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The aim of this study was to determine whether rheumatoid factor (RF) is associated with mortality from all-cause, cardiovascular disease (CVD), and cancer in the healthy adults. We recruited South Korean health check-up examinees without rheumatoid arthritis (RA). A cohort study was performed in 295,837 participants presumably free of osteoarthritis or RA, and who had undergone health screening between 2002 and 2012 and been followed up to determine the risk of all-cause, CVD, and cancer-specific mortality with respect to the presence or titer of RF. To determine whether the participants were deceased, we used National Death Index death certificates. The prevalence of RF positivity (≥20 IU/mL) was 4.4%. During 1,447,403 person-years of follow-up, 1402 participants died. Comparing subjects negative for RF with those positive for RF, the multivariable adjusted hazard ratio (HR; 95% CI) for all-cause and cancer mortality in subjects with RF-positivity was 1.50 (1.19-1.90) and 1.56 (1.12-2.16), respectively. Also, all-cause and cancer mortality risk was significantly greater in subjects with an RF titer greater than 100 IU/mL than in those with RF-negativity (HR = 2.68, 95% CI = 1.72-4.19; HR = 2.89, 95% CI = 1.58-5.28, respectively) after adjusting for multiple confounders. However, the HR for cardiovascular mortality was not higher in subjects with RF positivity than in those with RF negativity (HR = 0.98, 95% CI = 0.45-2.11). In Korean healthy adults, presumably without RA, RF was associated with a greater risk of all-cause and cancer mortality.

The aim of this study is to investigate the effects of CIP2A (Cancerous inhibitor of protein phosphatase 2A) on the apoptosis of RA FLS. Proliferation and apoptotic activity of RA FLS following treatment with CIP2A siRNA or control siRNA were analyzed using MTT assays and Cell Death Detection kit. RA FLS was treated with CIP2A siRNA or control siRNA in 3-, 6-, and 9-day intervals for a Western blot analysis to determine C-Myc expression. To evaluate the signal transduction pathways engaged in apoptosis, caspase-3 activity, caspase-9 activity, PARP, and phosphorylation of the Akt kinase were analyzed by Western blot. Cell viability of RA FLS was significantly lower in the CIP2A siRNA-treated group compared with the control after 7 days (p = 0.022). Apoptosis of RA FLS was significantly higher in the CIP2A siRNA-treated group compared with the control when incubated for 3, 6, and 9 days (p = 0.029, p = 0.021, p = 0.043, respectively). C-Myc expression did not change with the different incubation periods. CIP2A siRNA-treated FLS expressed higher level of activated caspase-3, caspase-9, and PARP (p = 0.014, p = 0.020, p = 0.021, respectively) and lower level of phosphorylated Akt (p = 0.001) compared with those treated with the control siRNA. Our data show that CIP2A expression in RA FLS is an important mediator of dysfunctional apoptosis independent of c-Myc stabilization. Expression of CIP2A may contribute to apoptotic resistance of RA FLS through the activation of Akt and deactivation of caspase-3, caspase-9, and PARP. Inhibition of CIP2A may therefore constitute a novel, promising therapeutic target in RA.

The classification system for antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis and polyarteritis nodosa had its limitations due to numerous overlapping features of these disease entities. The aim of this study is to investigate the clinical features and outcome of patients diagnosed with microscopic polyangiitis (MPA) according to the newly proposed consensus algorithm of ANCA-associated vasculitides and polyarteritis nodosa. Fifty-five cases of MPA, comprised of 33 men and 22 women, diagnosed according to a new consensus algorithm at a single tertiary hospital were identified for analysis. The main clinical features were constitutional symptoms (78.2%), followed by renal involvement (74.5%), musculoskeletal symptoms (67.3%), skin manifestations (50.9%), neurologic involvement (43.6%), and lung involvement (41.8%). P-ANCA and/or anti-myeloperoxidase antibody were present in 69.1%. Five Factor Score and Birmingham Vasculitis Activity Score (BVAS) at diagnosis were 1.1 ± 0.9 and 10.9 ± 4.9, respectively. Forty-four patients were available for a long-term follow-up, and six patients (13.6%) resulted in death. Mortality was associated with BVAS > 9 at the time of diagnosis, age > 60 years, and presence of cardiomyopathy and interstitial lung disease. The survival rate at 1 and 3 years was 93.9 and 89.2%, respectively. Eight patients (14.5%) required dialysis at the time of diagnosis. This is the first study to demonstrate the clinical features in patients with MPA using a new consensus algorithm. Survival rate was higher than previously reported, and interstitial lung disease was a new risk factor for death in patients with MPA.

