A Rarely Employed Therapeutic Pearl of Split-Dose Oral Corticosteroid in Severe Type 2 or Erythema Nodosum Leprosum Reaction in Lepromatous Leprosy and its Therapeutic Rationale

Sir,

Oral corticosteroids form the mainstay treatment of lepra reactions. However, often the patient becomes steroid-dependent, requiring higher doses. While the patient can be started on adjuvants as a steroid-sparing agents to help taper the dose of oral corticosteroids, this is often not achieved in chronic and/or severe erythema nodosum leprosum (ENL), and thus the patients suffer from steroid associated side effects. In such a scenario, a split-dose regimen of the existing once-daily oral steroids dose may help to manage the patient effectively, bypassing the need to increase the steroid dose. Herein, we report a 35-year-old male, known case of lepromatous leprosy with severe ENL, who showed dramatic, rapid and sustained response to a split-dose regime of oral corticosteroids.

A 35-year-old male, a known case of lepromatous leprosy with ENL, presented with multiple painful reddish skin lesions, associated with fever, joint pains and swelling of extremities. There was a history of a previous episode, 8 months back for which he was started on multibacillary multidrug therapy along with oral methylprednisolone and methotrexate, but the patient was irregular with his medication, which may have been the possible cause of this episode.

On examination, there were multiple erythematous, tender subcutaneous nodules, erythema-multiforme like and ulcerated lesions with central necrosis over the face and upper and lower extremities [Figure 1]. Few of the nodules had overlying vesicles and bullae. Bilateral ulnar nerves were enlarged, cord-like and non-tender. The ENLIST score was 21, suggestive of severe ENL, with a bacillary index of 3+. The histopathology was suggestive of ENL [Figure 2a and b].

Figure 1.

(a) Subcutaneous nodules, punched out ulcers and hypopigmented scars formed after healing of ulcers, present on extensors of bilateral lower limbs. (b) A well-defined oval 3 × 4 cm punched out ulcer over the extensor aspect of the right arm with necrotic slough in the floor. An overhanging necrotic skin is present at the lower end of the ulcer

Figure 2.

(a) Epidermis showing orthohyperkeratosis and neutrophilic infiltration. Mid dermis showing perivascular and periadnexal lymphohistiocytic infiltration with neutrophils and foam cells. There is evidence of septal panniculitis in subcutis [hematoxylin and eosin (H&E), 4×]. (b) Dense dermal neutrophilic infiltrates (H&E, 40×)

The patient was started on oral methylprednisolone 32 mg daily along with subcutaneous methotrexate 15 mg once weekly. Even after 4 weeks, he continued to develop new lesions. While the conventional norm is to increase the steroid dose, however, this often leads to steroid dependence. Thereafter, the single dose of methylprednisolone was split into a dose of 16 mg in the morning and evening. Within 2 days, the patient stopped developing new lesions and in 7 days achieved an ENLIST score of 0, suggesting a rapid response to split dosing. This dose regimen was maintained for 2 weeks following which the evening dose was tapered down by 4 mg every 7 days. Presently, the patient is well controlled on oral 16 mg methylprednisolone once daily with methotrexate 10 mg weekly.

The specific treatment for moderate to severe Type 2 lepra reaction includes oral steroids and thalidomide.[1] While clinical practice norms suggest the use of oral corticosteroids in a dose of 1–1.5 mg/kg/day for 2–4 weeks, followed by gradual tapering [Table 1], this is not successful in severe and chronic ENL and a prolonged and often individualized steroid regimen is needed.[1] The split-dose regimen has been ignored, even when its efficacy has been mentioned in the seminal textbooks of leprosy [Table 1].[1,2,3] One possible reason for the efficacy of a split dose is that ENL usually flares in the evening (between 17:00 and 18:00 hours), on account of the circadian rhythm of the daily secretion of cortisol which peaks at 8:00 AM and attains its nadir at midnight.[2,3]

Table 1.

Regimens for oral corticosteroid dose regimens in Type 2 lepra reactions treatment

Joplings Handbook of Leprosy[1,2]	Single morning dose: Oral Prednisolone 1-1.5 mg/kg/day for 2-4 weeks. Taper 10 mg every 2 weeks till 20 mg/day, followed by slow tapering of 5 mg every 2 weeks.
	Split-dose regimen: Initial phase: 80 mg prednisolone daily (should improve in 1-2 days). If there is deterioration after 12 h, the dose may be divided and given BD.
	Continue till skin changes have completely resolved, neuritic pain has cleared and neural function lost in the course of the reactive episode has begun to recover
	Reduction of steroid dose
	Attempt to reduce to single morning dose if used BD initially (either↓evening dose by 5 mg every 2-3 days or evening dose may be directly transferred and added to the morning dose).
	Tapering daily dose by 5 mg every 1-2 weeks.
Hastings leprosy[3]	Oral prednisolone 60 mg daily. Attempt to taper off over 2-3 months.
	Alternate day schedule may be tried for chronic reactions.

Akin to rheumatoid arthiritis, while there is a complementary increase in the cortisol levels by the hypothalamic–pituitary axis in response to inflammation, this does not override the severe inflammation and a relative cortisol deficit occurs, leading to further aggravation of inflammation.[4] A similar adrenal hypofunction has been described in leprosy.[5] A study to assess pharmacodynamic responses to single versus divided doses of methylprednisolone in healthy volunteers demonstrated that the latter led to an enhanced pharmacodynamic response, partly via a pharmacokinetic mechanism, leading to a dose sparing effect achieved by prolonging methylprednisolone plasma concentrations. Hence a lesser dose of methylprednisolone was able to achieve an equivalent effect, to that of a large single dose.[6] Even though divided doses of steroids are usually reserved for the management of severe, potentially life-threatening conditions, it is accepted that splitting the daily corticosteroid dose has more therapeutic benefits than administering equivalent daily doses, when a constant total daily dose is given, albeit with more hypothalamic–pituitary axis suppression.[6,7] This can be obviated by reverting to a morning dose when the reaction is under control.

Our patient was unresponsive to single daily dose of 32 mg methylprednisolone but responded extremely well when the same total dose was split into two doses, extolling the beneficial effect of this regime. While the so-called “steroid-sparing drugs” are advised to mitigate the severity ENL, apart from thalidomide[8] very few drugs can suppress an episode of severe ENL. Our patient too was unresponsive to methotrexate. The basic principle in severe ENL is to reduce steroid dependence as the duration of therapy is prolonged. Thus, instead of increasing the dose of steroids, splitting the same morning dose of corticosteroids into two divided doses may have practical utility.

Informed Consent

Informed consent from the patient was taken.

Ethical Statement

We declare that the research was conducted in compliance with the Declaration of Helsinki.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.