Comparison of complications during 1-year follow-up between remitting seronegative symmetrical synovitis with pitting edema syndrome and elderly-onset rheumatoid arthritis.

Remitting seronegative symmetrical synovitis with pitting edema syndrome (RS3PE), a rheumatic disease affecting the elderly, responds well to corticosteroids; however, our RS3PE patients' corticosteroid therapy is longer than expected. Elderly-onset rheumatoid arthritis (EORA) patients are reported to be at a significantly increased risk for steroid-related side effects including cardiovascular diseases (CVDs). To clarify the complications during a 1-year follow-up in corticosteroid-treated RS3PE patients compared to EORA patients. We retrospectively analyzed the records of 47 RS3PE patients (28 men, 19 women, age 78.4 ± 7.5 years) and 46 EORA patients (10 men, 36 women; 77.0 ± 6.8 yrs) to compare the complications over a 1-year follow-up. The RS3PE and EORA groups' average initial PSL doses were 16.5 ± 7.2 mg/day and 7.3 ± 4.6 mg/day, respectively. During the 1-year follow-up after treatment, there was no significant increase in CVDs in both groups. However, infections occurred in nine RS3PE patients, which is a significantly higher incidence compared to the EORA patients with infections (n = 3). The initial PSL dose was the independent variable associated with the incidence of infection. Infections were significantly increased during elderly RS3PE patients' steroid therapy. The initial corticosteroid dose was an infection-risk factor.Key messagesInfections are increased during steroid therapy in elderly patients with RS3PE syndrome.The initial dose of corticosteroids was one of the risk factors for infections.

Rheumatoid arthritis patients with low baseline Health Assessment Questionnaire scores have a risk of functional disability progression: a post hoc analysis of a nationwide longitudinal cohort in Japan.

OBJECTIVES: To determine prognostic factors for the Health Assessment Questionnaire-Disability Index (HAQ-DI) progression in patients with rheumatoid arthritis (RA) in clinical practice. METHODS: We evaluated 388 biological disease-modifying anti-rheumatic drug (bDMARD)-naïve Japanese patients with RA with moderate to high disease activity at study entry after being treated with conventional synthetic DMARDs. These patients were treated according to a treat-to-target (T2T) strategy for one year. The Disease Activity Score in 28 joints-erythrocyte sedimentation rate (DAS28-ESR) and the HAQ-DI were assessed every three months. We also evaluated joint destruction using a modified total Sharp score at baseline and at one year. HAQ-DI progression was defined as the yearly progression of HAQ-DI >0.1. We performed a multiple logistic regression analysis to explore the factors predicting HAQ-DI progression at one year. RESULTS: HAQ-DI progression was observed in 18% of the patients. The multiple logistic regression analysis revealed the independent variables associated with HAQ-DI progression were: DAS28-ESR >5.1 at baseline (odds ratio [OR] 0.31, 95% con dence interval [CI] 0.13-0.74, p=0.0083); HAQ-DI score at baseline <0.5 (OR 2.27, 95% CI 1.22-4.26, p=0.0102); and achievement of low disease activity at 12 weeks (OR 0.42, 95% CI 0.21-0.82, p=0.0112). CONCLUSIONS: Our data suggest that maintaining clinical improvement according to T2T and initiating the treatment at an early stage are important for functional improvement after one year and that patients with low baseline HAQ scores have a higher risk of HAQ disability progression.

Anti-citrullinated peptide antibodies are the strongest predictor of clinically relevant radiographic progression in rheumatoid arthritis patients achieving remission or low disease activity: A post hoc analysis of a nationwide cohort in Japan.

