Serial Salivary Gland Ultrasound Monitoring of Treatment Efficacy in IgG4-RD: A Case Report

A CASE OF IGG4-RELATED INTERSTITIAL LUNG DISEASE MANIFESTING AS RECURRENT NECROTIZING PNEUMONIA

IGG4-RELATED DISEASE PRESENTING AS A PULMONARY INFLAMMATORY PSEUDOTUMOR

BackgroundIgG4-related disease is a fibro-inflammatory disorder with an unknown etiology, which can affect multiple organ systems, including the cardiovascular system. While most reported cases of cardiovascular involvement are primarily associated with the aorta, there have been sporadic reports of isolated cardiac involvement.Case presentationThis paper presents a documented case of IgG4-related systemic disease with symptoms indicative of restrictive cardiomyopathy. Subsequent Cardiac Magnetic Resonance imaging revealed diffuse myopericardial involvement, characterized by pericardial thickening and enhancement, accompanied by subepicardial and myocardial infiltration. Considering the rarity of cardiac involvement in our case, we conducted a thorough review of the existing literature pertaining to various patterns of cardiac involvement in IgG4-related disease, as well as the diagnostic modalities that can be employed for accurate identification and assessment.ConclusionsThis case report sheds light on the importance of recognizing and evaluating cardiac manifestations in IgG4-related systemic disease to facilitate timely diagnosis and appropriate management.

Case report - IntroductionThe presence of autoantibodies in IgG4-related disease (IgG4-RD) can lead to confusion and we present a case to highlight the diagnostic difficulty in this condition.Case report - Case descriptionA 63-year-old Indian female presented with progressive ptosis and swelling of the left eyelid for 2 months. She was referred to the stroke clinic where she was found to have left ptosis with associated swelling. An MRI of the orbit revealed an enlarged left lacrimal gland and mucosal thickening in paranasal sinuses. Her ESR was 20, CRP 2, 15% peripheral eosinophils and IgG 17.55 g/L (6-16). A referral was made to rheumatology due to an abnormal immunological profile: cANCA +, MPO ANCA positive 32 IU/ml (0-3.5) and a strongly positive anti-Ro antibody >600 U/ml (0-10). Differential diagnosis considered: ANCA associated vasculitis (AAV), Primary Sjögren’s syndrome (SS), and IgG4-related orbital disease. She was assessed by the ENT surgeon and there was no sinusitis or evidence of vasculitis. Chest X-ray and CT scan of chest were normal.A left lacrimal gland biopsy revealed reactive lymphoid hyperplasia with numerous plasma cells and eosinophils. Immunohistochemistry revealed over 50% of plasma cells to be IgG4-positive (approximately 100/HPF) suggestive of IgG4-RD. There was no evidence of granuloma formation or malignancy. Serum IgG4 was raised 6.82 g/l (<1.3). A review by ophthalmology revealed no objective evidence of dry eyes. She was treated as IgG4-RD and demonstrated a marked improvement following treatment with oral steroids and azathioprine.Case report - DiscussionIgG4-RD is an immune-mediated systemic fibro inflammatory disease characterised by tumefactive lesions with abundant IgG4-positive plasma cells infiltrating into multiple organs. Isolated IgG4-related ophthalmic disease is present in 23% of patients with IgG4-RD, in whom the lacrimal gland is the most commonly involved structure, followed by orbital fat and extraocular muscles. IgG4-related ophthalmic disease is rare and we need to exclude commoner causes of orbital inflammation (such as thyroid ophthalmopathy, granulomatosis with poly-angiitis, sarcoidosis, and tuberculosis) or malignancy.Case report - Key learning pointsThe diagnosis of IgG4-RD is often challenging. It is well recognised that small vessel vasculitis can increase the number of IgG4-positive plasma cells in tissue biopsies. Additionally, literature reveals biopsy-proven IgG4-RD can have ANCA positivity with and without concomitant presence of ANCA-associated vasculitis and there are case reports of patients who fulfil criteria for both Sjogren’s syndrome and IgG4-RD. As such, diagnosis requires careful correlation of clinical, radiologic and histological features due to the overlapping features in differential diagnoses.

