Considering Immuno-autonomics in Stratifying Successful Treatment of Rheumatoid Arthritis with Tumor Necrosis Factor Inhibition: Comment on Cohen et al. Rheumatol Ther 2021 June 19.

Cohen et al. have significantly advanced a solution to arguably the most pervasive conundrum in rheumatology: how to target specific immunosuppressive therapy most effectively [1]. In infectious disease and oncology, targeted therapy has been based upon pathogen susceptibility and tissue surface receptor expression, respectively. Predicting either positive or negative response to specific therapies in rheumatoid arthritis (RA) is certainly welcome and the molecular signature response classifier (MSRC) appears most promising and useful.

However, two issues come to mind after reviewing this important paper. First, disease activity has been a consistent predictor of poor tumor necrosis factor inhibition (TNFi), yet demographic characteristics were reported as ‘not significantly different’ among those responsive and those unresponsive to TNFi. This seems curious.

Second, there was mention of many studies attempting unsuccessfully to identify biomarkers or models unable to predict TNFi outcome in RA. We wish to bring to the authors’ attention a 52-week, prospective, double-blind study of next-generation, high-fidelity heart rate variability (HRV) predicting TNFi outcome in RA and psoriatic arthritis [2]. Subjects with a poor autonomic nervous system (ANS) profile by the ‘parasympathetic’ measure (low) at day 0 achieved ACR (American College of Rheumatology) 20/50/70 outcomes of 40%/12%/0%, respectively. Subjects with a favorable ANS profile by the ‘parasympathetic’ measure (high) achieved an ACR20/50/70 outcomes of 100%/88%/65%, respectively.

The receiver operating characteristic (ROC) area under the curve (AUC) for the MSRC was 0.64 for ACR50 at 26 weeks, with secondary outcomes reaching a ROC AUC of up to 0.74 among TNFi naïve subjects. The ROC AUC for ‘parasympathetic’ and sympathetic ‘tension index’ using next-generation, high-fidelity HRV for ACR50 at 26 weeks were 0.858 and 0.869, respectively [3]. Of note, the ROC AUC for ACR70 at 52 weeks were 0.926 and 0.918, respectively. In turn, this link between the regulatory power of the ANS driving immune function, i.e., immuno-autonomics, is hypothesized to be agnostic to the immunosuppressive chosen. Of course, additional rigorous studies will be required to confirm or refute that supposition.

Lately, immuno-autonomics and ANS optimization have become a target strategy to reduce RA burden [4]. The most prominent example is vagus nerve stimulation (VNS) to reactivate a dormant cholinergic anti-inflammatory reflex [5]. Implanted (cervical and splenic) as well as external (ear bud) VNS have been explored in RA.

ANS sympathetic stress activates proinflammatory cytokines and a host of other immune functions driving autoimmune diseases to excess [6]. We submit that targeting immunosuppressive choice in combination with optimizing ANS state may offer complimentary value. We look forward to a study where targeted TNFi selection is blended with immuno-autonomic intervention to enhance RA treatment outcomes. This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.