OBJECTIVES: To determine prognostic factors of clinically relevant radiographic progression (CRRP) in patients with rheumatoid arthritis (RA) achieving remission or low disease activity (LDA) in clinical practice. METHODS: Using data from a nationwide, multicenter, prospective study in Japan, we evaluated 198 biological disease-modifying antirheumatic drug (bDMARD)-naïve RA patients who were in remission or had LDA at study entry after being treated with conventional synthetic DMARDs (csDMARDs). CRRP was defined as the yearly progression of modified total Sharp score (mTSS) >3.0 U. We performed a multiple logistic regression analysis to explore the factors to predict CRRP at 1 year. We used receiver operating characteristic (ROC) curve to estimate the performance of relevant variables for predicting CRRP. RESULTS: The mean Disease Activity Score in 28 joints-erythrocyte sedimentation rate (DAS28-ESR) was 2.32 ± 0.58 at study entry. During the 1-year observation, remission or LDA persisted in 72% of the patients. CRRP was observed in 7.6% of the patients. The multiple logistic regression analysis revealed that the independent variables to predict the development of CRRP were: anti-citrullinated peptide antibodies (ACPA) positivity at baseline (OR = 15.2, 95%CI 2.64-299), time-integrated DAS28-ESR during the 1 year post-baseline (7.85-unit increase, OR = 1.83, 95%CI 1.03-3.45), and the mTSS at baseline (13-unit increase, OR = 1.22, 95%CI 1.06-1.42). CONCLUSIONS: ACPA positivity was the strongest independent predictor of CRRP in patients with RA in remission or LDA. Physicians should recognize ACPA as a poor-prognosis factor regarding the radiographic outcome of RA, even among patients showing a clinically favorable response to DMARDs.

Clinical outcomes in the first year of remitting seronegative symmetrical synovitis with pitting edema (RS3PE) syndrome.

OBJECTIVE: We investigated clinical outcomes in patients with remitting seronegative symmetrical synovitis with pitting edema (RS3PE) syndrome. METHODS: This is a retrospective multicenter study conducted in Nagasaki, Japan. We consecutively diagnosed a total of 41 patients with RS3PE syndrome between October 2003 and September 2012 and evaluated their outcomes from medical records from the first year of follow-up. RESULTS: Although an excellent initial response to corticosteroids was noted in all 41 patients, 34 (82.9%) were still receiving corticosteroids and 13 (31.7%) showed elevated C-reactive protein (CRP) at one year. Multivariate analysis demonstrated that male gender and high CRP level at entry were independent variables associated with patients' one-year CRP level being ≥0.5 mg/dL. Odds ratios were 17.05 ([95% CI 2.41-370.12], p < 0.026) and 12.99 ([95% CI 1.78-269.62], p < 0.0096), respectively. Twenty-four patients (58.5%) were still receiving prednisolone (PSL) ≥ 5 mg/day at one year. Disease-modifying anti-rheumatic drugs including methotrexate were required in three patients (10.3%). Neoplasms were found in 14 patients (34.1%) and 1 of these had died due to lung cancer at one year. CONCLUSIONS: RS3PE syndrome initially responds well to corticosteroids with remission of symptoms. However, outcomes of RS3PE syndrome appear to be worse than expected, and may be influenced by gender and initial CRP level.

A multicenter phase II prospective clinical trial of glucocorticoid for patients with untreated IgG4-related disease.

OBJECTIVE: Although glucocorticoids are effective for patients with IgG4-related disease, the treatment has not yet been standardized. Therefore, the treatment strategy should be established. PATIENTS AND METHODS: Patients who fulfilled the comprehensive diagnostic criteria for definite IgG4-related disease were started on prednisolone (0.6 mg/kg body weight) with the dose reduced every two weeks. The subsequent maintenance dose and need for prednisolone were determined for individual patients. The primary endpoint was the complete remission (CR) rate at one year. Secondary endpoints included overall response rate (ORR), the maintenance dose, the relapse rate, and adverse events. RESULTS: This study enrolled 61 patients. After clinicopathological review, three patients were excluded, and one, 13, and 44 patients were diagnosed with probable, possible, and definite IgG4-related disease, respectively. Of the 44 patients with definite IgG4-RD, 29 (65.9%) achieved CR, and the ORR was 93.2%. No patient was refractory to primary treatment. The most frequent adverse events were glucose intolerance. Six patients relapsed. CONCLUSIONS: Glucocorticoid treatment is usually effective for patients with IgG4-RD, and we should examine the possibility of other disorders when a patient is glucocorticoid refractory. Some patients are misdiagnosed, making central clinicopathological review of diagnosis very important in conducting clinical studies.

