Polyangiitis overlap syndrome with eosinophilia associated with an elevated serum level of major basic protein.

Polyangiitis overlap syndrome is a new disease entity and the reported cases in the literature are still limited. We describe a female patient presenting with finger ulcers, skin eruptions, pleural effusion, interstitial pneumonia and eosinophilia. Skin biopsy showed systemic small-sized angiitis and thrombosis. She was diagnosed as having polyangiitis overlap syndrome and was successfully then treated with corticosteroid. It is also of interest that the disease activity was correlated with the number of eosinophils in peripheral blood. The measurement of the serum level of major basic protein released from eosinophils functioning as a coagulant indicated the possible association of eosinophilia with thrombosis and polyangiitis.

[An analysis of fever of unknown origin defined by newly proposed practical criteria. A prospective study of 56 cases].

The criteria proposed by Petersdorf has been in use internationally to define the fever of unknown origin (FUO) since 1961 and the research of FUO has progressed with this criteria. Mean-while, new diagnostic methods have been developed and illness behavior of febrile patients has changed considerablly. Accordingly, the definition by Petersdorf is becoming less matched to current clinical situation. Therefore, we have developed a new practical criteria of FUO; i.e., out-patients who are febrile more than 2 weeks, documented temperature higher than 37.5 degrees C at least on one occasion and undetermined diagnosis and in-patients who are febrile more than 1 week with documented temperature higher than 37.5 degrees C, and undetermined diagnosis. Between October 1, 1993, and October 31, 1996, we prospectively collected a series of febrile patients who fulfilled our new criteria. We identified 56 patients by our criteria (23 male and 33 female, age: 49.7 +/- 20.6. range 15 to 88). Of this 56 patients, 19 (32%) were found to have infections, 18 (31%) had collagen disorders, 5 (9%) had malignancy and 6 (10%) had died. Of 56 patients, 38 (68%) were in the newly added group. Of these 38 patients, 4 patients had subacute necrotizing lymphoadenitis, 4 cytomegalovirus infection, 3 polymyalgia rheumatica, 3 tuberculosis. Four patients (10%) died. With our criteria, febrile patients who previously had not been included were found to have as poor a prognosis as with the Petersdorf group.

[A case of Crow-Fukase syndrome associated with chronic pachymeningitis].

A 34-year-old woman was admitted to our hospital in 1991, because of progressive headache, nausea and generalized edema. She was diagnosed as Crow-Fukase syndrome associated with plasma cell dyscrasia (IgA lambda type) in 1987, presenting with polyneuropathy, edema, and dermatologic changes. Those manifestations were improved with irradiation and corticosteroids, but headache, nausea and generalized edema gradually developed after the discontinuation of corticosteroid therapy in 1991. On admission, marked bilateral papilledema was noted but fever and meningeal irritation signs were absent. A spinal tap showed a clear cerebrospinal fluid (CSF) with an open pressure of more than 400 mmH2O, normal cell count, total protein level of 87 mg/dl, and IgG level of 12.3 mg/dl. The CSF culture for microorganisms was negative and the cytological study of CSF also was normal. De novo synthesis rate of CSF IgG was markedly elevated (35.3 mg/day). MRI of the head using Gd-DTPA revealed diffuse hypertrophic dura mater, which made the diagnosis of chronic pachymeningitis. Cerebral angiographies were normal. An RI cisternography demonstrated delayed absorption of the CSF without ventricular reflux. Gallium and bone scintigrams did not show any pathological accumulation of the isotopes in the head. The lack of abnormalities causing chronic pachymeningitis in this case suggests that the chronic pachymeningitis might be associated with Crow-Fukase syndrome. The development of increased intracranial pressure is not rare in Crow-Fukase syndrome but the etiology remained unknown in most cases. We therefore suggest that MRI study with contrast enhancement should be performed in cases of this condition with increased intracranial pressure.

