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Mikulicz’s disease (MD) has been included within the diagnosis of primary Sjogren’s syndrome (SS), but it represents a unique condition involving the enlargement of the lacrimal and salivary glands and characterized by few autoimmune reaction (1). Glucocorticoid treatment is effective for the clinical improvement of this disease (2). Now it is considered that MD is quite a different disease from primary SS (1), and a type of IgG4-related disease (IgG4-RD) (3). IgG4-RD is characterized by a swelling of the affected organs along with elevated levels of serum IgG4, and abundant infiltration of IgG4-bearing plasma cells and fibrosis. IgG4-RD is a new concept of systemic and chronic inflammation (3), and usually includes MD, autoimmune pancreatitis (AIP) (4), and IgG4-related tubulointerstitial nephritis (5). IgG4-RD is an important disease for clinical physicians to discriminate from cancers and other rheumatic diseases. On the other hand, recent focus has been on the relationship between IgG4-RD and malignancies. IgG4-RD with pancreatic cancer has often been reported in cases of AIP (6, 7). It is known that positron emission tomography (PET) is very useful for systemic evaluation in IgG4RD (8, 9). Whenever we make a diagnosis of IgG4-RD, we consult PET images. In some instances, we are presented with cases involving abnormal accumulation at the lesion sites outside of the involved organs; this is known as organic dysfunction of IgG4-RD. Upon further examination, we often find that the lesion is cancer. In such instances, PET is very useful for detecting cancer. Our previous study (SMART database: Sapporo Medical University and Related institutes database for investigation and best treatments of IgG4-related disease) demonstrated that malignancies occurred in 10.4% of IgG4-RD cases. Using the database of national cancer registries in the monitoring of cancer incidence in Japan (2005) (10), the standardized incident ratio (SIR) for cancers in male patients with IgG4-RD was 331.1, and in female patients with IgG4-RD, 471.6. The total was 383.0. It was approximately 3.5 times higher than the incidence of cancer in the general population (11). Malignancies as complications of IgG4-RD are divided into lymphoma and non-lymphoid tumors. Lymphoma includes mucosa-associated lymphoid tissue (MALT) lymphoma and non-Hodgkin lymphoma. Lymphoma can present as a background of chronic inflammation. In SS, 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 (12). It is reported that the SIR for lymphoma in patients with SS was higher, 8.7 to 48.1 (13-15). It is suggested that this rate for lymphoma in MD is also high as well as in SS. In this issue of Internal Medicine, Uehara et al (16) report a 66-year-old man, who suffered from IgG4-RD, and performed autopsy. The patient had been followed as MD and IgG4-related pseudo-inflammatory tumor in the pelvis, but autopsy disclosed the coexistence of diffuse large B cell lymphoma. It could not be considered that lymphoma was complicated at the diagnosis of IgG4-RD. It is suggested that an activated B cell caused malignant transformation in the background of chronic inflammation. Therefore, it is critical to recognize the risk of lymphoma in MD as well as SS.

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.

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.

John H. Stone, Arezou Khosroshahi, Vikram Deshpande, John K. C. Chan, J. Godfrey Heathcote, Rob Aalberse, Atsushi Azumi, Donald B. Bloch, William R. Brugge, Mollie N. Carruthers, Wah Cheuk, Lynn Cornell, Carlos Fernandez-Del Castillo, Judith A. Ferry, David Forcione, Gunter Kloppel, Daniel L. Hamilos, Terumi Kamisawa, Satomi Kasashima, Shigeyuki Kawa, Mitsuhiro Kawano, Yasufumi Masaki, Kenji Notohara, Kazuichi Okazaki, Ji Kon Ryu, Takako Saeki, Dushyant Sahani, Yasuharu Sato, Thomas Smyrk, James R. Stone, Masayuki Takahira, Hisanori Umehara, George Webster, Motohisa Yamamoto, Eunhee Yi, Tadashi Yoshino, Giuseppe Zamboni, Yoh Zen, and Suresh Chari

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.

