A genome-wide association study identified AFF1 as a susceptibility locus for systemic lupus eyrthematosus in Japanese.

Systemic lupus erythematosus (SLE) is an autoimmune disease that causes multiple organ damage. Although recent genome-wide association studies (GWAS) have contributed to discovery of SLE susceptibility genes, few studies has been performed in Asian populations. Here, we report a GWAS for SLE examining 891 SLE cases and 3,384 controls and multi-stage replication studies examining 1,387 SLE cases and 28,564 controls in Japanese subjects. Considering that expression quantitative trait loci (eQTLs) have been implicated in genetic risks for autoimmune diseases, we integrated an eQTL study into the results of the GWAS. We observed enrichments of cis-eQTL positive loci among the known SLE susceptibility loci (30.8%) compared to the genome-wide SNPs (6.9%). In addition, we identified a novel association of a variant in the AF4/FMR2 family, member 1 (AFF1) gene at 4q21 with SLE susceptibility (rs340630; P = 8.3×10(-9), odds ratio = 1.21). The risk A allele of rs340630 demonstrated a cis-eQTL effect on the AFF1 transcript with enhanced expression levels (P<0.05). As AFF1 transcripts were prominently expressed in CD4(+) and CD19(+) peripheral blood lymphocytes, up-regulation of AFF1 may cause the abnormality in these lymphocytes, leading to disease onset.

Long-term follow-up of adalimumab monotherapy for rheumatoid arthritis in Japanese patients: a report of six cases.

We present six cases of patients with Japanese rheumatoid arthritis (RA) treated with a tumor necrosis factor (TNF)-alpha blocking agent, adalimumab as monotherapy for 220 weeks. All six patients were women, and the median age was 54.0 ± 7.07 years old. The median duration of the disease was 7.43 ± 11.1 years, and the median disease activity score (DAS28-CRP) was 5.35 ± 0.69. Three of six patients were able to continue to receive this treatment for 220 weeks successfully, and the DAS28-CRP decreased to 1.89 ± 0.75. Two patients withdrew because of lack of efficacy, and one patient withdrew because of adverse events (non-Hodgkin lymphoma). Adalimumab resulted in a sustained clinical response in RA patients during 220-week follow-up.

Magnetic resonance imaging (MRI) detection of synovitis and bone lesions of the wrists and finger joints in early-stage rheumatoid arthritis: comparison of the accuracy of plain MRI-based findings and gadolinium-diethylenetriamine pentaacetic acid-enhanced MRI-based findings.

OBJECTIVE: To explore whether synovitis and bone lesions in the wrists and finger joints visualized by plain magnetic resonance imaging (MRI)-based findings correspond exactly or not to those judged by gadolinium-diethylenetriamine pentaacetic acid (Gd-DTPA)-enhanced MRI-based findings. METHODS: Magnetic resonance imaging of the wrists and finger joints of both hands were examined in 51 early-stage rheumatoid arthritis (RA) patients whose median disease duration from the onset of articular manifestations to entry was 5 months, by both plain (T1 and short-time inversion recovery images) and Gd-DTPA-enhanced MRI (post-contrast fat-suppressed T1-weighted images) simultaneously. We focused on 15 sites per hand, to examine the presence of synovitis and bone lesions (bone edema and bone erosion). Gd-DTPA-enhanced MRI-based findings were considered "true" lesions, and we evaluated the accuracy of plain MRI-based findings in comparison to Gd-DTPA-enhanced MRI-based findings. RESULTS: Synovitis, judged by plain MRI-based findings, appeared as false-positive at pretty frequency; thus, the specificity, positive predictive value and accuracy of the findings were low. The rate of enhancement (E-rate) in false-positive synovitis sites was significantly low compared with true-positive synovitis sites where Gd-DTPA enhancement appears. In contrast to synovitis, the false-positivity of bone lesions, judged by plain MRI-based findings, was very low compared with Gd-DTPA-enhanced MRI-based findings. CONCLUSION: Synovitis judged by plain MRI-based findings is sometimes considered false-positive especially in sites where synovitis is mild. However, plain MRI is effective in identifying bone lesions in the wrist and finger joints in early-stage RA.

Contribution of an adenine to guanine single nucleotide polymorphism of the matrix metalloproteinase-13 (MMP-13) -77 promoter region to the production of anticyclic citrullinated peptide antibodies in patients with HLA-DRB1*shared epitope-negative rheumatoid arthritis.

