Clinical and Immunological Changes Following Dupilumab Treatment in Patients with IgG4-related Disease

Clinical and Immunological Changes Following Dupilumab Treatment in Patients with IgG4-related Disease | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Case Report Clinical and Immunological Changes Following Dupilumab Treatment in Patients with IgG4-related Disease Youngsoo Lee, Min Sook Ryu, Eun-Mi Yang, Jae-Hyuk Jang, Hae-Sim Park This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8429734/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background IgG4-related disease is a rare, immune-mediated fibroinflammatory condition that affects multiple organs. Despite concerns over long-term side effects and relapse, glucocorticoids and immunosuppressants remain the standard treatment. This study assesses the efficacy of dupilumab, a monoclonal antibody targeting IL-4Rα that blocks type 2 helper T cell-mediated inflammation, in patients with IgG4-related disease. Case presentation: Five individuals diagnosed based on the 2019 ACR/EULAR classification criteria received dupilumab (600 mg initially, followed by 300 mg biweekly) and were monitored for up to 64 weeks. Clinical evaluations included organ/site scores, IgG4 scores, and the IgG4-related disease responder index. Laboratory analyses measured serum immunoglobulin levels, IgG subclasses, and IgG4-RD-related biomarkers. Four of the five patients showed clinical improvement and reduced IgG4 levels following dupilumab treatment. However, one patient (Patient 4) had an atypical response, with increased IgG4 levels despite therapy. Organ/site scores declined in four patients but remained high in Patient 4. Serum IgG4 levels significantly decreased in four patients, normalizing in 3. A notable inverse correlation was found between cumulative oral corticosteroid dosage and dupilumab treatment duration ( r = − 0.5455, P < 0.0001). Among the biomarkers, galectin-3 levels showed a significant decline at 32 weeks ( P < 0.05). Conclusions Dupilumab may offer therapeutic benefit in IgG4-related disease, although individual responses vary, underscoring the need for personalized treatment strategies. IgG4 IgG4-related disease dupilumab IL-4 receptor biomarker Galectin-3 Figures Figure 1 Figure 2 Background IgG4-related disease (IgG4-RD) is a rare, immune-mediated fibroinflammatory condition affecting multiple organs [ 1 ]. Current first-line treatment with glucocorticoids, while effective, is associated with substantial long-term adverse effects and frequent disease relapses upon dose tapering [ 2 ]. Given the emerging role of type 2 T helper cell responses and IL-4/IL-13 signaling in IgG4-RD pathogenesis [ 3 ], we investigated the therapeutic potential of dupilumab, an IL-4 receptor α antagonist [ 4 ], in five patients with IgG4-RD. Several biomarkers have been reported in patients with IgG4-RD. Galectin-3, a β-galactoside-binding lectin is emerged as a biomarker or direct therapeutic target in fibrotic inflammatory diseases [ 5 ]. The average number of galectin-3 positive cells was higher in various organs of IgG4-RD patients, including salivary glands, lungs, and lymph nodes than in controls, and serum galectin-3 levels were higher in patients with IgG4-RD than in healthy donors [ 6 ]. Additionally, TGF-β, periostin, thymus and activation-regulated chemokine (TARC), eotaxin-2 and galectin-10 have been reported as potential biomarkers in patients with IgG4-RD [ 7 – 9 ]. To date, there are limited data on the efficacy of dupilumab in IgG4-RD. This prospective trial aims to evaluate the efficacy and safety of dupilumab treatment on clinical symptoms, serological markers, and biomarkers in 5 patients with IgG4-RD over a follow-up period of up to 64 weeks. Case presentation We enrolled five patients (Table) diagnosed according to the 2019 ACR/EULAR classification criteria [ 10 ]. All patients received subcutaneous dupilumab following the standard dosing regimen (600 mg loading dose, then 300 mg biweekly) for 52 weeks with extended follow-up to 64 weeks. Patient 1 was a 64-year-old man with allergic rhinitis and diabetes mellitus, who had an elevated serum IgG4 level (602 mg/dL). CT scans revealed mass lesions in the orbits, lacrimal glands, and pancreas. Patient 2 was a 33-year-old woman with atopic dermatitis and a mildly elevated serum IgG4 level (199 mg/dL). Mass lesions were identified in the lymph nodes. Patient 3 was a 66-year-old woman with allergic rhinitis, atopic dermatitis, and urticaria, along with markedly elevated serum IgG4 levels (1,850 mg/dL). Mass lesions were observed in the orbits, lacrimal glands, and salivary glands. Patient 4 was a 72-year-old man with a history of smoking, hypertension, diabetes mellitus, and allergic rhinitis. His serum IgG4 level was elevated (668 mg/dL), and CT imaging showed mass lesions in the orbits, lacrimal glands, and salivary glands. Patient 5 was a 19-year-old man with no significant medical history and a serum IgG4 level of 193 mg/dL. CT scans revealed a solitary mass in the small bowel, and endoscopic biopsy findings were compatible with IgG4-RD. Four patients (80%) demonstrated significant clinical