Although tubulointerstitial nephritis with IgG4+ plasma cell (PC) infiltration is a hallmark of IgG4-related kidney disease (IgG4-RKD), only a few studies are available about the minimum number of IgG4+ PC needed for diagnosis along with IgG4+/IgG+ PC ratio in the kidney. In addition, the significance of the deposition of IgG or complement as a reflection of humoral immunity involvement is still uncertain. In this study, we analyzed 20 Japanese patients with IgG4-RKD to evaluate the number of IgG4+ PCs along with IgG4+/IgG+ PC ratio and involvement of humoral immunity. The average number of IgG4+ PCs was 43.8/hpf and the average IgG4+/IgG+ or IgG4+/CD138+ ratio was 53%. IgG and C3 granular deposits on the tubular basement membrane (TBM) were detected by immunofluorescence microscopy in 13% and 47% of patients, respectively. Nine patients had a variety of glomerular lesions, and 7 of them had immunoglobulin or complement deposition in the glomerulus. In conclusion, we confirmed that infiltrating IgG4+ PCs > 10/hpf and/or IgG4/IgG (CD138)+ PCs > 40% was appropriate as an item of the diagnostic criteria for IgG4-RKD. A relatively high frequency of diverse glomerular lesions with immunoglobulin or complement deposits and deposits in TBM may be evidence of immune complex involvement in IgG4-related disease.

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.

Since Morgan's report in 1953, Mikulicz's disease (MD) has been considered part of primary Sjogren's syndrome (SS). However, MD has a unique presentation, including persistent swelling of the lacrimal and salivary glands, and is characterized by good responsiveness to glucocorticoids, leading to recovery of gland function. Recently, it has been revealed that MD patients show elevated serum immunoglobulin G4 (IgG4) levels and prominent infiltration of IgG4-positive plasmacytes. 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. Thus, MD is a systemic ''IgG4-related disease.'' In addition, recent analyses have revealed that Kuttner's tumor (KT), a chronic sclerosing sialadenitis that presents with asymmetrical firm swelling of the submandibular glands, is also associated with prominent infiltration of IgG4-positive plasmacytes. MD and KT differ from SS and are thought to be singular systemic IgG4-related plasmacytic diseases. Here we discuss the results of recent studies and provide an overview of MD as an IgG4-related disease. # 2011 Elsevier Ireland Ltd. All rights reserved.

IgG4-related systemic disease/systemic IgG4-related disease has been established as a new systemic disease entity. It is characterized by high serum IgG4 concentrations and abundant IgG4-bearing plasma cell infiltration in the involved organs. The chronic inflammation can attack lacrimal glands, salivary glands, the thyroid, lung, pancreas, kidney, and prostate. The concept includes Mikulicz's disease, Riedel's thyroiditis, pulmonary fibrosis, pulmonary pseudotumor, autoimmune pancreatitis, a part of tubulointerstitial nephritis, and chronic prostatitis. It is important to note that these lesions can occur at different times and sites. So, it is necessary to reconfirm the disease definition and entity in each specialized field. The diagnosis of this disease is confirmed by the above serological and histopathological characteristics. There are clinical diagnostic criteria of Mikulicz's disease (the Japanese Medical Society for Sjögren's Syndrome) and autoimmune pancreatitis (the Japanese Ministry of Health, Labour and Welfare, and the Japan Pancreas Society). They are convenient and useful. Glucocorticoid improves the physical abnormalities, and the initial dose of prednisolone is 30 mg/day, tapered in 5-mg reductions every two weeks. Nevertheless, there are some cases unable to achieve complete remission.

Objective Mikulicz's disease (MD) is differentiated from Sjogren's syndrome as an immunoglobulin G4 (IgG4) systemic disease. MD patients often report olfactory dysfunction (OD). To analyze cases of OD associated with MD, we studied clinicopathological and serological findings of MD patients. Methods A total of 44 MD patients (17 males and 27 females) were examined for OD. We evaluated clinicopathological and serological findings of these patients by dividing them into OD (+) and OD (−) groups. Results The mean IgG4 concentration (SD) in such cases was 950.5 (797.5) mg/dl. Of the 44 patients, 20 (45%) had OD even though no abnormalities, such as obstructive and inflammatory disease, were detected in their nasal cavities and sinuses. The two groups did not show significant differences in background characteristics, such as age, sex, IgG4 concentration, presence or absence of allergic rhinitis, and presence or absence of extrasalivary gland lesions. We found abundant IgG4-positive plasmacytes in the nasal mucosa specimens of the OD (+) group but not in that of the OD (−) group. Conclusions Nasal mucosa in the MD patients with OD was infiltrated with IgG4-positive plasmacytes. We concluded that OD may be associated with infiltration by IgG4-positive cells.

