RARE DISEASE
IgG4-related disease
IgG4-related disease
IgG4-related disease
Synonyms: IgG4-related sclerosing disease, Immunoglobulin G4-related sclerosing disease
Synonyms: IgG4-related sclerosing disease, Immunoglobulin G4-related sclerosing disease
Synonyms: IgG4-related sclerosing disease, Immunoglobulin G4-related sclerosing disease
Drug discovery
5
drugs
With orphan designations
Overview
IgG4-related disease (IgG4-RD) is a rare immune-mediated fibroinflammatory disorder characterized by tumor-like lesions, lymphoplasmacytic infiltrates rich in IgG4+ plasma cells, storiform fibrosis, and obliterative phlebitis. It affects multiple organs, including the pancreas, biliary tract, salivary glands, and kidneys, often mimicking malignancies or other systemic diseases. Diagnosis requires histopathology and elevated serum IgG4 (though nonspecific), with early glucocorticoid treatment critical to prevent irreversible fibrosis [1][3][18]. Relapses occur in ~40% of patients within 1 year [3][7].
Therapies
First-line: Glucocorticoids (0.6 mg/kg prednisone for 2–4 weeks, tapering over 3–6 months) [3][7][10]
Relapse management: Rituximab (B-cell depletion), steroid-sparing immunosuppressants (azathioprine, mycophenolate), or surgery for obstructive complications [3][16][20]
Emerging: Targeted biologics (anti-CD19/20, BTK inhibitors) in clinical trials [10][16]
Categories: rare systemic and rheumatological diseases
Research Papers
1,431 drug discovery papers about IgG4-related disease, with 2 first-in-class and 29 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
1,431 drug discovery papers about IgG4-related disease, with 2 first-in-class and 29 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-08-13 | [An unusual cause for unilateral eye pain with double vision].
A 48-year-old man was diagnosed with IgG4-related disease (IgG4-RD) during an evaluation for exophthalmos and unexplained pain on the left side of his face. The diagnosis was made by ruling out all other possible conditions and was based on histopathological findings. After initiating immunosuppressive therapy with corticosteroids (GC), most of the symptoms resolved. As the GC-dose was gradually reduced, a relapse occurred, leading to two courses of Rituximab. Reflecting the success of the therapy, long-term follow-up revealed a marked radiological reduction in the retrobulbar mass and a significant clinical improvement in pain.
2026-08-13 | Isolated IgG4-related lung disease: a case report.
IgG4-related disease (IgG4-RD) represents a chronic, immune-driven fibroinflammatory condition capable of affecting diverse organ systems; within this spectrum, pulmonary involvement (IgG4-RLD) remains comparatively uncommon. This case report outlines the clinical, imaging and pathological features of a patient with IgG4-related lung disease. We report a 60-year-old male patient with recurrent fever, chest pain, and cough with hemoptysis. Chest computed tomography (CT) initially showed right upper lobe lesions suggestive of pneumonia, but the patient failed to respond to multiple courses of antibiotics including levofloxacin, nemonoxacin malate, ceftizoxime, and amoxicillin. Further investigations revealed significantly elevated serum IgG4 level (266 mg/dL). Endobronchial ultrasound-guided transbronchial lung cryobiopsy (EBUS-GS-TBLC) confirmed dense lymphoplasmacytic infiltration in the lung tissue, with IgG4-positive plasma cells >50 per high powered field (HPF) and IgG4-positive/IgG-positive cell ratio >50%, consistent with the diagnosis of IgG4-related interstitial lung disease. The patient was treated with oral cyclosporine and mycophenolate mofetil, resulting in significant clinical and radiological improvement. IgG4-RLD should be considered in the differential diagnosis of patients with pulmonary lesions unresponsive to antibiotic therapy. Comprehensive evaluation including serum IgG4 measurement and targeted pathological biopsy is essential for accurate diagnosis. Early initiation of immunosuppressive therapy can effectively improve outcomes and prevent disease progression.
2026-08-11 | Treatment strategies for relapsing IgG4-RD: twelve-year experience from a prospective cohort.
Relapse is common in IgG4-related disease (IgG4-RD). While previous studies focus on treatments for active IgG4-RD, data on the management of relapsing IgG4-RD remains limited. We aimed to investigate the treatment strategies for relapsing IgG4-RD. This study analyzed data prospectively collected from an IgG4-RD cohort, including patients who experienced their first relapse and were followed for over 12 months. We compared the outcome among three groups: (1) Intensifying glucocorticoids (GC) only; (2) Intensifying immunosuppressants (IM) only; (3) Intensifying both GC and IM. The primary outcome was recurrent relapses. A decision tree model was developed to predict recurrent relapses. A total of 259 patients with IgG4-RD was included, with a male predominance (61.7%) and a median age of 54.0 years. Patients who intensified both GC and immunosuppressants (IM) (adjusted p 0.0002, HR 0.29, 95% CI: 0.16-0.52) experienced less relapses compared to those who intensified IM alone, while those who only intensified GC had a tendency to experience less relapses (adjusted p 0.0823, HR 0.51, 95% CI: 0.26-1.03). These differences were more pronounced in the subgroup with internal organ involvement. The decision tree indicated that those with an RI decrease to ≤ 2 and an IgG4 decrease ≥25% after treatment were more likely to stay free from recurrent relapses, with an AUC of 0.728 in the testing set. When treating relapse in IgG4-RD, GC-based treatment was associated with a lower hazard of recurrent relapse compared with only adjusting IMs, especially for those with internal organ involvement.
