Introduction:

• It is a fibro-inflammatory condition that can affect nearly any organ system characterised by IgG4 positive plasma cell enriched infiltrate.
• Common presentations include
  • Major salivary gland and lachrymal gland involvement
  • Orbital pseudotumor
  • Autoimmune pancreatitis
  • Retroperitoneal fibrosis
  • Tubulointerstitial nephritis
  • Lymphadenopathy

Epidemiology:

• Common in men
• Median age- 6^th to 7^th decade

Etiology:

• Chronic antigenic stimulation in genetically predisposed individual:
  • Self: annexin A11, laminin-511, galectin-3, prohibitin
  • Unidentified antigens

Pathogenesis

1.

Chronic antigenic stimulation

↓

Oligoclonal expansion of circulating plasmablasts and CD4+ cytotoxic T cells

2.

Increased folliculat T helper cells

↓

• Plasmablastic differentiation
• IgG4 isotype switching
• Germinal center formation in affected sites

Clinical Features:

• Orbital pseudotumor
• Lachrymal and salivary glands
  • Mikulicz disease
  • Kuttnertumor
• Trachealstenosis
• Riedel'sthyroiditis
• Pulmonary
  • Asthma
  • Interstitial pneumonitis
  • Inflammatory pseudotumor of lung
  • Pleural disease
• GIT
  • Autoimmune pancreatitis
  • Sclerosing cholangitis/ cholecystitis
  • Inflammatory mesenteritis
  • Gastritis
• Lymphadenopathy
• CNS
  • Hypophysitis
  • Hypertrophic pachymeningitis
• Skin- Erythematous/ flesh coloured papules
• Cardiovascular
  • Constrictive pericarditis
  • Peri-aortitis
  • Coronary arteritis
• Mediastinal and retroperitoneal fibrosis
• Renal 
  • Tubulointerstitial nephritis
  • Membranous glomerulopathy

Investigations:

• Tissue biopsy
  • Dense, polyclonal, lymphoplasmacytic infiltrate enriched with IgG4 positive plasma cells (IgG4/IgG ratio- >40%)
  • Storiform fibrosis
  • Obliterative phlebitis
• Hemogram- Eosinophilia
• ESR- Elevated
• SPE- Polyclonal hypergammaglobulinemia
• Serum IgG subclass analysis- Elevated levels of IgG4 (Correlates with disease activity but it is not specific for IgG4 related disease)
• ANA- Positive
• RA factor- Positive
• Complement levels: Low
• CRP and IL-6- Typically normal
• PET: Positive

Prognosis:

• Good response to therapy, with indolent course

Differential Diagnosis:

• MulticentricCastleman disease
• Lymphoma
• Plasma cell neoplasm
• Hyper-eosinophilic syndrome

Criteria for diagnosis:

Extranodal presentation:

• Essential
  • Lymphoplasmacytic infiltrate with increased IgG4+ plasma cells and IgG4/IgG ratio >40%
  • Storiform fibrosis
  • Exclusion of well-defined entities that mimic IgG4-RD (e.g., ANCA-associated vasculitis, rheumatoid arthritis, multicentric Castleman disease, Rosai-Dorfman disease, inflammatory myofibroblastic tumour, chronic infection, lymphoma, plasma cell neoplasia).
• Desirable
  • Obliterative phlebitis
  • Clinically compatible features: IgG4-RD in other body sites, elevated serum IgG4 and response to steroids/rituximab

Nodal presentation:

• Essential
  • Extranodal IgG4-RD (prior, ongoing or subsequent development)
  • Polytypic IgG4+ plasma cells >400/mm2 and an IgG4/IgG >40%
  • Exclusion of well-defined entities that mimic IgG4-RD (as listed above), hyper-IL6 syndrome and syphilis.
• Desirable
  • IgG4+ plasma cells and eosinophils in fibrotic and/or interfollicular zone of lymph node

Pretreatment Work-up:

• History
• Examination
• Hemoglobin
• TLC, DLC
• Platelet count
• Peripheral smear
• LFT- Bili- T/D     SGPT:     SGOT:Albumin: Globulin:
• Creatinine
• Electrolytes: Na:        K:      Ca:        Mg:     PO4
• LDH
• HIV: 
• HBsAg:
• HCV

Treatment:

• Corticosteroids-Prednisolone- 0.6mg/kg/day initially, then gradual decrease of 5mg every 2 weeks. Better to give maintenance dose of 5mg/day, to prevent relapse of disease.
• Rituximab- As first/ second line therapy
• Intensive lymphoma chemotherapy regimens such as R-Benda- For severe and refractory cases