We examined whether matrix metalloproteinase-13 (MMP-13) contributes to disease susceptibility or severity of rheumatoid arthritis (RA). Eighty-seven patients with RA whose disease duration was <2 years and 71 healthy controls were enrolled in the study. Adenine (A) to guanine (G) single nucleotide polymorphism (SNP) of the -77 MMP-13 promoter region in RA and healthy controls was determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique. Human leukocyte antigen (HLA)-DRB1 genotyping was also performed using the same populations. Anticyclic citrullinated peptide (anti-CCP) antibodies from RA patients at entry were studied, and their relationships were examined. The genotype and allele frequency of SNP of MMP-13 at -77 did not differ between RA patients and healthy controls. We focused on the RA patients who were negative for HLA-DRB1*shared epitope (SE) alleles and found that the seropositivity of anti-CCP antibodies with a titer >25 U/ml was high in the A/A genotype compared with the G/G genotype. The same characteristic was also found in HLA-DRB1*0405 allele-negative patients. Our data suggest that SNP of the -77 MMP-13 promoter region acts as a surrogate marker of anti-CCP antibody production in HLA-DRB1*SE allele-negative RA patients, which may reflect RA severity.

Comparative study of the detection of joint injury in early-stage rheumatoid arthritis by magnetic resonance imaging of the wrist and finger joints and physical examination.

OBJECTIVE: To verify whether magnetic resonance imaging (MRI)-proven joint injury is sensitive as compared with joint injury determined by physical examination. METHODS: MRI of the wrist and finger joints of both hands was examined in 51 early-stage rheumatoid arthritis (RA) patients by both plain and gadolinium diethylenetriaminepentaacetic acid-enhanced MRI. Synovitis, bone edema, and bone erosion (the latter two included as bone lesions at the wrist joints); metacarpophalangeal joints; and proximal interphalangeal joints were considered as MRI-proven joint injury. Japan College of Rheumatology-certified rheumatologists had given a physical examination just before the MRI study. The presence of tender and/or swollen joints in the same fields as MRI was considered as joint injury on physical examination. The association of MRI-proven joint injury with physical examination-proven joint injury was examined. RESULTS: A total of 1,110 sites were available to be examined. MRI-proven joint injury was found in 521 sites, whereas the other 589 sites were normal. Physical examination-proven joint injury was found in 305 sites, which was significantly low as compared with MRI-proven joint injury (P = 1.1 × 10(-12) versus MRI). Joint injury on physical examination was not found in 81.5% of the sites where MRI findings were normal. Furthermore, an association of the severity of MRI-proven joint injury with that of joint injury on physical examination was clearly demonstrated (P = 1.6 × 10(-15), r(s) = 0.469). CONCLUSION: Our present data suggest that MRI is not only sensitive but accurately reflects the joint injury in patients with early-stage RA.

Efficacy and safety of mizoribine by one single dose administration for patients with rheumatoid arthritis.

OBJECTIVE: Mizoribine (MZR) is an immunosuppressant that inhibits nucleic acid metabolism and is a relatively safe disease-modifying anti-rheumatic drug (DMARD). We evaluated the efficacy and safety of one single dose per day for patients with rheumatoid arthritis (RA). PATIENTS AND METHODS: In this study 32 patients with RA received MZR therapy. We evaluated the average dose of MZR and prednisolone, response to treatment and peak plasma level of MZR. RESULTS: The average dose of MZR was 146.1±31.2 (range: 50-200) mg/day. The average dose of prednisolone was 4.63±3.59 (range: 0-14) mg/day. The average plasma level of MZR, measured after 3 hours, was 2.20±0.49 µg/mL in the responder group and 1.59±0.82 µg/mL in the non-responder group (p=0.020). The treatment with MZR for 24 weeks was completed by 71.9% of patients and the proportion of patients who achieved a good and moderate response rate according to the European League Against Rheumatism (EULAR) criteria was 56.3% at 24 weeks. The plasma level of MZR which was greater than or equal to 2.12 µg/mL was significantly correlated with the clinical response (p<0.01). Only one of thirty-two cases discontinued the treatment, because of skin eruption. CONCLUSION: This study included patients that could not be treated with other DMARDs and/or biologic agents because of age, interstitial pneumonia and other complications. We show that MZR may be a useful and relatively safe therapy for patients in this group.

