2013 May - Any Clues to diagnosis?
Drs. Choi Wan YIP and Kam Kwok SHING,
Department of Medicine, Haven of Hope Hospital
Introduction
Lung involvement in IgG4-related disease has been increasingly described in various case series. Most cases are discovered after involvement of other organ systems, such as pancreas or hepatobiliary system, is discovered. Some cases would share the features of Sjogren’s syndrome and so diagnosis would be missed. We describe herein two cases of IgG4-related lung disease mimicking Sjogren’s syndrome, and have a short review of literature about its presentation
Case reports
A 59 year old male patient, who was non-smoker, presented with dry cough for 2 months . He also noted dry eyes, dry mouth and weight loss about 5 lbs. He had past medical history of allergic rhinitis and asthma. Medication and travel history was unremarkable. Physical examination revealed bilateral submandibular masses. Otherwise, his chest was clear and other systems were unremarkable.
A chest radiograph (Fig 1) on admission showed bilateral diffuse reticulonodular shadows and bilateral prominent hila. Laboratory examination revealed normal white cell counts but eosinophilia 1.9 x 109 / L (20.7%). His liver and renal function were normal. Autoimmune marker such as rheumatoid factor (RF), antinuclear antibody (ANA) and anti-ENA were all negative. Aspergillus antibody was also negative. But he was noted to have total IgE elevated to 909. Sputum bacterial culture, cytology and acid-fast bacilli smear were all negative.
Fig. 1
Computer tomography (CT) of chest was done (Fig 2A, 2B). It showed widespread tree-in-bud opacities, septal thickening, mild bronchiectasis and mildly dilated bronchi with wall thickening. The bone window of CT scan showed multiple enlarged mediastinal and hilar lymph nodes. Bronchoscopy with transbronchial biopsy at right lung found bronchiocentric foci of polymorphous inflammatory infiltrate with lymphocytes, plasma cells, eosinophils and neutrophils. There was no granuloma. It suggested interstitial inflammation with eosinophilia.
Fig. 2A
Fig. 2B
Because of the presentation of dry eyes, dry mouth and bilateral enlarged submandibular gland, Sjogren’s syndrome with lung involvement was one the differentials of this case. However, the negative ANA and anti-ENA serology made this case rather atypical for Sjogren’s syndrome. Other differential diagnosis could be allergic bronchopulmonary aspergillosis, eosinophilic lung disease, sarcoidosis and diffuse panbronchiolitis. However, there were no supporting evidences for these diagnoses.
Three months later, patient was admitted for obstructive jaundice. His liver function was deranged with bilirubin 132, ALP 386, ALT 346. Ultrasound abdomen showed dilated common bile duct. Patient had the endoscopic retrograde cholangiopancreatography (ERCP) done and it found smooth stricture at common hepatic duct close to hila. Ampulla biopsy showed benign small bowel mucosa with focal neutrophilic intraepithelial infiltration and ulceration. There was no evidence of malignancy. Contrast CT abdomen and pelvis was also performed. It revealed again dilated common bile duct. Also there were multiple enlarged portal, mesenteric, retroperitoneal and groin lymph nodes. He had a 1cm cystic lesion at the tail of pancreas. In view of suspected malignancy, positron emission tomography (PET) was done (Fig 3A, 3B). There was no hypermetabolic lesion in liver and pancreas, but multiple hypermetebolic lymph nodes were found in head, neck, thorax, abdomen and pelvis. Also the bilateral submandibular glands showed intense FDG uptake with SUV max 7.5.
Fig. 3A Fig. 3B
Excisional biopsy of submandibular gland with a diagnostic testing was performed. It showed lymphoid infiltrate with marked atrophy and perilobular and septal sclerotic fibrosis. The lymphoid infiltrate mainly consisted of small lymphocytes and large number of plasma cells. Immunohistochemical studies found most of the plasma cells positive for IgG and IgG4. So, the pathology suggested chronic sclerosing sialadenitis, consistent with IgG4-related disease. The ampulla specimen obtained in previous ERCP was also positive in IgG4 staining. The serum IgG4 level was checked and elevated to 102.9 g/L (normal range <2).
We reviewed the case and requested IgG4 staining for the transbronchial biopsy that obtained 3 months ago. The resulted showed many of the plasma cells positive cytoplasmic staining for both IgG and IgG4 (Fig 4A, 4B, 4C, 4D). It confirmed the pulmonary involvement of IgG4-related disease.
Fig. 4A marked chronic inflammatory infiltrate throughout the bronchial wall (H&E stain, panoramic view)
Fig. 4B the infiltrate between smooth muscle bundles of the bronchial wall. Note inflammatory infiltrate is rich in plasma cells (H&E stain, X20)
Fig. 4C IgG4 positive plasma cells
Fig. 4D IgG positive plasma cells
Patient was treated with prednisolone 30mg daily, and then had the prednisolone tailing down to 10mg daily with azathioprine 50mg daily added. The PET scan 3 months after treatment showed significant metabolic improvement (Fig 5). CT thorax also showed decreased tree-in-bud opacities and septal thickening.
