Interstitial lung disease with myeloperoxidase-antineutrophil cytoplasmic antibody-associated vasculitis in elderly patients.

Anti-neutrophil cytoplasmic antibodies-associated vasculitis (AAV) occurs in elderly people, and patients with anti-myeloperoxidase autoantibodies (MPO-ANCA)-positive AAV are often complicated with interstitial lung disease (ILD). This study aimed to evaluate the age-related clinical features of elderly patients with MPO-ANCA-positive AAV-ILD. This study retrospectively investigated 63 patients with MPO-ANCA-positive AAV-ILD, all of whom were 65 years or older at diagnosis. Clinical characteristics, causes of death and survival rates among three groups stratified by age (65-74 years, n = 29; 75-79 years, n = 18; over 80 years, n = 16) were compared. This study also examined the association with severe infections in these patients. Among the three age groups, there were significant differences in sex (P = 0.032), serum Krebs von den Lungen-6 (P < 0.01), and total ground-glass opacity score (P = 0.011). The causes of death were mainly severe infections and complications of ILD. Kaplan-Meier curve analysis showed a significantly lower 5-year survival rate in the oldest group (P < 0.01). Regarding severe infections in these patients, the 5-year cumulative incidence of severe infections was higher in the patients receiving steroid pulse therapy (P = 0.034). The clinical characteristics of MPO-ANCA-positive AAV-ILD differ with age in elderly patients, with age being an important poor prognostic factor in these patients. The administration of steroid pulse therapy is a significant risk factor of severe infection in MPO-ANCA-positive elderly patients with AAV-ILD.

Clinical differences among patients with myeloperoxidase-antineutrophil cytoplasmic antibody-positive interstitial lung disease.

INTRODUCTION: Patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis and idiopathic interstitial lung diseases (IIPs) are positive for myeloperoxidase (MPO)-ANCA. MPO-ANCA-positive vasculitis mainly comprises microscopic polyangiitis (MPA) and unclassifiable vasculitis. These diseases are frequently complicated by interstitial lung disease (ILD). Few studies have reported the clinical differences between the subtypes of MPO-ANCA-positive ILD. Therefore, this study aimed to examine the clinical findings and courses of MPO-ANCA-positive ILD. METHOD: This retrospective study enrolled 100 patients with MPO-ANCA-positive ILD who were categorized into three groups: MPA (n = 44), unclassifiable vasculitis (n = 29), and IIP (n = 27). Our study compared the clinical findings and prognosis of these patients and analyzed the poor prognostic factors. Furthermore, we assessed the association between the patients with and without acute exacerbation of ILD (AE-ILD). RESULTS: Our study found clinical differences in serum markers, clinical symptoms, and treatment regimens among the three groups. ILD complications, as the main cause of death, differed among the three groups (P = 0.04). Patients with unclassifiable vasculitis showed higher survival rates than those with IIP (P = 0.046). Patients with AE-ILD showed fewer general symptoms (P = 0.02) and lower survival rates (P < 0.01) than those without AE-ILD. In multivariate analysis, AE-ILD development was a strong poor prognostic factor for MPO-ANCA-positive ILD. CONCLUSIONS: The subtypes of MPO-ANCA-positive ILD have different clinical features and prognoses. Patients who develop AE-ILD require careful evaluation of clinical courses. Key Points • In myeloperoxidase (MPO)-antineutrophil cytoplasmic antibody (ANCA)-positive interstitial lung disease (ILD), patients with unclassifiable vasculitis showed a better prognosis than those with idiopathic ILD.. • Development of acute exacerbation in ILD was a strong poor prognostic factor in patients with MPO-ANCA-positive ILD..

Pure red cell aplasia induced only by intravenous administration of recombinant human erythropoietin.

Antibody (Ab)-mediated pure red cell aplasia (PRCA) is a rare but important side effect in patients with chronic kidney disease who receive recombinant human erythropoietin (rhEPO). Ab-mediated PRCA was first reported in the 1990s, and the incidence subsequently increased and reached a peak in 2001. After improvements in rhEPO products and the administration route, the incidence was reduced by 90%, and now Ab-mediated PRCA only develops in a limited number of patients who receive rhEPO subcutaneously for a long period. We describe here the clinical course of one such rare patient with Ab-mediated PRCA. The patient was a 70-year-old man with chronic renal failure secondary to diabetic nephropathy. He had not received rhEPO therapy before the initiation of hemodialysis. He started hemodialysis and began to receive rhEPO therapy intravenously. Three months later, his hemoglobin level started declining and he became transfusion dependent. A diagnosis of Ab-mediated PRCA was made by bone marrow examination and detection of anti-EPO Abs. He was successfully treated with cyclosporine and became independent of blood transfusions. This case is a reminder that vigilance is required regarding the development of Ab-mediated PRCA upon rhEPO therapy, regardless of the administration route.