improvement with decreased organ/site scores (Fig. 1 a), IgG4 scores (Fig. 1 b), and IgG4-RD Responder Index values (Fig. 1 c). Serum IgG4 levels substantially decreased in these responders, being normalized in three patients (Fig. 1 d). Remarkably, patients achieved meaningful oral corticosteroid (OCS) reduction (Fig. 1 e). We observed a significant inverse correlation between cumulative OCS dose and dupilumab treatment duration ( r = − 0.5455, P < 0.0001; Fig. 1 f). However, one patient (patient 4) exhibited an atypical response with persistent disease activity and paradoxically increased IgG4 levels, peaking at approximately 2,200 mg/dL around week 36. This heterogeneous response underscores the complex pathophysiology of IgG4-RD and suggests that distinct immunopathological mechanisms may be operative in different individuals. When serum biomarkers associated with IgG4-RD were measured by ELISA, galectin-3 levels decreased significantly at week 32 ( P < 0.05, Fig. 2 a); TARC levels decreased in four patients (Fig. 2 b), while no significant changes were noted in serum galectin-10/periostin/eotaxin-3/TGF-β levels (Fig. 2 c-f). Discussion This study provides preliminary evidence supporting the potential clinical efficacy of dupilumab in treating IgG4-RD, based on clinical outcomes from five patients. Four of the five patients demonstrated improvement in clinical symptoms, reduction in serum IgG4 levels, and successful tapering of OCS following dupilumab therapy. However, one patient (Patient 4) exhibited an atypical response, characterized by persistent disease activity and increasing serum IgG4 levels despite treatment. Dupilumab specifically targets T2-driven inflammation by blocking IL-4Rα. IL-4 promotes IgE and IgG4 production through activation of STAT6 signaling in B cells [ 11 ]. By blocking IL-4Rα, dupilumab inhibits this pathway, potentially reducing the synthesis of IgG4. However, incomplete responses observed in Patient 4 underscore that additional mechanisms are involved in the pathogenesis and clinical course of IgG4-RD. Nonetheless, the marked reductions in serum IgG4 levels observed in the four clinical responders support the hypothesis that T2 cytokines, particularly IL-4, play a pivotal role in IgG4 class switching in IgG4-RD [ 12 ]. The ability to reduce or discontinue OCS in the four patients represent a clinically meaningful benefit of dupilumab treatment. Long-term OCS use is associated with an array of adverse effects, including osteoporosis, diabetes, hypertension, and an increased risk of multiple infections [ 13 ]. The observed inverse correlation between cumulative OCS dose and dupilumab treatment duration suggests that dupilumab may serve as a steroid-sparing agent in clinically responsive patients. Among the biomarkers evaluated, galectin-3 showed the most consistent change, with significant decreases observed in all patients after 32 weeks of dupilumab treatment in this study. Elevated serum levels of galectin-3 have been reported in patients with IgG4-RD, which further increase during steroid treatment [ 6 ]. These findings could suggest that galectin-3 levels may reflect reduced fibrotic activity in response to dupilumab. However, the absence of consistent changes in other biomarkers, such as TARC, galectin-10, periostin, eotaxin-3, and TGF-β, indicates that the effect of dupilumab on IgG4-RD is complicated and may involve multiple pathways beyond T2 inflammation, warranting further investigation. The atypical response observed in Patient 4 merits special attention. Despite dupilumab therapy, this patient experienced persistently elevated disease activity and a paradoxical increase in serum IgG4 levels. Several hypotheses may explain this phenomenon: (1) The patient’s IgG4-RD may be primarily driven by non-T2 immune mechanisms, rendering IL-4Rα blockade ineffective; (2) the patient may have developed neutralizing antibodies against dupilumab, although this was not assessed in our study; (3) there may be compensatory upregulation of alternative pathways that promote IgG4 production, such as IL-10 or IL-21 [ 14 ]. Our study has several limitations. First, the small sample size restricts the generalizability of our findings and precludes definitive conclusions about the clinical efficacy of dupilumab in IgG4-RD. However, recruiting study subjects was challenging due to the very low prevalence of the disease. Second, the lack of a control group limits our ability to distinguish treatment effects from the natural disease course. Third, we did not perform tissue biopsies before or after treatment, which would have allowed the assessment of histopathological changes. Fourth, neutralizing antibodies against dupilumab were not measured, which could potentially impact treatment efficacy. Finally, although the follow-up period was longer than in many studies, it may still be insufficient to evaluate long-term clinical outcomes and potential late relapses. Despite these limitations, our findings offer valuable insights into the potential role of dupilumab in the management of IgG4-RD and underscore the heterogeneity of treatment responses. Future research should aim to identify