Hypertrophic pachymeningitis associated with antineutrophil cytoplasmic antibody-associated vasculitis: a case series of 15 patients.

OBJECTIVE: We aimed to describe the clinical characteristics and treatment course of hypertrophic pachymeningitis (HPM) in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). METHODS: We retrospectively analysed 15 patients (11 men and four women). HPM was diagnosed based on thickening and enhancing of the brain and/or spinal dura mater on gadolinium-enhanced magnetic resonance imaging (MRI) T1 sequence. RESULTS: The median age at HPM onset was 60 years. Headache and cranial nerve impairment were observed in 14 and 10 patients, respectively. Otitis media and/or mastoiditis were found as complications of AAV in 11 patients. Fourteen patients were classified as having granulomatosis with polyangiitis (GPA). Single-positive myeloperoxidase-ANCA, single-positive proteinase 3-ANCA, and double-positive ANCA were identified in seven patients, five patients, and one patient, respectively. With MRI, thickening of the dura mater in the cranial fossa and tentorium cerebelli was found in 10 and eight patients, respectively. For remission induction, all patients were treated with corticosteroids, and immunosuppressants were added in 10 patients. Dura mater thickening partially improved in all patients, and cranial neuropathy completely remitted in eight patients. In a median follow-up of 43 months, four patients had HPM relapse and underwent reinduction therapy. All six patients treated with cyclophosphamide at initial therapy did not relapse. CONCLUSIONS: HPM was mostly associated with patients with GPA with otitis media and/or mastoiditis having either type of ANCA serology. Treatment with corticosteroids with or without immunosuppressants was effective. However, HPM relapse occasionally occurred, especially when cyclophosphamide was not used in initial treatment.

The correlation of urinary podocytes and podocalyxin with histological features of lupus nephritis.

Objectives The objective of this study was to test the correlation of urinary podocyte number (U-Pod) and urinary podocalyxin levels (U-PCX) with histology of lupus nephritis. Methods This was an observational, cross-sectional study. Sixty-four patients were enrolled: 40 with lupus nephritis and 24 without lupus nephritis (12 lupus nephritis patients in complete remission and 12 systemic lupus erythematosus patients without lupus nephritis). Urine samples were collected before initiating treatment. U-Pod was determined by counting podocalyxin-positive cells, and U-PCX was measured by sandwich ELISA, normalized to urinary creatinine levels (U-Pod/Cr, U-PCX/Cr). Results Lupus nephritis patients showed significantly higher U-Pod/Cr and U-PCX/Cr compared with patients without lupus nephritis. U-Pod/Cr was high in proliferative lupus nephritis (class III±V/IV±V), especially in pure class IV (4.57 (2.02-16.75)), but low in pure class V (0.30 (0.00-0.71)). U-Pod/Cr showed a positive correlation with activity index ( r=0.50, P=0.0012) and was independently associated with cellular crescent formation. In contrast, U-PCX/Cr was high in both proliferative and membranous lupus nephritis. Receiver operating characteristic analysis revealed significant correlation of U-Pod/Cr with pure class IV, class IV±V and cellular crescent formation, and the combined values of U-Pod/Cr and U-PCX/Cr were shown to be associated with pure class V. Conclusions U-Pod/Cr and U-PCX/Cr correlate with histological features of lupus nephritis.

Analysis of cytochrome P450 gene polymorphism in a lupus nephritis patient in whom tacrolimus blood concentration was markedly elevated after administration of azole antifungal agents.

WHAT IS KNOWN AND OBJECTIVE: Both itraconazole (ITCZ) and voriconazole (VCZ) are potent inhibitors of cytochrome P450 (CYP) 3A, and their effects have been reported to be equal. However, ITCZ is metabolized by CYP3A, whereas VCZ is mainly metabolized by CYP2C9 and CYP2C19 and only partially by CYP3A. We experienced the case of a patient who showed a 5-fold increase in trough levels of tacrolimus (FK) level after switching from ITCZ to VCZ. Our objective is to discuss the mechanism of the increase drug-drug interaction in terms of serum concentration of the azole drugs and patient pharmacogenomics. CASE SUMMARY: A 53-year-old woman was treated with FK (1 mg/day) for lupus nephritis. Because fungal infection was suspected, she received ITCZ (100 mg/day). When ITCZ was replaced with VCZ (400 mg/day), the blood concentration of FK increased markedly from 6·1 to 34·2 ng/mL. During coadministration with FK, the levels of ITCZ and VCZ were 135·5 ng/mL and 5·5 µg/mL, respectively, with the VCZ level around 3-fold higher than the previously reported level (1·4-1·8 µg/mL). Her CYP genotypes were CYP2C19*1/*2, CYP3A4*1/*1 and CYP3A5*3/*3. WHAT IS NEW AND CONCLUSION: The patient was a CYP2C19 intermediate metabolizer (IM) and deficient in CYP3A5. The increase in plasma VCZ level appears to have been at least in part, associated with the CYP2C19 IM phenotype. One possible explanation for the marked increase in blood FK concentration was increased inhibition of CYP3A because of the impaired metabolism and subsequent increased plasma concentration of VCZ. This case shows that the severity of drug interactions may be influenced by metabolic gene polymorphism.