Wegener's granulomatosis (WG), Churg-Strauss syndrome, and microscopic polyangiitis (MPA) are closely related small vessel vasculitides characterized by anti-neutrophil cytoplasmic antibodies (ANCA). Although there were some reports of MPA presenting with claudication, there are very few reports on WG presenting with claudication of calf muscles. We report an unusual case of ANCA-associated vasculitis in a 75-year-old man who presented with bilateral calf claudication. Comprehensive evaluations, including electromyography, nerve conduction study, lower extremity magnetic resonance imaging, and Doppler scan, did not reveal any other cause of bilateral calf claudication. P-ANCA and anti-myeloperoxidase antibody was positive, but the anti-proteinase 3 antibody was negative. Chest computed tomography scan showed subpleural honeycombing and reticulation, predominantly in both basal lung areas. Biopsy of the calf muscle showed granulomatous vasculitis. Kidney biopsy was also performed which revealed focal necrotizing glomerulonephritis. Our patient does not exhibit typical clinical features for WG, but histopathologic findings of necrotizing granulomatous vasculitis in calf muscle biopsy is highly suggestive of WG.

Cancerous inhibitor of protein phosphatase 2A (CIP2A) is a recently identified oncoprotein that leads to cellular proliferation in cancer cells. We aim to investigate CIP2A expression in fibroblast-like synoviocytes (FLS) and its association with the histopathological grade of synovitis and the invasive function of FLS in rheumatoid arthritis (RA). CIP2A protein expression was measured in 8 RA FLS and 8 OA FLS using Western blot analysis. CIP2A mRNA expression from 19 RA FLS and 7 OA FLS was measured using real-time PCR. Synovitis score of RA FLS-matched synovial tissues was semiquantitatively measured by two independent pathologists. An in vitro cell invasion assay was performed using RA FLS treated with CIP2A small interfering RNA (siRNA) or with control vector. Western blot analysis showed that CIP2A is more frequently overexpressed in RA FLS compared with OA FLS. CIP2A mRNA expression was higher in RA FLS compared with those in OA FLS, but did not reach statistical significance (P = 0.076). In RA, total synovitis score was strongly correlated with FLS CIP2A mRNA expression (rs = 0.849, P = 0.043). TNF-α treatment induced a robust increase in the invasive function of control FLS (P = 0.0021), but no significant effect was observed in CIP2A siRNA-treated FLS. Our data demonstrate that CIP2A expression is closely associated with the histopathological score of synovitis and invasive function of FLS in RA. These results suggest that CIP2A may play a critical role in the destructive process in RA and warrant further investigation of CIP2A as a therapeutic target.

The outcome of systemic lupus erythematosus (SLE) is largely influenced by the existence of lupus nephritis (LN), and its histologic classification guides the treatment and prognosis of SLE. International Society of Nephrology-Renal Pathology Society (ISN-RPS) announced a revised classification of LN in 2004. The present study investigated the differential outcome of World Health Organization (WHO) class III LN when reclassified according to ISN-RPS classification. Forty-three patients with biopsy-proven WHO class III LN at a single tertiary hospital were included in the study. Baseline characteristics at the time of renal biopsy and clinical data during follow-up were obtained from medical records. Renal response to treatment at one-year follow-up was analyzed in three ways; complete response (CR), partial response (PR), and no response (NR). Of 43 patients with previous WHO class III LN, 12 cases were reclassified into ISN-RPS class IV (9 cases of class IV-S and 3 cases of IV-G). Baseline characteristics at the time of renal biopsy were not different between the reclassified class IV and remaining class III LN group except activity index on renal histology, which was significantly elevated in the reclassified class IV group (4.90 vs. 6.75; P = 0.02). Significantly higher number of patients with remaining class III LN achieved CR to treatment than those with reclassified class IV LN at one-year follow-up since initial biopsy (CR: PR: NR; 16:7:7 vs. 3:1:8; P = 0.032). Our study suggests that the ISN-RPS classification is more advantageous in predicting renal outcome and guiding treatment when evaluating previously classified WHO class III LN.

