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Scand J Rheumatol 2014;43:70–74
IgG4-related disease in a Chinese cohort: a prospective study H Chen1, W Lin1, Q Wang1, Q Wu1, L Wang1, Y Fei1, W Zheng1, G Fei2, P Li1, YZ Li1, W Zhang1, Y Zhao1, X Zeng1, F Zhang1
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1 Department of Rheumatology, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Science, Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing, and 2Department of Gastroenterology, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Science, Beijing, China
Objectives: To report the clinical, laboratory, and histological characteristics in a cohort of 28 Chinese patients with immunoglobulin G4-related disease (IgG4-RD). Method: The patients were admitted to, or were out-patients in, Peking Union Medical College Hospital (PUMCH) between January 2011 and May 2012 according to the criteria for IgG4-RD. Clinical presentations, imaging studies, serum Ig subclass assays, and histological examinations were performed in all patients. Results: The 28 patients (male-to-female ratio 1.8:1) enrolled in this study had a mean age at onset of disease of 51.5 years and the duration of symptoms before diagnosis was 20.4 months; 57% of the patients presented with a history of allergic disease. The most common symptoms were salivary and lacrimal gland swelling, and abdominal pain. Most patients (93%) presented with multiple organ involvement. Elevated erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels were observed in 16 (57%) and seven (25%) patients, respectively. The mean serum IgG4 level was 1142.3 mg/dL (range 149–3870 mg/dL). Eosinophilia was noted in 11 (39%) patients. IgE levels were elevated in all of eight patients examined. Lymphocyte and plasma cell infiltration and IgG4-positive plasma cell infiltration, together with tissue fibrosis, were the predominant histological findings. Most patients (93%) were given prednisone (0.5–0.8 mg/kg/day). Immunosuppressive agents were administered in 19 (68%) patients. Patients were followed for a mean of 6.3 months; efficacy was noted in more than 90% of cases. Conclusions: IgG4-RD is a chronic, systemic, multiorgan inflammatory disorder. IgG4-RD patients generally response well to glucocorticoids but the treatment should be individualized.
Immunoglobulin G4-related disease (IgG4-RD) is a recently defined emerging clinical entity characterized by tissue infiltration by IgG4-positive (IgG4+) plasma cells, tissue fibrosclerosis, and elevated serum IgG4 concentration (1). Hamano et al first reported elevated serum IgG4 levels in patients with autoimmune pancreatitis (AIP) (2). Subsequently, many associated clinical conditions were found to be associated with IgG4-RD, including sclerosing cholangitis, Mikulicz’s disease, retroperitoneal fibrosis, Riedel’s thyroiditis, Küttner’s tumour, mediastinal fibrosis, interstitial nephritis, and inflammatory pseudotumour (3–8). Currently, most of IgG4-RD studies are reported by Japanese investigators and no series have been reported from China. In this study, we report the clinical, laboratory, and histological characteristics of 28 Chinese patients with IgG4-RD.
Wen Zhang, Department of Rheumatology, Peking Union Medical College Hospital, 41 Da-Mu-Cang-Hu-Tong, Xicheng District, Beijing 100032, China. E-mail: [email protected]
Method Patients Adult patients who were admitted to, or were out-patients in, Peking Union Medical College Hospital (PUMC) between January 2011 and May 2012 were enrolled in this study. Patients were considered to have IgG4-RD if they fulfilled the following criteria: (i) clinical examination showing characteristic diffuse/localized swelling or masses in single or multiple organs; (ii) haematological examination showing elevated serum IgG4 concentration (> 135 mg/dL); and (iii) histopathological examination showing: (a) marked lymphocyte and plasma cell infiltration and fibrosis and (b) IgG4+ plasma cell infiltration: ratio of IgG4+ to IgG+ cells > 40% and more than 10 IgG4+ plasma cells per high power field (HPF). A definite diagnosis is (i) + (ii) + (iii), a probable diagnosis (i) + (iii), and a possible diagnosis (i) + (ii) (9). In this study, we only enrolled patients who fulfilled the definite diagnosis and we excluded those with malignant tumours. The study was approved by the ethics committee of PUMCH, and informed consent was obtained from all participants.
Accepted 1 July 2013 © 2014 Informa Healthcare on license from Scandinavian Rheumatology Research Foundation
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DOI: 10.3109/03009742.2013.822094
IgG4-RD in a Chinese cohort
71
Laboratory examinations and imaging studies All patients were tested for complete blood count (CBC), chemistry, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), Ig level, total IgE level, antinuclear antibodies (ANAs), and anti-neutrophil cytoplasmic autoantibodies (ANCAs). Serum levels of IgG subclasses were determined by the Ig subclass assay from Siemens N IgG1-2 and IgG3-4 (formerly Dade Behring, Marburg, Germany) on a Behring Nephelometry platform (BN Prospec). Imaging studies, including computed tomography (CT), magnetic resonance imaging (MRI), ultrasonography, and 18 F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET)/CT, were performed in most patients.
were used for immunohistochemical staining. IgG4 staining was performed using mouse anti-human IgG4 monoclonal antibody (IgG4 mAb at 1:100 dilution, MC011; The Binding Site, Birmingham, UK) (10).
Statistical analysis Standard descriptive summary statistics on all parameters were carried out with SPSS version 13.0 (SPSS, Chicago, IL, USA), including means, standard deviations (SD), minimum values, and maximum values. Results
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Patients’ demographic characteristics Histological examination All tissue biopsy samples were fixed in formalin and embedded in paraffin wax, then stained with haematoxylin and eosin (H&E). Antibodies against CD3, CD20, IgG, CD138, and CD38 (Dako UK Ltd, Cambridgeshire, UK)
A total of 28 patients were enrolled in this study (Table 1). The male-to-female ratio was 1.8:1. The mean age at onset of disease was 51.5 (range 24–73) years and the duration of symptoms before diagnosis was 20.4 (range 1–72) months.
