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Background: Rheumatoid arthritis (RA) is a disease with significant remaining unmet medical needs for better treatments. Vagus nerve stimulation (VNS) to activate the inflammatory reflex (cholinergic anti-inflammatory pathway) repre sents a novel experimental therapy for RA.1 Previously, we reported that inflam matory reflex activation by VNS reduced pro-inflammatory cytokine production and improved disease activity in a 17-patient rheumatoid arthritis (RA) proof-of concept study using a reprogrammed epilepsy stimulator2 ; clinical improvement was sustained for 24 months without untoward safety signals.3 Here we report the 48 months results from this long-term observational study. Objectives: Determine the long-term safety and efficacy of VNS for the treat ment of RA Methods: In the primary study, a VNS device was implanted into 17 RA patients, mostly with insufficient response to multiple conventional and biologic DMARDs, on stable background of methotrexate (≤25mg weekly) therapy2 . The device electrically stimulated the vagus nerve, 1- 4min/day, over a 12-week open label period. On completion, subjects were offered to enroll into a follow-up study, where the study physicians were given flexibility to alter VNS dosing parameters and/or to add a biologic disease-modifying antirheumatic drug (DMARD) to the treatment regimen to induce disease remission. Clinical disease activity meas ures and safety were accessed over 4 years. Results: All patients electively continued VNS treatment in the long-term follow-up study, 4 subjects withdrew prior to month 48. Reasons for discontinuation were withdrawal of consent (N=3) and adverse event due to device discomfort (N=1). At the start of the follow-up study, the mean DAS28-CRP, CDAI and HAQ-DI were significantly reduced compared to the pre-implant baseline (mean difference± SD: DAS28-CRP=-1.60± 1.13, p

Methotrexate (MTX) monotherapy is a common first treatment for rheumatoid arthritis (RA), but many patients do not respond adequately. In order to identify genetic predictors of response, we have combined data from two consortia to carry out a genome-wide study of response to MTX in 1424 early RA patients of European ancestry. Clinical endpoints were change from baseline to 6 months after starting treatment in swollen 28-joint count, tender 28-joint count, C-reactive protein and the overall 3-component disease activity score (DAS28). No single nucleotide polymorphism (SNP) reached genome-wide statistical significance for any outcome measure. The strongest evidence for association was with rs168201 in NRG3 (p = 10‾⁷ for change in DAS28). Some support was also seen for association with ZMIZ1, previously highlighted in a study of response to MTX in juvenile idiopathic arthritis. Follow-up in two smaller cohorts of 429 and 177 RA patients did not support these findings, although these cohorts were more heterogeneous.

The data presented here demonstrate that VNS in subjects with RA is associated with a substantial reduction in disease activity that is sustained for 24 months without untoward safety signals. Further, the data suggest that biological DMARDs may be initiated safely in combination with VNS treatment, though this requires validation in larger cohorts. These results support additional development of VNS devices as an alternative therapeutic approach for RA treatment, which potentially can safely be combined with biologic DMARDs.

Background/Purpose: RA is a debilitating chronic disease with an unmet need for additional therapeutic approaches. Modulating innate neuro-immune re ex pathways by stimulation of the vagus nerve (VNS) could represent a novel means of treating RA (van Maanen MA et al. Nat Rev Rheumatol. 2009 ; 5:229-32). We recently reported a 12-week proof of concept study using a VNS device, approved for drugresistant epilepsy, showing reductions in the DAS28-CRP and in TNF-α and IL-6 levels (Koopman FA et al. PNAS 2016 ; 113:8284). To understand the long term safety and e cacy of this novel treatment approach, we followed the patients in a 24 months long-term extension study and report on the safety and clinical e cacy data. Methods: In the primary study, VNS devices were implanted into 17 RA patients, mostly with insu cient response to multiple conventional and biologic DMARDs, on stable background of methotrexate (≤25 mg weekly) therapy. The devices electrically stimulated the vagus nerve, 1-4 min/day, over a 12 week open label period. On completion, subjects were o ered to enroll into a follow-up study, where the study physicians were given exibility to alter VNS dosing parameters and/or to add a biologic DMARD to the treatment regimen. DAS28-CRP and Health Assessment Questionnaire-Disability Index (HAQ-DI) were collected over 2 years. Results: All subjects electively continued on VNS treatment through 24 months of the long term follow-up study. Biologic DMARDs were started in 1 and restarted in 8 of 17 subjects ; of these, 4 were nonresponders to VNS in the primary study, and 5 had stable improvement but had not yet achieved disease remission on VNS alone (Table 1). At the start of the follow-up study, the mean DAS28-28 and HAQ-DI were signi cantly reduced compared to the pre-implant baseline (mean di erence± SE in DAS28-CRP = -1.60± 0.37, p

Objectives: Rituximab is an effective treatment in patients with established rheumatoid arthritis (RA). The objective of the IMAGE study was to determine the efficacy of rituximab in the prevention of joint damage and its safety in combination with methotrexate (MTX) in patients initiating treatment with MTX. Methods: In this double-blind randomised controlled phase III study, 755 MTX-naïve patients with active RA were randomly assigned to MTX alone, rituximab 2×500 mg + MTX or rituximab 2×1000 mg + MTX. The primary end point at week 52 was the change in joint damage measured using a Genant-modified Sharp score. Results: 249, 249 and 250 patients were randomly assigned to MTX alone, rituximab 2×500 mg + MTX or rituximab 2×1000 mg + MTX, respectively. At week 52, treatment with rituximab 2×1000 mg + MTX compared with MTX alone was associated with a reduction in progression of joint damage (mean change in total modified Sharp score 0.359 vs 1.079; p=0.0004) and an improvement in clinical outcomes (ACR50 65% vs 42%; p

Tertiary Lymphoid structures (TLSs) in chronic inflammation, including rheumatoid arthritis (RA) synovial tissue (ST), often contain high endothelial venules and follicular dendritic cells (FDCs). Endothelial cell (EC)-specific Lymphotoxin beta (LT beta) receptor signaling is critical for the formation of lymph nodes and high endothelial venules. FDCs arise from perivascular platelet-derived growth factor receptor beta(+) precursor cells (preFDCs) that require specific group 3 innate lymphoid cells (ILC3s) and LT beta for their expansion. Previously, we showed that RA ST contains ECs that express NF-kappa B-inducing kinase (NIK), which is pivotal in LT beta-induced noncanonical NF-kappa B signaling. We studied the relation between NIK+ ECs, (pre)FDCs, and ILC3s with respect to TLSs in RA ST. TLS+ tissues exhibited a significantly increased expression of genes involved in noncanonical NF-kappa B signaling, including NIK, and immunohistochemical analysis revealed that NIK was almost exclusively expressed by ECs. ILC3s were present in human RA ST in very low numbers, but not differentially in TLS+ tissues. In contrast, TLS+ tissues contained significantly more NIK+ ECs and perivascular platelet-derived growth factor receptor beta(+) preFDCs, which correlated significantly with the quantity of FDCs. We established a strong link between NIK+ ECs, (pre)FDCs, and the presence of TLSs, indicating that NIK+ ECs may not only be important orchestrators of Lymph node development but also contribute to the formation of TLSs in chronic inflammation.