Autoantibodies to killer cell immunoglobulin-like receptor 3DL1 in patients with systemic lupus erythematosus.

A genetic variant of the killer immunoglobulin-like receptor 3DL1 (KIR3DL1) has been found in patients with systemic lupus erythematosus (SLE). Herein, we investigated the presence of autoantibodies to KIR3DL1 in a cohort of patients with SLE. We tested sera from 28 patients with SLE, 11 patients with rheumatoid arthritis (RA) and 17 healthy control subjects for anti-KIR3DL1 activity by an enzyme-linked immunosorbent assay (ELISA) using recombinant KIR3DL1-enhanced green fluorescent protein (EGFP) and EGFP proteins. Anti-KIR3DL1 antibodies were detected in 22 (79%) of the 28 patients with SLE, whereas they were present in only three (27%) of the 11 patients with RA examined. Notably, 10 (91%) of the 11 samples from patients with SLE prior to therapy had anti-KIR3DL1 antibodies. None of the samples from healthy donors were positive for the antibodies. Here, we report the presence of anti-KIR3DL1 antibodies in the sera of patients with SLE for the first time. Anti-KIR3DL1 autoantibodies may be involved in the pathogenesis of autoimmune diseases.

Delayed lupus nephritis in the course of systemic lupus erythematosus is associated with a poorer treatment response: a multicentre, retrospective cohort study in Japan.

OBJECTIVE: The objective of this study was to investigate possible differences in treatment responses between two categories for the onset of lupus nephritis. METHODS: We performed a multicentre, retrospective cohort study of class III-V lupus nephritis patients diagnosed between 1997 and 2014. The renal responses to initial induction therapy were compared between patients who developed lupus nephritis within one year from diagnosis of systemic lupus erythematosus (early (E-) LN) and the remainder (delayed (D-) LN) using the Kaplan-Meier method. We determined the predictors of renal response as well as renal flares and long-term renal outcomes using multivariate Cox regression analyses. RESULTS: A total of 107 E-LN and 70 D-LN patients were followed up for a median of 10.2 years. Log-rank tests showed a lower cumulative incidence of complete response in D-LN compared with E-LN patients. Multivariate analysis identified D-LN (hazard ratio (HR) 0.48, 95% confidence interval (CI) 0.33-0.70), nephrotic syndrome at baseline, and a chronicity index greater than 2 as negative predictors of complete response. D-LN patients were more likely to experience renal flares. D-LN (HR 2.54, 95% CI 1.10-5.83) and decreased renal function were significant predictors of chronic kidney disease at baseline. CONCLUSION: D-LN was a predictor of poorer treatment outcomes, in addition to renal histology and severity of nephritis at lupus nephritis onset.

Chronic active Epstein-Barr virus infection mimicking autoimmune hepatitis exacerbation in a patient with systemic lupus erythematosus.

Chronic active Epstein-Barr virus infection (CAEBV) is characterized by chronic infectious mononucleosis-like symptoms. We report a very rare case with autoimmune hepatitis (AIH) complicated by CAEBV. A 50-year-old woman with systemic lupus erythematosus (SLE) complicated by AIH began to suffer from acute respiratory failure and her clinical symptoms improved rapidly in response to steroid treatment. However, during the gradual tapering of the steroid dose, a steady increase of the serum hepatobiliary enzyme levels subsequently was observed and the patient began to have continuous fever. Moreover, upper gastrointestinal endoscopy revealed multiple intractable gastric ulcers. When EBER-ISH was performed on liver biopsy and gastric mucosal biopsy specimens, EBER-positive lymphocytes were observed. When peripheral blood was examined, 2.1 × 10(6) copies/µg of EBV-DNA were observed in the CD4-positive T cells, confirming the diagnosis of CAEBV. A cooling therapy was started by steroid and cyclosporine. Thereafter, despite the start of CHOP therapy, she developed a malignant lymphoma (PTCL-NOS) and died of hepatic failure. When treatment-resistant AIH patients are encountered, not only AIH exacerbation but also CAEBV should be considered in the differential diagnosis.

A retrospective study of the fluctuation in serum levels of anti-cyclic citrullinated peptide antibody in patients with rheumatoid arthritis.