Type 1 autoimmune pancreatitis and IgG4-related sclerosing cholangitis (IgG4-SC) are the pancreatobiliary manifestations of IgG4-related disease. IgG4-related disease is a newly named fibroinflammatory condition that is characterized by tumefactive lesions that contain dense lymphoplasmacytic infiltrates rich in IgG4-positive cells and often by elevated serum IgG4 concentrations. IgG4-related pancreatobiliary disease is often disguised as pancreatobiliary malignancies owing to its tumefactive nature and clinical presentations, such as obstructive jaundice. The differentiation of IgG4-SC from primary sclerosing cholangitis is also essential because of the significant differences in treatment responses and prognosis. A timely diagnosis of IgG4-related pancreatobiliary disease can lead clinicians to prescribe adequate glucocorticoid treatment that can reverse the pancreatobiliary duct strictures and obstructive jaundice. On the other hand, the diagnosis of IgG4-related pancreatobiliary disease is sometimes challenging because there is no single diagnostic clinical test. The diagnosis of IgG4-related pancreatobiliary disease rests on fulfilling the diagnostic criteria, including imaging, serology, other organ involvement, histology, and response to steroids. Approximately 50% of patients with IgG4-related pancreatobiliary disease experience relapse, despite IgG4-related pancreatobiliary disease showings a favorable short-term prognosis after glucocorticoid therapy. To reduce the relapse, long maintenance treatment for 3 years may be necessary. The purposes of this review were to emphasize the clinical problem of diagnosing IgG4-related pancreatobiliary disease as well as to highlight the use of the published guidelines for the diagnosis and management of IgG4-related pancreatobiliary disease.

Interpretation of biopsies taken on suspicion of immunoglobulin (Ig)G4-related disease (IgG4-RD) may be hampered by uninterpretable immunohistochemical stains for IgG because of strong background signals. This study aims to determine the significance of tissue IgG2 positive plasma cell counts in IgG4-RD in comparison with non-IgG4-related inflammatory disorders. Descriptive, retrospective case-control study of 16 patients with IgG4-related orbital disease (IgG4-ROD) and 24 with extraorbital IgG4-RD. Histopathology and serology of this group was compared with 16 patients with orbital non-IgG4-related disorders and 22 patients with extraorbital non-IgG4-related disorders. The mean tissue IgG2/IgG4 ratio was 0.16 in IgG4-ROD and 0.27 in extraorbital IgG4-RD and far below 1 in 98% of patients. This was significantly lower compared with the non-IgG4-related disorders that showed a mean tissue IgG2/IgG4 ratio of 1.98 in the orbital and 2.20 in the extraorbital group (range: 0.20 to 10, P <0.05). In 74% of tissue samples an IgG2/IgG4 ratio >1 was seen. The tissue IgG2/IgG ratio was significantly lower in IgG4-RD compared with non-IgG4-related inflammatory disorders. Serum IgG2 concentration was not abnormal in patients with IgG4-RD. A significantly lower tissue IgG2/IgG4 and IgG2/IgG ratio was observed in IgG4-RD, compared with non-IgG4-related inflammatory disorders. Additional immunohistochemical staining for IgG2 positive plasma cells can be helpful in the diagnosis of IgG4-RD. Especially in cases with uninterpretable IgG staining, a well-recognized problem that may give rise to a failed interpretation of the biopsy.

