Mikulicz's disease combined with IgG4-related hypophysitis: a case report.

BACKGROUND: IgG4-related diseases are very uncommon, and its diagnosis and treatment are complicated as it encompasses multiple disciplines. CASE PRESENTATION: A 77-year-old woman was admitted with a jaw mass and nausea and vomiting. Laboratory tests showed elevated serum IgG4, pituitary MRI suggested thickening of the pituitary stalk, and head and neck CT suggested orbital and mandibular masses. Patients with mandibular mass were diagnosed with Mikulicz's disease with IgG4-related hypophysitis. We found no other evidence of causing thickening of the pituitary stalk. She was given oral prednisolone 30 mg daily, and her nausea and vomiting improved significantly, and the mandibular and ocular masses decreased in size. CONCLUSION: Mikulicz's disease combined with IgG4-related hypophysitis is a rare case of IgG4-RD in elderly women. IgG4-RD is one of the causes of head and neck exocrine gland mass and pituitary stalk thickening in the elderly.

Mikulicz Disease Mimicking Intraorbital Tumors.

We report a case of Mikulicz disease (MD), an immunoglobulin G4 (IgG4)-related disease that affects the lacrimal and salivary glands. IgG4-related disease is a relatively new clinical entity and is not commonly encountered by neurosurgeons. MD sometimes mimics intraorbital tumors such as malignant lymphoma but responds well to corticosteroid treatment. Thus it is important to recognize the clinical and radiographic features of MD.

[Comparative study of clinical features between unilateral and bilateral orbital IgG4-related disease]. / Estudio comparativo de los hallazgos clínicos en la enfermedad orbitaria asociada a IgG4 con afectación unilateral vs. bilateral.

OBJECTIVE: Descriptive and comparative study of patients with orbital IgG4-related disease. MATERIAL AND METHODS: A review and analysis of the cases diagnosed with inflammatory orbital lesion related to IgG4 by the Ophthalmic Pathology Service in the Dr. Luis Sánchez Bulnes Hospital. RESULTS: A total of 9 cases were found, in which 66% were women, and with a mean age of 48 years and time to diagnosis of 2 years. Unilateral involvement was observed in 56% of cases. All the females experienced pain, and there was an optimal response to corticosteroid treatment in 100% of patients who required medical treatment (one case showed spontaneous resolution). In bilateral cases (44%), only 25% were female, and none had pain as a presenting symptom. Furthermore, 25% of these patients required a combination with immunosuppressants to control inflammation. CONCLUSIONS: Clinical presentation of patients with unilateral orbital IgG4-related disease differs from those with bilateral involvement.

Ocular adnexal IgG4-related disease: clinical features, outcome, and factors associated with response to systemic steroids.

PURPOSE: The aim of this study was to investigate clinical characteristics, outcome, and factors associated with response to systemic administration of steroids in patients with ocular adnexal immunoglobulin G4 (IgG4)-related disease. METHODS: This was a retrospective evaluation of 11 patients with histopathologically verified ocular adnexal IgG4-related diseases at a medical center in Taiwan between January 2006 and December 2012. Clinical features and outcome, including serial change of serum IgG4 and clinical factors related to response to steroids systemically were evaluated. RESULTS: Seven men and four women, mean age 54.5 years and mean follow-up of 33.5 months, were evaluated. Elevated serum IgG4 levels (>135 mg/dl) were observed in ten patients (91%). Lacrimal gland involvement was noted in eight (72.7%), followed by orbit, extraocular muscles, and eyelids. Seven patients (63.6%) had bilateral ocular lesions and eight (72.7%) had extraorbital involvement. Eight of ten patients who underwent systemic steroid treatment responded well in the early phase. Recurrence developed in five patients (45%), requiring repeat steroid therapy and adjunctive treatment. Median serum levels of IgG4 reduced from 540 to 101 mg/dl in ten patients after systemic corticosteroid administration. Patients with lower serum IgG4 and IgG4:IgG ratio at diagnosis were associated with poor response (p = 0.037). CONCLUSIONS: Ocular adnexal IgG4-related disease predominantly involved the lacrimal glands bilaterally and was usually associated with high serum IgG4 levels and multiple organ involvement. Most patients responded well to steroid therapy, which was accompanied by a marked decrease in serum IgG4.

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.

Mechanisms and assessment of IgG4-related disease: lessons for the rheumatologist.

Recognition of IgG4-related disease as an independent chronic inflammatory disorder is a relatively new concept; previously, the condition was thought to represent a subtype of Sjögren's syndrome. IgG4-related disease is characterized by elevated serum levels of IgG4 and inflammation of various organs, with abundant infiltration of IgG4-bearing plasma cells, storiform fibrosis and obliterative phlebitis representing the major histopathological features of the swollen organs. The aetiology and pathogenesis of this disorder remain unclear, but inflammation and subsequent fibrosis occur due to excess production of type 2 T-helper-cell and regulatory T-cell cytokines. The disease can comprise various organ manifestations, such as dacryoadenitis and sialadenitis (also called Mikulicz disease), type 1 autoimmune pancreatitis, kidney dysfunction and lung disease. Early intervention using glucocorticoids can improve IgG4-related organ dysfunction; however, patients often relapse when doses of these agents are tapered. The disease has also been associated with an increased incidence of certain malignancies. Increased awareness of IgG4-related disease might lead to consultation with rheumatologists owing to its clinical, and potentially pathogenetic, similarities with certain rheumatic disorders. With this in mind, we describe the pathogenic mechanisms of IgG4-related disease, and outline considerations for diagnosis and treatment of the condition.