OBJECTIVE: To investigate the fluctuation in serum levels of anti-cyclic citrullinated peptide antibody (anti-CCP) retrospectively in patients with rheumatoid arthritis (RA). METHODS: Serum levels of anti-CCP were measured retrospectively in 131 patients with RA and 90 patients with non-RA rheumatic diseases using a commercially available kit. All sera were collected from patients during the 22-year period, 1982-2004. To analyze the fluctuation in anti-CCP levels, 17 RA patients were selected on the basis of showing a significantly higher anti-CCP level in a serum sample taken at the first visit (> 80 U/ml), and availability of preserved serum samples that had been taken from each patient at 10 time points. RESULTS: The test gave a sensitivity of 88% (115/131) and a specificity of 81% (73/90). The longitudinal study of 17 RA patients showed that anti-CCP levels were elevated at the first visit in 12 (71%) patients and then decreased gradually, whereas those in the other five (29%) patients fluctuated substantially. In both cases, anti-CCP levels tended to fluctuate in parallel with the erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) level, reflecting the spontaneous aggravation of arthritis and the efficacy of anti-rheumatic drugs. The courses of three representative RA patients are illustrated in detail along with their therapeutic regimens, and these further confirm the correlation of anti-CCP levels with laboratory parameters (ESR and CRP) as well as the activity of arthritis. CONCLUSION: Measurement of serum anti-CCP levels was found to be useful for not only the diagnosis but also the management of RA.

The longest-lived patient with homozygous familial hypercholesterolemia secondary to a defect in internalization of the LDL receptor.

The authors report the longest-lived patient with homozygous familial hypercholesterolemia, the seventh case of a defect in internalization of low-density lipoprotein (LDL). The patient is a 57-year-old man, whose plasma total cholesterol (TC) and LDL-cholesterol (LDL-C) concentrations were 465-660 mg/100 ml and 461 mg/100 ml, respectively, while his plasma high-density lipoprotein-cholesterol (HDL-C) was 13.6-16.9 mg/100 ml. He was the product of a consanguineous marriage, and his parents, brothers, and a sister had mild hypercholesterolemia. His coronary angiogram revealed diffuse coronary artery narrowing. Receptor studies revealed that his fibroblasts bound as much LDL as normal cells, but could not internalize or degrade LDL.

Reduction of factor XII in antiphospholipid antibody-positive patients with thrombotic events in the rheumatology clinic.

Although rheumatological diagnosis often includes an assessment of antiphospholipid (aPL) antibodies, the significance of other prothrombotic factors has not been established in thrombotic patients who are not afflicted with either arteriosclerosis or vasculitis syndrome. We have observed both the presence of antiphospholipid antibodies and a reduction of factor XII in such patients. Our results identified both lupus anticoagulant-positive (50%) and anticardiolipin antibody-positive (58%) patients. In addition, 83% of patients showed factor XII antigen level reduction. Furthermore, 70% of aPL-positive thrombotic patients showed factor XII antigen level reduction. Only two cases had antiphospholipid antibody alone, and 4/12 showed just factor XII antigen reduction. Recently, it has been reported that the presence of antiphospholipid antibodies induces factor XII reduction, and that anti-factor XII autoantibody can be detected in thrombotic patients. However, our results indicate that there are smaller factor XII reductions in non-thrombotic controls who are positive for antiphospholipid antibodies. Furthermore, anti-factor XII autoantibody was not detected in patients with decreased factor XII levels. Kindred research suggested that in two patients there was a genetic component to factor XII reduction. We concluded that the presence of both antiphospholipid antibodies and reduced serum factor XII was observed in most thrombotic patients from our rheumatology clinic. It is therefore possible to consider that the coexistence of these prothrombotic factors can contribute to the onset of thrombosis.

Clinical, serological and genetic study in patients with CREST syndrome.