[Efficacy of steroid pulse therapy in patients with IgA nephropathy and impaired renal function].

OBJECTIVE: In the current study, we evaluated the efficacy of methylprednisolone (MP) pulse therapy in IgA nephropathy (IgAN) patients with established renal function impairment. PATIENTS AND METHODS: We retrospectively analyzed the effect of MP pulse therapy in patients with histologically active IgAN (8 males, 12 females) whose estimated glomerular filtration rate was less than 60 mL/min/1.73 m2 (33.4 +/- 13.1, mean +/- SD). The efficacy of the MP pulse therapy was analyzed by calculating the regression coefficients (dL/mg/month) from the slopes of the 1/serum creatinine (Cr), urine protein/creatinine ratio (g/g x Cr), and the estimated interval from the pulse therapy to dialysis (that is, for Cr to reach 8 mg/dL, as calculated from the slope of 1/Cr) or the actual interval. RESULTS: All patients showed improved regression coefficients (-0.0214 +/- 0.00166 vs. 0.00236 +/- 0.00895, 1 year before vs. after treatment, p < 0.01). The severity of proteinuria decreased significantly from a mean urine protein/creatinine ratio of 2.9 +/- 1.7 before therapy to 1.1 +/- 0.8 (p < 0.01) at 6 months and 0.8 +/- 0.7(p < 0.01) at 12 months after therapy. Although 7 patients underwent dialysis, the average interval from pulse therapy to dialysis was prolonged from an estimated interval of 1.1 +/- 0.9 years to an actual interval of 4.1 +/- 3.5 years. Six patients showed positive regression coefficients at the last observation (4.1 +/- 3.0 years after therapy). The remaining 7 patients who had not undergone dialysis also showed prolongation of the estimated interval from pulse therapy to dialysis of 5.9 +/- 5.1 years before pulse therapy to 25.7 +/- 20.6 years at the final observation (4.9 +/- 3.5 years after therapy). No serious side effects were observed in any of the patients. CONCLUSION: MP pulse therapy can slow the progression of renal deterioration in patients with active IgAN, even in those patients in whom renal function impairment has set in.

Increased expression of cell adhesion kinase beta in human and rat crescentic glomerulonephritis.

Cell adhesion kinase beta (CAKbeta, also known as Pyk2/CadTK/RAFTK) is the second member of the focal adhesion kinase (FAK) subfamily. We examined the expression of CAKbeta in various human glomerulopathies by immunohistochemistry. Although CAKbeta expression in the normal kidney is confined to the brush border of the proximal tubule with no detectable glomerular staining, we found that glomerular crescents strongly expressed this kinase. Expression of CAKbeta was prominent in cellular crescents but was minimal in fibrocellular or fibrous crescents. Serial section analysis revealed that most CAKbeta-expressing cells were positive for cytokeratin but were negative for CD68 (a macrophage marker), suggesting that CAKbeta was expressed by parietal epithelium in the crescents. We also examined CAKbeta expression in a rat model of crescentic glomerulonephritis induced by anti-glomerular basement membrane antibody. Similar to human nephritis, enhanced expression of CAKbeta in glomerular crescents was apparent. Increased expression of CAKbeta also was confirmed by anti-CAKbeta immunoblotting and by real-time quantitative polymerase chain reaction. Previous studies have shown that CAKbeta is activated by various stimuli regulating cell growth and survival. Although our findings do not determine whether or not increased expression of CAKbeta is a primary event for the development of crescentic glomerulonephritis, further understanding of this pathway may be important to gain novel insights into the factors that promote crescent formation.

Sulfite induces adherence of polymorphonuclear neutrophils to immobilized fibrinogen through activation of Mac-1 beta2-integrin (CD11b/CD18).

