IgG4-Related Disease: A Primary Care Guide to Diagnosis and Referral

What is IgG4-related disease?

Immunoglobulin G4–related disease (IgG4-RD) is a chronic, immune-mediated fibroinflammatory disorder that can cause mass-like lesions, painless organ enlargement, progressive fibrosis, and irreversible organ dysfunction if diagnosis or treatment is delayed. IgG4-RD can affect virtually any organ system, but common sites include the pancreas, biliary tract, salivary and lacrimal glands, orbit, lungs, kidneys, retroperitoneum, aorta, lymph nodes, thyroid, and meninges.^1-4

For primary care physicians (PCPs), the central clinical challenge is not that IgG4-RD is commonly suspected at first presentation, but that it can masquerade as more familiar conditions, including malignancy, infection, Sjögren disease, sarcoidosis, lymphoma, antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis, primary sclerosing cholangitis, Castleman disease, and other autoimmune or fibroinflammatory disorders. In primary care, IgG4-RD is best understood as a secondary or tertiary differential diagnosis that should be considered when a patient has atypical, recurrent, mass-like, fibroinflammatory, or multiorgan disease that is not explained by more common diagnoses.^1-4

Serum IgG4 elevation can support clinical suspicion, but IgG4 is neither sufficiently sensitive nor specific to establish the diagnosis by itself. Diagnosis requires clinicopathologic correlation using history, examination, laboratory testing, imaging, and, when feasible, tissue biopsy.^1-4

Epidemiology and risk factors

IgG4-RD is rare but increasingly recognized in the United States and internationally.^1-5 In a US claims-based analysis, estimated incidence increased from 0.78 to 1.39 per 100,000 person-years from 2015 to 2019, and point prevalence was 5.3 per 100,000 persons on January 1, 2019.⁵ The same analysis found that IgG4-RD was associated with increased mortality compared with matched controls.

The classic patient is middle-aged or older, and many cohorts show male predominance, although IgG4-RD can occur in women and rarely in children.^1,2,4 Risk factors remain incompletely defined; current evidence supports immune dysregulation involving B cells, plasmablasts, CD4-positive cytotoxic T cells, T-follicular helper cells, and profibrotic pathways rather than a single causal autoantibody or environmental exposure.^1,4,6

Clinical patterns that should prompt consideration of IgG4-RD

IgG4-RD is unlikely to be the initial diagnosis in primary care, but PCPs may be the first clinicians to recognize a pattern that warrants referral. IgG4-RD should enter the broader differential when a patient has unexplained organ swelling, a mass-like lesion, recurrent pancreatitis, painless obstructive jaundice, salivary or lacrimal gland enlargement, orbital inflammation, retroperitoneal fibrosis, hydronephrosis, tubulointerstitial nephritis, unexplained pulmonary nodules or infiltrates, aortitis, or multisystem disease that does not fit a more common diagnosis.^1-4

Fever is uncommon and should prompt careful evaluation for infection, malignancy, or another inflammatory disease.² Weight loss can occur, particularly in pancreatobiliary disease, but should also heighten concern for cancer.^2,4 Common clinical phenotypes include pancreato-hepatobiliary disease, retroperitoneal fibrosis or aortitis, head and neck disease such as dacryoadenitis or sialadenitis, and systemic disease with multiple organ sites.^1-4

IgG4-related autoimmune pancreatitis can resemble pancreatic cancer, and IgG4-related sclerosing cholangitis can resemble cholangiocarcinoma or primary sclerosing cholangitis. Because unnecessary surgery can occur when IgG4-RD is mistaken for cancer, early specialty referral is appropriate when imaging and clinical features are suspicious but not definitive.^1-4

Urgent referral and red flags

Urgent referral is warranted when suspected IgG4-RD involves a potentially organ-threatening presentation. These include obstructive jaundice, suspected cholangitis, pancreatic mass with weight loss or ductal obstruction, hydronephrosis, rising creatinine, retroperitoneal fibrosis, aortitis, periaortitis, aneurysmal disease, orbital involvement with vision changes or diplopia, suspected optic neuropathy, hypertrophic pachymeningitis, neurologic deficits, progressive pulmonary disease, or rapidly progressive mass-like disease.^1-4

If malignancy remains plausible, referral should be expedited rather than delayed for prolonged outpatient observation. In most nonemergent cases, avoid empiric glucocorticoids until the diagnostic plan is established, because steroids may obscure malignancy, lymphoma, infection, or other inflammatory disorders.^1-4

Differential diagnosis

IgG4-RD should be evaluated in the context of a broad differential diagnosis that varies by organ involvement.

