Antibody response to pneumococcal and influenza vaccination in patients with rheumatoid arthritis receiving abatacept

Background Patients with rheumatoid arthritis (RA), including those treated with biologics, are at increased risk of some vaccine-preventable infections. We evaluated the antibody response to standard 23-valent pneumococcal polysaccharide vaccine (PPSV23) and the 2011–2012 trivalent seasonal influenza vaccine in adults with RA receiving subcutaneous (SC) abatacept and background disease-modifying anti-rheumatic drugs (DMARDs). Methods Two multicenter, open-label sub-studies enrolled patients from the ACQUIRE (pneumococcal and influenza) and ATTUNE (pneumococcal) studies at any point during their SC abatacept treatment cycle following completion of ≥3 months’ SC abatacept. All patients received fixed-dose abatacept 125 mg/week with background DMARDs. A pre-vaccination blood sample was taken, and after 28 ± 3 days a final post- vaccination sample was collected. The primary endpoint was the proportion of patients achieving an immunologic response to the vaccine at Day 28 among patients without a protective antibody level to the vaccine antigens at baseline (pneumococcal: defined as ≥2-fold increase in post-vaccination titers to ≥3 of 5 antigens and protective antibody level of ≥1.6 μg/mL to ≥3 of 5 antigens; influenza: defined as ≥4-fold increase in post-vaccination titers to ≥2 of 3 antigens and protective antibody level of ≥1:40 to ≥2 of 3 antigens). Safety and tolerability were evaluated throughout the sub-studies. Results Pre- and post-vaccination titers were available for 113/125 and 186/191 enrolled patients receiving the PPSV23 and influenza vaccine, respectively. Among vaccinated patients, 47/113 pneumococcal and 121/186 influenza patients were without protective antibody levels at baseline. Among patients with available data, 73.9 % (34/46) and 61.3 % (73/119) met the primary endpoint and achieved an immunologic response to PPSV23 or influenza vaccine, respectively. In patients with pre- and post-vaccination data available, 83.9 % in the pneumococcal study demonstrated protective antibody levels with PPSV23 (titer ≥1.6 μg/mL to ≥3 of 5 antigens), and 81.2 % in the influenza study achieved protective antibody levels (titer ≥1:40 to ≥2 of 3 antigens) at Day 28 post-vaccination. Vaccines were well tolerated with SC abatacept with background DMARDs. Conclusions In these sub-studies, patients with RA receiving SC abatacept and background DMARDs were able to mount an appropriate immune response to pneumococcal and influenza vaccines. Trial registration NCT00559585 (registered 15 November 2007) and NCT00663702 (registered 18 April 2008)

Enhanced reactivity to pain in patients with rheumatoid arthritis

Introduction: Maladaptive physiological responses to stress appear to play a role in chronic inflammatory diseases such as rheumatoid arthritis (RA). However, relatively little stress research in RA patients has involved the study of pain, the most commonly reported and most impairing stressor in RA. In the present study, we compared psychophysical and physiological responses to standardized noxious stimulation in 19 RA patients and 21 healthy controls. Methods: Participants underwent a single psychophysical testing session in which responses to a variety of painful stimuli were recorded, and blood samples were taken at multiple time points to evaluate the reactivity of cortisol, interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α) to the experience of acute pain. Results: The findings suggest that RA patients display a fairly general hyperalgesia to mechanical and thermal stimuli across several body sites. In addition, while serum cortisol levels did not differ at baseline or following pain testing in patients relative to controls, the RA patients tended to show elevations in serum IL-6 and demonstrated enhanced pain-reactivity of serum levels of TNF-α compared with the healthy controls (P < 0.05). Conclusions: These findings highlight the importance of pain as a stressor in RA patients and add to a small body of literature documenting amplified responses to pain in RA. Future studies of the pathophysiology of RA would benefit from the consideration of acute pain levels when comparing RA patients with other groups, and future trials of analgesic interventions in RA patients may benefit from evaluating the effects of such interventions on inflammatory activity

Smoking is not linked to the development of anti-peptidylarginine deiminase 4 autoantibodies in rheumatoid arthritis