Fig. 5
Another case was about a 76-year old male, who was ex-smoker, presented with chronic cough for years. He also complained dry eyes and dry mouth as the first case. His past medical history also revealed atopic conditions, allergic rhinitis and asthma. His chest radiography showed fleeting lung shadow at right lower zone (Fig 6A, 6B). Blood test found eosinophilia up to 0.9 x 109 /L. His serum ANCA was weakly positive, showing atypical pattern. Anti-PR3 was negative. CT thorax revealed multiple patches of ground glass opacities over right lower lobe. The transbronchial biopsy found atypical lymphoid infiltrate. Labial gland biopsy was done and its initial report showed diffuse infiltration by lymphocytes and plasma cells with acinar destruction. The features were consistent with Sjogren’s syndrome.
Fig. 6A
Fig. 6B
Four years later, patient was admitted for obstructive jaundice. Both CT abdomen and ERCP showed stricture at common bile duct, dilated common bile duct and pancreatic duct. The gastroenterologist suggested possible autoimmune cause of the stricture or primary sclerosing cholangitis in view of history of Sjogren’s syndrome, and so started prednsiolone. The liver function was normalized after the treatment. However, the serum IgG4 level later came back to be elevated up to 840mg/dL (NR <291mg/dL). The transbronchial biopsy and labial biopsy which were obtained previously were then reviewed. Both specimens were found to have IgG4 plasma cells positive. And so the diagnosis was confirmed to be IgG4-related disease.
Discussion
IgG4-related disease is a fibroinflammatory condition characterized by tumefactive lesions, dense lymphoplasmacytic infiltrate rich in IgG4-positive plasma cells, storiform fibrosis, and, often but not always, elevated serum IgG4 concentration. It was initially described mainly focus on pancreas, and recognized as systemic condition in 2003 when extra-pancreatic manifestations were identified in patients with autoimmune pancreatitis (1). There was a list of previously recognized conditions now acknowledged to fall into the spectrum of IgG4-related disease (table 1). IgG4-related disease mainly occurred in male (62-83%), with majority more than 50 years old (2). Until 2004, two cases of IgG4-related lung disease were published, describing 2 men with autoimmune pancreatitis who were found to have lung parenchymal infiltrates incidentally. There serum IgG4 levels were elevated and lung infiltrates responded with oral prednisolone.
Table 1. List of conditions in the spectrum of IgG4-related diseases
IgG4 accounts for less than 5% of total IgG in healthy persons. It is the least abundant IgG subclass with normal range 0.01-1.4mg/ml. It is characterized with “half-antibody exchange reaction” or “fragment antigen-binding (Fab)-arm exchange”, making it not able to activate the classical complement pathway effectively and so play a limited role in immune activation. Its production is mainly mediated by T-helper 2 (Th2) cells. The Th2 cells produce cytokines such as interleukin-5 to produce more eosinophil, interleukin-4 and interleukin -13 to enhance the production of both IgG4 and IgE. On the other hand, the regulatory T-cells will also be activated by Th2 cells to produce interleukin-10, which in turn helps to shift the balance between IgG4 and IgE, favouring IgG4 production. The regulatory T cells also produces more transforming growth factor β, which promotes fibrosis in IgG4-related disease.
However, the pathogenesis still remains unclear. Genetic factor is suggested with HLA DRB1*0405 and DQB1*0401 increase the susceptibility in Japanese populations, while HLA DQβ1-57 without aspartic acid is associated with disease relapse in Korean populations. Single-nucleotide polymorphisms encoding proteins, such as cytotoxic T-lymphocyte-associated antigen 4, TNFα and Fc receptor-like 3, are involved in disease susceptibility or recurrence. Another postulated mechanism is bacterial infection with molecular mimicry. The plasminogen-binding protein of H. pylori has homology with ubiquitin-protein ligase E3 component n-recognin 2 in pancreatic acinar cells. And so antibodies directed against bacterial components can behave as autoantibodies by means of molecular mimicry in genetically predisposed persons. Autoimmunity can also be possible mechanism which requires further study. Despite of the effort to find out the pathogenesis, the role of IgG4 is still unknown. It is thought to be less likely to participate in tissue-destructive immune response because of its Fab-arm exchange characteristic. Possible role of IgG4 can be protective or bystander to the inflammatory process.
