Mami Tamai

A prediction rule for disease outcome in patients with undifferentiated arthritis using magnetic resonance imaging of the wrists and finger joints and serologic autoantibodies

OBJECTIVE To evaluate whether magnetic resonance imaging (MRI) of the wrists and finger joints and an analysis of serologic autoantibodies are clinically meaningful for the subsequent development of rheumatoid arthritis (RA) in patients with undifferentiated arthritis (UA). METHODS A total of 129 patients with UA, a disease status formally confirmed by a rheumatologist over a period of at least 1 year, were included. Gadolinium-diethylenetriamine-enhanced MRI of both wrists and finger joints and serologic variables were examined upon admission to our Early Arthritis Clinic at Nagasaki University. After a prospective followup of 1 year, a predictive value for the development of RA was determined for each patient. RESULTS The subjects were evaluated for their positive or negative status with respect to 3 objective measures at study entry: anti-cyclic citrullinated peptide (anti-CCP) antibodies and/or IgM-rheumatoid factor, MRI-proven symmetric synovitis, and MRI-proven bone edema and/or bone erosion. The patients who were positive for at least 2 of these measures progressed to RA at 1 year with a 79.7% positive predictive value (PPV), 63.0% negative predictive value, 75.9% specificity, 68.0% sensitivity, and 71.3% accuracy. Furthermore, in 22 UA patients positive for both anti-CCP antibodies and MRI-proven bone edema who were considered to have progressed to RA at 1 year, the PPV was increased to 100%. A close correlation was found between the present rule and that established in the Leiden Early Arthritis Cohort. CONCLUSION MRI-proven early joint damage in conjunction with serologic autoantibodies is efficient in predicting progression from UA to RA. This method can be used to identify patients who would benefit from early treatment with disease-modifying antirheumatic drugs.

The diagnostic utility of anti-melanoma differentiation-associated gene 5 antibody testing for predicting the prognosis of Japanese patients with DM

OBJECTIVE Interstitial lung disease (ILD), especially rapidly progressive ILD (RPILD), is a major poor prognostic factor in patients with DM. We investigated the association of anti-melanoma differentiation-associated gene 5 (MDA5) antibody (Ab) with clinical characteristics and mortality in Japanese patients with DM. METHODS Seventy-nine DM patients, comprising 58 classic DM and 21 clinically amyopathic DM (CADM) patients, were enrolled. Serum Abs were screened by immunoprecipitation assays, and an immunosorbent assay (ELISA) was used for MDA5. The relationships of clinical characteristics and mortality with each Ab were investigated. RESULTS Anti-MDA5 Ab was detected in 17 patients. Anti-clinically amyopathic DM 140  kDa polypeptide Abs (anti-CADM-140 Abs) were found in 16 of the 17 anti-MDA5 Ab(+) patients. Skin ulcers, palmar papules, CADM, RPILD and mediastinal emphysema were widely distributed in anti-MDA5 Ab(+) patients. Mortality at 6 months as well as 5 years was also significantly higher in anti-MDA5 Ab(+) patients than in anti-MDA5 Ab(-) patients. In a multivariable Cox regression analysis, mortality was independently associated with anti-MDA5 Ab (relative hazard 6.33; 95% CI 1.43, 28.0). All of the deaths in anti-MDA5 Ab(+) patients were attributed to respiratory failure of RPILD; however, RPILD did not worsen in any of the anti-MDA5 Ab(+) patients who survived the first 6 months. CONCLUSION The presence of anti-MDA5 Ab identifies the characteristic skin, musculoskeletal, pulmonary and prognostic features in patients with DM. In addition, anti-MDA5 Ab seems to predict a group of patients with CADM-complicated fatal RPILD.