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 Mikulicz's disease (MD). MD has long been considered a manifestation of Sjogren's 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 23-year-old Japanese woman was diagnosed with lupus nephritis on May 2007. The patient was prescribed 30 mg/day of prednisolone, but developed a pulmonary abscess and was admitted to Sapporo Medical University Hospital in March 2008. Antibiotics improved the symptoms. We prescribed trimethoprim-sulfamethoxazole as prophylaxis for pneumocystis pneumonia; however, the patient developed fever and thrombocytopenia with hyperferritinemia after a week of this prophylaxis. We considered that she was developing hemophagocytic syndrome, and administered methylprednisolone pulse therapy. The clinical findings soon improved. However, when the prophylaxis was restarted, the patient developed fever, headache, and anaphylaxis the same day. Symptomatic therapy resolved these symptoms after three days, but they recurred on recommencing trimethoprim-sulfamethoxazole. Analysis of the cerebrospinal fluid revealed aseptic meningitis. These episodes were thought to be induced by trimethoprim-sulfamethoxazole. As trimethoprim-sulfamethoxazole is frequently used as prophylaxis for pneumocystis infection in immunosuppressed patients, clinicians should be vigilant regarding the complications of this treatment, particularly the rare occurrence of aseptic meningitis and anaphylaxis.

Purpose Recent studies have revealed that Mikulicz disease (MD) differs from Sjogren syndrome and is an immunoglobulin G 4 (IgG 4 )–related systemic disease. Kuttner tumor (KT) is also reported to be an IgG 4 -related disease. In this study, we examined the clinicopathologic and serologic findings in MD (39 patients) and KT (6 patients) and attempted to discern the similarities between MD and KT. Materials and methods We diagnosed 39 patients with MD and 6 patients with KT. We analyzed the clinicopathologic and serologic findings (IgG subclasses) in 39 patients with MD and 6 patients with KT. Submandibular and labial salivary gland specimens obtained from patients with MD and KT were stained with anti-IgG 4 antibodies. Results The mean IgG 4 concentration (±SD) was 931.1 ± 796.2 mg/dL in patients with MD and 756.2 ± 449.2 mg/dL in patients with KT. Abundant infiltration of IgG 4 -positive plasmacytes into the salivary glands was observed in both patients with MD and patients with KT. Conclusion The serologic and histopathologic findings in MD and KT are very similar, and these 2 conditions may be IgG 4 -related systemic diseases.

Mikulicz's disease represents persistent enlargement of the lacrimal and salivary glands, and autoimmune pancreatitis is shown with diffuse pancreatic swelling. Both diseases are characterized with elevated IgG4 concentrations in the serum and prominent infiltration by plasmacytes expressing IgG4 in the glands. Clinical analyses were performed in 40 patients with systemic IgG4-related plasmacytic syndrome (SIPS) who consulted the doctors in Sapporo Medical University Hospital. Our patients were mainly middle-aged or elderly females. The average age was 58.9 years. The diagnosis was following ; 33 cases with Mikulicz's disease, 3 cases with Kuttner's tumor, and 4 cases with IgG4-related dacryoadenitis. Slight dysfunction of lacrimal and salivary gland was observed in about 60% of them. Antinuclear antibodies were detected in only 15% of the cases with SIPS. Almost all, except one case, did not have anti-SS-A or anti-SS-B antibodies. Interestingly, hypocomplementemia was revealed in 30% of them. The complications of SIPS include autoimmune pancreatitis, tubulointerstitial nephritis, retroperitoneal fibrosis, prostatitis, and so on. SIPS is mainly treated by the administration of steroids. We started to prescribe much quantity of prednisolone to the patients with organ failure. The recurrence was admitted in the 3 patients for the followed 16 years. We present here the problems and prospects in SIPS.