There is still no published consensus about the diagnostic criteria of igG4-related disease. Most studies are using diagnostic criteria by Umehara and colleagues in 2011: 1) clinically showing characteristic diffuse or localized swelling or masses in single or multiple organs, 2) hematological examination shows increased serum IgG4 concentration, 3) histopathologic examination showing a) marked lymphocyte and plasmacytic infiltration and fibrosis, and, b) infiltration of IgG4 + plasma cells: ratio of IgG4+/IgG+ cells more than 40% and more than 10 IgG4+ plasma cells per high power field. Patient can be diagnosed as definite (fulfill all 3 criteria), probable (fulfill the 1st and 3rd criteria), and possible (fulfill the 1st and 2nd criteria) IgG4-related disease (3). According to 2 series from Japan, the incidence of lung involvement of IgG4-related disease can range from 14 to 54% (4,5). There are two relatively large scale case series published by Matsui S in Respirology 2013 and Zen Y in Am J Surg Pathol 2009 to describe the clinical features of patients with IgG4-related lung disease. Both series showed male predominance around 80%. There were 12% and 43% of patients in respective series having allergic history like rhinosinusitis and asthma. Only 28% and 47% of patient in respective series having pulmonary symptoms and mostly complained cough. The radiological features of lung manifestation were described in Zen study, which can be nodular, bronchovascular interstitial, ground-glass opacity or pleural lesion. (table 2,3) The possible radiological findings of IgG4-related lung disease were also described in review article by Ryu in Eur Respi J 2012 (table 4) (6).
Table 2: clinical features of IgG4-related lung disease in 2 case series
Table 3: clinical features of IgG4-related lung disease in 2 case series
Table 4: radiological findings of IgG4-related lung disease
Definitive treatment is suggested for vital organ involvement because it can lead to serious organ dysfunction and failure. The treatment suggestion is mainly based on the experience in treating IgG4-related autoimmune pancreatitis. The first treatment of choice is glucocorticoid. From the concensus statement from 17 centers in Japan, it is suggested to treat with prednsiolone at a dose of 0.6mg/kg/day for 2-4 weeks initially, followed by tapering to 5mg/day over 3-6 months, and continued at 2.5-5mg/day for up to 3 years (7). Azathioprine, mycophenolate mofetil and methotrexate are used as glucocorticoid-sparing agents or remission-maintenance drugs after glucocorticoid-induced remissions. But their efficacy has not be tested in clinical trials. Another drug of choice is rituximab, which is monoclonal antibody against B-cell. For the clinical trials, it showed to decrease serum IgG4 level sharply with clinical improvement within weeks (8). However, the data regarding the use of serial measurements of IgG4 concentration as indicators of disease activity are mixed. 30-63% of patient failed to have IgG4 level normalized after treatment despite the diseases remain in remission in some patients. Also, 10% of patients with normal IgG4 concentration would have relapses (9). Some cases may not have complete resolution of disease and still have persistent radiological abnormalities. But so far the response of IgG4-related lung disease after treatment is favorable from cases reported in literature. Long term follow-up data is still needed to help developing consensus about the treatment.
Conclusion
Two cases with clinical presentation as Sjogren’s syndrome were described. But there were some clues suggestive of alternative diagnosis: eosinophilia, elevated IgE level and negative ANA and anti-ENA. IgG4-related lung disease should be considered in cases of suspected Sjogren’s syndrome with atypical features.
References
- Kamisawa T, Funata N, Hayashi Y, et al. A new clinicopathological entity of IgG4-related autoimmune disease. J Gastroenterol 2003;38:982-4
- Raina A, Yadav D, Krasinskas AM, et al. Evaluation and management of autoimmune pancreatitis: experience at a large US center. Am J Gastroenterol 2009; 104:2295-306
- H. Umehara, K. Okazaki, Y. Masaki et al. Comprehensive diagnostic criteria for IgG4-related disease (IgG4-RD). Modern Rheumatology vol 22, no.1, pp21-30, 2011
- Zen Y, Nakanuma YL. IgG4-related disease: a cross-sectional study of 114 cases. Am J Surg Pathol 2010; 34: 1812–1819
- Fujinaga Y, Kadoya M, Kawa S, et al. Characteristic findings in images of extra-pancreatic lesions associated with autoimmune pancreatitis. Eur J Radiol 2010; 76: 228–238
- J.H.Ryu, H.Sekiguchi and E.S. Yi. Pulmonary manifestations of immunoglobulin G4-related sclerosing disease. Eur Respir J 2012; 39:180-186
- Kamisawa T, Okazaki K, Kawa S, et al. Japanese consensus guidelines for management of autoimmune pancreatitis. III. Treatment and prognosis of AIP. J Gastroenterol 2010;45:471-7
- Khosroshahi A, Carruthers M, Deshpande V, Unizony S, Bloch DB, Stone JH. Rituximab for the treatment of IgG4-related disease: lessons from ten consecutive patients. Medicine (Baltimore) 2012; 91:57-66
- Kamisawa T, Shimosegawa T, Okazaki K, et al. Standard steroid treatment for autoimmune pancreatitis. Gut 2009;58: 1504-7