OBJECTIVE: To assess the clinical, serological and genetic features of Japanese patients with CREST syndrome. PATIENTS AND METHODS: Clinical features, autoantibodies and human histocompatibility leukocyte antigen (HLA) typing were studied in thirty patients with CREST syndrome, including 29 females and one male, with a mean age of 59.0 years (ranging from 40 to 76 years). RESULTS: Interstitial pneumonia on chest X-ray and renal involvement were rare. Mitral regurgitation and tricuspid regurgitation were present in 56.7% and 76.7%, respectively. Sjören's syndrome (SS) and primary biliary cirrhosis (PBC) were highly associated, however the positivity of the marker antibodies to those syndromes, such as anti-SSA, anti-SSB, anti-mitochondrial (AMA) and anti-smooth muscle autoantibodies were less frequent than that of primary SS and PBC without the other autoimmune diseases. The histological findings of PBC were all early stages in Scheuer's classification. HLA-Cw6 were associated with CREST-PBC overlap syndrome (p<0.05). However the HLA antigen was not correlated with CREST syndrome, and the frequency of HLA-DR2 between CREST syndrome with or without PBC was significantly different (p<0.01). CONCLUSION: It was suggested that there was a genetic difference between CREST syndrome alone and CREST-PBC overlap syndrome and there were differences (the positivity of AMA and the severity of bile duct lesion) between PBC and CREST-PBC overlap syndrome.

Histiocytic cytophagic panniculitis which developed during interferon-alpha therapy.

A 59-year-old woman developed edema of the face and eyelids during interferon (IFN)-alpha-2b therapy for chronic hepatitis C with a cumulative dose of 6 million x 47 units. Despite cessation of the therapy, the edema progressed and was followed by exophthalmos, pyrexia, liver dysfunction, pancytopenia, and disseminated intravascular coagulation. Two months after initial presentation, she died of hemorrhagic shock and was diagnosed with histiocytic cytophagic panniculitis at autopsy. This may be a hitherto unrecognized adverse effect of therapeutic IFN alpha.

[Case of fulminant mixed cryoglobulinemia developing after atrial myxoma resection].

A 63-year-old man, with a 13-year history of asymptomatic proteinuria, was diagnosed with left atrial myxoma at the onset of heart failure. After resection of the tumor by hypothermal surgery, the patient developed fever, renal failure and skin rash. The diagnosis was type II mixed cryoglobulinemia accompanied by an IgMlambda clone with high titers of rheumatoid factor activity and polyclonal IgG. Treatment with high doses of steroids and plasmapheresis was ineffective, and the patient died of colon necrosis due to thrombotic occlusion in the supra-mesenteric arteries. Although the patient had suffered from sporadic Raynaud's phenomenon and purpura of the lower extremities from the age of 60 years, cryoglobulinemia was not suspected before surgery because of the atrial myxoma. Thus, we suggest that it is important to perform laboratory tests for cryoproteins before hypothermal surgery.

[Three patients with systemic lupus erythematosus complicated by cytomegalovirus colitis].

We report three female patients with systemic lupus erythematosus complicated by massive intestinal hemorrhage during the recovery from lupus nephritis (case 1, 2) or central nervous system lupus (case 3) on high dose corticosteroid therapy. Large number of cytomegalovirus (CMV) antigen-positive leukocytes and cessation of bleeding with concurrent disappearance of the viral antigens after ganciclovir therapy indicated CMV colitis in all of the three patients. No recurrence of the symptom and a favorable response to ganciclovir without reduction in steroid regimen was common to these patients.

[Three patients with systemic sclerosis complicated by microangiopathic hemolytic anemia and thrombocytopenia].

Clinical profiles and the treatment process of three female patients with systemic sclerosis (cases 1, 2, and 3) complicated by thrombotic microangiopathic hemolytic anemia (TMHA) were described. Thrombocytopenia preceded renal damage and hypertension in cases 1 and 2, although the chronological relationship between these parameters were unknown in case 3. Plasma exchange therapy using fresh frozen plasma was beneficial in cases 1 and 2. Cases land 3 presented with delirium and fluctuating psychosis, respectively. Early detection of thrombocytopenia and insidious hemolysis might be essential for starting effective plasmapheresis treatment in a part of patients with scleroderma kidney who present with thrombotic thrombocytopenic purpura (TTP) like disorder.

[Adult Still's disease].