Prognostic Factors Toward Clinically Relevant Radiographic Progression in Patients With Rheumatoid Arthritis in Clinical Practice: A Japanese Multicenter, Prospective Longitudinal Cohort Study for Achieving a Treat-to-Target Strategy.

To determine prognostic factors of clinically relevant radiographic progression (CRRP) in patients with rheumatoid arthritis (RA) in clinical practice.We performed a multicenter prospective study in Japan of biological disease-modifying antirheumatic drug (bDMARD)-naive RA patients with moderate to high disease activity treated with conventional synthetic DMARDs (csDMARDs) at study entry. We longitudinally observed 408 patients for 1 year and assessed disease activity every 3 months. CRRP was defined as yearly progression of modified total Sharp score (mTSS) > 3.0 U. We also divided the cohort into 2 groups based on disease duration (<3 vs ≥3 years) and performed a subgroup analysis.CRRP was found in 10.3% of the patients. A multiple logistic regression analysis revealed that the independent variables to predict the development of CRRP were: CRP at baseline (0.30 mg/dL increase, 95% confidence interval [CI] 1.01-1.11), time-integrated Disease Activity Score in 28 joints-erythrocyte sedimentation rate (DAS28-ESR) during the 1 year postbaseline (12.4-unit increase, 95%CI 1.17-2.59), RA typical erosion at baseline (95%CI 1.56-21.1), and the introduction of bDMARDs (95%CI 0.06-0.38). The subgroup analysis revealed that time-integrated DAS28-ESR is not a predictor whereas the introduction of bDMARDs is a significant protective factor for CRRP in RA patients with disease duration <3 years.We identified factors that could be used to predict the development of CRRP in RA patients treated with DMARDs. These variables appear to be different based on the RA patients' disease durations.

Decreased Expression of Innate Immunity-Related Genes in Peripheral Blood Mononuclear Cells from Patients with IgG4-Related Disease.

BACKGROUND: IgG4-related disease (IgG4-RD) is a new clinical entity of unknown etiology characterized by elevated serum IgG4 and tissue infiltration by IgG4-positive plasma cells. Although aberrancies in acquired immune system functions, including increases in Th2 and Treg cytokines observed in patients with IgG4-RD, its true etiology remains unclear. To investigate the pathogenesis of IgG4-RD, this study compared the expression of genes related to innate immunity in patients with IgG4-RD and healthy controls. MATERIALS AND METHODS: Peripheral blood mononuclear cells (PBMCs) were obtained from patients with IgG4-RD before and after steroid therapy and from healthy controls. Total RNA was extracted and DNA microarray analysis was performed in two IgG4-RD patients to screen for genes showing changes in expression. Candidate genes were validated by real-time RT-PCR in 27 patients with IgG4-RD and 13 healthy controls. RESULTS: DNA microarray analysis identified 21 genes that showed a greater than 3-fold difference in expression between IgG4-RD patients and healthy controls and 30 genes that showed a greater than 3-fold change in IgG4-RD patients following steroid therapy. Candidate genes related to innate immunity, including those encoding Charcot-Leyden crystal protein (CLC), membrane-spanning 4-domain subfamily A member 3 (MS4A3), defensin alpha (DEFA) 3 and 4, and interleukin-8 receptors (IL8R), were validated by real-time RT-PCR. Expression of all genes was significantly lower in IgG4-RD patients than in healthy controls. Steroid therapy significantly increased the expression of DEFA3, DEFA4 and MS4A3, but had no effect on the expression of CLC, IL8RA and IL8RB. CONCLUSIONS: The expression of genes related to allergy or innate immunity, including CLC, MS4A3, DEFA3, DEFA4, IL8RA and IL8RB, was lower in PBMCs from patients with IgG4-RD than from healthy controls. Although there is the limitation in the number of patients applied in DNA microarray, impaired expression of genes related to innate immunity may be involved in the pathogenesis of IgG4-RD as well as in abnormalities of acquired immunity.

