Tacrolimus Induction Therapy for Nephrotic Syndrome Caused by Minimal Mesangial Lupus Nephritis with Lupus Podocytopathy: A Case-Based Review.

BACKGROUND Nephrotic syndrome caused by minimal mesangial lupus nephritis is considered rare. Nephrotic syndrome can be caused by minimal mesangial lupus nephritis with diffuse epithelial foot-process effacement and lupus podocytopathy. CASE REPORT A 23-year-old Japanese woman diagnosed with mixed connective tissue disease was admitted because of weight gain and generalized edema for 2 weeks prior to admission. She had butterfly-shaped erythema on her cheeks, proteinuria, leukocytopenia with lymphocytopenia, and hypoalbuminemia. She was positive for antinuclear antibodies, and specific autoantibodies were only positive for the ribonucleoprotein (RNP) antigen. She was diagnosed with systemic lupus erythematosus. Renal biopsy showed minor glomerular abnormalities, and immunofluorescence revealed peripheral deposits of IgM and complement C3c. Electron microscopy revealed diffuse podocyte foot-process effacement of >80% of the capillary loop surfaces, with only a few subendothelial deposits. Consequently, we diagnosed minimal mesangial lupus nephritis with lupus podocytopathy. On hospital day 4, we administered 1000 mg/day of methylprednisolone for 3 days, followed by prednisolone 50 mg/day, but proteinuria persisted. On day 12, we administered tacrolimus (3 mg/day). Proteinuria improved and then disappeared on day 17. Prednisolone was gradually tapered and stopped after 3 years, although tacrolimus 3 mg/day was continued. No flare-up was observed 4 years after admission. CONCLUSIONS Tacrolimus showed good efficacy in this case of minimal mesangial lupus nephritis with lupus podocytopathy. Prospective and randomized controlled trials should be conducted to demonstrate the efficacy of tacrolimus for this indication.

Serum levels of galectin-3 in idiopathic inflammatory myopathies: a potential biomarker of disease activity.

OBJECTIVES: Galectin-3 is involved in various biological activities, including immune activations and fibrosis. Idiopathic inflammatory myopathies (IIMs) are autoimmune diseases of unknown aetiology, often complicated by interstitial lung disease (ILD). The aim of this study was to evaluate the expression of galectin-3 in sera and tissues of patients with IIM and assess the associations of galectin-3 with patient characteristics and disease activity. RESULTS: Serum galectin-3 levels were significantly higher in IIM patients than in healthy controls. The serum galectin-3 levels positively correlated with serum levels of inflammatory markers and proinflammatory cytokines/chemokines and the Myositis Intention-to-Treat Activity Index. Stratification analysis revealed that patients with IIM-associated ILD (IIM-ILD) had significantly higher levels of serum galectin-3 than those without IIM-ILD. In addition, patients with acute/subacute interstitial pneumonia had significantly higher levels of serum galectin-3 than those with chronic interstitial pneumonia. Furthermore, serum galectin-3 levels in IIM-ILD patients correlated with the radiological assessments of parenchymal lung involvement and treatment response. Immunohistochemical analysis revealed that galectin-3 was expressed in inflammatory cells of myositis and dermatitis sections, whereas in ILD sections, galectin-3 was expressed in interstitial fibrosis and inflammatory cells. CONCLUSION: Galectin-3 may be involved in the pathogenesis of inflammatory and fibrotic conditions in IIM and can serve as a potential biomarker of disease activity, especially in patients with IIM-ILD.

Predictive factors for sustained remission with stratification by myositis-specific autoantibodies in adult polymyositis/dermatomyositis.

