Elena Massarotti

Platelets Amplify Inflammation in Arthritis via Collagen-Dependent Microparticle Production

Platelet Microparticles Drive Inflammatory Arthritis Platelets are best known for their critical role in blood clot formation during wound repair, but an appreciation for their role in inflammatory processes is growing. Platelet-derived cellular microparticles (MPs) are small membrane vesicles released from platelets in response to cell activation that can transport biomolecules throughout the body that have also been implicated in inflammatory processes. Boilard et al. (p. 580; see the Perspective by Zimmerman and Weyrich) have now found that platelet-derived MPs probably contribute to the inflammatory processes underlying rheumatoid arthritis, an autoimmune disease. The majority of MPs in synovial fluid from patients with various types of inflammatory arthritis were platelet-derived and, importantly, platelet-derived MPs were lacking in synovial fluid from osteoarthritis patients. Furthermore, platelet depletion abrogated disease development in a mouse model of inflammatory arthritis. Microparticles released by platelets contribute to inflammation underlying rheumatoid arthritis. In addition to their pivotal role in thrombosis and wound repair, platelets participate in inflammatory responses. We investigated the role of platelets in the autoimmune disease rheumatoid arthritis. We identified platelet microparticles—submicrometer vesicles elaborated by activated platelets—in joint fluid from patients with rheumatoid arthritis and other forms of inflammatory arthritis, but not in joint fluid from patients with osteoarthritis. Platelet microparticles were proinflammatory, eliciting cytokine responses from synovial fibroblasts via interleukin-1. Consistent with these findings, depletion of platelets attenuated murine inflammatory arthritis. Using both pharmacologic and genetic approaches, we identified the collagen receptor glycoprotein VI as a key trigger for platelet microparticle generation in arthritis pathophysiology. Thus, these findings demonstrate a previously unappreciated role for platelets and their activation-induced microparticles in inflammatory joint diseases.

Association Between Disease-Modifying Antirheumatic Drugs and Diabetes Risk in Patients With Rheumatoid Arthritis and Psoriasis

CONTEXT Rheumatoid arthritis (RA) and psoriasis have been linked with insulin resistance and diabetes mellitus (DM). Prior investigations suggest that systemic immunosuppressive drugs may improve insulin resistance and reduce the risk of DM. OBJECTIVE To compare the risk of newly recorded DM among participants diagnosed with RA or psoriasis based on use of a variety of disease-modifying antirheumatic drugs (DMARDs). DESIGN, SETTING, AND PARTICIPANTS A retrospective cohort study among 121,280 patients with a diagnosis of either RA or psoriasis on at least 2 visits. The analyses were conducted in the context of 2 large health insurance programs, 1 in Canada and 1 in the United States, using administrative data. The mean follow-up was 5.8 months and began with the first prescription for a DMARD after study eligibility was met. Drug regimens were categorized into 4 mutually exclusive groups: (1) tumor necrosis factor (TNF) inhibitors with or without other DMARDs; (2) methotrexate without TNF inhibitors or hydroxychloroquine; (3) hydroxychloroquine without TNF inhibitors or methotrexate; or (4) other nonbiologic DMARDs without TNF inhibitors, methotrexate, or hydroxychloroquine (reference exposure). MAIN OUTCOME MEASURE Newly recorded DM as evidenced by a new diagnosis of DM with use of a DM-specific medication. RESULTS The study cohort consisted of 13,905 participants with 22,493 treatment episodes starting 1 of the categories of DMARD regimens between January 1996 and June 2008. New diabetes cases and respective incidence rates per 1000 person-years were: other nonbiologic DMARDs (55 cases among 3993 treatment episodes; rate, 50.2; 95% confidence interval [CI], 47.3-53.2); TNF inhibitors (80 cases among 4623 treatment episodes; rate, 19.7; 95% CI, 19.1-20.3); methotrexate (82 cases among 8195 treatment episodes; rate, 23.8; 95% CI, 23.0-24.6); and hydroxychloroquine (50 cases among 5682 treatment episodes; rate, 22.2; 95% CI, 21.3-23.1). The multivariate adjusted hazard ratios for DM were 0.62 (95% CI, 0.42-0.91) for TNF inhibitors, 0.77 (95% CI, 0.53-1.13) for methotrexate, and 0.54 (95% CI, 0.36-0.80) for hydroxychloroquine compared with other nonbiologic DMARDS. CONCLUSION Among patients with RA or psoriasis, the adjusted risk of DM was lower for individuals starting a TNF inhibitor or hydroxychloroquine compared with initiation of other nonbiologic DMARDs.

