Tracking the Trickster, Or: The Confounding Tale of IgG4-RD (Chapter I)


IgG4-Related Disease (IgG4-RD): one of the most perplexing culprits ever to defy a rheumatologist. Here, we present a few basics about its shadowy past and its current known identity. Later Chapters in our series will invite you to track the diagnosis yourself and to discover the best treatment strategies.

Surely IgG4-Related Disease (IgG4-RD) is one of the most perplexing culprits ever to defy a rheumatologist. Here, in this first chapter of our series on the subject, we present a few basics about its shadowy past and its current known identity (including the curious fact that, although we can track it down, it still goes by an alias).

In the second Chapter you can follow a trail of quizzes to see whether you could capture a diagnosis.

In our final installment, we willdeliver the sentence: The most effective strategies for treatment.

But first:

The Elusive History of IgG4-RD  

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The Elusive History of IgG4-RD

What we now call the IgG4-RD spectrum includes many seemingly disparate eponymic syndromes of the previous century,1-3 including

• Küttner’s Tumor (enlargement of the submandibular glands),[[{"type":"media","view_mode":"media_crop","fid":"22700","attributes":{"alt":"","class":"media-image media-image-right","id":"media_crop_8934528686983","media_crop_h":"0","media_crop_image_style":"-1","media_crop_instance":"1674","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":"height: 207px; width: 145px; float: right;","title":" ","typeof":"foaf:Image"}}]]

• Miklucz’s Disease (enlargement of salivary gland, including the parotid and submandibular),

• Ormond’s Disease (retroperitoneal fibrosis), and

• Riedel’s Thyroiditis (fibrotic replacement of thyroid, often extending beyond the gland)

as well as:

• Sclerosing pancreatitits (autoimmune pancreatitis, Type 1), and

• Idiopathic orbital inflammation/pseudotumor.

These many pieces began to fall into place in 2001, when Japanese investigators observed that patients with sclerosing pancreatitis had elevated concentrations of serum IgG4.4

However, the plot has thickened, as we have discovered that:

!!!   30% of patients with IgG4-RD actually have a normal serum IgG4 concentration.5

!!!   An elevated serum IgG4 concentration is neither highly specific nor sensitive for the diagnosis of IgG4-RD.6

!!!    IgG4+ plasma cell infiltrates seen in IgG4-RD are also characteristic of granulomatosis with polyangiitis, malignancies, and a number of other conditions.7,8

So where does that leave us?

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So where does that leave us?

The pathologic features of IgG4-RD are not unique to this condition. It is the combination of findings that is unique, and the shared features of the disease, irrespective of the organ involved.

The spectrum of IgG4-RD includes diseases that are:

•  Immune-mediated

•  Fibro-inflammatory

•  Often tumefactive (responsible for pseudotumor lesions and/or focal inflammation)

•  Likely to cause organ dysfunction and failure if inadequately treated.1

Despite all of the confounding factors relating to IgG4 in this condition, it is named for the immunoglobulin nonetheless. Two years ago, experts agreed in a consensus statement on terminology to refer to this condition as IgG4-Related Disease.9 Standard terminology for specific organ involvement has also been defined; for instance, Kuttner’s disease is now referred to as IgG4-Related Sialoadenitis.9

The Culprit’s Known Whereabouts:

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The Culprit’s Known Whereabouts:

IgG4-RD may affect any of a number of anatomic locations. Some of the common sites appear in the graphic below:2-3

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The disease may be either:

synchronous:  lesions at multiple sites at the same time


metachronous:  lesions at a single site with a probable history of IgG4-RD at another site.

Some time in the past:  Sclerosing pancreatitis)

Patient demographics do not offer any useful clues. Patients are:

•  Often middle-aged, between 50 and 60 (but not always);

•  Often men (but manifestations in the head and neck are equally common in both genders);11

•  Of various ethnic backgrounds.3,19


Click here for the Diagnostic Puzzler. Will you be able to track the Trickster, or will IgG4 Related Disease elude you, as it has so many others?


1. Stone JH, Zen Y, Deshpande V. IgG4-related disease. N Engl J Med (2012) 366:539-551.

2. Carruthers MN, Stone JH, Khosroshahi A. The latest on IgG4-RD: a rapidly emerging disease. Curr Opin Rheumatol (2012) 24:60-69.|

3. Ebbo M, Daniel L, Pavic M, et al. IgG4-related systemic disease: features and treatment response in a French cohort: results of a multicenter registry. Medicine (Baltimore) (2012) 91:49-56.