A 52-year-old female visited the outpatient department of Sapporo Medical University hospital in 1984 due to a refractory rash on the skin of the trunk. Histological findings of a skin biopsy specimen indicated a diagnosis of lupus erythematosus profundus (LEP). The eruption remained quiescent with moderate doses of prednisolone. In October 2003, she was suddenly admitted to our hospital with abdominal pain, fever and bloody stool. Lupus enteritis was diagnosed based on an elevated level of anti-DNA antibody, low complementemia and diffuse edematous change of the intestinal walls on CT scans. Although high doses of corticosteroids resulted in transient improvement, melena developed again on the 24th hospital day. Colonoscopy revealed deep ulceration at the rectum and a gastrografin enema indicated perforation. Accordingly, the involved rectum was resected and an artificial anus was constructed on the 50th hospital day. Examination of the resected specimen by microscopy showed that the ulceration approached at the depth of the subserosal layer with intense infiltration of inflammatory cells around the vessels. The pathogenesis of the rectal lesion might have been due to vasculitis associated with systemic lupus erythematosus (SLE). The disease did not recur under the administration of 10 mg of prednisolone daily until November 2004. Colonic function made a remarkably untroubled recovery after the artificial anus was closed in February 2005. The LEP was generally accompanied by a mild form of SLE. This case seemed to be rare in that SLE was associated with severe lupus enteritis and a refractory rectal ulcer developed from LEP. Patients with SLE and intestinal involvement should be carefully monitored in cooperation with a surgeon.

Background IgG4-related disease (IgG4-RD) is a recently recognized systemic inflammatory disease [1-3]. In parallel with its increasing recognition, the number of new patients (pts) diagnosed with IgG4-RD is also increasing. However, owing to its extremely diverse clinical picture, each clinician encounters a clinically distinct pt group depending on his/her specialty, and it is difficult to avoid institutional bias when evaluating the clinical features of IgG4-RD in a single center. This prompted us to conduct a relatively large-scale multicenter study with well-experienced physicians of IgG4-RD including rheumatologists, gastroenterologists, and nephrologists. Objectives To clarify the clinical and laboratory features of IgG4-RD using a relatively large-scale cohort of 328 IgG4-RD pts. Methods Between 2001 and 2014, we retrospectively evaluated 328 pts with IgG4-RD in four institutions. The diagnosis of IgG4-RD was made based on the comprehensive diagnostic criteria or criteria of each organ, which include elevated serum levels of IgG4 and pathological findings with supporting clinical course and imaging findings, with the final judgment made by the experts of IgG4-RD at each hospital. We analyzed the serum levels of IgG, IgG4, C3, C4, CH50 and CRP, the affected organs, the target organs for biopsy and treatment. Then we analyzed the organ specific features. Results Two hundred and one pts were male, and 127 pts were female (male 61.3%). The mean age was 63.8 years (range 25-91). At diagnosis, mean serum IgG and IgG4 were 2389 mg/dL and 747 mg/dL respectively. Serum IgG4 was not elevated in 15 of 327 (4.6%). Hypocomplementemia was seen in 133 of 322 (41.3%). Serum level of CRP was less than 1.0 mg/dL in 90.1%. Mean number of organs involved was 3.2 (range 1-11); salivary gland (SG) was the most frequently involved organ (72.3%), followed by lacrimal glands (LG) (57.3%), pancreas (25.6%), retroperitoneal fibrosis/periaortitis (25.0%), kidney (24.1%), and lung (22.3%). Single organ involvement was seen in 63 of 322 (19.2%), with the most frequently affected organs being SG (26 pts) followed by LG (20 pts). Biopsy was performed in 265 of 328 (80.8%), with SG 39.2%, minor SG 16.5%, pancreas 15.5%, kidney 15.2%, lung 11.0%. Corticosteroid therapy was performed in 240 of 308 (79.5%), and the mean initial dose of prednisolone (PSL) was 30.4 mg/day. Hypocomplementemia was seen in pts with kidney lesions more often than in those without it (59.5% vs. 35.4%, p Conclusions The present study clarified the organs most frequently affected by IgG4-RD by a retrospective multicenter study. In addition, we reconfirmed the high frequency of hypocomplementemia in pts with kidney involvement. Moreover, in more than 95% of pts, serum elevated IgG4 levels were useful for the diagnosis of IgG4-RD. References Stone JH et al. N Engl J Med. 9;366(6):539-51, 2012. Masaki Y et al. Ann Rheum Dis. 68(8):1310-5, 2009. Zen Y et al. Am J Surg Pathol. 34(12):1812-9, 2010. Disclosure of Interest None declared