predictive biomarkers of clinical response to dupilumab and elucidate the immunological mechanisms underlying the observed effects. This study suggests that dupilumab may be beneficial for patients with IgG4-RD, contributing to clinical improvement, reductions in serum IgG4 levels, and decreased OCS dependence. The atypical response observed in one patient underscores the importance of close clinical monitoring and the need to consider alternative therapeutic strategies for potential non-responders. The observed heterogeneity in clinical responsiveness highlights the complex immunopathology of IgG4-RD and supports the need for personalized treatment approaches. Conclusion The observed treatment heterogeneity, particularly the non-response in one patient, highlights the need for personalized therapeutic approaches and identification of predictive biomarkers to optimize patient selection. Future studies should focus on elucidating the immunological mechanisms underlying variable treatment responses and developing strategies to identify patients most likely to benefit from dupilumab therapy. Abbreviations IgG4-RD IgG4-related disease OCS Oral corticosteroid TARC Thymus and activation-regulated chemokine Declarations Ethics approval and consent to participate Informed written consent were obtained from patients. Consent for publication Not applicable Competing interests All authors declare no competing financial and nonfinancial interests. Funding This study was supported by Sanofi-Aventis Korea and the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), which is funded by the Ministry of Health & Welfare, South Korea (grant numbers: HR16C0001 and RS-2024-00439277). Author Contribution H-S Park and Y Lee were involved in the study design. MS Ryu and E-M Yang performed research and analyzed data. MS Ryu and Y Lee wrote the draft of the manuscript. H-S Park, Y Lee, and J-H Jang recruited study subjects. H-S Park supervised all the study processes. Acknowledgement The study was approved by the Institutional Review Board of Ajou University Hospital (AJIRB-MED-BDR-21-011). We thank the patients in this study and the clinical staff for assisting in patient care and data collection. References Kamisawa T, Zen Y, Pillai S, Stone JH. IgG4-related disease. Lancet. 2015;385(9976):1460–71. Khosroshahi A, Wallace ZS, Crowe JL, Akamizu T, Azumi A, Carruthers MN, et al. International Consensus Guidance Statement on the Management and Treatment of IgG4-Related Disease. Arthritis Rheumatol. 2015;67(7):1688–99. Della-Torre E, Lanzillotta M, Doglioni C. Immunology of IgG4-related disease. Clin Exp Immunol. 2015;181(2):191–206. Gandhi NA, Bennett BL, Graham NM, Pirozzi G, Stahl N, Yancopoulos GD. Targeting key proximal drivers of type 2 inflammation in disease. Nat Rev Drug Discov. 2016;15(1):35–50. Bouffette S, Botez I, De Ceuninck F. Targeting galectin-3 in inflammatory and fibrotic diseases. Trends Pharmacol Sci. 2023;44(8):519–31. Salah A, Yoshifuji H, Ito S, Kitagori K, Kiso K, Yamada N, et al. High Expression of Galectin-3 in Patients with IgG4-Related Disease: A Proteomic Approach. Patholog Res Int. 2017;2017:9312142. Ohta N, Kurakami K, Ishida A, Furukawa T, Suzuki Y, Aoyagi M, et al. Roles of TGF-beta and periostin in fibrosclerosis in patients with IgG4-related diseases. Acta Otolaryngol. 2013;133(12):1322–7. Iaccarino L, Talarico R, Bozzalla-Cassione E, Burmester GR, Culver EL, Doria A, et al. Blood biomarkers recommended for diagnosing and monitoring IgG4-related disease. Considerations from the ERN ReCONNET and collaborating partners. Clin Exp Rheumatol. 2022;40(Suppl 134):71–80. Amano S, Nishiguchi S, Mochida Y, Teshima S, Ueki S. IgG4-related disease with eosinophil extracellular traps. QJM. 2025;118(6):457–9. Wallace ZS, Naden RP, Chari S, Choi HK, Della-Torre E, Dicaire JF, et al. The 2019 American College of Rheumatology/European League Against Rheumatism classification criteria for IgG4-related disease. Ann Rheum Dis. 2020;79(1):77–87. Gould HJ, Sutton BJ. IgE in allergy and asthma today. Nat Rev Immunol. 2008;8(3):205–17. Jeannin P, Lecoanet S, Delneste Y, Gauchat JF, Bonnefoy JY. IgE versus IgG4 production can be differentially regulated by IL-10. J Immunol. 1998;160(7):3555–61. Liu D, Ahmet A, Ward L, Krishnamoorthy P, Mandelcorn ED, Leigh R, et al. A practical guide to the monitoring and management of the complications of systemic corticosteroid therapy. Allergy Asthma Clin Immunol. 2013;9(1):30. Lighaam LC, Rispens T. The Immunobiology of Immunoglobulin G4. Semin Liver Dis. 2016;36(3):200–15. Tables Table. Demographics and characteristics of the study subjects. Variables Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Age, year (sex) 64 (male) 33 (female) 66 (female) 72 (male) 19 (male) Body mass index, kg/m 2 21.3 31.1 25.0 22.2 20.5 History and comorbidity Smoking No No No Ex-smoker No Hypertension No No No Yes No Diabetes mellitus Yes No No Yes No Allergic rhinitis Yes No Yes Yes No Atopic dermatitis No Yes Yes No No Involved organ (sclerosis/mass formation) Orbits and lacrimal glands, pancreas Lymph nodes Orbits and lacrimal glands, salivary glands Orbits and lacrimal glands, salivary glands Small bowel Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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1","display":"","copyAsset":false,"role":"figure","size":570334,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eTime course of clinical/ laboratory changes in 5 patients with IgG4-RD following dupilumab treatment. \u003c/strong\u003eChanges in organ/site score (a), IgG4 score (b), IgG4-RD Responder Index (c), serum IgG4 levels (d), and cumulative OCS dose (e) are shown. A significantly negative correlation was observed between cumulative OCS dose and the duration of dupilumab therapy (f).