The Work Limitations Questionnaire's validity and reliability among patients with osteoarthritis

The 25-item Work Limitations Questionnaire (WLQ) was recently developed to measure health-related decrements in ability to perform job roles among employed individuals. Research has demonstrated its validity and reliability in several populations. We assessed the WLQs performance when administered to patients with osteoarthritis (OA), which is a leading cause of work disability and productivity loss. We recruited a representative sample of 230 employed, confirmed OA patients and a comparison group of 37 healthy employed controls. Subjects completed a mail survey. In tests of the WLQs scale internal reliability, the questionnaire met all established criteria. Additionally, in construct validity tests, the WLQ correctly detected OA vs. control group differences, and correlated significantly with arthritis pain, stiffness, and functional limitation, and self-reported work productivity. The WLQ is an accurate and reliable source of information for assessing the work impact of OA.

The PTPN22 R620W polymorphism associates with RF positive rheumatoid arthritis in a dose-dependent manner but not with HLA-SE status

We have recently described the association between rheumatoid arthritis and a coding single-nucleotide polymorphism in the intracellular protein tyrosine phosphatase, PTPN22. The disease-associated polymorphism, 1858 C/T (rs2476601), encodes an amino-acid change (R620W) in one of four SH3 domain binding sites in the PTPN22 molecule. We have now extended our initial studies to address three questions: (1) Is the association with rheumatoid arthritis limited to rheumatoid factor (RF) positive disease? (2) Does homozygosity for PTPN22 R620W substantially increase disease susceptibility? (3) Is there an interaction between PTPN22 and the rheumatoid arthritis (RA)-associated HLA-DRB1 shared epitope alleles? A total of 1413 Caucasian rheumatoid arthritis patients and 1401 Caucasian controls were genotyped. The results support the view that PTPN22 was strongly and preferentially associated with RF positive disease (OR=1.75, 95% CI 1.46–2.10, P=1.3 × 10−9). The PTPN22 risk allele was not significantly associated with RF negative disease (OR=1.19, 95% CI 0.92–1.53, P=0.18), although a very weak association cannot be completely excluded. There was a strong dose effect on disease risk; two copies of the PTPN22 R620W allele more than doubles the risk for RF positive RA (OR=4.57, 95% CI 2.35–8.89). There was no evidence of a genetic association between PTPN22 and HLA susceptibility alleles.

Treatment of early lyme disease

PURPOSE To compare the safety and efficacy of azithromycin, amoxicillin/probenecid, and doxycycline for the treatment of early Lyme disease, to identify risk factors for treatment failure, and to describe the serologic response in treated patients. PATIENTS AND METHODS Fifty-five patients with erythema migrans and two patients with flu-like symptoms alone and fourfold changes in antibody titers to Borrelia burgdorferi were randomized to receive (1) oral azithromycin, 500 mg on the first day followed by 250 mg once a day for 4 days; (2) oral amoxicillin 500 mg and probenecid 500 mg, three times a day for each for 10 days; or (3) doxcycline, 100 mg twice a day for 10 days. If symptoms were still present at 10 days, treatment was extended with amoxicillin/probenecid or doxycycline for 10 more days. Evaluations were done at study entry and 10, 30, and 180 days later. RESULTS Three of the patients who initially had symptoms suggestive of spread of the spirochete to the nervous system, one from each antibiotic treatment group, subsequently developed neurologic abnormalities, but symptoms in the other 54 patients resolved within 3 to 30 days after study entry. Six of the 19 patients (32%) (95% confidence interval, 13% to 57%) given amoxicillin/probenecid developed a drug eruption, whereas none of the patients given azithromycin or doxycycline had this complication. The presence of dysesthesias at study entry was the only risk factor significantly associated with treatment failure (p less than 0.001). By convalescence, 72% of the patients were seropositive, and 56% still had detectable IgM responses to the spirochete 6 months later. CONCLUSIONS The three antibiotic regimens tested in this study were generally effective for the treatment of early Lyme disease, but the regimens differ in the frequency of side effects and in ease of administration.

