Susumu Sugai

American College of Rheumatology classification criteria for Sjögren's syndrome: a data-driven, expert consensus approach in the Sjögren's International Collaborative Clinical Alliance cohort.

We propose new classification criteria for Sjögrens syndrome (SS), which are needed considering the emergence of biologic agents as potential treatments and their associated comorbidity. These criteria target individuals with signs/symptoms suggestive of SS.

Proposal for a new clinical entity, IgG4-positive multiorgan lymphoproliferative syndrome: analysis of 64 cases of IgG4-related disorders

Background: Mikulicz’s disease (MD) has been considered as one manifestation of Sjögren’s syndrome (SS). Recently, it has also been considered as an IgG4-related disorder. Objective: To determine the differences between IgG4-related disorders including MD and SS. Methods: A study was undertaken to investigate patients with MD and IgG4-related disorders registered in Japan and to set up provisional criteria for the new clinical entity IgG4-positive multiorgan lymphoproliferative syndrome (IgG4+MOLPS). The preliminary diagnostic criteria include raised serum levels of IgG4 (>135 mg/dl) and infiltration of IgG4+ plasma cells in the tissue (IgG4+/IgG+ plasma cells >50%) with fibrosis or sclerosis. The clinical features, laboratory data and pathologies of 64 patients with IgG4+MOLPS and 31 patients with typical SS were compared. Results: The incidence of xerostomia, xerophthalmia and arthralgia, rheumatoid factor and antinuclear, antiSS-A/Ro and antiSS-B/La antibodies was significantly lower in patients with IgG4+MOLPS than in those with typical SS. Allergic rhinitis and autoimmune pancreatitis were significantly more frequent and total IgG, IgG2, IgG4 and IgE levels were significantly increased in IgG4+MOLPS. Histological specimens from patients with IgG4+MOLPS revealed marked IgG4+ plasma cell infiltration. Many patients with IgG4+MOLPS had lymphocytic follicle formation, but lymphoepithelial lesions were rare. Few IgG4+ cells were seen in the tissue of patients with typical SS. Thirty-eight patients with IgG4+MOLPS treated with glucocorticoids showed marked clinical improvement. Conclusion: Despite similarities in the involved organs, there are considerable clinical and pathological differences between IgG4+MOLPS and SS. Based on the clinical features and good response to glucocorticoids, we propose a new clinical entity: IgG4+MOLPS.

IgG4-related Diseases Including Mikulicz’s Disease and Sclerosing Pancreatitis: Diagnostic Insights

Since the first report of serum IgG4 elevation in sclerosing pancreatitis in 2001, various systemic disorders have been reported to elevate IgG4, and many names have been proposed from the perspective of the systemic condition. Despite similarities in the organs damaged in IgG4-related Mikulicz’s disease and Sjögren’s syndrome, there are marked clinical and pathological differences between the 2 entities. The majority of cases diagnosed with autoimmune pancreatitis in Japan are IgG4-related sclerosing pancreatitis, and it should be recognized that this is distinct from the Western type. Diagnosis of IgG4-related disease is defined by both elevated serum IgG4 (> 1.35 g/l) and histopathological features, including lymphocyte and IgG4+ plasma cell infiltration (IgG4+ plasma cells/IgG+ plasma cells > 50% on a highly magnified slide checked at 5 points). Differential diagnosis from other distinct disorders is necessary: these include sarcoidosis, Castleman’s disease, Wegener’s granulomatosis, lymphoma, cancer, and other existing conditions. The Japanese IgG4 research group has begun multicenter prospective studies to improve diagnostic criteria and treatment strategies.

Lymphoproliferative disorders in Sjögren's syndrome.

Sjögrens syndrome (SS) is a chronic organ-specific autoimmune disease characterized by lymphocytic infiltration into the salivary and lacrimal glands. About half of primary SS patients develop systemic disorders. Primary SS can be divided into three stages according to the extent of organ damage and the course of the disease. In stage I, (approx. 45% of cases), patients have only sicca syndrome and do not experience any systemic involvement, even after 10 years. In stage II (approx. 50% of cases), patients experience lymphocytic organ damage, which may involve the pulmonary, renal, hepatic, hematologic, and/or dermatologic systems, among others. Finally, in stage III (approx. 5% of cases), patients develop malignant lymphomas. Lymphomas in salivary glands are thought to arise from lymphoepithelial lesions in which there are close interactions among epithelial cells, T cells, and B cells. The B cells in the lesions become activated through the interaction between CD40L and CD40. The progression from polyclonal lymphoproliferation to monoclonal lymphoproliferation, to mucosa-associated lymphoid tissue (MALT) lymphoma, and finally to high-grade malignant lymphoma is regarded as a multi-step process. Antigenic activation of B cells, together with oncogenic events, including p53 inactivation and bcl-2 activation, may play important roles in B cell monoclonal proliferation and malignant transformation. The rheumatoid factor clone is regarded as a candidate B cell clone that undergoes transformation.

Cutoff Values of Serum IgG4 and Histopathological IgG4+ Plasma Cells for Diagnosis of Patients with IgG4-Related Disease.