OBJECTIVE: The aim of this study was to clarify predictive factors for sustained remission in adult patients with PM/DM, particularly focusing on stratification by myositis-specific autoantibodies (MSAs). METHODS: A total of 162 adult patients with PM/DM who were followed up for >1 year after diagnosis were retrospectively enrolled. MSAs were evaluated comprehensively in 102 patients whose sera were available. Sustained remission was defined as no evidence of disease activity (active skin rash, active myositis or active interstitial lung disease) for longer than a 6-month continuous period while undergoing myositis therapy or no medication. Clinical data were reviewed in patients' medical charts. RESULTS: The sustained remission rate for all patients was 58% during the median follow-up period at 4 years. With regard to MSAs, the achievement rate of sustained remission among MSA-negative patients was significantly higher than that for patients with anti-aminoacyl-tRNA synthetase (P = 0.004), anti-melanoma differentiation-associated gene 5 (P = 0.037) or anti-transcriptional intermediary factor 1-γ (P = 0.013) antibodies. MSA-negative status (odds ratio 5.84, P = 0.009) and absence of severe muscle weakness requiring assistance at diagnosis (odds ratio 43.6, P < 0.001) were independent factors associated with sustained remission in multivariate analysis. Cumulative remission rates were significantly higher (P < 0.001) in patients with both the MSA-negative status and absence of severe muscle weakness at diagnosis than the others. CONCLUSION: MSA-negative status and the absence of severe muscle weakness requiring assistance at diagnosis are independent predictive factors for sustained remission in adult PM/DM patients.

Unclassified Vasculitis with Episcleritis, Thrombophlebitis, Deep Vein Thrombosis, Pulmonary Vasculitis, and Intracranial Vasculitis: An Autopsy Case Report.

BACKGROUND Systemic vasculitides constitute heterogenous conditions affecting many organs and systems through blood vessel inflammation. Although there are some classifications for vasculitis, several vasculitides are "unclassified" because they cannot be clearly assigned to one of the known entities. CASE REPORT We report an autopsy case of a 67-year-old Japanese man who presented with fever, ocular pain, erythema, chest pain, and headache. The disease caused episcleritis, thrombophlebitis, extensive deep vein thrombosis, multiple pulmonary nodules and masses, hypertrophic pachymeningitis, and hyper-intensity areas in brain parenchyma on magnetic resonance images. Histopathology of the pulmonary nodule confirmed vasculitis affecting medium-to-small veins and arteries without necrotizing vasculitis or granulomatous inflammation. We diagnosed the patient with unclassified vasculitis based on the clinicopathological characteristics. Steroids in combination with immunosuppressants were used, but the disease was refractory and relapsing. The disease activity was eventually controlled with rituximab, but the patient died of bronchopneumonia. On autopsy, lung and brain findings indicated healed vascular inflammation. CONCLUSIONS This is the first case report of unclassified vasculitis, which is characterized as medium-to-small-sized arteritis and phlebitis, causing episcleritis, thrombophlebitis, deep vein thrombosis, pulmonary vasculitis, and intracranial vasculitis. The clinical conditions share some similarities with granulomatosis with polyangiitis and Behçet's disease; however, they meet no classification criteria of any specific vasculitis. More cases need to be analyzed to confirm our findings.

Scleroderma renal crisis with coexisting segmental arterial mediolysis presenting as intraperitoneal bleeding: a case report.

BACKGROUND: Segmental arterial mediolysis is a rare nonarteriosclerotic and noninflammatory vascular disease that may cause intraperitoneal bleeding. Scleroderma renal crisis is a rare complication of systemic sclerosis, leading to severe hypertension and renal dysfunction. To the best of our knowledge, this is the first reported case of a patient with concurrent systemic sclerosis with scleroderma renal crisis and pathologically confirmed segmental arterial mediolysis. CASE PRESENTATION: We report a case of a 68-year-old Chinese woman diagnosed with systemic sclerosis who was found to have coexisting segmental arterial mediolysis. She presented with back pain, and massive intraperitoneal bleeding was detected by computed tomography. She underwent laparotomy, and the bleeding was found to originate from the gastroepiploic artery. The pathological examination demonstrated gastroepiploic arterial dissection caused by segmental arterial mediolysis. After surgery, she developed severe hypertension with hyperreninemia and progressive renal dysfunction. Given the risk factors of corticosteroid administration and the presence of anti-ribonucleic acid polymerase III antibody, she was diagnosed with scleroderma renal crisis. The patient was proved to have a very rare case of coexisting scleroderma renal crisis and segmental arterial mediolysis. CONCLUSIONS: There is no known etiological connection between segmental arterial mediolysis and systemic sclerosis or scleroderma renal crisis, but it is possible that coexisting segmental arterial mediolysis and scleroderma renal crisis may have interacted to trigger the development of the other in our patient.

Rheumatoid factor is correlated with disease activity and inflammatory markers in antineutrophil cytoplasmic antibody-associated vasculitis.