4. Hamano H, Kawa S, Horiuchi A, et al. High serum IgG4 concentrations in patients with sclerosing pancreatitis. N Engl J Med (2001) 344:732-738.

5. Khosroshahi A, Stone JH. IgG4-related systemic disease: the age of discovery. Curr Opin Rheumatol (2011) 23:72-73.

6. Khosroshahi A, Cheryk L, Carruthers M, et al. Spuriously Low Serum IgG4 Concentrations Caused by the Prozone Phenomenon in IgG4-Related Disease. Arthritis Rheum (2013) 66:213-217.

7. Brenner I, Roth S, Puppe B, et al. Primary cutaneous marginal zone lymphomas with plasmacytic differentiation show frequent IgG4 expression. Mod Pathol (2013) 26:1568-1576.

8. Strehl JD, Hartmann A, Agaimy A. Numerous IgG4-positive plasma cells are ubiquitous in diverse localised non-specific chronic inflammatory conditions and need to be distinguished from IgG4-related systemic disorders. J Clin Pathol (2011) 237-243.

9. Stone JH, Khosroshahi A, Deshpande V, et al. Recommendations for the nomenclature of IgG4-related disease and its individual organ system manifestations. Arthritis Rheum (2012) 64:3061-3067.

10. Kamisawa T, Chari ST, Lerch MM, et al. Recent advances in autoimmune pancreatitis: type 1 and type 2. Gut (2013) 62:1373-1380.

11. Ferry JA, Deshpande V. IgG4-related disease in the head and neck. Semin Diagn Pathol (2012) 29:235-244.

12.  Khosroshahi A, Carruthers MN, Stone JH, et al.Rethinking Ormond's disease: "idiopathic" retroperitoneal fibrosis in the era of IgG4-related disease. Medicine (Baltimore) (2013) 92:82-91.

13. Stone JR. Aortitis, periaortitis, and retroperitoneal fibrosis, as manifestations of IgG4-related systemic disease. Curr Opin Rheumatol (2011) 23:88-94.

14.  Stone JH, Khosroshahi A, Hilgenberg A, et al. IgG4-related systemic disease and lymphoplasmacytic aortitis. Arthritis Rheum (2009) 60:3139-3145.

15. Stone JH, Khosroshahi A, Deshpande V, Stone JR. IgG4-related systemic disease accounts for a significant proportion of thoracic lymphoplasmacytic aortitis cases. Arthritis Care Res (Hoboken) (2010) 62:316-322.

16. Cheuk W, Chan JK. Lymphadenopathy of IgG4-related disease: an underdiagnosed and overdiagnosed entity. Semin Diagn Pathol (2012) 29:226-234.

17. Saeki T, Kawano M. IgG4-related kidney disease. Kidney Int (2013)

18. Bourlon MT, Sanchez-Avila M, Chable-Montero F, Arceo-Olaiz R. IgG4-Related Autoimmune Prostatitis: Is It an Unusual or Underdiagnosed Manifestation of IgG4-Related Disease? Case Rep Urol (2013) 2013:295472.

19. Ebbo M, Schleinitz N. IgG4-related disease (IgG4-RD). Ann Pathol (2012) 32(5 Suppl):S70-71.

20. Deshpande V, Zen Y, Chan JK, et al. Consensus statement on the pathology of IgG4-related disease. Mod Pathol (2012) 25:1181-1192.

21. Sumimoto K, Uchida K, Mitsuyama T, et al. A proposal of a diagnostic algorithm with validation of International Consensus Diagnostic Criteria for autoimmune pancreatitis in a Japanese cohort. Pancreatology (2013) 13:230-237.

22. Khosroshahi A, Stone JH. Treatment approaches to IgG4-related systemic disease. Curr Opin Rheumatol (2011) 23:67-71.

23. Khosroshahi A, Carruthers MN, Deshpande V, et al. Rituximab for the treatment of IgG4-related disease: lessons from 10 consecutive patients. Medicine (Baltimore) (2012) 91:57-66.

24. Khosroshahi A, Bloch DB, Deshpande V, Stone JH. Rituximab therapy leads to rapid decline of serum IgG4 levels and prompt clinical improvement in IgG4-related systemic disease. Arthritis Rheum (2010) 62:1755-1762.

25. Nirula A, Glaser SM, Kalled SL, Taylor FR. What is IgG4? A review of the biology of a unique immunoglobulin subtype. Curr Opin Rheumatol (2011) 23:119-124.





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