Table 1. Baseline characteristics and treatment of IgG4-RD patients. Patient no.
Age Duration of disease (years)/Sex (months) Manifestation
1 2 3 4 5 6
63/M 66/M 66/M 56/M 53/F 29/M
4 8 3 6 24 18
7 8
41/F 61/F
12 36
9 10 11 12 13 14 15
52/F 65/M 32/M 60/M 65/F 46/F 40/M
48 72 24 7 60 12 12
16 17 18 19 20 21 22 23 24 25 26 27 28
56/M 51/M 57/M 73/M 31/F 49/M 59/F 66/F 24/M 24/F 57/M 44/M 57/M
3 10 40 1 36 3 10 47 4 6 12 48 6
Allergy
Eosinophilia
Biopsy
Treatment
AIP, SC TIN, aortitis RPF, LN AIP, SC ,MD, prostatitis AIP, SC, MD MD, LN, interstitial pneumonitis AIP, MD RPF
No Yes No No No Yes
Yes No Yes Yes No No
Lung Kidney LN SMG SMG LN
No No
No No
SMG Retroperitoneal
MD MD MD, IPT (orbital) SC AIP, SC, MD, MF MD, sinusitis MD, LN, IPT (retropharyngeal) MD, IPT (brain) AIP, MD MD, MF, prostatitis RPF, TIN, LN, MD MD, LN AIP, MD, SC MD, LN AIP, SC, MD, LN MD, LN, TIN MD, LN MD, LN, prostatitis MD, LN AIP. SC, LN, prostatitis
No Yes Yes No Yes Yes Yes
No No No Yes No No Yes
SG SG Orbital Liver SMG SMG SMG
Pred Pred Pred Pred Pred, TwHF Pred, CYC, MTX Pred, CYC Pred, TwHF, tamoxifen Pred, MTX TwHF Pred, CYC Pred, CTX Pred, AZA Pred, MTX Pred, MTX
Yes Yes Yes Yes Yes Yes Yes Yes No No No Yes No
Yes No Yes No No Yes No No Yes Yes No Yes No
Brain, SMG Pancreas Parotid SMG LN Pancreas LN SMG LN SMG LN LN Pancreas
Pred, CYC Pred, MMF Pred, CYC Pred, MMF Pred, CYC Pred, CYC Pred, CYC None Pred Pred, CYC Pred, CYC Pred, CYC Pred, CYC
M, Male; F, female; AIP, autoimmune pancreatitis; SC, sclerosing cholangitis; MD, Mikulicz’s disease (defined as both salivary and lachrymal gland enlargement); TIN, tubulointerstitial nephritis; RPF, retroperitoneal fibrosis; LN, lymphadenopathy; IPT, inflammatory pseudotumour; MF, mediastinal fibrosis; SMG, submandibular gland; SG, salivary gland. Pred, prednisone; TwHF, chloroform/methanol extract of Tripterygium wilfordii Hook F; CYC, cyclophosphamide; MTX, methotrexate; AZA, azathioprine; MMF, mycophenolate mofetil.
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Table 2. Clinical features of IgG4-RD patients (n = 28). Signs and symptoms
n (%)
Salivary gland swelling History of allergy Lacrimal gland swelling Lymphadenopathy Abdominal pain Nausea and vomiting Jaundice Parotid gland swelling Pruritus Oedema Dysuria Low back pain Rhinostegnosis Cough Ophthalmoptosis Arthralgia Fever
17 (61) 16 (57) 13 (46) 11 (39) 11 (39) 8 (29) 7 (25) 5 (18) 4 (14) 4 (14) 4 (14) 3 (11) 2 (7) 2 (7) 1 (4) 1 (4) 1 (4)
Laboratory findings
Table 3. Organ involvement of IgG4-RD patients (n = 28). Organ involvement
n (%)
Sialadenitis Dacryoadenitis Lymphadenopathy Autoimmune pancreatitis Sclerosing cholangitis Prostatitis Retroperitoneal fibrosis Inflammatory pseudotumour * Interstitial nephritis Mediastinal fibrosis Interstitial pneumonitis Aortic involvement Sinusitis
22 (79) 13 (46) 12 (43) 9 (32) 8 (29) 4 (14) 3 (11) 3 (11) 3 (11) 2 (7) 1 (4) 1 (4) 1 (4)
* Orbital, retropharyngeal, and brain. Table 4. Laboratory characteristics of IgG4-RD patients (n = 28). Elevated ESR (> 20 mm/h), % (n) Elevated CRP (> 8 mg/L), % (n) IgG4/IgG, mean (SD) IgG (g/L), mean (SD) IgG4 (mg/dL), mean (SD) IgG1 (mg/dL), mean (SD) IgG2 (mg/dL), mean (SD) IgG3 (mg/dL), mean (SD) Positive ANA, % (n) Positive anti-SSA/SSB, % (n) Eosinophilia (Eos > 500/μL), % (n) Elevated IgE (> 60k UI/L), % (n)
57 (16) 25 (7) 34 (17) 24.1 (9.8) 1142.3 (969.0) 1101.5 (765.7) 678.4 (471.3) 90.3 (75.4) 7 (2) 0 (0) 39 (11) 100 (8)
ESR, Erythrocyte sedimentation rate, CRP, C-reactive protein, ANA, antinuclear antibodies; SD, standard deviation.Incidence rates (numbers of positive patients) are shown for elevated ESR, elevated CRP, ANA, anti-SSA/SSB, eosinophilia, and elevated IgE. IgE was examined in eight patients.
