Kiyoshi Nakazono

Development of fulminant hepatitis B (precore variant mutant type) after the discontinuation of low-dose methotrexate therapy in a rheumatoid arthritis patient.

A 75-year-old female rheumatoid arthritis patient who was positive for hepatitis B surface antigen and for antibodies to hepatitis Be antigen showed liver dysfunction, and therefore methotrexate (MTX) therapy was discontinued. Her drug lymphocyte stimulation test indicated positivity for MTX. Her liver dysfunction improved briefly, but she developed fulminant hepatitis with elevated levels of hepatitis B virus (HBV)/DNA polymerase and subsequently died. HBV/DNA analysis performed with polymerase chain reaction-mutation site-specific assay revealed that the fulminant hepatitis was caused by a precore mutant virus. Sudden reactivation of the immune system by discontinuation of MTX may have led to the attack on infected cells. Even when hepatitis Be antibodies are present, MTX should not be used in patients who have chronic infection with HBV.

Comparison of gastroduodenal, renal and abdominal fat biopsies for diagnosing amyloidosis in rheumatoid arthritis.

Abstract: The aim of the study was to determine the frequency of amyloidosis detected by gastroduodenal biopsy in rheumatoid arthritis (RA) patients, and to investigate correlations between the results of gastroduodenal biopsy and abdominal fat and renal biopsies. A total of consecutive 1006 RA patients underwent gastroduodenal biopsy. The 71 patients who tested positive for gastrointestinal (GI) amyloidosis were asked to undergo renal and abdominal fat biopsies, and 21 did so. Renal biopsies were also performed on 12 patients with no amyloidosis but indicators of drug-induced renal damage, and abdominal fat biopsies were performed on 50 RA patients with no indication of amyloidosis. The prevalence of GI amyloidosis was 7.1%. Urinary abnormalities and GI symptoms were common in GI amyloidisis, and inflammatory markers were elevated. Sixty-one (86%) had either depressed creatinine clearance or urinary symptoms. Nineteen of the 21 patients (91%) with GI amyloidosis who underwent renal biopsies also had renal amyloid deposits. Eleven of the 21 (52%) had amyloidosis on abdominal fat biopsy. None of the 12 patients without GI amyloidosis had renal amyloidosis on renal biopsy, and none of the 50 patients without GI amyloidosis had amyloidosis on abdominal fat biopsy. Gastroduodenal biopsy reveals a high prevalence of amyloidosis in RA patients. Amyloidosis is often associated with signs of renal impairment. Results of GI biopsy are highly correlated with those of renal biopsy, but the results of fat biopsy are not. We recommend GI biopsy for RA patients for the screening of systemic amyloidosis.

Risk factors for vertebral fracture in menopausal or postmenopausal Japanese women with rheumatoid arthritis: a cross-sectional and longitudinal study

The occurrence of vertebral fracture was examined cross-sectionally and longitudinally over a 4-year interval in 117 menopausal and postmenopausal Japanese women with rheumatoid arthritis (RA), whose ages ranged from 50 to 64 years. Patients treated with bisphosphonate were excluded. Vertebral fracture was diagnosed by lateral thoracic and lumbar spine radiography at the start and end of a 4-year period. Bone mineral density (BMD) at L2–L4 according to dual-energy X-ray absorptiometry (DXA), the administration of corticosteroids or methotrexate, and urinary excretion of N-telopeptide of type I collagen (NTx) were also recorded. In the cross-sectional study, the prevalence of vertebral fracture in the initial radiographs of RA patients was 21%, while it was 5% in healthy age-matched controls. Among RA patients treated with corticosteroids, 33% had vertebral fracture, which was a significantly higher prevalence than that in RA patients without steroid administration. In the longitudinal study, vertebral fracture prevalence was also increased in patients more than 60 years old. RA patients having steroid treatment and a BMD/YAM (young adult mean) ratio below 70% had higher risk of vertebral fracture than patients with a BMD/YAM ratio of 70%–80%, which in turn exceeded the risk with a BMD of 80% or more. No adverse effect of low-dose methotrexate on vertebral fracture was found. Urinary NTx was high in RA patients, as reported previously, and did not differ between patients with or without new fracture after 4 years. In conclusion, Japanese RA patients more than 60 years old who were treated with corticosteroid or had a BMD below 80% had high risk of vertebral fracture.