Background IgG4-related disease (IgG4-RD) is a recently recognized systemic inflammatory disorder that can affect many organs [1]. It frequently causes various renal lesions, which are collectively referred to as IgG4-related kidney disease (IgG4-RKD) [2]. In this disease, focal or diffuse renal cortical atrophy is often observed in the clinical course after corticosteroid (CS) therapy [3]. However, the factors related to such renal atrophy have not been well clarified. Objectives To clarify the factors related to renal atrophy after CS therapy in IgG4-RKD. Methods We retrospectively evaluated clinical features including laboratory data, computed tomography (CT) findings before and after CS therapy in 22 patients diagnosed with IgG4-RKD based on the diagnostic criteria for IgG4-RKD [2], all of whom were followed up for more than 20 months. Results Sixteen patients were men, and six were women (average age 61.5 years). Average follow-up period was 52.4 months (range 20-93). At diagnosis, their serum IgG4 level was 1043±531 mg/dL, and 7 patients showed hypocomplementemia. The average estimated glomerular filtration rate (eGFR) was 67.9 mL/min/1.73m 2 . All patients had extra-renal organ involvement. Multiple low-density lesions (LDLs) on contrast-enhanced CT were observed before CS therapy in all patients. All patients were treated with prednisolone (PSL) at an average initial dose of 35.5±8.4 mg/day (range 20-50), and showed disappearance or reduction of LDLs. At least a part of LDLs resulted in partial renal cortical atrophy in 13 patients (Group A), whereas complete recovery with normal contrast enhancement without a residual cortical scar was achieved in 9 patients (Group B). Pre-treatment eGFR in Group A was significantly lower than that in Group B (60.2±23.4 mL/min/1.73m 2 vs 79.0±19.4 mL/min/1.73m 2 , P =0.035), and the percentage of patients with less than 70 mL/min/1.73m 2 of eGFR in Group A was significantly higher than that in Group B (69.2% vs 22.2%, P =0.040). None of the other factors including age, gender, number of involved organs, serum IgG4 and complement levels, initial dose of PSL, renal function after therapy, recurrence rate of renal lesions, prevalence of diabetes mellitus or hypertension, and follow-up period significantly differed between the two groups. Conclusions The present study suggests that pre-treatment renal insufficiency may relate to renal atrophy after CS therapy in IgG4-RKD. Whether an early initiation of therapy before renal function declines would prevent the development of renal atrophy remains to be clarified through a larger-scale prospective study. References Stone JH et al. IgG4-related disease. N Engl J Med. 2012 Feb 9;366(6):539-51. Kawano M et al. Proposal for diagnostic criteria for IgG4-related kidney disease. Clin Exp Nephrol. 2011 Oct;15(5):615-26. Saeki T et al. The clinical course of patients with IgG4-related kidney disease. Kidney Int. 2013 Oct;84(4):826-33. Disclosure of Interest None declared

A prospective open-label trial of rituximab (RTX) for IgG4-related disease (IgG4-RD) was recently described in the Annals of the Rheumatic Diseases by Carruthers et al .1 According to their results, RTX is effective as induction therapy for IgG4-RD without glucocorticoid in the short term. We agree and support their results. We have also prescribed RTX for typical cases of IgG4-RD, showing characteristics of younger age, experience of several relapses, no history of hepatitis B and, since 2011, hesitation to increase the dose of glucocorticoid due to complications. We are currently treating three cases using RTX. Our protocol is as follows. We prescribe 500 mg/body of RTX at the onset of relapse. Meanwhile, the dose of glucocorticoid is decreased as much as possible. The patients visit our hospital for blood tests once every few months. Whole-body CT is routinely performed once a year. When relapse is suspected, we examine the whole body by CT. …

In rheumatoid arthritis (RA) patients treated with infliximab (IFX), QuantiFERON-TB Gold (QFT-G), an interferon gamma 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.

Many risk factors have been proposed for systemic lupus erythematosus (SLE). However, there is little information about the relationship between lifestyles and SLE in Japan. Two case control studies were conducted in Kyushu, southern Japan, and in Hokkaido, northern Japan, to examine the relationship between lifestyles and development of SLE in females. The participants were 78 patients and 329 controls in Kyushu and 35 patients and 188 controls in Hokkaido. Smoking was associated with an increased risk of SLE after adjusting for age in both regions. However, in Hokkaido, this association between smoking and SLE did not reach statistical significance after adjusting for alcohol drinking. The present study suggests that smoking may increase the risk of SLE among Japanese females.