BACKGROUND: Some patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) also have positivity of rheumatoid factor (RF). However, the clinical significance of this occurrence remains unknown in AAV patients. The aim of this study was to clarify an association between the presence of RF and clinical features in patients with AAV. RESULTS: Forty-seven patients diagnosed with AAV who were not complicated with RA were enrolled in this study. We compared clinical manifestations of AAV between an RF-positive subset (n = 29) and an RF-negative subset (n = 18). The Birmingham Vasculitis Activity Score (BVAS) was higher (P = 0.026) in the RF-positive subset than in the RF-negative subset. The levels of CRP and ESR were higher in the RF-positive patients (P = 0.020 and P = 0.007, respectively) compared to the RF-negative subset. IgM-RF titers were significantly correlated with the BVAS (r = 0.50, P = 0.0004). In addition, the IgM-RF titers had significant correlations with the levels of CRP (r = 0.41, P = 0.004), ESR (r = 0.39, P = 0.016), IgM (r = 0.36, P = 0.016) and IgG (r = 0.37, P = 0.015). The frequency of commencement of dialysis therapy, usage of mechanical ventilation and mortality were higher in the RF-positive subset than in the RF-negative subset. CONCLUSIONS: In patients with AAV, RF titers were significantly correlated with disease activity and the levels of inflammatory markers. The presence of RF could be a poor prognostic factor in patients with AAV.

Synovitis-acne-pustulosis-hyperostosis-osteitis (SAPHO) Syndrome with Significant Bilateral Pleural Effusions.

We herein report a rare case of a 66-year-old woman who had synovitis-acne-pustulosis-hyperostosis-osteitis (SAPHO) syndrome with marked sternal osteitis and bilateral pleural effusions. SAPHO syndrome was diagnosed based on the characteristic features of a hyperostotic sternum and thoracic spine. The inflammatory changes of sternal osteitis and involvement of the adjacent soft tissue were assumed to be the cause of the pleural effusions. The effusions decreased during the natural course of the disease and resolved after methotrexate therapy. The pain dramatically decreased with oral tramadol. Physicians should consider the possibility of SAPHO syndrome in patients with anterior chest pain and pleural effusions.

Successful Tocilizumab Therapy for Macrophage Activation Syndrome Associated with Adult-Onset Still's Disease: A Case-Based Review.

We report the case of a 71-year-old Japanese woman with adult-onset Still's disease (AOSD) in whom macrophage activation syndrome (MAS) developed despite therapy with oral high-dose prednisolone and intravenous methylprednisolone pulse therapy twice. She was successfully treated with tocilizumab (TCZ). Soon afterward, her fever ceased and high levels of both ferritin and C-reactive protein levels decreased. Her course was complicated by disseminated intravascular coagulation, cytomegalovirus infection, and Pneumocystis jirovecii pneumonia. After these were resolved, AOSD-associated MAS was well controlled. She was discharged on hospital day 87. Although biologics such as TCZ are becoming established for the treatment of AOSD, there is no recommended therapy for AOSD-associated MAS. Several biologics have been tried for this complication, but their efficacy and safety remain controversial. We reviewed reported cases of AOSD-associated MAS successfully treated with various biologics. TCZ initiation after adequate nonselective immunosuppressive therapy, such as methylprednisolone pulse therapy or a prednisolone-based combination of immunosuppressants, can be an effective treatment for AOSD-associated MAS. On the other hand, biologics given after insufficient immunosuppressive therapy may cause MAS. A strategy combining adequate immunosuppression and a biologic could be safe if special attention is given to adverse events such as opportunistic infections or biologic-associated MAS.

Familial Mediterranean fever: genotype-phenotype correlations in Japanese patients.

