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.

Loss of interleukin-21 leads to atrophic germinal centers in multicentric Castleman's disease.

Both multicentric Castleman's disease (MCD) and immunoglobulin (Ig)G4-related disease (IgG4-RD) are systemic diseases, presenting with hypergammaglobulinemia and elevated serum levels of IgG4. However, with regard to histopathological findings, MCD shows atrophic germinal centers. On the other hand, expanded germinal centers are detected in IgG4-RD. We extracted germinal centers from specimens of each disorder by microdissection and analyzed the expression of mRNAs by real-time polymerase chain reaction to clarify the mechanisms underlying atrophied germinal centers in MCD. This analysis disclosed loss of interleukin (IL)-21 and B cell lymphoma (Bcl)-6 in the germinal centers of MCD. Loss of IL-21 is considered to be involved in the disappearance of Bcl-6 and leads to atrophied germinal centers in MCD.

Loss of HER2 Positivity after Trastuzumab in HER2-Positive Gastric Cancer: Is Change in HER2 Status Significantly Frequent?

Trastuzumab has recently been introduced as a treatment for HER2-positive metastatic and/or unresectable gastric cancer (MUGC); however, compared with breast cancer, some issues concerning HER2 and trastuzumab therapy for gastric cancer remain unclear. A 74-year-old woman received trastuzumab-containing chemotherapy for HER2-positive MUGC. She had a marked response to 8 months of chemotherapy, and gastrectomy and hepatic metastasectomy with curative intent were performed. The resected specimen showed complete loss of HER2 positivity in the residual tumor. For MUGC, a change in HER2 status during the course of the disease with or without chemotherapy has rarely been reported. However, in breast cancer, a significant frequency of change in HER2 status during the course of disease has been reported, and reevaluation of HER2 positivity in metastatic/recurrent sites is recommended. The choice of trastuzumab for MUGC is currently based on the HER2 status of the primary tumor at the time of initial diagnosis, without reassessment of HER2 status during the course of disease and/or in metastatic/recurrent sites, on the assumption that HER2 status is stable. However, our case casts doubt on the stability of HER2 in gastric cancer.

CCAAT/enhancer binding protein α (C/EBPα)(+) M2 macrophages contribute to fibrosis in IgG4-related disease?

IgG4-related disease (IgG4-RD) is a new disease entity characterized by type 2 helper T (Th2)-dominant inflammation and progressive fibrosis. We found the infiltration of strange cell populations in the fibrotic lesions of submandibular gland specimens obtained from 15 patients with IgG4-RD. These cells expressed CCAAT/enhancer binding protein a (C/EBPα). Many of the cell populations were identified with M2 macrophages. The degrees of infiltration of C/EBPα(+)M2 macrophages and the ratio of fibrotic lesions in the specimens were correlated (r(2) = 0.83, p < 0.01). We also analyzed the expression of C/EBPα in other chronic inflammatory disorders: synovium in rheumatoid arthritis (RA), liver tissue in chronic viral hepatitis, and mucosa in ulcerative colitis. The specimens from RA and chronic viral hepatitis showed infiltration of C/EBPα(+) cells, but there were few C/EBPα-positive cells in ulcerative colitis. Fibrosis is not a major issue in ulcerative colitis. In conclusion, we found the remarkable infiltration of C/EBPα(+)M2 macrophages in cases of chronic inflammation with fibrosis, including IgG4-RD. This primitive study also disclosed that most of C/EBPα(+)M2 macrophages localized in fibrotic lesions, and the degree of the infiltration and the ratio of fibrotic area were correlated.

Identification of relapse predictors in IgG4-related disease using multivariate analysis of clinical data at the first visit and initial treatment.

OBJECTIVES: Inducting clinical remission by glucocorticoid treatment is relatively easy in IgG4-related disease (IgG4-RD), but relapse also occurs easily with tapering of the steroid dose. The present study tried to analyse the cases to extract predictors of relapse present at the diagnosis of IgG4-RD. METHODS: Subjects comprised 79 patients with IgG4-related dacryoadenitis and sialadenitis, known as Mikulicz's disease, who were diagnosed between April 1997 and October 2013 and followed-up for >2 years from the initial induction treatment. They were applied to Cox proportional hazard modelling, based on the outcome of interval to relapse. We performed multivariate analysis for the clinical factors of these cases and identified predictors of relapse. RESULTS: Identified factors were male sex and younger onset in cases without organ involvement at diagnosis and low levels of serum IgG4 in cases with organ dysfunction at diagnosis. Complication with autoimmune pancreatitis and low steroid dose at initial treatment also tended to be associated with recurrence. CONCLUSION: Follow-up is important in cases with recognized risk factors for relapse, including male sex and younger onset in cases without organ damage.

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.

[Human herpesvirus 6 encephalitis in a patient with glucocorticoid therapy for inflammatory abdominal aortic aneurysm].

