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ID PMID Title PublicationDate abstract
21146146 Tumor necrosis factor-α blockade, cardiovascular outcomes, and survival in rheumatoid art 2011 Jan The effect of TNF-α blockade on the risk of cardiovascular outcomes and long-term survival in patients with rheumatoid arthritis (RA) is not known. We assembled a cohort of 20,811 (75,329 person-years) U.S. veterans who were diagnosed with RA between October 1998 and September 2005, and who were treated with a disease-modifying anti-rheumatic drug (DMARD). Cox survival models were built to examine the effect of TNF-α antagonists on the risk of a composite endpoint of cardiovascular outcomes defined as the occurrence of atherosclerotic heart disease, congestive heart failure, peripheral artery disease, or cerebrovascular disease, and on the risk of death. Treatment with TNF-α antagonists was not associated with a significant effect on the composite endpoint of cardiovascular outcomes. When each outcome was examined separately, the use TNF-α antagonists was not associated with an increased risk of atherosclerotic heart disease, congestive heart failure, or peripheral artery disease, but it was associated with decreased risk of cerebrovascular disease (hazard ratio [HR] = 0.83; confidence interval [CI] = 0.70-0.98). The use of TNF-α antagonists did not affect the risk of death (HR = 0.99; CI = 0.87-1.14). In subgroup analyses, the use TNF-α antagonists was associated with a reduced risk of cardiovascular outcomes (HR = 0.90, CI = 0.83-0.98) in patients younger than the median age of our cohort (63 years). The use TNF-α antagonists was not associated with a change in the risk of death in any other subgroup. These results show that the risk of cardiovascular events and survival in patients who receive TNF-α antagonists is not different than those who receive other DMARDs.
19967426 Cost-effectiveness analysis of rituximab treatment in patients in Germany with rheumatoid 2010 Feb OBJECTIVE: The present health economic analysis investigated the cost-effectiveness-ratios of either (1) rituximab or (2) an alternative TNF-alpha-inhibiting agent as second line biological treatment in patients with active rheumatoid arthritis (RA) and an inadequate response to etanercept therapy. METHODS: Incremental cost per quality-adjusted life-year (QALY) gained by rituximab treatment of RA is compared to TNF-inhibitor change (standard sequence) in a Markov-model (perspective: health care payer, full life-time approach). Direct cost components taken into account were treatment costs (medication-, administration- and monitoring costs) and resource utilisation (outpatient costs, inpatient costs). Indirect costs were estimated separately by the assessment of impaired work capacity due to RA (2008 Euro currency, discount rate 3.5%). Utility measures for the different treatment options were obtained from the ACR-response rates of published pivotal clinical trials. RESULTS: Direct costs amount to euro 178,373 (standard sequence) and euro 192,295 (rituximab sequence), respectively, rendering incremental direct costs of euro 13,922. Incremental utilities yield 0.57 QALYs and the incremental cost-effectiveness-ratio (ICER) of rituximab compared to the standard sequence amounts to euro 24,517. Inclusion of indirect costs leads to less incremental costs and a lower ICER of euro 15,565/QALY. Thus, ICERs stay beneath the accepted threshold of euro 50,000/QALY. CONCLUSION: Rituximab appears to be a cost-effective treatment alternative compared to the switch between TNF-inhibitors as second line biological treatment in patients with active RA having failed etanercept.
