehensive vaccination (especially against pneumococci, influenza, herpes zoster, and SARS-CoV-2 infections), which often considerably delays the start of rituximab application. Therefore, there is a high medical need for innovative therapeutic approaches that have fewer side effects and a better controllability and allow faster disease control of pemphigus. 

One such therapeutic strategy is the blockade of the neonatal Fc receptor, FcRn, which not only accomplishes the diaplacental transfer of immunoglobulin G (IgG) as well as albumin from mother to fetus during pregnancy, but also protects IgG from degradation throughout life, thus explaining the long half-life of IgGs in serum. (11) Considering its central role for IgG homeostasis, blockade of FcRn can reduce levels of circulating IgG including pathogenic IgG autoantibodies directed against Dsg3 and/or Dsg1, the autoantigens of PV and PF. Interestingly, the contribution of FcRn-mediated IgG recycling to the maintenance of serum IgG levels is significantly greater than that of IgG production; thus, FcRn appears to be a very attractive target for the therapy of blistering autoimmune dermatoses as well as of other IgG autoantibody-mediated diseases. 

Currently, the most extensively studied FcRn inhibitor in clinical trials is efgartigimod, a genetically engineered human IgG1 Fc fragment that binds with high affinity to the FcRn. In a multicenter adaptive phase II study, of 31 patients included in the efficacy analysis who received efgartigimod either as monotherapy or in combination with a low dose of prednisone, 28 (90%) showed disease control after a median of just 17 days. (1) In view of its good tolerability and its rapid mode of action, a multicenter placebo-controlled study (by the way, the largest controlled study conducted to date on pemphigus disease) was initiated. The recruitment to this study (ADDRESS study, NCT04598451) has been completed and first results are expected here in 2024.   

Importantly, another placebo-controlled multicenter study (BALLAD, NCT05267600) has been launched to study the efficacy and safety of efgartigimod in bullous pemphigoid (BP), which in Western countries is much more common than pemphigus. Individuals affected by BP are significantly older than pemphigus patients and accordingly more often suffer from relevant comorbidities, so that novel therapeutic approaches with low risk of adverse events are of particular importance in this patient group. The safety profile of efgartigimod appears to have the potential to deliver on this point. (12)  

Efgartigimod and other FcRn-blocking agents may be effective therapeutics with a good risk-benefit profile that hopefully will extend our armamentarium against IgG-autoantibody-mediated disease including pemphigus and other autoimmune bullous disorders. (13)  

1. Goebeler M, Bata-Csörgő Z, De Simone C, Didona B, Remenyik E, Reznichenko N, Stoevesandt J, Ward ES, Parys W, de Haard H, Dupuy P, Verheesen P, Schmidt E, Joly P; ARGX-113-1701 Investigator Study Group. Treatment of pemphigus vulgaris and foliaceus with efgartigimod, a neonatal Fc receptor inhibitor: a phase II multicentre, open-label feasibility trial. Br J Dermatol. 2022 Mar;186(3):429-439. doi: 10.1111/bjd.20782. Epub 2021 Nov 28. PMID: 34608631. 

2. Zakrzewicz A, Würth C, Beckert B, Feldhoff S, Vanderheyden K, Foss S, Andersen JT, Haard H, Verheesen P, Bobkov V, Tikkanen R. Stabilization of Keratinocyte Monolayer Integrity in the Presence of Anti-Desmoglein-3 Antibodies through FcRn Blockade with Efgartigimod: Novel Treatment Paradigm for Pemphigus? Cells. 2022 Mar 10;11(6):942. doi: 10.3390/cells11060942. Erratum in: Cells. 2022 May 20;11(10): PMID: 35326398; PMCID: PMC8946243. 

3. Heymann WR. Progress in pemphigus: Solidifying rituximab’s role. Dermatology World Insights and Inquiries 2021; vol 3, No 27. https://www.aad.org/dw/dw-insights-and-inquiries/archive/2021/progress-pemphigus-solidifying-rituximab-role 

4. Ulrichts P, Guglietta A, Dreier T, van Bragt T, Hanssens V, Hofman E, Vankerckhoven B, Verheesen P, Ongenae N, Lykhopiy V, Enriquez FJ, Cho J, Ober RJ, Ward ES, de Haard H, Leupin N. Neonatal Fc receptor antagonist efgartigimod safely and sustainably reduces IgGs in humans. J Clin Invest. 2018 Oct 1;128(10):4372-4386. doi: 10.1172/JCI97911. Epub 2018 Jul 24. PMID: 30040076; PMCID: PMC6159959. 

5. Tran MH. "Plasma exchange in a bottle": An overview of efgartigimod for apheresis practitioners. J Clin Apher. 2022 Oct;37(5):512-515. doi: 10.1002/jca.22002. Epub 2022 Aug 23. PMID: 35997018. 

6. Heo YA. Efgartigimod: First Approval. Drugs. 2022 Feb;82(3):341-348. doi: 10.1007/s40265-022-01678-3. Erratum in: Drugs. 2022 Apr;82(5):611. PMID: 35179720; PMCID: PMC8855644. 

7. Werth VP, Culton DA, Concha JSS, Graydon JS, Blumberg LJ, Okawa J, Pyzik M, Blumberg RS, Hall RP 3rd. Safety, Tolerability, and Activity of ALXN1830 Targeting the Neonatal Fc Receptor in Chronic Pemphigus. J Invest Dermatol. 2021 Dec;141(12):2858-2865.e4. doi: 10.1016/j.jid.2021.04.031. Epub 2021 Jun 12. PMID: 34126109. 

8. Zakrzewicz A, Würth C, Beckert B, Feldhoff S, Vanderheyden K, Foss S, Andersen JT, Haard H, Verheesen P, Bobkov V, Tikkanen R. Stabilization of Keratinocyte Monolayer Integrity in the Presence of Anti-Desmoglein-3 Antibodies through FcRn Blockade with Efgartigimod: Novel Treatment Paradigm for Pemphigus? Cells. 2022 Mar 10;11(6):942. doi: 10.3390/cells11060942. Erratum in: Cells. 2022 May 20;11(10): PMID: 35326398; PMCID: PMC8946243. 

9. Bhandari V, Bril V. FcRN receptor antagonists in the management of myasthenia gravis. Front Neurol. 2023 Aug 4;14:1229112. doi: 10.3389/fneur.2023.1229112. PMID: 37602255; PMCID: PMC10439012. 

10. Brambell FW, Hemmings WA, Morris IG. A Theoretical Model of Gamma-Globulin Catabolism. Nature. 1964;203:1352-1354. doi:10.1038/2031352a0 

11. Roopenian DC, Akilesh S. FcRn: the neonatal Fc receptor comes of age. Nat Rev Immunol 7, 715-725 (2007) 

12. Gwathmey K, Broome C, Goebeler M, Murai H, Bata-Csörgö Z, Newland A, Ulrichts P, Kerstens R, Guptill J, Agha S, Jiang M, Howard J. Overview of the Safety Profile from Efgartigimod Clinical Trials in Participants with Diverse IgG-Mediated Autoimmune Diseases. Neurology 100, 17 Supplement 2 (Abstract) (2023) 

13. Pyzik M, Kozicky L, Gandhi AK, Blumberg RS. The therapeutic age of the neonatal Fc receptor. Nat Rev Immunol 23, 415-432 (2023)  

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