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ID PMID Title PublicationDate abstract
19734133 A CLEC16A variant confers risk for juvenile idiopathic arthritis and anti-cyclic citrullin 2010 Aug OBJECTIVE: Variants in CLEC16A have conferred susceptibility to autoimmune diseases in genome-wide association studies. The present work aimed to investigate the locus' involvements in juvenile idiopathic arthritis (JIA) and further explore the association with rheumatoid arthritis (RA), type 1 diabetes (T1D) and Addison's disease (AD) in the Norwegian population. METHODS: Three single nucleotide polymorphisms (SNPs) were genotyped in patients with RA (n=809), JIA (n=509), T1D (n=1211) and AD (n=414) and in healthy controls (n=2149). RESULTS: All diseases were associated with CLEC16A, but with different SNPs. The intron 22 SNP, rs6498169, was associated with RA (p=0.006) and JIA (p=0.016) and the intron 19 SNPs, rs12708716/rs12917716, with T1D (p=1x10-5) and AD (p=2x10-4). The RA association was confined to the anti-cyclic citrullinated peptide antibody (anti-CCP) negative subgroup (p=2x10-4). CONCLUSION: This is the first report of a CLEC16A association with JIA and a split of the RA association according to anti-CCP status. Different causative variants underlie the rheumatic versus the organ specific diseases.
20925596 Anti-IL-17A therapy protects against bone erosion in experimental models of rheumatoid art 2011 May Interleukin-17A (IL-17A) is a pro-inflammatory cytokine secreted by a subset of memory T cells and other innate immune cells. It is associated with rheumatoid arthritis (RA) due to IL-17A expression in RA synovial fluid. The severe bone erosive rat adjuvant-induced arthritis (rAIA) and mouse collagen-induced arthritis (mCIA) models were used to address the therapeutic efficacy of anti-IL-17A treatment with a focused investigation on bone protection. In the rAIA model, treatment with anti-IL-17A completely alleviated arthritis, lowered the level of receptor activator of NFκB ligand (RANKL), and inhibited structural damage to the bones. In the mCIA model, IL-17A neutralization coincident with arthritis development or in mice with established arthritis diminished joint swelling by inhibiting disease initiation and progression. Intriguingly, even the few joints that became outwardly severely inflamed in the presence of an anti-IL-17A antagonist had diminished joint histopathology scores compared to severely inflamed, control-treated mice. The bone-preserving property correlated with decreased RANKL message in severely inflamed paws of arthritic mice. These data identify IL-17A as a key factor in inflammation-mediated bone destruction and support anti-IL-17A therapy for the treatment of inflammatory bone diseases such as RA.
20890038 [Cytokines in bone diseases. Anti-cytokine therapies for bone and joint diseases]. 2010 Oct The efficacy of biologics targeting inflammatory cytokines such as TNF and IL-6 for bone and joint diseases has been emerging. Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by chronic synovitis and bone damage. By the use of TNF-inhibitors, clinical remission, structural remission and functional remission have become possible during the treatment of RA. Especially, the progress of joint and bone destruction is completely suppressed by TNF-inhibitors in the vast majority of RA patients. On the other hand, anti-RANKL antibody inhibits joint destruction as well as systemic osteoporosis, though no effects on synovitis of RA. Thus, differential efficacy of different therapies in bone destruction and osteoporosis would warrant further study to clarify the mechanisms of bone and joints diseases.
