IgG4-related disease—rare but you should not forget it

Pinheiro, Frederico Augusto Gurgel; Pereira, Ivanio Alves; de Souza, Alexandre Wagner Silva; Giardini, Henrique Ayres Mayrink; Cordeiro, Rafael Alves

doi:10.1186/s42358-024-00374-y

Frederico Augusto Gurgel Pinheiro ^**Correspondence: Frederico Augusto Gurgel Pinheiro fredagp@hotmail.com

contributed equally to this manuscript

read and approved the final manuscript

Rheumatology Division, Universidade Federal de São Paulo (UNIFESP), São Paulo, SP, Brazil

Universidade Federal de São Paulo – Disciplina de Reumatologia, Rua Botucatu, 740, 3o andar, São Paulo, SP 04023-062, Brazil

https://orcid.org/0000-0002-9023-3144

Ivanio Alves Pereira

contributed equally to this manuscript

read and approved the final manuscript

Universidade do Sul de Santa Catarina (UNISUL), Florianopolis, SC, Brazil

Alexandre Wagner Silva de Souza

contributed equally to this manuscript

read and approved the final manuscript

Rheumatology Division, Universidade Federal de São Paulo (UNIFESP), São Paulo, SP, Brazil

Henrique Ayres Mayrink Giardini

contributed equally to this manuscript

read and approved the final manuscript

Rheumatology Division, Faculdade de Medicina FMUSP, Universidade de Sao Paulo, Sao Paulo, SP, Brazil

Rafael Alves Cordeiro

contributed equally to this manuscript

read and approved the final manuscript

Rheumatology Division, Faculdade de Medicina FMUSP, Universidade de Sao Paulo, Sao Paulo, SP, Brazil

*Correspondence: Frederico Augusto Gurgel Pinheiro fredagp@hotmail.com

Competing interests

The authors declare that they have no competing interests.

Organ involvement	Manifestations	Clinical presentation/radiological or laboratory findings
Head and neck
Eye and orbit	Dacryoadenitis Dacryocystitis Orbital myositis Orbital pseudotumor Scleritis (rare) Uveitis (rare)	Lacrimal gland enlargement (typically bilateral) Syndrome sicca Diplopia Proptosis Ptosis Red eye, ocular pain
Salivary glands	Sialadenitis of submandibular, parotid and/or sublingual	Glandular swelling Typically, bilateral Nontender or occasionally mild tender Syndrome sicca
Ear, nose, and throat	Chronic rhinosinusitis Midline destructive lesion Pharyngitis Supraglottic stenosis Vocal cord lesion	Allergic rhinitis symptoms, sinusitis, nasal polyps, rhinorrhea, nasal obstruction Nasal septum perforation (rare) Anosmia, middle ear effusion Hoarseness, Dyspnea
Thyroid gland	IgG4-related thyroiditis (Riedel)	Neck mass (woody) and pressure Hypothyroidism Recurrent laryngeal nerve palsy
Thorax
Lungs and pleura	Parenchymal lung disease Pleural disease	Thickening of the bronco vascular bundles Interstitial lung disease, ground glass opacities Pulmonary nodules Pleural: effusion, thickening or nodules
Heart and pericardium	Coronary arteritis Pericarditis Pseudotumor	Perivasculitis around coronary arteries Coronary artery aneurysms Pericardial effusion Pericardial thickening Cardiac mass
Mediastinum	Fibrosing mediastinitis Paravertebral mass	Dyspnea, chest pain Mediastinal mass with compression of structures Paravertebral soft tissue, usually right-sided and located between T8-T11
Great vessels	Aortitis Periaortitis	Aortic wall thickening and enhancement Perivascular soft tissue around great vessels
Breast	IgG4-related mastitis	Painless breast mass
Abdomen and pelvis
Pancreas	Autoimmune pancreatitis type 1 Pseudotumor	Obstructive jaundice, abdominal pain, diabetes mellitus, malabsorption Diffuse pancreatic enlargement (sausage-shaped pancreas) Capsule-like pancreatic rim Pancreatic atrophy (long-standing disease) Irregular narrowing of pancreatic duct Pancreatic mass (simulating adenocarcinoma)
Hepatobiliary system	Sclerosing cholangitis Sclerosing cholecystitis Hepatic inflammatory pseudotumor	Jaundice, weight loss, abdominal pain Mass mimicking cholangiocarcinoma Intra- and extrahepatic biliary ductal dilatation Gallbladder wall thickening Hepatic mass, transaminitis
Kidneys	Tubulointerstitial nephritis Membranous glomerulonephritis	Elevated creatinine, proteinuria, hematuria, nephritic/nephrotic syndrome Diffuse kidney enlargement Renal cortical hypodensities Renal pelvic wall thickening Renal atrophy (long-standing disease)
Retroperitoneum	Retroperitoneal fibrosis (Ormond's disease) Aortitis and periaortitis	Back/flank pain, leg edema, hydronephrosis, deep venous thrombosis, varicocele Retroperitoneal mass or fat stranding Periaortic inflammation involving all or parts of the aorta distal to the renal arteries, extending to the iliac arteries
Nervous system
Pituitary	Hypophysitis	Hypopituitarism, diabetes insipidus, headache Pituitary enlargement Thickened pituitary stalk
Meninges	Hypertrophic pachymeningitis	Headache, cranial nerve palsies, vision disturbance, sensorineural hearing loss, seizures, motor weakness, limb numbness Hypertrophic and nodular meningeal thickening Hydrocephalus
Central nervous system		Dementia, hemiparesis, multifocal neurological defects
Peripheral nerves	Often asymptomatic— incidental radiological finding	Perineuritis, most typically of the infraorbital nerve
Lymph nodes	Often asymptomatic	Lymph node enlargement (generalized or localized), generally 1–3 cm in diameter, non-tender Does not have a preference for any set of lymph node