Mikulicz's disease has recently been included within primary Sjogren's 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 Mikulicz's disease in order to determine the differences between Mikulicz's disease and Sjogren's syndrome. The study showed that serum IgG4 concentrations are elevated in patients with Mikulicz's disease, but not in those with Sjogren's syndrome.

A case of sclerodermapolymyositis overlap syndrome in which octreotide exacerbated abdominal symptoms Chisako SUZUKI1, Mikiko OHARA1, Motohisa YAMAMOTO1, Yasuyoshi NAISHIRO1, Hiroyuki YAMAMOTO1, Hiroki TAKAHASHI1, Takashi ABE2 and Kohzoh IMAI1 1First Department of Internal Medicine, Sapporo Medical University, School of Medicine 2Department of Internal MedicineRheumatology, Kushiro City General Hospital

Objective. Mikulicz's disease (MD) has been included within the diagnosis of primary Sjogren's syndrome (SS), but represents a unique condition involving enlargement of the lachrymal and salivary glands and characterized by few autoimmune reactions and good responsiveness to glucocorticoids. We have previously described elevated immunoglobulin (Ig) G4 in the serum of four patients with MD. In this paper, we accumulated more MD cases and undertook clinical and histopathological analysis of these patients to clarify differences between MD and SS. Methods. We diagnosed seven patients with MD according to the following criteria: (i) visual confirmation of symmetrical and persistent swelling in more than two lachrymal and major salivary glands; (ii) prominent mononuclear infiltration of lachrymal and salivary glands; and (iii) exclusion of other diseases that present with glandular swelling, such as sarcoidosis and lymphoproliferative disease. We summarized the clinical and serological characteristics (IgG subclasses and IFN-c/IL-4 ratio) of seven patients with MD, compared with SS with glandular swelling (SSw) and without glandular swelling (SSo). After steroid administration, we analysed changes in IgG subclasses in MD. Labial salivary gland specimens in MD, SSw and SSo were stained with anti-IgG4 antibodies. Results. The concentration (� S.D.) of IgG4 was 1169.7 � 892.2 mg/dl in MD, 24.4 � 7.0 mg/dl in SSw (P

Mikulicz's disease (MD) has been considered part of primary Sjogren's syndrome (SS) since Morgan's report in 1953. MD represents a unique condition involving enlargement of the lacrimal and salivary glands, as is also seen in SS; however, MD is characterized by few autoimmune reaction and its good responsiveness to glucocorticoid. Recent reports have shown that the frequency of apoptosis in glands of MD patients is lower when compared with SS. This phenomenon reflects the histologically reversible gland secretion in MD. Elevated IgG4 concentrations in the serum and prominent infiltration by plasmacytes expressing IgG4 in the lacrimal and salivary glands have also been confirmed in MD. Plasma cells expressing IgG4 are also detected in lymph nodes and bone marrow. MD may be a systemic disease, rather than a lacrimal and salivary gland disease. We here propose the new entity "IgG4-related plasmacytic exocrinopathy" and expect future development with regard to its relationship with autoimmune pancreatitis, which similarly presents elevated serum IgG4 levels.

A 54-year-old female experienced morning stiffness and arthralgia of the hands from November 2001 and consulted her local doctor in January 2002. Hematological data showed liver dysfunction and antinuclear antibody was positive. In February 2002, the patient was admitted to our hospital to investigate these abnormalities of liver function further. The features of arthritis, thrombocytopenia with elevated platelet-associated IgG, positive antinuclear antibody, and anti-DNA antibody lead to a diagnosis of systemic lupus erythematosus. Liver biopsy revealed infiltration of Glisson's capsule by plasma cells, compatible with autoimmune hepatitis. We performed hepatic venography to investigate severe pancytopenia, remarkable splenomegaly and esophageal varices. Wedged hepatic venous pressure was mildly elevated, and hepatic veins displayed sharp angles, smooth walls and development of anastomosis with each other. These findings suggested idiopathic portal hypertension. Cytopenia and liver dysfunction gradually improved on treatment with 40 mg/day prednisolone. Esophageal varices were disappeared, and splenomegaly had improved after 6 months. As autoimmune factors are considered to underlie the development of idiopathic portal hypertension with systemic lupus erythematosus, steroid administration represents a therapeutic option in this condition.