Rheumatoid Arthritis: An Overview of New and Emerging Therapies

Rheumatoid arthritis (RA) is a chronic, inflammatory, systemic autoimmune disorder characterized by symmetric inflammation of synovial joints leading to progressive erosion of cartilage and bone. The aim of treatment is to mitigate joint destruction, preserve function, and prevent disability. The American College of Rheumatology guidelines for the treatment of RA recommend that newly diagnosed patients with RA begin treatment with disease‐modifying antirheumatic drugs (DMARDs) within 3 months of diagnosis. Methotrexate remains the most commonly prescribed DMARD and is the standard by which recent new and emerging therapies are measured. Increasing knowledge regarding the immunologic basis of RA and advances in biotechnology have resulted in new, targeted biological therapies against proinflammatory cytokines that have dramatically changed the treatment paradigm and outcomes of patients with RA. This article reviews the pharmacological rationale underlying RA therapy, with a focus on currently available biological therapies and new therapies in development.

Trends in the Incidence, Demographics, and Outcomes of End-Stage Renal Disease Due to Lupus Nephritis in the US From 1995 to 2006

OBJECTIVE This study was undertaken to investigate whether recent advances in lupus nephritis treatment have led to changes in the incidence of end-stage renal disease (ESRD) secondary to lupus nephritis, or in the characteristics, treatments, and outcomes of patients with lupus nephritis ESRD. METHODS Patients with incident lupus nephritis ESRD (1995-2006) were identified in the US Renal Data System. Trends in sociodemographic and clinical characteristics were assessed. We tested for temporal changes in standardized incidence rates (SIRs) for sociodemographic groups using Poisson regression. Changes in rates of waitlisting for kidney transplant, kidney transplantation, and all-cause mortality were examined using crude and adjusted time-to-event analyses. RESULTS We identified 12,344 incident cases of lupus nephritis ESRD. Mean age at ESRD onset was 41 years; 81.6% of the patients were women and 49.5% were African American. SIRs for lupus nephritis ESRD among those who were ages 5-39 years, African American, or lived in the southeastern US increased significantly from 1995 to 2006. Increases in body mass index and in the prevalence of both diabetes mellitus and hypertension were detected. Mean serum hemoglobin level at ESRD onset increased, while that of serum creatinine decreased over time. More patients received hemodialysis and fewer received peritoneal dialysis. There was a slight increase in the frequency of preemptive kidney transplantation at ESRD onset, but kidney transplantation rates within the first 3 years of ESRD declined. Mortality did not change over the 12 years of study. CONCLUSION Our findings indicate that the characteristics of patients with lupus nephritis ESRD and initial therapies have changed in recent years. While SIRs rose in younger patients, among African Americans, and in the South, outcomes did not improve in over a decade of evaluation.

