Masato Moriguchi

Relative transcriptional activities of SAA1 promoters polymorphic at position −13(T/C): Potential association between increased transcription and amyloidosis

The risk associated with the serum amyloid A (SAA) 1 gene and developing AA-amyloidosis is still controversial. In familial Mediterranean fever or Caucasoid rheumatoid arthritis (RA), the SAA1.1 allele is a risk factor for the development of AA-amyloidosis. However, individuals with the SAA1.3 allele are susceptible to AA-amyloidosis in the Japanese RA population, but those with the SAA1.1 are not. Previous reports have indicated that the − 13T/C single nucleotide polymorphism (SNP) at the 5’-flanking region of SAA1 appears to be a better marker of AA-amyloidosis than the exon-3 based haplotype, i.e., SAA1.1 or SAA1.3, in both Japanese and American Caucasian populations. So far, it is unknown why the − 13T SNP increases the amyloidogenicity of the patients. In the present study, a luciferase reporter gene assay showed that the transcriptional activity of the SAA1 having the − 13T-containing promoter was significantly higher than activities of those with − 13C-containing promoters (Fishers protected least significance difference test). We suggest that having the − 13T SNP in the SAA1 promoter correlates with the amyloidogenicity in part as a result of this increased transcriptional activity.

Genotypes at SAA1 locus correlate with the clinical severity of AA-amyloidosis.

he frequency of AA-amyloidosis secondary to rheumatoid arthritis (RA) varies among different ethnic T groups. For example, about 5-10 % of Japanese RA patients suffer from AA-amyloidosis, while in the USA, the frequency of RA patients developing AA-amyloidosis is less than 1 %’. 2. The reasons underlying such regional or racial differences are still unclear, but genetic factors may well phy an important role. Baba’s group was the first to discover that the risk for AA-amyloidosis was higher in individuals homozygous for SAA 1.3 (formerly designated SdA1 y) as compared with those with other genotypes in the Japanese population3. We also found an association between the SAAI gene and the susceptibility to AA-amyloidosis in a Japanese population with the calculated relative risk of developing AA-amyloidosis for RA patients homozygous for SAA1.3 being 4.5. We also found that the number of SdA1.3 alleles was not only related to the susceptibility to AA-amyloidosis, but was also associated with the time that elapsed from the onset of RA to the clinical diagnosis of AA-amyloidosis4. However, the mechanism by which SAA1.3 alleles influence the susceptibility to AA-amyloidpsis in Japanese RA patients is currently unknown. To investigate this issue further, we examined the correlation between SAA I genotypes and the clinical traits of this disease. In addition, we evaluated the extent of AA-amyloid deposition in renal tissues to examine possible histological differences among patients with different genotypes at the SAA I locus.

A case of IgG4-related disease with features of Mikulicz’s disease, and retroperitoneal fibrosis and lymphadenopathy mimicking Castleman’s disease

A 51-year-old man developed painless enlargement of the bilateral submandibular and lacrimal glands without xerostomia or xerophthalmia in the absence of autoantibodies to SS-A (Ro) and SS-B (La). In a few years, he developed generalized lymphadenopathy, with markedly elevated serum IgG4, and a computed tomography scan revealed soft-tissue-density lesions around the abdominal aorta, a finding consistent with retroperitoneal fibrosis. Biopsy of the cervical lymph node showed an expansion of the interfollicular area by heavily infiltrating plasma cells, consistent with multicentric Castleman’s disease. Immunohistochemical analysis revealed that the IgG4-positive/IgG-positive plasma cell ratio was 80%, leading us to a single diagnosis of IgG4-related disease. High-dose corticosteroid treatment resulted in prompt resolution of the physical, serological, and imaging abnormalities. Although IgG4-related disease can mimic multicentric Castleman’s disease, as in our patient, the two diseases have effective but distinct treatments, and thus measurement of serum IgG4 levels and specific immunohistochemical analysis for determining the IgG4-positive/IgG-positive plasma cell ratio are recommended if IgG4-related disease is suspected.

Renal function estimated from serum creatinine is overestimated in patients with rheumatoid arthritis because of their muscle atrophy

Abstract We evaluated the reliability of serum creatinine concentration (Scr) to estimate renal function in patients with rheumatoid arthritis (RA). To quantify muscle volume (study 1) the lean body mass (LBM) in 25 women RA patients and 10 controls was measured using dual X-ray absorptiometry (DEXA). The 60-min creatinine clearance (Ccr60) and 60-min urinary excretion of creatinine (Ucr60) were also determined. The Ucr60 and LBM of the extremities, which were significantly correlated (r = 0.757, P < 0.0001), were lower in patients with long-standing and advanced RA than in controls. In study 2, the 24-h creatinine clearance (Ccr24) and 24-h urinary excretion of creatinine (Ucr24) were determined retrospectively in 82 women RA patients and 120 controls with normal Scr. The Ccr of long-standing and advanced RA patients was significantly lower than that of the controls, although the Scr of the long-standing RA patients was significantly lower than that of the advanced RA patients. The upper limit of the normal Scr for RA patients was calculated as being approximately 10% lower than that for controls. Thus, the renal function estimated from Scr may be overestimated in patients with long-standing and advanced RA because of their muscle atrophy.

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

Abstract 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.