20649960 Alterations in the self-renewal and differentiation ability of bone marrow mesenchymal ste 2010 INTRODUCTION: Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease primarily involving the synovium. Evidence in recent years has suggested that the bone marrow (BM) may be involved, and may even be the initiating site of the disease. Abnormalities in haemopoietic stem cells' (HSC) survival, proliferation and aging have been described in patients affected by RA and ascribed to abnormal support by the BM microenvironment. Mesenchymal stem cells (MSC) and their progeny constitute important components of the BM niche. In this study we test the hypothesis that the onset of inflammatory arthritis is associated with altered self-renewal and differentiation of bone marrow MSC, which alters the composition of the BM microenvironment. METHODS: We have used Balb/C Interleukin-1 receptor antagonist knock-out mice, which spontaneously develop RA-like disease in 100% of mice by 20 weeks of age to determine the number of mesenchymal progenitors and their differentiated progeny before, at the start and with progression of the disease. RESULTS: We showed a decrease in the number of mesenchymal progenitors with adipogenic potential and decreased bone marrow adipogenesis before disease onset. This is associated with a decrease in osteoclastogenesis. Moreover, at the onset of disease a significant increase in all mesenchymal progenitors is observed together with a block in their differentiation to osteoblasts. This is associated with accelerated bone loss. CONCLUSIONS: Significant changes occur in the BM niche with the establishment and progression of RA-like disease. Those changes may be responsible for aspects of the disease, including the advance of osteoporosis. An understanding of the molecular mechanisms leading to those changes may lead to new strategies for therapeutic intervention.
21098575 Beneficial and harmful effects of shoulder arthroplasty in patients with rheumatoid arthri 2011 Mar OBJECTIVE: To assess beneficial and harmful effects of arthroplasty in the shoulder joint in patients with RA. METHODS: A systematic review within the framework of the Cochrane Collaboration identified randomized controlled trials (RCTs), controlled clinical trials and case series (included for assessment of complications) published between 1995 and 2008. Articles considered potentially relevant were retrieved in full text and assessed independently by two authors. Risk of bias and level of evidence were assessed according to the established criteria. RESULTS: One RCT (26 shoulders) compared cemented and uncemented humeral stem fixation during arthroplasty, reporting no significant differences between groups at 2-year follow-up (low-quality evidence). Nineteen case series (1155 shoulders) reported component loosening requiring revision at 5%, infections at 2% and minor complications at 7% (very low-quality evidence). The retrospective case series had several limitations related to methodological quality and standards of reporting. CONCLUSION: At present, there is very little research evidence supporting decisions about shoulder joint arthroplasty in patients with RA.
19375267 Patient assessment of medication information leaflets and validation of the Evaluative Lin 2009 Nov OBJECTIVE: To obtain patient feedback about the structure and quality of medication information leaflets and validate the usefulness of the Evaluative Linguistic Framework (ELF) for improving written communication with patients. METHODS: Triangulated feedback about a set of rheumatoid arthritis (RA) medication leaflets, some developed with knowledge of the ELF, was obtained from 27 people with RA from interviews, focus group discussion and self-administered questionnaires. The principal elements of the framework were investigated: overall generic structure and functions of each stage, interpersonal relationship between writer and reader, technicality of language and density of information. RESULTS: Participant assessments of the leaflets aligned with the framework in terms of what constituted a good leaflet. While the main purpose of the leaflets was identified as being information provision, participants also wanted clear instructions, benefits to be highlighted and side effects to be comprehensively listed. For comprehensiveness and user-friendliness, leaflets developed with guidance of the ELF were consistently preferred. CONCLUSION: According to people with RA, leaflets generated from a linguistic framework are clearer and more effective in communicating information about medications. PRACTICE IMPLICATIONS: The ELF is a user-friendly, structured analytic system that can assist with the development of effective high quality patient information materials.
20436074 Antibodies to porphyromonas gingivalis are associated with anticitrullinated protein antib 2010 Jun OBJECTIVE: Anticitrullinated protein antibodies (ACPA) are relatively specific for rheumatoid arthritis (RA), and predate disease. The oral pathogen Porphyromonas gingivalis may play a role in breaking immune tolerance to citrullinated antigens. We studied a cohort of patients with RA and their relatives looking for associations between anti-P. gingivalis antibodies and ACPA. METHODS: Patients with RA (n = 82) and their relatives (n = 205) from a North American Native (NAN) population were studied, along with 47 NAN and 60 non-NAN controls. IgM and IgA rheumatoid factor (RF) were tested by nephelometry and ELISA. Second-generation anticyclic citrullinated peptide (anti-CCP2) isotypes and IgG anti-P. gingivalis lipopolysaccharides were tested by ELISA. HLA-DRB1 typing was performed by sequencing. Oral hygiene and smoking habits were assessed by questionnaires. RESULTS: Autoantibody frequency in patients with RA and relatives: ACPA 91% vs 19%, respectively; IgM RF 82% vs 17%; IgA RF 48% vs 22%. Anti-P. gingivalis levels were higher in patients with RA compared to relatives and controls (p = 0.005) and higher in ACPA-positive patients with RA than in ACPA-negative patients with RA (p = 0.04) and relatives (p < 0.001), but comparable in RF-positive and RF-negative patients and relatives. Poor oral hygiene and smoking were prevalent, but with no clear association with autoantibodies. Relatives with 2 shared-epitope alleles were more likely to be ACPA-positive (OR 2.5, p = 0.02). CONCLUSION: In a genetically predisposed population of NAN patients with RA and their relatives, anti-P. gingivalis antibodies were associated with ACPA. These findings suggest that immune responses to P. gingivalis may be involved in breaking immune tolerance to citrullinated antigens.
