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Lepr Rev (2006) 77, 225– 229
CASE REPORT
Role of azathioprine in preventing recurrences
in a patient of recurrent erythema nodosum
leprosum
KAUSHAL K. VERMA*, P. SRIVASTAVA*, ANIL MINZ*
& KAMNA VERMA**
*Department of Dermatology and Venereology, and
**Ophthalmology, All India Institute of Medical Sciences,
New Delhi, India
Accepted for publication 19 June 2006
Summary The pathogenesis of erythema nodosum leprosum (ENL) involves both
immune complex deposition and dysfunction of cell mediated immunity. Tumour
necrosis factor-a (TNF-a) plays an important role in its pathogenesis. Thalidomide and
corticosteroids are the mainstay of treatment for ENL. However, there are often severe
limitations to their use. We report a case of recurrent ENL treated successfully with
azathioprine. A 15-year-old unmarried girl with lepromatous leprosy had recurrent
ENL for 2 years. She was treated with WHO-MB MDT and prednisolone in doses of
40 – 90 mg a day for 2 – 12 weeks. Her condition was inadequately controlled. The
patient was therefore treated with thalidomide 300 mg and prednisolone 40 mg. The
symptoms subsided after 5 days and ENL lesions healed in 2 weeks. Prednisolone was
reduced by 10 mg per week and stopped, while thalidomide was reduced to 100 twice
daily after 4 weeks. Azathioprine 100 mg (2 mg/kg per day) daily orally was added to
prevent recurrences. Thalidomide was further reduced and stopped after another 4
weeks while she continued with azathioprine in the same doses for 8 months. There was
no recurrence of ENL lesions and no side effects of the therapy. MB-MDT was stopped
1 year ago, and she is on follow-up without any relapse. Azathioprine, therefore,
appears to be an effective and safe drug to prevent recurrences of ENL.
Introduction
Erythema nodosum leprosum (ENL) is a common and serious immuno-inflammatory
complication of multibacillary leprosy. It affects up to 50% of patients with lepromatous
leprosy,1 usually during treatment with anti-leprosy drugs. Systemic manifestations often
associated with ENL include fever, malaise, lymphadenopathy, neuritis and arthralgia which
Correspondence to: K. K. Verma, Department of Dermatology and Venereology, All India Institute of Medical
Sciences, New Delhi 110029, India (Tel: þ91 11 26593453; Fax: þ 91 11 26588663/26588641; e-mail:
[email protected])
0305-7518/06/064053+05 $1.00
q Lepra
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are often severe, causing significant morbidity in these patients. The condition may be
chronic and recurrent. Immune complex deposition and immune dysfunction are the key
pathogenic events in ENL, causing activation of complements and migration of polymorphs
with release of tissue damaging enzymes.2 – 4 An imbalance of immunoregulatory T-cell
subsets has also been demonstrated in ENL.5 Tumour necrosis factor-a (TNF-a), a proinflammatory cytokine, plays an important role in the pathogenesis of ENL. There is
activation of T-cells and macrophages, inducing production of large amounts of TNF-a.
Plasma levels of this cytokine have been found to be high during the episodes of
ENL.6 Thalidomide and corticosteroids are the two main drugs used for treatment of ENL.
Thalidomide is the drug of choice. It quickly controls the condition with relief in signs and
symptoms, but it is a teratogenic, poorly accessible and expensive drug. High doses of
corticosteroids may control the disease, but their prolonged use is associated with serious side
effects.7 Azathioprine is a known T-cell inhibitor and a potent anti-inflammatory agent. It has
been shown to inhibit TNF-a,8 though the evidence is not conclusive. We used azathioprine
in a young girl with recurrent ENL to prevent recurrences.
Case report
A 15-year-old unmarried girl, a resident of Bihar, India, had had hypopigmented and
hypoaesthetic patches over the extensor aspect of her left arm for 7 years. Three years later,
she noticed similar lesions on both forearms and the lateral aspect of thighs and legs, which
gradually increased in size. Within 2 years of the appearance of these lesions, she developed
multiple, tender, erythematous nodules on both the extremities associated with fever, joint
pain and redness of both eyes. She was diagnosed to have multibacillary leprosy, and started
on (WHO) MB MDT by a local medical practitioner. Prednisolone 40 mg once daily orally
was added for treatment of ENL, which was tapered over 3 months and stopped. The ENL
was controlled with this treatment and the patient became asymptomatic. One month after
stopping prednisolone, she developed a recurrence of ENL as erythematous, tender nodules
with fever and joint pain. She was again started on prednisolone 40 mg once daily orally by
the same practitioner, which she continued for 3 months on his advice. There was no adequate
control of ENL with this treatment. Moreover, she continued to develop similar new lesions
with fever and the joints pain persisted. The dose of prednisolone was increased to 60 mg
daily for 2 weeks, then 80 mg daily for 2 weeks, and finally 90 mg daily orally for 2 weeks.