[Occurrence of malignancy in patients with biopsy-proven temporal arteritis].

A woman of 79 years was admitted to our hospital because of headache and high erythrocyte sedimentation rate (ESR). Temporal artery biopsy demonstrated giant cell arteritis and nonsteroidal antiinflammatory drugs were effective. Another woman of 69 years was admitted because of headache, high ESR, and polymyalgia. Temporal arteritis (TA) with polymyalgia rheumatica (PMR) was established in biopsy of the temporal artery, and steroid therapy was effective. In our hospital, a third patient of 81 years was also suffering from TA with PMR, but temporal artery biopsy was not performed. Those three cases were followed for several years after the diagnosis of TA. Two years later, cancer in cervix of uterus was diagnosed in first case, and acute myelogenous leukemia in second case. However, such symptoms were not observed in third case. These findings and recently described reports suggest that the patients with biopsy-proven TA may have an increased risk of developing malignancy.

[A case of Sjögren's syndrome complicated by polymyositis and sarcoidosis with HLA-B7 and DR 8: common causes of susceptibility for these diseases].

We describe a case of a Japanese patient initially presenting with Sjögren's syndrome who later developed polymyositis and sarcoidosis. A 67-year-old woman with a 4 month history of myalgia was admitted in April 1998 for examination. The patient had a 10 year history of symptoms consistent with Sjögren's syndrome. A diagnosis of polymyositis was made based on a biopsy of the muscle and an electromyogram. Positive Shirmer and Rose Bengal tests and results of a minor salivary gland biopsy were all consistent with Sjögren's syndrome. Chest computed tomography detected a bilateral hilar lymphadenopathy. Microscopic examination of a mediastinal lymph node demonstrated multiple noncaseating granulomas with multiple epithelioid cells and Langhans-like giant cells. A diagnosis of sarcoidosis was made based on these findings. Hepatitis C infection was also detected by elevated antibody levels. The patient was given 40 mg/day of oral prednisolone and a remission of her myositis and lymphadenopathy was obtained. The patient exhibited HLA-B7 and HLA-DR 8. HLA-DR 8 is commonly associated with these three disorders, and HLA-B7 is also associated with overlap syndrome in Japanese patients. The present case suggested the possibility of a common etiological background for these three disorders. Furthermore, the importance of genetic background, including HLA phenotype, in determining susceptibility to these disorders was demonstrated.

[The effect of beraprost sodium on the Raynaud's phenomenon].

We investigated the effect of beraprost sodium (BPS) on the Raynaud's phenomenon on 15 patients with systemic sclerosis, 3 with mixed connective tissue disease and 1 with Raynaud's disease, respectively. After 12 weeks of administration of 60 micrograms/d BPS, the duration and the incidence of the Raynaud's symptom were significantly reduced and the dermal temperature on the fingers was found to be elevated. Of the parameters which are known to reflect vascular endothelial damages such as tissue plasminogen activator (t-PA), von Willebrand's factor (vWF) and endothelin, the plasma level of t-PA was significantly reduced by BPS. Furthermore, the capillary loop in the nail bed of the fingers seemed to increase in one patient by the treatment with BPS. These results suggest that BPS has a capacity to repair peripheral vascular damages resulting in the improvement of Raynaud's phenomenon.

[A case of POEMS syndrome with various complications].

A 65-year old man presented with complaints of sclerosis of skin and numbness in the extremities. During last 10 year, he had developed monoclonal gammopathy, Raynaud's phenomenon, ischemic heart disease, sigmoid colon cancer, hyperkalemia, polyneuropathy and scleroderma-like skin changes. Laboratory examinations revealed a monoclonal protein (IgA-lambda) and an elevated serum level of IL-6. Subsequently a diagnosis of POEMS syndrome was made based on the clinical features and laboratory findings which were characteristic of this syndrome. Further examinations showed the presence of glomerulonephritis and brain tumor. These various complications are of great interest in understanding the pathogenesis of POEMS syndrome.