Clinical features Clinical features at presentation are shown in Table 2. The most common symptoms were salivary gland swelling
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(61%), lacrimal gland swelling (46%), and abdominal pain (39%). Only one patient presented with low-grade fever. Lymphadenopathy (39%) and jaundice (25%) were frequent on examination. Sixteen (57%) patients presented with a history of allergic disease, defined as allergic rhinitis, chronic eczema, and/or bronchial asthma. Most patients (93%) presented with multiple organ involvement (range 2–4 organs) (Table 1). One patient with involvement of only one organ presented with sclerosing cholangitis and another with retroperitoneal fibrosis. The most common tissues involved were the salivary gland (79%), lacrimal gland (46%), lymph nodes (43%), pancreas (32%), biliary duct (25%), and prostate (14%) (Table 3). Other manifestations included retroperitoneal fibrosis, tubulointerstitial nephritis, inflammatory pseudotumour, mediastinal fibrosis, aortitis, interstitial lung disease, and sinusitis.
The baseline laboratory findings are summarized in Table 4. Elevated ESR and CRP (> 8 mg/L) were observed in 16 (57%) and seven (25%) patients, respectively. Serum IgG and IgG4 levels are shown in Figure 1. Polyclonal hypergammaglobulinaemia was noted in 20 (71%) patients. The mean serum IgG level was 24. 1 g/L (SD = 9.8, range 11.4– 50.4 g/L). IgG4 levels were elevated in all patients at baseline. The mean IgG4 level was 1142.3 mg/dL (SD = 969.0, range 149–3870 mg/dL). The serum IgG4/IgG ratio was 34 (SD = 17, range 10–68). Eosinophilia was noted in 11 (39%) patients. Serum total IgE levels were elevated in all of the eight patients examined. ANAs were positive at dilutions of 1:100 (> 1:100 is defined to be positive) in two of the 28 patients. None of the patients had anti-SSA or anti-SSB antibodies, or ANCAs. Imaging studies found various organ and/or tissue swelling. 18F-FDG PET/CT was performed in 13 patients and showed multiple intense uptake lesions, especially in the salivary gland (9/13), lymph nodes (7/13), retroperitoneum (3/13), pancreas (3/ 13), and kidney (3/13). In 10 patients most of the abnormal uptakes had decreased dramatically when 18F-FDG PET/ CT was repeated after 2–4 weeks.
Histological findings For all patients, one or two tissue biopsies were performed. Histological examination on H&E staining was performed in all tissue samples, as well as immunohistochemical staining with anti-CD38, anti-CD138, anti-IgG, and anti-IgG4 mAb. Massive lymphocyte and plasma cell infiltration was the most prominent feature, revealed in all tissues. Extranodal lymphoid follicle formation was seen in 10 patients. Fibrosis was found in most patients. IgG4 immunostaining showed a markedly increased number of IgG4+ plasma cells (> 10 plasma cells/) in all patients, and a ratio of IgG4+/IgG+ cells > 40 (Figure 2).
IgG4-RD in a Chinese cohort A
100
80
CRP (mg/L)
ESR (mm/1stHr)
100
73
60 40 20 0
0
1
3 Months
10 1 0.1 0.01
6
C
1 3 Months
6
0
1 3 Months
6
40000 IgG4 (mg/L)
IgG (g/L) Scand J Rheumatol Downloaded from informahealthcare.com by Nyu Medical Center on 05/29/15 For personal use only.
0 D
60 40 20 0
Figure 1. Changes from baseline in laboratory values over 6 months: (A) erythrocyte sedimentation rate (ESR); (B) C-reactive protein (CRP); (C) IgG; (D) IgG4.
B
0
1 3 Months
6
30000 20000 10000 0
Treatment and follow-up Treatment regimens are reported in Table 1. Upon inclusion, prednisone was administered in most patients (93%, n = 26), with an initial dosage of 0.5–0.8 mg/kg/day (mean 42.9, SD = 7.0, range 30–60 mg/day) for 1 month, then tapered gradually to 7.5 mg/day. Immunosuppressive agents were initially started in 19 (68%) patients, including cyclophosphamide (43%, n = 12), methotrexate (11%, n = 3), mycophenolate mofetil (7%, n = 2), and azathioprine (4%, n = 1). One patient (patient no. 6) received cyclophosphamide combined with methotrexate therapy because of refractory disease. Three patients with mild disease receive a Chinese traditional herb, Tripterygium wilfordii Hook F (TwHF), including one patient with retroperitoneal fibrosis who received TwHF combined with tamoxifen. Patients were followed up for a mean of 6.3 (range 2–13) months. Efficacy was noted in more than 90% of cases assessed by clinical, laboratory, radiological, and
A
B
Figure 2. Immunohistochemical staining of IgG4. The submaxillary salivary gland of a patient with Mikulicz’s disease and autoimmune pancreatitis: (A) 60; (B) 300. Lymphocytic infiltration and polyclonal plasma cell infiltration, mainly IgG4+ plasma cells, were noted.
physician’s global assessment. None of the patients died. ESR and CRP were significantly decreased after treatment (Figures 1A and 1B). Serum IgG and IgG4 levels decreased over time. (Figures 1C and 1D).