Malignant mimics include pancreatic adenocarcinoma, cholangiocarcinoma, lymphoma, lung cancer, renal malignancy, orbital tumors, and retroperitoneal malignancy. Autoimmune and inflammatory mimics include Sjögren disease, sarcoidosis, ANCA-associated vasculitis, systemic lupus erythematosus, primary sclerosing cholangitis, idiopathic retroperitoneal fibrosis, Castleman disease, histiocytoses, and inflammatory pseudotumor. Infectious mimics should be considered when fever, systemic toxicity, immunosuppression, pulmonary lesions, lymphadenopathy, or organ-specific infectious features are present.^1-4

This differential diagnosis is central to safe management because IgG4-RD often responds to glucocorticoids, but steroid responsiveness alone is not diagnostic and may delay correct diagnosis of cancer, lymphoma, or infection.^1-4

Diagnostic approach for PCPs

Initial primary care evaluation should define the pattern of organ involvement, assess for organ-threatening disease, and identify mimics that require urgent evaluation.^1-4

Initial PCP workup

A reasonable initial workup includes complete blood count with differential, comprehensive metabolic panel, liver enzymes and bilirubin, urinalysis, urine protein assessment, erythrocyte sedimentation rate, C-reactive protein, total IgG, IgG subclasses including IgG4, complement C3 and C4, and IgE. Elevated serum IgG4, eosinophilia, hypergammaglobulinemia, elevated IgE, or hypocomplementemia may support suspicion but cannot confirm IgG4-RD alone.^1-4

Organ-directed testing

Testing should be directed by the involved organ system. Pancreaticobiliary symptoms may warrant liver tests, bilirubin, pancreatic enzymes when clinically appropriate, abdominal imaging, and MRCP or endoscopic evaluation through gastroenterology. Renal or retroperitoneal presentations may require creatinine, urinalysis, urine protein assessment, renal ultrasound, CT, or MRI. Orbital symptoms should prompt ophthalmology evaluation, particularly when vision is affected. Pulmonary symptoms may require chest imaging and pulmonary evaluation.^1-4

Imaging

CT, MRI, MRCP, ultrasound, PET/CT, and organ-specific studies can identify mass-like disease, glandular enlargement, biliary strictures, renal lesions, retroperitoneal fibrosis, aortitis, or occult multiorgan involvement. PET/CT may help specialists map disease burden and identify a biopsy target, but imaging findings are not pathognomonic.^1-4

Biopsy and pathology

Biopsy is generally recommended when safely obtainable, especially for mass-like lesions, single-organ disease, atypical presentations, or any presentation in which malignancy, lymphoma, infection, or another diagnosis remains possible. Characteristic pathology includes dense lymphoplasmacytic infiltrate, storiform fibrosis, obliterative phlebitis, and increased IgG4-positive plasma cells, interpreted according to organ site and clinical context. Increased IgG4-positive plasma cells alone are not sufficient for diagnosis.^1-4

Classification criteria can support structured assessment, but they are primarily designed for research cohorts and should not be used as the sole basis for diagnosing or excluding IgG4-RD in an individual patient.^3,4

Management principles and referral

IgG4-RD management is usually multidisciplinary and should generally be coordinated by rheumatology, with organ-specific specialists involved according to the dominant disease site.^1,2,4 Gastroenterology may be needed for pancreaticobiliary disease, nephrology for renal involvement, ophthalmology for orbital disease, otolaryngology for salivary or lacrimal gland disease, pulmonology for lung disease, urology for retroperitoneal fibrosis or hydronephrosis, vascular medicine or surgery for aortitis or aneurysmal disease, and oncology or surgical subspecialists when malignancy remains a concern.^1-4

Treatment is generally indicated for active symptomatic disease, organ-threatening disease, or disease likely to cause irreversible fibrosis or dysfunction.^1,4,6,7 Observation may be reasonable for selected asymptomatic patients with mild, non–organ-threatening disease, but that decision should be made with specialist input because subclinical progression and relapse can occur.^1,4,6