Lichen planus–like eruptions: An emerging side effect of tumor necrosis factor-α antagonists

As tumor necrosis factor (TNF)-alpha inhibitors gain wider use in clinical practice, it is becoming increasingly evident that these potent immunosuppressants can also induce inflammatory reactions. We present two cases of lichen planus-like eruptions after infliximab and adalimumab therapy for psoriasis, and review the literature on this phenomenon. Eleven cases of lichen planus or lichenoid drug eruptions have been previously reported in patients taking TNF-alpha inhibitors, in addition to several cases of psoriasiform eruptions with a lichenoid histology. Because TNF-alpha has been implicated in the pathogenesis of lichen planus, induction of lichenoid reactions by TNF-alpha inhibition is somewhat unexpected. We consider potential immunologic mechanisms, and suggest that TNF-alpha inhibition may precipitate lichenoid reactions through disruption of a delicate balance between TNF-alpha and interferon-alpha in susceptible patients.

Efficacy and safety of certolizumab pegol in a broad population of patients with active rheumatoid arthritis: results from the REALISTIC phase IIIb study

OBJECTIVE To investigate the efficacy and safety of certolizumab pegol (CZP) in a broad population of patients with active RA. METHODS In this 12-week, double-blind period of the phase IIIb trial, RA patients with inadequate response to at least one DMARD were randomized 4:1 to CZP (400 mg at weeks 0, 2 and 4, followed by 200 mg every 2 weeks) or placebo (every 2 weeks) plus current therapy stratified by previous TNF inhibitor use, concomitant methotrexate use and disease duration (<2 vs ≥2 years). The primary outcome was ACR20 response rate at week 12. RESULTS Of 1063 patients (CZP = 851; placebo = 212), 37.6% had previous TNF inhibitor use. Baseline mean HAQ Disability Index (HAQ-DI) and DAS 28-joint assessment-ESR [DAS28(ESR)] values were 1.5 and 6.4 in the CZP group, and 1.6 and 6.4 in the placebo group, respectively. The primary endpoint was significant (week 12 ACR20, CZP vs placebo: 51.1 vs 25.9%; P < 0.001); differences were noted at week 2 (31.8 vs 8.5%; P < 0.001). HAQ-DI and DAS28(ESR) change from baseline and ACR50 were significant from week 2. Week 12 ACR20 responses were similar across CZP patient subgroups regardless of concomitant DMARD use at baseline. Adverse and serious adverse events were comparable between CZP and placebo, with no new safety signals. CONCLUSION CZP was associated with rapid and consistent clinical responses and improved physical function in a diverse group of RA patients, irrespective of concomitant or previous therapy. TRIAL REGISTRATION ClinicalTrials.gov, http://clinicaltrials.gov/, NCT00717236.

Pathologically expanded peripheral T helper cell subset drives B cells in rheumatoid arthritis

CD4+ T cells are central mediators of autoimmune pathology; however, defining their key effector functions in specific autoimmune diseases remains challenging. Pathogenic CD4+ T cells within affected tissues may be identified by expression of markers of recent activation. Here we use mass cytometry to analyse activated T cells in joint tissue from patients with rheumatoid arthritis, a chronic immune-mediated arthritis that affects up to 1% of the population. This approach revealed a markedly expanded population of PD-1hiCXCR5−CD4+ T cells in synovium of patients with rheumatoid arthritis. However, these cells are not exhausted, despite high PD-1 expression. Rather, using multidimensional cytometry, transcriptomics, and functional assays, we define a population of PD-1hiCXCR5− ‘peripheral helper’ T (TPH) cells that express factors enabling B-cell help, including IL-21, CXCL13, ICOS, and MAF. Like PD-1hiCXCR5+ T follicular helper cells, TPH cells induce plasma cell differentiation in vitro through IL-21 secretion and SLAMF5 interaction (refs 3, 4). However, global transcriptomics highlight differences between TPH cells and T follicular helper cells, including altered expression of BCL6 and BLIMP1 and unique expression of chemokine receptors that direct migration to inflamed sites, such as CCR2, CX3CR1, and CCR5, in TPH cells. TPH cells appear to be uniquely poised to promote B-cell responses and antibody production within pathologically inflamed non-lymphoid tissues.