20626209 Mycophenolate mofetil in the treatment of adults with advanced rheumatoid arthritis: three 2010 BACKGROUND: Mycophenolate mofetil is an immunosuppressive agent approved for the prophylaxis of renal, cardiac and hepatic transplant rejection. With its proven immunosuppressive effects and favourable toxicity profile, mycophenolate mofetil was postulated as a potential candidate for treating rheumatoid arthritis. OBJECTIVES: To evaluate the efficacy and safety profile of mycophenolate mofetil in the treatment of adults with advanced refractory rheumatoid arthritis. METHODS: The effectiveness of mycophenolate mofetil (1 g twice daily) in the treatment of advanced refractory rheumatoid arthritis was assessed in three 24-week, randomized, double-blind, parallel-group trials (two placebo-controlled [n = 229 and n = 214] and one with ciclosporin 2.5-4 mg/kg/day as a comparator [n = 842]). Patients had American Rheumatism Association functional class II or III disease, a mean disease duration of 9.8-13 years, and had failed treatment with a median of three to four disease-modifying antirheumatic drugs. Overall, 959/1262 (76%) of patients in the main analysis group were female and 1189/1262 (94%) were Caucasian. RESULTS: In the placebo-controlled trials, the American College of Rheumatology 20% responder index rate did not differ significantly between mycophenolate mofetil and placebo (19.7% [29/147] vs 13.0% [9/69] and 15.8% [22/139] vs 10.1% [7/69]; p > 0.05 for both studies). Consequently, the active-comparator trial was stopped prematurely before completion and efficacy analyses were not performed. Treatment-emergent adverse events were experienced by 51.6% (371/719), 73.1% (304/416) and 36.1% (53/147) of patients receiving mycophenolate mofetil, ciclosporin and placebo, respectively. Hypertension, increased serum creatinine, muscle cramps, hirsutism and hypertrichosis were more than twice as common with ciclosporin as with mycophenolate mofetil. In all three trials, the incidence of serious adverse events with mycophenolate mofetil was 12.1% (compared with 11.3% and 7.5% for ciclosporin and placebo, respectively). CONCLUSION: Mycophenolate mofetil did not achieve a significant difference from placebo in terms of disease improvement in patients with refractory rheumatoid arthritis. A descriptive analysis of adverse events suggests mycophenolate mofetil was generally as well tolerated as ciclosporin in this patient population.
20189834 The metal-backed glenoid component in rheumatoid disease: eight- to fourteen-year follow-u 2010 Jul HYPOTHESIS: We believe the variable reported survivorship of the metal-backed glenoid is related to the design of the component. This study reports the outcome and survivorship of the uncemented glenoid in rheumatoid patients with an intact or repairable rotator cuff at surgery, and considers the key design features that may predict longevity of this component. METHOD: Forty-six shoulders in 39 patients (31 women), with a mean age of 55 years (range, 35-86 years) received a total shoulder replacement with a screw-fixed porous coated metal-back glenoid. Twenty-nine patients (36 shoulders) were monitored for a mean of 132 months (96-168 months), and 10 were lost to follow-up or died before 8 years of follow-up. A Constant score was measured preoperatively and annually from the time of surgery. Radiographs were assessed for lucency, loosening, and superior subluxation of the humeral head. RESULTS: The Constant score improved from a mean of 20.6 preoperatively to 33.5 at last follow-up (P < .001). Implant survivorship at 10 years was 89%. Five were revised: 3 for pain with associated superior subluxation, 1 for infection, and 1 for aseptic loosening. In the 4 patients with lucent zones around the glenoid, superior subluxation of the humeral head had occurred 2 to 4 years before the observed lucent lines. DISCUSSION: The uncemented glenoid performs well in the rheumatoid shoulder, giving pain relief and improved functional outcome. The survivorship is comparable to previously reported studies. CONCLUSION: We believe the key design features in the survivorship of the metal-backed glenoid are: a low-profile tray, with a fully coated bone ingrowth substance at the plate-bone interface, a conical stem, and secure screw fixation.
21087862 Imidazo[4,5-d]thiazolo[5,4-b]pyridine based inhibitors of IKK2: synthesis, SAR, PK/PD and 2011 Jan 1 The synthesis, structure-activity relationships (SAR) and biological evaluation of thiazole based tricyclic inhibitors of IKK2 are described. Compound 9 was determined to be orally efficacious in a murine model of rheumatoid arthritis.