A 73-year-old man with inflammatory abdominal aortic aneurysm was admitted with headache and fever. Chest computed tomography (CT) revealed pneumonia and antibiotic therapy was started. Short-term memory impairment was observed and his consciousness had been rapidly deteriorated with seazure. Fluid-attenuated inversion recovery (FLAIR) image and diffusion-weighted magnetic resonance image (DWI) showed high intensity signals around bilateral limbic areas and herpes simplex encephalitis was suspected. After human herpesvirus (HHV)-6 DNA was amplified from cerebrospinal fluid, he was diagnosed with HHV-6 encephalitis and treated with gancyclovir. Clinicians need to be aware that glucocorticoid treatment for elderly can cause HHV-6 encephalitis.

The role of cytotoxic T cells in IgG4-related dacryoadenitis and sialadenitis, the so-called Mikulicz's disease.

OBJECTIVES: Immunoglobulin (Ig) G4-related dacryoadenitis and sialadenitis, the so-called Mikulicz's disease (MD), is a chronic inflammatory disease. However, little is known about its pathogenesis and pathological condition. In the present study, we used immunohistological techniques to compare the roles of cytotoxic T lymphocytes (CTLs) in MD and primary Sjogren's syndrome (SS). We examined the state of CTLs [cytotoxic granule-positive rate and programmed death-1 (PD-1) expression rate] in the salivary glands. METHODS: The study samples comprised 12 submaxillary glands from untreated MD patients and 12 labial glands from SS patients. We performed immunofluorescence and multicolor immunofluorescence to stain CD8, perforin (PRF), granzyme B (GZMB), and PD-1. We measured the total number of CTLs as well as the PRF(+)CTLs, GZMB(+)CTLs, and PD-1(+)CTLs. RESULTS: We found that the degree of infiltration of CTLs was equal in MD and SS, but the rate of CTLs with cytotoxic granules, especially PRF, in MD was less than in SS. In addition, the frequency of PD-1(+)CTLs in MD was higher than that in SS. CONCLUSIONS: Cytotoxic granule-positive CTLs were in the minority in D salivary glands, and this regulation might relate to PD-1 signals like the state of exhaustion and anergy.

Necessity of early intervention for IgG4-related disease--delayed treatment induces fibrosis progression.

OBJECTIVE: Despite ongoing research, the clinical and histopathological natural history of immunoglobulin (Ig) G4-related disease (IgG4-RD) remains unclear and the optimal time to initiate treatment is unknown. A focus on clinical symptoms rather than image finding is recommended for therapeutic initiation in autoimmune pancreatitis, but evidence for this approach is lacking. We aimed to retrospectively analyse disease duration, efficacy of treatment with glucocorticoids and results of histopathological examination of submandibular gland specimens to clarify the necessity for early intervention in IgG4-RD. METHODS: Salivary secretions were assessed before and after treatment in 26 cases of IgG4-related Mikulicz's disease (IgG4-MD). Relationships between disease duration, amount of salivary secretion before treatment, improvement of salivary secretion and ratios of areas of residual acini, fibrosis and lymphoid follicles in the involved submandibular gland specimens were analysed. RESULTS: Salivary secretions were significantly reduced in cases with illness of >2 years (P < 0.05). An inverse correlation was seen between improved amount of salivary secretion and amount of salivary secretion before treatment (r = -0.60). Improved amount of salivary secretion was also associated with each histological factor (acini, r = 0.29; fibrosis, r = -0.23; lymphoid follicles, r = -0.31), which showed interrelationships (acini and lymphoid follicles, r = -0.23; acini and fibrosis, r = 0.42; lymphoid follicles and fibrosis, r = 0.30). CONCLUSION: Salivary secretion can be improved even in cases with lower levels of salivary secretion before treatment in IgG4-RD, but improvements in the amount of salivary secretion decrease with histological changes with delayed therapeutic intervention. These data suggest that early intervention is needed to improve outcomes in patients with IgG4-MD.

[A case of esophageal endocrine cell carcinoma with multiple liver metastases that had a complete response to multidisciplinary therapy].

A 71-year-old man was admitted to our hospital because of dysphagia, and primary endocrine cell carcinoma of the esophagus with multiple liver metastases was diagnosed. After 6 courses of CPT-11+CDDP combination chemotherapy, the liver metastases disappeared, although the esophageal squamous cell carcinoma component remained. Radiation therapy was added to treat the residual esophageal tumor, and a complete response was obtained. This case seems to suggest that multidisciplinary therapy, including chemotherapy, may be effective for treating esophageal endocrine cell carcinoma with other types of organ metastasis.

Evaluation and Clinical Validity of a New Questionnaire for Mikulicz's Disease.