Type of biomarker	Examples	Comments
Diagnosis	Serum IgG4 Serum IgG4/IgG ratio Serum IgE and eosinophils CSF IgG4 indices Plasmablasts and plasma cells Serum C3 and C4 CD4 and/or CD8 SLAMF7 + CTLs ¹⁸FDG-PET	Elevated in 55–97% of patients. Correlates with disease burden When > 10%, it increases specificity in the case of normal serum IgG4 Elevated in 30% of patients regardless of atopic background High in IgG4-related hypertrophic pachymeningitis Expanded in peripheral blood regardless of serum IgG4 concentration Reduced levels suggest active disease, particularly in patients with IgG4-related kidney disease (mostly tubulointerstitial nephritis) Expanded in peripheral blood during active disease Useful for staging purposes and the definition of alternative biopsy sites. Caution when interpreting lymph nodes (indistinguishable from reactive and neoplastic lymph nodes)
Disease activity	Serum IgG4, IgE, and eosinophils Serum IgG4/IgG ratio CSF IgG4 indices Plasmablasts and plasma cells Serum C3 and C4 Serum ESR/CRP* CD4 and/or CD8 SLAMF7 + CTLs ¹⁸FDG-PET	Decrease with disease response to treatment. It may not normalize at disease remission. Marked (> 2x) increase after remission should raise the possibility of disease flare Decrease in disease response to treatment Decrease in disease response to treatment Decrease in disease response to treatment and increase at flare They may normalize in remission and decrease during flares, especially in kidney involvement Correlate with disease activity, especially in retroperitoneal and aortic involvement Decrease with disease response to treatment and increase with flare ¹⁸FDG uptake reduced after treatment. Caution when interpreting lymph nodes (indistinguishable from reactive and neoplastic lymph nodes)

[1] *Correspondence: Frederico Augusto Gurgel Pinheiro fredagp@hotmail.com

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IgG4-related disease—rare but you should not forget it

Abstract