Mikulicz's disease. A case report.

CASE REPORT: We report the case of a 48 year-old male with bilateral involvement of the salivary and lacrimal glands, which was diagnosed as Mikulicz's disease by incisional biopsy of the affected lacrimal glands, which was completely resolved after corticosteroid treatment. DISCUSSION: Sclerosing sialadenitis and/or dacryoadenitis are chronic inflammatory diseases that are currently classified into IgG4-related diseases. Specifically, Mikulicz's disease is defined by a persistent and symmetrical swelling of the lacrimal and salivary glands together with elevated serum concentration of IgG4 and tissue infiltration by IgG4 (+) plasma cells.

[Interdisciplinary approach in a patient with IgG4-associated Mikulicz's disease]. / Interdisziplinäres Vorgehen bei einem Patienten mit IgG4-assoziiertem Morbus Mikulicz.

The clinical picture of enlarged submandibular gland and/or enlarged lacrimal gland often leads to difficulties in differential diagnostics. From the perspective of rheumatology Sjögren's syndrome should be excluded especially in patients who complained of xerophthalmia and xerostomia for longer than 3 months. In this article the authors report the case of a patient who presented to clarify swelling of the submandibular gland and xerostomia. In close cooperation with rheumatologists, otolaryngologists and pathologists the diagnosis of IgG4-associated sialoadenitis (IgG4-associated Mikulicz's disease) could be reached.

Clinical significance of complement as a biomarker of disease activity in 4 cases of IgG4-related disease with retroperitoneal fibrosis.

Hypocomplementaemia is frequently observed in IgG4-related diseases, however the clinical significance is unclear. We describe herein the clinical courses of 4 patients with IgG4-related disease with hypocomplementaemia. Our cases showed autoimmune pancreatitis, retroperitoneal fibrosis, Mikulicz's disease, interstitial lung disease, lymphadenopathy and mesenteric fibrosis around the aorta. A decrease in serum complement preceded deterioration of the disease and clinical improvement was observed in accordance with normalisation of serum complement. These clinical courses suggest that serum complement is a biomarker of the disease activity.

IgG4-related Mikulicz's disease: ultrasonography of the salivary and lacrimal glands for monitoring the efficacy of corticosteroid therapy.

OBJECTIVES: IgG4-related Mikulicz's disease (IgG4-MD) has been recently established as a subtype of IgG4-related diseases involving the salivary and lacrimal glands, and the diseased glands are characteristically and highly responsive to corticosteroid therapy. We retrospectively evaluated ultrasonography (US) of the salivary and lacrimal glands for monitoring the efficacy of corticosteroid treatment in patients with IgG4-MD. METHODS: US features of the salivary and lacrimal glands were assessed and compared with the serum IgG4 levels in 8 patients with IgG4-MD before and at various stages after initiation of oral corticosteroids. RESULTS: US features of the lacrimal and salivary glands of patients with IgG4-MD were characterised by multiple hypoechoic areas in enlarged glands. The submandibular glands were most frequently involved by the disease, and bilateral glands of the same type were similarly affected exhibiting the same hypoechoic pattern. Alleviations of abnormal gland architecture and size in response to corticosteroid therapy were effectively detected with US. The US findings of the involved glands were proportional to the serum IgG4 level before and during the corticosteroid therapy. CONCLUSIONS: US helps monitor the efficacy of corticosteroid treatment in patients with IgG4-MD.

IgG4-related systemic disease: an uncommon presentation for an uncommon disease.

IgG4-related systemic disease is an emerging disease process that manifests with a constellation of features, most commonly but not exclusive to swelling and tuberous growth in the lacrimal and salivary glands, potentially involving many other organ systems. This condition often prompts investigations into malignancy or needless radical surgical procedures. A 58-year-old male was presented to a rheumatologist after several biopsies were done that were suspicious for neoplasia, involving the lacrimal gland and lung. The diagnosis was confirmed when tissue from the lacrimal gland biopsy was reviewed with special stains for IgG4, performed at the Mayo Clinic. This patient is interesting because his disease included bilateral lacrimal glands--at different intervals, the submandibular glands, the lung, and the thyroid gland. His disease responded to immunosuppression. Literature has shown resolution of the tumors upon starting glucocorticoids or rituximab. Our patient was given a course of prednisone and methotrexate with normal follow-up CT chest and physical exam.

IgG4-related Mikulicz's disease is a multiorgan lymphoproliferative disease distinct from Sjögren's syndrome: a Caucasian patient and literature review.