\u003c/p\u003e","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8429734/v1/3a3a3cec68c895884ae98cef.jpeg"},{"id":100583284,"identity":"35da54ca-bb26-49e5-908f-4f259469778e","added_by":"auto","created_at":"2026-01-19 11:31:30","extension":"jpeg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":412886,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eChanges in serum biomarkers in 5 patients with IgG4-RD after 32 weeks of dupilumab treatment.\u003c/strong\u003e Serum levels of galectin-3 (a), TARC (b), galectin-10 (c), periostin (d), eotaxin-3 (e), and TGF-β (f) were measured at baseline and at 32 weeks. \u003cem\u003eP-\u003c/em\u003evalues were calculated using the Mann–Whitney U test. \u003csup\u003e*\u003c/sup\u003e\u003cem\u003eP\u003c/em\u003e \u0026lt; 0.05 indicates a statistically significant difference between baseline and 32 weeks.\u003c/p\u003e","description":"","filename":"floatimage2.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8429734/v1/a9f0385878f6271cf0592782.jpeg"},{"id":102748596,"identity":"d8094758-91e2-408a-b150-50ef011455bc","added_by":"auto","created_at":"2026-02-16 09:11:15","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1490987,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8429734/v1/8adb05c3-0ce5-476c-932a-4267dc11c6bf.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Clinical and Immunological Changes Following Dupilumab Treatment in Patients with IgG4-related Disease","fulltext":[{"header":"Background","content":"\u003cp\u003eIgG4-related disease (IgG4-RD) is a rare, immune-mediated fibroinflammatory condition affecting multiple organs [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Current first-line treatment with glucocorticoids, while effective, is associated with substantial long-term adverse effects and frequent disease relapses upon dose tapering [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Given the emerging role of type 2 T helper cell responses and IL-4/IL-13 signaling in IgG4-RD pathogenesis [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e], we investigated the therapeutic potential of dupilumab, an IL-4 receptor α antagonist [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e], in five patients with IgG4-RD.\u003c/p\u003e \u003cp\u003eSeveral biomarkers have been reported in patients with IgG4-RD. Galectin-3, a β-galactoside-binding lectin is emerged as a biomarker or direct therapeutic target in fibrotic inflammatory diseases [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. The average number of galectin-3 positive cells was higher in various organs of IgG4-RD patients, including salivary glands, lungs, and lymph nodes than in controls, and serum galectin-3 levels were higher in patients with IgG4-RD than in healthy donors [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Additionally, TGF-β, periostin, thymus and activation-regulated chemokine (TARC), eotaxin-2 and galectin-10 have been reported as potential biomarkers in patients with IgG4-RD [\u003cspan additionalcitationids=\"CR8\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eTo date, there are limited data on the efficacy of dupilumab in IgG4-RD. This prospective trial aims to evaluate the efficacy and safety of dupilumab treatment on clinical symptoms, serological markers, and biomarkers in 5 patients with IgG4-RD over a follow-up period of up to 64 weeks.\u003c/p\u003e"},{"header":"Case presentation","content":"\u003cp\u003eWe enrolled five patients (Table) diagnosed according to the 2019 ACR/EULAR classification criteria [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. All patients received subcutaneous dupilumab following the standard dosing regimen (600 mg loading dose, then 300 mg biweekly) for 52 weeks with extended follow-up to 64 weeks. Patient 1 was a 64-year-old man with allergic rhinitis and diabetes mellitus, who had an elevated serum IgG4 level (602 mg/dL). CT scans revealed mass lesions in the orbits, lacrimal glands, and pancreas. Patient 2 was a 33-year-old woman with atopic dermatitis and a mildly elevated serum IgG4 level (199 mg/dL). Mass lesions were identified in the lymph nodes. Patient 3 was a 66-year-old woman with allergic rhinitis, atopic dermatitis, and urticaria, along with markedly elevated serum IgG4 levels (1,850 mg/dL). Mass lesions were observed in the orbits, lacrimal glands, and salivary glands. Patient 4 was a 72-year-old man with a history of smoking, hypertension, diabetes mellitus, and allergic rhinitis. His serum IgG4 level was elevated (668 mg/dL), and CT imaging showed