19404965 Transmembrane BAFF from rheumatoid synoviocytes requires interleukin-6 to induce the expre 2009 May OBJECTIVE: B cells that accumulate in the synovial tissue of rheumatoid arthritis (RA) patients revise their receptors due to coordinate expression of recombination-activating gene 1 (RAG-1) and RAG-2 genes. The aim of this study was to determine the mechanisms that control this re-expression. METHODS: B cells from healthy control subjects were cocultured with fibroblast-like synoviocytes (FLS) from patients with RA and osteoarthritis (OA). Re-expression of RAG messenger RNA (mRNA) and proteins was analyzed by reverse transcription-polymerase chain reaction (RT-PCR) and indirect immunofluorescence. Activity of RAG enzymes was evaluated by flow cytometry to measure variations in immunoglobulin kappa and lambda light chain expression and by ligation-mediated-PCR to assess specific DNA breaks. Blocking antibodies, short hairpin RNA, and recombinant cytokine were used to identify the molecules involved in RAG re-expression. RESULTS: RA FLS, but not OA FLS, induced B cells to re-express RAG mRNA and proteins. Enzymes were functional, since the kappa-to-lambda ratios decreased and specific DNA breaks were detectable after coculture with RA FLS. Transmembrane BAFF provided the first signal of RAG re-expression, since its down-regulation in RA FLS prevented RAG gene transcription in B cells. The failure of transmembrane BAFF from OA FLS to induce RAG suggests that a second signal was provided by RA FLS. Interleukin-6 (IL-6) is a candidate, since blockade of its receptors precluded transcription of RAG genes by RA FLS. Unless supplemented with IL-6, OA FLS were unable to induce RAG gene expression in normal B cells. CONCLUSION: Two independent signals are required for the induction of RAG gene expression in B cells that infiltrate the synovium of patients with RA.
19248111 Familial associations of rheumatoid arthritis with autoimmune diseases and related conditi 2009 Mar OBJECTIVE: In the era of genome-wide association studies, familial risks are used to estimate disease heritability and the likelihood of candidate-gene identification. This study was undertaken to estimate associations of rheumatoid arthritis (RA) with any of 33 autoimmune diseases and related conditions among parents and offspring, singleton siblings, twins, and spouses. METHODS: The Multigeneration Register in Sweden was used as a reliable source of information on Swedish families throughout the last century. Data on autoimmune diseases in individual family members were obtained through linkage to the Hospital Discharge Register. The standardized incidence ratio (SIR) was calculated as a measure of the relative risk of RA in family members of patients with RA or any of 33 other autoimmune diseases or related conditions, as compared with the relative risk of RA in those lacking an affected family member. RESULTS: Among a total of 447,704 patients, 47,361 were diagnosed as having RA. The SIRs for RA were 3.02 in offspring of affected parents, 4.64 in siblings, 9.31 in multiplex families, 6.48 in twins, and 1.17 in spouses. Significant associations with the familial risk of RA in offspring according to parental proband were observed for ankylosing spondylitis (SIR 2.96), localized scleroderma (SIR 2.40), Sjögren's syndrome (SIR 2.25), systemic lupus erythematosus (SIR 2.13), systemic sclerosis (SIR 1.65), Hashimoto thyroiditis/hypothyroidism (SIR 1.54), pernicious anemia (SIR 1.53), sarcoidosis (SIR 1.40), psoriasis (SIR 1.36), Wegener's granulomatosis (SIR 1.34), and asthma or polymyalgia rheumatica (SIR 1.32). CONCLUSION: This is the first study to compare the familial risks of RA in relation to a large number of autoimmune diseases and related conditions using data from a single population. The high discordant familial risks in this population suggest that there is extensive genetic sharing between RA and the associated diseases.
19800761 Self heat-shock protein 65-mediated regulation of autoimmune arthritis. 2009 Nov Heat-shock proteins (Hsps) have been invoked in the pathogenesis of a variety of autoimmune diseases. The mycobacterial heat-shock protein 65 (Bhsp65) has been studied extensively as one of the antigenic triggers of autoimmunity in experimental models of, as well as patients with, rheumatoid arthritis. As Hsps are highly conserved and immunogenic, it is generally anticipated that self Hsps might serve as the endogenous targets of the immune response initiated by the homologous foreign Hsps. Contrary to this expectation, studies in the rat adjuvant arthritis (AA) model have revealed that priming of the self (rat) hsp65 (Rhsp65)-directed T cells in the Lewis rat leads to protection against AA instead of disease induction or aggravation. The arthritis-protective attribute of the self hsp65 is also evident following spontaneous priming of the anti-Rhsp65 T cells during the natural course of AA. Furthermore, immunization of rats with human hsp60, or with Bhsp65 peptides that are crossreactive with the corresponding self hsp65 peptides, leads to protection against AA. Importantly, high levels of T cell reactivity against self hsp60 in patients with juvenile idiopathic arthritis positively correlate with a favorable outcome of the disease. Thus, immune response against self hsp65 in autoimmune arthritis is protective rather than being pathogenic.