Discussion This is the first serial report of IgG4-RD in China. The incidence of IgG4-RD in Japan is estimated to be 0.28– 1.08 per 100 000, with 336–1300 patients newly diagnosed each year (11). Although the incidence in China is still unknown, we have found that it is not a rare disease. In this study, 28 definite cases, including Mikulicz’s disease, autoimmune pancreatitis, interstitial nephritis, retroperitoneal fibrosis, and inflammatory pseudotumour, were diagnosed in a single centre in 1 year. The mean age (51.5 years) is comparable with French and Japanese cases. The male-to-female ratio (1.8:1) is similar to that of the French cohort but is much lower (0.94:1) in the Japanese cohort (4, 10). In this study, the most significant clinical feature of IgG4-RD was multiple organ involvement. Most patients (26/28) concurrently had more than one organ involvement;10 and eight patients had three and four organs involved, respectively. This is consistent with the French cohort, in which 88% patients had multiple organ involvement (4). Furthermore, in some of the patients who underwent 18F-FDG PET/CT, lesions without clinical symptoms were found. Therefore, our data strongly suggest that IgG4-RD is a systemic disease (11, 12). Our study shows that 57% of the patients had a history of allergic disease, 39% patients had increased eosinophil cells, and all eight patients examined had elevated total IgE levels. These conditions were found in both the Japanese and the Caucasian cohorts (11, 12). Sato et al reported tissue infiltration of eosinophil and elevation of serum IgE in systemic IgG4-related lymphadenopathy (13). T-helper (Th)2 cytokines, including interleukin
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(IL)-4, -5, -10, and -13, are elevated in lesions and potentially medicated the allergic condition (14, 15). In general, IgG4-RD responds well to steroid therapy symptomatically, radiologically, and serologically. In this study, all but one of the patients were treated with oral prednisone (0.5–0.8 mg/kg/day) for 4 weeks, gradually tapered to a maintenance dose of less than 10 mg/day. Immunosuppressive agents, including cyclophosphamide, azathioprine, mycophenolate mofetil, and methotrexate, were frequently used as combination therapy, especially in patients with multiple organ involvement. Two patients (nos 10 and 23) had a long history and slow disease progression. Patient 10 was treated with TwHF, a Chinese traditional medicine. Patient 23 received no treatment. They were closely monitored and no significant progression was found. In our opinion, IgG4-RD is a heterogeneous disease and the patients should be treated individually. The clinical condition of most patients improved after treatment. The change in uptake lesions on 18F-FDG PET/ CT correlated with the clinical conditions (16). In most patients, ESR, CRP, and serum IgG4 levels decreased over time. However, the serum IgG4 levels of two patients did not decrease after treatment although their clinical manifestations improved. Moreover, in some patients, IgG4 levels could not be reduced to the normal range with the current treatment. Therefore, although the serum IgG4 levels correlate with organ damage in most, but not all, patients, and despite recent progress in the measurement of disease activity (17), the remission criteria for IgG4-RD, including clinical, serological, and histological remission criteria, remain unclear. A long-term prospective study is warranted to investigate the remission criteria and to define the optimal treatment target. In the Asian diagnostic criteria (Japan–Korea consensus) for autoimmune pancreatitis, the response to glucocorticoid is an optional criterion (18). According to our follow-up data, we propose that the good response to glucocorticoid should be the candidate criteria for the diagnosis of IgG4-RD. If a patient’s condition is refractory to the dosage of 0.8 mg/kg/day of prednisone, an alternative diagnosis should be considered. However, sarcoidosis, vasculitis, and lymphoma may respond to glucocorticoids and should be considered in a differential diagnosis (13, 19, 20). In conclusion, IgG4-RD is a chronic, systemic, multiorgan inflammatory disorder characterized by elevated levels of IgG4, large amounts of lymphocyte and IgG4+ plasmocyte infiltration, with fibrosis in the involved organs. IgG4-RD generally responds well to glucocorticoids, but as a heterogeneous disease, the treatment should be individualized. Acknowledgements This work was supported by National Natural Science Foundation (81172858), Beijing Natural Science Foundation (7132206) and Chinese Medical Assoication Foundation (12040680368).
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H Chen et al
References 1. Stone JH, Zen Y, Deshpande V. IgG4-related disease. N Engl J Med 2012;366:539–51. 2. Hamano H, Kawa S, Horiuchi A, Unno H, Furuya N, Akamatsu T, et al. High serum IgG4 concentrations in patients with sclerosing pancreatitis. N Engl J Med 2001;344:732–8. 3. Bourlon MT, Chapa M, Chable Montero F, Hernandez Calleros J. Immunoglobulin G4-associated to multiorganic lymphoproliferative disease [in Spanish]. Gac Med Mex 2011;147:545–50. 4. Ebbo M, Daniel L, Pavic M, Sève P, Hamidou M, Andres E, 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. 5. Hsu B-B, Lai N-S, Tung C-H. Clinical images: lacrimal gland and renal involvement in IgG4-related sclerosing disease. Arthritis Rheum 2011;63:3875. 6. Kamisawa T, Funata N, Hayashi Y, Eishi Y, Koike M, Tsuruta K, et al. A new clinicopathological entity of IgG4-related autoimmune disease. J Gastroenterol 2003;38:982–4. 7. Raina A, Yadav D, Krasinskas AM, McGrath KM, Khalid A, Sanders M, et al. Evaluation and management of autoimmune pancreatitis: experience at a large US center. Am J Gastroenterol 2009;104:2295–306. 