Analysis of serum IgG subclasses in Churg-Strauss syndrome--the meaning of elevated serum levels of IgG4.

OBJECTIVE: Mikulicz's disease (MD) is characterized by symmetrical and persistent enlargement of the lacrimal and salivary glands. Recently it has been categorized as an 'Ig (immunoglobulin) G4-related disease.' It presents with elevated serum levels of IgG4 and abundant infiltration of IgG4-bearing plasmacytes in involved organs. Allergic symptoms are often observed in patients with IgG4-related disease. On the other hand, allergic diseases are often complicated with Churg-Strauss syndrome (CSS). Here we focused on CSS and analyzed the relation of IgG4 in its pathogenesis. MATERIALS AND METHODS: We analyzed five patients (2 men and 3 women) with CSS and 51 patients (20 men and 31 women) with MD who presented at Sapporo Medical University Hospital since 2001. We measured the serum concentrations of IgG subclasses in the patients with MD and CSS, and evaluated renal specimens from CSS patients, staining them for anti-IgG4 antibody. RESULTS: We surprisingly found elevated serum levels of IgG4 not only in MD but also in CSS patients. The renal specimens in CSS patients revealed the infiltration of IgG4-positive plasmacytes. CONCLUSION: IgG4-bearing plasmacytes may be involved in the pathogenesis of CSS, and it is possible that an allergic reaction plays an important role in the pathogenesis of IgG4-related disease.

Mikulicz's disease and systemic IgG4-related plasmacytic syndrome (SIPS).

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 Küttner'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.

[Evidence of cartilaginous benefit of treatment with infliximab in rheumatoid arthritis using measurement of serum COMP].

Recently, it has become possible to measure the concentration of serum cartilage oligomeric matrix protein (COMP) in various arthritis, and it is expected to be a novel biomarker indicative of cartilage destruction. In this study, we evaluated the diagnostic effectiveness of serum COMP in rheumatic diseases and analyzed the inhibition of cartilage destruction in patients with rheumatoid arthritis who were prescribed with infliximab (IFX) for one year. The changes in the concentration of serum COMP and the joint narrow space of Sharp score (Delta Sharp-JNS) were evaluated. The level of serum COMP decreased from 23.04+/-7.14 U/l to 8.69+/-2.89 U/l (p<0.005) and improved Delta Sharp-JNS (-0.50+/-6.38 points). We believed that these results were influenced by the effects of methotrexate (MTX) that was prescribed together with IFX, and we analyzed the group that was administered only MTX therapy as a reference. However, the serum COMP concentration and Sharp-JNS in the MTX group did not decrease. The serological and radiological results revealed that IFX inhibited cartilage destruction, and it is possible that serum COMP is one of the novel biomarkers in RA patients treated with anti-tumor necrosis factor-alpha antibody therapy.

[A case of lupus erythematosus profundus followed by systemic lupus erythematosus presenting with severe intestinal involvement].

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.

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

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

[A case in which the subject was affected by Listeia meningoencephalitis during administration of infliximab for steroid-dependent adult onset Still's disease].

The subject was a 22-year-old woman who developed high fever and arthralgias and eruptions in the extremities around June 2005. She sought medical advice at a nearby dermatology clinic, where hepatic dysfunction was noted on blood testing. The patient was thus hospitalized the next day. Although CRP levels were significantly high, no sign of infection was observed and bone marrow cell differentiation was normal. Adult onset Still's disease was diagnosed based on the observation of persistent high fever >39 degrees C, eruptions, increased leukocytes, pharyngeal pain, splenomegaly, hepatic dysfunction, negative autoantibody results from blood testing, and high serum ferritin levels. Administration of prednisolone 30 mg/day was initiated, but proved ineffective. Steroid pulse therapy was conducted, and the subject was transferred to our medical facility for continued treatment. Attempts were made to control the disease using combined steroid and cyclosporine administration; but exacerbation of high serum ferritin levels and hepatic dysfunctions were observed, so a second course of steroid pulse therapy was conducted. Symptoms improved temporarily, but steroid levels were difficult to reduce. Cyclosporine was therefore replaced by methotrexate, and administration of infliximab was initiated. In the course of treatment, administration of a sulfamethoxazole/trimethoprim combination was initiated, but was discontinued due to suspicion of drug-induced hepatic injury. A second administration of infliximab was conducted in late August, and rapid improvements in clinical symptoms and abnormal test values was observed. However, high fever and headache developed suddenly in early September. Based on the results of spinal fluid testing, blood and spinal fluid cultures and MRI of the head, Listeria meningoencephalitis was diagnosed. Diplopia and impaired consciousness occurred during the disease course, and formation of a brain abscess was observed on imaging. However, symptoms were controlled by long-term combination administration of ampicillin and gentamicin. Administration of infliximab was discontinued for treatment of adult onset Still's disease, and steroid levels were reduced following double-membrane filtration plasma exchange. On follow-up, no relapse of symptoms or abnormalities in blood test values were observed, so the subject was discharged from our medical facility in December 2005. In treatment for rheumatic diseases, a dramatic improvement in treatment results for pathologies displaying tolerance against conventional treatments has been acquired with the development of biological drugs. However, opportunistic infections represent a serious problem, and appropriate preventative measures are required. The present report describes a case in which the subject was affected by Listeria meningoencephalitis during administration of infliximab for steroid-dependent adult Still's disease. Since listeriosis is one of the complications, along with tuberculosis, that warrants precautionary measures, this case is reported and discussed.