Treatment options

Glucocorticoids have historically been used for induction because IgG4-RD often responds rapidly; however, relapse after tapering and cumulative glucocorticoid toxicity have driven increasing use of steroid-sparing, B-cell–directed strategies. Selection among glucocorticoids, B-cell–directed therapy, and other steroid-sparing approaches should be individualized according to disease severity, organ involvement, relapse risk, comorbidities, pregnancy considerations, infection risk, access, and specialist assessment.^1,4,6,7

Steroid-sparing immunosuppressive agents such as azathioprine, mycophenolate mofetil, methotrexate, and other conventional disease-modifying antirheumatic drugs have been used, but evidence is less robust than for B-cell–directed therapy. Rituximab has been used off label and can reduce disease activity, particularly in relapsing disease or when prolonged glucocorticoid exposure is undesirable.^1,6,7

In 2025, inebilizumab-cdon became the first FDA-approved treatment for adults with IgG4-RD.^8,9 Inebilizumab is a CD19-directed B-cell–depleting monoclonal antibody, and approval was supported by the phase 3 MITIGATE trial in adults with IgG4-RD.^8,9  In the FDA label, IgG4-RD flares occurred in 7 of 68 patients treated with inebilizumab vs 40 of 67 patients receiving placebo, corresponding to a hazard ratio of 0.13 and an 87% lower flare risk during the 52-week randomized period.^8,9 Treatment-free, flare-free complete remission at week 52 occurred in 57.4% of inebilizumab-treated patients vs 22.4% of placebo-treated patients, and corticosteroid-free, flare-free complete remission occurred in 58.8% vs 22.4%, respectively.⁸ Common adverse reactions in IgG4-RD included lymphopenia and urinary tract infection, and prescribers should follow label-directed screening, vaccination, infection-risk, infusion-reaction, pregnancy-risk, and immunoglobulin-monitoring precautions.⁸

Obexelimab is an investigational bifunctional monoclonal antibody that inhibits B-cell activity through coengagement of CD19 and FcγRIIb without inducing B-cell depletion.^10,11 In the phase 3, double-blind, randomized, placebo-controlled INDIGO trial, 194 adults with active IgG4-RD were assigned to weekly subcutaneous obexelimab 250 mg or placebo for 52 weeks after standardized glucocorticoid induction and taper to discontinuation by week 8. Time to first disease flare requiring rescue therapy was significantly longer with obexelimab than placebo; flares occurred in 26.8% of patients receiving obexelimab vs 54.6% receiving placebo, with a hazard ratio of 0.44 (95% CI, 0.28-0.71; P < .001). Complete remission at week 52 occurred in 37.1% of patients receiving obexelimab vs 19.6% receiving placebo (P = .005), and cumulative glucocorticoid rescue exposure was lower with obexelimab. Reported adverse events included arthralgia, hypersensitivity, and diarrhea, and serious adverse events occurred in 10.3% of patients in the obexelimab group and 18.6% in the placebo group.¹⁰

The accompanying NEJM editorial emphasized the conceptual importance of nondepleting B-cell therapy in IgG4-RD, particularly the possibility of inhibiting pathogenic B-cell activity while avoiding some risks associated with prolonged B-cell depletion.¹¹ Obexelimab remains investigational unless and until approved by regulatory authorities, and its future role will depend on regulatory review, longer-term safety data, comparative effectiveness, access, and patient selection.^10,11

Monitoring and long-term follow-up

Monitoring should combine symptoms, physical examination, organ-specific laboratory tests, imaging when appropriate, and treatment-toxicity surveillance. Serum IgG4 may be useful in some patients but should not be the sole marker of disease activity because levels may be normal in active disease or remain elevated despite clinical control.^1,4,6 Specialists may use structured tools such as the IgG4-RD Responder Index to assess disease activity and treatment response over time.^1,4

Primary care follow-up should include vaccination review, infection-risk counseling, bone health, glucose and blood pressure monitoring during glucocorticoid exposure, cardiovascular risk management, and screening for medication adverse effects.^1,2,6,8 Patients receiving B-cell–directed therapy need coordinated monitoring for infections, infusion or injection reactions, immunoglobulin changes, vaccination timing, and therapy-specific precautions.^8,11

