IgG4-related disease

IgG4-related disease (IgG4‑RD) is a systemic fibroinflammatory condition characterized by tumor‑like swelling of affected organs, a dense lymphoplasmacytic infiltrate rich in IgG4‑positive plasma cells, storiform fibrosis, and often elevated serum IgG4 concentrations. The disease can involve virtually any organ, most commonly the pancreas, salivary and lacrimal glands, retroperitoneum, kidneys, lungs, and lymph nodes.

Epidemiology
IgG4‑RD predominantly affects middle‑aged to older adults, with a higher prevalence in men than women. Precise incidence and prevalence rates are uncertain because of historical under‑recognition and evolving diagnostic criteria.

Pathophysiology
The exact etiology remains incompletely understood. Current evidence suggests an aberrant immune response involving both humoral and cellular components:

• Elevated serum IgG4 and tissue infiltration by IgG4‑positive plasma cells.
• Clonal expansion of plasmablasts and a Th2‑skewed cytokine milieu (e.g., IL‑4, IL‑13, IL‑10).
• Regulatory T‑cell activation and fibrosis mediated by transforming growth factor‑β (TGF‑β).

Although IgG4 antibodies are typically considered anti‑inflammatory, their role in disease propagation is still under investigation.

Clinical Manifestations
Presentation varies according to organ involvement:

• Pancreas – Autoimmune pancreatitis (type 1) presenting with painless jaundice, abdominal discomfort, and pancreatic enlargement.
• Salivary and lacrimal glands – Swelling of the parotid, submandibular, and lacrimal glands (Mikulicz disease).
• Retroperitoneum – Fibroinflammatory mass encasing the aorta and ureters (retroperitoneal fibrosis).
• Kidneys – Tubulointerstitial nephritis with cortical low‑density lesions.
• Lungs – Nodules, interstitial pneumonitis, or pleural effusions.
• Other sites – Thyroid (Riedel thyroiditis), orbit (orbital inflammatory disease), pericardium, and meninges.

Patients may have constitutional symptoms such as mild fever, weight loss, or fatigue, but many remain asymptomatic apart from organ enlargement.

Diagnosis
Diagnostic criteria combine clinical, serologic, radiologic, and histopathologic findings:

1. Imaging – Organ enlargement or mass‑like lesions on CT, MRI, or PET‑CT.
2. Serology – Elevated serum IgG4 (>135 mg/dL) supports the diagnosis but is not mandatory.
3. Histopathology – Core biopsy showing dense lymphoplasmacytic infiltrate, storiform fibrosis, obliterative phlebitis, and IgG4‑positive plasma cells (>10 per high‑power field and IgG4/IgG ratio >40%).
4. Response to glucocorticoids – Rapid clinical improvement after steroid therapy is considered supportive.

International consensus statements (e.g., the 2019 ACR/EULAR classification criteria) provide standardized algorithms for classification.

Treatment

• Glucocorticoids – First‑line therapy; typical initial prednisone dose of 0.6 mg/kg/day tapered over 3–6 months. Most patients experience rapid symptom relief.
• Immunosuppressive agents – Azathioprine, mycophenolate mofetil, or methotrexate are employed for steroid‑sparing maintenance or relapse prevention.
• Rituximab – Anti‑CD20 monoclonal antibody shown to induce remission in refractory or relapsing disease, particularly in patients with high plasmablast counts.
• Surgical intervention – Reserved for organ‑specific complications (e.g., obstructive jaundice, ureteral obstruction) when medical therapy is insufficient.

Long‑term follow‑up is essential due to the risk of relapse and possible development of fibrostenotic damage.

Prognosis
With appropriate immunosuppressive therapy, most patients achieve disease control and preservation of organ function. However, chronic fibrosis can lead to irreversible organ damage, and relapses occur in up to 30–40 % of cases. Overall survival is comparable to age‑matched controls, although complications such as renal insufficiency or aortic involvement can affect outcomes.

History
The condition was first described in the early 2000s when clusters of patients with autoimmune pancreatitis demonstrated elevated serum IgG4. Subsequent case series recognized similar histopathologic patterns in other organs, leading to the unifying concept of IgG4‑related disease. Consensus classification and diagnostic guidelines were established by international working groups between 2011 and 2019.

References

• Not included per instruction; information synthesized from peer‑reviewed medical literature up to 2024.