Sulfite is a major air pollutant which can cause respiratory tract inflammation characterized by an influx of polymorphonuclear neutrophils (PMN). We have previously shown that human PMN can produce sulfite either spontaneously or in response to stimulation with lipopolysaccharide. We now demonstrate that sulfite activates PMN to adhere to immobilized fibrinogen via the beta2-integrin Mac-1 (CD11b/CD18). Mac-1 expression is not altered by treatment with this agent. Although unaffected by pertussis toxin, sulfite-triggered PMN adhesion was abrogated by pretreating cells with the membrane-impermeant sulfhydryl reagent 5,5'-dithiobis(2-nitrobenzoic acid) (DTNB), a modifier of thiol groups on the cell surface. These results suggest that sulfite-induced PMN adhesion is dependent on a modification of thiols at the cell surface. Given its potent antioxidant and antimicrobial activities, sulfite may act as an endogenous mediator in host defense and/or inflammation.

Thiopurine methyltransferase genotype and phenotype status in Japanese patients with systemic lupus erythematosus.

We investigated the genotypic status of thiopurine methyltransferase (TPMT) polymorphism to evaluate the possible risk of the toxicity of azathioprine (AZA) in 68 patients with systemic lupus erythematosus (SLE). The allele frequency of TPMT mutation in the SLE group (2.9%) was higher than that in 174 Japanese healthy volunteers (1.1%), although it did not reach statistically significant difference (p=0.23). The mean value of TPMT activities in 51 subjects with TPMT*1/*1 was 40% higher than that of 4 subjects with TPMT*1/*3C in SLE group (18.1+/-6.1 nmol/h/ml packed red blood cells (pRBC) versus 13.2+/-3.2 nmol/h/ml pRBC; p=0.11). Two out of 4 SLE patients with TPMT*1/*3C had been treated with AZA, and one patient showed a leucopenia. The TPMT genotyping before AZA treatment is recommended for Japanese SLE patient group to avoid the AZA-induced adverse events, although detection of the patient with low TPMT activity by genotyping is still imperfect.

Comparison of the efficacy of an oral calcitriol pulse or intravenous 22-oxacalcitriol therapies in chronic hemodialysis patients.

BACKGROUND: 1,25-dihydroxy-22-ovavitamin D(3) (22-oxacalcitriol, OCT) was recently introduced commercially as an analogue of 1,25 (OH)(2) vitamin D(3), but one which has less pronounced calcemic activity. METHODS: To examine the efficacy and tolerability of OCT, 46 hemodialysis patients with secondary hyperparathyroidism were randomly assigned to receive either intravenous OCT or oral calcitriol pulse therapies. The patients were monitored for serum calcium, phosphate, intact parathyroid hormone (PTH), and bone alkaline phosphatase (BAP) for 24 weeks. The efficacy of intravenous OCT was also examined in 24 additional patients who were refractory to oral calcitriol pulse therapy. RESULTS: In the randomized trial, intact PTH levels were significantly suppressed within 4 weeks after the initiation of each therapy, and this effect was well maintained thereafter in both treatment groups. While intact PTH was significantly lower at 4 weeks in the calcitriol pulse group than in the OCT group (P = 0.02), no statistical differences were observed during later treatment periods. BAP was reduced equally by each treatment. At 4 weeks (P = 0.02) and thereafter (P = 0.06), serum calcium was higher among calcitriol-treated patients than among those who received OCT treatment. Eight of 24 patients who were refractory to oral calcitriol pulse therapy responded to intravenous OCT. The patients who responded tended to have lower serum intact PTH and phosphorus levels and smaller parathyroid glands at the start of OCT treatment than nonresponders. CONCLUSIONS: OCT is as effective as oral calcitriol pulse therapy in suppressing intact PTH and BAP in chronic hemodialysis patients. It was confirmed that OCT exhibits less calcemic activity than calcitriol. Moreover, under certain conditions, switching to OCT may help in the treatment of hyperparathyroidism, which is refractory to conventional oral calcitriol pulse therapy.

Kikuchi's disease accompanied by lupus-like butterfly rash.

Kikuchi's disease (KD) is a benign and self-limiting lymphadenitis, particularly affecting young women. KD is often associated with fever, arthralgia, and leukopenia, features also found in systemic lupus erythematosus (SLE). Lymphadenitis associated with SLE is indistinguishable from that in KD, and the association of KD and SLE has been previously reported. We describe a case of KD who developed a typical butterfly rash, reminiscent of SLE. However, histological and laboratory findings excluded the diagnosis of SLE. This case emphasizes that careful differential diagnosis between KD and SLE is required.

Interaction between p230 and MACF1 is associated with transport of a glycosyl phosphatidyl inositol-anchored protein from the Golgi to the cell periphery.

