The diagnostic utility of labial salivary gland biopsy in IgG4-related disease

Objective: For the definitive diagnosis of IgG4-related disease (IgG4-RD), biopsies of local lesions are recommended so as to exclude other diseases, including lymphoma and cancer. However, performing biopsies of underlying organs is technically difficult. In this study, we examined the diagnostic utility of labial salivary gland (LSG) biopsy as a less invasive procedure.

Methods: Sixty-six patients with suspected IgG4-RD by clinical findings or high serum IgG4 underwent LSG biopsy. We examined the relationship between the number of IgG4-positive plasma cells in LSG and clinical findings.

Results: The final diagnosis was 45 patients with IgG4-RD, 12 with Sjögren’s syndrome, four with suspected Sjögren’s syndrome, three with malignant lymphoma, one with systemic lupus erythematosus, and one with Warthin’s tumor. The sensitivity, specificity, and accuracy of LSG biopsy were 55.6%, 100.0%, and 70.0%, respectively. Forty-five IgG4-RD patients were divided into two groups: 1) 25 with lesions of salivary glands (IgG4-RD S+) and 2) 20 without these lesions (IgG4-RD S?). Seventeen of 25 (68.0%) IgG4-RD S?+?and 8 of 20 (40.0%) IgG4-RD S???patients were positive for LSG biopsy. In the IgG4-RD S???patients, the mean number of affected organs and serum IgG4 in the positive cases for LSG biopsy were significantly higher than in the negative cases.

Conclusion: A solo LSG biopsy is insufficient for the diagnosis of IgG4-RD because of its low sensitivity. However, LSG biopsy combined with clinical findings, including serum IgG4 and number of affected organs, may contribute towards a diagnosis of IgG4-RD patients with affected underlying organs.     

Clinical features of patients with IgG4-related disease complicated with perivascular lesions

Abstract

Objective. To define the clinical features of IgG4-related disease (IgG4-RD) complicated with perivascular lesions.

Methods. The clinical features of seven patients with IgG4-RD and perivascular lesions diagnosed at the University of Tsukuba Hospital between October 2008 and October 2013, were analyzed, including clinical background, results of imaging studies, satisfaction of the 2011 comprehensive diagnostic criteria (CDC) for IgG4-RD, laboratory data, distribution of perivascular lesions, involvement of other organs, and response to steroid therapy.

Results. We studied six men and one woman with a mean age of 66.9 ± 6.7 years (± SD). Six of seven patients were diagnosed as definite IgG4-RD, while the seventh was considered possible IgG4-RD, based on the CDC for IgG4-RD. Serum IgG4 levels at diagnosis were higher than 135 mg/dl in all seven patients (mean, 933 ± 527). Serum C-reactive protein (CRP) levels were elevated in two only (mean, 1.42 ± 3.56 mg/dl). The perivascular lesions were located in the pulmonary artery (n = 1), thoracic aorta (n = 2), abdominal aorta (n = 6), coronary (n = 1), celiac (n = 1), superior mesenteric (n = 1), renal (n = 2), inferior mesenteric (n = 5), and iliac (n = 3) arteries. In addition to perivascular lesions, six patients showed involvement of other organs. All seven patients were treated with prednisolone (0.6 mg/kg/day), which rapidly improved the perivascular and other organ lesions in six patients (the other one patient have not yet been evaluated due to the short follow-up).

Conclusion. Perivascular lesions show wide distribution in patients with IgG4-RD. Serum CRP levels are not necessarily elevated in these patients. Steroid therapy is effective in IgG4-RD and results in resolution of lesions.     

Everyday clinical practice in IgG4-related dacryoadenitis and/or sialadenitis: Results from the SMART database

Abstract

Objective. Immunoglobulin (Ig)G4-related disease (IgG4-RD) is a new disease entity that has only been identified this century. Clinical information is thus lacking. We established the Sapporo Medical University and Related Institutes Database for Investigation and Best Treatments of IgG4-related Disease (SMART) to clarify the clinical features of IgG4-RD and provide useful information for clinicians.

Methods. Participants comprised 122 patients with IgG4-related dacryoadenitis and/or sialadenitis (IgG4-DS), representing lacrimal and/or salivary lesions of IgG4-RD, followed-up in December 2013. We analyzed the sex ratio, mean age at onset, organ dysfunction, history or complications of malignancy, treatments, rate of clinical remission, and relapse.