Familial Mediterranean fever (FMF) is an autoinflammatory disease caused by MEditerranean FeVer gene (MEFV) mutations. In Japan, patients with FMF have been previously reported, including a mild or incomplete form. Several factors are presumed to contribute to the variable penetrance and to the phenotypic variability of FMF. We conducted the current study to investigate the correlation of variable clinical presentations and MEFV genotypic distributions in Japanese FMF patients.We analyzed demographic, clinical, and genetic data for 311 FMF patients enrolled in the study. Clinically, we classified FMF into 2 phenotypes: 1) the "typical" form of FMF, and 2) the "atypical" form of FMF according to the Tel Hashomer criteria. Patients with the typical FMF phenotype had a higher frequency of febrile episodes, a shorter duration of febrile attacks, more frequent thoracic pain, abdominal pain, a family history of FMF, and MEFV exon 10 mutations. Conversely, patients with the atypical FMF phenotype had a lower frequency of fever episodes and more frequent arthritis in atypical distribution, myalgia, and MEFV exon 3 mutations. Multivariate analysis showed that the variable associated with typical FMF presentation was the presence of MEFV exon 10 mutations. Typical FMF phenotype frequencies were decreased in patients carrying 2 or a single low-penetrance mutations compared with those carrying 2 or a single high-penetrance mutations (M694I), with an opposite trend for the atypical FMF phenotype. In addition, patients having more than 2 MEFV mutations had a younger disease onset and a higher prevalence of thoracic pain than those carrying a single or no mutations. Thus, MEFV exon 10 mutations are associated with the more typical FMF phenotype. In contrast, more than half of the Japanese FMF patients without MEFV exon 10 mutations presented with an atypical FMF phenotype, indicating that Japanese FMF patients tend to be divided into 2 phenotypes by a variation of MEFV mutations.

The efficacy of mizoribine for the treatment of rheumatoid arthritis and its correlation with renal function.

OBJECTIVES: To evaluate the correlation between the efficacy of mizoribine (MZR) and the factors that might effect MZR concentration: renal function and dosage and administration of MZR in patients with rheumatoid arthritis (RA). METHODS: The efficacy of MZR treatment was prospectively evaluated in 97 RA regardless of dosage, at the 14 participated institutions. The Disease Activity Score 28-CRP3 was used to assess RA activity. The renal function was evaluated based on the serum creatinine and serum cystatin-C (Cys-C). The patients were followed up for 24 weeks. RESULTS: The patients with a mean age 66.2 years included 18 male. The renal function assessment showed increased creatinine in 16.4% of patients and increased Cys-C in 54.5%, suggesting the higher sensitivity of Cys-C to detect impaired renal function than creatinine. In patients with good or moderate response according to the European League against Rheumatism classification criteria, the Cys-C was significantly higher compared with those with no response. MZR treatment was significantly more effective in patients with an arithmetic product of the single MZR dose used and Cys-C of 179 or more. CONCLUSIONS: The efficacy of MZR may increase in proportion to its single dose, or increased Cys-C level in patients with impaired renal function.

[A case of isolated polyarteritis nodosa appeared in bilateral epididymides with asynchronous onset].

A 78-year-old man visited a hospital with a complaint of painful and swelling scrotums for 7 months. Although left epididymitis was suspected, antibiotic and non-steroidal anti-inflammatory drugs (NSAIDs) had no effects. After visit to our department, we performed left orchiectomy for the diagnosis and pain control. Pathological examinations showed necrotizing vasculitis in the epididymis, so he was diagnosed as polyarteritis nodosa (PN) in the left epididymis. He had no systemic symptoms, which made the diagnosis of isolated PN. One and a half years after operation, he felt the same pain in the right scrotum. We performed right orchiectomy. Pathological findings showed necrotizing vasculitis in the epididymis. Blood examinations revealed negative for myeloperoxidase anti-neutrophil cytoplasmic antibody (ANCA) and proteinase 3-ANCA, and computed tomography revealed that other organs were not involved. One year later, he had no recurrence.

Rapidly progressive respiratory failure in mixed connective tissue disease: report of an autopsy case.

A 64-year-old woman presented with exertional dyspnea. The case was diagnosed as mixed connective tissue disease (MCTD) due to presence of swollen fingers, Raynaud's phenomenon, muscle weakness, positive anti-U1RNP antibody, pericarditis and interstitial pneumonia. Although the histology from a transbronchial lung biopsy (TBLB) indicated organizing pneumonia, corticosteroid therapy was postponed for two months at the patient's request. She died 8 weeks later from acute progressive interstitial pneumonia in spite of the administration of intravenous cyclophosphamide combined with prednisolone. The autopsy revealed exudative and organizing diffuse alveolar damage (DAD). Previous reports have shown that DAD is an extremely rare pulmonary complication in MCTD. This report presents a case of MCTD with acute respiratory failure. This case thus suggests that this therapy should be administered as soon as possible.