Adult onset Still's disease was first reported by Bywaters in 1971. It is a systemic inflammatory disorder of unknown etiology, characterized by spiking fever, macular rash and polyarthritis. Although the prognosis is generally good, severe cases have been published. They include those with disseminated intravascular coagulation (DIC), hemophagocytosis, amyloidosis and respiratory failure. Among them, DIC is not uncommon. Prednisolone in a dose of 20-60 mg/day is required when patients fail to respond to nonsteroidal anti-inflammatory drugs (NSAIDs) or when they are accompanied by complications including pleuritis, pericarditis, liver dysfunction, severe arthritis and DIC. Recently, disease-modifying antirheumatic drugs (DMARDs) and immunosuppressive agents including cyclophosphamide and methotrexate have been shown to be effective for alleviating refractory cases and chronic arthritis.

Expression of BAFF and BAFF-R in the synovial tissue of patients with rheumatoid arthritis.

OBJECTIVE: The elevated expression of B-cell-activating factor belonging to the TNF family (BAFF) is associated with systemic autoimmune disease, including rheumatoid arthritis (RA). The present study was undertaken to determine the distribution of BAFF and its receptor BAFF-R in the cells residing in the rheumatoid synovium. METHODS: The expression of BAFF and BAFF-R in synovial tissues obtained from 12 RA patients was examined by immunohistochemistry and flow cytometry. The mRNA expression of these molecules was determined by reverse transcriptase polymerase chain reaction (RT-PCR). Soluble BAFF levels were measured with an enzyme-linked immunosorbent assay (ELISA). Fibroblast-like synoviocytes (FLS) purified from the RA (RA-FLS) were co-cultured with peripheral B cells. The degree of apoptosis in the B cells was measured to assess the effects on the viability of the B cells. RESULTS: The RA synovium showed focal or diffuse infiltration of mononuclear cells (MNCs), and one specimen showed germinal centre (GC)-like structures. Synovial sublining cells, but not lining cells, expressed BAFF. These sublining cells were negative for BAFF-R. BAFF and BAFF-R were expressed in B and T cells extracted from the RA synovium. Notably, RA-FLS spontaneously expressed cytoplasmic BAFF after 4-6 passages; however, they did not express BAFF or BAFF-R on their cell surface. RA-FLS could support the survival of B cells by preventing their apoptosis, but its effect on B cells might not be BAFF dependent. CONCLUSIONS: BAFF and BAFF-R are widely expressed in the RA synovium. The cells residing in the RA synovium might affect each other through BAFF.

Clinical and immunological features of systemic lupus erythematosus complicated by Jaccoud's arthropathy.

Abstract This work was undertaken to evaluate clinical and immunological features in patients with systemic lupus erythematosus (SLE) complicated by Jaccoud's arthropathy. Patients diagnosed with SLE between 1985 and 1999, and who met the criteria of Villiaumey et al., were checked for Jaccoud's arthropathy. Clinical features were retrospectively analysed for patients with both diseases. Sjögren's syndrome and human leukocyte antigens (HLA) in these patients were evaluated. Jaccoud's arthropathy was found in 15 (4.4%) of 340 patients with SLE. The mean age at the time of SLE diagnosis was significantly higher in these patients than in our control SLE patients, which was 51.2 ± 13.0 years (n = 15) and 29.6 ± 13.0 years (n = 222) (p = 2.1 × 10(-8)). Sjögren's syndrome was diagnosed according to the European Community Study Group's criteria in 10 (91%) of 11 patients examined. The incidence of HLA-A11 (5/9, 55%) and -B61(40) (5/9, 55%) in patients with Jaccoud's arthropathy was higher in the Japanese population (A11, 17.4%, p < 0.05; B61, 17.5%, p < 0.057. Jaccoud's arthropathy in patients with SLE is associated with Sjögren's syndrome, elderly SLE, HLA-A11, and HLA-B61. These clinical features might be characteristic of patients with Jaccoud's arthropathy and SLE.

Prevalence of antihuman parvovirus B19 IgG antibodies in patients with refractory rheumatoid arthritis and polyarticular juvenile rheumatoid arthritis.

