Intern Med

□

ORIGINAL ARTICLE

□

Serial Changes of Elevated Serum IgG4 Levels in IgG4-related Systemic Disease Taku Tabata 1, Terumi Kamisawa 1, Kensuke Takuma 1, Naoto Egawa 1, Keigo Setoguchi 1, Koji Tsuruta 2, Taminori Obayashi 3 and Tsuneo Sasaki 4

Abstract Objective Autoimmune pancreatitis (AIP) and Mikulicz’s disease have recently been recognized as pancreatic or salivary gland lesions of IgG4-related systemic disease. These are frequently associated with elevated serum IgG4 levels. This study aimed to clarify clinical implications of serial changes of elevated serum IgG4 levels in IgG4-related systemic diseases. Methods Serial changes of elevated serum IgG4 levels were examined in patients with IgG4-related systemic diseases. Patients Serial changes of elevated serum IgG4 levels were examined in 44 patients: AIP (n=24), Mikulicz’s disease (n=8), pancreatic cancer (n=5), bile duct cancer (n=1), sclerosing cholangitis (n=1), hypereosinophilic syndrome (n=1), chronic thyroiditis (n=1), hypophysitis (n=1), idiopathic pancreatitis (n=1), and Behcet’s disease (n=1). Results The serum IgG4 levels decreased in all patients with AIP and Mikulicz’s disease after steroid therapy. The serum IgG4 levels were normalized in 46% of AIP patients and 38% of Mikulicz’s disease patients. The serum IgG4 levels were not normalized at remission in 3 of 4 relapsed AIP patients, and re-elevation of serum IgG4 levels was detected in all relapsed patients. Elevated serum IgG4 levels decreased in 3 patients with pancreatic cancer after resection or chemotherapy, and decreased in patients with hypereosinophilic syndrome, sclerosing cholangitis, and hypophysitis after steroid therapy. Conclusion Measurement of serial serum IgG4 levels is useful to determine the disease activity of IgG4related systemic diseases. Key words: IgG4, autoimmune pancreatitis, Mikulicz’s disease, pancreatic cancer (Intern Med 50: 69-75, 2011) (DOI: 10.2169/internalmedicine.50.4321)

after steroid therapy. Furthermore, whether changes in serum IgG4 levels can predict or detect early recurrence of AIP is also not known. Since abundant infiltration of IgG4-positive cells and T lymphocytes with fibrosis has been detected in various organs of AIP patients, we proposed the existence of a novel clinicopathological entity, an IgG4-related systemic (sclerosing) disease, and suggested that AIP is a pancreatic lesion of this systemic disease. Serum IgG4 levels are most frequently elevated in IgG4-related systemic disease (4-6). Mikulicz’s disease is a unique condition that involves bi-

Introduction Autoimmune pancreatitis (AIP) is a particular type of pancreatitis with a presumed autoimmune etiology. Serum IgG4 levels are frequently and significantly elevated in AIP patients (1, 2). AIP responds well to steroid therapy, but some AIP cases recur (3). Serum IgG4 levels decrease after steroid therapy in AIP patients, but the precise serial changes are unknown. It is not known when and what percentage of serum IgG4 levels are normalized in AIP patients １

Department of Internal Medicine, Tokyo Metropolitan Komagome Hospital, Japan, ２Department of Surgery, Tokyo Metropolitan Komagome Hospital, Japan, ３Department of Laboratory Medicine, Tokyo Metropolitan Komagome Hospital, Japan and ４Department of Chemotherapy, Tokyo Metropolitan Komagome Hospital, Japan Received for publication August 4, 2010; Accepted for publication September 30, 2010 Correspondence to Dr. Terumi Kamisawa, [email protected]

69

Intern Med 50: 69-75, 2011

DOI: 10.2169/internalmedicine.50.4321

Table 1. Patients with Elevated Serum IgG4 Levels Diagosis

Total cases

Elevated IgG4

Rate

Mean value, mg/dL (Range)

47

34

72.3%

437.8 (11-2490)

Mikulicz’s disease

19

19

100%

602.6 (21-1910)

Pancreatic cancer

136

8

5.9%

57.4 (280 mg/ dL, compared with 53% of AIP patients (11). In this series, elevated serum IgG4 levels decreased in 2 patients with pancreatic cancer after pancreatoduodenectomy or distal pancreatectomy and in 1 patient with advanced pancreatic cancer after chemotherapy. These patients had no serological, radiological, or histological evidence of AIP. Abundant infiltration of IgG4-positive plasma cells was detected in the cancerous areas of the pancreas, duodenal mucosa, and the swollen regional lymph nodes in the 2 patients whose serum IgG4 levels decreased after resection, but it was detected only in the peripancreatic lymph nodes in another patient whose serum IgG4 levels did not change after resection. Raina et al. re-

vated serum IgG4 levels decreased spontaneously without any medication. In a patient with advanced bile duct cancer, the serum IgG4 levels increased 1 year later without any therapy. In patients with Behcet’s disease and idiopathic pancreatitis, the serum IgG4 levels did not change (Table 4).

