Yoshito Tsukada

Adult Still's disease as a paraneoplastic manifestation of breast cancer

We treated a patient who developed symptoms and findings indistinguishable from those of adult Stills disease as a manifestation of metastatic breast cancer 7 years after treatment for a stage 1 tumor. Although clinical features fulfilled diagnostic criteria for adult Stills disease, examination of a bone marrow biopsy specimen indicated that the apparent adult Stills disease was a paraneoplastic manifestation associated with diffuse marrow infiltration by breast cancer. The fever and polyarthralgia resolved with administration of prednisolone, and antiestrogen therapy with tamoxifen citrate was also started.We treated a patient who developed symptoms and findings indistinguishable from those of adult Stills disease as a manifestation of metastatic breast cancer 7 years after treatment for a stage 1 tumor. Although clinical features fulfilled diagnostic criteria for adult Stills disease, examination of a bone marrow biopsy specimen indicated that the apparent adult Stills disease was a paraneoplastic manifestation associated with diffuse marrow infiltration by breast cancer. The fever and polyarthralgia resolved with administration of prednisolone, and antiestrogen therapy with tamoxifen citrate was also started.

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.

FK506, a novel immunosuppressive agent, induces antigen-specific immunotolerance in active Heymann's nephritis and in the autologous phase of Masugi nephritis.

FK506 is a new drug which has potent immunosuppressive activity. We studied its immunosuppressive effects on active Heymanns nephritis and the aulologous phase of Masugi nephritis. The induction of active Heymanns nephritis was completely suppressed by FK506 injected simultaneously with the antigen (day 1) and then daily for 14 days at a dose of 0.64 mg/kg per day or more. With a lower dosage of this agent, antibody production and immune deposits in the glomerular basement membrane occurred despite the suppression of proteinuria. Similar results were obtained in rats on other treatment schedules (1–7 days or day 8–14 days duration). Rats that were prevented from developing Heymanns nephritis or the autologous phase of nephrotoxic antiserum nephritis by FK506 treatment exhibited a suppressed immune response to a second immunization of the same antigen even 4 weeks after cessation of drug administration; however, they developed antibodies when inoculated with other antigens. Rat peripheral leucocyte counts and scrum creatinin were not remarkably influenced by the administration of FK506. These results indicate that FK506 has potent immunosuppressive activity, and it is suggested that it is able to induce an antigen‐specific immunotolerance.

Extracorporeal membrane oxygenation for the management of respiratory failure due to ANCA-associated vasculitis.

We present here two patients whose near fatal respiratory distress was caused by pulmonary hemorrhage, and who were treated successfully by extracorporeal membrane oxygenation (ECMO). The underlying disease was antineutrophil cytoplasmic antibody (ANCA)-associated systemic vasculitis. They were initially treated with methylprednisolone pulse therapy along with cyclophosphamide. However, their respiratory failure progressed with a low PaO2/FiO2 ratio (<100 mmHg) despite mechanical ventilation, and ECMO was initiated. After several days, the pulmonary hemorrhage subsided, and the patients were weaned successfully from ECMO. We suggest that ECMO may be used to manage life-threatening pulmonary hemorrhage in patients suffering from ANCA-associated systemic vasculitis.We present here two patients whose near fatal respiratory distress was caused by pulmonary hemorrhage, and who were treated successfully by extracorporeal membrane oxygenation (ECMO). The underlying disease was anti-neutrophil cytoplasmic antibody (ANCA)-associated systemic vasculitis. They were initially treated with methylprednisolone pulse therapy along with cyclophosphamide. However, their respiratory failure progressed with a low PaO2/FiO2 ratio (< 100 mmHg) despite mechanical ventilation, and ECMO was initiated. After several days, the pulmonary hemorrhage subsided, and the patients were weaned successfully from ECMO. We suggest that ECMO may be used to manage life-threatening pulmonary hemorrhage in patients suffering from ANCA-associated systemic vasculitis.

Novel variant of p230 trans-Golgi network protein identified by serum from Sjögren's syndrome patient.

Trans-Golgi network (TGN) protein p230 is a peripheral membrane protein associated with the cytoplasmic face of the TGN. TGNp230 is an extensively coiled-coil protein with flexible amino- and carboxyl-terminal ends, associates with non-clathrin-coated vesicles arising from the TGN, and is implicated in vesicle biogenesis. Here we used an autoimmune serum from a patient with S ogrens syndrome to clone partial cDNAs from a human hepatoma HepG2 expression library. The partial cDNAs encoded a novel amino-terminal splice variant of TGNp230. Specific reactivity of the autoimmune serum for p230 is supported by immunofluorescene staining of the Golgi apparatus, immunoblotting of a > 200-kDa HeLa cell protein, and reactivity with a bacterially expressed GST-p230 fusion protein. The alternative splicing occurs within the first proline-rich domain of p230. It comprises a deletion of 30 bp followed immediately by an additional 66 bp absent in the published sequence. RT-PCR analysis indicated that the splicing occurs independently of previously reported carboxyl-terminal splicing, and that this novel splice variant is more frequent than the previously reported p230. The novel splice variant of p230 is also located at the TGN. We propose that p230 splice variants may be implicated in selection of cargo molecules for vesicles arising from the TGN.

Treatment of adult Still's disease with dexamethasone, an alternative to prednisolone.