Background: Defining environmental factors responsible for development of autoimmunity in rheumatoid arthritis (RA) is critical for understanding mechanisms of disease initiation and propagation. Notably, a history of cigarette smoking has been implicated in the genesis of RA and is associated with worse disease outcomes. Antibodies to peptidylarginine deiminase 4 (PAD4) are also associated with more severe RA. A subset of patients who have PAD4 autoantibodies that cross-react with PAD3 (anti-PAD3/4) are at the highest risk for interstitial lung disease, and this risk is augmented by a history of cigarette smoking. It is unclear, however, if smoking is etiologically linked to the development of anti-PAD4 antibodies. Methods: Patients were included in this study if they had physician-diagnosed RA as well as DNA, serum, and a date-matched clinical assessment (n = 274). Anti-PAD4 and anti-CCP antibodies were measured by immunoprecipitation and ELISA, respectively; shared epitope (SE) status was determined by HLA-DRβ1 genotyping. Logistic regression analysis was used to evaluate associations of smoking with PAD4 antibodies, with adjustment for relevant demographic and clinical features. Stratified analyses by disease duration and shared epitope status were also performed. Results: Anti-PAD4 antibodies were present in 25% of RA patients, with 50% of these individuals having anti-PAD3/4 cross-reactive antibodies. Anti-PAD4 antibodies were significantly associated with a longer disease duration, SE alleles, and anti-CCP antibodies. Importantly, there were no significant differences in smoking history between anti-PAD4 positive and negative groups in univariate analyses, stratified analyses, or multivariable models. However, an inverse relationship between smoking and anti-PAD4 antibodies was suggested by a lower prevalence of current smokers among patients with anti-PAD3/4 antibodies compared to antibody negative individuals (p = 0.04). Further, the lowest levels of anti-PAD4 antibodies were observed in current smokers (p = 0.14), and a significant association of SE and anti-PAD4 antibodies was only present among never smokers (p = 0.01). Conclusions: Smoking history was not associated with anti-PAD4 antibodies in patients with RA. The finding that anti-PAD4 antibodies were not associated with smoking suggests that other environmental factors may contribute to the development of autoimmunity to PAD4 in these patients

Association of Pain Centralization and Patient‐Reported Pain in Active Rheumatoid Arthritis

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/156205/2/acr23994_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/156205/1/acr23994.pd

Association Between Pain Sensitization and Disease Activity in Patients With Rheumatoid Arthritis: A Cross‐Sectional Study

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/141868/1/acr23266.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/141868/2/acr23266_am.pd

Physician Views On the Provision of information On Immune Checkpoint inhibitor therapy to Patients With Cancer and Pre-Existing autoimmune Disease: a Qualitative Study

Immune checkpoint inhibitors (ICIs) have improved cancer outcomes but can cause severe immune-related adverse events (irAEs) and flares of autoimmune conditions in cancer patients with pre-existing autoimmune disease. The objective of this study was to identify the information physicians perceived as most useful for these patients when discussing treatment initiation with ICIs. Twenty physicians at a cancer institution with experience in the treatment of irAEs were interviewed. Qualitative thematic analysis was performed to organize and interpret data. The physicians were 11 medical oncologists and 9 non-oncology specialists. The following themes were identified: (1) current methods used by physicians to provide information to patients and delivery options; (2) factors to make decisions about whether or not to start ICIs in patients who have cancer and pre-existing autoimmune conditions; (3) learning points for patients to understand; (4) preferences for the delivery of ICI information; and (5) barriers to the implementation of ICI information in clinics. Regarding points to discuss with patients, physicians agreed that the benefits of ICIs, the probability of irAEs, and risks of underlying autoimmune condition flares with the use of ICIs were most important. Non-oncologists were additionally concerned about how ICIs affect the autoimmune disease (e.g., impact on disease activity, need for changes in medications for the autoimmune disease, and monitoring of autoimmune conditions)