19273451 Safety and efficacy of the selective costimulation modulator abatacept in patients with rh 2009 Apr OBJECTIVE: To evaluate the safety and efficacy of abatacept plus methotrexate (MTX) over 5 years in patients with rheumatoid arthritis. METHODS: Patients were randomized to abatacept 10 or 2 mg/kg or placebo, plus MTX. Patients completing the 1-year, double-blind period entered the longterm extension, where all patients received a fixed dose of abatacept ~10 mg/kg. We describe safety analyses for all patients who received at least 1 dose of abatacept and efficacy analyses for the original ~10 mg/kg abatacept-treated group, over 5 years. RESULTS: Of the 235 abatacept- or placebo-treated patients completing the double-blind period, 219 entered the longterm extension; 130 (59.4%) were continuing at Year 5. No unexpected safety events were observed during the longterm extension compared with the double-blind period. Incidence rates of adverse events (AE) and serious AE were 489.7 and 20.0/100 patient-years in Year 1 versus 374.9 and 18.9/100 patient-years in the cumulative period, respectively. Using exploratory analyses, improvements observed at Year 1 in the 10 mg/kg group were maintained at Year 5, as assessed by ACR responses (ACR20=77.1% vs 82.7%; ACR50=53.0% vs 65.4%; ACR70=28.9% vs 40.4% at Years 1 and 5, respectively) and disease activity (Low Disease Activity State=48.2% vs 58.5%; Disease Activity Score-28-defined remission=25.3% vs 45.3% at Years 1 and 5, respectively). CONCLUSION: Abatacept maintained the efficacy observed at Year 1 over 5 years of treatment, and demonstrated consistent safety and tolerability. These data, along with relatively high retention rates, support the longterm clinical benefit provided by selective T cell costimulation modulation. CLINICAL TRIAL REGISTRY: ClinicalTrials.gov; clinical trial registration number: NCT00254293.
20955456 T-cell expression of CD91 - a marker of unresponsiveness to anti-TNF therapy in rheumatoid 2010 Nov The aim of this study was to investigate the expression of thrombospondin-1 (TSP-1) and its receptors, lipoprotein receptor-related protein/cluster of differentiation (CD)91, calreticulin (CRT), and CD47, on T cells and monocytes from patients with rheumatoid arthritis (RA) treated with anti-tumor necrosis factor (TNF) therapy. The surface expression of CD91 and associated components on CD3- and CD14-positive cells was examined using flow cytometry in 12 patients with established RA before and after beginning therapy and compared with that of 9 healthy controls and 12 patients with early RA treated with conventional therapies. CD3-positive cells from anti-TNF non-responders showed significantly greater expression of CD91 expression than those from responders (p<0.05) after 6 weeks and when all measurements were pooled (p<0.001). CD91 expression on CD3-positive cells from non-responders to other therapies was at the same level as in healthy controls. In contrast, CD14-positive cells showed no differences in CD91 expression between patients and controls or between responders and non-responders to anti-TNF therapy. The expression of TSP-1, CRT, and CD47 showed no differences between responders and non-responders. The results suggest T-lymphocyte expression of CD91 to be a biomarker that signifies unresponsiveness to anti-TNF therapy in patients with RA and may be used to identify potential responders and non-responders.
20346234 Association study of ghrelin receptor gene polymorphisms in rheumatoid arthritis. 2010 Jan OBJECTIVES: Ghrelin is a newly characterised growth hormone (GH) releasing peptide widely distributed that may play an important role in the regulation of metabolic balance in inflammatory diseases such as rheumatoid arthritis (RA) by decreasing the pro-inflammatory Th1 responses. In this study we investigated the possible contribution of several polymorphisms in the functional Ghrelin receptor to RA susceptibility. METHODS: A screening of 3 single nucleotide polymorphisms (SNPs) was performed in a total of 950 RA patients and 990 healthy controls of Spanish Caucasian origin. Genotyping of all 3 SNPs was performed by real-time polymerase chain reaction technology, using the TaqMan 5'-allele discrimination assay. RESULTS: We observed no statistically significant deviation between RA patients and controls for the GHSR SNPs analysed. In addition, we performed a haplotype analysis that did not reveal an association with RA susceptibility. The stratification analysis for the presence of shared epitope (SE), rheumatoid factor (RF) or antibodies anti cyclic citrullinated peptide (anti-CCP) did not detect significant association of the GHSR polymorphisms with RA. CONCLUSIONS: These findings suggest that the GHSR gene polymorphisms do not appear to play a major role in RA genetic predisposition in our population.