Discussion IgG4 is a subtype of immunoglobulin G (IgG), which accounts for 3-6% of total IgG. It is unique among the IgG subclass in its inability to bind C1q complement, and in its low affinity for target antigen (17). Hamano et al. reported the frequent and significant elevation of serum IgG4 levels in AIP patients and reported that an IgG4 cutoff value of 135 mg/dL resulted in high accuracy (97%), sensitivity (95%), and specificity (97%) in distinguishing AIP from pancreatic cancer (12). Based on histological and immunohistochemical examination of various organs of AIP patients, we proposed the existence of a novel clinicopathological entity, an “IgG4-related systemic (sclerosing) disease”; we suggested that AIP is a pancreatic lesion of this systemic disease, and that the extrapancreatic lesions of AIP are clinical manifestations of organs involved in this disease (4-6). AIP responds well to steroid therapy, and serum IgG4 levels decrease along with amelioration of pancreatic imaging findings. However, although recurrence occurs in about 30-40% of AIP patients during steroid tapering, maintenance therapy, or after cessation of steroid therapy, there are no definite markers to predict or detect relapse early (18). In this study, elevated serum IgG4 levels decreased in all AIP patients after steroid therapy. Elevated serum IgG4 levels became normalized in 17% at 1 month, and in 46% at 3 months after starting steroid, but they failed to be normalized in 54% 12 months later. Elevated serum IgG4 levels were not normalized in 3 of 4 relapsed patients. In the other relapsed patient, normalized serum IgG4 levels began to increase gradually after cessation of steroid therapy. Although serum IgG4 levels were not associated with an increased risk of relapse on multivariate analysis in the study of 73

Intern Med 50: 69-75, 2011


should be undertaken on the serial changes of serum IgG4 levels. In conclusion, the measurement of serial serum IgG4 levels is useful to determine disease activity of IgG4-related systemic diseases.

ported that abundant infiltration of IgG4-positive plasma cells was detected in the common bile duct of one patient, in the lymph nodes of one patient, and in the duodenal mucosa of one patient with pancreatic cancer and elevated serum IgG4 levels (20). It is unknown whether pancreatic cancer can initiate an immunological response with subsequent infiltration of IgG4-positive plasma cells in the pancreatic and peripancreatic area, or whether pancreatic cancer occurs independently in patients with subclinical IgG4-related systemic disease who had infiltration of IgG4-positive plasma cells in various organs but did not show symptoms. However, it is true that elevated serum IgG4 levels decreased with remission of pancreatic cancer with IgG4-related manifestations. The reduction of the organs or tissues involved in IgG4-related disease may contribute to the decrease of the serum IgG4 levels. The elevated serum IgG4 levels decreased after steroid therapy in a patient with hypereosinophilic syndrome, in a patient with sclerosing cholangitis, and in a patient with hypophysitis. Some cases of sclerosing cholangitis (6, 9, 21) and hypophysitis (22) have been reported to be associated with AIP, and they appear to be part of IgG4-related systemic disease. Although the relationship between hypereosinophilic syndrome and IgG4-related sclerosing disease is unclear, AIP patients sometimes show peripheral blood eosinophilia (23). Zen et al. reported that IgG4-related disease is characterized by an immune reaction predominantly mediated by T helper (Th) 2 cells producing interleukin (IL)-5 or IL-13 (24). IL-5 is important for eosinophilic infiltration and activation, and IL-13 is another T-cell-derived cytokine involved in the eosinophilic infiltration (25). Elevated serum IgG4 levels in a patient with chronic thyroiditis decreased spontaneously. The relationship between chronic thyroiditis and IgG4 is unknown, but hypothyroidism has been reported in 22% of AIP patients (9). Considering that some AIP cases improve spontaneously (18), chronic thyroiditis in this case may be associated with IgG4related systemic disease. Elevated serum IgG4 levels also decreased in patients with IgG4-related systemic disease other than AIP and Mikulicz’s disease, with or without steroid therapy. In summary, the present study demonstrated the following: 1) elevated serum IgG4 levels decreased after steroid therapy in all patients with IgG4-related systemic disease, but about half of them were not normalized; 2) persistent elevated serum IgG4 levels may be a predictor for relapse, and re-elevation of serum IgG4 levels suggests relapse; and 3) serum IgG4 levels may decrease with reduction of lesions involved in IgG4-related disease. The biggest weakness of this study is small number of cases which might not render it sufficient to generalize the results, especially with regard to the findings based on only one patient. However, most IgG4-related systemic diseases are relatively rare, and follow-up measurement of serum IgG4 levels is sometimes difficult. Further prospective study

The authors state that they have no Conflict of Interest (COI). Acknowledgement The Research Committee of Intractable Pancreatic Diseases (Principal investigator: Tooru Shimosegawa) provided by the Ministry of Health, Labour, and Welfare of Japan.