Periodontal and serum protein profiles in patients with rheumatoid arthritis treated with tumor necrosis factor inhibitor adalimumab.

BACKGROUND Tumor necrosis factor (TNF)-α inhibitor has been shown to affect the periodontal condition of patients with rheumatoid arthritis (RA). The aim of the present study is to assess the effect of a fully humanized anti-TNF-α monoclonal antibody, adalimumab (ADA), on the periodontal condition of patients with RA and to compare serum protein profiles before and after ADA therapy. METHODS The study participants consisted of 20 patients with RA treated with ADA. Clinical periodontal and rheumatologic parameters and serum cytokine levels were evaluated at baseline and 3 months later. Serum protein spot volume was examined with two-dimensional sodium dodecyl sulfate polyacrylamide gel electrophoresis. Proteins with significant difference in abundance before and after ADA therapy were found and identified using mass spectrometry and protein databases. RESULTS The patients showed a significant decrease in gingival index (P = 0.002), bleeding on probing (P = 0.003), probing depth (P = 0.002), disease activity score including 28 joints using C-reactive protein (P <0.001), and serum levels of TNF-α (P <0.001) and interleukin-6 (P <0.001) after ADA medication, although plaque levels were comparable. Among a total of 495 protein spots obtained, nine spots were significantly decreased in abundance at reassessment, corresponding to complement factor H, phospholipase D, serum amyloid A, complement component 4, and α-1-acid glycoprotein (P <0.01). CONCLUSION These results suggest a beneficial effect of ADA therapy on the periodontal condition of patients with RA, which might be related to differences in serum protein profiles before and after ADA therapy.

Expression of anti-Porphyromonas gingivalis peptidylarginine deiminase immunoglobulin G and peptidylarginine deiminase-4 in patients with rheumatoid arthritis and periodontitis

BACKGROUND AND OBJECTIVE Autoimmunity against citrullinated proteins through peptidylarginine deiminase (PAD) may be involved in the pathophysiology of rheumatoid arthritis (RA). The present study evaluated the serum levels of antibodies to citrullinated proteins and to Porphyromonas gingivalis PAD (PPAD), and the endogenous expression of PAD-4, in individuals with and without RA, as well as before and after periodontal treatment. MATERIAL AND METHODS The study participants consisted of 52 patients with RA (RA group) and 26 age-, gender- and smoking status-matched healthy controls (non-RA group). Of the 52 patients, 26 were randomly assigned to receive oral hygiene instruction and supragingival scaling (RA subgroup). After periodontal and rheumatologic assessments, the serum levels of anti-cyclic citrullinated peptide (CCP) immunoglobulin G (IgG), anti-PPAD IgG and PAD-4 were determined using ELISA. RESULTS The serum levels of anti-CCP IgG and anti-PPAD IgG were significantly higher in the RA group than in the non-RA group (p < 0.001 and p = 0.03). A significant, positive correlation was observed between the serum levels of anti-PPAD IgG and anti-CCP IgG (p = 0.04), but not between the serum levels of PAD-4 and anti-CCP IgG. Multiple logistic regression analyses revealed a significant association between anti-PPAD IgG responses and RA after adjustment for age, gender and smoking (p = 0.004). Supragingival scaling significantly improved the periodontal condition and disease activity of RA (p < 0.05), but failed to decrease the serum levels of anti-CCP IgG, anti-PPAD IgG and PAD-4 after 2 mo of treatment. CONCLUSION These results might suggest an association between anti-PPAD IgG and anti-CCP IgG responses, implicating a role for PPAD in protein citrullination in patients with RA and periodontitis.

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.