20825487 Changes in arterial stiffness during continued infliximab treatment in patients with infla 2011 Aug Chronic inflammatory arthropathies such as rheumatoid arthritis (RA), ankylosing spondylitis (AS), and psoriatic arthritis (PsA) are associated with an increased risk of cardiovascular disease. TNF-α antagonists may improve vascular function in these patients and thus be beneficial with regard to cardiovascular disease. This study evaluated arterial stiffness and disease activity between two infusions with a TNF-α antagonist (infliximab) in patients with inflammatory arthropathies on long-term infliximab therapy. Augmentation index (AIx), aortic pulse wave velocity (aPWV), and disease activity were measured in 17 patients with RA, AS, or PsA who had been treated with infliximab for at least 12 months. The patients were examined immediately before their infliximab infusion and thereafter every 10th day until their next infusion scheduled at week 4-8. AIx and aPWV did not change during the period between two infliximab infusions. The patients had a temporary improvement in the general disease activity assessed on visual analogue scales by the patients (P = 0.04) and the investigator (P = 0.02) after the infusion. In the group of patients with RA, the Disease Activity Score (DAS28) changed significantly in a similar manner (P = 0.003). C-reactive protein and erythrocyte sedimentation rate remained unchanged. Infliximab infusions did not alter aortic pulse wave velocity or augmentation index in patients with inflammatory arthropathies who were on long-term infliximab therapy. Reductions in the general disease activity and DAS28 were not reflected in alterations of aortic stiffness or augmentation index.
19377156 Designing artificial jaw joints (AJJs) in VR space for patients with rheumatoid arthritis. 2009 In this present study, we will report on a case of a patient with sleep-disordered breathing (SDB). She suffered a condyle fracture that led to rheumatoid arthritis. Furthermore, we will review how we planned her treatment and designed her artificial jaw joints (AJJs) via 3D imaging in VR space.We decided the mandibular position based on the facial aesthetic line (E-line) and the occlusion. Then we designed her AJJs to comply with the translated mandible via 3D-modeling software.The upper airway obstruction is assumed to occur in the present case due to a pharyngeal obstruction, as in other patients with micrognathia or Sleep Apnea Syndrome. Therefore we had to take the sleep disorder into consideration in addition to occlusal management, based on experience with situations similar to this present case. Furthermore, designing a custom-made AJJs via a 3D model could prove insightful when it came to arranging the treatment plan of SDB patients.
20007620 A new design for registration trials in rheumatoid arthritis allowing secondary head-to-he 2010 Jan Current drug development programs produce high quality data on the efficacy of new drugs, substantial data on safety, but little data on actual applicability of the new product compared to standard of care. After successful registration and launch, such data require years to accumulate and often remain incomplete. This viewpoint proposes a new trial design for phase 2 and 3 drug trials in rheumatoid arthritis. In this design the trial starts conventionally: patients that are inadequate responders to standard treatment (usually methotrexate) are randomised to receive the experimental drug or placebo on the background of continued (methotrexate) treatment. However, after 3 months all patients in the placebo group are additionally treated with one and the same standard of care treatment (usually an inhibitor of tumour necrosis factor) and all patients in the experimental group are additionally treated with a placebo corresponding to the chosen standard of care treatment. This design allows primary assessment of efficacy and safety of the experimental drug compared with placebo at the ethically acceptable limit of 3 months, followed by secondary assessments of efficacy (including durability) and safety compared to standard of care. The secondary assessments are observational and thus more prone to bias, but it is argued that the potential for bias is limited in this setting. Widespread adoption of the design will greatly help to determine the place of a new product in the spectrum of treatment possibilities of rheumatoid arthritis.