RS3PE syndrome presenting as vascular endothelial growth factor associated disorder

Objectives: To characterise serum concentrations of various cytokines and detection by magnetic resonance imaging (MRI) of synovial hypervascularity in patients with remitting seronegative symmetrical synovitis with pitting oedema (RS3PE) syndrome before and after corticosteroid treatment. Methods: Vascular endothelial growth factor165 (VEGF165), tumour necrosis factor α (TNFα), and interleukin 1β (IL1β) were measured by enzyme linked immunosorbent assay (ELISA) in serum samples from three patients with RS3PE syndrome. As controls, serum samples from 26 healthy volunteers, 12 patients with rheumatoid arthritis, 10 patients with systemic lupus erythematosus, 13 patients with polymyositis/dermatomyositis, 13 patients with vasculitis syndrome, and 6 patients with mixed connective tissue disease were also analysed. Synovial hypervascularity of patients with RS3PE syndrome was estimated by rate of enhancement (E-rate) in a dynamic MRI study. Results: Serum concentrations of VEGF165 (mean (SD) 2223.3 (156.3) pg/ml) were significantly higher in patients with active RS3PE syndrome than in controls before corticosteroid treatment. TNFα and IL1β levels were similar in patients and controls. Synovial hypervascularity in affected joints and subcutaneous oedema decreased during corticosteroid treatment, in parallel with the fall in serum VEGF165. Conclusions: VEGF promotes synovial inflammation and vascular permeability in patients with RS3PE syndrome, suggesting that RS3PE can be classified as a VEGF associated disorder.

Osteoprotegerin (OPG) acts as an endogenous decoy receptor in tumour necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis of fibroblast-like synovial cells

We examined the role of osteoprotegerin (OPG) on tumour necrosis factor‐related apoptosis‐inducing ligand (TRAIL)‐induced apoptosis in rheumatoid fibroblast‐like synovial cells (FLS). OPG protein concentrations in synovial fluid from patients with rheumatoid arthritis (RA) correlated with those of interleukin (IL)‐1β or IL‐6. A similar correlation was present between IL‐1β and IL‐6 concentrations. Rheumatoid FLS in vitro expressed both death domain‐containing receptors [death receptor 4 (DR4) and DR5] and decoy receptors [decoy receptor 1 (DcR1) and DcR2]. DR4 expression on FLS was weak compared with the expression of DR5, DcR1 and DcR2. Recombinant TRAIL (rTRAIL) rapidly induced apoptosis of FLS. DR5 as well as DR4 were functional with regard to TRAIL‐mediated apoptosis induction in FLS; however, DR5 appeared be more efficient than DR4. In addition to soluble DR5 (sDR5) and sDR4, OPG administration significantly inhibited TRAIL‐induced apoptogenic activity. OPG was identified in the culture supernatants of FLS, and its concentration increased significantly by the addition of IL‐1β in a time‐dependent manner. Neither IL‐6 nor tumour necrosis factor (TNF)‐α increased the production of OPG from FLS. TRAIL‐induced apoptogenic activity towards FLS was reduced when rTRAIL was added without exchanging the culture media, and this was particularly noticeable in the IL‐1β‐stimulated FLS culture; however, the sensitivity of FLS to TRAIL‐induced apoptosis itself was not changed by IL‐1β. Interestingly, neutralization of endogenous OPG by adding anti‐OPG monoclonal antibody (MoAb) to FLS culture restored TRAIL‐mediated apoptosis. Our data demonstrate that OPG is an endogenous decoy receptor for TRAIL‐induced apoptosis of FLS. In addition, IL‐1β seems to promote the growth of rheumatoid synovial tissues through stimulation of OPG production, which interferes with TRAIL death signals in a competitive manner.

The power Doppler ultrasonography score from 24 synovial sites or 6 simplified synovial sites, including the metacarpophalangeal joints, reflects the clinical disease activity and level of serum biomarkers in patients with rheumatoid arthritis