In August 1994, a 19-year-old woman presented to her dermatologist with a slight fever, arthralgia, and a butterfly rash. Discoid lupus erythematosus was suspected, and serological testing yielded positive results for antinuclear antibody. She was diagnosed with systemic lupus erythematosus without organ failure and was treated with only nonsteroidal antiinflammatory drugs. She became pregnant in June 2001, at age 26. In November her obstetrician noted that she had severe hypertension, edema of the low limbs, and proteinuria. On admission, she was diagnosed with severe preeclampsia, and cesarean section was performed. On hospital day 3 the patient developed sudden epigastric pain and vomiting. Laboratory tests revealed thrombocytopenia, liver dysfunction, and microangiopathic hemolytic anemia, leading to a diagnosis of HELLP (hemolysis, elevated liver enzymes, and low platelet count) syndrome. Plasma exchange was performed for 5 days. The thrombocytopenia, liver dysfunction, and proteinuria diminished quickly. Later testing revealed a high titer of plasma phosphatidylserine-dependent anti-prothrombin antibody. This case is useful for exploring the relations between SLE, HELLP syndrome, and anti-prothrombin antibody.

We investigated the incidence of B-cell clonality in the minor salivary gland and liver (extra-glandular lesion) of patients with Sjögren's syndrome (SS). We also compared B-cell clonality in the minor salivary gland and liver in the same individuals, and compared its incidence among patients with various liver diseases, such as primary biliary cirrhosis (PBC) and autoimmune hepatitis (AIH).A minor salivary gland biopsy was performed on 35 patients with SS (30 patients with primary SS, and five patients with secondary SS). A liver biopsy was performed on nine patients with SS associated with bile duct lesions, two patients with PBC, one patient with AIH, one patient with drug-induced liver dysfunction, and three patients with viral hepatitis. DNA was extracted from each tissue sample and then subjected to Polymerase Chain Reaction (PCR). B-cell clonality was analysed by assessing the rearrangement of the immunoglobulin heavy chain (IgH) gene by PCR.B-cell clonality was confirmed in the minor salivary gland biopsy sample in 23 of the 35 patients (65.7%), and in the liver biopsy sample (non-exocrine organ involvement) in seven of the nine patients (77.8%). The presence or absence of B-cell clonality was investigated in both the minor salivary gland and liver in seven patients, but B-cell clonality was confirmed in both tissues in only one patient, and the pattern of clonality in the minor salivary gland differed from that in the liver. B-cell clonality was detected in the liver of the PBC and AIH patients.B-cell clonality is a phenomenon that is observed frequently in SS lesions in the salivary glands and liver. The appearance of B-cell clonality was shown to be attributable to antigen-driven clonal expansion.

A 65-year-old female began experiencing arthralgia, morning stiffness and psychroesthesia in April 2000. She visited a rheumatologist and was suspected of having early-stage rheumatoid arthritis. She was referred to our hospital, and was admitted in December 2000. At that time, sclerosis of the skin was advanced, and Raynaud's phenomenon was confirmed. The patient also exhibited nailfold bleeding, and was diagnosed as having systemic scleroderma. She visited a gynecologist for screening and cervical uteri carcinoma was confirmed. She underwent surgery in March 2001, and subsequently, sclerosis in her skin was almost stopped. We believe that these clinical symptoms were related to paraneoplastic syndrome. We therefore immunochemically investigated the pathogenesis of paraneoplastic syndrome and found that connective tissue growth factor (CTGF) might be involved and transforming growth factor-beta (TGF-beta) might not be involved in this case.

was published in 1953, Miku-licz’s disease (MD) has been considered a part of pri-mary Sjogren’s syndrome (SS). However, certain clinicaldifferences exist between MD and SS. The characteristics ofMD include persistent swelling of the lacrimal and salivaryglands, undetectable or slight secretory dysfunction, andresponsiveness to steroid treatment. With regard to serolog-ical findings, MD patients exhibit a lack of anti-SS-A andanti-SS-B antibodies.