Interleukin-10 gene polymorphism reflects the severity of chronic immune thrombocytopenia in Japanese patients.

INTRODUCTION: T-helper cell type 1 (Th1) polarization of the immune response has been documented in patients with chronic immune thrombocytopenia (ITP). Interleukin (IL)-10 is the most important factor regulating Th1 and T-helper type 2 cytokine synthesis. This study evaluated the impact of IL-10 polymorphisms on both susceptibility to, and severity of, chronic ITP. METHODS: We analyzed -1082(G/A), -812(C/T), and -592(C/A) IL-10 polymorphisms in 90 patients with adult chronic ITP and 202 race- and sex-matched healthy controls. RESULTS: No significant differences in the genotype or haplotype frequencies were observed between the patient with chronic ITP and the control group. However, more patients with the -592AA genotype showed a severe thrombocytopenic state (platelet count <10 x 109/l) than those with the -592CC/CA genotypes (44.1%vs. 19.6%, P = 0.01). Furthermore, more patients with the ATA/ATA haplotype showed a severe thrombocytopenic state than those without the ATA/ATA haplotype (44.1%vs. 19.6%, P = 0.01). CONCLUSION: According to our data, patients with low producer type of IL-10 polymorphisms have more severe thrombocytopenia, suggesting that IL-10 gene polymorphisms may reflect the severity of ITP.

Pro32Thr polymorphism of inosine triphosphate pyrophosphatase gene predicts efficacy of low-dose azathioprine for patients with systemic lupus erythematosus.

We evaluated the relationship between the efficacy of low-dose azathioprine (AZA) therapy and the inosine triphosphate pyrophosphatase (ITPA) 94C>A (Pro32Thr) polymorphism in patients with systemic lupus erythematosus (SLE). We performed a multiple regression analysis to assess the influence of various factors on the reduction in SLE disease activity index (SLEDAI) scores. The ITPA 94C>A polymorphism had the highest correlation with the change in SLEDAI score (r = 0.354, P = 0.006).

Revised classification of lupus nephritis is valuable in predicting renal outcome with an indication of the proportion of glomeruli affected by chronic lesions.

OBJECTIVES: To determine if the International Society of Nephrology/Renal Pathology Society (ISN/RPS) 2003 classification of lupus nephritis (LN) is helpful in predicting renal outcome. METHODS: A total of 92 patients with LN who underwent renal biopsy in our hospital were re-classified according to the ISN/RPS 2003 criteria. RESULTS: The mean patient age was 36.8 yrs and the median observation period was 65 months. The relative frequency for each class was as follows: Class I (minimal mesangial LN) 0%, Class II (mesangial proliferative LN) 13%, Class III (focal LN) 17%, Class IV (diffuse LN) 60% and Class V (membranous LN) 10%. Within Class IV, diffuse segmental (Class IV-S) was 25% and diffuse global (Class IV-G) 75%. During the observation period, renal function was more likely to deteriorate in Class IV-G cases than in Class IV-S cases. Importantly, when Class IV-G was subdivided into cases involving active lesion alone [IV-G (A)] or chronic lesion [IV-G (A/C)], the majority of cases in IV-G (A) was nephrotic, but responded well to therapy. In contrast, renal function declined only in IV-G (A/C) cases. Patients with Class IV-G (A/C) had persistent proteinuria in spite of intensified therapies. Moreover, the higher proportion of chronic lesions was related with the deterioration of renal function. CONCLUSIONS: This study showed that in Class IV-G cases, renal outcome differed in the presence of chronicity. Chronicity could be a critical factor in predicting outcome. Thus, the revised classification of LN is clinically valuable in identifying different renal outcomes among patients with diffuse LN.