Two cases of refractory polymyositis accompanied with steroid myopathy.

Polymyositis (PM) is an inflammatory muscle disease characterized by chronic inflammation in skeletal muscle. Although most patients with PM respond to corticosteroids, some cases show an unsatisfactory response and other therapeutic options must be considered. Furthermore, glucocorticosteroid (GC) toxicity leads to a significant disability known as steroid myopathy, particularly in elderly patients. Here we report two patients with refractory PM. Combined treatment with high-dose GCs, tacrolimus, and intravenous immunoglobulin resulted in beneficial effects against myositis. However, muscle weakness and the disability progressed due to steroid myopathy, and subsequent oral intake became impossible because of swallowing disturbance in these two patients. Nutritional intervention, including branched-chain amino acids (BCAAs) and rehabilitation, was undertaken in addition to treatment against myositis. These treatments finally improved the muscle weakness and activities of daily living, and the two patients were discharged after recovery. The high-dose GC treatment caused elevation of serum levels of amino acids, including BCAAs, but these amino acids subsequently declined during BCAA replacement therapy. These findings suggest that the catabolic effects of the glucocorticoid treatment impair the balance of amino acids, including BCAAs, within the muscle, leading to steroid myopathy.

Safety of tacrolimus treatment during pregnancy and lactation in systemic lupus erythematosus: a report of two patients.

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease that affects women of childbearing years. Pregnancy with SLE is associated with an increase risk of adverse maternal and fetal outcomes. Recently, tacrolimus has been used for steroid-resistant SLE. However, because of limited information regarding the use of immunosuppressants during pregnancy, many SLE patients give up pregnancy. We report two SLE patients receiving tacrolimus who hoped to become pregnant. Patient 1 was a 31-year-old woman diagnosed with SLE 6 years earlier and treated with tacrolimus for 3 years because her symptoms were not controlled with other immunosuppressants. Patient 2 was a 28-year-old woman diagnosed with SLE 13 years earlier and treated with tacrolimus for 3 years because her symptoms were not controlled with prednisolone alone. The medical ethics board in our hospital approved the use of tacrolimus during pregnancy and lactation, and informed consent was obtained from the patients. Both patients were well controlled during pregnancy with prednisolone (Patient 1: 12 mg/day and Patient 2: 10 mg/day) and tacrolimus therapy (3 mg/day). They had healthy newborns and continued breastfeeding with tacrolimus therapy. The blood concentrations of tacrolimus 12 hours after taking tacrolimus was 3.0 ng/ml in Patient 1 and 2.9 ng/ml in Patient 2, and their newborns' blood concentrations of tacrolimus 1 hour after breastfeeding were 0.2 ng/ml and 0.5 ng/ml, respectively. Both newborns are healthy for at least 3 years after birth. This is the first report on the safety of tacrolimus for pregnancy and lactation in patients with SLE.

HLA-DRB1*08:02 Is Associated with Bucillamine-Induced Proteinuria in Japanese Rheumatoid Arthritis Patients.

