A Study to Evaluate the Efficacy and Safety of Apremilast in Patients of Chronic and Recurrent Erythema Nodosum Leprosum
A Study to Evaluate the Efficacy and Safety of Apremilast in Patients of Chronic and Recurrent Erythema Nodosum Leprosum
Leprosy is a chronic infectious disease caused by Mycobacterium leprae. The disease manifests
 with a varied spectrum, ranging from localized tuberculoid leprosy (TT) to generalized
 lepromatous leprosy (LL) types. The normal course of leprosy is interrupted by troublesome
 immune reactions, namely lepra reactions. ENL (a type 2 lepra reaction) is an immune-mediated
 hypersensitivity reaction, presenting as erythematous, tender, papulo-nodules and associated
 with constitutional symptoms (fever, arthralgias etc). Pro-inflammatory mediators are
 elevated, especially tumour necrosis factor α (TNF-α), interferon-γ (IFN- γ) and interleukins
 (IL-2, IL-6, IL-12). LL type and high bacteriological index are considered to be risk factors
 for ENL. Lesions usually appear after starting MDT, although it may also be presenting
 feature. Diagnosis is made by characteristic lesions associated with constitutional symptoms
 and painful nerve thickening. Mild episodes of ENL respond to adequate rest and oral aspirin.
 Severe episodes necessitate anti-inflammatory drugs like corticosteroids (e.g. Prednisolone)
 and/or thalidomide. Use of high-dose prednisolone increases risk of steroid toxicity.
 Thalidomide is category X drug (unsafe in pregnancy), not freely available and has
 cost-limitations. Clofazimine requires higher doses, takes 4 to 6 weeks to be effective and
 produces gastrointestinal side-effects and skin discoloration. Minocycline has been tried as
 an alternative; however the drug itself has been reported to precipitate ENL in some
 patients. Thus, a safe and effective steroid-sparing agent for ENL remains elusive.

 Cyclic adenosine monophosphate (cAMP) is an intracellular signal molecule. Phosphodiesterases
 (PDEs) catalyse degradation of cAMP leading to its inactivation. Inhibition of PDEs leads to
 increased intracellular cAMP, which has anti-inflammatory actions. PDE-4 isoenzymes are the
 predominant cAMP degrading enzymes in most immune cells. Apremilast is an oral
 phosphodiesterase-4 (PDE-4) inhibitor currently used clinically for the treatment of
 psoriasis and other chronic inflammatory diseases. The anti-inflammatory effects of
 apremilast shown in-vitro includes downregulating TNF-α, IFN-γ, IL-2, IL-12 and IL-23.
 Although apremilast is not yet clinically indicated in ENL, its anti-inflammatory spectrum
 targeting the same molecules as those implicated in ENL and efficacy seen in other
 inflammatory conditions warrants its trial in chronic, recurrent ENL patients.
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.

 Use and safety of apremilast in other dermatoses Apremilast has been extensively used in
 dermatology in psoriasis and psoriatic arthropathy and is FDA-approved for both the
 indications. Multiple randomized controlled trials (RCTs) have shown efficacy of oral
 apremilast in moderate to severe chronic plaque psoriasis. In an RCT involving 352 adult
 patients of moderate to severe psoriasis, oral apremilast was well-tolerated, safe and
 produced significant improvement in psoriasis area and severity index (PASI) scores, when
 used in dosage of 20 mg twice daily or 30 mg twice daily as compared to placebo and lower
 doses (p<0.0001).

 In another multi-centric RCT in 259 patients of psoriasis, apremilast produced significant
 reduction in PASI scores over 12 weeks and was well-tolerated20.

 In the three programs conducted under the title of Psoriatic Arthritis Long term Assessment
 of Clinical Efficacy (PALACE), when given in dose of 20 or 30 mg twice daily for 52 weeks,
 apremilast was significantly effective in improving the swollen joint count and the tender
 joint counts in psoriatic arthropathy without any serious adverse effects.

 In a study performed in 15 patients with cutaneous sarcoidosis, oral apremilast at a dose of
 20 mg twice daily, was shown to produce clinical improvement in paired photographs as well as
 significant decrease in sarcoidosis activity and severity index (SASI) scores with 12 weeks
 of therapy. The therapy was safe and no serious side-effects were reported.

 The most common adverse drug reactions (ADRs) recorded in previous studies were diarrhoea,
 nausea, upper respiratory tract infection and headache. Other ADRs included dyspepsia,
 decreased appetite, migraine, back pain, bronchitis etc. However, most of these side effects
 have a mild to moderate intensity, with a self limiting nature. In a study by Crowley et al,
 safety findings were reported for 0 to ≥156 weeks from the Efficacy and Safety Trial
 Evaluating the Effects of Apremilast in Psoriasis (ESTEEM) 1 and 2 and the authors concluded
 that apremilast had an acceptable safety profile and was well-tolerated despite use for ≥156
 weeks. Although there are no reports of use of apremilast in leprosy, the use is not expected
 to cause any significant adverse effects in view of its relative safe profile in other
 inflammatory dermatoses.