The dose of clofazimine was also increased to 100 mg thrice daily for 4 weeks. Even with this
treatment, there was no control and she developed severe ENL with erythematous necrotic
lesions. Thereafter the patient was referred to us. She presented to us with hypoaesthetic
macules and erythematous nodules over both extremities, with fever and joint pain.
On examination, she had diffuse infiltration of both ear lobes and face with multiple
hypoaesthetic patches of varying sizes on the trunk and proximal parts of the extremities,
peripheral hypoaesthesia and symmetrical nerve thickening involving both ulnar, radial,
lateral popliteal and right posterior tibial nerves, without significant nerve tenderness and no
clinically detectable nerve function impairment. There were multiple erythematous, tender
nodules and a necrotic ulcer over both forearms and legs. Ocular examination did not reveal
any abnormality. Examination of other systems was unremarkable. All the routine
investigations, including haemogram, liver and renal function tests, urine, stool and chest
X-ray, were within normal limits. Slit skin smear examination revealed a bacteriological
Azathioprine in recurrent erythema nodosum
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index of 2 þ from the ear lobes and 3 þ from the patch. Electrophysiological studies
showed asymmetrical axonal sensorimotor neuropathy. Skin biopsy from a nodule showed
histopathological features consistent with lepromatous leprosy with erythema nodosum
leprosum. A urinary pregnancy test was performed twice and was negative, and
ultrasonography of the abdomen did not reveal a gestational sac. The patient was treated
with (WHO) MB MDT, prednisolone 40 mg daily and thalidomide 100 mg thrice daily orally.
The patient was informed about the teratogenic effects of the drug and counselled about
complete abstinence while on therapy. After 5 days of this treatment, there was no fever and
the joints pain were alleviated. The ENL lesions also started healing, with complete relief in 2
weeks. Prednisolone was reduced by 10 mg every week and then stopped after 4 weeks while
thalidomide was reduced to 100 mg twice daily. Azathioprine at a dose of 50 mg twice daily
orally (2 mg/kg per day approximately) was added (her body weight was 55 kg). One week
later, thalidomide was further reduced to 100 mg daily for 4 weeks and then stopped. The
patient received thalidomide for 9 weeks. During the first 6 weeks, she was given thalidomide
as an in-patient followed by 3 weeks outpatient treatment. Urine pregnancy test was repeated
monthly while she was on thalidomide. Azathioprine was continued in the same dose for 8
months. During azathioprine therapy complete blood count, liver and renal function tests
were repeated every month which remained unremarkable. She did not develop any further
episodes of ENL. There were no significant side effects of the treatment. The patient
continued (WHO) MB MDT for 2 years, due to clinical activity of leprosy but without any
ENL episodes (Figure 1).
Discussion
The management of ENL is still a challenge for clinicians. Out of the various drugs used for
treatment of ENL, thalidomide and corticosteroids remain the mainstay of therapy.
Thalidomide is a highly effective drug for acute severe ENL. It causes rapid improvement in
clinical symptoms with reduction in TNF-a levels. It also acts on T-cells, reducing the CD4
cells and increasing the CD8 cell counts. There are, however, serious limitations to its use due
to its teratogenic effects and potential neurotoxicity. The drug has a very restricted
availability and a high cost in India which further limits its use. We used thalidomide in this
young unmarried teenage girl in addition to prednisolone to control ENL, which was not
getting better even with high doses of corticosteroids alone. The patient was informed about
the teratogenic effects of the drug and counselled about complete sexual abstinence while on
therapy. She was also treated as an in-patient for 6 weeks out of 9 whilst on thalidomide
therapy. With a combination of prednisolone and thalidomide, her ENL completely subsided
in 2 weeks; prednisolone and thalidomide were gradually tapered and stopped, while she
continued azathioprine for 8 months without any further recurrences.
Azathioprine is a 6-mercaptopurine derivative, which inhibits purine synthesis and is a
potent T-cell inhibitor. It also inhibits B-cell proliferation and antibody production, and
probably monocyte and polymorphonuclear cell function as well. It also has a strong antiinflammatory effect and has also been shown to inhibit TNF-a,8 a procytokine primarily
responsible for ENL lesions. Therefore, we tried azathioprine in this patient to prevent
recurrences. Azathioprine with corticosteroids has also been used in ENL by other workers.9
Marlowe et al. have used azathioprine with prednisolone to treat severe type 1 reaction.10
They used azathioprine as a steroid-sparing agent. The drug has been effectively used on a
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Figure 1. ENL treatment and response.
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long-term basis in patients with Parthenium dermatitis as a corticosteroid-sparing agent.11 Its
long-term safety, adverse effects and monitoring have been well studied.12 We arbitrarily
decided to continue azathioprine for 8 months. There were no adverse effects of the drug.
Azathioprine probably prevented further recurrences of ENL in this patient. Further studies,
however, are needed to confirm its role in this condition.
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