Expression of IL-19 and its receptors in RA: potential role for synovial hyperplasia formation.

OBJECTIVE: IL-19 is a novel cytokine of the IL-10 family. In this study, we sought to examine whether IL-19 plays a role in the pathogenesis of RA. METHODS: Expression of IL-19, IL-20 receptor 1 (IL-20R1) and IL-20R2 was examined by RT-PCR and immunohistochemical analysis in rheumatoid synovium. The effects of IL-19 on synovial cells established from rheumatoid synovium (RASCs), with regard to IL-6 production and signal transducers and activators of transcription3 (STAT3) activation, were examined by ELISA and western blot analysis, respectively. The effect of IL-19 on RASC apoptosis was examined by Hoechst staining, flow cytometry analysis of annexin V binding and caspase-3 activity. RESULTS: IL-19, IL-20R1 and IL-20R2 mRNA were detected by RT-PCR in synovial tissues from RA patients. Immunohistochemical analysis showed IL-19 was predominantly expressed in the hyperplastic lining layers of RA synovial tissues. The majority of IL-19-positive cells were vimentin-positive and CD68-positive synovial cells, serving as markers of fibroblasts and macrophages, respectively. IL-20R1 and IL-20R2 (IL-20Rs) were expressed in both the lining and sublining layers of RA synovium. In RASC, IL-19 was induced by lipopolysaccharide stimulation and constitutive expression of IL-20Rs was observed, suggesting IL-19 has an autocrine action. In terms of this function, IL-19 induced STAT3 activation and increased IL-6 production by RASC above the medium control. Moreover, IL-19 significantly reduced RASC apoptosis induced by serum starvation. CONCLUSIONS: These data suggest that IL-19, produced by synovial cells, promotes joint inflammation in RA by inducing IL-6 production and decreasing synovial cell apoptosis.

Autoimmune pancreatitis as the initial presentation of systemic lupus erythematosus.

Pancreatitis is a relatively rare complication in systemic lupus erythematosus (SLE). Here we present a case of SLE associated with autoimmune pancreatitis. A 37-year old woman was admitted to our hospital because of fever, skin rash, proteinuria and abdominal pain. A diagnosis of SLE was made based on her clinical, laboratory and renal histological findings showing diffuse proliferative lupus nephritis. Elevated serum amylase, typical radiographic findings and selective increase in serum IgG4 all suggested that the patient also had autoimmune pancreatitis. Systemic administration of glucocorticoid successfully induced remission of pancreatitis and nephritis along with the reduction of IgG4. Autoimmune pancreatitis is a newly recognized type of pancreatitis, in which IgG4 immune response is thought to participate pathophysiologically. Although the disease has been observed to develop in patients having various connective tissue diseases, our report is the first to describe IgG4-related autoimmune pancreatitis in a patient with SLE.

Nestin expression in the kidney with an obstructed ureter.

Nestin is an intermediate filament protein originally identified in neuroepithelial stem cells. This cytoskeletal-associated protein is also expressed in some non-neuronal organs including renal tubular cells and glomerular endothelial cells during kidney development. Little is known, however, about nestin expression in the kidney during injury. In this study, we find nestin expression induced in renal tubular and interstitial myofibroblasts in the adult rat kidney following unilateral ureteral obstruction. The degree of nestin expression was well correlated with the degree of tubulointerstitial fibrosis. Immunohistochemical identification of specific nephron segments showed that nestin was primarily expressed by proximal tubules, partially by distal tubules and thick ascending limbs of Henle but not by collecting ducts. The nestin-positive tubular cells also expressed vimentin and heat-shock protein 47 (HSP47) suggesting these cells reverted to a mesenchymal phenotype. Not all vimentin- or HSP-expressing cells expressed nestin; however, suggesting that nestin is distinct from these conventional mesenchymal markers. Nestin expression was also found associated with phenotypical changes in cultured renal cells induced by hypoxia or transforming growth factor-beta. Nestin expression was located in hypoxic regions of the kidney with an obstructed ureter. Our results indicate that nestin could be a novel marker for tubulointerstitial injury.

Expression of CD55 and CD59 on peripheral blood cells in patients with lymphoproliferative disease of granular lymphocytes.

