Chisako Suzuki

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

Mikuliczs disease (MD) has been included within the diagnosis of primary Sjögrens 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. Mikuliczs 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 Riedels thyroiditis, all of which show IgG4 involvement in their pathogenesis. Mikuliczs disease thus differs from SS and may be a systemic IgG4-related plasmacytic disease.

Elevated IgG4 concentrations in serum of patients with Mikulicz's disease

Mikuliczs disease has recently been included within primary Sjögrens syndrome. It is a unique condition involving enlargement of the lacrimal and salivary glands, characterized by few autoimmune reactions. It is responsive to glucocorticoid treatment. Analysis of IgG fractions was performed in patients with Mikuliczs disease in order to determine the differences between Mikuliczs disease and Sjögrens syndrome. The study showed that serum IgG4 concentrations are elevated in patients with Mikuliczs disease, but not in those with Sjögrens syndrome.

The birthday of a new syndrome: IgG4-related diseases constitute a clinical entity.

IgG4-related disease is a distinct clinical entity, whose characteristic features are the following; Serum IgG4 is prominently elevated, IgG4-positive plasma cells infiltrate in involved tissues, various mass-forming lesions with fibrosis develop in a timely and spatial manner and the response to corticosteroids is prompt and good. IgG4-related diseases mainly target two organs. One is the pancreas (autoimmune pancreatitis; AIP), and the other comprises the lacrimal and salivary glands, the clinical phenotype is Mikuliczs disease (MD). MD has long been considered a manifestation of Sjögrens syndrome (SS). However, we noticed several clinical differences in case of MD from SS; no deflection of female sex differences, mild sicca syndrome, good response to corticosteroids, no positivity of anti-SS-A/SS-B antibodies. In addition, elevated level of serum IgG4 and abundant infiltration of plasma cells expressing IgG4 were reported in MD patients. Those are common features of IgG4-related diseases. MD often coexisted with IgG4-related diseases such as AIP, retroperitoneal fibrosis, and IgG4-associated nephropathy. Based on those findings, it has been considered to recognize IgG4-related diseases including MD as a new clinical entity. The etiology of IgG4-related systemic diseases remains to be elucidated. It is necessary to accumulate and analyze larger data from patients worldwide.

A case of Mikulicz's disease (IgG4‐related plasmacytic disease) complicated by autoimmune hypophysitis

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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.

Interferon γ assay for detecting latent tuberculosis infection in rheumatoid arthritis patients during infliximab administration

In rheumatoid arthritis (RA) patients treated with infliximab (IFX), QuantiFERON-TB Gold (QFT-G), an interferon γ assay for diagnosing tuberculosis infection, was performed to compare its effectiveness to conventional diagnostic procedures (tuberculin skin test, imaging and medical history) in diagnosing latent tuberculosis infection (LTBI). QFT-G was measured bimonthly in 14 rheumatoid arthritis patients during IFX treatment. Seven of 14 patients were confirmed as LTBI positive by at least one method. Of these, four were positive on QFT-G during the study period, and two were positive before the start of IFX administration. For two of the four QFT-G-positive patients, LTBI was diagnosed only by QFT-G. The rate of agreement between QFT-G and conventional procedures was 64.3%. A total of 5% of QFT-G tests were impossible to judge due to decreased reactions in the positive control. These results suggest that QFT-G is able to detect LTBI in RA patients overlooked by conventional methods. Conventional procedures and QFT-G should be employed in parallel, and LTBI should be assumed when one technique gives a positive result.

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.

The analysis of interleukin-6 in patients with systemic IgG4-related plasmacytic syndrome—expansion of SIPS to the territory of Castleman's disease

vasculitis [8] and autoimmune thyroid disease [5]. High levels of lymph node mRNA expression and serum levels of TNFand IL-6 have been reported [9, 10], suggesting a hypercytokinaemia commonly seen in CTDs. Frequently, considerable effort must be spent in order to differentiate this entity from adult onset Still’s disease, RA and SLE [3, 5, 6]. The clinical outcome of AILT remains poor (median survival <3 years, 5-year survival 30–35%) [5]. Combination chemotherapy may lead to complete remission (50%) but relapse rates remain high. Overall combination chemotherapy appears to be superior to glucocorticosteroids alone [5] but studies are limited. Furthermore, some patients develop secondary diffuse large B-cell lymphoma (DLBCL) [3]. Recognition of AILT is therefore important as the management of the differential diagnoses may lead to inappropriate treatment. In summary, we present a rare case of AILT with clinical features of autoimmune disease. Rapid escalation and deescalation of the lymphadenopathy, combined with more prominent symptoms from the joints, gave the strong impression of an underlying disorder like RA. AILT should be considered in the differential diagnosis of late-onset RA or Still’s disease in older patients presenting with a recent history of lymphadenopathy and fever. In such patients, sites of lymph-node involvement nonapparent by physical examination should be investigated.

The immunobiology and clinical characteristics of IgG4 related diseases.

Having the characteristic features of elevated serum IgG4 levels and prominent infiltration of IgG4-positive plasma cells with fibrosis in lesions, Mikuliczs disease (MD) has been recognized as an IgG4-related disease (IgG4-RD). Although incidence of autoimmune pancreatitis (AIP), one of the organ characteristics of IgG4-RD, has been internationally reported, there are only a few such reports of IgG4-related MD. The limited number of reports might be attributable to the low recognition of IgG4-related MD as a clinical entity as well as its misdiagnosis as Sjögrens syndrome (SS). Thus, we compared several clinical features of MD with SS to improve proper clinical diagnosis of MD in the clinical setting. A total of 70 SS and 70 MD cases evaluated at Sapporo Medical University Hospital were retrospectively analyzed. In SS patients, sicca symptoms were the most frequent (87%), followed by articular symptoms (23%), while lacrimal and salivary gland swelling were a rare (10%) and transient manifestation. In contrast, lacrimal or salivary gland swelling was observed in all patients with MD. Although nearly 60% of MD patients complained of sicca syndrome, skin rash and arthralgia were rare symptoms. Hypergammaglobulinemia was recognized in both SS and MD patients, but the occurrence of autoantibodies in patients with IgG4-related MD was low. Extraglandular organ involvement, often involving the retroperitoneum, pancreas, kidney and lung, was often discovered at the time of IgG4-related MD diagnosis. Although corticosteroid therapy tended to delay the hypofunction of salivary gland in SS patients, recovery of decreased function of salivary glands were observed in IgG4-related MD patients. These results suggest the beneficial effect of aggressive corticosteroid intervention in patients with IgG4-related MD. Although SS and MD are both chronic inflammatory diseases affecting the lacrimal and salivary glands, their clinical features and corticosteroid responsiveness are different. Thus, differential diagnosis of these conditions is warranted.

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 …