Background IgG4-related disease (IgG4-RD) is considered a systemic, chronic and inflammatory disorder that is characterized by elevated levels of serum IgG4 and abundant infiltration of IgG4-bearing plasmacytes and storiform fibrosis in the involved organs. It includes autoimmune pancreatitis type I, Mikulicz’s disease (MD; IgG4-related dacryoadenitis and sialadenitis), and a part of tubulointerstitial nephritis (IgG4-related tubulointerstitial nephritis). It is necessary to manage this disease as soon as possible to prevent permanent organ damages. Glucocorticoid treatment is currently performed in most cases of IgG4-RD and could lead to the clinical remission at once, but we often experience the flare-up by reducing steroid. We have to add on immunosuppressants in that case, but we don’t know what is the most effective drug. Objectives To evaluate the efficacy of rituximab and other immunosuppressant treatment for IgG4-RD. Methods The study subjects included 80 patients with IgG4-RD who had been referred to our hospital and the related institutes (registered to SMART database: Sapporo Medical university And Related institutes database for investigation and best Treatments of IgG4-RD), and performed some therapies since April 1997. Out of the 80 patients, 55 were diagnosed with MD, 16 with Kuttner’s tumor (IgG4-related sialadenitis), 9 with IgG4-related dacryoadenitis. We analyzed the treatments performed for IgG4-RD, and the response to each drug. Results Oral glucocorticoid treatment (≥0.4 mg/kg/day) is significantly effective for all cases with IgG4-RD. Enlargement of involved glands and their gland function was improved in the short term. There were three patients with complete remission and drug-free condition, but 21 patients presented with recurrent in decreasing steroid. In the relapse cases, the same organs were re-affected, or new involvements appeared in the other organs. Almost patients needed glucocorticoid (5∼15 mg/day) for their symptoms. The amounts of steroid were increased to 17 patients. Azathioprine were added on to five patients, cyclosporine A to four patients, mizoribine to three patients, and methotrexate and cyclophosphamide to each one patient. Rituximab was prescribed to two patients. Increase of glucocorticoid was effective for clinical remission, but almost cases presented with the resistant to reducing steroid again. Other oral immunosuppressants could not improve steroid-dependency. Rituximab could reduce the amounts of steroid, but the cases presented with relapse within a year. Conclusions We realize that glucocorticoid is effective for the relief of symptoms in IgG4-RD, but it is difficult to lead to drug-free or long term remission by only steroid in almost cases. Oral immunosuppressants have little efficacy for reducing steroid. It is possible that rituximab improves steroid-dependency, but it is necessary for the maintenance therapy. This suggests that new therapeutic approaches are necessary for IgG4-RD. Disclosure of Interest None Declared

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 …

Background Although renal dysfunction in IgG4-related kidney disease (IgG4-RKD) shows rapid resolution with glucocorticoid therapy, little is known about the appropriate initial glucocorticoid dose for induction therapy or long-term renal outcome. Methods We retrospectively examined the differences in recovery of renal function according to the dose of glucocorticoid used for induction therapy and the long-term renal outcome in 43 patients with definite IgG4-RKD (mostly IgG4-tubulointerstitial nephritis), in whom the estimated glomerular filtration rate (eGFR) before glucocorticoid therapy was 0.6 mg/kg/day (mean 0.81) in 16 patients (group H). In both groups, the pretreatment eGFR was significantly improved at 1 month after the start of glucocorticoid therapy and the degree of improvement showed no significant inter-group difference. Relapse of IgG4-RKD occurred in 16.7 % of the group L patients and 13.3 % of the group H patients (p = 0.78). Among 29 patients who were followed up for over 36 months (mean 74 months) and had been maintained on glucocorticoid, none showed progression to end-stage renal disease and there was no significant difference between eGFR at 1 month after treatment and eGFR at the last review. Conclusion In glucocorticoid monotherapy for IgG4-RKD, a moderate dose is sufficient for induction, and recovery of renal function can be maintained for a long period on low-dose maintenance, although relapse can occur even in patients receiving maintenance therapy.

IgG4-related disease (IgG4RD) is a novel clinical disease entity characterized by elevated serum IgG4 concentration and tumefaction or tissue infiltration by IgG4-positive plasma cells. IgG4RD may be present in a certain proportion of patients with a wide variety of diseases, including Mikulicz’s disease, autoimmune pancreatitis, hypophysitis, Riedel thyroiditis, interstitial pneumonitis, interstitial nephritis, prostatitis, lymphadenopathy, retroperitoneal fibrosis, inflammatory aortic aneurysm, and inflammatory pseudotumor. Although IgG4RD forms a distinct, clinically independent disease category and is attracting strong attention as a new clinical entity, many questions and problems still remain to be elucidated, including its pathogenesis, the establishment of diagnostic criteria, and the role of IgG4. Here we describe the concept of IgG4RD and up-to-date information on this emerging disease entity.