Lymphoproliferative disease of granular lymphocytes (LDGL) is a disorder characterized by the clonal expansion of granular lymphocytes. It has recently been shown that the clonal expansion of granular lymphocytes occurs in patients with paroxysmal nocturnal hemoglobinuria (PNH) in a subclinical fashion. To test the possibility that LDGL patients share a PNH phenotype, we obtained peripheral blood cells from 20 patients with LDGL and examined the expression of the glycosylphosphatidyl inositol (GPI)-anchored proteins, CD55 and CD59. Compared with normal controls, however, a defective expression of CD55/59 was not observed on either granulocytes or erythrocytes from LDGL patients. An unexpected finding was the significantly lower CD55/59 expression on granular lymphocytes from patients with CD16(+)CD56(-) phenotype LDGL than from patients with CD16(+)CD56(+) phenotype LDGL, or natural killer (NK) and NK/T lymphocytes from healthy individuals. The positive correlation between the expression of CD56 and CD55/59 might have some relevance to the functional properties of the CD56(+) subset of large granular lymphocytes.

Widespread crystalline inclusions affecting podocytes, tubular cells and interstitial histiocytes in the myeloma kidney.

Numerous crystalline inclusions were observed in glomerular and tubular epithelial cells in a 46-year-old female patient with multiple myeloma and renal dysfunction. On light microscopy, epithelial cells were filled with homogenous materials and were remarkably swollen. Infiltrations of histiocytes with expanded cytoplasm were also seen in the interstitium of the kidney and bone marrow. On electron microscopy, cytoplasmic inclusions had crystalline structure showing rhomboid and oval shapes. Immunofluorescence study revealed that these cells were positive for IgG-kappa. The combination chemotherapy followed by autologous stem cell transplantation led to a partial resolution of her renal dysfunction, continued by a slight reduction in the number of crystalline-containing podocytes at the second renal biopsy. Crystal inclusions in the kidney are rarely found and cause renal impairment in multiple myeloma.

Durable remission induced by rituximab-containing chemotherapy in a patient with primary refractory Burkitt's lymphoma.

We describe a 65-year-old man diagnosed with Burkitt's lymphoma arising from the intestine. The tumor cells had a mature B-cell immunophenotype and rearrangement of the c-myc gene. The patient was treated with intensive multiagent chemotherapy. After four courses of chemotherapy, an ileus developed due to a residual abdominal disease. We administered rituximab in combination with the same chemotherapy regimen. A dramatic clinical improvement was observed and abnormal uptake by 18F-fluorodeoxyglucose positron emission tomography disappeared. The patient experienced complete remission for 1 year. This encouraging result indicates that rituximab might be an important treatment choice in management of Burkitt's lymphoma.

Increased levels of platelet-associated immunoglobulin G in a patient with mixed connective tissue disease.

We report the case of a 71-year-old Japanese woman with mixed connective tissue disease and increased levels of platelet-associated immunoglobulin G. After administration of oral prednisolone, platelet-associated immunoglobulin G levels decreased with a simultaneous increase in the number of platelets, suggesting that the thrombocytopenia observed in this patient was mediated by immune mechanisms. This is the first reported case of increased platelet-associated immunoglobulin G levels in a patient with mixed connective tissue disease.

Zn deficiency aggravates hypertension in spontaneously hypertensive rats: possible role of Cu/Zn-superoxide dismutase.