References 1. Finkelberg DL, Sahani D, Deshpande V, Brugge WR. Autoimmune pancreatitis. N Engl J Med 355: 2670-2676, 2006. 2. Park DH, Kim MH, Chari ST. Recent advances in autoimmune pancreatitis. Gut 58: 1680-1689, 2009. 3. Kamisawa T, Shimosegawa T, Okazaki K, et al. Standard steroid treatment for autoimmune pancreatitis. Gut 58: 1504-1507, 2009. 4. Kamisawa T, Funata N, Hayashi Y, et al. A new clinicopathological entity of IgG4-related autoimmune disease. J Gastroenterol 38: 982-984, 2003. 5. Kamisawa T, Nakajima H, Egawa N, Funata N, Tsuruta K, Okamoto A. IgG4-related sclerosing disease incorporating sclerosing pancreatitis, cholangitis, sialadenitis and retroperitoneal fibrosis with lymphadenopathy. Pancreatology 6: 132-137, 2006. 6. Kamisawa T, Okamoto A. Autoimmune pancreatitis: proposal of IgG4-related sclerosing disease. J Gastroenterol 41: 613-625, 2006. 7. Mikulicz J. Uber eine eigenartige symmetrische Erkrankung der Thranen- und Mundspeicheldrusen. Beitr. z. Chir. Festschr. f. Theodor Billroth, Stuttgart; 610-630, 1892 (in German). 8. Yamamoto M, Takahashi H, Ohara M, et al. A new conceptualization for Mikulicz’s disease as an IgG4-related plasmacytic disease. Mod Rheumatol 16: 335-340, 2006. 9. Hamano H, Arakura N, Muraki T, Ozaki Y, Kiyosawa K, Kawa S. Prevalence and distribution of extrapancreatic lesions complicating autoimmune pancreatitis. J Gastroenterol 41: 1197-1205, 2006. 10. Tabata T, Kamisawa T, Takuma K, Anjiki H, Egawa N. Serum IgG4 concentrations and IgG4-related sclerosing disease. Clin Chim Acta 408: 25-28, 2009. 11. Ghazale A, Chari ST, Smyrk TC, et al. Value of serum IgG4 in the diagnosis of autoimmune pancreatitis and in distinguishing it from pancreatic cancer. Am J Gastroenterol 102: 1646-1653, 2007. 12. Hamano H, Kawa S, Horiuchi A, et al. High serum IgG4 concentrations in patients with sclerosing pancreatitis. N Engl J Med 344: 732-738, 2001. 13. Otsuki M, Chung JB, Okazaki K, et al. Asian diagnostic criteria for autoimmune pancreatitis: consensus of the Japan-Korea symposium on autoimmune pancreatitis. J Gastroenterol 43: 403-408, 2008. 14. Yamamoto M, Ohara M, Suzuki C, et al. Elevated IgG4 concentrations in serum of patients with Mikulicz’s disease. Scand J Rheumatol 33: 432-433, 2004. 15. Kamisawa T, Chen PY, Tu Y, et al. Pancreatic cancer with a high serum IgG4 concentration. World J Gastroenterol 12: 6225-6228, 2006. 16. Kamisawa T, Shimosegawa T, Okazaki K, et al. Standard steroid treatment for autoimmune pancreatitis. Gut 58: 1504-1507, 2009. 17. Van der Zee JS, van Swieten P, Aalberse RC. Inhibition of complement activation by IgG4 antibodies. Clin Exp Immunol 64: 415-422, 1986.

74

Intern Med 50: 69-75, 2011


18. Kamisawa T, Okazaki K, Kawa S, Shimosegawa T, Tanaka M. Japanese consensus guidelines for management of autoimmune pancreatitis: III. Treatment and prognosis of AIP. J Gastroenterol 45: 471-477, 2010. 19. Kubota K, Iida H, Fujisawa T, et al. Clinical factors predictive of spontaneous remission or relapse in cases of autoimmune pancreatitis. Gastrointest Endosc 66: 1142-1151, 2007. 20. Raina A, Krasinskas AM, Greer JB, et al. Serum immunoglobulin G fraction 4 levels in pancreatic cancer. Elevations not associated with autoimmune pancreatitis. Arch Pathol Lab Med 132: 48-53, 2008. 21. Kamisawa T, Takuma K, Anjiki H, et al. Sclerosing cholangitis associated with autoimmune pancreatitis differs from primary scle-

rosing cholangitis. World J Gastroenterol 15: 2357-2360, 2009. 22. Wong S, Lam WY, Wong WK, Lee KC. Hypophysitis presented as inflammatory pseudotumor in immunoglobulin G4-related systemic disease. Hum Pathol 38: 1720-1723, 2007. 23. Kamisawa T, Anjiki H, Egawa N, Kubota N. Allergic manifestations in autoimmune pancreatitis. Eur J Gastroenterol Hepatol 21: 1136-1139, 2009. 24. Zen Y, Fujii T, Harada K, et al. Th2 and regulatory immune reactions are increased in immunoglobulin G4-related sclerosing pancreatitis and cholangitis. Hepatology 45: 1538-1546, 2007. 25. Romagnani S. Regulation of the development of type 2 T-helper cells in allergy. Curr Opin Immunol 6: 838-846, 1994.

Ⓒ 2011 The Japanese Society of Internal Medicine http://www.naika.or.jp/imindex.html

75