8. Watanabe T, Maruyama M, Ito T, Fujinaga Y, Ozaki Y, Kodama R, et al. Clinical features of a new disease concept, IgG4-related thyroiditis. Scand J Rheumatol. Published online: 16 March 2013. doi:10.3109/03009742.2012.761281. 9. Umehara H, Okazaki K, Masaki Y, Kawano M, Yamamoto M, Saeki T, et al. Comprehensive diagnostic criteria for IgG4-related disease (IgG4-RD), 2011. Mod Rheumatol 2012;22:21–30. 10. Masaki Y, Dong L, Kurose N, Kitagawa K, Morikawa Y, Yamamoto M, et al. Proposal for a new clinical entity, IgG4positive multiorgan lymphoproliferative syndrome: analysis of 64 cases of IgG4-related disorders. Ann Rheum Dis 2009;68:1310–15. 11. Umehara H, Okazaki K, Masaki Y, Kawano M, Yamamoto M, Saeki T, et al. A novel clinical entity, IgG4-related disease (IgG4RD): general concept and details. Mod Rheumatol 2012;22:1–14. 12. van der Vliet HJJ, Perenboom RM. Multiple pseudotumors in IgG4associated multifocal systemic fibrosis. Ann Int Med 2004;141: 896–7. 13. Sato Y, Kojima M, Takata K, Morito T, Asaoku H, Takeuchi T, et al. Systemic IgG4-related lymphadenopathy: a clinical and pathologic comparison to multicentric Castleman’s disease. Mod Pathol 2009;22:589–99. 14. Kamisawa T, Anjiki H, Egawa N, Kubota N. Allergic manifestations in autoimmune pancreatitis. Eur J Gastroenterol Hepatol 2009;21:1136–9. 15. Zen Y, Fujii T, Harada K, Kawano M, Yamada K, Takahira M, et al. Th2 and regulatory immune reactions are increased in immunoglobin G4-related sclerosing pancreatitis and cholangitis. Hepatology 2007;45:1538–46. 16. Nakatani K, Nakamoto Y, Togashi K. Utility of FDG PET/CT in IgG4-related systemic disease. Clin Radiol 2012;67:297–305. 17. Carruthers MN, Stone JH, Deshpande V, Khosroshahi A. Development of an IgG4-RD responder index. Int J Rheumatol 2012; Article ID 259408. 18. Moon SH, Kim MH, Park DH, Hwang CY, Park SJ, Lee SS, et al. Is a 2-week steroid trial after initial negative investigation for malignancy useful in differentiating autoimmune pancreatitis from pancreatic cancer? A prospective outcome study. Gut 2008;57:1704–12. 19. Masaki Y, Kurose N, Yamamoto M, Takahashi H, Saeki T, Azumi A, et al. Cutoff values of serum IgG4 and histopathological IgG4+ plasma cells for diagnosis of patients with IgG4-related disease. Int J Rheumatol 2012; Article ID 580814. 20. Terzin V, Földesi I, Kovács L, Pokorny G, Wittmann T, Czakó L. Association between autoimmune pancreatitis and systemic autoimmune diseases. World J Gastroenterol 2012;18:2649–53.
Scand J Rheumatol 2014;43:70–74
IgG4-related disease in a Chinese cohort: a prospective study H Chen1, W Lin1, Q Wang1, Q Wu1, L Wang1, Y Fei1, W Zheng1, G Fei2, P Li1, YZ Li1, W Zhang1, Y Zhao1, X Zeng1, F Zhang1
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1 Department of Rheumatology, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Science, Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing, and 2Department of Gastroenterology, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Science, Beijing, China
Objectives: To report the clinical, laboratory, and histological characteristics in a cohort of 28 Chinese patients with immunoglobulin G4-related disease (IgG4-RD). Method: The patients were admitted to, or were out-patients in, Peking Union Medical College Hospital (PUMCH) between January 2011 and May 2012 according to the criteria for IgG4-RD. Clinical presentations, imaging studies, serum Ig subclass assays, and histological examinations were performed in all patients. Results: The 28 patients (male-to-female ratio 1.8:1) enrolled in this study had a mean age at onset of disease of 51.5 years and the duration of symptoms before diagnosis was 20.4 months; 57% of the patients presented with a history of allergic disease. The most common symptoms were salivary and lacrimal gland swelling, and abdominal pain. Most patients (93%) presented with multiple organ involvement. Elevated erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels were observed in 16 (57%) and seven (25%) patients, respectively. The mean serum IgG4 level was 1142.3 mg/dL (range 149–3870 mg/dL). Eosinophilia was noted in 11 (39%) patients. IgE levels were elevated in all of eight patients examined. Lymphocyte and plasma cell infiltration and IgG4-positive plasma cell infiltration, together with tissue fibrosis, were the predominant histological findings. Most patients (93%) were given prednisone (0.5–0.8 mg/kg/day). Immunosuppressive agents were administered in 19 (68%) patients. Patients were followed for a mean of 6.3 months; efficacy was noted in more than 90% of cases. Conclusions: IgG4-RD is a chronic, systemic, multiorgan inflammatory disorder. IgG4-RD patients generally response well to glucocorticoids but the treatment should be individualized.
Immunoglobulin G4-related disease (IgG4-RD) is a recently defined emerging clinical entity characterized by tissue infiltration by IgG4-positive (IgG4+) plasma cells, tissue fibrosclerosis, and elevated serum IgG4 concentration (1). Hamano et al first reported elevated serum IgG4 levels in patients with autoimmune pancreatitis (AIP) (2). Subsequently, many associated clinical conditions were found to be associated with IgG4-RD, including sclerosing cholangitis, Mikulicz’s disease, retroperitoneal fibrosis, Riedel’s thyroiditis, Küttner’s tumour, mediastinal fibrosis, interstitial nephritis, and inflammatory pseudotumour (3–8). Currently, most of IgG4-RD studies are reported by Japanese investigators and no series have been reported from China. In this study, we report the clinical, laboratory, and histological characteristics of 28 Chinese patients with IgG4-RD.