BACKGROUND: Drug-induced proteinuria can occur in rheumatoid arthritis (RA) patients treated with d-penicillamine, gold salts, or bucillamine (Buc), and represents a drug hypersensitivity reaction. Striking associations of human leukocyte antigen (HLA) alleles with adverse reactions have recently been reported for many drugs. METHODS: We investigated the association of HLA class II with Buc-induced proteinuria (BI-Pro) in 485 Japanese RA patients treated with Buc, of whom 25 had developed BI-Pro. RESULTS AND CONCLUSION: This preliminary study showed a highly significant association of DRB1*08:02 with BI-Pro (P = 1.09 × 10(-6), corrected P [Pc] = 1.96 × 10(-5), odds ratio [OR] 25.17, 95% confidence interval [CI] 7.98-79.38). DQB1*04:02 was also significantly associated with increased risk of BI-Pro (P = 2.44 × 10(-5), Pc = 2.69 × 10(-4), OR 10.35, 95%CI 3.99-26.83). These findings provide useful information for promoting personalized medicine for RA.

[An usual case of vasculo- and neuro-Behçet's disease with MEFV mutations].

  A 35-year-old man had a 2-year history of uveitis and arterial wall thickening of an aortic branching artery detected by magnetic resonance imaging. He was admitted to our hospital because of mental exaltation. He had been treated with a moderate dose of prednisolone (30 mg/ml) plus methotrexate (6 mg/week) under the diagnosis of Takayasu arteritis for 2 years. Neurological examinations and brain magnetic resonance imaging taken on admission showed no abnormal findings. Although cerebrospinal fluid showed four cells/mm3 and 45 mg/dl of protein, cerebrospinal fluid interleukin-6 levels were markedly elevated (65.4 pg/mL), suggesting the neuro-Behçet's disease. The diagnosis of coexistence of vasculo- and neuro-Behçet's disease was made because vascular lesions are considered as a complication of Behçet's disease. We performed DNA testing using direct sequencing of all exons of the MEFV gene because of the patient's history of periodic fever since 30 year-old. The E148Q/L110P compound heterozygous mutation was found. His neurological symptoms and periodic fever were well controlled after the administration of infliximab (5 mg/kg every 2-month interval). Although occurrence by chance cannot be ruled out, the unusual findings of this patient suggest that MEFV mutations have some etiopathogenic mechanisms of an atypical phenotype of Behçet's disease.

IgG4-related epididymo-orchitis associated with bladder cancer: possible involvement of BAFF/BAFF-R interaction in IgG4-related urogenital disease.

We describe herein a patient who presented with immunoglobulin G4-related disease (IgG4-RD) involving the testis and prostate as well as the submandibular glands. Massive infiltration of IgG4-expressing plasma cells was observed in testis and prostate tissues. Serum concentrations of B cell activating factor belonging to the tumor necrosis factor family (BAFF) were elevated in parallel with serum IgG4 concentrations, and infiltration of BAFF-receptor (BAFF-R)-expressing B cells and BAFF-expressing lymphoid cells was observed around the ectopic lymphoid foci in the affected urogenital tissues. To date, testicular involvement in a patient diagnosed with IgG4-RD had not been reported, making this the first reported case of IgG4-related epididymo-orchitis. These findings suggest that the immune mechanism underlying ectopic lymphoneogenesis in IgG4-RD may involve enhanced BAFF/BAFF-R interactions among lymphoid cells.

A case of cutaneous polyarteritis nodosa with elevated serum interleukin-6 levels complicated by leg arterial stenosis and destructive arthropathy of the left ankle.

We report a case of a 60-year-old female with cutaneous polyarteritis nodosa (CPN) of the left ankle, accompanied by elevated serum interleukin (IL)-6 levels. Computed tomographic angiography revealed severe narrowing of medium-sized arteries in her left leg. Destructive arthropathy in the left ankle was identified by X-ray and magnetic resonance imaging. This is the first Japanese case of severe CPN complicated by destructive arthropathy. Quantification of serum IL-6 might be useful in diagnosis and evaluation of CPN.

Coexistence of familial Mediterranean fever and rheumatoid arthritis.

Familial Mediterranean fever (FMF) is an autoinflammatory disorder characterized by recurrent febrile polyserositis and arthritis. Although accompanying seronegative spondyloarthropathy has been reported in FMF, coexistence with rheumatoid arthritis (RA) is very rare. This case report describes a Japanese female RA patient who presented with periodic fever. Genetic analysis revealed compound heterozygous mutations in exon 2 and 3 of the MEFV gene (E148Q/G304R/P369S/R408Q). The patient was successfully treated with colchicine with 3-year follow-up.

