Hiroko Kanda

Systemic lupus erythematosus and thrombotic thrombocytopenic purpura: a case report and literature review.

AbstractWe describe a patient with systemic lupus erythematosus (SLE) who developed severe and acute thrombotic thrombocytopenic purpura (TTP). Detection of the fragmentation of peripheral red blood cells (RBC) helped the early diagnosis of TTP and the patient was rescued by extensive plasma exchange started promptly after the diagnosis. Because manifestations of TTP are similar to those in SLE, it is sometimes difficult to make an accurate diagnosis of TTP in SLE patients. We emphasise here the significance of the early diagnosis of TTP by the observation of fragmented RBC and the intensive therapy, including plasma exchange, for this very severe condition.

Antiproteinuric effect of ARB in lupus nephritis patients with persistent proteinuria despite immunosuppressive therapy

Recent immunosuppressive treatments for lupus nephritis have improved renal survival rate, however, there still exists lupus nephritis refractory to these treatments. Angiotensin receptor blockers (ARBs) are known not only to decrease blood pressure but also to have an independent renoprotecting effect by interrupting renin-angiotensin system. The aim of this study was to evaluate whether ARBs have an additive effect on refractory lupus nephritis. Enrolled in this trial were twelve patients with lupus nephritis who were diagnosed by renal biopsy and remained proteinuria despite corticosteroids and/or immunosuppressive treatments. ARB, losartan or candesartan, was administered for six months. Various clinical parameters were compared before and after ARB administration. Proteinuria decreased after ARB treatment in 83% of the patients and the median amount of proteinuria significantly decreased from 2530 mg/gCr to 459 mg/gCr (P = 0.03). In addition, serum albumin and cholesterol levels were significantly improved. Systolic blood pressure significantly decreased, but none had symptoms of hypotension. The antiproteinuric effect of ARB did not correlate with the reduction of blood pressure. Interestingly, higher total complement activity levels before ARB treatment were associated with a greater reduction of proteinuria. The addition of ARB would be a safe and effective treatment for lupus nephritis with persistent proteinuria despite corticosteroids and/or immunosuppressive treatments.

Successful treatment with tocilizumab in a case of Cogan’s syndrome complicated with aortitis

A 69-year-old man with sensorineural hearing loss and iritis was diagnosed with atypical Cogan’s syndrome. He had several systematic manifestations: aortitis, meningitis, panniculitis and seronegative arthritis. Remission induced by treatment with high doses of prednisolone was followed by relapse within 1 year. Although his condition was resistant to various immunosuppressive drugs, including methotrexate, cyclosporine, azathioprine and adalimumab, his symptoms, inflammatory response and quality of life measures were successfully improved by tocilizumab, a humanized anti-interleukin-6 receptor antibody.

Polymyositis associated with focal mesangial proliferative glomerulonephritis with depositions of immune complexes

A 58-year-old man concurrently developed polymyositis (PM), interstitial lung disease, and nephrotic-range proteinuria. Renal biopsy revealed focal mesangial proliferative glomerulonephritis (mesPGN) with depositions of immunoglobulin and complements. A combination therapy of corticosteroid, intravenous immunoglobulin, and cyclosporine was found very effective for the patient. Glomerulonephritis associated with PM/dermatomyositis (DM) is rare. In our review of related literature, mesPGN was exclusively observed in polymyositis while membranous nephropathy in DM. The mechanism underlying the association between myositis and glomerulonephritis remains to be elucidated.

Glomerular overexpression and increased tyrosine phosphorylation of focal adhesion kinase p125FAK in lupus-prone MRL/MP-lpr/lpr mice.

Much progress has been made in understanding how mammalian cells receive a diverse array of external stimuli and convert them into intracellular biochemical signals. Such efforts have identified a large number of signalling molecules. However, our knowledge is limited as to their pathophysiological role in particular diseases. We demonstrate herein that an integrin‐linked signalling molecule, focal adhesion kinase p125FAK (FAK), is overexpressed in glomeruli of lupus‐prone MRL/MP‐lpr/lpr (MRL‐lpr) mouse as compared to its congeneic MRL‐+/+ strain. Increased expression was specifically demonstrated in glomeruli but not in other tissues examined. The overexpression was observed in 16‐week‐old MRL‐lpr mice with active nephritis, as well as in younger animals at 4 weeks of age. Thus, the upregulation of FAK clearly preceded the clinical onset of nephritis. FAK in MRL‐lpr glomeruli is highly tyrosine phosphorylated and is associated with adapter protein Grb2. Previous in vitro studies have shown that the association of FAK/Grb2 links cell adhesion to the Ras pathway, which ultimately stimulates mitogen‐activated protein (MAP) kinase, an important regulator of cell proliferation. In accordance, we observed constitutive MAP kinase activation in MRL‐lpr glomeruli. Our findings suggest that signalling pathways involving FAK are activated in MRL‐lpr glomeruli, and are likely to play a role in the development and progression of autoimmune‐mediated murine nephritis.