Results. The sex ratio was roughly equal. Mean age at diagnosis was 59.0 years. Positron emission tomography revealed that the ratio of other organ involvements was 61.4%. Complications of malignancy were observed in 7.4% of cases. Glucocorticoid was used to treat 92.1% of cases, and the mean maintenance dose of prednisolone was 4.8 mg/day. Rituximab was added in three cases, and showed good steroid-sparing effect. The clinical remission rate was 73.8%, and the annual relapse rate was 11.5%. Half of the cases experienced relapses within 7 years of initial treatment.

Conclusion. We analyzed the clinical features and treatments of IgG4-DS using SMART, providing useful information for everyday clinical practice.     

Successful treatment of a patient with IgG4-related disease with a paravertebral mass lesion

Abstract

A 68-year-old woman was admitted with bleary eyes and lacrimal gland swelling. A biopsy specimen from a right paravertebral mass lesion detected by computed tomography showed remarkable IgG4-positive plasma cells. Because serum IgG4 was elevated to 3300 mg/dl, IgG4-related disease was diagnosed, with the assistance of fluorodeoxyglucose positron emission tomography (FDG-PET)/computed tomography (CT). Administration of 30 mg of oral prednisolone effectively reduced the lacrimal gland swelling and paravertebral mass volume. Nine months after the initiation of prednisolone, serum IgG4 was reduced to 31.4 mg/dl, and there was norecurrence.     

Ophthalmic manifestations of IgG4-related disease: Single-center experience and literature review

ObjectivesIgG4-related disease (IgG4-RD) is an inflammatory disorder responsible for fibrosing, tumefactive lesions that can involve the lacrimal gland as well as the extraocular muscles, orbital soft tissues, sclera, and local nerves. We reviewed IgG4-related ophthalmic disease (IgG4-ROD), including the natural history, pathology, and treatment, based on our center's experience and that reported in the literature.MethodsWe identified 27 patients with orbital manifestations from our IgG4-RD registry; six were excluded because no pathology was available for review. All 21 cases included had histopathologically confirmed diagnoses of IgG4-RD, 11 of which were of the orbital tissue. Other data were obtained by a retrospective medical records review. MEDLINE and PubMed literature searches in English were conducted to identify articles for a literature review on the topic.ResultsPatients with IgG4-ROD were predominantly male (57%) and had an average age at symptom onset of 50 years (range: 21–79 years). The lacrimal gland was the most commonly involved structure (62%). Most patients (71%) had bilateral disease and extra-orbital involvement (71%); these patients also had elevated serum IgG4 concentrations compared to those with unilateral disease and no extra-orbital disease. Ten patients improved following rituximab treatment.ConclusionsOphthalmic involvement is a common manifestation of IgG4-RD and can affect nearly every orbital structure. Consideration of IgG4-RD and accurate diagnosis by biopsy have important implications for prognosis and treatment following the distinction of this condition from the Sjögren syndrome (SjS), granulomatosis with polyangiitis (GPA, formerly Wegener's), sarcoidosis, lymphoma, infection, and other disorders. Rituximab holds promise as an effective steroid-sparing agent or therapy for steroid-resistant cases.     

Diagnostic sensitivity of cutoff values of IgG4-positive plasma cell number and IgG4-positive/CD138-positive cell ratio in typical multiple lesions of patients with IgG4-related disease

Objectives: This study aimed to investigate the diagnostic sensitivity of the cutoff values of IgG4-positive plasma cell (PC) number and IgG4-positive/CD138-positive cell ratio proposed by the International consensus statement (ICS) on the pathology of IgG4-related disease (IgG4-RD) in typical multiple lesions of patients with IgG4-RD.

Methods: We evaluated IgG4-positive PC number and IgG4-positive/CD138-positive cell ratio in 39 samples from 18 IgG4-RD patients having more than two typical lesions of IgG4-RD.