mass lesions in the orbits, lacrimal glands, and salivary glands. Patient 5 was a 19-year-old man with no significant medical history and a serum IgG4 level of 193 mg/dL. CT scans revealed a solitary mass in the small bowel, and endoscopic biopsy findings were compatible with IgG4-RD. Four patients (80%) demonstrated significant clinical improvement with decreased organ/site scores (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ea), IgG4 scores (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eb), and IgG4-RD Responder Index values (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ec). Serum IgG4 levels substantially decreased in these responders, being normalized in three patients (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ed). Remarkably, patients achieved meaningful oral corticosteroid (OCS) reduction (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ee). We observed a significant inverse correlation between cumulative OCS dose and dupilumab treatment duration (\u003cem\u003er\u003c/em\u003e\u0026thinsp;=\u0026thinsp;\u0026minus;\u0026thinsp;0.5455, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.0001; Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ef). However, one patient (patient 4) exhibited an atypical response with persistent disease activity and paradoxically increased IgG4 levels, peaking at approximately 2,200 mg/dL around week 36. This heterogeneous response underscores the complex pathophysiology of IgG4-RD and suggests that distinct immunopathological mechanisms may be operative in different individuals.\u003c/p\u003e \u003cp\u003eWhen serum biomarkers associated with IgG4-RD were measured by ELISA, galectin-3 levels decreased significantly at week 32 (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05, Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ea); TARC levels decreased in four patients (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eb), while no significant changes were noted in serum galectin-10/periostin/eotaxin-3/TGF-β levels (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ec-f).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis study provides preliminary evidence supporting the potential clinical efficacy of dupilumab in treating IgG4-RD, based on clinical outcomes from five patients. Four of the five patients demonstrated improvement in clinical symptoms, reduction in serum IgG4 levels, and successful tapering of OCS following dupilumab therapy. However, one patient (Patient 4) exhibited an atypical response, characterized by persistent disease activity and increasing serum IgG4 levels despite treatment.\u003c/p\u003e \u003cp\u003eDupilumab specifically targets T2-driven inflammation by blocking IL-4Rα. IL-4 promotes IgE and IgG4 production through activation of STAT6 signaling in B cells [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. By blocking IL-4Rα, dupilumab inhibits this pathway, potentially reducing the synthesis of IgG4. However, incomplete responses observed in Patient 4 underscore that additional mechanisms are involved in the pathogenesis and clinical course of IgG4-RD. Nonetheless, the marked reductions in serum IgG4 levels observed in the four clinical responders support the hypothesis that T2 cytokines, particularly IL-4, play a pivotal role in IgG4 class switching in IgG4-RD [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. The ability to reduce or discontinue OCS in the four patients represent a clinically meaningful benefit of dupilumab treatment. Long-term OCS use is associated with an array of adverse effects, including osteoporosis, diabetes, hypertension, and an increased risk of multiple infections [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. The observed inverse correlation between cumulative OCS dose and dupilumab treatment duration suggests that dupilumab may serve as a steroid-sparing agent in clinically responsive patients.\u003c/p\u003e \u003cp\u003eAmong the biomarkers evaluated, galectin-3 showed the most consistent change, with significant decreases observed in all patients after 32 weeks of dupilumab treatment in this study. Elevated serum levels of galectin-3 have been reported in patients with IgG4-RD, which further increase during steroid treatment [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. These findings could suggest that galectin-3 levels may reflect reduced fibrotic activity in response to dupilumab. However, the absence of consistent changes in other biomarkers, such as TARC, galectin-10, periostin, eotaxin-3, and TGF-β, indicates that the effect of dupilumab on IgG4-RD is complicated and may involve multiple pathways beyond T2 inflammation, warranting further investigation.