OBJECTIVE We evaluated the significance of the power Doppler ultrasonography (PDUS) score by comparing it with serum biomarkers and clinical disease activity. METHODS We measured the PDUS scores of 24 synovial sites in 12 joints in 22 RA patients. For convenience, the PDUS scores of six synovial sites in six joints were also examined. Each joint was scored for a power Doppler (PD) signal on a scale from 0 to 3. The PDUS scores are the sums of the PD signal scores for the 24 synovial sites or the 6 synovial sites. On the same day, serum variables as well as clinical disease activity were evaluated. RESULTS The PDUS scores from the 24 joint sites were significantly positively correlated with DAS of 28 joints (DAS-28), simplified disease activity index (SDAI), clinical disease activity index (CDAI) and serum biomarkers including MMP-3, VEGF and tissue inhibitor of metalloproteinases-1 (TIMP-1). Accordingly, the PDUS scores from the six synovial sites greatly correlated with those from the 24 joint sites. Clinical disease activities as well as serum variables were also clearly correlated with the PDUS scores from the six synovial sites. CONCLUSION The standard as well as the simplified PDUS scores well reflected clinical disease activity and serum variables, including angiogenic factors. Our data reaffirm the utility of ultrasonography for monitoring disease activity in patients with RA.

Association of distinct clinical subsets with myositis-specific autoantibodies towards anti-155/140-kDa polypeptides, anti-140-kDa polypeptides, and anti-aminoacyl tRNA synthetases in Japanese patients with dermatomyositis: a single-centre, cross-sectional study.

Objective: To determine the association of distinct clinical subsets with myositis‐specific autoantibodies (MSAs) towards anti‐155/140‐kDa polypeptides [anti‐155/140 antibodies (Abs)], anti‐140‐kDa polypeptides (anti‐140 Abs), and anti‐aminoacyl tRNA synthetases (ARS Abs) in Japanese patients with dermatomyositis (DM). Methods: We compared the clinical features and short‐term prognoses of 30 DM patients whose serological status included these MSAs. The MSAs were determined by immunoprecipitation. Results: Anti‐155/140 Abs (n = 5), anti‐140 Abs (n = 8), and anti‐ARS Abs (n = 7) did not overlap each other. All of the anti‐155/140 Ab‐positive patients (n = 5) were complicated by malignancies, as were all of the anti‐140 Ab‐positive patients (n = 8), who showed rapidly progressive interstitial lung disease (ILD). The survival rate at 6 months from the diagnosis of DM was significantly lower in the anti‐140 Ab‐positive patients than in the other patients. Conclusion: This is the first study to report, in a single cohort of DM patients, that distinct clinical subsets are distributed in an anti‐155/140 Ab‐positive group, an anti‐140 Ab‐positive group, or an anti‐ARS Ab‐positive group. Our data also confirm previous evidence that anti‐155/140 Abs are involved in malignancies and that anti‐140 Abs are involved in rapidly progressive ILD.

A significantly impaired natural killer cell activity due to a low activity on a per-cell basis in rheumatoid arthritis.

To elucidate the characterization of peripheral natural killer (NK) cells in patients with rheumatoid arthritis (RA), we investigated the NK cell activity, the expression of NK cell activating receptors and intracellular molecules. The NK activity was analyzed in 27 RA patients, 22 primary Sjögren’s syndrome (SS) patients, and 15 healthy individuals using the 51Chrominium release assay. The expression of NK cell activating receptors (NKG2D, CD244, CD2, and CD16) and intracellular molecules (granzyme B, perforin, and TCR ζ chain) in CD3-CD56+ cells were characterized by flow cytometry. The serum cytokine levels (IL-6, TNFα, and IL-18) were measured using ELISA. Both the NK cell activity and the activity on a per-cell basis were observed to significantly decrease in the RA patients in comparison to the controls. The expression of NKG2D and CD244 also significantly decreased in both the RA and primary SS patients, whereas the significant decrease in the CD16 expression was only observed in the RA patients. The titer of the serum IL-6, TNFα, and IL-18 was significantly higher in the RA patients than in the controls. These data suggest that a low NK activity on a per-cell basis might therefore contribute to an impaired NK activity in the patients with RA.