Objectives. The characteristic features of Mikulicz's disease (MD) are diffuse enlargement of the lacrimal and submandibular glands, elevated levels of serum immunoglobulin (Ig)G4, and abundant infiltration of IgG4-positive plasmacytes into both glands. No disease index is available to properly evaluate MD, so we developed a functional assessment of MD, the Mikulicz's disease activity questionnaire (MAQ), and evaluated its clinical efficacy. Methods. We selected 18 patients who were either being treated for MD or who had presented with recurrence. The patients completed a self-assessment and were scored according to the MAQ sheet during each visit between December 2009 and August 2011. Assessment items were in regard to increases or decreases in lacrimal and salivary gland enlargement and severity of sicca symptoms. Results. On the first visits, MAQ scores were high, but scores decreased rapidly as treatment progressed. When doses of glucocorticoid were reduced, some patients showed increased scores. Dry-symptom scores increased initially. MAQ scores for patients with recurrent MD gradually increased over several months before relapse. However, some patients displayed no elevation in MAQ scores due to relapses at other sites. Conclusion. MAQ score can be used to quantify flares and treatment response and is useful for functional assessment of MD.

[Usefulness of measuring serum IgG4 level as diagnostic and treatment marker in IgG4-related disease].

IgG4-related disease is a chronic disorder, which is characterized with elevated levels of serum immunoglobulin (Ig)G4 and abundant infiltration of IgG4-positive plasmacyte and storiform fibrosis in the enlarged organs. It includes Mikulicz's disease (IgG4-related dacryoadenitis and sialadenitis), autoimmune pancreatitis type I, and so on. In Japan, we have been able to measure the IgG4 levels in our clinic since 2010, and we knew that various diseases except IgG4-related disease, also presented with elevated levels of serum IgG4. Eosinopihic disorders, such as Chrug-Strauss syndrome, a part of rheumatoid arthritis and systemic sclerosis can present with high levels of serum IgG4. So the confusion is seen in some clinicians, but we have to recognize that only serological findings cannot lead to the correct diagnosis in IgG4-related disease. The pathological and image findings also are needed. With regard of the treatments for IgG4-related disease, the levels of serum IgG4 often reflected with the therapeutic response, and were also the markers, which predicted the relapse. We describe herein the significance of measuring serum IgG4 levels in the diagnosis and during the treatment for IgG4-related disease.

Tophaceous gout in the cervical spine.

A 58-year-old woman with a three-year progressive history of chronic arthritis, had become disabled due to general malaise and fever. Her laboratory data revealed hyperuricemia and elevated levels of C-reactive protein. Neither rheumatoid factor nor anti-citrullinated peptide antibodies were present. We diagnosed her with tophaceous gout with uric crystalline revealed by the arthrocentesis of the elbow. (99m)Tc scintigraphy also disclosed a significant uptake in the cervical spine. The CT of the patient's cervical spine revealed significant bone erosion and destruction. We diagnosed the cervical involvement of gout based on the exclusion of infections and sarcoidosis. Rheumatologists should be aware of this rare association.

Value of serum IgG4 in the diagnosis of IgG4-related disease and in differentiation from rheumatic diseases and other diseases.

IgG4-related disease (IgG4-RD) is a novel disease entity that includes Mikulicz's disease, autoimmune pancreatitis (AIP), and many other conditions. It is characterized by elevated serum IgG4 levels and abundant IgG4-bearing plasmacyte infiltration of involved organs. We postulated that high levels of serum IgG4 would comprise a useful diagnostic tool, but little information is available about IgG4 in conditions other than IgG4-RD, including rheumatic diseases. Several reports have described cutoff values for serum IgG4 when diagnosing IgG4-RD, but these studies mostly used 135 mg/dL in AIP to differentiate from pancreatic cancer instead of rheumatic and other common diseases. There is no evidence for a cutoff serum IgG4 level of 135 mg/dL for rheumatic diseases and common diseases that are often complicated with rheumatic diseases. The aim of this work was to re-evaluate the usual cutoff serum IgG4 value in AIP (135 mg/dL) that is used to diagnose whole IgG4-RD in the setting of a rheumatic clinic by measuring serum IgG4 levels in IgG4-RD and various disorders. We therefore constructed ROC curves of serum IgG4 levels in 418 patients who attended Sapporo Medical University Hospital due to IgG4-RD and various rheumatic and common disorders. The optimal cut-off value of serum IgG4 for a diagnosis of IgG4-RD was 144 mg/dL, and the sensitivity and specificity were 95.10 and 90.76%, respectively. Levels of serum IgG4 were elevated in IgG4-RD, Churg-Strauss syndrome, multicentric Castleman's disease, eosinophilic disorders, and in some patients with rheumatoid arthritis, systemic sclerosis, chronic hepatitis, and liver cirrhosis. The usual cut-off value of 135 mg/dL in AIP is useful for diagnosing whole IgG4-RD, but high levels of serum IgG4 are sometimes observed in not only IgG4-RD but also other rheumatic and common diseases.