Hiroe Sato

Allelotype frequency of the thiopurine methyltransferase (TPMT) gene in Japanese.

Polymorphisms at three loci in the thiopurine methyltransferase (TPMT) gene are known to be responsible for azathioprine and 6-mercaptopurine (6MP) toxicity. Among them, only TPMT*3C variant allele with A719G mutation was found in 15/522 (2.9%; 17/1044 alleles; 1.6%) Japanese individuals including two homozygotes. The allele frequency was different from that in Caucasians, and investigation of TPMT polymorphisms with consideration of ethnic differences before administration of azathioprine or 6MP may provide clinically useful information.

Procalcitonin is a specific marker for detecting bacterial infection in patients with rheumatoid arthritis.

Objective. Rheumatoid arthritis (RA) is a chronic inflammatory disease accompanied by many complications, and serious infections are associated with many of the advanced therapeutics used to treat it. We assessed serum procalcitonin (PCT) levels to distinguish bacterial infection from other complications in patients with RA. Methods. One hundred eighteen patients experiencing an RA flare, noninfectious complication of RA or its treatment, nonbacterial infection, or bacterial infection were studied. Serum PCT concentrations were determined with a chemiluminescent enzyme immunoassay. Results. All patients experiencing an RA flare showed negative PCT levels (≤ 0.1 ng/ml; n = 18). The PCT level was higher in the bacterial infection group (25.8% had levels ≥ 0.5 ng/ml) than in the other 3 groups (0.0–4.3% had levels ≥ 0.5 ng/ml) and the difference was significant among groups (p = 0.003). Conversely, no statistically significant difference was observed among the groups with C-reactive protein (CRP) concentration ≥ 0.3 mg/dl (p = 0.513), white blood cell (WBC) count > 8500/mm3 (p = 0.053), or erythrocyte sedimentation rate (ESR) > 15 mm/h (p = 0.328). The OR of high PCT level (≥ 0.5 ng/ml) for detection of bacterial infection was 19.13 (95% CI 2.44–149.78, p = 0.005). Specificity and positive likelihood ratio of PCT ≥ 0.5 ng/ml were highest (98.2% and 14.33, respectively) for detection of bacterial infection, although the sensitivity was low (25.8%). Conclusion. Serum PCT level is a more specific marker for detection of bacterial infection than either CRP, ESR, or WBC count in patients with RA. High PCT levels (≥ 0.5 ng/ml) strongly suggest bacterial infection. However, PCT < 0.5 ng/ml, even if < 0.2 ng/ml, does not rule out bacterial infection and physicians should treat appropriately.

Allelotype and loss of heterozygosity around the L-myc gene locus in primary lung cancers

L-myc S-allele was reported to be associated with metastasis of lung cancer, indicating the existence of a putative tumor suppressor gene around the L-myc locus, in linkage disequilibrium. The relationship between the S-allele and inactivation of some tumor suppressor gene should be indicated by allelic loss. Therefore, we examined the association between the L-myc S-allele and loss of heterozygosity at 11 loci around the L-myc locus (1p34.3) in primary lesions or other biological characteristics in lung cancer. No associations between the S-allele and allelic loss around the L-myc locus or other characteristics were found. According to the deletion map, three shortest regions of overlap between D1S230 and D1S76 were identified. While loss of heterozygosity at SRO1, between D1S2797 and MYCL1, showed no relationship with the pathological stage, it was more frequently observed in squamous cell carcinoma than adenocarcinoma (P=0.019), and associated with high telomerase activity (P=0.046), an indicator of cellular immortality. In conclusion, we found three shortest regions of overlap (SROs) from D1S2797 to pter, and a tumor suppressor gene, which might be associated with suppression of lung cancer development but not with L-myc S-allele, may exist in SRO1.

Treatment with Biologic Agents Improves the Prognosis of Patients with Rheumatoid Arthritis and Amyloidosis

Objective. Reactive amyloid A (AA) amyloidosis is a serious and life-threatening systemic complication of rheumatoid arthritis (RA). We evaluated the safety of therapy with anti-tumor necrosis factor and anti-interleukin 6 biologic agents in RA patients with reactive AA amyloidosis, together with prognosis and hemodialysis (HD)-free survival, in comparison with patients with AA amyloidosis without such therapy. Methods. One hundred thirty-three patients with an established diagnosis of reactive AA amyloidosis participated in the study. Clinical data were assessed from patient records at the time of amyloid detection and administration of biologics. Survival was calculated from the date when amyloid was first demonstrated histologically or the date when biologic therapy was started until the time of death or to the end of 2010 for surviving patients. Patients who had started HD were selected for inclusion only after the presence of amyloid was demonstrated. Results. Fifty-three patients were treated with biologic agents (biologic group) and 80 were not (nonbiologic group). Survival rate was significantly higher in the biologic group than in the nonbiologic group. Nine patients in the biologics group and 33 in the nonbiologic group started HD. Biologic therapy had a tendency for reduced risk of initiation of HD without any statistical significance. Conclusion. Patients with amyloidosis have a higher mortality rate, but the use of biologic agents can reduce risk of death. The use of biologics may not significantly influence the HD-free survival rate.

