Background/Purpose:   Certain rheumatic diseases including systemic sclerosis (SSc) are characterized by chronic activation of innate immune responses, leading to excessive fibrosis.  A normal innate immune response is comprised of an onset phase characterised by generation of pro-inflammatory lipid mediators, chemokines, adhesion molecules, and tissue infiltration of inflammatory cells.  This is followed by a resolution phase where the balance of lipid mediators shifts from pro-inflammatory mediators to novel Specialized Pro‑resolving Lipid Mediators (SPMs), pro-inflammatory cytokines and chemokines are inhibited, pathogens and inflammatory cells are cleared from involved tissues, and active wound healing processes are completed.  Persistent inflammation and progressive fibrosis can reflect an imbalance that favors onset phase over resolution phase.  Anabasum (JBT-101) is a cannabinoid receptor type 2 agonist that showed evidence of clinical benefit on Phase 2 testing in systemic sclerosis. Anabasum activates resolution of skin and lung inflammation in animal models of SSc.  Using a novel in vivo human skin challenge model of an innate immune response, we tested the effect of anabasum on inflammatory onset and resolution and compared it to prednisolone.

Methods:   In this placebo-controlled study, subjects (N = 20) received placebo (n = 5), oral anabasum 5 mg BID (n = 5), anabasum 20 mg BID (n = 5), or prednisolone 15 mg OD (n = 5) for 4 days.  On the 4th day, acute inflammation was triggered by intradermal injection of ultraviolet light-killed E coli on both the forearms of healthy subjects.  Local inflammatory exudate was acquired into a suction blister raised at 4 hr on one forearm (onset time point) and at 10 hr on the contralateral forearm (resolution time point).  Inflammatory exudate was analyzed for soluble mediators and immune cells.  Blood flow to the site of inflammation was monitored by laser doppler.

Results:   Anabasum exerted a profound anti-inflammatory effect in this model by accelerating the resolution phase of the innate immune response.  Anabasum: increased blood flow during the resolution phase at 10 hours; reduced IL-8 and neutrophils in blister exudate 10 hours post-challenge, as did prednisolone; reduced the proinflammatory lipid mediators LTB4, PGF₂a, TxB₂ and PGE₂; increased the SPMs lipoxins (LXA₄, LXB₄) and resolvins (RvD1, RvD3, RvD5); and hastened bacterial clearance, whereas prednisolone slowed bacterial clearance during the resolution phase (resolution toxic).

Conclusion:   Anabasum has novel biologic effects on infection-induced innate immune responses as it exerts a striking anti-inflammatory effect greater than that of prednisone and leading to timely resolution of inflammation.  This activity offers promise for anabasum in the treatment of SSc.