[A case of Wegener's granulomatosis associated with refractory bowel granulomatous ulcers].

We describe a 58-year-old woman who developed Wegener's granulomatosis (WG) complicated by a perforation of the transverse colon caused by necrotizing granulomatous vasculitis. In addition, her colon lesion continued in spite of high dose corticosteroid and cyclophosphamide therapy. She was admitted to our hospital because of her severe tonsillitis in Dec., 1994. She was diagnosed as having WG because she had oral ulcer, antibiotics-resistant lung infiltration, renal dysfunction and positive C-ANCA. Just after we started high dose steroid therapy, the transverse colon was perforated because of vasculitis, and she underwent emergency operation. Many vasculitic lesions were found in the small intestine, colon, and mesenterium. The disease was improved by corticosteroid and cyclophosphamide therapy except for a sustained ulcer with necrotizing vasculitis in the sigmoid colon region even 1 year after the operation. Although WG rarely complicates digestive tract lesions as initial manifestations, they reach 12% of the causes of death of WG in Japan. Therefore, we should take care of digestive tract lesions when we follow-up patients with WG.

[Autoimmune hepatitis associated with mixed connective tissue disease: report of a case and a review of the literature].

A case is reported of a 29 year old female who had autoimmune hepatitis associated with mixed connective tissue disease (MCTD). The patient developed MCTD at the age of 19, and was treated with prednisolone. Liver dysfunction developed 7 years later, which exacerbated shortly after the patient suffered intrauterine fetal death during the second trimester of pregnancy. Laboratory data showed negative anti-hepatitis C antibody and hepatitis B antigen, but positive anti-smooth muscle antibody. A liver biopsy showed chronic active hepatitis. Referring to the criteria we diagnosed her as having autoimmune hepatitis. Although hepatomegaly is sometimes observed in MCTD patients, only 5 cases of autoimmune hepatitis associated with MCTD have been reported in the past. In our case, it is of note that autoimmune hepatitis developed while symptoms of MCTD were in remission, and that autoimmune hepatitis exacerbated with the emergence of anti-smooth muscle antibody following the termination of pregnancy.

[A case of Takayasu arteritis diagnosed by magnetic resonance imaging].

We report a case of Takayasu arteritis. A woman, 24 years old, was admitted because of fever of unknown etiology. Infection was ruled out. Bruit and asymmetrical pulsation were not found. Ga-scintigram showed abnormal uptake in her upper abdomen. Abdominal echogram revealed neither evidence of abscess nor lymphadenopathy. On abdominal computed tomography, a wall thickening of the abdominal aorta was revealed. In addition, abdominal magnetic resonance imaging(MRI) showed a wall thickening and an enhanced image by gadrinium enhancement. Although we could not carry out conventional aortography because of an allergy to lidocaine, she was diagnosed as having Takayasu arteritis. In response to steroid therapy, the fever promptly dropped and the data indicating inflammation were improved. On the MRI examination after 40 days of steroid therapy, the wall thickening of the abdominal aorta was found to be less prominent. We conclude magnetic resonance imaging is useful for diagnosis and follow-up of early and acute stage of Takayasu arteritis.

Development of microscopic polyangiitis in patients with chronic airway disease.