 AIMS AND METHODS

 Primary objective To assess the efficacy of apremilast in patients of chronic and recurrent
 ENL, who have not responded to either clofazimine or minocycline

 Secondary objective To evaluate the safety profile and document adverse effects of oral
 apremilast in chronic recurrent ENL

 MATERIALS AND METHODS

 Study period: November 2018 to April 2019 Number of patients to be enrolled in pilot study:
 10 This will be a pilot study to assess the efficacy and safety of Apremilast in chronic and
 recurrent Erythema Nodosum Leprosum (ENL) conducted in the department of Dermatology,
 Venereology and Leprology, PGIMER, Chandigarh after obtaining approval from the institutional
 ethics committee.

 Definitions Erythema Nodosum Leprosum (ENL) is diagnosed when a patient with leprosy has
 crops of tender subcutaneous skin lesions. Systemic features are recorded separately and
 include: fever (temperature >38°C), neuritis, joint pain, bone tenderness, orchitis, iritis,
 oedema, malaise, anorexia and lymphadenopathy

 Chronic ENL: ENL occurring for 24 weeks or more during which a patient requires ENL treatment
 either continuously or where any treatment free period has been 27 days or less.

 Recurrent ENL: If a patient experiences a second or subsequent episode of ENL occurring 28
 days or more after stopping treatment for ENL

 Data collection All the diagnosed patients of chronic and recurrent ENL will be screened for
 the eligibility. Patients who give consent and fulfil the eligibility criteria in the study
 period will be consecutively enrolled in the study.

 Drug protocol to be used:

 Oral tablet of Apremilast 30 mg twice in a day daily for 6 months after an initial titration
 schedule.

 Titration schedule shall be as follows:

 The study patients will be treated with oral apremilast, administered initially a dose of 10
 mg once daily, gradually increasing to reach the maximal therapeutic dosage of 30 mg twice
 daily before end of 1st week of starting the therapy.

 The treatment will be continued till 6 months and we will taper the steroids by 10mg/ 2 weeks
 till 20mg and then 5 mg/ 2 weeks till discontinuation of steroids.

 If a patient worsens after treatment or develops any serious adverse event after initiation
 of treatment, he will be withdrawn from the study.

 If there is no response to the treatment and we are unable to taper steroids after 12 weeks
 of therapy then the patient will be withdrawn from the study.

 STATISTICAL ANALYSIS The statistical analysis will be carried out using Statistical Package
 for Social Sciences (SPSS Inc., Chicago, IL, version 20.0 for Windows). All quantitative
 variables (age, duration of the symptoms, age at onset) will be estimated using measures of
 central location (mean, median) and measures of dispersion (standard deviation and standard
 error). Normality of data will be checked by measures of Kolmogorov Smirnov tests of
 normality. For normally distributed data means will be compared using student's t-test. For
 skewed data or for scores, Mann-Whitney test will be applied & IQR will also be calculated.
 For time related variables, Wilcoxon Signed rank test will be applied. Qualitative or
 categorical variables will be described as frequencies and proportions. Proportions will be
 compared using Chi square or Fisher's exact test whichever is applicable. All statistical
 tests will be two-sided and will be performed at a significance level of α=.05.

 ETHICAL JUSTIFICATION Apremilast is one of the newer and safe oral therapies currently used
 for treating patients with severe psoriasis and psoriatic arthropathy due to its
 anti-inflammatory effects. ENL is an immune-mediated inflammatory response occurring in
 patients of multibacillary leprosy. Although apremilast targets those inflammatory mediators,
 which are also implicated in ENL, the exact role and possible efficacy of apremilast in
 patients with chronic and recurrent ENL is not yet clear and has not been evaluated before.
 This study aims to study the efficacy and safety of oral apremilast in ENL patients. All
 patients will be recruited voluntarily after obtaining informed consent. Hence, the study is
 ethically justified.

 Clinical assessment and follow-up visits will be performed during scheduled visits. There
 will be no financial burden on the patient for the study purpose as apremilast will be
 provided by the investigators and the patients will not be compensated financially for
 participating in the study. Treatment of the patient will not be altered by the refusal or
 agreement of the patient to participate in this study.
Inclusion Criteria:

 1. Chronic and recurrent ENL cases of leprosy regardless of age, sex and treatment status
 with MDT

 2. Patients not responded with paracetamol, clofazimine, pentoxifylline, colchicine,
 methotrexate, azathioprine, TNF inhibitors etc.,

 3. Patients who can give valid consent.

 4. Willing for monthly follow-up visits for at least 3 months.

 Exclusion Criteria:

 1. Pregnant and lactating mothers

 2. Severe renal dysfunction

 3. Patients with HIV, Hepatitis B and Hepatitis C

 4. Inability to come for monthly follow up visits for 6 months

 5. Those who cannot provide consent for the study

 6. Known case of psychiatric disease