19936725 The addition of tocilizumab to DMARD therapy for rheumatoid arthritis: a meta-analysis of 2010 Jan PURPOSE: Tocilizumab is a humanized monoclonal antibody that binds to the interleukin-6 receptor. The purpose of this study was to evaluate the effect of adding tocilizumab to disease-modifying antirheumatic drug (DMARD) therapy for the treatment of rheumatoid arthritis (RA). METHODS: We performed a meta-analysis of relevant randomized controlled trials (RCTs) identified in PubMed, Cochrane library, and Embase. The primary efficacy outcome was the proportion of patients with a 20% improvement in RA signs and symptoms according to American College of Rheumatology (ACR) criteria (ACR20 response). The primary safety outcomes were the proportion of patients reporting at least one adverse event and the proportion of patients reporting at least one serious adverse event. RESULTS: Four RCTs, involving 2701 patients, were included in our meta-analysis. The addition of tocilizumab to therapeutic regimens with DMARDs was associated both clinically and statistically with an increased number of patients achieving the ACR20 response [8 mg/kg, risk ratio (RR) 2.53, 95% confidence interval (CI) 1.89-3.39; 4 mg/kg, RR 1.96, 95% CI 1.40-2.73], as well as the ACR50 and ACR70 response, and showing remission according to the Disease Activity Score based on 28 joints. However, the benefits were gained at the expense of the tendency of the patient to experience more adverse events (8 mg/kg, RR 1.12, 95% CI 1.03-1.20; 4 mg/kg, RR 1.08, 95% CI 1.00-1.17). The new finding was that the clinical benefit from the increased tocilizumab dose (from 4 to 8 mg/kg) was not correlated with a higher incidence of adverse events. CONCLUSIONS: The superior efficacy of combined tocilizumab + DMARD therapy is associated with the tendency for the patient to have more adverse events. Consequently, the benefits and disadvantages of such combined treatments should be carefully balanced against each other in RA therapy. We suggest that 8 mg/kg every 4 weeks should be the recommended dose of tocilizumab.
19369178 Randomized, double-blind, placebo-controlled, comparative study of human anti-TNF antibody 2009 Apr BACKGROUND/PURPOSE: Adalimumab is a fully humanized monoclonal antibody that blocks tumor necrosis factor (TNF)-alpha, which is effective in the treatment of patients with rheumatoid arthritis (RA). The purpose of this study was to compare the efficacy and safety of adalimumab plus methotrexate (MTX) and MTX alone in Taiwanese patients with active RA. METHODS: Forty-seven patients with active RA who were maintained on MTX therapy at a stable dose of 10-15 mg/week for 4 weeks were randomized blindly to receive adalimumab 40 mg (n = 35) or placebo (n = 12) by subcutaneous injection every other week over a period of 12 weeks. The primary endpoint was a reduction in tender and swollen joint counts of 20% (ACR20), 50% (ACR50) and 70% (ACR70), as determined by the American College of Rheumatology criteria in week 12. The occurrence of treatment-emergent adverse events (TEAEs) was the primary safety variable. RESULTS: Addition of adalimumab to MTX resulted in a significant reduction in the number of swollen joints (12.6 vs. 5.6; p = 0.011), patients' global assessment of disease activity (18.0 vs. 4.8; p = 0.040), pain visual analog scale (18.3 vs. 1.3; p = 0.015), and disability indices of the Health Assessment Questionnaire (0.6 vs. 0.2; p = 0.031), compared with MTX alone after 12 weeks of therapy. Overall improvement in disease activity was assessed by ACR20 (54.3% vs. 33.3%), ACR50 (34.3% vs. 16.7%) and ACR70 (14.3% vs. 0%), and all favored the adalimumab plus MTX group. TEAEs were comparable between the treatment groups, except for a slightly higher incidence of severe infection in the adalimumab plus MTX group. CONCLUSION: Adalimumab in combination with MTX is well tolerated and provides significantly more clinical benefits than MTX alone in Taiwanese patients with active RA.
