Molecular Effects of Apremilast in the Synovium of Psoriatic Arthritis Patients (MEAS Study)

1. INTRODUCTION 1.1 BACKGROUND Psoriasis and Psoriatic Arthritis Psoriasis is a chronic relapsing immunologically mediated skin disease manifesting as red scaly plaques, which affects about 1-3% of the population.(ref.1-3). Ten to 20% of the people with psoriasis may develop an arthropathy, which affects small or large joints in a symmetrical or asymmetrical fashion(ref.4). Psoriatic arthritis (PsA) is the second most common inflammatory arthritis after rheumatoid arthritis, accounting for 10% to 15% of the patients attending early arthritis clinics(ref.5).

PsA is a heterogeneous disease affecting 0.3 to 1% of the population(ref.6) and recent evidence showed significant disability if this condition is not adequately treated. About 15-35% had marked limitations of their functional capacity. Moreover patients with PsA have an increased mortality risk compared to the general population. A 59 and 65%-increased death rate was seen among respectively male and female PsA patients(ref.7).

Different systemic treatments such as sulfasalazine, leflunomide, methotrexate, and biologics are widely used to treat PsA (ref.8) but not all patients respond to or tolerate these treatments. In addition, not all manifestations of PsA (like joints, dactylitis, scalp, enthesitis, or nails) may respond equally well.

Apremilast Mechanism of action and indications Otezla (apremilast) is an innovative oral small-molecule inhibitor of phosphodiesterase (PDE) 4 that works intracellularly to modulate a network of pro- and anti-inflammatory mediators (ref.9,10). PDE4 is a cyclic adenosine monophosphate (cAMP)-specific PDE and is the dominant PDE in inflammatory cells. Inhibition of PDE4 elevates intracellular cAMP levels, which in turn down-regulates the inflammatory response by modulating the expression of tumour necrosis factor alpha (TNF-α), interleukin (IL)-23, IL-17, and other pro-inflammatory cytokines. Elevation of cAMP also increases anti-inflammatory cytokines. These pro- and anti-inflammatory mediators have been implicated in psoriasis and PsA. The pro-inflammatory mediators that are upregulated in PsA include the cytokines TNF-α, IL-1, IL-6, and IL-8, and the chemokines monocyte chemotactic protein-1 and macrophage inflammatory protein-1 beta (ref.9,11-13,17).

Based on these effects, apremilast has been developed for use in the treatment of various immune-mediated inflammatory conditions such as psoriasis and PsA and it is under investigation in Behçet disease. A total of 4,089 patients have been exposed to apremilast across multiple indications, including 1,945 patients in the PsA Phase 3 clinical program (PALACE program)(Ref.14) and 1,184 patients in the psoriasis Phase III clinical program (ESTEEM program)(Ref.15,16).