Successful treatment of chronic lupus myocarditis with prednisolone and mizoribine.

A 36-year-old female patient who was diagnosed with chronic myocarditis as an initial manifestation of systemic lupus erythematosus (SLE) was admitted to our hospital. At her third occurrence of heart failure, we performed an endomyocardial biopsy and proved chronic myocarditis with SLE. Subsequently, she was treated with prednisolone and the immunosuppressive agent mizoribine (MZR), and her cardiac function improved. We describe for the first time treatment with MZR for chronic cardiac involvement of SLE.

Regulation of disease susceptibility and mononuclear cell infiltration into the labial salivary glands of Sjögren's syndrome by monocyte chemotactic protein-1.

OBJECTIVE: To investigate how monocyte chemotactic protein-1 (MCP-1) is involved in the pathological process of primary SS (pSS). METHODS: Guanine (G) to adenine (A) single nucleotide polymorphism (SNP) of the -2518 MCP-1 promoter region in pSS and healthy controls was determined by the PCR-restriction fragment length polymorphism technique. Immunohistochemical staining towards MCP-1 and C-C motif chemokine receptor-2 (CCR2), a receptor of MCP-1, of the labial salivary glands of pSS was investigated. Furthermore, the expression of MCP-1 and CCR2 from the cultured primary salivary epithelial cells was studied by RT-PCR, ELISA and western blotting. RESULTS: The genotype and allele frequency of SNP of MCP-1 at -2518 showed that the G/G genotype is low but the presence of allele A as well as the A-allele frequency are high in pSS (n = 52) as compared with healthy controls (n = 164). Immunohistochemistry showed in situ expression of MCP-1 and CCR2 in the ductal structure and infiltrating mononuclear cells (MNCs) of patients with pSS. Primary salivary epithelial cells in vitro from pSS produced MCP-1, which was significantly stimulated by IFN-gamma, as identified by both ELISA and RT-PCR. In contrast to MCP-1, CCR2 expression of primary salivary epithelial cells in vitro was not so changed by IFN-gamma. CONCLUSIONS: MCP-1 is involved in the disease susceptibility of pSS in the Japanese population. MCP-1 interactions with CCR2, which may be facilitated by IFN-gamma, are thought to perpetuate MNC infiltration into the salivary glands of SS.

Switching to the anti-interleukin-6 receptor antibody tocilizumab in rheumatoid arthritis patients refractory to antitumor necrosis factor biologics.

We evaluated the short-term effects of the anti-interleukin-6 (IL-6) receptor antibody tocilizumab (TCZ) in six patients with rheumatoid arthritis (RA) who had been refractory to tumor necrosis factor (TNF) antagonist therapy. All subjects were considered to be secondary nonresponders to TNF antagonists as decided by each physician. The Disease Activity Score of 28 Joints (DAS28) appeared to improve slowly by TCZ compared with TNF antagonist therapy, but significantly decreased at 24 weeks. One patient achieved DAS28 remission [DAS28-erythrocyte sedimentation rate (ESR) <2.60, and 5 of 6 patients showed good or moderate clinical response. The change in the clinical Disease Activity Index was similar to that of the DAS28-ESR. The serum level of matrix metalloproteinase-3 (MMP-3), a marker for synovial overgrowth, also significantly decreased after the treatment (518 +/- 567 at baseline, 141 +/- 90 ng/ml at 24 weeks, p < 0.05). One patient discontinued TCZ because of tuberculous peritonitis. Although physicians need to watch for infectious adverse events, these data indicate that TCZ is effective for treating RA patients refractory to TNF antagonists.

Cutaneous vasculitis induced by TNF inhibitors: a report of three cases.

We describe 3 rheumatoid arthritis (RA) patients with anti-tumor necrosis factor (TNF) therapy-induced cutaneous vasculitis. Two cases were induced by infliximab and the other, in whom cutaneous vasculitis was found early at the start of therapy, was induced by etanercept. Skin biopsy was obtained in 2 patients, with histology-proven leukocytoclastic vasculitis. One patient spontaneously improved after cessation of the TNF inhibitor. Two patients required oral corticosteroid, the efficacy of which was observed to be excellent and rapid.