IntroductionIgG4-related disease was first reported in 2001 and was officially named in 2010. It is now considered as a systemic disease that might affect any organ system. The characteristic pathological changes of IgG4-related disease are extensive infiltration of IgG4-positive plasma cells. IgG4-related disease is a kind of benign lesions, but there has not been well-defined standard treatment so far. Patients usually respond well to corticosteroids. The prognosis of IgG4-related disease is perhaps good as long as early detection and treatment.Case descriptionWe report one case of IgG4-related disease with a 16-years anamnesis with multi-pseudotumor masses. He was diagnosed with chronic kidney disease with wide interstitial renal fibrosis. And he received glucocorticoids therapy. After 2 month therapy, the serum creatinine, erythrocyte sedimentation rate, and serum IgG4 decreased significantly. The discussion includes presentation, clinical course, diagnosis, and prognosis of IgG4-related disease. The case and discussion highlight the importance of diagnosis and the good prognosis of IgG4-related diseases.Discussion and evaluationOur case highlights the importance of diagnosis and the good prognosis of IgG4-related diseases. IgG4-related disease is a systemic fibro-inflammatory immune-mediated disorder and now recognized in almost every major organs. Characteristics of the disease is multiple lymph nodes and the response to glucocorticoids therapy is well. In such case, he had a history of 16 years with multi-pseudotumor masses and misdiagnosed for 16 years, if the doctors were not awareness of higher serum immunoglobulin G4 (IgG4) than normal, the correct diagnosis may be missed or delayed. Consequently, appropriate treatment for IgG4-related disease would also be delayed or not provided and likely result in increased morbidity and mortality.ConclusionsIgG4-related disease is a systemic fibro-inflammatory immune-mediated disorder and progresses slowly. In the present patient the course of IgG4-related disease appears to be benign. The prognosis of IgG4-related disease depend on early diagnosis and treatment.

IGG4-RELATED LUNG DISEASE MASKING LUNG CANCER

IgG4-related disease (IgG4-RD) is an inflammatory disorder characterized by tumor-like swelling in one or more organs, elevated serum IgG4 levels, and histological alterations with infiltration of IgG4-positive plasma cells. IgG4-RD is rare and likely underdiagnosed in children. We report a case of a 16-year-old girl with IgG4-positive colitis that developed weeks after IgG4-related ophthalmic disease and discuss diagnosis and treatment in the context of the literature available. Since the pathophysiology of IgG4-RD is unknown, treatment options are empiric and, for the most part, untargeted. Systemic corticosteroid treatment is the basis of anti-inflammatory treatment in IgG4-RD and induced early remission in our patient. During corticosteroid taper, the patient developed weight loss and intestinal inflammation. Histopathological assessment of the intestinal walls confirmed IgG4-positive colitis. Immune-modulating treatment with non-biologic (e.g., methotrexate (MTX) and mycophenolate mofetil) or biologic (rituximab) disease-modifying antirheumatic drugs has been reported in treatment refractory or corticosteroid-dependent patients. The patient responded to treatment with anti-inflammatory therapy with food rich in TGF-β2 (modulen) and MTX. This is one of the first pediatric patients reported with IgG4-related colitis extending the phenotype of pediatric IgG4-RD. International collaboration to prospectively document clinical presentation and treatment responses may help to further establish the phenotype and treatment options and to raise awareness for IgG4-RD.

IgG4-related disease is a recently recognized autoimmune systemic disorder that has been described in various organs. The disease is characterized histologically by a dense lymphoplasmocytic infiltrate of IgG4-positive cells, storiform fibrosis and can be associated with tumefactive lesions. IgG4-related disease involving the upper gastrointestinal tract is rare and only two previous case reports have reported IgG4-related esophageal disease. We report the case of a 63-year-old female patient with a long-standing history of severe dysphagia and odynophagia with an initial diagnosis of reflux esophagitis. Symptoms persisted despite anti-acid therapy and control esophagogastroduodenoscopy (EGD) revealed endoscopic images consistent with esophagitis dissecans superficialis (sloughing esophagitis). An underlying autoimmune process was suspected and immunosuppressant agents were tried to control her disease. The patient eventually developed disabling dysphagia secondary to multiple chronic esophageal strictures. A diagnosis of IgG4-related disease was eventually made after reviewing esophageal biopsies and performing an immunohistochemical study with an anti-IgG4 antibody. Treatment attempts with corticosteroids and rituximab was not associated with a significant improvement of the symptoms of dysphagia and odynophagia, possibly because of the chronic nature of the disease associated with a high fibrotic component. Our case report describes this unique case of IgG4-related esophageal disease presenting as chronic esophagitis dissecans with strictures. We also briefly review the main histopathological features and treatment options in IgG4-related disease.

