Yui Shimizu

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 Mikuliczs 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.

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.

Relapse patterns in IgG4-related disease

Immunoglobulin (Ig)G4-related disease (IgG4-RD) is a chronic inflammatory disorder characterised by elevated levels of serum IgG4 and swollen organs with fibrosis and infiltration by abundant IgG4-positive plasmacytes.1 ,2 Glucocorticoid treatment is effective for achieving clinical remission in the short term,3 but about 20%–30% of cases present with relapse after steroid doses are reduced.4 Serial changes of serum IgG4 levels are often considered to reflect the disease activity in routine clinical practice,5 but how disease relapse occurs is not well understood. We therefore analysed relapse patterns in IgG4-RD on the basis of data from the Sapporo Medical university And …

Efficacy of abatacept for IgG4-related disease over 8 months

It was recently pointed out that rituximab (RTX) is effective against IgG4-related disease (IgG4-RD).1 We found that RTX is effective as an induction therapy for IgG4-RD in the short term, but that it is necessary to repeat the prescription of RTX. Furthermore, we had a patient who presented with resistance to RTX.2 After obtaining informed consent, we started the patient on abatacept (ABT) treatment. We have followed the patient for 8 months, and the patient presented with good response to ABT. This is the first report of the efficacy of ABT against IgG4-RD. The patient was a 65-year-old Japanese woman who presented with IgG4-related dacryoadenitis and sialadenitis, and autoimmune pancreatitis. A submandibular gland biopsy specimen showed prominent infiltration of IgG4-bearing plasma cells (the ratio of IgG4/IgG-positive cells: 40%) with fibrosis and germinal centres (figure 1A, B). We diagnosed this case as IgG4-RD.3 She was initially treated with 40 mg/day of prednisolone, but several relapses occurred with tapering the dose to 10 mg/day. We administered ciclosporin A and mizoribine with steroid, …

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 Mikuliczs 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.

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

Objectives. The characteristic features of Mikuliczs 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 Mikuliczs 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.

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

Abstract 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 (r2 = 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.

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.

Tofacitinib can decrease anti-DNA antibody titers in inactive systemic lupus erythematosus complicated by rheumatoid arthritis

ies. Additionally the values of anti-DNA antibodies were almost unchanged, and the complement levels were not decreased. The patient also did not have fever, erythema, and nephritis. We diagnosed RA complicated by SLE. In terms of RA activity, 28-joint disease activity score based on C-reactive protein (DAS28-CRP) was 5.88 and clinical disease activity index (CDAI) was 38.00. The titer of RF was high, and anti-DNA antibodies were positive instead of no organ involvement. We started to add MTX and increased it to 12 mg/week in October 2013. However, the clinical eff ect of MTX was insuffi cient. She requested prompt improvement. When we added tofacitinib at 10 mg/day, CRP soon disappeared and both DAS28-CRP and CDAI also decreased. Glucocorticoid was discontinued, and the patient has since remained on MTX and tofacitinib. Serologically, the titer of RF decreased after adding MTX, and the titer of anti-DNA antibodies decreased after adding

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

Abstract Objectives. Immunoglobulin (Ig) G4-related dacryoadenitis and sialadenitis, the so-called Mikuliczs 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 Sjogrens 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 MD salivary glands, and this regulation might relate to PD-1 signals like the state of exhaustion and anergy.