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 1beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha), or IL-17. IL-1beta was the most potent for stimulating the production of CCL20. CCL20 production was synergistically augmented by a combination of IL-1beta, TNF-alpha, and IL-17. In contrast, interferon-gamma suppressed IL-1beta-induced CCL20 production. IL-6, in combination with soluble IL-6 receptor (sIL-6R), did not modulate CCL20 production, whereas IL-1beta-induced, TNF-alpha-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.

Different expression levels of TNF receptors on the rheumatoid synovial macrophages derived from surgery and a synovectomy as detected by a new flow cytometric analysis.

TNFalpha plays a crucial role in the pathogenesis of rheumatoid arthritis. It is very important to examine the expression of the TNF receptors, the ligand of TNFalpha. In this study, we developed a triple-color flow cytometric analysis using CD45 and CD14 monoclonal antibodies to simply detect the expression of the TNF receptors on the heterogeneous rheumatoid synovial cells. Using this system, we detected a higher population of macrophages and a greater TNF receptor expression on the synovial macrophages derived from a synovectomy in comparison to the findings obtained from knee joint replacement surgery.

Prediction of DAS28-CRP remission in patients with rheumatoid arthritis treated with tacrolimus at 6 months by baseline variables.

We attempted to determine what baseline variables are responsible for the efficacy of tacrolimus at 6 months in Japanese patients with rheumatoid arthritis (RA). One hundred and six RA patients treated with tacrolimus for 6 months were entered in this study. The outcome was set as the achievement of Disease Activity Score 28 C-reactive protein (DAS28-CRP) remission at 6 months. We examined the association of gender, DAS28-CRP at baseline, concomitant use of methotrexate (MTX), and concomitant use of prednisolone with the achievement of DAS28-CRP remission at 6 months by logistic regression analysis. Twenty-three of 106 patients (21.7%) achieved DAS28-CRP remission at 6 months. There was concomitant use of MTX by 20 patients (18.9%), prednisolone by 93 (87.7%), and prednisolone [5 mg/day by 43 (40.6%) at baseline. Logistic regression analysis showed that male gender (first) and moderate disease activity at baseline (second) are independent predictors toward achieving DAS28-CRP remission at 6 months. Maximum tacrolimus dosage administrated for patients over a 6-month period appeared not to be predictive for the DAS28-CRP remission at 6 months. In conclusion, we revealed for the first time that good outcome in RA patients treated with tacrolimus can be predictive by some baseline variables. That is clinically valuable for daily practice in the choice of disease-modifying antirheumatic drugs (DMARDs), especially tacrolimus.

[A case of microscopic polyangiitis relapsed with diffuse alveolar hemorrhage and rapidly progressive glomerulonephritis].

The patient was a 63-year-old woman. She was admitted to our hospital with acute renal failure and multiple mononeuritis in 2002. She was diagnosed as microscopic polyangiitis based on positive for MPO-ANCA. Remission was induced by combination therapy with methylprednisolone pulse therapy and plasma exchange. Because condition of the disease was stable, prednisolone was discontinued from August 2006. Elevation of serum creatinine and microscopic hematuria was detected in November 2007. Fever and dyspnea occurred in January 24 2008. Elevation of CRP and serum creatinine was found, and infiltration in bilateral lung was noted on chest X-ray. She was admitted on the same day. After admission, she presented with hemosputum and exacerbation of dyspnea. Chest CT revealed diffuse consolidation and ground glass opacity, and MPO-ANCA converted to be positive. Diagnosis of diffuse alveolar hemorrhage and rapidly progressive glomerulonephritis with microscopic polyangiitis was made, and she was managed by artificial respirator and CHDF in ICU. Combination therapy with steroid pulse therapy and plasma exchange re-induced remission. Mizoribine was administrated as maintenance therapy with oral prednisolone.

Prediction of DAS28-ESR remission at 6 months by baseline variables in patients with rheumatoid arthritis treated with etanercept in Japanese population.