\u003c/p\u003e \u003cp\u003eThe atypical response observed in Patient 4 merits special attention. Despite dupilumab therapy, this patient experienced persistently elevated disease activity and a paradoxical increase in serum IgG4 levels. Several hypotheses may explain this phenomenon: (1) The patient\u0026rsquo;s IgG4-RD may be primarily driven by non-T2 immune mechanisms, rendering IL-4Rα blockade ineffective; (2) the patient may have developed neutralizing antibodies against dupilumab, although this was not assessed in our study; (3) there may be compensatory upregulation of alternative pathways that promote IgG4 production, such as IL-10 or IL-21 [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eOur study has several limitations. First, the small sample size restricts the generalizability of our findings and precludes definitive conclusions about the clinical efficacy of dupilumab in IgG4-RD. However, recruiting study subjects was challenging due to the very low prevalence of the disease. Second, the lack of a control group limits our ability to distinguish treatment effects from the natural disease course. Third, we did not perform tissue biopsies before or after treatment, which would have allowed the assessment of histopathological changes. Fourth, neutralizing antibodies against dupilumab were not measured, which could potentially impact treatment efficacy. Finally, although the follow-up period was longer than in many studies, it may still be insufficient to evaluate long-term clinical outcomes and potential late relapses. Despite these limitations, our findings offer valuable insights into the potential role of dupilumab in the management of IgG4-RD and underscore the heterogeneity of treatment responses. Future research should aim to identify predictive biomarkers of clinical response to dupilumab and elucidate the immunological mechanisms underlying the observed effects.\u003c/p\u003e \u003cp\u003eThis study suggests that dupilumab may be beneficial for patients with IgG4-RD, contributing to clinical improvement, reductions in serum IgG4 levels, and decreased OCS dependence. The atypical response observed in one patient underscores the importance of close clinical monitoring and the need to consider alternative therapeutic strategies for potential non-responders. The observed heterogeneity in clinical responsiveness highlights the complex immunopathology of IgG4-RD and supports the need for personalized treatment approaches.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThe observed treatment heterogeneity, particularly the non-response in one patient, highlights the need for personalized therapeutic approaches and identification of predictive biomarkers to optimize patient selection. Future studies should focus on elucidating the immunological mechanisms underlying variable treatment responses and developing strategies to identify patients most likely to benefit from dupilumab therapy.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eIgG4-RD\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;IgG4-related disease\u003c/p\u003e\n\u003cp\u003eOCS\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Oral corticosteroid\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTARC \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Thymus and activation-regulated chemokine\u003c/p\u003e"},{"header":"Declarations","content":" \u003ch2\u003eEthics approval and consent to participate\u003c/h2\u003e \u003cp\u003eInformed written consent were obtained from patients.\u003c/p\u003e \u003cp\u003e \u003cstrong\u003eConsent for publication\u003c/strong\u003e \u003cp\u003eNot applicable\u003c/p\u003e \u003cp\u003e \u003cstrong\u003eCompeting interests\u003c/strong\u003e \u003cp\u003eAll authors declare no competing financial and nonfinancial interests.\u003c/p\u003e \u003ch2\u003eFunding\u003c/h2\u003e \u003cp\u003eThis study was supported by Sanofi-Aventis Korea and the Korea Health Technology R\u0026amp;D Project through the Korea Health Industry Development Institute (KHIDI), which is funded by the Ministry of Health \u0026amp; Welfare, South Korea (grant numbers: HR16C0001 and RS-2024-00439277).\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eH-S Park and Y Lee were involved in the study design. MS Ryu and E-M Yang performed research and analyzed data. MS Ryu and Y Lee wrote the draft of the manuscript. H-S Park, Y Lee, and J-H Jang recruited study subjects. H-S Park supervised all the study processes.\u003c/p\u003e\u003ch2\u003eAcknowledgement\u003c/h2\u003e\u003cp\u003eThe study was approved by the Institutional Review Board of Ajou University Hospital (AJIRB-MED-BDR-21-011). We thank the patients in this study and the clinical staff for assisting in patient care and data collection.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eKamisawa T, Zen Y, Pillai S, Stone JH. IgG4-related disease. Lancet. 2015;385(9976):1460\u0026ndash;71.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKhosroshahi A, Wallace ZS, Crowe JL, Akamizu T, Azumi A, Carruthers MN, et al. International Consensus Guidance Statement on the Management and Treatment of IgG4-Related Disease. Arthritis Rheumatol. 2015;67(7):1688\u0026ndash;99.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDella-Torre E, Lanzillotta M, Doglioni C. Immunology of IgG4-related disease. Clin Exp Immunol. 2015;181(2):191\u0026ndash;206.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGandhi NA, Bennett BL, Graham NM, Pirozzi G, Stahl N, Yancopoulos GD. Targeting key proximal drivers of type 2 inflammation in disease. Nat Rev Drug Discov. 2016;15(1):35\u0026ndash;50.