Microscopic polyangiitis (MPA) is a rare systemic vasculitis syndrome, which is often accompanied by positive myeloperoxidase-specific antineutrophil cytoplasmic antibody (MPO-ANCA). While pulmonary involvement of MPA consists mainly of diffuse alveolar hemorrhage and interstitial pneumonia, bronchiectasis has been reported as a pulmonary lesion in association with MPA. To investigate the clinical features of patients with MPA, focusing on the presence or the absence of preceding chronic airway diseases (CAD), we conducted a retrospective observational study of 26 patients in the last 13 years at Saga University Hospital. The clinical records and radiologic chest examinations were reviewed retrospectively. Pulmonary manifestations were alveolar hemorrhage in 3 patients (12%) and interstitial pneumonia in 5 (19%). Bronchiectasis, defined by the findings of chest radiograph and computed tomography, was found in 9 patients (35%). Four patients (15%) with bronchiectasis and one patient (4%) with chronic bronchitis had experienced chronic bronchial suppuration prior to the onset of MPA. Ten patients were classified as having chronic airway disease (CAD) before the onset of MPA. MPO-ANCA tended to be lower in the CAD group than in the non-CAD group. None of the patients in the CAD group had pulmonary hemorrhage or interstitial pneumonia. Only one patient (10%) in the CAD group died within 90 days of the onset of MPA, while 7 (43.8%) of the non-CAD group died. Our study suggests that MPA may result in part from CAD and that the clinical course of MPA with CAD may be different from MPA without CAD.

[A case of malignant rheumatoid arthritis with long-term improvement by regular use of cryofiltration plasmapheresis].

A Japanese man, 25 years old, suffered from stiffness, swelling, and pain of his joints in May 1983. He was diagnosed as rheumatoid arthritis and was given steroid unsuccessfully. Then, he was admitted to our hospital in February 1984. Because of the presence of high fever and rash on admission, differential diagnosis of RA from adult Stills disease was difficult. However, skin biopsy disclosed apparent vasculitis, leading to the definite diagnosis of malignant RA (MRA). We could not induce any remission by large dose of steroid including pulse therapy, various immuno-suppressants, and anti-rheumatic agents, because of lack of effectiveness and side effects of the drugs. Double filtration plasmapheresis (PA) was performed, but its beneficial effect soon disappeared. On the other hand, cryofiltration PA caused more beneficial and prolonged effect, resulting in improvement. Thereafter, he was successfully followed on regular use of PA for about 6 years. His condition depended on the interval between PA and next PA and on the volume of filtrated plasma. He died of septicemia on March, 1991. We report here the case of MRA with long time improvement by regular use of cryofiltration PA.

Familial Pelger-Huet anomaly accompanied by tuberculosis and complicated by acute polyarthritis.

A patient with familial Pelger-Huet (PH) anomaly, which accompanied tuberculosis, and acute polyarthritis is described. Investigations surrounding this case suggests that the immunological abnormalities may be associated with the PH anomaly and the tuberculosis, and that the complications may be related to the development of the acute polyarthritis.

Increased entry of CD4+ T cells into the Th1 cytokine effector pathway during T-cell division following stimulation in Behcet's disease.

OBJECTIVES: To investigate the relationship between the production of Th1/Th2 cytokines and cell kinetics, cell division and proliferation in patients with Behçet's disease (BD). METHODS: Peripheral venous blood was drawn from patients with BD (n = 24; 10 patients with active and 14 patients with inactive BD) and normal subjects (n = 22). Peripheral blood mononuclear cells were separated immediately and were cultured with concanavalin A (Con A) followed by phorbol 12-myristate 13-acetate and ionomycin (PMA+Ion). Intracellular cytokine production of interferon-gamma (IFN-gamma) (Th1) and IL-4 (Th2) in CD4(+) T cells was determined by flow cytometry. Furthermore, CD4(+) T cells labelled with CFSE [5 (and 6) carboxyfluorescein diacretate, succinimidyl ester] were stimulated and the cells were analysed for entry into the cytokine production effector pathway during cell division in active BD and normal subjects. RESULTS: In active BD, enhanced entry into the Th1 response effector pathway of CD4(+) T cells was observed after stimulation with Con A followed by PMA+Ion. Analysis of CD4(+) T cells at an identical cell division number in response to Con A followed by PMA+Ion revealed that IFN-gamma-producing cells were increased in active BD patients compared with normal subjects. These results suggest that the Th1 response of dividing CD4(+) T cells is predominantly operating in active BD. Dividing CD4(+) T cells stimulated with Con A followed by PMA+Ion showed a phenotype of activated effector memory T cells (CD45RA(low), CD45RO(+), CD69(high)). CONCLUSIONS: Cell kinetics play a crucial role in Th1 cell differentiation and pathophysiology in BD.