19000788 Differential influences of bucillamine and methotrexate on the generation of fibroblast-li 2009 Jan We have recently demonstrated that bone marrow CD34+ cells from rheumatoid arthritis (RA) patients displayed abnormal capacities to respond to TNF-alpha and to differentiate into fibroblast-like cells producing MMP-1 (type B synoviocyte -like cells). The current study examined the effects of representative potent disease-modifying antirheumatic drugs, including bucillamine (BUC) and methotrexate (MTX) on the in vitro generation of fibroblast-like cells from RA bone marrow CD34+ cells. CD34+ cells purified from bone marrow specimens of 8 patients with active RA were cultured in the presence or absence of pharmacologically attainable concentrations of intramolecular disulfide form of bucillamine (BUC-ID, 3 microM), a major metabolite of BUC or MTX (20 nM). After incubation for 28 days, the generation of fibroblast-like cells was assessed under phase-contrast light microscopy and the concentrations of MMP-1 and VEGF in the culture supernatants were measured by ELISA. BUC-ID, but not MTX, significantly suppressed the generation of fibroblast-like cells from RA bone marrow CD34+ cells stimulated with SCF, GM-CSF and TNF-alpha (p=0.024 as determined by Wilcoxon signed rank test). Accordingly, BUC-ID, but not MTX, significantly suppressed the production of MMP-1 (p=0.017) and VEGF (p=0.017) by RA bone marrow CD34+ cells, without inhibition of beta2-microglobulin production. These results demonstrate that BUC-ID, but not MTX, is a potent inhibitor of differentiation of fibroblast-like cells from RA bone marrow CD34+ cells. Since MTX, but not BUC, has been previously shown to influence on type A synoviocytes, the data provide rationale of combination of BUC and MTX in the treatment of RA.
20679475 Decrease in immunoglobulin free light chains in patients with rheumatoid arthritis upon ri 2010 Dec OBJECTIVES: Immunoglobulin (Ig) free light chains (FLCs) are short-lived B cell products that contribute to inflammation in several experimental disease models. In this study, FLC concentrations in inflamed joints of patients with rheumatoid arthritis (RA) as compared to patients with osteoarthritis were investigated. In addition, the relationship of FLCs and disease activity upon B cell depletion (rituximab) in patients with RA was studied. METHODS: Synovial fluid (SF) and tissue from patients with RA were analysed for local presence of FLCs using ELISA and immunohistochemistry. In addition, FLC concentrations were measured (at baseline, 3 and 6 months after treatment) in 50 patients with RA with active disease who were treated with rituximab. Changes in FLCs were correlated to changes in disease activity and compared to alterations in IgM, IgG, IgA, IgM-rheumatoid factor (RF) and IgG-anti-citrullinated protein antibody (ACPA) concentrations. RESULTS: FLCs were detected in synovial tissue from patients with RA, and high FLC concentrations were found in SF from inflamed joints, which positively correlate with serum FLC concentrations. Serum FLC concentrations significantly correlated with disease activity score using 28 joint counts, erythrocyte sedimentation rate (ESR) and C reactive protein, and changes in FLC correlated with clinical improvement after rituximab treatment. Moreover, effect of treatment on FLC concentrations discriminated clinical responders from non-responders, whereas IgM-RF and IgG-ACPA significantly decreased in both patient groups. CONCLUSIONS: FLCs are abundantly present in inflamed joints and FLC levels correlate with disease activity. The correlation of FLC concentrations and disease activity indicates that FLCs may be relevant biomarkers for treatment response to rituximab in patients with RA and suggests that targeting FLC may be of importance in the therapy of RA.
