Tracking the Trickster, Or: The Confounding Tale of IgG4RD (Chapter II)

February 11, 2014

In Chapter I, you read the history and baffling description of IgG4-Related Disease, which goes by so many disguises, and learned of its previously known whereabouts. Herein, you have the opportunity to track it by solving a series of challenges.

In Chapter I, already presented, you read the history and baffling description of the culprit that goes by so many disguises, and learned of its previously known whereabouts.

Herein, you have the opportunity to track IgG4-Related Disease (IgG4-RD) by solving a series of challenges.

The Diagnostic Puzzlers

Patients with IgG4-RD present a wide variety of clues to their condition, often related to the affected organ. In following this trail of quizzes, tread carefully to avoid going up a blind alley that would lead you to the wrong suspect.

  • Swelling is a common presenting feature in IgG4-RD. Lymphadenopathy may be the sole manifestation, or it may arise in patients with involvement in other organs. Swelling also commonly affects the
  • lacrimal gland(s),
  • salivary gland(s), and
  • orbital adnexal structures.

True or False:  In IgG4-RD, salivary gland swelling is almost always associated with symptoms of sicca.

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[False. Salivary gland involvement is often not associated with sicca symptoms]

  • Pain is a common presenting symptom among patients with IgG4-RD and which of the following conditions:
  • Retroperitoneal fibrosis
  • Swelling of the head and neck structures
  • Pancreatitis

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[A and C. Swelling of the head and neck structures is often not painful.]

       [True:  Patients often feel well, except for the pain and swelling. Constitutional symptoms such as fatigue and weight loss are rarely the prominent feature of the presentation. In fact, “B symptoms” including fevers and night sweats are uncommon and should raise concern for an alternative process.]

  •  Which of the following is not a characteristic of IgG4-RD?
  • Arthralgia
  • Ensethopathy
  • Painless jaundice
  • Complete absence of symptoms or lesions
  • None of the above

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[E. None of the above. Any or all of these may occur. Patients commonly describe symptoms of arthralgia and enthesopathy (as opposed to true synovitis), although these features have been under-reported in the literature. Patients with pancreatic involvement may present with painless jaundice, and are often taken to the operating room for a Whipple procedure for presumed pancreatic cancer. Some patients are identified incidentally during imaging for unrelated reasons, and have not noticed any symptoms or lesions.]

  • Your female patient has sialoadenitis. A blood panel comes back positive for both Ro and La antibodies.

True or False: This antibody profile clinches the diagnosis as IgG4-RD.

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[False. Unlike many patients with Sjögren syndrome, patients with IgG4-RD who have sialoadenitis do not typically have Ro or La antibodies. Besides, and this is crucial: Only a biopsy can diagnose IgG4 definitively.20]

  • Repeat: Only a biopsy can diagnose IgG4-RD definitively. However, radiologic features may be useful, in association with an elevated serum IgG4 concentration, in only one of the following conditions. Which one?
  • Interstitial nephritis
  • Retroperitoneal fibrosis
  • Sialoadenitis
  • Sclerosing pancreatitis
  • Prostatitis

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[D. IgG4-related pancreatitis.21 Radiologic diagnosis is not useful for disease at any other sites.]

Read on for an illustrated guide to the histopathology of IgG4.

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Are you ready to learn about treatment? Click here for Chapter III.


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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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