Wen Zhang, Department of Rheumatology, Peking Union Medical College Hospital, 41 Da-Mu-Cang-Hu-Tong, Xicheng District, Beijing 100032, China. E-mail: [email protected]
Method Patients Adult patients who were admitted to, or were out-patients in, Peking Union Medical College Hospital (PUMC) between January 2011 and May 2012 were enrolled in this study. Patients were considered to have IgG4-RD if they fulfilled the following criteria: (i) clinical examination showing characteristic diffuse/localized swelling or masses in single or multiple organs; (ii) haematological examination showing elevated serum IgG4 concentration (> 135 mg/dL); and (iii) histopathological examination showing: (a) marked lymphocyte and plasma cell infiltration and fibrosis and (b) IgG4+ plasma cell infiltration: ratio of IgG4+ to IgG+ cells > 40% and more than 10 IgG4+ plasma cells per high power field (HPF). A definite diagnosis is (i) + (ii) + (iii), a probable diagnosis (i) + (iii), and a possible diagnosis (i) + (ii) (9). In this study, we only enrolled patients who fulfilled the definite diagnosis and we excluded those with malignant tumours. The study was approved by the ethics committee of PUMCH, and informed consent was obtained from all participants.
Accepted 1 July 2013 © 2014 Informa Healthcare on license from Scandinavian Rheumatology Research Foundation
www.scandjrheumatol.dk
DOI: 10.3109/03009742.2013.822094
IgG4-RD in a Chinese cohort
71
Laboratory examinations and imaging studies All patients were tested for complete blood count (CBC), chemistry, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), Ig level, total IgE level, antinuclear antibodies (ANAs), and anti-neutrophil cytoplasmic autoantibodies (ANCAs). Serum levels of IgG subclasses were determined by the Ig subclass assay from Siemens N IgG1-2 and IgG3-4 (formerly Dade Behring, Marburg, Germany) on a Behring Nephelometry platform (BN Prospec). Imaging studies, including computed tomography (CT), magnetic resonance imaging (MRI), ultrasonography, and 18 F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET)/CT, were performed in most patients.
were used for immunohistochemical staining. IgG4 staining was performed using mouse anti-human IgG4 monoclonal antibody (IgG4 mAb at 1:100 dilution, MC011; The Binding Site, Birmingham, UK) (10).
Statistical analysis Standard descriptive summary statistics on all parameters were carried out with SPSS version 13.0 (SPSS, Chicago, IL, USA), including means, standard deviations (SD), minimum values, and maximum values. Results
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Patients’ demographic characteristics Histological examination All tissue biopsy samples were fixed in formalin and embedded in paraffin wax, then stained with haematoxylin and eosin (H&E). Antibodies against CD3, CD20, IgG, CD138, and CD38 (Dako UK Ltd, Cambridgeshire, UK)
A total of 28 patients were enrolled in this study (Table 1). The male-to-female ratio was 1.8:1. The mean age at onset of disease was 51.5 (range 24–73) years and the duration of symptoms before diagnosis was 20.4 (range 1–72) months.
Table 1. Baseline characteristics and treatment of IgG4-RD patients. Patient no.
Age Duration of disease (years)/Sex (months) Manifestation
1 2 3 4 5 6
63/M 66/M 66/M 56/M 53/F 29/M
4 8 3 6 24 18
7 8
41/F 61/F
12 36
9 10 11 12 13 14 15
52/F 65/M 32/M 60/M 65/F 46/F 40/M
48 72 24 7 60 12 12
16 17 18 19 20 21 22 23 24 25 26 27 28
56/M 51/M 57/M 73/M 31/F 49/M 59/F 66/F 24/M 24/F 57/M 44/M 57/M
3 10 40 1 36 3 10 47 4 6 12 48 6
Allergy
Eosinophilia
Biopsy
Treatment
AIP, SC TIN, aortitis RPF, LN AIP, SC ,MD, prostatitis AIP, SC, MD MD, LN, interstitial pneumonitis AIP, MD RPF
No Yes No No No Yes
Yes No Yes Yes No No
Lung Kidney LN SMG SMG LN
No No
No No
SMG Retroperitoneal
MD MD MD, IPT (orbital) SC AIP, SC, MD, MF MD, sinusitis MD, LN, IPT (retropharyngeal) MD, IPT (brain) AIP, MD MD, MF, prostatitis RPF, TIN, LN, MD MD, LN AIP, MD, SC MD, LN AIP, SC, MD, LN MD, LN, TIN MD, LN MD, LN, prostatitis MD, LN AIP. SC, LN, prostatitis
No Yes Yes No Yes Yes Yes
No No No Yes No No Yes
SG SG Orbital Liver SMG SMG SMG
Pred Pred Pred Pred Pred, TwHF Pred, CYC, MTX Pred, CYC Pred, TwHF, tamoxifen Pred, MTX TwHF Pred, CYC Pred, CTX Pred, AZA Pred, MTX Pred, MTX
Yes Yes Yes Yes Yes Yes Yes Yes No No No Yes No
Yes No Yes No No Yes No No Yes Yes No Yes No
Brain, SMG Pancreas Parotid SMG LN Pancreas LN SMG LN SMG LN LN Pancreas
Pred, CYC Pred, MMF Pred, CYC Pred, MMF Pred, CYC Pred, CYC Pred, CYC None Pred Pred, CYC Pred, CYC Pred, CYC Pred, CYC
M, Male; F, female; AIP, autoimmune pancreatitis; SC, sclerosing cholangitis; MD, Mikulicz’s disease (defined as both salivary and lachrymal gland enlargement); TIN, tubulointerstitial nephritis; RPF, retroperitoneal fibrosis; LN, lymphadenopathy; IPT, inflammatory pseudotumour; MF, mediastinal fibrosis; SMG, submandibular gland; SG, salivary gland. Pred, prednisone; TwHF, chloroform/methanol extract of Tripterygium wilfordii Hook F; CYC, cyclophosphamide; MTX, methotrexate; AZA, azathioprine; MMF, mycophenolate mofetil.