Results: We evaluated 12 submandibular, 12 ophthalmic, six skin, five kidney, two pancreatic, and one bronchus and prostate lesion each in 18 patients with typical clinical, serological, and radiographic features. Concerning IgG4?+?PC number per high-power field, most ophthalmic (11/12), kidney (5/5), pancreatic (2/2), and bronchial lesions (1/1) fulfilled the cutoff value of ICS, whereas many of the submandibular (6/12) and skin lesions (0/6) did not. In contrast to the absolute number, all lesions fulfilled the cutoff value of IgG4+/CD138?+?cell ratio. In eight cases, only one or two lesions in the same patient fulfilled the cutoff value of ICS, while the others did not.

Conclusions: These results suggest that ICS criteria have different sensitivities among the affected organs for the diagnosis of IgG4-RD.     

Ophthalmic manifestations of IgG4-related disease: Single-center experience and literature review

Objectives

IgG4-related disease (IgG4-RD) is an inflammatory disorder responsible for fibrosing, tumefactive lesions that can involve the lacrimal gland as well as the extraocular muscles, orbital soft tissues, sclera, and local nerves. We reviewed IgG4-related ophthalmic disease (IgG4-ROD), including the natural history, pathology, and treatment, based on our center's experience and that reported in the literature.

Methods

We identified 27 patients with orbital manifestations from our IgG4-RD registry; six were excluded because no pathology was available for review. All 21 cases included had histopathologically confirmed diagnoses of IgG4-RD, 11 of which were of the orbital tissue. Other data were obtained by a retrospective medical records review. MEDLINE and PubMed literature searches in English were conducted to identify articles for a literature review on the topic.

Results

Patients with IgG4-ROD were predominantly male (57%) and had an average age at symptom onset of 50 years (range: 21–79 years). The lacrimal gland was the most commonly involved structure (62%). Most patients (71%) had bilateral disease and extra-orbital involvement (71%); these patients also had elevated serum IgG4 concentrations compared to those with unilateral disease and no extra-orbital disease. Ten patients improved following rituximab treatment.

Conclusions

Ophthalmic involvement is a common manifestation of IgG4-RD and can affect nearly every orbital structure. Consideration of IgG4-RD and accurate diagnosis by biopsy have important implications for prognosis and treatment following the distinction of this condition from the Sjögren syndrome (SjS), granulomatosis with polyangiitis (GPA, formerly Wegener's), sarcoidosis, lymphoma, infection, and other disorders. Rituximab holds promise as an effective steroid-sparing agent or therapy for steroid-resistant cases.     

Infrequent organ involvement of IgG4-related diseases: a literature review

IgG4-related disease (IgG4-RD) is a chronic and systemic disease that can involve multiple organs. The most commonly involved organs include the salivary glands, orbital adnexal structures, paranasal sinus, thyroid, lungs, breasts, aorta, pancreas, biliary ducts, kidneys, retroperitoneum, lymph nodes, prostate, pituitary, and endocranium. Due to increased disease research, several new site-specific nuances of IgG4-RD have been described. The authors have reviewed the recent literature and briefly summarize the infrequent organ involvement of IgG4-RD.     

Autoimmune hepatitis and IgG4-related disease

IgG4-related disease(IgG4-RD) is a chronic-fibroinflammatory disorder affecting a wide range of organs. Elevation of serum IgG4 concentrations and abundant infiltration of IgG4-expressing plasma cells are key diagnostic features of this autoimmune disease. Although common organ involvement of IgG4-RD includes the salivary glands, pancreas, and bile duct, hepatic involvement is less well established. Recently, five studies identified a subtype of autoimmune hepatitis(AIH), called IgG4-associated AIH(IgG4-AIH). IgG4-AIH is diagnosed based on significant accumulation of IgG4-expressing plasmacytes in the liver in patients who met the diagnostic criteria for classical AIH. Although four of the five reports regarded IgG4-AIH based on hepatic accumulation of IgG4-positive cells alone, one report diagnosed IgG4-AIH based on both hepatic accumulation of IgG4-positive cells and elevated serum concentrations of IgG4. IgG4-AIH diagnosed based on the latter criteria may be a hepatic manifestation of IgG4-RD whereas IgG4-AIH diagnosed based on the former criteria may be a subtype of AIH. In this review article, we summarize and discuss clinicopathological features of IgG4-AIH.     