Flexor tenosynovitis of the hands as an initial manifestation of systemic lupus erythematosus.

Abstract We describe a patient who presented with flexion contractures of the bilateral fingers due to tenosynovitis of the flexor digitorum tendons as an initial manifestation of systemic lupus erythematosus (SLE). A 17-year-old woman had abrupt onset of diffuse swelling and flexion contractures in the bilateral fingers, accompanied by polyarthritis and cervical lymphadenopathy. Magnetic resonance imaging (MRI) showed flexor tenosynovitis of the hands. A diagnosis of SLE was made by immunological and hematological tests, and treatment with oral corticosteroids resulted in a rapid and complete disappearance of the flexion contractures.

Retinal findings in systemic sclerosis: a comparison with nailfold capillaroscopic patterns.

OBJECTIVE: To determine the prevalence of retinal disease in systemic sclerosis (SSc) and to characterise the findings of retinopathy. Additionally, to analyse the association of retinal disease with other clinical/laboratory findings, particularly the findings of nailfold capillaries in patients with SSc. METHODS: Photographs of the ocular fundi were taken and were evaluated by an ophthalmologist who was unaware of the SSc status of the patients. The nailfold capillaries were analysed with a dermatoscope. Patients were divided into two groups according to the presence (group A) or absence (group B) of retinal disease. RESULTS: Retinal findings of the patients with SSc consisted of hard exudates, vascular tortuosity, microhaemorrhage, and macular degeneration. The prevalence of retinal disease among the patients with SSc was 34% (10/29), compared with 8%(3/38) among the controls (p=0.011). The mean systolic blood pressure and the age of the patients in group A were significantly higher than those in group B. However, there was no significant difference in the nailfold capillary damage between groups A and B. CONCLUSION: Retinal abnormalities are often seen in patients with SSc and they may reflect the vascular changes characteristic of SSc. However, retinal changes may differ in quality from the changes of nailfold capillaries.

CD28-deficient mice are highly resistant to collagen-induced arthritis.

CD28 provides a critical costimulatory signal in Ag-specific T cell activation. Recent studies have revealed an important role for CD28 in the development of autoimmune diseases. We have examined the role of CD28 in collagen-induced arthritis (CIA) by inducing CIA in CD28-deficient DBA/1 mice. CD28-deficient mice never developed arthritis and showed markedly decreased levels of IgG and IgM anti-type II collagen (CII) Abs. In addition, the CD28+/- mice had similar levels of IgG1 and IgG2a anti-CII Abs, whereas in the CD28-deficient mice the level of IgG1 anti-CII Abs was decreased compared with that of IgG2a. IFN-gamma production by lymph node cells in response to CII was also reduced. CD28-deficient mice were either immunized four times with CII in CFA to augment Ag loading or given low doses of IL-12 to enhance Thl type responses. Both treatments resulted in a very low incidence of CIA development and minimal disease. CD28-deficient mice developed arthritis from injection of lymph node cells from CII-immunized wild-type mice, followed by immunization with CII in CFA. Taken together, these results indicate that costimulation of CD28 cannot be replaced by repeated activation through TCR or other costimulatory molecules. Thus, CD28 plays a critical role in both cellular and humoral immunity against CII and is indispensable for the development of CIA.

B cells lacking RP105, a novel B cell antigen, in systemic lupus erythematosus.