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Table 2. Clinical features of IgG4-RD patients (n = 28). Signs and symptoms
n (%)
Salivary gland swelling History of allergy Lacrimal gland swelling Lymphadenopathy Abdominal pain Nausea and vomiting Jaundice Parotid gland swelling Pruritus Oedema Dysuria Low back pain Rhinostegnosis Cough Ophthalmoptosis Arthralgia Fever
17 (61) 16 (57) 13 (46) 11 (39) 11 (39) 8 (29) 7 (25) 5 (18) 4 (14) 4 (14) 4 (14) 3 (11) 2 (7) 2 (7) 1 (4) 1 (4) 1 (4)
Laboratory findings
Table 3. Organ involvement of IgG4-RD patients (n = 28). Organ involvement
n (%)
Sialadenitis Dacryoadenitis Lymphadenopathy Autoimmune pancreatitis Sclerosing cholangitis Prostatitis Retroperitoneal fibrosis Inflammatory pseudotumour * Interstitial nephritis Mediastinal fibrosis Interstitial pneumonitis Aortic involvement Sinusitis
22 (79) 13 (46) 12 (43) 9 (32) 8 (29) 4 (14) 3 (11) 3 (11) 3 (11) 2 (7) 1 (4) 1 (4) 1 (4)
* Orbital, retropharyngeal, and brain. Table 4. Laboratory characteristics of IgG4-RD patients (n = 28). Elevated ESR (> 20 mm/h), % (n) Elevated CRP (> 8 mg/L), % (n) IgG4/IgG, mean (SD) IgG (g/L), mean (SD) IgG4 (mg/dL), mean (SD) IgG1 (mg/dL), mean (SD) IgG2 (mg/dL), mean (SD) IgG3 (mg/dL), mean (SD) Positive ANA, % (n) Positive anti-SSA/SSB, % (n) Eosinophilia (Eos > 500/μL), % (n) Elevated IgE (> 60k UI/L), % (n)
57 (16) 25 (7) 34 (17) 24.1 (9.8) 1142.3 (969.0) 1101.5 (765.7) 678.4 (471.3) 90.3 (75.4) 7 (2) 0 (0) 39 (11) 100 (8)
ESR, Erythrocyte sedimentation rate, CRP, C-reactive protein, ANA, antinuclear antibodies; SD, standard deviation.Incidence rates (numbers of positive patients) are shown for elevated ESR, elevated CRP, ANA, anti-SSA/SSB, eosinophilia, and elevated IgE. IgE was examined in eight patients.
Clinical features Clinical features at presentation are shown in Table 2. The most common symptoms were salivary gland swelling
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(61%), lacrimal gland swelling (46%), and abdominal pain (39%). Only one patient presented with low-grade fever. Lymphadenopathy (39%) and jaundice (25%) were frequent on examination. Sixteen (57%) patients presented with a history of allergic disease, defined as allergic rhinitis, chronic eczema, and/or bronchial asthma. Most patients (93%) presented with multiple organ involvement (range 2–4 organs) (Table 1). One patient with involvement of only one organ presented with sclerosing cholangitis and another with retroperitoneal fibrosis. The most common tissues involved were the salivary gland (79%), lacrimal gland (46%), lymph nodes (43%), pancreas (32%), biliary duct (25%), and prostate (14%) (Table 3). Other manifestations included retroperitoneal fibrosis, tubulointerstitial nephritis, inflammatory pseudotumour, mediastinal fibrosis, aortitis, interstitial lung disease, and sinusitis.
The baseline laboratory findings are summarized in Table 4. Elevated ESR and CRP (> 8 mg/L) were observed in 16 (57%) and seven (25%) patients, respectively. Serum IgG and IgG4 levels are shown in Figure 1. Polyclonal hypergammaglobulinaemia was noted in 20 (71%) patients. The mean serum IgG level was 24. 1 g/L (SD = 9.8, range 11.4– 50.4 g/L). IgG4 levels were elevated in all patients at baseline. The mean IgG4 level was 1142.3 mg/dL (SD = 969.0, range 149–3870 mg/dL). The serum IgG4/IgG ratio was 34 (SD = 17, range 10–68). Eosinophilia was noted in 11 (39%) patients. Serum total IgE levels were elevated in all of the eight patients examined. ANAs were positive at dilutions of 1:100 (> 1:100 is defined to be positive) in two of the 28 patients. None of the patients had anti-SSA or anti-SSB antibodies, or ANCAs. Imaging studies found various organ and/or tissue swelling. 18F-FDG PET/CT was performed in 13 patients and showed multiple intense uptake lesions, especially in the salivary gland (9/13), lymph nodes (7/13), retroperitoneum (3/13), pancreas (3/ 13), and kidney (3/13). In 10 patients most of the abnormal uptakes had decreased dramatically when 18F-FDG PET/ CT was repeated after 2–4 weeks.
Histological findings For all patients, one or two tissue biopsies were performed. Histological examination on H&E staining was performed in all tissue samples, as well as immunohistochemical staining with anti-CD38, anti-CD138, anti-IgG, and anti-IgG4 mAb. Massive lymphocyte and plasma cell infiltration was the most prominent feature, revealed in all tissues. Extranodal lymphoid follicle formation was seen in 10 patients. Fibrosis was found in most patients. IgG4 immunostaining showed a markedly increased number of IgG4+ plasma cells (> 10 plasma cells/) in all patients, and a ratio of IgG4+/IgG+ cells > 40 (Figure 2).
IgG4-RD in a Chinese cohort A
100
80
CRP (mg/L)
ESR (mm/1stHr)
100
73
60 40 20 0
0
1
3 Months
10 1 0.1 0.01
6
C
1 3 Months
6
0
1 3 Months
6
40000 IgG4 (mg/L)
IgG (g/L) Scand J Rheumatol Downloaded from informahealthcare.com by Nyu Medical Center on 05/29/15 For personal use only.
0 D
60 40 20 0
Figure 1. Changes from baseline in laboratory values over 6 months: (A) erythrocyte sedimentation rate (ESR); (B) C-reactive protein (CRP); (C) IgG; (D) IgG4.