2026-08-07 | Directional Coronary Atherectomy as a Diagnostic Adjunct in Suspected IgG4-Related Coronary Artery Disease.
Immunoglobulin (Ig) G4-related disease can involve the cardiovascular system, and isolated vessel involvement is diagnostically challenging. A 79-year-old Japanese man with a history of percutaneous coronary intervention presented with exertional angina. Imaging demonstrated in-stent occlusion of the left anterior descending artery, severe distal left circumflex artery stenosis, and marked adventitial thickening of the coronary arteries and aorta. Serum IgG4 levels were markedly elevated. Directional coronary atherectomy (DCA) enabled retrieval of intimal tissue. Although the pathological findings did not fulfill formal classification criteria, tissue sampling provided supportive histopathological evidence for IgG4-related disease. Prednisolone therapy resulted in regression of adventitial thickening and reduction of nonrevascularized coronary lesions. DCA may serve as both a therapeutic strategy and an adjunctive diagnostic approach. DCA may provide supportive histopathological information when conventional biopsy is not feasible, and steroid therapy can be effective for cases of vascular involvement in IgG4-related disease.
2026-07-30 | Case Report: Immune checkpoint inhibitor-induced IgG4-related disease mimicking renal metastatic progression: successful steroid-sparing management with rituximab.
Immune checkpoint inhibitors (ICIs) can induce a broad spectrum of immune-related adverse events (irAEs), including rare fibroinflammatory autoimmune manifestations. IgG4-related disease (IgG4-RD) has only exceptionally been described following dual ICI therapy. We report a 65-year-old man with metastatic clear cell renal carcinoma treated with nivolumab plus ipilimumab after nephrectomy. Despite initial radiologic stability, follow-up computed tomography revealed newly developed mass-like lesions in the solitary remaining kidney, raising suspicion of metastatic progression. CT-guided biopsy demonstrated subacute pyelonephritis, acute tubular injury, storiform fibrosis, and dense IgG4-positive plasma cell infiltration consistent with IgG4-RD. Because glucocorticoids were considered potentially detrimental to antitumor immune surveillance, rituximab was selected as steroid-sparing first-line therapy. Two infusions of rituximab (1000 mg each) led to radiologic stabilization/regression of renal lesions while pulmonary metastases remained under oncologic control. This case highlights IgG4-RD as a rare but clinically important underrecognized irAE of dual ICI therapy that may mimic malignant progression. Histologic confirmation is crucial, and B-cell depletion with rituximab may represent an effective treatment strategy when preservation of antitumor immunity is a priority.
2026-08-13 | [An unusual cause for unilateral eye pain with double vision].
A 48-year-old man was diagnosed with IgG4-related disease (IgG4-RD) during an evaluation for exophthalmos and unexplained pain on the left side of his face. The diagnosis was made by ruling out all other possible conditions and was based on histopathological findings. After initiating immunosuppressive therapy with corticosteroids (GC), most of the symptoms resolved. As the GC-dose was gradually reduced, a relapse occurred, leading to two courses of Rituximab. Reflecting the success of the therapy, long-term follow-up revealed a marked radiological reduction in the retrobulbar mass and a significant clinical improvement in pain.
2026-08-13 | Isolated IgG4-related lung disease: a case report.
IgG4-related disease (IgG4-RD) represents a chronic, immune-driven fibroinflammatory condition capable of affecting diverse organ systems; within this spectrum, pulmonary involvement (IgG4-RLD) remains comparatively uncommon. This case report outlines the clinical, imaging and pathological features of a patient with IgG4-related lung disease. We report a 60-year-old male patient with recurrent fever, chest pain, and cough with hemoptysis. Chest computed tomography (CT) initially showed right upper lobe lesions suggestive of pneumonia, but the patient failed to respond to multiple courses of antibiotics including levofloxacin, nemonoxacin malate, ceftizoxime, and amoxicillin. Further investigations revealed significantly elevated serum IgG4 level (266 mg/dL). Endobronchial ultrasound-guided transbronchial lung cryobiopsy (EBUS-GS-TBLC) confirmed dense lymphoplasmacytic infiltration in the lung tissue, with IgG4-positive plasma cells >50 per high powered field (HPF) and IgG4-positive/IgG-positive cell ratio >50%, consistent with the diagnosis of IgG4-related interstitial lung disease. The patient was treated with oral cyclosporine and mycophenolate mofetil, resulting in significant clinical and radiological improvement. IgG4-RLD should be considered in the differential diagnosis of patients with pulmonary lesions unresponsive to antibiotic therapy. Comprehensive evaluation including serum IgG4 measurement and targeted pathological biopsy is essential for accurate diagnosis. Early initiation of immunosuppressive therapy can effectively improve outcomes and prevent disease progression.
