A Pilot Study to Evaluate the Efficacy and Safety of Apremilast in Patients of Chronic and Recurrent Erythema Nodosum Leprosum

ENL is confined to leprosy patients classified as BL or LL (Ridley-Jopling), which in turn comprise the multi-bacillary (MB) patient group, as defined by WHO. ENL presents as new, red, painful and tender nodules in the skin, usually on the legs and arms, and sometimes on the trunk. ENL varies in severity. When the reaction is mild, only the skin is affected and there may be low grade fever. When the reaction is severe, the nodules are multiple and may ulcerate, and other organs may be inflamed, such as the nerves, eyes, joints, testes, and lymph nodes. ENL may occur before, during or after MDT treatment, and several years later. It can occur as a single acute episode, but frequently develops into a chronic condition with recurrent episodes. Immune responses causing ENL are triggered by high loads of fragmented bacilli in skin tissue. The complex mechanisms underlying ENL are not fully understood yet which makes treatment difficult.

Treatment of ENL is much debated and a very challenging issue. There is no universally accepted regimen that is fully effective. Most therapies for ENL aim to control the acute inflammation, relieving the pain and preventing further damage or new episodes. Several treatments are available for ENL. The conventional treatment for mild ENL is rest and anti-inflammatory medication. Aspirin was the most commonly used anti-inflammatory medication, but indomethacin, chloroquine and colchicine have been tested as well. There is not much evidence that these drugs are more beneficial than aspirin. For severe ENL, prednisolone, the most widely available corticosteroid, and clofazimine are most commonly used. ENL is often recurrent or chronic and requires high-dose and prolonged courses of prednisolone for disease control. This increases the risk of adverse events, such as hypertension or diabetes, and steroid dependency.

Apremilast is a novel, phosphodiesterase 4 (PDE 4) antagonist, and an orally administered small molecule, acts by specifically targeting a central pathogenic mechanism, binding directly to the PDE-4 enzyme and evading complex antigen-receptor interactive immunoregulatory mechanisms. Apremilast is an immune modulator rather than an immunosuppressant.

Anti-inflammatory actions of Apremilast includes

1. Increased levels of cAMP, which reduces the levels of pro- inflammatory cytokines (such as tumor necrosis factor (TNF)-α, interleukin (IL)-23, IL-12, and leukotriene B4) and also increases the levels of anti-inflammatory cytokines (such as IL-10)
2. Binds to toll-like receptor 4 in peripheral blood mononuclear cells, which further decrease the production of pro-inflammatory cytokines
3. Decreases the activity of nitric oxide synthase Because of its anti-inflammatory actions, Apremilast may have a significant role in the treatment of patients with Erythema Nodosum Leprosum who have not responded to other conventional treatment.