Immunophenotyping of rheumatoid arthritis reveals a linkage between HLA-DRB1 genotype, CXCR4 expression on memory CD4+ T cells, and disease activity

Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease that leads to destructive arthritis. Although the HLA class II locus is the strongest genetic risk factor for rheumatoid arthritis, the relationship between HLA class II alleles and lymphocyte activation remains unclear. We performed immunophenotyping of peripheral blood mononuclear cells on 91 HLA-DRB1-genotyped RA patients and 110 healthy donors. The frequency of memory CXCR4+CD4+ T cells, and not Th1 and Th17 cells, was significantly associated with disease severity by multiple linear regression analysis. RA patients with one or more susceptible HLA-DR haplotypes (shared epitope: SE) displayed a significantly higher frequency of memory CXCR4+CD4+ T cells. Moreover, the frequency of memory CXCR4+CD4+ T cells significantly correlated with the expression level of HLA-DR on B cells, which was elevated in RA patients with SE. In vitro analysis and transcriptomic pathway analysis suggested that the interaction between HLA-DR and T cell receptors is an important regulator of memory CXCR4+CD4+ T cells. Clinically, a higher frequency of memory CXCR4+CD4+ T cells predicted a better response to CTLA4-Ig. Memory CXCR4+CD4+ T cells may serve as a powerful biomarker for unraveling the linkage between HLA-DRB1 genotype and disease activity in RA.

Membranous nephropathy with repeated flares in IgG4-related disease

IgG4-related disease (IgG4-RD) is associated with the infiltration of IgG4-positive plasma cells into various organs. Nephropathy of IgG4-RD is generally interstitial nephritis and glomerulonephritis is rare. We describe a case of membranous nephropathy (MN) without interstitial nephritis associated with IgG4-RD symptoms including lymphadenopathy and pulmonary and pleural lesions. Treatment with steroids improved these clinical symptoms, but withdrawal of steroids induced the repeated relapse of MN. Finally, flaring of MN was prevented by the combination of steroids and cyclosporine. This is the first report of the successful treatment of MN associated with IgG4-RD by this combination therapy.

DEVELOPMENT OF SYSTEMIC LUPUS ERYTHEMATOSUS IN A RHEUMATOID ARTHRITIS PATIENT WITH ANTI-RIBOSOMAL P PROTEIN ANTIBODY

We describe a patient with rheumatoid arthritis (RA) whose sera contained a high titre of an antibody targeting cytoplasmic ribosomal P proteins (anti-P). This association preceded by 6 years the development of serological and clinical manifestations of systemic lupus erythematosus (SLE). The clinical significance of anti-P for the diagnosis of SLE is discussed.

Association between type 1 diabetes mellitus and remitting seronegative symmetrical synovitis with pitting edema: A case report

A 59-year-old female with type 1 diabetes and RS3PE had HLA types known to be associated with both diseases. Type 1 diabetes patients suffering from polyarthritis and pitting edema should be examined for possible RS3PE and glucocorticoid therapy may be indicated despite the diabetes.

Three cases of lupus nephritis patients with serum interleukin-32γ detection

Purpose Interleukin-32 (IL-32) is an inflammatory cytokine that is associated with the pathogenesis of several connective tissue diseases. We measured serum IL-32γ concentrations of systemic lupus erythematosus (SLE) patients. Methods Serum samples were obtained from SLE patients (n = 51), and healthy controls (n = 15). Serum IL-32 concentrations were measured using ELISA. Clinical information was obtained from medical records. Results Serum IL-32γ was detectable in three cases of SLE patients, whereas it was not detected in any healthy controls. Case 1: a 44-year-old female with lupus nephritis (LN) (Class II) and antiphospholipid antibody syndrome. Serum IL-32γ was 5.1 pg/ml. Case 2: a 30-year-old female with a history of diffuse proliferative LN (Class IV G (A/C)) and pulmonary hemorrhage. Serum IL-32γ was 8.9 pg/ml. Case 3: a 45-year-old female with chronic LN. Serum IL-32γ was 9.1 pg/ml. All three cases of IL-32γ-detectable patients had histories of LN and one had an active disease. In the context of LN, serum IL-32γ was detectable in 18.8% (three of 16) of SLE patients with histories of LN. Conclusion We suppose that IL-32γ could contribute to the pathogenesis of renal diseases in some LN patients.