19368499 Herpes zoster risk factors in a national cohort of veterans with rheumatoid arthritis. 2009 May 15 BACKGROUND: Herpes zoster occurs more commonly in patients taking immunosuppressive medications, although the risk associated with different medications is poorly understood. METHODS: We conducted a retrospective cohort study involving 20,357 patients who were followed in the Veterans Affairs healthcare system and treated for rheumatoid arthritis from October 1998 through June 2005. Cox proportional hazards regression was used to determine risk factors for herpes zoster and herpes zoster-free survival. Chart review was performed to validate the diagnosis of herpes zoster. RESULTS: The incidence of herpes zoster was 9.96 episodes per 1000 patient-years. In time-to-event analysis, patients receiving medications used to treat mild rheumatoid arthritis were less likely to have an episode of herpes zoster than patients receiving medications used to treat moderate and severe rheumatoid arthritis (P < .001). Independent risk factors for herpes zoster included older age, prednisone use, medications used to treat moderate and severe rheumatoid arthritis, malignancy, chronic lung disease, renal failure, and liver disease. Among patients receiving tumor necrosis factor-alpha antagonists, etanercept (hazard ratio, 0.62) and adalimumab (hazard ratio, 0.53) were associated with a lower risk of herpes zoster. There was excellent agreement between the International Classification of Diseases, Version 9, Clinical Modification diagnosis of herpes zoster and diagnosis by chart review (kappa = 0.92). CONCLUSIONS: Risk factors for herpes zoster included older age, prednisone use, medications used to treat moderate and severe rheumatoid arthritis, and several comorbid medical conditions. These results demonstrate that the Department of Veterans Affairs' national administrative databases can be used to study rare adverse drug events.
18817899 Cardiovascular involvement in systemic autoimmune diseases. 2009 Feb Autoimmune diseases, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), primary antiphospholipid syndrome (APS), systemic sclerosis and systemic vasculitis, affect a large number of people in whom one of the leading causes of morbidity and mortality is cardiovascular disease. Cardiovascular disease is associated with the development of accelerated atherosclerosis. It seems to occur at a younger age than in the general population, is often asymptomatic and, in addition to traditional risk factors, also involves specific risk factors as chronic inflammation, the duration and activity of the autoimmune disease, and immunosuppressive therapy. The early phases of cardiovascular involvement in patients with autoimmune diseases may be clinically silent, with only a microcirculation disorder present. There are various means of detecting morphological cardiac damage: coronary angiography remains the gold standard for diagnosing coronary stenosis, but new, non invasive and more reliable methods have been introduced into clinical practice in order to detect subclinical microcirculation abnormalities.
19447827 Development of quality indicators for monitoring of the disease course in rheumatoid arthr 2009 Dec OBJECTIVES: To suppress rheumatoid arthritis (RA) patients' disease activity, it should be periodically measured and patients should be treated on the basis of the disease activity outcomes. Insight into the actual care, by using quality indicators, is the first step in achieving optimal care. The objective of this study was to develop a set of quality indicators to evaluate RA disease course monitoring of rheumatologists in daily clinical practice. METHODS: A RAND-modified Delphi method in a five-step procedure was applied: a literature search for quality indicators and recommendations about disease course monitoring; a first questionnaire round; a consensus meeting; a second questionnaire round and drawing up the final set. RESULTS: The systematic procedure resulted in the development of 18 quality indicators: 10 process, five structure and three outcome indicators that describe seven domains of disease course monitoring: schedule follow-up visits; measure disease activity; functional impairment; structural damage; change medication; preconditions for measuring disease activity and outcome measures in terms of disease activity. CONCLUSIONS: This quality indicator set can be used to assess the quality of disease course monitoring of rheumatologists in daily clinical practice, and to determine for which aspects of disease course monitoring rheumatologists perform well, or where there is room for improvement. This information can be used to improve the quality of disease course monitoring.