Relapse can occur after glucocorticoid tapering or discontinuation, so patients should be instructed to report recurrent gland swelling, jaundice, abdominal pain, flank pain, reduced urine output, dyspnea, visual symptoms, constitutional changes, or new mass-like symptoms.^1,4,6 Patients with retroperitoneal fibrosis, renal disease, pancreatobiliary disease, aortitis, or orbital disease need especially close coordination because delayed recognition may lead to permanent organ damage.^1,4

Patient education, caregiver support, and lifestyle considerations

Primary care physicians can explain that IgG4-RD is a treatable immune-mediated condition, while emphasizing that malignancy and infection often must be excluded before the diagnosis is confirmed. Education should reinforce adherence to follow-up, prompt reporting of relapse symptoms, and the rationale for biopsy, repeat imaging, or specialty evaluation when clinical uncertainty remains.^1-4

No specific diet or lifestyle intervention has been proven to treat IgG4-RD directly, but general measures can reduce treatment complications and support overall health.^1,2,6 Patients receiving glucocorticoids should receive counseling on weight gain, mood changes, hyperglycemia, hypertension, osteoporosis, infection risk, and sleep disturbance.^1,2,8 Patients with pancreatic disease may need evaluation for diabetes, exocrine pancreatic insufficiency, fat-soluble vitamin deficiency, and nutrition support. Caregivers can help track symptoms, appointments, medication schedules, infusion or injection visits, and red-flag changes that warrant urgent evaluation.^1,2

Practical takeaways for primary care

IgG4-RD is rarely the first diagnosis suspected in primary care, but it should enter the broader differential when patients have unexplained mass-like lesions, painless organ enlargement, autoimmune pancreatitis, sclerosing cholangitis, retroperitoneal fibrosis, salivary or lacrimal gland enlargement, orbital inflammation, renal lesions, aortitis, or multiorgan fibroinflammatory disease. Serum IgG4 can support suspicion but should not be used as a stand-alone diagnostic test. Biopsy and clinicopathologic correlation remain central, especially when malignancy is possible.^1-4 Rheumatology generally coordinates care, with organ-specific specialists involved according to disease site.^1,2,4 With FDA-approved inebilizumab and investigational obexelimab data now available, IgG4-RD management is moving from prolonged glucocorticoid dependence toward more targeted, steroid-sparing B-cell–directed strategies.^8-11

Frequently Asked Questions for Primary Care Physicians

When should IgG4-RD enter my differential?

IgG4-RD should enter the broader differential when a patient has atypical, recurrent, mass-like, fibroinflammatory, or multiorgan disease that is not explained by more common diagnoses. Examples include autoimmune pancreatitis, sclerosing cholangitis, retroperitoneal fibrosis, salivary or lacrimal gland enlargement, orbital inflammation, renal lesions, aortitis, unexplained pulmonary lesions, or recurrent inflammatory disease across more than 1 organ system.^1-4

What should I order before referral?

For suspected IgG4-RD, initial PCP testing can include complete blood count with differential, comprehensive metabolic panel, liver enzymes and bilirubin, urinalysis, urine protein assessment, erythrocyte sedimentation rate, C-reactive protein, total IgG, IgG subclasses including IgG4, complement C3 and C4, and IgE. Additional testing should be guided by the organ system involved and by the need to exclude mimics such as malignancy, infection, Sjögren disease, sarcoidosis, lymphoma, ANCA-associated vasculitis, primary sclerosing cholangitis, and Castleman disease.^1-4

When should I refer urgently?

Refer urgently for suspected IgG4-RD with obstructive jaundice, pancreatic or biliary mass, renal impairment, hydronephrosis, retroperitoneal fibrosis, aortitis, aneurysmal disease, visual symptoms, diplopia, neurologic deficits, progressive pulmonary disease, rapidly progressive mass-like disease, or any presentation in which malignancy cannot be excluded.^1-4

What should I avoid before referral?

Avoid overinterpreting serum IgG4 as a stand-alone diagnostic test, because normal levels do not exclude IgG4-RD and elevated levels do not confirm it. In most nonemergent mass-like presentations, glucocorticoids should be deferred until malignancy and infection have been reasonably excluded and a biopsy or diagnostic plan is in place.^1-4

How should I monitor patients after diagnosis?