Proinflammatory Cytokines Synergistically Enhance the Production of Chemokine Ligand 20 (CCL20) from Rheumatoid Fibroblast-like Synovial Cells in vitro and Serum CCL20 Is Reduced in vivo by Biologic Disease-modifying Antirheumatic Drugs

Objective. Chemokine ligand 20 (CCL20) is a selective ligand for chemokine receptor 6 (CCR6). We investigated, both in vitro and in vivo, whether CCL20 is critically involved in the disease process of rheumatoid arthritis (RA). Methods. In vitro study investigated the effect of proinflammatory cytokines and biologic disease-modifying antirheumatic drugs (DMARD) on the production of CCL20 by rheumatoid fibroblast-like synovial cells (FLS). The in vivo role of CCL20 was studied by screening for serum CCL20 concentration in patients with RA during the therapeutic course of biologic DMARD, i.e., infliximab, etanercept, and tocilizumab. Results. Spontaneous CCL20 production from rheumatoid FLS was minimal; however, its production was significantly stimulated by interleukin 1ß (IL-1ß), tumor necrosis factor-α (TNF-α), or IL-17. IL-1ß was the most potent for stimulating the production of CCL20. CCL20 production was synergistically augmented by a combination of IL-1ß, TNF-α, and IL-17. In contrast, interferon-γ suppressed IL-1ß-induced CCL20 production. IL-6, in combination with soluble IL-6 receptor (sIL-6R), did not modulate CCL20 production, whereas IL-1ß-induced, TNF-α-induced, and IL-17-induced production were increased by IL-6. These production levels were clearly suppressed by biologic DMARD in vitro. Serum CCL20 was significantly higher in RA than in control subjects, and was clearly decreased by the treatment with infliximab, etanercept, and tocilizumab. Conclusion. Proinflammatory cytokines modulate the production of CCL20 from FLS. Our data suggest that therapeutic efficacy of biologic DMARD may result from the inhibition of CCL20 production in rheumatoid synovium.

The presence of anti-cyclic citrullinated peptide antibody is associated with magnetic resonance imaging detection of bone marrow oedema in early stage rheumatoid arthritis

Early prediction of erosive joint damage is very important in rheumatoid arthritis (RA) because significant articular damage in patients is evident radiologically within the first few years of the disease.1 This study was designed to confirm whether anti-cyclic citrullinated peptide antibodies (anti-CCP Ab) define the subset of patients with early stage RA who have bone marrow oedema, observed by magnetic resonance imaging (MRI). Patients were referred from the Early Arthritis Clinic, started in 2001 at the First Department of Internal Medicine, Graduate School of Biomedical Sciences, Nagasaki University. After prospective follow up, diagnosis of RA was made by the 1987 criteria for RA of the American College of Rheumatology.2 Eighty patients who gave their informed consent to the protocol that was approved by the Institutional Review Board …

Ultrasonographic examination of rheumatoid arthritis patients who are free of physical synovitis: power Doppler subclinical synovitis is associated with bone erosion

OBJECTIVE The aim of this study was to investigate the characteristics of power Doppler (PD) subclinical synovitis in patients with RA who achieve clinical remission free from physical synovitis. METHODS Twenty-nine RA patients were consecutively enrolled. All of the patients had achieved clinical remission [simplified disease activity index (SDAI) 3.3] for at least 6 months at the musculoskeletal ultrasound (MSKUS) examination. Additionally, none of the patients exhibited tender joints at 68 sites or swollen joints at 66 sites. MSKUS of bilateral wrist and finger joints, including the first to fifth MCP joints, the first IP joint and the second to fifth PIP joints, was performed and the findings obtained by grey scale (GS) and PD were graded on a semi-quantitative scale from 0 to 3. RESULTS The median disease duration upon the introduction of DMARDs was 3 months and that at MSKUS examination was 21 months. The percentages of patients with PD synovitis in at least one joint were PD grade 1, 58.6%; PD grade 2, 31.0% and PD grade 3, 6.9%. The use of biological agents was low in patients with PD synovitis grade 2 (P < 0.05). The presence of US bone erosion was high by patient (P < 0.05) and by joint (P < 0.0001) with PD synovitis as compared with those without PD synovitis. However, no correlations were found between PD synovitis measures and serum biomarkers, including angiogenesis factors. CONCLUSION PD subclinical synovitis correlates with several clinical characteristics, whereas conventional serum biomarkers are not useful for indicating the presence of subclinical PD synovitis.