IgG4-related Mikulicz's disease: ultrasonography of the salivary and lacrimal glands for monitoring the efficacy of corticosteroid therapy.

OBJECTIVES: IgG4-related Mikulicz's disease (IgG4-MD) has been recently established as a subtype of IgG4-related diseases involving the salivary and lacrimal glands, and the diseased glands are characteristically and highly responsive to corticosteroid therapy. We retrospectively evaluated ultrasonography (US) of the salivary and lacrimal glands for monitoring the efficacy of corticosteroid treatment in patients with IgG4-MD. METHODS: US features of the salivary and lacrimal glands were assessed and compared with the serum IgG4 levels in 8 patients with IgG4-MD before and at various stages after initiation of oral corticosteroids. RESULTS: US features of the lacrimal and salivary glands of patients with IgG4-MD were characterised by multiple hypoechoic areas in enlarged glands. The submandibular glands were most frequently involved by the disease, and bilateral glands of the same type were similarly affected exhibiting the same hypoechoic pattern. Alleviations of abnormal gland architecture and size in response to corticosteroid therapy were effectively detected with US. The US findings of the involved glands were proportional to the serum IgG4 level before and during the corticosteroid therapy. CONCLUSIONS: US helps monitor the efficacy of corticosteroid treatment in patients with IgG4-MD.

Association of increased frequencies of HLA-DPB1*05:01 with the presence of anti-Ro/SS-A and anti-La/SS-B antibodies in Japanese rheumatoid arthritis and systemic lupus erythematosus patients.

INTRODUCTION: Autoantibodies to ribonucleoprotein are associated with a variety of autoimmune diseases, including rheumatoid arthritis (RA). Many studies on associations between human leukocyte antigen (HLA) alleles and RA have been reported, but few have been validated in RA subpopulations with anti-La/SS-B or anti-Ro/SS-A antibodies. Here, we investigated associations of HLA class II alleles with the presence of anti-Ro/SS-A or anti-La/SS-B antibodies in RA. METHODS: An association study was conducted for HLA-DRB1, DQB1, and DPB1 in Japanese RA and systemic lupus erythematosus (SLE) patients that were positive or negative for anti-Ro/SS-A and/or anti-La/SS-B antibodies. RESULTS: An increased prevalence of certain class II alleles was associated with the presence of anti-Ro/SS-A antibodies as follows: DRB1*08:03 (Pc = 3.79×10(-5), odds ratio [OR] 3.06, 95% confidence interval [CI] 1.98-4.73), DQB1*06:01 (Pc = 0.0106, OR 1.70, 95%CI 1.26-2.31), and DPB1*05:01 (Pc = 0.0040, OR 1.55, 95%CI 1.23-1.96). On the other hand, DRB1*15:01 (Pc = 0.0470, OR 3.14, 95%CI 1.63-6.05), DQB1*06:02 (Pc = 0.0252, OR 3.14, 95%CI 1.63-6.05), and DPB1*05:01 (Pc = 0.0069, OR 2.27, 95% CI 1.44-3.57) were associated with anti-La/SS-B antibodies. The DPB1*05:01 allele was associated with anti-Ro/SS-A (Pc = 0.0408, OR 1.69, 95% CI 1.19-2.41) and anti-La/SS-B antibodies (Pc = 2.48×10(-5), OR 3.31, 95%CI 2.02-5.43) in SLE patients. CONCLUSION: HLA-DPB1*05:01 was the only allele associated with the presence of both anti-Ro/SS-A and anti-La/SS-B antibodies in Japanese RA and SLE patients.

Coexistence of polymyositis and familial Mediterranean fever.