19597699 Autoantibodies and other serological markers in rheumatoid arthritis: predictors of diseas 2009 Oct The description of potential serological markers of rheumatoid arthritis (RA) activity can be quite useful in optimizing RA treatment, since the laboratory markers currently used, namely erythrocyte sedimentation rate and C-reactive protein, are not specific for RA and are influenced by several other variables. The markers proposed for assessing RA activity include rheumatoid factor, anti-citrullinated protein/peptide antibodies, immunoglobulin M (IgM) anti-IgG advanced glycation end products, markers of bone/cartilage metabolism, mannose-binding lectin, E-selectin, interleukin-6, and leptin. Various studies have investigated the correlation between some of these markers and other variables that might indicate disease activity, e.g., inflammatory activity tests and disease activity scores. However, there is as yet insufficient evidence that any of these markers, in isolation or in combination, are useful in the assessment of RA activity.
20017356 [Comparative analysis of effectiveness and safety of diclofenac and nimesulide in patients 2009 The aim of the work was to evaluate effectiveness and safety of diclofenac and nimesulide in patients with early RA. The open clinical study included 80 outpatients (mean age 49.0 +/- 11.1 years) within the first year after development RA (mean duration of the disease 4.9 +/- 3.1 months prior to the onset of basic therapy). The patients were divided into 2 groups of 40 persons each depending on the type of non-steroidal anti-inflammatory agents they received. Patients in group 1 were treated with 100 mg of diclofenac daily and in group 2 with 100 mg BID of generic nimesulide preparation (nais, Dr. Reddy Co.). Duration of therapy was 30 days in both cases. The two drugs were roughly identical in terms of therapeutic effect although nimesulide produced fewer side effects. Subjective complaints of gastrointestinal problems were recorded in 11 (27.5%) patients f group 1 and in 8 (20%) of group 2. It is concluded that timely prescription of proton pump inhibitors permits to avoid premature withdrawal of non-steroidal anti-inflammatory agents at patient discretion.
19949831 Comparison of tuberculin skin test and QuantiFERON-TB gold in tube test in patients with c 2010 Sep We aimed to compare tuberculin skin test (TST) and QuantiFERON-TB gold in tube (QFT-IT) in patients with chronic inflammatory diseases living in a population where tuberculosis is endemic and BCG vaccination is routine. Twenty-five patients with rheumatoid arthritis (RA), 16 patients with spondilarthropathy (SpA) and 7 healthy volunteers were recruited in the study. Blood samples were collected for QFT-IT test followed by TST. TST was considered to be positive with an enduration of 5 mm and over in patients with RA and SpA. The cutoff point for TST for the healthy control (HC) was 10 mm. Median TST result of patients who were using immunosuppressive drugs was significantly lower than that of patients who were not [5 (14.5), 13.5 (9.5), respectively, P = 0.04]. Poor agreement between TST and QFT-IT was seen in patients with RA (kappa = 0.141) and in patients with SpA (kappa = 0.190). We found poor concordance between QFT-IT and TST in patients with chronic inflammatory diseases, and TST response was suppressed in patients treated with immunosuppressive drugs.
19686595 Short- and long-term effects of anti-CD20 treatment on B cell ontogeny in bone marrow of p 2009 INTRODUCTION: In the present study we evaluated changes in the B cell phenotype in peripheral blood and bone marrow (BM) of patients with rheumatoid arthritis (RA) following anti-CD20 treatment using rituximab. METHODS: Blood and BM samples were obtained from 37 patients with RA prior to rituximab treatment. Ten of these patients were resampled 1 month following rituximab, 14 patients after 3 months and the remaining 13 patients were included in the long-term follow up. B cell populations were characterized by CD27/IgD/CD38/CD24 expression. RESULTS: One and three months following rituximab BM retained up to 30% of B cells while circulation was totally depleted of B cells. Analysis of the remaining BM B cells showed prevalence of immature and/or transitional B cells (CD38++CD24++) and CD27+IgD- memory cells, while IgD+ cells were completely depleted. A significant reduction of CD27+ cells in BM and in circulation was observed long after rituximab treatment (mean 22 months), while levels of naive B cells in BM and in circulation were increased. The levels of rheumatoid factor decline after rituximab treatment but returned to baseline levels at the time of retreatment. CONCLUSIONS: Anti-CD20 treatment achieves a depletion of IgD+ B cells shortly after the treatment. At the long term follow up, a reduction of CD27+ B cells was observed in blood and BM. The prolonged inability to up-regulate CD27 may inhibit the renewal of memory B cells. This reduction of CD27+ B cells does not prevent autoantibody production suggesting that mechanisms regulating the formation of auto reactive clones are not disrupted by rituximab.