19273452 Circulating leptin and adiponectin concentrations during tumor necrosis factor blockade in 2009 Apr OBJECTIVE: Adipocytokines, including leptin and adiponectin, may play an important role in the pathogenesis of rheumatoid arthritis (RA). We investigated the effects of longterm therapeutic tumor necrosis factor (TNF) blockade on adipocytokine concentrations in patients with RA. METHODS: We studied 58 RA patients starting anti-TNF therapy and 58 healthy controls matched for age, sex, and body mass index (BMI). Fasting blood samples were drawn at baseline, 2 weeks, and 6 months after the start of anti-TNF therapy and serum levels of leptin and adiponectin were measured. RESULTS: Patients with RA had increased adiponectin (p<0.001) and similar leptin concentrations compared with the controls. Leptin concentrations were significantly higher in patients with high BMI (p<0.001) and correlated positively with BMI at all timepoints (r>0.75). In contrast, serum adiponectin tended to be higher in lean RA patients and did not correlate with BMI at any timepoint. There were no clear correlations between serum concentrations of adipocytokines and disease activity (Disease Activity Score 28). Short or longterm TNF blockade alone had no influence on circulating leptin and adiponectin concentrations. Patients treated with anti-TNF and concomitant corticosteroids on a stable basis showed a significant decrease in adiponectin levels after 6 months of therapy (p<0.025). CONCLUSION: In patients with RA, chronic inflammation and its suppression during anti-TNF therapy have limited influence on plasma leptin concentrations, while significantly decreasing circulating adiponectin levels. Our findings question the suggested key role of inflammatory markers in regulating adipocytokine patterns in RA.
21085018 The safety and effectiveness of a chloroform/methanol extract of Tripterygium wilfordii Ho 2010 Dec OBJECTIVES: The objective of the study was to assess the safety and effectiveness of the chloroform/methanol extract of Tripterygium wilfordii Hook F (T2) plus methotrexate (MTX) in treating patients with rheumatoid arthritis (RA). METHODS: One hundred sixty-six patients with RA, who started the combination therapy of T2 (20 mg b.i.d. or t.i.d.) and MTX (10-12.5 mg/wk), were enrolled, and these patients were followed up for at least 1 year. Demographics, disease severity, markers of disease activity before and after the combination therapy, and incidence of adverse events were evaluated. RESULTS: The patients were predominantly female (n = 134, 81%) with a mean age of 58.0 (SD, 7.9) years (range, 39-79 years) and a mean disease duration of 55.0 (SD, 72.2) months (range, 0-456 months). A total of 161, 161, 146, and 85 patients had received at least 1, 3, 12, and 24 months of the combination of T2 and MTX, with a total of 4162 patient-months' exposure to the combination therapy. The combination therapy reduced tender and swollen joint counts, morning stiffness, inflammatory indices such as ESR and CRP, and improved disease activity as measured by the DAS28 significantly by 3 months as well as 12 months (P < 0.05). Most of the adverse events noted during this study were mild. Menstrual irregularity occurred in 72.7% (16/22) of premenopausal female. Only 10 (6.0%) and 8 (4.8%) subjects withdrew because of adverse events or lack of efficacy, respectively. Severe infections were very rare. CONCLUSION: T2 plus MTX is an effective and relatively safe treatment for RA patients.
20079789 IL-21 regulates Th17 cells in rheumatoid arthritis. 2010 Apr IL-21 is a type I cytokine that like IL-2, IL-4, IL-7, IL-9, and IL-15 uses the common gamma chain of cytokine receptor. IL-21 has been shown to regulate the function of T cells, B cells, natural killer cells, and dendritic cells in immune responses. Although activated CD4(+) T cells produce IL-21, recent data suggest that novel subsets of effector T cells are the major producers in immune responses. In this study, we show that IL-21 expression correlates with the presence of Th17 cells in synovial fluid (SF) and peripheral blood in rheumatoid arthritis patients. Human CCR6+ CD4(+) T cells produce high levels of both IL-21 and IL-17. Similar to mouse T cells, IL-21 auto-regulates its own production in human CD4(+) T cells. IL-21 potently enhances Th17 proliferation and suppresses Foxp3 expression, leading to the expression of RORC. IL-21 is therefore an autocrine cytokine that regulates human Th17 cells in rheumatoid arthritis, and serves as a good target for treating this autoimmune disease.
