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Keywords:

  • epidermolysis bullosa pruriginosa;
  • thalidomide

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Case 1
  5. Case 2
  6. Discussion
  7. References

Epidermolysis bullosa pruriginosa is a rare distinctive variant of dystrophic epidermolysis bullosa characterized by intense pruritus, lichenified plaques in linear distribution, and anonychia. It is a difficult condition to treat and causes a great deal of distress. The present authors report two cases showing good response to low-dose thalidomide, with clinical and symptomatic improvement. The exact mechanism of action is not yet clear.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Case 1
  5. Case 2
  6. Discussion
  7. References

Epidermolysis bullosa pruriginosa (EBP) is a distinctive mechanobullous disorder characterized by prurigo-nodularis-like lesions and violaceous linear scarring, associated with intense itching, milia, and nail dystrophy. The inheritance follows various patterns and patients can have variable phenotypic features. It has been postulated that management directed at the pruritus has a beneficial effect on the course of the illness. To this end, topical tacrolimus and thalidomide have been tried in this chronic disorder. The present authors report the successful management of two cases of epidermolysis bullosa pruriginosa with thalidomide.

Case 1

  1. Top of page
  2. Abstract
  3. Introduction
  4. Case 1
  5. Case 2
  6. Discussion
  7. References

A 61-year-old woman presented with recurrent episodes of itching, blistering, and pigmentation over the lower limbs since the age of 10. She also reported a similar complaint in her younger sister. She had been treated with oral and topical corticosteroids, dapsone, and topical tacrolimus in the past with minimal relief. Examination revealed the presence of numerous violaceous papules and plaques (FIG. 1), few bullae, multiple atrophic scars over the dorsum of feet, shins, and anterior thighs, with anonychia of both the great and second toe nails. Skin biopsy from a blister showed a subepidermal blister with a very sparse infiltrate (FIG. 2). Periodic acid Schiff stain revealed that the basement membrane was forming the roof of the blister. Direct immunoflourescence did not show deposition of immunoreactants. Electron microscopy, immunoflourescence mapping, and mutation analysis could not be done due to financial constraints. Serum immunoglobulin E (IgE) levels were within normal limits. The patient was started on 50 mg per day of oral thalidomide (Tab. Nudorix, Zee Laboratories, Haryana, India), after baseline sensory nerve conduction studies (SNAP) as part of monitoring for thalidomide-induced peripheral neuropathy, with 25 mg of oral hydroxyzine at bedtime. There was subjective improvement in pruritus by 50% in 2 weeks. Two months later, all the lesions had healed (FIG. 3) and she required hydroxyzine for symptom relief once in 15 days. Four months later, after tapering thalidomide to 100 mg/week, she was off hydroxyzine as her pruritus had completely subsided. One year later, she is on 50 mg per week of thalidomide until present. SNAP was repeated every 6 months and did not show any decrease in the amplitude of action potentials from baseline values. She developed dysgeusia along with abdominal pain 2 months after start of therapy, which resolved after decreasing the dose.

figure

Figure 1. Hyperpigmented and violaceous papules and plaques with scarring on both shins.

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figure

Figure 2. Histopathology showing hyperkeratosis, acanthosis, and subepidermal bulla with scant infiltrate (H & E, 40×).

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Figure 3. Flattening of lesions on right leg and reduction in number of lesions on left leg after thalidomide.