Possible clinical significance of serum soluble interleukin-2 receptor level in primary bone lymphoma: two case reports.

In two patients with primary bone lymphoma (PBL) treated in our clinic, serum levels of soluble interleukin-2 receptor (sIL-2R) reflected the clinical course. In both cases, sIL-2R levels were high before treatment and normalized with the therapeutic effects of chemotherapy, coinciding with the changes in lactate dehydrogenase levels and radiographic findings. Adding to the recently reported results of the diagnostic ability of sIL-2R in PBL, our case study highlights the clinical significance of serum sIL-2R levels as a tumor marker in PBL cases.

Prognostic significance of HLA class I expression in Ewing's sarcoma family of tumors.

BACKGROUND: Ewing's sarcoma family of tumors (ESFT) is one of the most malignant groups of tumors in young people. Human leukocyte antigen (HLA) class I displays endogenously processed peptides to CD8+ T lymphocytes and has a key role for host immune surveillance. In ESFT, the investigation concerning both HLA class I expression and T-cell infiltration has yet to be reported. METHODS: Biopsy specimens from 28 ESFT patients were evaluated by immunohistochemistry with the anti-HLA class I monoclonal antibody (mAb) EMR8-5 and anti-CD8 mAb, respectively. RESULTS: Expression of HLA class I was negative in 10 tumors and down-regulated in 22 tumors. The status of CD8+ T cell infiltration was closely associated with the expression levels of HLA class I. ESFT patients with down-regulated or negative expression of HLA class I showed significantly poorer survival than the rest of the patients. CONCLUSIONS: Our results suggested that CD8+ T cell-mediated immune response restricted by HLA class I might play an important role in immune surveillance of ESFT, and we revealed for the first time that the status of HLA class I expression affects the survival of the patients with ESFT.

Association of STAT4 with susceptibility to rheumatoid arthritis and systemic lupus erythematosus in the Japanese population.

OBJECTIVE: STAT4 encodes a transcriptional factor that transmits signals induced by several key cytokines, and it might be a key molecule in the development of autoimmune diseases. Recently, a STAT4 haplotype was reported to be associated with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) in Caucasian populations. This was replicated in a Korean RA population. Interestingly, the degree of risk of RA susceptibility with the STAT4 haplotype was similar in the Caucasian and Korean populations. The present study was undertaken to investigate the effect of STAT4 on susceptibility to RA and SLE in the Japanese. METHODS: We performed an association study using 3 independent Japanese RA case-control populations (total 3,567 cases and 2,199 controls) and 3 independent Japanese SLE populations (total 591 cases). All samples were genotyped using the TaqMan fluorogenic 5' nuclease assay for single-nucleotide polymorphism (SNP) rs7574865, which tags the susceptibility haplotype. The association of the SNP with disease susceptibility in each case-control study was calculated using Fisher's exact test, and the results were combined, using the Mantel-Haenszel method, to obtain combined odds ratios (ORs). RESULTS: We observed a significant association of the STAT4 polymorphism with susceptibility to both RA and SLE. The combined ORs for RA and SLE, respectively, were 1.27 (P = 8.4 x 10(-9)) and 1.61 (P = 2.1 x 10(-11)) for allele frequency distribution; these ORs were quite similar to those previously observed in the Caucasian population. CONCLUSION: We conclude that STAT4 is associated with RA and SLE in the Japanese. Our results indicate that STAT4 is a common genetic risk factor for autoimmune diseases, with similar strength across major racial groups.

C4B deficiency associated with membranoproliferative glomerulonephritis.

A 10-year-old girl was noted to have microscopic hematuria and proteinuria in 1986. As her urinary abnormalities were persistent, she underwent a renal biopsy on 4 occasions until 2003. Although the appearances of the renal biopsies were strongly suspicious of systemic lupus erythematosus, she never exhibited specific autoantibodies or distinctive symptoms. She received corticosteroid therapy and the urinary findings responded. The 4th component of complement remained low during the period of the observation. Both genotyping and allotyping analysis revealed complete C4B deficiency. Some case reports have mentioned renal disease associated with C4B deficiency and we consider the nephropathy in this case to be related to the C4B deficiency.