Serum Immunoglobulin G Levels to Porphyromonas gingivalis Peptidylarginine Deiminase Affect Clinical Response to Biological Disease-Modifying Antirheumatic Drug in Rheumatoid Arthritis

Objectives To determine whether serum immunity to Porphyromonas gingivalis peptidylarginine deiminase (PPAD) affects the clinical response to biological disease-modifying antirheumatic drug (bDMARD) in patients with rheumatoid arthritis (RA). Methods In a retrospective study, rheumatologic and periodontal conditions of 60 patients with RA who had been treated with conventional synthetic DMARD were evaluated before (baseline) and after 3 and 6 months of bDMARD therapy. After serum levels of anti-PPAD immunoglobulin G (IgG) were determined at baseline, the patients were respectively divided into two groups for high and low anti-PPAD IgG titers according to the median measurements. Genotypes at 8 functional single nucleotide polymorphisms (SNPs) related to RA were also determined. Results After 3 and 6 months of therapy, patients with low anti-PPAD IgG titers showed a significantly greater decrease in changes in the Disease Activity Score including 28 joints using C-reactive protein (DAS28-CRP) (P = 0.04 for both) and anti-cyclic citrullinated peptide (CCP) IgG levels (P = 0.03 and P = 0.04) than patients with high anti-PPAD IgG titers, although these parameter values were comparable at baseline. The anti-PPAD IgG titers were significantly positively correlated with changes in the DAS28-CRP (P = 0.01 for both) and the anti-CCP IgG levels (P = 0.02 for both) from baseline to 3 and 6 months later. A multiple regression analysis revealed a significantly positive association between the anti-PPAD IgG titers and changes in the DAS28-CRP after 6 months of bDMARD therapy (P = 0.006), after adjusting for age, gender, smoking, periodontal condition, and RA-related SNPs. Conclusion The serum IgG levels to PPAD affect the clinical response to bDMARD in patients with RA.

A comparison of the ultrasonography images of the joints of patients with rheumatoid arthritis and the corresponding synovial histological findings.

Abstract Objectives: The objective of this study is to investigate whether ultrasonography (US) images of joints that underwent surgery reflected the synovial histological findings or clinical indicators and to compare the results of the findings related to large joints (LJs) with those of small joints (SJs). Methods: The operations were performed on 215 joints in 177 patients with rheumatoid arthritis (RA). The 215 joints included 64 LJs and 151 SJs. The joints with the power Doppler (PD) signal grades 0 and 1 were assigned to group L, while those with grades 2 and 3 were assigned to group H. The Rooney score, Disease Activity Score-erythrocyte sedimentation rate (DAS28), serum matrix metallopeptidase 3 (MMP-3), and C-reactive protein (CRP) levels were determined. Results: The Rooney score, DAS28, MMP-3, and CRP levels of the LJs were significantly lower in group L than in group H. In group H, similar results were found in the LJs and SJs, with a significant increase in the disease activity, CRP and MMP-3 levels and the histological findings in comparison to group L. Conclusions: The PD signal grade was one of the indicators that reflected the degree of synovitis in the histological findings of the active joints of RA patients.

Interleukin-2 Levels are Elevated in the Bone Marrow Serum of Patients with Mutilans-Type Rheumatoid Arthritis

Abstract: In order to investigate the pathogenesis of mutilans-type rheumatoid arthritis (RA), we measured cytokine levels in the bone marrow serum of patients with RA. We studied 35 patients with non-mutilans RA, 19 with mutilans RA, and 20 patients with osteoarthritis (OA) undergoing joint surgery. At the time of surgery, iliac bone marrow and peripheral blood were sampled from all 74 patients and cytokine levels measured. The serum levels of five cytokines (IL-1β, IL-2, IL-3, IL-6 and GM-CSF) were measured by ELISA. Haematologic and inflammatory factors were also measured. Levels of IL-2, IL-6 and GM-CSF in bone marrow serum were significantly higher in all RA patients than in those with OA. Mean (þSD) IL-2 levels were significantly higher in patients with mutilans-type RA (309.8þ686.3 pg/ml) than in patients with other types of RA (66.5þ173.1 pg/ml; P<0.01). IL-2 was detected significantly more often in patients with mutilans-type RA than in patients with other types of RA (P<0.01). Inflammatory factors were higher in all RA groups than in OA patients. However, the haematologic and immunologic variables were no different between mutilans RA and other types of RA. No correlations were observed between IL-1β, IL-2, IL-3, IL-6 and GM-CSF levels and these laboratory variables. In patients with mutilans-type RA, IL-2 levels in the bone marrow serum were significantly higher than in patients with other types of RA or with OA. This elevation does not appear to be related to systemic inflammation, as there was no correlation with other inflammatory factors.

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.