PCPs should monitor symptoms, organ-specific laboratory abnormalities, medication adverse effects, vaccination status, infection risk, bone health, blood pressure, glucose, renal function, liver tests, and relapse symptoms.^1-4,6,8 Serum IgG4 can be followed in some patients but should not be used as the only marker of activity or relapse.^1,4,6

When should I suspect relapse?

Relapse should be considered when prior IgG4-RD symptoms recur or when patients develop new gland swelling, jaundice, abdominal pain, flank pain, renal dysfunction, dyspnea, visual symptoms, neurologic symptoms, constitutional changes, or new mass-like findings, particularly after glucocorticoid tapering or treatment changes.^1,4,6

Clinical pearls for primary care

• IgG4-RD is rarely the first diagnosis suspected in primary care; it is more often a secondary or tertiary differential when common diagnoses do not fully explain an atypical, mass-like, recurrent, fibroinflammatory, or multiorgan pattern.^1-4
• Serum IgG4 is supportive, not diagnostic; a normal IgG4 level does not exclude IgG4-RD, and an elevated IgG4 level does not confirm it.^1-4
• Mass-like IgG4-RD can mimic malignancy, particularly pancreatic cancer, cholangiocarcinoma, lymphoma, lung cancer, and retroperitoneal malignancy; biopsy and clinicopathologic correlation are often needed when cancer remains plausible.^1-4
• Rheumatology generally coordinates care, with organ-specific specialists involved according to disease site; organ-threatening presentations warrant urgent referral.^1,2,4
• Glucocorticoids can improve IgG4-RD rapidly, but they should generally be deferred in nonemergent mass-like presentations until malignancy and infection have been reasonably excluded and a biopsy or diagnostic plan is in place.^1-4

References

1. Wallace ZS, Katz G, Hernandez-Barco YG, Baker MC. Current and future advances in practice: IgG4-related disease. Rheumatol Adv Pract. 2024;8(2). doi:10.1093/rap/rkae020
2. Perugino C. IgG4-related disease. Merck Manual Professional Edition. Reviewed/revised November 2024. Accessed June 24, 2026.
3. Kogami M, Abe Y, Ando T, Makiyama A, Yamaji K, Tamura N. Performance of classification and diagnostic criteria for IgG4-related disease and comparison of patients with and without IgG4-related disease. Sci Rep. 2023;13:2509. doi:10.1038/s41598-023-29645-2
4. Peyronel F, Della-Torre E, Maritati F, Urban ML, Bajema I, Schleinitz N, Vaglio A. IgG4-related disease and other fibro-inflammatory conditions. Nat Rev Rheumatol. 2025;21(5):275-290. doi:10.1038/s41584-025-01240-x
5. Wallace ZS, Miles G, Smolkina E, et al. Incidence, prevalence and mortality of IgG4-related disease in the USA: a claims-based analysis of commercially insured adults. Ann Rheum Dis. 2023;82(7):957-962. doi:10.1136/ard-2023-223950
6. Pinheiro FAG, Pereira IA, Souza AWS, Giardini HAM, Cordeiro RA. IgG4-related disease—rare but you should not forget it. Adv Rheumatol. 2024;64:35. doi:10.1186/s42358-024-00374-y
7. Akiyama M, Alshehri W, Saito K, Takeuchi T, Kaneko Y. Pharmacological management of IgG4-related disease: from traditional to mechanism-based targeted therapies. Drugs Aging. 2025;42(2):111-126. doi:10.1007/s40266-024-01172-3
8. UPLIZNA (inebilizumab-cdon) injection, for intravenous use. Prescribing information. Amgen Inc; revised 2025. Accessed June 24, 2026.
9. Stone JH, Khosroshahi A, Zhang W, et al; MITIGATE Trial Investigators. Inebilizumab for treatment of IgG4-related disease. N Engl J Med. 2025;392(12):1168-1177. doi:10.1056/NEJMoa2409712
10. Della-Torre E, Baker MC, Zhang W, et al. Obexelimab for the treatment of IgG4-related disease. N Engl J Med. Published online June 2, 2026. doi:10.1056/NEJMoa2601337
11. Dörner T. Obexelimab and the promise of nondepleting B-cell therapy in IgG4-related disease. N Engl J Med. Published online June 2, 2026. doi:10.1056/NEJMe2605617

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