We sought to evaluate the frequency of cervical spine (C-spine) involvement, and associated risk factors for this disorder and its progression in Korean patients with rheumatoid arthritis (RA). From 1995 to 2008, we recruited patients with RA attending the rheumatology clinic of a single tertiary care hospital, and evaluated 1,120 of the patients who had neck pain for C-spine involvement. A diagnosis of C-spine involvement was made in 28.6% of patients evaluated, and within this group, anterior atlantoaxial subluxation (AAS) and subaxial subluxation were found in 89.7 and 15%, respectively. Of the 1,120 patients, 570 patients were followed for more than 3 years. Comparing the clinical characteristics of 193 patients with C-spine involvement and 377 patients without C-spine involvement, we found the associations with female gender, RA diagnosis at or before age 45, erosive changes in hand or foot radiographs, C-reactive protein levels and erythrocyte sedimentation rates at the time of first visit, and combination disease-modifying anti-rheumatic drug (DMARD) therapy. We found using logistic regression analysis that significant predictors of C-spine involvement included erosion in hand or foot radiographs (OR = 2.22, p = 0.001) and RA diagnosis at or before age 45 (OR = 2.26, p < 0.001). Among 137 patients followed for more than 3 years, for whom at least two consecutive X-rays were available, we observed radiographic progression in 60.4%. Patients with and without radiologic evidence for cervical progression did not differ significantly in clinical characteristics. In conclusion, Korean patients with RA frequently show radiographic evidence for progressive involvement of the cervical spine. Significant risk factors for C-spine involvement may be associated with erosive peripheral joint disease and RA diagnosis at an early age.

The aim of this study was to determine the clinical characteristics of Behcet's disease (BD) complicated with malignancy in Korea. Of 1,769 patients with BD in our hospital, 32 patients (1.8%, 21 in solid cancer, 11 in hematologic malignancy) developed cancer. In 10 of the 32 subjects (31.3%), malignancy was diagnosed before or concomitantly with BD. Twelve cases (37.5%) occurred within the first 2 years of disease and 9 cases (28.1%) occurred 5 years after the diagnosis of BD. Myelodysplastic syndrome (MDS) was the most common disease (n = 7) followed by thyroid cancer (n = 4), breast cancer, cervix cancer, stomach cancer, rectal cancer, hepatoma, aplastic anemia (n = 3, each), renal cell cancer, endometrial cancer, lymphoma (n = 1, each). There were no significant differences in the clinical characteristic between patients with or without malignancy. Intestinal involvement were more frequent in patients with malignancy than those without, but was not statistically significant (p = 0.083). Our results demonstrate that MDS and thyroid cancer are the most common hematologic disease and solid cancer associated with BD, respectively. Further studies will be required to ascertain the pathogenic link between BD and malignancy and the prevalence of malignancy in BD.

The authors report an unusual case of myelodysplastic syndrome (MDS) associated with ankylosing spondylitis (AS). A 40-year-old-man with MDS presented with chronic low back pain for 6 years. Four years ago, MDS was diagnosed during routine blood analysis for the work-up of his articular complaints. His initial articular complaints were attributed to extramedullary manifestations of MDS. Persistent low back pain with increasing intensity finally led the patient to seek medical attention. Radiograph of the pelvis showed bilateral asymmetric sacroiliitis. A diagnosis of AS was established on the basis of modified New York criteria. Although various autoimmune phenomena associated with MDS have been described, this is the first report of AS in the setting of MDS. Causal relationship between these two disorders is currently unknown. Increased risk of hematological diseases as well as AS in individuals with a positive HLA-B27 provides a feasible explanation for this rare observation.