OBJECTIVE: RP105 is a leucine-rich repeat (LRR) protein found on all mature mouse B cells. Its function is poorly defined, although it has been suggested that RP105 activates B cells to make them resistant to apoptosis. The human homolog of RP105 has been reported, but knowledge of its function is limited. We explored the expression and the function of the human homolog of murine RP105 on B cells in patients with systemic lupus erythematosus (SLE). METHODS: The expression of RP105 and various markers on B cells in patients with SLE was analyzed using monoclonal antibodies and flow cytometry. Susceptibility to corticosteroid-induced apoptosis was examined by annexin V binding, and the production of immunoglobulin by RP105-negative B cells was examined by intracellular staining of IgG. RESULTS: As in mice, virtually all B cells in the peripheral blood of normal humans expressed the RP105 molecule. However, a significant proportion of circulating B cells (15.9%) in SLE patients were RP105 negative. Serial analyses of B cells in 7 SLE patients revealed that RP105-negative B cells markedly decreased in parallel with a reduction in disease activity (from 35.2% to 3.3%; P = 0.000003). The SLE Disease Activity Index and serum levels of IgG also correlated with the percentage of RP105-negative B cells. The phenotype of RP105-negative B cells was defined as CD95-positive, CD86-positive, CD38-bright, IgD-negative, IgM-dull, indicating that the cells were highly activated, as further suggested by the detection of intracellular IgG. RP105-negative B cells were clearly distinct from CD5-positive B1 cells. In vitro experiments indicated that RP105-negative B cells were susceptible to corticosteroid-induced apoptosis. CONCLUSION: These findings suggest that loss of RP105 is associated with B cell activation and increased disease activity in SLE patients.

Retinal disease in patients with systemic lupus erythematosus.

OBJECTIVE: To investigate the incidence of retinopathy in systemic lupus erythematosus (SLE) and to clarify its significance in relation to other clinical manifestations. METHODS: A cross sectional study on lupus retinopathy was made in 69 patients with SLE. One expert ophthalmologist examined the ocular fundi of the lupus patients without any information of their disease state. Clinical and laboratory findings in the patients with retinopathy and those without were compared. RESULTS: Retinopathy was found in 7/69 (10%) patients. The findings included haemorrhages, vasculitis, cotton wool spots, and hard exudates, all of which were considered to reflect vascular damage. Retinopathy was found to be associated with the presence of anticardiolipin antibody (p<0.05) and with central nervous system lupus (p<0.01). The patients with retinopathy had higher levels of serum creatinine than the patients without retinopathy (p<0.01). The disease activity of lupus, as assessed by the maximum SLE disease activity index (SLEDAI) score of the patients, was also significantly higher in the patients with retinopathy (p<0.03). CONCLUSION: Incidence of retinopathy in SLE was similar to that in previous reports and it may reflect tissue microangiopathy, particularly associated with vasculitis or anticardiolipin antibodies, or both.

Role of the costimulatory molecule CD28 in the development of lupus in MRL/lpr mice.

MRL/Mpj-lpr/lpr (MRL/lpr) mice develop autoimmune disorders, including lymphoproliferation, glomerulonephritis, autoantibody production, and hypergammaglobulinemia. To investigate the role of the costimulatory molecule CD28 in the development of these disorders, MRL/lpr mice lacking CD28 were generated by gene targeting. Compared with CD28+/+ MRL/lpr mice, CD28-/- MRL/lpr mice showed decreased lymphadenopathy but increased splenomegaly associated with the expansion of abnormal B220+ TCRalphabeta+ T cells. Although levels of IgM Abs were unchanged in CD28-/- MRL/lpr mice, the production of anti-DNA IgG Abs and IgG rheumatoid factors were suppressed. IgG deposition in the glomeruli was markedly decreased, and the development of glomerulonephritis was significantly retarded. Furthermore, renal vasculitis and arthritis were absent in CD28-/- MRL/lpr mice. These results indicate that, although CD28 is not required for the generation of the abnormal T cell population in MRL/lpr mice, it does play an important role in the development of autoimmune disease in these animals.