IgG4-related disease is a new disease classification established in Japan in the 21st century. Patients with IgG4-related disease display hyper-IgG4-gammaglobulinemia, massive infiltration of IgG4+ plasma cells into tissue, and good response to glucocorticoids. Since IgG4 overexpression is also observed in other disorders, it is necessary to diagnose IgG4-related disease carefully and correctly. We therefore sought to determine cutoff values for serum IgG4 and IgG4/IgG and for IgG4+/IgG+ plasma cells in tissue diagnostic of IgG4-related disease. Patients and Methods. We retrospectively analyzed serum IgG4 concentrations and IgG4/IgG ratio and IgG4+/IgG+ plasma cell ratio in tissues of 132 patients with IgG4-related disease and 48 patients with other disorders. Result. Serum IgG4 >135  mg/dl demonstrated a sensitivity of 97.0% and a specificity of 79.6% in diagnosing IgG4-related disease, and serum IgG4/IgG ratios >8% had a sensitivity and specificity of 95.5% and 87.5%, respectively. IgG4+cell/IgG+ cell ratio in tissues >40% had a sensitivity and specificity of 94.4% and 85.7%, respectively. However, the number of IgG4+ cells was reduced in severely fibrotic parts of tissues. Conclusion. Although a recent unanimous consensus of all relevant researchers in Japan recently established the diagnostic criteria for IgG4-related disease, findings such as ours indicate that further discussion is needed.

Primary Sjögren’s Syndrome as a systemic disease: a study of participants enrolled in an international Sjögren’s Syndrome registry

To study the prevalence of extraglandular manifestations in primary Sjögrens syndrome (SS) among participants enrolled in the Sjögrens International Collaborative Clinical Alliance (SICCA) Registry.

A comparative study between MR sialography and salivary gland scintigraphy in the diagnosis of Sjögren syndrome.

Purpose The purpose of this work was to compare the diagnostic accuracy of MR sialography with that of salivary gland scintigraphy in Sjögren syndrome. Method One hundred thirty patients clinically suspected of having Sjögren syndrome were examined by MR sialography and salivary gland scintigraphy. A labial gland biopsy was performed in all patients. Imaging findings of MR sialography and salivary gland scintigraphy were compared with the results of labial gland biopsy. Results From the results of labial gland biopsy, the diagnosis of Sjögren syndrome was established in 80 patients. Abnormally high T2 signal intensity areas on MR sialography and decreased uptake and delayed excretion of [99mTc]pertechnetate on salivary gland scintigraphy were well seen in patients with Sjögren syndrome. For the diagnosis of Sjögren syndrome, salivary gland scintigraphy showed higher sensitivity than MR sialography. On the other hand, MR sialography showed higher specificity and positive predictive value (PPV) than salivary gland scintigraphy. Overall diagnostic accuracy was 83% for MR sialography and 72% for salivary gland scintigraphy. Conclusion The high PPV of MR sialography suggests that MR sialography is the preferred imaging modality in patients suspected of having Sjögren syndrome.

Sweet's syndrome during therapy with granulocyte colony-stimulating factor in a patient with aplastic anaemia

Summary. A patient with aplastic anaemia developed Sweets syndrome (a febrile neutrophilic dermatosis) during granulocyte colony‐stimulating factor (G‐CSF) therapy. Three repeated episodes of appearance and disappearance of erythematous nodules after administration and withdrawal of G‐CSF confirmed that G‐CSF induced Sweets syndrome in the patient. Sweets syndrome has been reported in patients with myelodysplastic syndrome and acute leukaemia, but not in patients with aplastic anaemia. This is the first report of a patient with aplastic anaemia who developed G‐CSF‐induced Sweets syndrome.

Non-IgM monoclonal gammopathy in patients with Sjögren's syndrome

Two Japanese patients with Sjögrens syndrome with non-immunoglobulin M(IgM) class monoclonal gammopathy are described. The monoclonal IgA lambda detected in the serum and saliva was confirmed to possess rheumatoid factor activity in the first patient with a hypergammaglobulinemic purpura and hyperviscosity syndrome. Idiotype specificity was present on the surface membrane of peripheral blood lymphocytes as well as in the cytoplasm of infiltrating cells in the salivary glands. Common idiotypic specificity was found in four of 60 other patients who had rheumatoid factors. In the serum and saliva of the other patient, a monoclonal immunoglobulin G, kappa type (IgG kappa), was detected. Kappa type IgG was found in most of the infiltrating cells in the salivary glands and also in the saline extract from a resected submandibular gland. Our findings indicate that non-IgM class monoclonal gammopathy is also one of the complications of Sjögrens syndrome.

Clinical and imaging findings of lymphoma in patients with Sjögren syndrome.

Objective To describe and correlate the clinical and imaging findings of lymphomas in patients with Sjögren syndrome. Methods The authors reviewed the medical and imaging records of 27 cases of lymphoma from among a total of 463 patients with Sjögren syndrome. The estimated prevalence of lymphoma in patients with Sjögren syndrome was 5.8%. There were 22 women and 5 men. Histopathologically, 26 of the 27 neoplasms were non-Hodgkin lymphoma, including 6 mucosa-associated lymphoid tissue lymphomas, and the other neoplasm was Hodgkin lymphoma. The clinical and imaging findings of lymphomas were analyzed. Results No obvious correlations were present between the duration or severity of Sjögren syndrome and the lymphoma development. At the initial diagnosis, extranodal involvement was observed in 14 (52%) of the 27 patients, including the salivary gland (n = 9), lacrimal gland (n = 2), lung (n = 2), and thyroid gland (n = 1), mostly in the neck organs. On the other hand, nodal involvement was observed in 21 (78%) of the 27 patients. Of these 21 patients, 19 had at least cervical lymph node involvement. Conclusion Patients with Sjögren syndrome are at increased risk of lymphoma development. Because most lymphomas initially involve the neck organs, including the lymph nodes, meticulous imaging studies mainly focused on the cervical regions are recommended in the follow-up of patients with Sjögren syndrome.