20806997 Bugs as drugs, Part 1: Insects: the "new" alternative medicine for the 21st century? 2010 Jul Insects and insect-derived products have been widely used in folk healing in many parts of the world since ancient times. Promising treatments have at least preliminarily been studied experimentally. Maggots and honey have been used to heal chronic and post-surgical wounds and have been shown to be comparable to conventional dressings in numerous settings. Honey has also been applied to treat burns. Honey has been combined with beeswax in the care of several dermatologic disorders, including psoriasis, atopic dermatitis, tinea, pityriasis versicolor, and diaper dermatitis. Royal jelly has been used to treat postmenopausal symptoms. Bee and ant venom have reduced the number of swollen joints in patients with rheumatoid arthritis. Propolis, a hive sealant made by bees, has been utilized to cure aphthous stomatitis. Cantharidin, a derivative of the bodies of blister beetles, has been applied to treat warts and molluscum contagiosum. Combining insects with conventional treatments may provide further benefit.
19143467 Ectopic lymphoid structures support ongoing production of class-switched autoantibodies in 2009 Jan 13 BACKGROUND: Follicular structures resembling germinal centres (GCs) that are characterized by follicular dendritic cell (FDC) networks have long been recognized in chronically inflamed tissues in autoimmune diseases, including the synovium of rheumatoid arthritis (RA). However, it is debated whether these ectopic structures promote autoimmunity and chronic inflammation driving the production of pathogenic autoantibodies. Anti-citrullinated protein/peptide antibodies (ACPA) are highly specific markers of RA, predict a poor prognosis, and have been suggested to be pathogenic. Therefore, the main study objectives were to determine whether ectopic lymphoid structures in RA synovium: (i) express activation-induced cytidine deaminase (AID), the enzyme required for somatic hypermutation and class-switch recombination (CSR) of Ig genes; (ii) support ongoing CSR and ACPA production; and (iii) remain functional in a RA/severe combined immunodeficiency (SCID) chimera model devoid of new immune cell influx into the synovium. METHODS AND FINDINGS: Using immunohistochemistry (IHC) and quantitative Taqman real-time PCR (QT-PCR) in synovial tissue from 55 patients with RA, we demonstrated that FDC+ structures invariably expressed AID with a distribution resembling secondary lymphoid organs. Further, AID+/CD21+ follicular structures were surrounded by ACPA+/CD138+ plasma cells, as demonstrated by immune reactivity to citrullinated fibrinogen. Moreover, we identified a novel subset of synovial AID+/CD20+ B cells outside GCs resembling interfollicular large B cells. In order to gain direct functional evidence that AID+ structures support CSR and in situ manufacturing of class-switched ACPA, 34 SCID mice were transplanted with RA synovium and humanely killed at 4 wk for harvesting of transplants and sera. Persistent expression of AID and Igamma-Cmu circular transcripts (identifying ongoing IgM-IgG class-switching) was observed in synovial grafts expressing FDCs/CD21L. Furthermore, synovial mRNA levels of AID were closely associated with circulating human IgG ACPA in mouse sera. Finally, the survival and proliferation of functional B cell niches was associated with persistent overexpression of genes regulating ectopic lymphoneogenesis. CONCLUSIONS: Our demonstration that FDC+ follicular units invariably express AID and are surrounded by ACPA-producing plasma cells provides strong evidence that ectopic lymphoid structures in the RA synovium are functional and support autoantibody production. This concept is further confirmed by evidence of sustained AID expression, B cell proliferation, ongoing CSR, and production of human IgG ACPA from GC+ synovial tissue transplanted into SCID mice, independently of new B cell influx from the systemic circulation. These data identify AID as a potential therapeutic target in RA and suggest that survival of functional synovial B cell niches may profoundly influence chronic inflammation, autoimmunity, and response to B cell-depleting therapies.
21107991 Contribution of an adenine to guanine single nucleotide polymorphism of the matrix metallo 2011 Jun 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.