[A case of Mikulicz's disease complicated by autoimmune pancreatitis, in which impaired glucose tolerance was improved by glucocorticoid treatment].

A 73-year-old woman had experienced dry mouth and swellings of both upper eyelids from 1998. In October 2003, she also developed bilateral submandibular swellings, and was diagnosed with diabetes mellitus and prescribed antidiabetic medication. She consulted our hospital in the summer of 2004 due to the exacerbation of eyelid swelling, and was admitted in October 2004. Keratoconjunctivitis sicca was not present. CT and MRI of the head showed bilateral enlargement of the lacrimal and submandibular glands. Serological investigations revealed hypergammaglobulinemia, but as antinuclear antibody and anti-SS-A antibody were absent, further investigation was performed. Serum concentrations of IgG4 were elevated and biopsy of the minor salivary gland revealed a severe infiltration of IgG4-positive plasmacytes. The patient was therefore diagnosed with Mikulicz's disease. Abdominal CT demonstrated diffuse pancreatic swelling, and endoscopic retrograde cholangio-pancreatography revealed stricture of the common bile duct and main pancreatic duct, suggesting the complication of autoimmune pancreatitis. Treatment was commenced with 40 mg/day of prednisolone. This resulted in rapid resolution of the lacrimal and submandibular gland swellings and recovery of salivary gland function. Diffuse swelling of the pancreas and stricture of the common bile duct and main pancreatic duct also improved, and endogenous insulin secretion increased. Both Mikulicz's disease and autoimmune pancreatitis presented with elevated serum IgG4 and infiltration of IgG4-expressing plasma cells into the glandular tissues. We recently proposed the new diagnostic entity of "IgG4-related plasmacytic exocrinopathy"; however, if diabetes mellitus in autoimmune pancreatitis was caused by direct dysfunction of pancreatic cells, we must reconsider this pathogenesis and consider a wider concept including exocrine as well as endocrine glands. This case, in which both types of glands were affected, is therefore of considerable interest.

[Collagen diseases with gastrointestinal manifestations].

Collagen vascular diseases are known to present with a diverse array of gastrointestinal manifestations. These can be classified as: 1) gastrointestinal damage due to the collagen vascular disease itself; 2) adverse events caused by pharmacotherapies; or 3) gastrointestinal infections following immunosuppression due to corticosteroid (CS) administration. The first group includes lupus enteritis and protein-losing gastroenteropathy in systemic lupus erythematosus (SLE), reflux esophagitis, chronic intestinal pseudo-obstruction, and pneumatosis cystoids intestinalis in systemic sclerosis, amyloidosis in rheumatoid arthritis, bowel ulcer and bleeding in rheumatoid vasculitis and microscopic polyangiitis, and ileocecal ulcer in Behcet disease. In particular, colonic ulcers associated with SLE represent refractory lesions resistant to CS. Analysis of reported cases showing colonic lesions with SLE (22 cases in Japan) revealed that mean duration of SLE was 9.9 years and 77% of colonic lesions were observed in the rectum and sigmoid colon. Half of the patients developed intestinal perforation or penetration, and 6 of the 11 patients with perforation died. The second group includes lesions in the small and large intestine due to nonsteroidal anti-inflammatory drugs (NSAIDs) and CSs, in addition to peptic ulcers. As perforation in CS-treated patients displays relatively high incidence with poor prognosis, careful attention to such complications is needed. The third group includes candidal esophagitis and cytomegalovirus (CMV) enteritis. Prompt diagnosis is required to prevent colonic bleeding and perforation due to CMV.

[Beneficial effect of glucocorticosteroids for esophageal varices due to idiopathic portal hypertension following systemic lupus erythematosus].

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.

A case of systemic lupus erythematosus with postpartum hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome and concomitant high phosphatidylserine-dependent anti-prothrombin antibody levels.

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.