Familial Mediterranean fever (FMF) is an autosomal recessive disease affecting populations surrounding the Mediterranean area. In this case report, we report a Japanese female patient with polymyositis (PM) who presented with periodic fever. Genetic analysis revealed that she had compound heterozygous mutations in exon 2 of the MEFV gene (L110P/E148Q/R202Q). Treatment with colchicines (1.0 mg/day) successfully eliminated febrile attack and normalized the elevated levels of neutrophil CD64 expression, leading to the diagnosis of FMF. The association of FMF and PM has not previously been reported, so we discuss this rare association.

A case of apoplectic lymphocytic hypophysitis complicated by polymyalgia rheumatica.

A case of apoplectic lymphocytic hypophysitis complicated by polymyalgia rheumatica (PMA) is described. A 72-year-old man was admitted to our hospital due to severe headache. Two months prior to admission, the patients had exhibited recent-onset stiffness and myalgia of shoulder and pelvic girdle that was compatible with PMR. Magnetic resonance imaging revealed a mass lesion in the pituitary fossa with focal hemorrhage. Endocrinologic studies demonstrated hypopituitarism. The headache and myalgia were improving with corticosteroid treatment; however, a trans-sphenoidal surgery was performed due to visual field loss. A white-colored mass was resected, and histologic examination showed diffuse infiltration of lymphocytes and plasma cells consistent with lymphocytic hypophysitis. Post-operatively, the headache and visual field loss resolved completely. This is the first documented case of apoplectic lymphocytic hypophysitis complicating PMR, and a possible mechanism for this rare association was discussed.

Epstein-Barr virus and methotrexate-related CNS lymphoma in a patient with rheumatoid arthritis.

Patients with rheumatoid arthritis (RA), especially those treated with methotrexate (MTX), might have an increased risk of lymphoproliferative disorders that are associated with Epstein-Barr virus (EBV). We describe a case of EBV-associated central nervous system (CNS) lymphoma (diffuse large B-cell lymphoma) in a patient with RA on a short course of MTX treatment. The neoplastic cells express the B-cell surface markers (CD20, Pax-5 and CD30), and EBV-encoded RNA was demonstrated by in situ hybridization. The patient's lymphoma did not recur for the 8-year follow-up period after the tumor resection and cessation of MTX. MTX may promote EBV-positive CNS lymphoma in RA patient due to its immunosuppressive properties as well as reactivating latent EBV infection.

Serum amyloid A (SAA) induces pentraxin 3 (PTX3) production in rheumatoid synoviocytes.

OBJECTIVE: Pentraxin 3 (PTX3) is an acute-phase reactant that is involved in amplification of the inflammatory response and innate immunity. In the present study, we evaluated the relationship between PTX3 and serum amyloid A (SAA), another acute-phase reactant, in rheumatoid synoviocytes. METHODS: PTX3 mRNA expression was examined by reverse transcription polymerase chain reaction, and PTX3 protein was measured by enzyme-linked immunosorbent assay. RESULTS: SAA induced PTX3 mRNA and PTX3 protein expression in rheumatoid synoviocytes. SAA-induced PTX3 expression was attenuated when rheumatoid synoviocytes were nucleofected with N-formyl peptide receptor ligand-1 (FPRL-1)-specific siRNA, suggesting the involvement of FPRL-1. Furthermore, SAA-induced PTX3 expression was inhibited by NF-κB or mitogen-activated protein kinase-specific inhibitors. Neither soluble TNF receptor (etanercept) nor recombinant IL-1 receptor antagonist affected PTX3 production by SAA-stimulated synoviocytes, suggesting that SAA directly induces PTX3. CONCLUSION: Our data suggest that SAA plays a role in the proinflammatory and immune responses in rheumatoid synovium by inducing PTX3. We provide the first evidence that the acute-phase reactant SAA, which is produced systemically by hepatocytes, perpetuates the rheumatoid inflammatory processes by inducing another proinflammatory molecule, PTX3, locally in rheumatoid synovial tissues.