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Primer: IgG4-Related Diseases

IgG4-related diseases first appeared in the medical literature in 2003, but greater awareness is needed to ensure early diagnosis.

IgG4-related disease can sometimes be confused for sarcoidosis and some forms of systemic vasculitis and other protein diseases.

This immune-mediated condition affects multiple organs and it links many disorders previously considered isolated, such as single organ diseases.

IgG4-related diseases first appeared in the medical literature in 2003. Since then, the disease has been identified in nearly every organ system and most clinical features have been mapped1. Effective treatments have been identified and important advances made in disease pathophysiology, though it’s not yet fully understood, write John H. Stone and colleagues in a December 2014 review published in The Lancet.

“Greater awareness in the medical community of this protein disease is needed to ensure earlier diagnoses, which can prevent severe organ damage, disabling tissue fibrosis and death,” the researchers wrote.  [[{"type":"media","view_mode":"media_crop","fid":"49026","attributes":{"alt":"©emresenkartalShutterstock.com","class":"media-image media-image-right","id":"media_crop_4186637394580","media_crop_h":"0","media_crop_image_style":"-1","media_crop_instance":"5893","media_crop_rotate":"0","media_crop_scale_h":"0","media_crop_scale_w":"0","media_crop_w":"0","media_crop_x":"0","media_crop_y":"0","style":"font-size: 13.008px; line-height: 1.538em; float: right;","title":"©emresenkartalShutterstock.com","typeof":"foaf:Image"}}]]

IgG4-related disease is probably underdiagnosed, especially in North America and Europe 2.  

Typically, patients with IgG4-related disease are middle-aged men.

The authors of the Lancet review write that IgG4-related diseases deserve more awareness because it is treatable, but also learning more about the immune dysregulation associated with IgG4-related disease can explain much about the human immune system.

Writing in the Feb. 15 issue of Therapeutics and Clinical Risk Management, J. Zwerina of the Ludwig Boltzmann-Institute of Osteology in Austria, addresses the challenges of long-term disease management.

“The true challenge in IgG4-RD is probably its long-term management, as relapses happen frequently, regardless of the therapy chosen. Thus, further advances in the treatment of IgG4-RD will most likely rather come with new parameters such as plasmablasts, which could allow monitoring of disease activity and exact timing of retreatment in order to prevent relapses before they actually happen,” Zwerina writes.


Tissue biopsy is the key to diagnosis of IgG4-related disease 1. Primary features include lymphoplasmacytic infiltration, obliterative phlebitis and storiform fibrosis. Eosinophils are also commonly present.

Organ Involvement

Organ dysfunction could be evident for months or years before diagnosis. Disease can progress with occasional spontaneous improvements or long plateaus of disease quiescence.

Therapeutic Approaches

Treatment is vastly different from autoimmune diseases, such as Sjogren’s syndrome, granulomatosis with polyangiitis, and membranous nephropathy.


An accurate diagnosis requires a biopsy, interpretation of the pathology and a rigorous clinicopathological correlation.

Conditions known to be part of IgG4-related disease include:

  • Autoimmune pancreatitis (lymphoplasmacytic sclerosing pancreatitis)
  • Eosinophilic angiocentric fibrosis (affecting the orbits and upper respiratory tract)
  • Fibrosing mediastinitis
  • Hypertrophic pachymeningitis
  • Idiopathic hypocomplementaemic tubulointerstitial nephritis with extensive tubulointerstitial deposits
  • Inflammatory pseudotumor (affecting the orbits, lungs, kidneys, and other organs)
  • Kuttner’s tumour (affecting the submandibular glands)
  • Mikulicz’s disease (affecting the salivary and lacrimal glands)
  • Multifocal fibrosclerosis (commonly affecting the orbits, thyroid gland, retroperitoneum, mediastinum, and other tissues and organs)
  • Periaortitis and periarteritis
  • Inflammatory aortic aneurysm.
  • Retroperitoneal fibrosis (Ormond’s disease)
  • Riedel’s thyroiditis
  • Sclerosing mesenteritis



(1) Terumi Kamisawa, Yoh Zen, Shiv Pillai, John H Stone. "IgG4-related disease," Dec. 3, 21014,

The Lancet.

http://dx.doi.org/10.1016/S0140-6736(14)60720-0 (2) Lang D, Zwerina J, Pieringer H. "IgG4-related disease: current challenges and future prospects,"

Therapeutics and Clinical Risk Management.

Feb. 15, 2016.