Ocular adnexal marginal zone lymphoma arising in a patient with IgG4-related ophthalmic disease

Abstract

A 41-year-old man was diagnosed with immunoglobulin G4-related disease (IgG4-RD) in both eyelids 4 years ago and exhibited good response to steroid therapy. However, rapid swelling of the right eyelid lesion was recently observed. As IgG4-RD progression was suspected, biopsy was performed. Although the histology was consistent with IgG4-RD, the infiltrating large atypical lymphoid cells showed immunoglobulin light-chain restriction and IgH gene rearrangement. Consequently, he was diagnosed with extranodal marginal zone lymphoma with abundant IgG4-positive cells.     

A new conceptualization for Mikulicz's disease as an IgG4-related plasmacytic disease

Abstract

Mikulicz's disease (MD) has been included within the diagnosis of primary Sjögren's syndrome (SS), but it represents a unique condition involving persistent enlargement of the lacrimal and salivary glands characterized by few autoimmune reactions and good responsiveness to glucocorticoids, leading to the recovery of gland function. Mikulicz's disease was recently reported to be associated with elevated immunoglobulin G4 (IgG4) concentrations in the serum and prominent infiltration of plasmacytes expressing IgG4 into the lacrimal and salivary glands. The following features were used for diagnosis: (1) visual confirmation of symmetrical and persistent swelling in more than two lacrimal and major salivary glands; (2) prominent mononuclear cell infiltration of lacrimal and salivary glands; and (3) exclusion of other diseases that present with glandular swelling, such as sarcoidosis and lymphoproliferative disease. These features are not observed in most SS cases. The complications of MD include autoimmune pancreatitis, retroperitoneal fibrosis, tubulointerstitial nephritis, autoimmune hypophysitis, and Riedel's thyroiditis, all of which show IgG4 involvement in their pathogenesis. Mikulicz's disease thus differs from SS and may be a systemic IgG4-related plasmacytic disease.     

Role of interleukin-32 in the mechanism of chronic inflammation in IgG4-related disease and as a predictive biomarker for drug-free remission

Objectives: In immunoglobulin (Ig) G4-related disease (IgG4-RD), the mechanism of chronic inflammation and predictive factors for drug-free remission is still unclear. To examine the issues, we focused on tuberculosis, a chronic infection, and on the role of interleukin (IL)-32.

Methods: We examined the positive rate of QuantiFERON TB-2G (QFT-2G) in 126 patients with IgG4-RD, and compared with the rate in the general population. Furthermore, specimens of submandibular glands from the maintenance treatment group and drug-free group of IgG4-RD and specimens of small salivary glands from primary Sjögren’s syndrome (SS) were stained with anti-IL-32 antibody and anti-protease-activated receptor 2 antibody, and the number of positive cells was compared between these groups.

Results: The positive rate of QFT-2G was 19.8% in IgG4-RD patients, which is higher than in the general population. The expression of IL-32 and PAR2 in the submandibular glands of the maintenance treatment group of IgG4-RD was significantly greater than that of the drug-free remission group and SS patients.

Conclusions: This study indicates the possibility that IL-32 is associated with chronic inflammation and that it can be a predictive factor for drug-free remission in IgG4-RD.     

Dacrioadenitis por enfermedad relacionada con IgG4 en una adolescente afrodescendiente de Colombia

IgG4-related disease (IgG4-RD) is a recently recognized clinical condition with multiple aspects not yet elucidated. It is characterized by a fibrous inflammatory process that involves multiple organs and clinical, serological and histopathological findings, which represent a major challenge for the clinician. Classically described as an expansive tumor lesion with storiform fibrosis, lymphoplasmacytic infiltration (IgG4-positive) and elevated serum IgG4. Clinical features are variable, and pancreatic as well as extrapancreatic involvement has been reported, more frequently in Asian men over 50 years and rarely described in black people. We report the case of an Afro-Colombian teenage woman, who had a unilateral ocular protrusion of unknown cause, with histopathologic findings that revealed infiltration of lymphocyte and plasma cells into the lacrimal gland. It was positive for IgG4, ruling out other conditions, and confirming IgG4-related dacryoadenitis.     

Deconstructing IgG4-related disease involvement of midline structures: Comparison to common mimickers

Objective: A series of destructive and tumefactive lesions of the midline structures have been recently added to the spectrum of IgG4-related disease (IgG4-RD). We examined the clinical, serological, endoscopic, radiological, and histological features that might be of utility in distinguishing IgG4-RD from other forms of inflammatory conditions with the potential to involve the sinonasal area and the oral cavity.