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBouffette S, Botez I, De Ceuninck F. Targeting galectin-3 in inflammatory and fibrotic diseases. Trends Pharmacol Sci. 2023;44(8):519\u0026ndash;31.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSalah A, Yoshifuji H, Ito S, Kitagori K, Kiso K, Yamada N, et al. High Expression of Galectin-3 in Patients with IgG4-Related Disease: A Proteomic Approach. Patholog Res Int. 2017;2017:9312142.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOhta N, Kurakami K, Ishida A, Furukawa T, Suzuki Y, Aoyagi M, et al. Roles of TGF-beta and periostin in fibrosclerosis in patients with IgG4-related diseases. Acta Otolaryngol. 2013;133(12):1322\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eIaccarino L, Talarico R, Bozzalla-Cassione E, Burmester GR, Culver EL, Doria A, et al. Blood biomarkers recommended for diagnosing and monitoring IgG4-related disease. Considerations from the ERN ReCONNET and collaborating partners. Clin Exp Rheumatol. 2022;40(Suppl 134):71\u0026ndash;80.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAmano S, Nishiguchi S, Mochida Y, Teshima S, Ueki S. IgG4-related disease with eosinophil extracellular traps. QJM. 2025;118(6):457\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWallace ZS, Naden RP, Chari S, Choi HK, Della-Torre E, Dicaire JF, et al. The 2019 American College of Rheumatology/European League Against Rheumatism classification criteria for IgG4-related disease. Ann Rheum Dis. 2020;79(1):77\u0026ndash;87.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGould HJ, Sutton BJ. IgE in allergy and asthma today. Nat Rev Immunol. 2008;8(3):205\u0026ndash;17.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJeannin P, Lecoanet S, Delneste Y, Gauchat JF, Bonnefoy JY. IgE versus IgG4 production can be differentially regulated by IL-10. J Immunol. 1998;160(7):3555\u0026ndash;61.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLiu D, Ahmet A, Ward L, Krishnamoorthy P, Mandelcorn ED, Leigh R, et al. A practical guide to the monitoring and management of the complications of systemic corticosteroid therapy. Allergy Asthma Clin Immunol. 2013;9(1):30.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLighaam LC, Rispens T. The Immunobiology of Immunoglobulin G4. Semin Liver Dis. 2016;36(3):200\u0026ndash;15.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003ch2\u003eTable. \u0026nbsp;Demographics and characteristics of the study subjects.\u003c/h2\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"576\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 180px;\"\u003e\n \u003cp\u003eVariables\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 79px;\"\u003e\n \u003cp\u003ePatient 1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 79px;\"\u003e\n \u003cp\u003ePatient 2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 79px;\"\u003e\n \u003cp\u003ePatient 3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 79px;\"\u003e\n \u003cp\u003ePatient 4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 79px;\"\u003e\n \u003cp\u003ePatient 5\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 180px;\"\u003e\n \u003cp\u003eAge, year (sex)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 79px;\"\u003e\n \u003cp\u003e64\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e(male)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 79px;\"\u003e\n \u003cp\u003e33 (female)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 79px;\"\u003e\n \u003cp\u003e66 (female)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 79px;\"\u003e\n \u003cp\u003e72\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e(male)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 79px;\"\u003e\n \u003cp\u003e19\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e(male)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 180px;\"\u003e\n \u003cp\u003eBody mass index, kg/m\u003csup\u003e2\u003c/sup\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 79px;\"\u003e\n \u003cp\u003e21.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 79px;\"\u003e\n \u003cp\u003e31.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 79px;\"\u003e\n \u003cp\u003e25.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 79px;\"\u003e\n \u003cp\u003e22.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 79px;\"\u003e\n \u003cp\u003e20.5\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 180px;\"\u003e\n \u003cp\u003eHistory and comorbidity\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 79px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 79px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 79px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 79px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 79px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 180px;\"\u003e\n \u003cp\u003eSmoking\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 79px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 79px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 79px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 79px;\"\u003e\n \u003cp\u003eEx-smoker\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 