B
0
1 3 Months
6
30000 20000 10000 0
Treatment and follow-up Treatment regimens are reported in Table 1. Upon inclusion, prednisone was administered in most patients (93%, n = 26), with an initial dosage of 0.5–0.8 mg/kg/day (mean 42.9, SD = 7.0, range 30–60 mg/day) for 1 month, then tapered gradually to 7.5 mg/day. Immunosuppressive agents were initially started in 19 (68%) patients, including cyclophosphamide (43%, n = 12), methotrexate (11%, n = 3), mycophenolate mofetil (7%, n = 2), and azathioprine (4%, n = 1). One patient (patient no. 6) received cyclophosphamide combined with methotrexate therapy because of refractory disease. Three patients with mild disease receive a Chinese traditional herb, Tripterygium wilfordii Hook F (TwHF), including one patient with retroperitoneal fibrosis who received TwHF combined with tamoxifen. Patients were followed up for a mean of 6.3 (range 2–13) months. Efficacy was noted in more than 90% of cases assessed by clinical, laboratory, radiological, and
A
B
Figure 2. Immunohistochemical staining of IgG4. The submaxillary salivary gland of a patient with Mikulicz’s disease and autoimmune pancreatitis: (A) 60; (B) 300. Lymphocytic infiltration and polyclonal plasma cell infiltration, mainly IgG4+ plasma cells, were noted.
physician’s global assessment. None of the patients died. ESR and CRP were significantly decreased after treatment (Figures 1A and 1B). Serum IgG and IgG4 levels decreased over time. (Figures 1C and 1D).
Discussion This is the first serial report of IgG4-RD in China. The incidence of IgG4-RD in Japan is estimated to be 0.28– 1.08 per 100 000, with 336–1300 patients newly diagnosed each year (11). Although the incidence in China is still unknown, we have found that it is not a rare disease. In this study, 28 definite cases, including Mikulicz’s disease, autoimmune pancreatitis, interstitial nephritis, retroperitoneal fibrosis, and inflammatory pseudotumour, were diagnosed in a single centre in 1 year. The mean age (51.5 years) is comparable with French and Japanese cases. The male-to-female ratio (1.8:1) is similar to that of the French cohort but is much lower (0.94:1) in the Japanese cohort (4, 10). In this study, the most significant clinical feature of IgG4-RD was multiple organ involvement. Most patients (26/28) concurrently had more than one organ involvement;10 and eight patients had three and four organs involved, respectively. This is consistent with the French cohort, in which 88% patients had multiple organ involvement (4). Furthermore, in some of the patients who underwent 18F-FDG PET/CT, lesions without clinical symptoms were found. Therefore, our data strongly suggest that IgG4-RD is a systemic disease (11, 12). Our study shows that 57% of the patients had a history of allergic disease, 39% patients had increased eosinophil cells, and all eight patients examined had elevated total IgE levels. These conditions were found in both the Japanese and the Caucasian cohorts (11, 12). Sato et al reported tissue infiltration of eosinophil and elevation of serum IgE in systemic IgG4-related lymphadenopathy (13). T-helper (Th)2 cytokines, including interleukin
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(IL)-4, -5, -10, and -13, are elevated in lesions and potentially medicated the allergic condition (14, 15). In general, IgG4-RD responds well to steroid therapy symptomatically, radiologically, and serologically. In this study, all but one of the patients were treated with oral prednisone (0.5–0.8 mg/kg/day) for 4 weeks, gradually tapered to a maintenance dose of less than 10 mg/day. Immunosuppressive agents, including cyclophosphamide, azathioprine, mycophenolate mofetil, and methotrexate, were frequently used as combination therapy, especially in patients with multiple organ involvement. Two patients (nos 10 and 23) had a long history and slow disease progression. Patient 10 was treated with TwHF, a Chinese traditional medicine. Patient 23 received no treatment. They were closely monitored and no significant progression was found. In our opinion, IgG4-RD is a heterogeneous disease and the patients should be treated individually. The clinical condition of most patients improved after treatment. The change in uptake lesions on 18F-FDG PET/ CT correlated with the clinical conditions (16). In most patients, ESR, CRP, and serum IgG4 levels decreased over time. However, the serum IgG4 levels of two patients did not decrease after treatment although their clinical manifestations improved. Moreover, in some patients, IgG4 levels could not be reduced to the normal range with the current treatment. Therefore, although the serum IgG4 levels correlate with organ damage in most, but not all, patients, and despite recent progress in the measurement of disease activity (17), the remission criteria for IgG4-RD, including clinical, serological, and histological remission criteria, remain unclear. A long-term prospective study is warranted to investigate the remission criteria and to define the optimal treatment target. In the Asian diagnostic criteria (Japan–Korea consensus) for autoimmune pancreatitis, the response to glucocorticoid is an optional criterion (18). According to our follow-up data, we propose that the good response to glucocorticoid should be the candidate criteria for the diagnosis of IgG4-RD. If a patient’s condition is refractory to the dosage of 0.8 mg/kg/day of prednisone, an alternative diagnosis should be considered. However, sarcoidosis, vasculitis, and lymphoma may respond to glucocorticoids and should be considered in a differential diagnosis (13, 19, 20). In conclusion, IgG4-RD is a chronic, systemic, multiorgan inflammatory disorder characterized by elevated levels of IgG4, large amounts of lymphocyte and IgG4+ plasmocyte infiltration, with fibrosis in the involved organs. IgG4-RD generally responds well to glucocorticoids, but as a heterogeneous disease, the treatment should be individualized. Acknowledgements This work was supported by National Natural Science Foundation (81172858), Beijing Natural Science Foundation (7132206) and Chinese Medical Assoication Foundation (12040680368).
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