We successfully treated three cases of adult Stills disease (ASD) with dexamethasone. High dose prednisolone, which was initially used to treat these patients, failed to remit the disease in all cases. Although they were resistant to prednisolone, all these patients had remarkable improvements in clinical and laboratory findings after switching to an equivalent dose of dexamethasone. We propose using dexamethasone as an alternative for treating ASD before adding immunosuppressants or disease modifying anti-rheumatic drugs (DMARD), when prednisolone therapy does not suppress disease activity sufficiently.We successfully treated three cases of adult Stills disease (ASD) with dexamethasone. High dose prednisolone, which was initially used to treat these patients, failed to remit the disease in all cases. Although they were resistant to prednisolone, all these patients had remarkable improvements in clinical and laboratory findings after switching to an equivalent dose of dexamethasone. We propose using dexamethasone as an alternative for treating ASD before adding immunosuppressants or disease modifying anti-rheumatic drugs (DMARD), when prednisolone therapy does not suppress disease activity sufficiently.

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

Background1,25-dihydroxy-22-ovavitamin D3 (22-oxacalcitriol, OCT) was recently introduced commercially as an analogue of 1,25 (OH)2 vitamin D3, but one which has less pronounced calcemic activity.MethodsTo 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.ResultsIn 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.ConclusionsOCT 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.

Successful Treatment of Patients with Rheumatic Disorders and Acquired Factor VIII Inhibitors with Cyclophosphamide and Prednisolone Combination Therapy: Two Case Reports

Acquired haemophilia associated with autoimmune disorders can be fatal and has been reported to be refractory to steroid therapy alone. We report two cases of female patients, aged 24 years and 54 years, with acquired haemophilia caused by factor VIII inhibitors. Underlying diseases were systemic lupus erythematosus in the 24-year-old patient and rheumatoid arthritis in the 54-year-old patient. Both conditions were nearly quiescent when the patients manifested haemorrhagic diathesis. In response to combination therapy with prednisolone and cyclophosphamide, coagulation abnormalities were resolved together with complete elimination of factor VIII inhibitors in both patients. Thus, combination therapy with alkylating agents may be recommended as initial therapy for the management of autoimmune patients with factor VIII inhibitors.

A major pathogenic antigen of Heymann nephritis is present exclusively in the renal proximal tubule brush border—studies with a monoclonal antibody against pronase‐digested tubular antigen

We have isolated a nephritogenic 120‐kD antigen from rat renal tubule brush border that induces rat Heymann nephritis. A MoAb that recognized this antigen reacted exclusively with the brush border on indirect immunofluorescence and immunoelectron microscopy. Rabbit antiserum against this antigen also reacted exclusively with the brush border. With the injection of this antiserum, rabbit IgG became detectable along the glomerular basement membrane (GBM) after 3 days. Our 120‐kD antigen was shown to have a close relationship with gp330 based on the following: (i) this antigen can induce active Heymann nephritis as gp330: (ii) our MoAb reacted with the immune deposits of nephritic kidneys induced not only by the 120‐kD antigen but also by gp330, and conversely, rabbit antiserum against gp330 reacted with those induced by the 120‐kD antigen as well as gp330; and (iii) by immunoblotting, polyclonal antibodies against the 120‐kD antigen reacted with gp330 and polyclonal antibodies against gp330 reacted with the 120‐kD antigen. These observations indicate that antigen present exclusively in the brush border can induce active Heymann nephritis, and the common antigenic determinants shared by brush border and the coated pits of glomerular epithelium may not be a prerequisite to induce nephritis. A more precise relationship between the 120‐kD antigen and reported C14 fusion protein or 40‐kD α2MRAP remains to be established.

Nephrotic Syndrome Associated with Liver Metastasis of Rectal Cancer

Keiju Hiromura MD, Third Department of Internal Medicine, Gunma University School of Medicine, Maebashi 371 (Japan) Dear Sir, The most common renal lesion associated with carcinoma is membranous nephrop-athy [1]. We present an unusual case of non-membranous nephrotic syndrome associated with liver metastasis of a rectal cancer. A 66-year-old Japanese man was admitted to the surgical ward on September 17, 1992, because of edema of the lower extremities. His medical history revealed that a rectal cancer, i.e., a moderately differentiated adenocarcinoma, had been resected on October 7, 1991. Although the serum tumor markers CA19-9 and carcinoembryonic antigen (CEA) were mildly increased, abdominal CT scan and ultrasonography initially revealed no evidence of relapse or of metastasis of the rectal cancer. The nephrotic syndrome was diagnosed, and prednisolone, 30 mg daily for 1 month, was administered without improvement. The patient was referred from the surgical to the medical ward on November 24, 1992. Edema of face and lower extremities was present. Daily urinary protein excretion was 15-25 g without occult blood or sugar. Blood urea nitrogen was 58 mg/dl, creatinine 1.6 mg/dl (142 μmol/l), total cholesterol 279 mg/dl, total protein 4.3 g/dl, albumin 2.3 g/dl, aspartate aminotransferase 36 IU/1, alanine aminotransferase 29IU/1, alkaline phosphatase 147 IU/1 and creatinine clearance 35.4 ml/min. A renal biopsy was performed on November 26, 1992 (yield 22 glo-meruli per specimen). Eleven glomeruli showed minor abnormalities: 3 showed mild to moderate segmental mesangial proliferation: 2 showed segmental mesangiolysis, and 5 were completely sclerosed (fig. 1). Immunofiuorescent study revealed no significant deposition of immunoglobulins or complements. Electron microscopy demonstrated the effacement of foot processes of the epithelial cells. No electron-dense deposits were detected in the glomerular basement membrane (fig. 2). The dose of prednisolone was increased from 30 to 60 mg daily on December 2, 1992. Nevertheless, the intravenous administration of albumin and diuretics was required to maintain sufficient urine output.