Background/Purpose: As a proposed inflammatory biomarker for autoimmune disease^1,2, the autonomic nervous system (ANS) has been assessed as a predictor of anti-TNF treatment outcome³ and as an adjunctive therapeutic target^4-6 to elevate a stagnant remission rate in rheumatoid arthritis which has languished at 27% by ACR70 response⁷for many years.  

Methods: This retrospective, community-based study assessed consecutive patients initiating biologic treatment of inflammatory arthritis.   In an effort to improve outcome by 28-joint count (swollen and tender), neuroregulatory medications, many of which reduce ANS sympathetic tone, were added to etanercept for patients exhibiting an incomplete therapeutic response to traditional immunosuppression (etanercept combined with DMARDs, prednisone and/or NSAID). Statistical analysis included t-test and logistic regression.

Results: Sixty-six patients  (70% female, mean age of 50.8±13.0 years, mean duration of disease 9.7±6.4 years, mean prior DMARD use 2.3±1.4, mean ESR 26.6±27.8) initiated etanercept at 25mg BIW for treatment of their inflammatory joint disease (39 seropositive rheumatoid, 13 seronegative rheumatoid, 14 psoriatic arthritis by ACR criteria).  All but five continued etanercept for a mean 20.7±7.7 months for an etanercept retention rate of 92%.  Three subjects discontinued for personal reasons, one died of unrelated issues and one was lost to follow-up.   Overall, initial joint count decreased after addition of etanercept from 11.6 to 1.3 with 79% achieving >=70% reduction in joint count by LOCF (74% by BOCF).  

Baseline doses of prednisone and methotrexate were 6.7 mg/d (n=42) and 19.14 mg/wk (n=32), respectively.  Ultimately, prednisone was discontinued in 62% (26 of 42); methotrexate was discontinued in 75% (24 of 32); other DMARDs were discontinued in 79% (22 of 28); and NSAIDs were discontinued in 48% (14 of 29).   Neuroregulatory medications were used by 36 subjects (55%), including lorazepam 1-2 mg po qhs (18%), clonazepam 1-2 mg po qhs (15%), pramipexole 0.5-4.5 mg po qhs (29%), trazodone 50-100 mg po qhs (21%), other antidepressants (14%), and anti-epileptics  (1%).  Regression analysis was unable to identify any factor beyond the frequent use of neuroregulatory medications able to reconcile the clinical treatment response to etanercept seen in this cohort relative to historical etanercept treatment outcomes.

Conclusion: Pure ANS therapies, such as vagal nerve stimulation, are already in human RA trials.   Although uncontrolled, this data continues to suggest the relevance of further inquiry into the potential benefit of employing an adjunctive neuroregulatory ANS strategy to improve outcomes with immunosuppressive therapies.

1.  Elenkov IJ et al  Pharmacological Reviews 2000;52:595-638.  2.  Koopman FA et al  Mol Med 2011;17(9-10):937-948.  3.  Holman AJ et al Autonomic Neurosci Basic Clinical 2008 Dec 5;143(1-2):58-67.   4.  Koopman FA et al ACR 2012 abstract #451.   5.  Shimizu M et al ACR 2003 abstract #114   6.  Bencherif M et al Mol Life Sci. 2011;68(6):931-949.   7.  Moreland LW et al J Rheum 2006 May;33(5):854-61.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/use-of-adjunctive-neuroregulatory-medication-to-improve-etanercept-treatment-response-for-patients-with-inflammatory-arthritis-a-pilot-study/