Personal non-commercial use only

ABSTRACT. Objective. To evaluate the effects of intravenous (IV) golimumab 2 mg/kg + methotrexate (MTX) on patient-reported measures of health-related quality of life (HRQOL) in patients with active rheumatoid arthritis (RA) despite prior MTX therapy. Methods. In this randomized, multicenter, double-blind, placebo-controlled, phase III trial, adults with RA were randomly assigned to receive IV placebo (n = 197) or golimumab 2 mg/kg (n = 395) infusions at Week 0, Week 4, and every 8 weeks thereafter. Results. Mean HAQ-DI improvements from baseline were significantly greater with golimumab + MTX than placebo + MTX at Week 14 and Week 24 (p &lt; 0.001). Significantly greater improvements in all 8 individual SF-36 subscores and both the SF-36 PCS and MCS scores (p &lt; 0.001) also accompanied golimumab + MTX therapy. Improved EQ-5D and EQ-5D VAS (p &lt; 0.001) and FACIT-Fatigue (p &lt; 0.001) scores were also observed for golimumab + MTX-treated patients at Week 12, Week 16, and Week 24, and greater proportions of golimumab + MTX-treated patients had clinically meaningful improvements in these measures. Greater reductions in disease effect on productivity were observed with golimumab + MTX versus placebo + MTX at Week 24 (p &lt; 0.001)

Core Domain Set Selection According to OMERACT Filter 2.1: The OMERACT Methodology

Objective: To describe the Outcome Measures in Rheumatology (OMERACT) Filter 2.1 methodology for core domain set selection. Methods: The “OMERACT Way for Core Domain Set selection” framework consists of 3 stages: first, generating candidate domains through literature reviews and qualitative work, then a process of consensus to obtain agreement from those involved, and finally formal voting on the OMERACT Onion. The OMERACT Onion describes the placement of domains in layers/circles: mandatory in all trials/mandatory in specific circumstances (inner circle); important but optional (middle circle); or research agenda (outer circle). Five OMERACT working groups presented their core domain sets for endorsement by the OMERACT community. Tools including a workbook and whiteboard video were created to assist the process. The methods workshop at OMERACT 2018 introduced participants to this framework. Results: The 5 OMERACT working groups achieved consensus on their proposed core domain sets. After the Methodology Workshop training exercise at OMERACT 2018, over 90% of participants voted that they were confident that they understood the process of core domain set selection. Conclusion: The methods described in this paper were successfully used by the 5 working groups voting on domains at the OMERACT 2018 meeting, demonstrating the feasibility of the process. In addition, participants at OMERACT 2018 expressed increased confidence and understanding of the core domain set selection process after the training exercise. This methodology will continue to evolve, and we will use innovative technology such as whiteboard videos as a key part of our dissemination and implementation strategy for new methods

Autoantibodies to Peptidylarginine Deiminase 2 Are Associated With Less Severe Disease in Rheumatoid Arthritis

Objective: Peptidylarginine deiminases (PAD) 2 and 4 are key enzymes in rheumatoid arthritis (RA) pathogenesis due to their ability to generate the protein targets of anti-citrullinated protein antibodies (ACPA). Anti-PAD4 antibodies that cross-react with PAD3 (anti-PAD3/4) have been identified and are associated with severe joint and lung disease. Here, we examined whether anti-PAD2 antibodies were present in patients with RA and defined their clinical significance.Patients and Methods: A PAD2 ELISA was established to screen for anti-PAD2 IgG in sera from RA patients from a prospective observational cohort study (n = 184) and healthy controls (n = 100). RA patient characteristics were compared according to anti-PAD2 antibody status. Multivariable models were constructed to explore the independent associations of anti-PAD2 antibodies with clinical variables.Results: Anti-PAD2 antibodies were found in 18.5% of RA patients and 3% of healthy controls (p &lt; 0.001). Among RA patients, anti-PAD2 antibodies were not associated with traditional genetic or serologic RA risk factors, including HLA-DRβ1 shared epitope alleles, ACPA, rheumatoid factor (RF), or anti-PAD3/4 antibodies. In addition, antibodies to PAD2 were associated with fewer swollen joints, a lower prevalence of interstitial lung disease, and less progression of joint damage. In subset analyses in which patients were stratified by the baseline presence of ACPA/RF or anti-PAD3/4 antibodies, anti-PAD2 antibodies provided additional value in identifying patients with the least progressive joint disease.Conclusions: Anti-PAD2 antibodies represent a novel serologic marker in RA that identifies a genetically and clinically unique subset of patients with less severe joint and lung disease