79px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 180px;\"\u003e\n \u003cp\u003eHypertension\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 79px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 79px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 79px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 79px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 79px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 180px;\"\u003e\n \u003cp\u003eDiabetes mellitus\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 79px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 79px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 79px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 79px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 79px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 180px;\"\u003e\n \u003cp\u003eAllergic rhinitis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 79px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 79px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 79px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 79px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 79px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 180px;\"\u003e\n \u003cp\u003eAtopic dermatitis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 79px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 79px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 79px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 79px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 79px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 180px;\"\u003e\n \u003cp\u003e\u0026nbsp;Involved organ\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e(sclerosis/mass formation)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 79px;\"\u003e\n \u003cp\u003eOrbits and lacrimal glands, pancreas\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 79px;\"\u003e\n \u003cp\u003eLymph nodes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 79px;\"\u003e\n \u003cp\u003eOrbits and lacrimal glands, salivary glands\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 79px;\"\u003e\n \u003cp\u003eOrbits and lacrimal glands, salivary glands\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 79px;\"\u003e\n \u003cp\u003eSmall bowel\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"IgG4, IgG4-related disease, dupilumab, IL-4 receptor, biomarker, Galectin-3","lastPublishedDoi":"10.21203/rs.3.rs-8429734/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8429734/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eIgG4-related disease is a rare, immune-mediated fibroinflammatory condition that affects multiple organs. Despite concerns over long-term side effects and relapse, glucocorticoids and immunosuppressants remain the standard treatment. This study assesses the efficacy of dupilumab, a monoclonal antibody targeting IL-4Rα that blocks type 2 helper T cell-mediated inflammation, in patients with IgG4-related disease.\u003c/p\u003e\u003ch2\u003eCase presentation:\u003c/h2\u003e \u003cp\u003eFive individuals diagnosed based on the 2019 ACR/EULAR classification criteria received dupilumab (600 mg initially, followed by 300 mg biweekly) and were monitored for up to 64 weeks. Clinical evaluations included organ/site scores, IgG4 scores, and the IgG4-related disease responder index. Laboratory analyses measured serum immunoglobulin levels, IgG subclasses, and IgG4-RD-related biomarkers. Four of the five patients showed clinical improvement and reduced IgG4 levels following dupilumab treatment. However, one patient (Patient 4) had an atypical response, with increased IgG4 levels despite therapy. Organ/site scores declined in four patients but remained high in Patient 4. Serum IgG4 levels significantly decreased in four patients, normalizing in 3. A notable inverse correlation was found between cumulative oral corticosteroid dosage and dupilumab treatment duration (\u003cem\u003er\u003c/em\u003e\u0026thinsp;=\u0026thinsp;\u0026minus;\u0026thinsp;0.5455, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.0001). Among the biomarkers, galectin-3 levels showed a significant decline at 32 weeks (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05).\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eDupilumab may offer therapeutic benefit in IgG4-related disease, although individual responses vary, underscoring the need for personalized treatment strategies.\u003c/p\u003e","manuscriptTitle":"Clinical and Immunological Changes Following Dupilumab Treatment in Patients with IgG4-related Disease","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-01-19 11:24:07","doi":"10.21203/rs.3.rs-8429734/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"4eb3e6c0-8db6-4ba5-8497-34f937ad8c0d","owner":[],"postedDate":"January 19th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-02-14T21:38:44+00:00","versionOfRecord":[],"versionCreatedAt":"2026-01-19 11:24:07","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8429734","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8429734","identity":"rs-8429734","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}