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Clinical characteristics of Mikulicz’s disease as an IgG4-related disease

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Mikulicz’s disease (MD) was considered to be a subtype of Sjögren’s syndrome (SS), based on histopathological similarities. However, recent studies have indicated that patients with MD show high serum IgG4 concentration, and suggested that MD is one of “IgG4-related disease” and distinguishable from SS. Therefore, we clinically and histopathologically examined the disease states of MD and SS in detail.

Materials and methods

Twenty patients with Mikulicz’s disease and 18 with SS were comparatively studied to determine clinical characteristics in MD patients.


Sialography in MD patients did not show the “apple-tree sign” typically seen in SS. Serologically, high serum IgG4 levels but not anti-SS-A or anti-SS-B antibodies were observed in MD. SS showed lymphocytic infiltration of various subsets with atrophy or severe destruction of the acini, while MD showed selective infiltration of IgG4+ plasma cells with hyperplastic germinal centers and mild acini destruction. Corticosteroid treatment of MD reduced IgG and IgG4 levels and improved salivary function. A negative correlation between disease duration and increasing rate of salivary flow was observed in MD.


These results suggested that the pathogenesis of MD might be different from those of SS. Clinical Relevance: early diagnosis and treatment of MD is important for the improvement of salivary function.

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  1. Morgan WS, Castleman B (1953) A clinicopathologic study of Mikulicz’s disease. Am J Pathol 29(3):471–503.20

    PubMed  Google Scholar 

  2. Yamamoto M, Takahashi H, Naishiro Y, Isshiki H, Ohara M, Suzuki C, Yamamoto H, Kokai Y, Himi T, Imai K, Shinomura Y (2008) Mikulicz’s disease and systemic IgG4-related plasmacytic syndrome (SIPS). Nihon Rinsho Men’eki Gakkai kaishi = Japanese Journal Of Clinical Immunology 31(1):1–8

    Article  PubMed  Google Scholar 

  3. Yamamoto M, Takahashi H, Ohara M, Suzuki C, Naishiro Y, Yamamoto H, Shinomura Y, Imai K (2006) A new conceptualization for Mikulicz’s disease as an IgG4-related plasmacytic disease. Modern rheumatology/the Japan Rheumatism Association 16(6):335–340

    Article  PubMed  Google Scholar 

  4. Yamamoto M, Takahashi H, Sugai S, Imai K (2005) Clinical and pathological characteristics of Mikulicz’s disease (IgG4-related plasmacytic exocrinopathy). Autoimmun Rev 4(4):195–200

    Article  PubMed  Google Scholar 

  5. Hamano H, Kawa S, Horiuchi A, Unno H, Furuya N, Akamatsu T, Fukushima M, Nikaido T, Nakayama K, Usuda N, Kiyosawa K (2001) High serum IgG4 concentrations in patients with sclerosing pancreatitis. N Engl J Med 344(10):732–738

    Article  PubMed  Google Scholar 

  6. Zen Y, Harada K, Sasaki M, Sato Y, Tsuneyama K, Haratake J, Kurumaya H, Katayanagi K, Masuda S, Niwa H, Morimoto H, Miwa A, Uchiyama A, Portmann BC, Nakanuma Y (2004) IgG4-related sclerosing cholangitis with and without hepatic inflammatory pseudotumor, and sclerosing pancreatitis-associated sclerosing cholangitis: do they belong to a spectrum of sclerosing pancreatitis? Am J Surg Pathol 28(9):1193–1203

    Article  PubMed  Google Scholar 

  7. Takeda S, Haratake J, Kasai T, Takaeda C, Takazakura E (2004) IgG4-associated idiopathic tubulointerstitial nephritis complicating autoimmune pancreatitis. Nephrology, dialysis, transplantation: official publication of the European Dialysis and Transplant Association - European Renal Association 19(2):474–476

    Article  Google Scholar 

  8. Zen Y, Kitagawa S, Minato H, Kurumaya H, Katayanagi K, Masuda S, Niwa H, Fujimura M, Nakanuma Y (2005) IgG4-positive plasma cells in inflammatory pseudotumor (plasma cell granuloma) of the lung. Hum Pathol 36(7):710–717

    Article  PubMed  Google Scholar 

  9. Hamed G, Tsushima K, Yasuo M, Kubo K, Yamazaki S, Kawa S, Hamano H, Yamamoto H (2007) Inflammatory lesions of the lung, submandibular gland, bile duct and prostate in a patient with IgG4-associated multifocal systemic fibrosclerosis. Respirology (Carlton, Vic) 12(3):455–457

    Article  Google Scholar 

  10. Kitagawa S, Zen Y, Harada K, Sasaki M, Sato Y, Minato H, Watanabe K, Kurumaya H, Katayanagi K, Masuda S, Niwa H, Tsuneyama K, Saito K, Haratake J, Takagawa K, Nakanuma Y (2005) Abundant IgG4-positive plasma cell infiltration characterizes chronic sclerosing sialadenitis (Kuttner’s tumor). Am J Surg Pathol 29(6):783–791