2026-08-11 | Treatment strategies for relapsing IgG4-RD: twelve-year experience from a prospective cohort.
Relapse is common in IgG4-related disease (IgG4-RD). While previous studies focus on treatments for active IgG4-RD, data on the management of relapsing IgG4-RD remains limited. We aimed to investigate the treatment strategies for relapsing IgG4-RD. This study analyzed data prospectively collected from an IgG4-RD cohort, including patients who experienced their first relapse and were followed for over 12 months. We compared the outcome among three groups: (1) Intensifying glucocorticoids (GC) only; (2) Intensifying immunosuppressants (IM) only; (3) Intensifying both GC and IM. The primary outcome was recurrent relapses. A decision tree model was developed to predict recurrent relapses. A total of 259 patients with IgG4-RD was included, with a male predominance (61.7%) and a median age of 54.0 years. Patients who intensified both GC and immunosuppressants (IM) (adjusted p 0.0002, HR 0.29, 95% CI: 0.16-0.52) experienced less relapses compared to those who intensified IM alone, while those who only intensified GC had a tendency to experience less relapses (adjusted p 0.0823, HR 0.51, 95% CI: 0.26-1.03). These differences were more pronounced in the subgroup with internal organ involvement. The decision tree indicated that those with an RI decrease to ≤ 2 and an IgG4 decrease ≥25% after treatment were more likely to stay free from recurrent relapses, with an AUC of 0.728 in the testing set. When treating relapse in IgG4-RD, GC-based treatment was associated with a lower hazard of recurrent relapse compared with only adjusting IMs, especially for those with internal organ involvement.
2026-08-07 | Directional Coronary Atherectomy as a Diagnostic Adjunct in Suspected IgG4-Related Coronary Artery Disease.
Immunoglobulin (Ig) G4-related disease can involve the cardiovascular system, and isolated vessel involvement is diagnostically challenging. A 79-year-old Japanese man with a history of percutaneous coronary intervention presented with exertional angina. Imaging demonstrated in-stent occlusion of the left anterior descending artery, severe distal left circumflex artery stenosis, and marked adventitial thickening of the coronary arteries and aorta. Serum IgG4 levels were markedly elevated. Directional coronary atherectomy (DCA) enabled retrieval of intimal tissue. Although the pathological findings did not fulfill formal classification criteria, tissue sampling provided supportive histopathological evidence for IgG4-related disease. Prednisolone therapy resulted in regression of adventitial thickening and reduction of nonrevascularized coronary lesions. DCA may serve as both a therapeutic strategy and an adjunctive diagnostic approach. DCA may provide supportive histopathological information when conventional biopsy is not feasible, and steroid therapy can be effective for cases of vascular involvement in IgG4-related disease.
2026-07-30 | Case Report: Immune checkpoint inhibitor-induced IgG4-related disease mimicking renal metastatic progression: successful steroid-sparing management with rituximab.
Immune checkpoint inhibitors (ICIs) can induce a broad spectrum of immune-related adverse events (irAEs), including rare fibroinflammatory autoimmune manifestations. IgG4-related disease (IgG4-RD) has only exceptionally been described following dual ICI therapy. We report a 65-year-old man with metastatic clear cell renal carcinoma treated with nivolumab plus ipilimumab after nephrectomy. Despite initial radiologic stability, follow-up computed tomography revealed newly developed mass-like lesions in the solitary remaining kidney, raising suspicion of metastatic progression. CT-guided biopsy demonstrated subacute pyelonephritis, acute tubular injury, storiform fibrosis, and dense IgG4-positive plasma cell infiltration consistent with IgG4-RD. Because glucocorticoids were considered potentially detrimental to antitumor immune surveillance, rituximab was selected as steroid-sparing first-line therapy. Two infusions of rituximab (1000 mg each) led to radiologic stabilization/regression of renal lesions while pulmonary metastases remained under oncologic control. This case highlights IgG4-RD as a rare but clinically important underrecognized irAE of dual ICI therapy that may mimic malignant progression. Histologic confirmation is crucial, and B-cell depletion with rituximab may represent an effective treatment strategy when preservation of antitumor immunity is a priority.
Access all drug discovery papers and probability of success in trials forecasts:
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Drug Discovery Landscape
5 orphan drug designations for IgG4-related disease, including 1 approved therapy.
5 orphan drug designations for IgG4-related disease, including 1 approved therapy.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
inebilizumab-cdon [Uplizna] | antibodies | FDA | 2026-05-01 | 2025-04-03 | Horizon Therapeutics Ireland DAC |
Rilzabrutinib | small molecules | EMA | 2025-08-22 | — | Sanofi B.V. |
rilzabrutinib | small molecules | FDA | 2025-04-01 | — | Sanofi US Services, Inc |
Humanised Fc-engineered monoclonal antibody against CD19 | antibodies | EMA | 2018-01-17 | — | Zenas BioPharma B.V. |
obexelimab | antibodies | FDA | 2017-05-09 | — | Zenas BioPharma (USA) LLC. |
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