Using spontaneously hypertensive rats (SHR) fed a standard or a Zn-deficient diet for 4 weeks, we examined whether Zn deficiency affects systemic blood pressure (BP) levels in a genetically hypertensive state through a fall in the activity of Cu/Zn-superoxide dismutase (SOD). SHR fed a Zn-deficient diet had a progressive increase in systolic BP during the dietary conditioning. Consequently, SHR fed a Zn-deficient diet exhibited significantly increased levels of systolic BP by 2 weeks after the start of dietary treatment when compared with SHR fed a standard diet. Similarly, levels of basal mean arterial pressure (MAP) observed at the end of dietary treatment were SHR fed a Zn-deficient diet > SHR fed a standard diet. Administration of the nitric oxide synthase (NOS) inhibitor, L-NAME, caused an increase in MAP levels in the two groups of rats, demonstrating the involvement of the vasodilator, nitric oxide (NO), in the regulation of systemic BP in a genetically hypertensive state. The expression of endothelial (e) NOS mRNA and protein in the thoracic aorta paralleled basal MAP levels in the two groups of rats, suggesting the counter-regulation of eNOS against the developed hypertensive state in SHR fed a Zn-deficient diet. On the other hand, administration of the superoxide scavenger, tempol (a SOD mimetic compound), led to a decrease in MAP levels in the two groups of rats, indicating the participation of the oxygen free radical, superoxide, in an increase in systemic BP in a genetically hypertensive state. As reported recently, the mechanism involved is due likely to a decrease in the action of the vasodilator, NO, based on the formation of peroxynitrite coming from the non-enzymatic reaction of superoxide and NO. In addition, tempol treatment completely restored MAP levels in SHR fed a Zn-deficient diet to levels comparable to those observed in SHR fed a standard diet, indicating that a further increase in systemic BP levels seen in SHR fed a Zn-deficient vs. a standard diet is presumably brought by a reduction in the action of the vasodilator, NO, resulting from an increase in the action of superoxide. The activity of the superoxide scavenger, Cu/Zn-SOD, in the thoracic aorta was significantly decreased in SHR fed a Zn-deficient diet relative to SHR fed a standard diet. It appears that a decrease in the activity of Cu/Zn-SOD observed in the thoracic aorta of SHR fed a Zn-deficient diet at least in part plays a role in an increase in the action of superoxide in this model. Thus, Zn deficiency may be a factor to develop genetic hypertension presumably through the oxidative stress caused by superoxide.

Extremely high levels of C-reactive protein in patients with acute lupus serositis.

Abstract We present the cases of two patients (19- and 40-year-old women) with systemic lupus erythematosus (SLE) who showed marked elevation of C-reactive protein (CRP). In both patients, pleural and/or peritoneal effusions were caused by lupus serositis. Methylprednisolone pulse therapy was effective in improving the serositis and normalizing CRP. Although it is generally considered that the CRP response is relatively weak in lupus patients, these cases suggest that a strong CRP response can occur in a subset of SLE.

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.

X chromosome methylation-based chimerism assay for sex-mismatched hematopoietic stem cell transplantation.

Analysis of hematopoietic chimerism is important for monitoring engraftment, graft failure, and disease recurrence. Although several techniques are now available, their sensitivity is unsatisfactory. In sex-mismatched stem cell transplantation (SCT) with a female donor, Y chromosome-specific sequences have proven the most sensitive marker. However, in the case of a male donor, no such reliable marker has been available to date. In this study, we report a novel method we developed to detect microchimerism in female recipients who receive SCT from male donors. The X-linked human androgen receptor gene (HUMARA) contains a highly polymorphic CAG trinucleotide repeat. Near this polymorphic site are methyl-sensitive HpaII restriction enzyme sites. After HpaII digestion, unmethylated male HUMARA sequences are completely digested, while methylated female ones remain intact among the male origin cells. This allows a highly efficient detection of a small number of female cells. Combined with the nested PCR technique, the X chromosome methylation-based chimerism assay could attain a 10(-4) level of sensitivity, which is 1000-fold higher than that of conventional assays. The applicability of the method was confirmed in two transplant cases. This highly sensitive method can also be applied to detect minimal residual disease or microchimerism in conditions other than hematopoietic SCT.

Analysis of the distribution of CAG repeats and X-chromosome inactivation status of HUMARA gene in healthy female subjects using improved fluorescence-based assay.

We investigated the polymorphic CAG-repeat distribution and the X-inactivation status of the human androgen receptor (HUMARA) gene in 58 female Japanese volunteers. Polymerase chain reaction amplification was performed using a fluorescent-dye-labeled primer under conditions specific for GC-rich targets, and fragments were analyzed. To estimate the length of these fragments, FAM-labeled (blue fluorescent) products were simultaneously compared with ROM-labeled size markers (red) that were created by sequencing various HUMARA fragments. The number of polymorphic CAG repeats of HUMARA in 116 alleles from 58 female subjects ranged from 15 to 28. Of the 58 volunteers, 51 (88.0%) were heterozygous. In 96% of the heterozygous female subjects, the allelic differences were no greater than 6 repeats. X-chromosome inactivation was calculated as the ratio of the area of the smaller peak to the sum of the areas of the smaller and larger peaks. The average ratio was 0.38 (range, 0.09-0.50). Preferential use of 1 allele, by more than 75% (ratio. <0.25). was observed in 5 volunteers (10.9%). The clonal nature of a patient with chronic myelogenous leukemia was easily identified. This method is sensitive enough to discriminate a difference of 1 triplet repeat.