We investigated the prevalence of antihuman parvovirus B19 immunoglobulin G (IgG) antibody in 108 Japanese patients with rheumatoid arthritis (RA) and 11 patients with polyarticular juvenile rheumatoid arthritis (JRA). Seropositivity of anti-B19 was significantly higher in patients with refractory RA (57.6%, 38/66) compared with patients with remittent RA (19.0%, 8/42; P < 0.001) or age-matched controls (24.3%, 19/78; P < 0.001). Patients with refractory polyarticular JRA had a significantly higher frequency of anti-B19 seropositivity (71.4%, 5/7) than age-matched controls (8.3%, 5/60; P < 0.001), while none of the remittent group was positive for the antibody (0/4).

Nucleolin as the earliest target molecule of autoantibodies produced in MRL/lpr lupus-prone mice.

To elucidate the autoantigen against which autoantibodies are produced in the earliest phase of the disease process of systemic lupus erythematosus (SLE), serum samples were collected individually and serially from 10 NZB/NZW F1 and 10 MRL/lpr mice. Using immunoblots with mouse thymoma cell (EL-4) lysates as substrates, all mice were found to generate autoantibody against an either 150-kDa, 110-kDa, 75-kDa, or 55-kDa molecule in as early as 4 weeks. Anti-DNA antibodies occurred almost at the same time or after those against these four molecules. The number of antigens reactive with autoantibodies in immunoblots increased gradually with age. Antibodies against histone molecules were produced after 8 weeks of age. Among the four antigens, the 110-kDa molecule was identified as nucleolin, which is an abundant nucleolar phosphoprotein. Nucleolin binds DNA, RNA, and nucleic acid-binding proteins such as histone H1. Nucleolin is a target of granzyme A of cytotoxic T cells, and autoantibodies against it are found in sera from patients with SLE as well as from those with various viral infections. These results indicate that nucleolin is one of the immunodominant molecules that break down self-tolerance and initiate autoantibody-spreading in a mouse model of SLE.

[Progressive systemic sclerosis (PSS) and cancer--increasing coincidence rate of cancer in 67 PSS patients].

The coincidence rate of cancer and PSS has been increasing according to reports from Nippon Byori Boken Shuho (Annual of Pathological Autopsy Cases in Japan), reaching 12.3% in the most recent report. Therefore we reviewed the histories of 67 PSS patients seen at our division over an 18-year period between 1974 and 1992, and found a high coincidence rate (14.6%) of cancer, reflecting the increasing tendency reported in the Nippon Byori Boken Shuho. The most frequent type of cancer was gastrointestinal cancer, including gastric and colon cancer and duodenal carcinoid. There were no significant differences in the clinical and laboratory findings between PSS patients with cancer and those without. Twenty-six of the 67 PSS patients died. Cancer was the cause of death in four, ranking second behind respiratory failure. The reason for the increasing coincidence rate of cancer and PSS is unclear at present. However, it is very important to discover cancer in PSS patients as early as possible, since it has a marked effect on prognosis.

Endothelin-1 release from cultured endothelial cells induced by sera from patients with systemic lupus erythematosus.

OBJECTIVES: To clarify the pathophysiological role of endothelin-1 (ET-1) in the vascular injury associated with systemic lupus erythematosus (SLE) by investigating the effect of sera from patients with SLE on ET-1 release from cultured human umbilical vein endothelial cells. METHODS: Confluent monolayers of cultured human umbilical vein endothelial cells were incubated with serum samples (diluted 1:10) from 25 patients with SLE and 16 normal controls for two hours at 37 degrees C and ET-1 concentration in the culture supernatant was measured by enzyme immunoassay. RESULTS: The mean release of ET-1 from endothelial cells in the presence of serum from SLE patients was greater than in the presence of serum from normal controls (p < 0.005). ET-1 release from endothelial cells significantly correlated with the titre of IgM anti-endothelial cell antibodies (IgM-AECA) and immune complex concentration in sera from SLE patients (p < 0.05 and p < 0.01, respectively). After gel chromatography of the serum from an SLE patient, those fractions containing IgM-AECA or immune complex were shown to stimulate ET-1 release from endothelial cells. Heat aggregated IgG also stimulated ET-1 release from endothelial cells in a concentration dependent manner. CONCLUSIONS: IgM-AECA and immune complexes may stimulate ET-1 release from endothelial cells and ET-1 may play an important role in the initiation and development of vascular injury, such as pulmonary hypertension and lupus nephritis, in SLE.