Methods: We studied 11 consecutive patients with erosive and/or tumefactive lesions of the midline structures referred to our tertiary care center. All patients underwent serum IgG4 measurement, flow cytometry for circulating plasmablast counts, nasal endoscopy, radiological studies, and histological evaluation of tissue specimens. The histological studies included immunostaining studies to assess the number of IgG4?+?plasma cells/HPF for calculation of the IgG4+/IgG?+?plasma cell ratio.

Results: Five patients with granulomatosis with polyangiitis (GPA), three with cocaine-induced midline destructive lesions (CIMDL), and three with IgG4-RD were studied. We found no clinical, endoscopic, or radiological findings specific for IgG4-RD. Increased serum IgG4 and plasmablasts levels were not specific for IgG4-RD. Rather, all 11 patients had elevated blood plasmablast concentrations, and several patients with GPA and CIMDL had elevated serum IgG4 levels. Storiform fibrosis and an IgG4+/IgG?+?plasma cell ratio >20% on histological examination, however, were observed only in patients with IgG4-RD.

Conclusions: Histological examination of bioptic samples from the sinonasal area and oral cavity represents the mainstay for the diagnosis of IgG4-RD involvement of the midline structures.     

IgG4-related epididymo-orchitis associated with bladder cancer: possible involvement of BAFF/BAFF-R interaction in IgG4-related urogenital disease

Abstract

We describe herein a patient who presented with immunoglobulin G4-related disease (IgG4-RD) involving the testis and prostate as well as the submandibular glands. Massive infiltration of IgG4-expressing plasma cells was observed in testis and prostate tissues. Serum concentrations of B cell activating factor belonging to the tumor necrosis factor family (BAFF) were elevated in parallel with serum IgG4 concentrations, and infiltration of BAFF-receptor (BAFF-R)-expressing B cells and BAFF-expressing lymphoid cells was observed around the ectopic lymphoid foci in the affected urogenital tissues. To date, testicular involvement in a patient diagnosed with IgG4-RD had not been reported, making this the first reported case of IgG4-related epididymo-orchitis. These findings suggest that the immune mechanism underlying ectopic lymphoneogenesis in IgG4-RD may involve enhanced BAFF/BAFF-R interactions among lymphoid cells.     

Rituximab for the treatment of IgG4-related disease: lessons from 10 consecutive patients

Patients with IgG4-related disease (IgG4-RD) typically have elevated serum concentrations of IgG4 and share histopathologic features that are similar across affected organ(s). IgG4-RD patients frequently require prolonged treatment with glucocorticoids and are often unable to taper these medications. Traditional disease-modifying antirheumatic drugs (DMARDs) are generally ineffective. We assessed the clinical and serologic responses to B lymphocyte depletion therapy in 10 consecutive patients with steroid- and DMARD-refractory IgG4-RD.Ten patients with IgG4-RD were treated with rituximab (RTX) (2 infusions of 1000 mg, 15 days apart). Clinical improvement was assessed by monitoring the patient's ability to taper prednisone to discontinuation and to stop DMARDs; by serial measurements of total IgG and IgG subclasses; and by follow-up radiologic assessments guided by the patient's particular pattern of organ involvement. We also developed and retrospectively applied the IgG4-RD Disease Activity Index and Flare Tool.Organ involvement included the pancreas, biliary tree, aorta, salivary glands (submandibular and parotid), lacrimal glands, lymph nodes, thyroid gland, and retroperitoneum. Nine of 10 patients demonstrated striking clinical improvement within 1 month of starting RTX. One patient with advanced thyroid fibrosis associated with Riedel thyroiditis and a history of disease in multiple other organ systems did not have improvement in the thyroid gland, but the disease did not progress to involve new organs. All 10 patients were able to discontinue prednisone and DMARDs following RTX therapy. Significant decreases in IgG concentrations were observed for the IgG4 subclass only. Four patients were re-treated with RTX after 6 months because of either symptom recurrence and increasing IgG4 concentration at the time of peripheral B cell reconstitution (n = 2) or because of physician discretion (n = 2). Repeated courses of RTX maintained their effectiveness and resulted in further decreases in IgG4 concentrations. In patients who had an increased IgG4 concentration at the time of presentation, the level of serum IgG4 appeared to be a reliable measure of disease activity.IgG4-RD is an idiopathic, multiorgan inflammatory disease in which diverse organ manifestations are linked by characteristic histopathologic and immunohistochemical features. Treatment with RTX led to prompt clinical and serologic improvement in refractory IgG4-RD in all patients with active inflammation. Serial treatments with RTX may lead to progressive declines in serum IgG4 concentrations and better disease control. Serum IgG4 concentrations may remain low, and clinical disease activity may remain quiescent even after B cell reconstitution in a significant proportion of patients.     