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Case 2

  1. Top of page
  2. Abstract
  3. Introduction
  4. Case 1
  5. Case 2
  6. Discussion
  7. References

A 35-year-old female patient presented to the clinic with intense itching, blistering, scarring, and prurigo-like lesions over both the lower limbs and upper limbs of 1 year and 3 months duration, respectively. She had been treated elsewhere, previously, with potent topical steroids, topical tacrolimus, and oral antihistamines with little improvement. She had numerous violaceous papules and plaques, arranged linearly over both the legs and discretely over the forearms and lower back, with excoriations, clear blisters, and hypopigmented atrophic scars. Serum IgE levels were within normal limits. Skin biopsy from a blister over the right leg revealed a subepidermal blister with a mild infiltrate of neutrophils and eosinophils. Periodic acid Schiff stain demonstrated basement membrane forming the roof of the blister. Direct immunofluorescence did not reveal the presence of any immunoreactant. We could not do electron microscopy, immunostaining and mutation analysis because of lack of resources. She was advised intrauterine contraceptive device insertion along with a barrier contraceptive device. After that, she was prescribed oral thalidomide at a dose of 100 mg per day, after a normal baseline SNAP, along with levocetrizine 10 mg in the morning and hydroxyzine 25 mg at bedtime. Two and a half months after start of therapy, skin lesions had cleared by 50% and levocetrizine was stopped; dose of hydroxyzine was reduced to 10 mg. Six months later, when thalidomide was tapered to 50 mg on alternate days, she continued to be in partial remission. She did not develop any adverse effects. Patient was later lost to follow-up.

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Case 1
  5. Case 2
  6. Discussion
  7. References

EBP is an unusual clinical variant of dystrophic epidermolysis bullosa, characterized by intense pruritus, skin fragility, and occasional trauma-induced blistering leading to hypertrophic lichenified nodules and plaques, milia, and violaceous linear scarring involving predominantly, but not exclusively, the shins [1]. It may not develop clinically until adult life [1] (latest onset has been after 40 years) [2], leading to diagnostic confusion with acquired disorders, such as nodular prurigo, lichen simplex chronicus, bullous lichen planus, pemphigoid nodularis, or dermatitis artefacta. Molecular analysis of these patients gives no clear association between the site and nature of mutations in the type VII collagen gene and the expression of the “pruriginosa” phenotype, suggesting that additional factors may be responsible [2]; but no universal modifying factor, until date, has been able to explain the characteristic presentation of EBP [3]. The pathophysiology of pruritus in EBP is also not well understood. It is said that patients have raised IgE levels and could be reactive to environmental allergens. However, as was the case in our patients, this was not consistently seen in all reported patients. It is possible that it is not the level of pruritus that is abnormal in EBP, but the patients’ response to the itch [4].

The therapy of EBP is focused mainly on relief of pruritus, and has been quite disappointing until now. Various modalities like potent topical steroids under occlusion, intralesional steroids, oral antihistamines, systemic steroids, oral retinoids, or ultraviolet B phototherapy have failed to produce satisfactory or sustained improvement [1]. Yamasaki et al. [5] have reported control of pruritus in 2 weeks time with cyclosporine at a dose of 3.6 mg/kg/day, with a maintenance dose of 2.47 mg/kg on alternate days; but the renal side effects of cyclosporine prevented its long-term use. Banky et al. [6] reported successful use of topical tacrolimus (0.03%) twice daily in EBP with substantial reduction in pruritus and progression of lesions but with persistence of older lesions.

We tried thalidomide because of its established use in prurigo (7), and because our patients had not responded to tacrolimus. There has been a single report of safe and successful use of thalidomide in a 14-year-old girl with EBP [8]. The mechanism of action of thalidomide in the management of pruriginous disorders is not yet completely understood. Most recent studies point that thalidomide may suppress excessive production of tumor necrosis factor-α, modulate certain cytokines and down-regulate cell surface adhesion molecules involved in leukocyte migration [9]. There is some evidence that thalidomide might increase keratinocyte migration and proliferation [10] and can promote wound healing [8, 11].

The present authors could achieve improvement with low-dose thalidomide of 50–100 mg (complete remission in case 1 and considerable improvement in case 2). We were able to taper the drug and maintain our patients on low-dose weekly or alternate day therapy within a period of 6 months with sustained remission. Even though peripheral neuropathy is an important side effect of thalidomide, we did not encounter it in either of our patients. We would like to reiterate that thalidomide can be considered as a safe therapeutic option for sustained remission in patients of EBP with severe pruritus not responding to conventional topical methods of treatment.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Case 1
  5. Case 2
  6. Discussion
  7. References