Introduction: IgG4-related disease (IgG4-RD) is a fibroinflammatory disorder that may involve almost each organ or system. IgG4-related kidney disease (IgG4-RKD) refers to renal lesions associated with IgG4-RD. The most frequent morphological type of renal lesions is IgG4-related tubulointerstitial nephritis (IgG4-TIN) which is associated with increased IgG4-positive plasma cell infiltration and interstitial fibrosis. Case Report: Herein, we present a rare case with coexisting IgG4-RKD and acute crescent glomerulonephritis with concomitant severe tubulointerstitial lesions instead of classic IgG4-TIN. Conclusion: IgG4-RKD and acute crescent glomerulonephritis can occur in the same patient. This case may give us a clearer viewpoint of the disease.

Background:Immunoglobulin G4-related disease (IgG4-RD) is a rare multisystemic idiopathic fibroinflammatory disorder. The rare form of IgG4-RD with isolated thorax involvement is called immunoglobulin G4-related respiratory disease (IgG4-RRD). IgG4-RRD, which is reported in a limited number of cases in the literature, can be categorized into four types on the prevalent chest computed tomography (CCT) findings: solid nodular, round-shaped ground-glass opacity, alveolar interstitial, and bronchovascular. Solid nodular form of IgG4-RRD with mass-like lesions is sporadic and described in the literature with a small number of case reports.Objectives/Methods:We aim to present the radiologic, pathologic, and clinical findings of three cases of IgG4-RRD mimicking lung cancer.Results:In all three patients, IgG4-RRD occurred with mass-like lesions in the thorax. In case-1 and 2, CCT showed multiple, nodular lesions and multiple mediastinal lymph nodes. On positron emission tomography with 2-deoxy-2-[fluorine-18] fluoro- D-glucose integrated with computed tomography (18F-FDG PET/CT), the masses showed increased 18F-FDG uptake in case-2 and 3. The gold standard histopathological verification for IgG4-RRD was provided for all cases.Conclusions:IgG4-RD is an immune-mediated condition comprised of a collection of disorders that share particular pathologic, radiologic, serologic, and clinical features. Isolated IgG4-RRD is rarely seen and is available in the literature as case reports. IgG4-RRD, which can make lung involvement in different patterns, rarely appears with mass-like lesions. Still, IgG4-RRD must be considered in the differential diagnosis of mass lesions detected in CCT. Laboratory, radiological, and histopathological findings of the disease should be evaluated together for an accurate diagnosis.