We tried to determine which baseline variables are responsible for remission induction at 6 months in unselected rheumatoid arthritis (RA) patients of Japanese population treated with etanercept. One hundred forty-one patients with RA who were administered etanercept were registered. Thirty-four patients were started on etanercept monotherapy, 60 patients on cotherapy with methotrexate (MTX) (MTX cotherapy), and 47 patients on cotherapy with other non-MTX nonbiologic disease-modifying antirheumatic drugs (DMARDs) (non-MTX cotherapy). None of the patients were treated with both MTX and non-MTX nonbiologic DMARDs at entry. Outcome was set as achievement of disease activity score 28 (DAS28)-ESR remission at 6 months. We examined association of gender, DAS at baseline, MTX cotherapy at baseline, non-MTX cotherapy at baseline, and prednisolone use at baseline with achievement of remission at 6 months by logistic regression analysis. All subjects were classified as having high (N = 109) or moderate disease activity (N = 32) at entry. One hundred twenty out of 141 patients (85.1%) continued treatment with etanercept at 6 months. Continuation rate was statistically higher in MTX cotherapy (93.3%) compared with etanercept monotherapy (73.5%), and tended to be higher than with non-MTX cotherapy (85.1%). Logistic regression analysis identified that MTX cotherapy at entry and moderate disease activity at entry were independent variables for remission induction at 6 months. Accordingly, DAS28-ESR at 6 months was significantly lower with MTX cotherapy as compared with etanercept monotherapy or non-MTX cotherapy. To a lesser extent, DAS28-ESR with non-MTX cotherapy at 6 months was lower than with etanercept monotherapy. In this study of unselected patients, use of MTX and moderate disease activity at entry were associated with higher likelihood of response to etanercept. Non-MTX nonbiologic DMARDs may be an alternative in RA patients administrated etanercept who are intolerant to MTX.

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.

High serum cartilage oligomeric matrix protein determines the subset of patients with early-stage rheumatoid arthritis with high serum C-reactive protein, matrix metalloproteinase-3, and MRI-proven bone erosion.

OBJECTIVE: To identify the significance of serum cartilage oligomeric matrix protein (COMP), a marker of cartilage turnover, in patients with early-stage rheumatoid arthritis (RA) in relation to other serologic variables and magnetic resonance imaging (MRI) features. METHODS: Ninety-eight patients with early-stage RA, whose disease duration from onset was less than 2 years, were enrolled. The objective measures at baseline were Disease Activity Score (DAS28), serum C-reactive protein (CRP), serum matrix metalloproteinase-3 (MMP-3), serum antibodies against cyclic citrullinated peptide (anti-CCP), and MRI features of both wrist and finger joints. The MRI features included the number of sites scored positive for synovitis, bone edema, and bone erosion. RESULTS: Serum COMP concentration was not different among groups identified with low, moderate, and high DAS28-CRP values. However, COMP values were statistically high in subjects positive for bone erosions on MRI compared with the subjects who were negative for bone erosions. A positive correlation of COMP with CRP and with MMP-3 values was also identified. CONCLUSION: Elevation of COMP may reflect joint damage that is dependent on the synovial inflammatory process in early-stage RA.

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 (51)Chrominium release assay. The expression of NK cell activating receptors (NKG2D, CD244, CD2, and CD16) and intracellular molecules (granzyme B, perforin, and TCR zeta chain) in CD3-CD56+ cells were characterized by flow cytometry. The serum cytokine levels (IL-6, TNFalpha, 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, TNFalpha, 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.

Determination of the subset of Sjogren's syndrome with articular manifestations by anticyclic citrullinated peptide antibodies.

OBJECTIVE: To investigate whether anticyclic citrullinated peptide antibodies (anti-CCP) predict the subset of Japanese patients with Sjögren's syndrome (SS) with articular manifestations. METHODS: Eighty-seven patients with SS were enrolled. Prevalence of anti-CCP antibodies, IgM rheumatoid factor, anti-Ro/SSA antibody, anti-La/SSB antibody, and serum IgG concentration and their relation to articular manifestations were examined. Articular manifestations included morning stiffness and the presence of tender or swollen joints. RESULTS: Eighty-seven SS patients were divided into 3 groups: 14 secondary SS with nonerosive rheumatoid arthritis (RA); 47 primary SS with articular manifestations; and 26 primary SS without articular manifestations. Ten out of 14 secondary SS with nonerosive RA expressed anti-CCP. Anti-CCP was the only statistically proven marker preferentially distributed in patients with articular manifestations (the first 2 groups) compared to primary SS without such manifestations; however, its frequency was low in primary SS. No patient with primary SS without articular manifestations expressed anti-CCP. CONCLUSION: Anti-CCP is found in the subset of Japanese with SS with articular manifestations although most of those with anti-CCP-positive SS were classified as secondary SS with RA.