Faculty Bibliography

Background/Purpose: Low dose weekly MTX remains the anchor drug for treatment of Rheumatoid Arthritis. The principal mechanism by which MTX suppresses inflammation in Rheumatoid Arthritis is thought to be enhanced adenosine release from cells which suppresses inflammation by stimulating adenosine receptors on T cells, macrophages and other inflammatory cells (Nature Rev Rheumatol 13:41, 2017). Many patients do not respond to low dose MTX and studies in mice suggest that MTX resistance may be due to inadequately increased adenosine release (Clin Exp Rheumatol 31:433, 2013). Because adenosine is primarily taken up by cells from the extracellular space via the nucleoside transporter ent1 we asked whether an agent that blocks adenosine uptake could enhance the effect of MTX in the treatment of RA. We therefore carried out an open label 1 month study, adding an inhibitor of adenosine uptake via ent1, ticagrelor (a P2Y12 inhibitor that is approved for inhibition of platelet aggregation to prevent severe cardiovascular events) (Nat Rev Cardiology12:156,2014), to patients who were poorly controlled with low dose methotrexate therapy for RA. (NCT02874092) Methods: Patients (5 female/1 male, mean age 49.6 years) who all met ACR criteria for RA and had active disease, as defined by DAS28 (ESR) > 3.6 and who were on stable doses of MTX monotherapy (for a minimum of 12 weeks), were recruited from the Bellevue Hospital Center Arthritis Clinic. Patients had no known contraindication to ticagrelor and had no history of coronary artery disease. After giving informed consent patients entered an open label protocol in which they were administered Ticagrelor (90mg) twice daily for one month in addition to their stable dose of MTX. Disease activity was reassessed and change in activity from the start of the trial was noted. This study was approved by the NYULMCBellevue IRB.
Result(s): Five of six patient achieved an improvement in their DAS28(ESR) >0.6. Half of the patients (3 patients) achieved a reduction in DAS28 (ESR) >1.2, 2 patients achieved a reduction in DAS28 (ESR) >0.6 but less than 1.2 and 1 patient showed no improvement. Four of six patients had a reduction in their tender joints and all had a reduction in swollen joints. No patients reported any adverse reactions, including excessive bleeding.
Conclusion(s): The results of this small open label trial suggest that treatment with ticagrelor enhances the effect of MTX on RA and may be a useful addition to the therapeutic armamentarium. Moreover, these results offer further support for the hypothesis that enhanced adenosine release at inflamed sites mediates the anti-inflammatory effects of MTX therapy. The limitations of this trial include the fact that it was an open label trial in a small group of patients but the results support further study of ticagrelor in combination with MTX. (Table Presented)

OBJECTIVE: In RA, autoreactive B cells are pathogenic drivers and sources of anti-citrullinated protein antibodies (ACPA) that serve as a diagnostic biomarker and predictor of worse long-term prognosis. Yet the immunobiologic significance of persistent ACPA production at a cellular level is poorly understood. METHODS: In a cross-sectional study of RA patients, we investigated for the presence of continued defects in immune homeostasis as a function of disease activity. Using an ELISA and a sensitive multiplex bead-based immunoassay, we characterized fine-binding antibody-specificities in sera, synovial fluid (SF) and B-cell culture supernatants. In this manner, we determined the frequency and epitope reactivity patterns of ACPA produced by SF B cells and switched-memory blood B cells, and compared the latter to serum ACPA levels and disease activity scores. RESULTS: Cultured B cells from SF were shown to spontaneously secrete ACPA, while constitutive IgG-autoantibody production by PBMC was substantially less frequent. After in vitro stimulation, PBMC secreted IgG ACPA that was overwhelmingly from switched-memory B-cells, across all patient groups treated with MTX and/or a TNF-inhibitor. Intriguingly, frequencies of ACPA-producing switched-memory B cells significantly correlated with serum IgG anti-CCP3 (r=0.57, p=0.003). Moreover, treatment-induced clinical remission had little or no effect on the circulating burden of switched-memory ACPA-producing B cells, in part explaining the continued dysregulation of humoral immunity. CONCLUSIONS: Our findings rationalize why therapeutic cessation most often results in disease reactivation and clinical flare. Hence, a clinical disease activity score is not a reliable indicator of the resolution of pathologic recirculating B-cell autoimmunity

OBJECTIVE: To evaluate the relationships between both quantitative and semiquantitative assessments of the degree of knee synovitis on 3T magnetic resonance imaging (MRI) and the severity of knee osteoarthritis (OA) on radiography. METHODS: Fifty-eight patients with knee OA underwent nonfluoroscopic fixed-flexion knee radiography. In addition, dynamic contrast-enhanced 3T MRI of the knees was performed, before and after gadolinium administration, to quantify synovial membrane volume (SV) as a measure of synovial proliferation (expressed as the quantitative SV), and semiquantitative measures of synovitis were also applied using both contrast-enhanced and unenhanced images. Two radiologists scored the knee radiographs using the Osteoarthritis Research Society International atlas; interreader agreement was assessed using kappa statistics and concordance correlation coefficients. Multiple linear and logistic regression analyses were used to assess associations among variables, while controlling for the effects of age, body mass index, sex, and meniscal extrusion. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated for measures of disease activity. RESULTS: The Kellgren/Lawrence (K/L) grade of radiographic knee OA severity (beta = 0.78), the diseased compartment joint space width (dcJSW) (beta = -0.22), and the diseased compartment joint space narrowing (dcJSN) score (beta = 0.53) were each significantly associated with the quantitative SV (P = 0.0001, P = 0.0003, and P = 0.0001, respectively). Furthermore, the quantitative SV strongly correlated with the total volume of subchondral bone marrow lesions (BMLs) (beta = 0.22, P = 0.0003). The K/L grade, dcJSW, and dcJSN score were each significantly associated with the semiquantitative Boston Leeds Osteoarthritis Knee Score (BLOKS) for the extent of infrapatellar synovitis (OR 9.05 [95% CI 1.94, 42.3] for K/L grade; OR 0.75 [95% CI 0.54, 1.03] for dcJSW; and OR 2.22 [95% CI 1.15, 4.31] for dcJSN score) and extent of joint effusion (OR 5.75 [95% CI 1.23, 26.8] for K/L grade; OR 0.70 [95% CI 0.50, 0.98] for dcJSW; and OR 1.96 [95% CI 1.02, 3.74] for dcJSN score). In addition, the semiquantitative synovitis grade on contrast-enhanced MRI was significantly associated with the K/L grade (beta = 0.036, P = 0.0040) and dcJSN score (beta = 0.015, P = 0.0266), and also significantly associated with the BLOKS synovitis score. CONCLUSION: Synovitis is a characteristic feature of advancing knee OA and is significantly associated with the K/L grade, JSW, JSN score, and total volume of BMLs on radiographs. Furthermore, BLOKS scoring of synovitis on unenhanced MRI is associated with measurements of synovitis on contrast-enhanced MRI