OBJECTIVES: This paper aims to report a case of IgG4-related Mikulicz's disease with a systematic review. METHODS: The relevant English literature was searched using the keywords 'Mikulicz's disease' and 'IgG4'. Original and review articles were reviewed, and the clinical scenarios were exemplified with a case report. RESULTS: A 49-year-old Caucasian man presented with axillary lymphadenopathy and bilateral parotid/submandibular enlargement. A chest computerized tomography showed mediastinal lymphadenopathy, with low metabolic activity on the position emission tomography. A histopathological study showed an IgG4/IgG ratio of 75% in the plasma cells of the submandibular glands, associated with high levels of total serum IgG and IgG4. He had dry mouth, but minor salivary gland biopsy was negative without xerophthalmia. He had nasal obstruction and dyspnea, notably with supine position/cervical rotation, which substantially improved with glucocorticoid treatment. He had newly diagnosed diabetes mellitus with hyperlipasaemia and diffuse pancreatic swelling supportive of autoimmune pancreatitis. CONCLUSIONS: Our case report supports the literature that there are similarities between IgG4-related Mikulicz's disease and Sjögren's syndrome, but the differences are significant. IgG4-related Mikulicz's disease is a multi-organ lymphoproliferative disease distinct from Sjögren's syndrome.

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.

High risk of osteonecrosis of the femoral head in autoimmune disease patients showing no immediate increase in hepatic enzyme under steroid therapy.

Aim of the study is to determine the relationship between liver function and the incidence of ONF after steroid therapy in AID patients. The present study investigated 58 AID patients who had received high-dose systemic steroid therapy to determine whether a correlation exists between parameters of hepatic function and steroid-induced ONF at the precise time-point when steroid-induced ONF develops. The patients were divided into two groups on the basis of MRI findings: ONF (n = 31) and non-ONF (n = 27). The ONF group showed no increase in AST, ALT, or LDH within 4 weeks after the commencement of steroid therapy. By contrast, the non-ONF group showed an immediate and significant increase in all of these parameters. In the ONF group, hepatic steatosis and elevated triglyceride levels were also observed. Following 4 weeks of steroid therapy, there were no significant differences in biochemical data between two groups. Patients showing no immediate increase in ALT and AST in response to steroid therapy were at high risk of ONF. These findings provide important insights into the pathogenesis of steroid-induced ONF and may facilitate the development of prevention strategies in patients with AID.

Clinical characteristics of Mikulicz's disease as an IgG4-related disease.

OBJECTIVES: Mikulicz's disease (MD) was considered to be a subtype of Sjögren's syndrome (SS), based on histopathological similarities. However, recent studies have indicated that patients with MD show high serum IgG4 concentration, and suggested that MD is one of "IgG4-related disease" and distinguishable from SS. Therefore, we clinically and histopathologically examined the disease states of MD and SS in detail. MATERIALS AND METHODS: Twenty patients with Mikulicz's disease and 18 with SS were comparatively studied to determine clinical characteristics in MD patients. RESULTS: Sialography in MD patients did not show the "apple-tree sign" typically seen in SS. Serologically, high serum IgG4 levels but not anti-SS-A or anti-SS-B antibodies were observed in MD. SS showed lymphocytic infiltration of various subsets with atrophy or severe destruction of the acini, while MD showed selective infiltration of IgG4+ plasma cells with hyperplastic germinal centers and mild acini destruction. Corticosteroid treatment of MD reduced IgG and IgG4 levels and improved salivary function. A negative correlation between disease duration and increasing rate of salivary flow was observed in MD. CONCLUSIONS: These results suggested that the pathogenesis of MD might be different from those of SS. CLINICAL RELEVANCE: early diagnosis and treatment of MD is important for the improvement of salivary function.

Long-term outcomes and necessity of early intervention for IgG4-related disease.

IgG4-related disease is thought to show good prognosis because of positive responsiveness to corticosteroids. Increased long-term observations of IgG4-related disease have provided clinical data regarding the functional prognosis of organs. We analyzed the necessity for early intervention based on those findings and our own experience. It is important for the recovery and maintenance of salivary gland function to start corticosteroid treatment within 2 years after onset, and to maintain clinical remission in cases of IgG4-related dacryoadenitis and sialoadenitis (so-called Mikulicz's disease). Early intervention might be useful in cases of IgG4-related kidney disease because recovery of renal function is insufficient when estimated glomerular filtration before treatment is <60 ml/min. Corticosteroid treatment significantly suppresses relapse in patients with autoimmune pancreatitis showing a relatively high rate of spontaneous remission. Long-term observational studies have demonstrated the transformation of autoimmune pancreatitis into chronic pancreatitis presenting with pancreatic atrophy and stone formation. The treatment protocol and timing of initiation should thus be considered. Although organ dysfunction in IgG4-related disease proceeds more slowly than in conventional chronic inflammatory disorders, sustained IgG4-related lesions still cause accumulation of organ damage with expansion of fibrosis. Intervention as soon as possible would favorably impact IgG4-related disease, considering the side effects of treatments such as corticosteroids.