Serum Fibroblast Growth Factor 23 (FGF23) in Patients with Rheumatoid Arthritis

Objective Rheumatoid arthritis (RA) is a chronic inflammatory disease accompanied by periarticular and systemic osteoporosis. Fibroblast growth factor 23 (FGF23), which is mainly produced by osteocytes, circulates to the kidneys and regulates bone metabolism. We herein assessed serum FGF23 and its relationship to inflammation and osteoporosis in patients with RA. Methods Sixty-one patients with RA were included. Serum concentrations of FGF23 were determined using a sandwich enzyme-linked immunosorbent assay. Results The mean (± standard deviation) serum FGF23 concentration was 34.9±9.2 (range, 21.0-61.0) pg/mL. The serum FGF23 level was significantly and positively correlated with the erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) levels, disease activity score-28 based on the ESR (DAS-28 ESR) and DAS-28 CRP (r=0.261, p=0.044, r=0.280, p=0.029, r=0.409, p=0.001 and r=0.421, p=0.001, respectively). The serum matrix metalloproteinase-3 level was also significantly and positively correlated with the serum FGF23 level (r=0.331, p=0.015). Concentrations of type I collagen cross-linked N-telopeptide in the serum was significantly correlated with the serum FGF23 level (r=0.272, p=0.034). Neither the bone mineral density in the femoral neck nor lumbar was significantly correlated with the serum FGF23 level. Serum phosphate, calcium, 25-hydroxy vitamin D, and intact parathyroid hormone were not related to the serum FGF23 level. Conclusion In patients with RA, serum FGF23 is correlated with inflammation, the disease activity of RA, and bone absorption markers. Serum FGF23 may be associated with abnormal bone absorption related to RA inflammation. Further studies are necessary to clarify the mechanism underlying this association.

Utility of estimated glomerular filtration rate using cystatin C and its interpretation in patients with rheumatoid arthritis under glucocorticoid therapy

BACKGROUND Patients with rheumatoid arthritis (RA) often have reduced muscle mass. Estimated glomerular filtration ratio using the serum cystatin C concentration (eGFRcys) is more accurate than eGFR using the serum creatinine (eGFRcreat) because cystatin C is not influenced by muscle mass, but glucocorticoid therapy may affect serum cystatin C concentration. METHODS Fifty patients with RA were included in this study. Renal inulin clearance (Cin) was measured and compared with eGFRcreat, eGFRcys, or the mean of eGFRcreat and eGFRcys (eGFRavg). RESULTS The mean creatine kinase (CK) concentration was low (36.8 ± 24.4 U/l).The eGFRcreat and eGFRcys regression lines were significantly different from y = x. The mean eGFRcreat value was significantly higher than Cin and that of eGFRcys was lower than Cin. The difference between eGFRcys and Cin was negatively correlated with daily PSL dose. The mean eGFRcys value of patients taking <10 mg PSL was not different from Cin and the eGFRcys regression line was not different from y = x. CONCLUSION eGFRcys of patients taking a daily PSL dose ≥10 mg was inaccurate, while eGFRcys was underestimated. eGFRcys was more accurate than eGFRcreat or eGFRavg for patients taking a daily PSL dose of <10 mg.

Bone Formation Parameters of the Biopsied Ilium Differ between Subtrochanteric and Diaphyseal Atypical Femoral Fractures in Bisphosphonate-Treated Patients

Atypical femoral fractures (AFFs) are defined as atraumatic or low-trauma fractures located in the subtrochanteric or diaphyseal sites. Long-term bisphosphonates (BPs) are administered to prevent fragility fractures in patients with primary osteoporosis or collagen diseases who are already taking glucocorticoids (GCs). Long-term BP use is one of the most important risk factors for AFFs. Its pathogenesis is characterized by severely suppressed bone turnover (SSBT), but whether the characteristics of patients are different regarding to location of fracture site remains unknown. In this study, we compared the characteristics and bone histomorphometric findings between subtrochanteric and diaphyseal sites in patients with BP-associated AFFs. Nine women with BP-associated AFFs were recruited, including 3 with systemic lupus erythematosus, 2 with rheumatoid arthritis, 2 with primary osteoporosis, 1 with polymyalgia rheumatica, and 1 with sarcoidosis. Patients were divided into the subtrochanteric group (n = 5; average age, 52 years; BP treatment, 5.9 years) and the diaphyseal group (n = 4; average age, 77 years; BP treatment, 2.6 years). Compared with the diaphyseal group, the subtrochanteric group had significantly higher daily GC doses (average, 10.9 vs. 2.3 mg/day) and significantly lower serum 25-hydroxyvitamin-D levels (17.8 vs. 25.6 ng/mL). Bone histomorphometry of the biopsied iliac bone showed SSBT in 3 cases (subtrochanteric, n = 1; diaphyseal, n = 2). Osteoid volume and trabecular thickness were significantly lower in the subtrochanteric group than in the diaphyseal group. Bone formation was inhibited more severely in subtrochanteric than in the diaphyseal group due to the higher GC doses used.