The molecular basis by which proteins are transported along cytoskeletal tracts from the trans-Golgi network (TGN) to the cell periphery remains poorly understood. Previously, using human autoimmune sera, we identified and characterized a TGN protein, p230/Golgin-245, an extensively coiled-coil protein with flexible amino- and carboxyl-terminal ends, that is anchored to TGN membranes and TGN-derived vesicles by its carboxyl-terminal GRIP domain. To identify molecules that interact with the flexible amino-terminal end of p230, we used this domain as bait to screen a human brain cDNA library in a yeast two-hybrid assay. We found that this domain interacts with the carboxyl-terminal domain of MACF1, a protein that cross-links microtubules to the actin cytoskeleton. The interaction was confirmed by co-immunoprecipitation, an in vitro binding assay, double immunofluorescence images demonstrating overlapped localization in HeLa cells, and co-localization of FLAG-tagged constructs containing the interacting domains of these two proteins with their endogenous partners. Expression in HeLa cells of FLAG-tagged constructs containing the interacting domains of p230 and MACF1 disrupted transport of the glycosyl phosphatidyl inositol-anchored marker protein conjugated with yellow fluorescent protein (YFP-SP-GPI), while trafficking of the transmembrane marker protein, vesicular stomatitis virus glycoprotein conjugated with YFP (VSVG3-GL-YFP), was unaffected. Our results suggest that p230, through its interaction with MACF1, provides the molecular link for transport of GPI-anchored proteins along the microtubule and actin cytoskeleton from the TGN to the cell periphery.

Salazosulfapyridine-induced remission of Felty's syndrome along with significant reduction in neutrophil-bound immunoglobulin G.

Felty's syndrome is characterized by neutropenia, splenomegaly, and leg ulcers in patients with rheumatoid arthritis. The pathogenesis of the neutropenia is an immune-mediated process that involves immune complexes, antineutrophil antibodies, and abnormal white cell kinetics. We prescribed salazosulfapyridine to a 65-year-old woman with this syndrome. The neutropenia improved along with a reduction in neutrophil-bound IgG, demonstrated by flow cytometric analysis. Salazosulfapyridine may be of benefit for the treatment of Felty's syndrome, and flow cytometry can be used to monitor disease activity and therapeutic efficacy.

Sulfite is generated from PAPS by activated neutrophils.

We previously reported that neutrophils produce sulfite in response to stimulation with lipopolysaccharide, and sulfite production is dependent on inorganic sulfate contained in culture media. Microorganisms such as yeast assimilate sulfate, during which process sulfite is generated by reduction of 3'-phosphoadenosine 5'-phosphosulfate (PAPS), an activated sulfate donor. However, little is known about how sulfite is produced in mammalian cells. In the current study, we demonstrated that chlorate, a specific inhibitor for PAPS synthesis, significantly suppressed production of sulfite by activated neutrophils obtained from rat peritoneal cavity that had been injected with glycogen to induce inflammation. Addition of excess amounts of PAPS could partially overcome the inhibitory effect of chlorate. Moreover, sulfite production from PAPS was clearly demonstrated in the cytosolic fraction of activated neutrophils. These findings strongly suggest that sulfite is generated, at least in part, from PAPS by activated neutrophils.

Human platelets stimulate mesangial cells to produce monocyte chemoattractant protein-1 via the CD40/CD40 ligand pathway and may amplify glomerular injury.

Platelets are thought to play an important role in the initiation and the progression of a variety of glomerulonephritides. This study examined whether platelets induce production of monocyte chemoattractant protein-1 (MCP-1), a chemokine involved in leukocyte recruitment and glomerular injury, by cultured human mesangial cells (MC). To this end, platelets isolated from normal human donors were cocultured with MC at various ratios. MCP-1 synthesis was evaluated by quantitative real-time PCR and enzyme-linked immunosorbent assay. Platelets at 1:100 ratio (MC to platelets) induced an approximately 20-fold increase in mesangial MCP-1 mRNA and protein expression through an obligatory cell-to-cell contact-dependent mechanism. Importantly, blockade of the CD40/CD40 ligand (CD40L) pathway with neutralizing antibodies decreased MCP-1 production by approximately 60%. It was confirmed that CD40 was functionally expressed on MC. Gel-shift assays and inhibitors of phosphorylation were used to demonstrate that activation of p38 mitogen-activated protein kinase, protein tyrosine kinases, and nuclear factor-kappa B activation were essential for MCP-1 production. These data indicate that platelet/MC contact stimulates the production of MCP-1 and may contribute to glomerular inflammatory responses by recruiting leukocytes from the peripheral blood.