20732645 Pharmacotherapy: concepts of pathogenesis and emerging treatments. Co-stimulation and T ce 2010 Aug Full activation and differentiation of resting T cells into effector T cells requires at least two signals, the first through engagement of the T cell antigen receptor (TCR) by the antigen-major histocompatibility complex (MHC) on antigen-presenting cells (APCs), and the second by engagement of co-stimulatory molecules such as CD28, on T cells by ligands such as CD80/86 on APCs. Effector T cell differentiation is associated with proliferation, secretion of cytokines and expression of additional surface molecules. These inducible structures may have stimulatory (ICOS, OX40 and 4-1BB) or inhibitory (cytotoxic T-lymphocyte antigen (CTLA)-4) potential. To the extent that T cells have a role in particular immune-mediated diseases, interruption of T cell co-stimulation is a potentially worthwhile approach to the treatment of those conditions. This article summarises the experience in treating rheumatological disease by perturbation of T cell co-stimulation, and also describes structures that could be future targets for this type of therapeutic approach.
20866164 Outcomes of a rheumatoid arthritis disease therapy management program focusing on medicati 2010 Oct BACKGROUND: A national pharmacy benefits management company implemented a rheumatoid arthritis (RA) disease therapy management (DTM) program as an enhanced offering to patients receiving specialty pharmacy services. The program was designed to improve medication adherence, maximize therapeutic outcomes, and enhance physical functioning and health-related quality of life (HRQOL) by empowering patients and improving their knowledge of RA. OBJECTIVES: To evaluate (a) adherence to injectable RA medications for patients participating in an RA DTM program compared with nonparticipating patients receiving injectable RA medications at specialty or community pharmacies and (b) HRQOL, work productivity, and physical functioning before versus after completing the RA DTM program. METHODS: Patients who had an RA diagnosis and a pharmacy claim for an injectable RA medication during the identification period (August 2007 through September 2008) and were continuously enrolled with the plan from 4 months before through 8 months after the identification date were stratified into 3 patient cohorts: DTM, specialty pharmacy, and community pharmacy. DTM patients were further categorized into a DTM intent-to-treat (ITT) cohort (all 340 DTM-enrolled patients) and a DTM completer cohort (subset of 266 ITT patients who completed the month 6 consultation). DTM completer, specialty, and community pharmacy cohorts were matched 1:1:1 (n = 244 in each cohort after matching) using a propensity score that represented the likelihood of completing the DTM program. The primary outcome was adherence to injectable RA medications, measured as the proportion of days covered (PDC) over an 8-month post-identification period. Patient-reported outcomes (short form [SF]-12, Work Productivity Activity Impairment [WPAI], and Health Assessment Questionnaire-Disability Index [HAQ-DI]) were evaluated among all 371 DTM patients who completed the month 0 and month 6 consultations regardless of whether they met continuous enrollment requirements (patient-reported sample). RESULTS: Of specialty pharmacy patients, approximately 14% chose DTM participation. During the post-identification period, mean PDC was 0.83 for DTM ITT, 0.89 for DTM completer, 0.81 for specialty pharmacy, and 0.60 for community pharmacy patients. Differences were statistically significant for both DTM cohorts compared with the community pharmacy cohort (P < 0.001) and for the DTM completer cohort compared with the specialty pharmacy cohort (P < 0.001), but not for the DTM ITT cohort compared with the specialty pharmacy cohort (P = 0.291). In the patient-reported sample, mean SF-12 physical component scores significantly increased by 1.1 points (P = 0.048); mean SF-12 mental component scores were not significantly changed (P = 0.679); mean WPAI work productivity decreased by 10.8 percentage points (P = 0.045); and mean HAQ-DI scores significantly improved by 0.08 points (P < 0.001). CONCLUSIONS: Patients participating in the RA DTM program had significantly higher injectable RA medication adherence compared with community pharmacy patients. Adherence to injectable RA medications was significantly higher for patients completing the RA DTM program, but not for the DTM ITT group, compared with patients receiving specialty pharmacy services alone. Patients completing the RA DTM program experienced improvements in SF-12 physical component and HAQ-DI scores but did not demonstrate improvements to SF-12 mental scores or work productivity.