Risk of malignancies in IgG4-related disease

Abstract

IgG4-related disease (IgG4-RD) is considered a systemic, chronic, and inflammatory disorder that is characterized by the enlargement of involved organs, elevated levels of IgG4, and abundant infiltration of plasmacytes with IgG4 and fibrosis in involved organs. It is necessary to differentiate IgG4-RD from malignant tumors. Recently we have looked at case reports of IgG4-RD with malignancy that was discovered at systemic screening. In this study, we analyzed the relationship between IgG4-RD and malignancies. The study subjects were 106 patients with IgG4-RD who had been referred to our hospital since April 1997. We analyzed the clinical characteristics of IgG4-RD patients who had cancer that was observed upon the initial diagnosis of IgG4-RD or that occurred during an average follow-up period of 3.1 years. Using data from national cancer registries that monitor cancer incidence in Japan, we evaluated the standardized incidence ratio (SIR) for malignancies in IgG4-RD. Malignancies were observed in 11 of the IgG4-RD patients (10.4%). The malignancies were all different and included lung cancer, colon cancer, and lymphoma. With the exception of the age at which the IgG4-RD diagnosis was made, there were no common features in patients with cancer and those without. The SIR for these malignancies in IgG4-RD was 383.0, which was higher than that for the general population. We should be cognizant of the possible existence of malignancies in patients with IgG4-RD at the time of diagnosis and during follow-up care.     

Successful treatment of a patient with IgG4-related disease with a paravertebral mass lesion

A 68-year-old woman was admitted with bleary eyes and lacrimal gland swelling. A biopsy specimen from a right paravertebral mass lesion detected by computed tomography showed remarkable IgG4-positive plasma cells. Because serum IgG4 was elevated to 3300 mg/dl, IgG4-related disease was diagnosed, with the assistance of fluorodeoxyglucose positron emission tomography (FDG-PET)/computed tomography (CT). Administration of 30 mg of oral prednisolone effectively reduced the lacrimal gland swelling and paravertebral mass volume. Nine months after the initiation of prednisolone, serum IgG4 was reduced to 31.4 mg/dl, and there was norecurrence.     

Immune complexome analysis of antigens in circulating immune complexes isolated from patients with IgG4-related dacryoadenitis and/or sialadenitis

Objectives. IgG4-related disease (IgG4-RD) is characterized by various serological abnormalities. Some patients with IgG4-RD present with hypergammaglobulinemia, hypocomplementemia, and autoantibodies recognizing rheumatoid factors and nuclear factors. However, whether IgG4-RD is an autoimmune disease remains unclear.

Methods. Here, we used immune complexome analysis to comprehensively identify constituent antigens of circulating immune complexes isolated from 10 patients with IgG4-related dacryoadenitis and/or sialadenitis (IgG4-RDS) which is one condition associated with IgG4-RD.

Results. We detected each of 125 distinct antigens in independent samples from two or more patients with IgG4-RDS. Of them, 17 antigens were found to be specific to patients with IgG4-RDS by comparing 125 antigens with all the antigens found in other connective tissue diseases (antineutrophil cytoplasmic antibody-associated vasculitis, Takayasu's arteritis, mixed connective tissue disease, dermatomyositis, Sjögren's syndrome, systemic scleroderma, and systemic lupus erythematosus) or healthy donors. The number of disease-specific antigens associated with IgG4-RDS was comparable to those autoimmune diseases.

Conclusions. Studies of the 17 IgG4-RDS-specific antigens might lead to a better understanding of the pathogenesis of IgG4-RD, but further study of the prevalence of these CIC-associated antigens that involves a selective and sensitive assay will be needed to determine their potential as diagnostic or pathogenic biomarkers.