    Article  PubMed  Google Scholar 

  11. Masaki Y, Umehara H (2009) IgG4-related disease-the diagnostic confusion and how to avoid it. Nihon Rinsho Men’eki Gakkai kaishi/Japanese Journal Of Clinical Immunology 32(6):478–483

    Article  Google Scholar 

  12. Umehara H, Okazaki K, Masaki Y, Kawano M, Yamamoto M, Saeki T, Matsui S, Sumida T, Mimori T, Tanaka Y, Tsubota K, Yoshino T, Kawa S, Suzuki R, Takegami T, Tomosugi N, Kurose N, Ishigaki Y, Azumi A, Kojima M, Nakamura S, Inoue D, The Research Program for Intractable Disease by Ministry of Health, Labor and Welfare (MHLW) Japan G4 team (2011) A novel clinical entity, IgG4-related disease (IgG4RD): general concept and details. Mod Rheumatol 22(1):1–14

    Article  PubMed  Google Scholar 

  13. Umehara H, Okazaki K, Masaki Y, Kawano M, Yamamoto M, Saeki T, Matsui S, Yoshino T, Nakamura S, Kawa S, Hamano H, Kamisawa T, Shimosegawa T, Shimatsu A, Nakamura S, Ito T, Notohara K, Sumida T, Tanaka Y, Mimori T, Chiba T, Mishima M, Hibi T, Tsubouchi H, Inui K, Ohara H (2012) Comprehensive diagnostic criteria for IgG4-related disease (IgG4-RD). Mod Rheumatol 22:21–30

    Article  PubMed  Google Scholar 

  14. Tanaka A, Moriyama M, Nakashima H, Miyake K, Hayashida JN, Maehara T, Shinozaki S, Kubo Y, Nakamura S (2012) Th2 and regulatory immune reactions contributes to IgG4 production and the initiation of Mikulicz’s disease. Arthritis and Rheumatism 64:254–263

    Article  PubMed  Google Scholar 

  15. Ray K (2011) Connective tissue diseases: Immune responses in Mikulicz disease differ from those in SS. Nature reviews. Rheumatology 11:621

    Google Scholar 

  16. Fujibayashi T, Sugai S, Miyasaka N, Hayashi Y, Tsubota K (2004) Revised Japanese criteria for Sjögren’s syndrome (1999). Mod Rheumatol 14:425–34

    Article  Google Scholar 

  17. Vitali C, Bombardieri S, Jonsson R, Moutsopoulos HM, Alexander EL, Carsons SE, Daniels TE, Fox PC, Fox RI, Kassan SS, Pillemer SR, Talal N, Weisman MH, European Study Group on Classification Criteria for Sjogren’s Syndrome (2002) Classification criteria for Sjogren’s syndrome: a revised version of the European criteria proposed by the American–European Consensus Group. Ann Rheum Dis 61(6):554–558

    Article  PubMed  Google Scholar 

  18. Greenspan JS, Daniels TE, Talal N, Sylvester RA (1974) The histopathology of Sjogren’s syndrome in labial salivary gland biopsies. Oral surgery, oral medicine, and oral pathology 37(2):217–229.23

    Article  PubMed  Google Scholar 

  19. Rubin P, Holt JF (1957) Secretory sialograpy in diseases of the major salivary glands. Am J Roentgenol Radium Ther Nucl Med 77(4):75–598

    Google Scholar 

  20. Chisholm DM, Mason DK (1968) Labial salivary gland biopsy in Sjogren’s disease. J Clin Pathol 21(5):656–660

    Article  PubMed  Google Scholar 

  21. Hiroki A, Nakamura S, Shinohara M, Gondo H, Ohyama Y, Hayashi S, Harada M, Niho Y, Oka M (1996) A comparison of glandular involvement between chronic graft-versus-host disease and Sjogren’s syndrome. International journal of oral and maxillofacial surgery 25(4):298–307

    Article  PubMed  Google Scholar 

  22. Shimizu M, Moriyama M, Okamura K, Kawazu T, Chikui T, Goto TK, Ohyama Y, Nakamura S, Yoshiura K (2009) Sonographic diagnosis for Mikulicz disease. Oral surgery, oral medicine, oral pathology, oral radiology, and endodontics 108(1):105–113

    Article  PubMed  Google Scholar 

  23. Küttner H (1896) Uber entzndliche tumoren der submaxillarspeicheldruse. Beitr Klin Chir 15:815–834

    Google Scholar 

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This work was supported by “Research on Measures for Intractable Diseases” Project: matching fund subsidy from the Ministry of Health Labour and Welfare, Japan.

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The authors declare that they have no conflict of interest.

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Correspondence to Seiji Nakamura.

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Moriyama, M., Tanaka, A., Maehara, T. et al. Clinical characteristics of Mikulicz’s disease as an IgG4-related disease. Clin Oral Invest 17, 1995–2002 (2013).

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