Case report - IntroductionMajor salivary gland (sialadenitis) and lacrimal gland (dacryoadenitis) involvement can be a common feature of IgG4-related disease. There can be involvement of lacrimal and parotid gland which was previously called as Mikulicz disease and/or submandibular gland enlargement which was previously called Küttner tumour. These were previously mistakenly considered to be subcategories of Sjogren’s syndrome, but are now classified as IgG4-related disease. Here we discuss a case report of a patient who presented with bilateral dacryoadenitis and unilateral submandibular gland enlargement which initially was thought to be IgG4-related disease but turned out to be low-grade lymphoma.Case report - Case descriptionA 15-year-old boy presented with 6-month history of bilateral eyelid swelling. The swelling was more on the lateral side of the eyelids and was painless. It had come on suddenly over a couple of days. No history of weight loss, dry eyes, dry mouth, joint issues or skin rashes or any other symptoms. Physical examination revealed bilateral ptosis, no visual impairment and systemic examination revealed an enlarged right submandibular gland. He had initially been to a local hospital where he had investigations which included autoimmune screen including ANA, ENA, ANCA, dsDNA, serum ace and complement levels which were all negative. C1 esterase inhibitor was normal. Routine bloods including complete blood count, urea and electrolytes, thyroid stimulating hormone and erythrocyte sedimentation rate were within normal limits. Urine albumin to creatinine ratio was not raised. Hepatitis serology including Hepatitis B & C and HIV was negative. Ultrasound abdomen was unremarkable. CT scan of orbits showed bilateral enlarged lacrimal glands with patchy post contrast enhancement and the glands extending up to insertion of lateral rectus muscle. CT chest some enlarged axillary lymph nodes and nodes in lung query infective etiology. CT abdomen and pelvis was unremarkable. Ultrasound neck showed right submandibular node enlargement with colour doppler showing increased vascularity. Fine needle aspirate of the submandibular gland showed reactive lymphoid hyperplasia. He was given two short courses of steroids and each time the swelling rapidly responded to the steroids but recurred on cessation of the steroids. IgG subset analyses revealed elevated IgG4 levels of 1152mg/dl. The differential here was IgG4-related disease but as there was no clear tissue diagnosis a core biopsy of the right submandibular gland was done. This revealed tissue suspicious of low grade (extranodal marginal zone and mucosa-associated lymphoid tissue [MALT]) lymphoma and excision biopsy was performed for definitive diagnosis.Case report - DiscussionIgG4-related disease is an immune mediated fibroinflammatory condition which can affect a variety of organs and can present as tumour-like enlargement and/or organ dysfunction. The pathological findings in IgG4-related disease are lymphoplasmocytic infiltrates of IgG4-positive cells along with increased levels of serum IgG4 levels. Salivary and lacrimal glands can be commonly affected and present as enlargement, which is usually painless and bilateral. The combination of lacrimal gland enlargement with both parotid and submandibular gland enlargement is called IgG4-related Mikulicz disease.Apart from salivary glands, another commonly affected organ is the pancreas which can present as a pancreatic mass and painless jaundice, sclerosing cholangitis, retroperitoneal fibrosis, aortitis and periaortitis. Less commonly it can affect thyroid, kidney and lungs.Early recognition, diagnoses and treatment is important due to the fibroinflammatory nature of the disease. Malignancy is always in the differential and should be excluded. Steroids are the mainstay of treatment. If patients experience flare, rituximab can be added.Diagnosis should be confirmed with biopsy but histopathological findings are never alone diagnostic of IgG4-related disease and should be interpreted with clinical, serological and radiological findings.Case report - Key learning pointsAlthough this patient had typical presentation of IgG4-related disease with painless enlargement of salivary and lacrimal glands and elevated IgG4 serum levels, biopsy was imperative to get to the diagnoses of low-grade lymphoma and fine needle aspirate was not adequate. As mentioned above, biopsy in IgG4-related disease will confirm the diagnosis provided there are other supporting features (radiological and serological). However, it is imperative for excluding other important diseases like lymphoproliferative disorders.

IgG4-related disease in the Japanese population: a genome-wide association study.

To explore the clinical features of immunoglobin (IgG4)-related Mikulicz's disease (MD). Since December 2010, a prospective cohort study of IgG4 related disease (IgG4RD) was performed our hospital. A total of 42 IgG4RD patients were recruited along with 18 MD patients. Their clinical, laboratory and histopathological features and response to treatment were analyzed. The 18 MD patients accounted for 42.9% of IgG4RD. There were 10 males and 8 females with a mean age of (48 ± 14) years. The mean follow-up period was 8.18 months. All of them had an involvement of salivary and lacrimal glands. Fifteen cases suffered other organs' damage, including autoimmune pancreatitis (n = 7), sclerosing cholangitis (n = 4) and lymph nodes (n = 6). And 10 patients complained of a history of allergies. All serum levels of IgG4 subclass significantly increased. Histological examinations in 16 patients revealed massive infiltration of lymphocytes and IgG4 positive plasma cells with obvious tissue fibrosis. Glucocorticoid and immunosuppressive therapies were effective for MD. As an IgG4-related systemic disease involving predominantly lacrimal and salivary glands without autoantibodies, MD is treated optimally with a combination therapy of glucocorticoid and immunosuppressive drugs.