Breaking the relentless course of Hallopeau’s acrodermatitis by dapsone

ARTICLE

Acrodermatitis continua of Hallopeau (ACH) is a rare, chronic, recurrent pustular acral eruption, particularly of the distal phalanges of the hands and feet [1]. Its etiology remains elusive. More women than men are affected by ACH. Atrophic skin changes and onychomadesis are frequently present. The disease resembles in many aspects palmoplantar psoriasis. However, it may be individualized by its chronic course and resistance to the usual anti-psoriasic drugs [2]. Outbreaks of generalized pustular eruptions may occur.

Dapsone (4-4' diaminodiphenyl sulfone, DDS) is an ancillary drug exhibiting a potent inhibition of neutrophil functions. It is frequently used with success in neutrophilic-dependent dermatoses [3]. Its use in ACH has only been sporadically mentioned in dermatology textbooks [4, 5], and rarely documented in the literature [6, 7]. We present a patient suffering from severe ACH refractory to numerous treatment options. The acropustulosis responded well to DDS therapy without drug-related side-effects.

Case report

A 74-year-old man suffered for four years from severe ACH that was sometimes accompanied by generalized pustular eruptions. All his finger tips showed onychomadesis and sclero-atrophic changes (Fig. 1). No systemic complaints were experienced, except during generalized episodes. Medical history was not contributory except for hypertension. Drug intakes were limited to fluoxetin, nifedipine and lormetazepam. A search for any underlying condition and infection remained negative. Histology was indistinguisable from pustular psoriasis with intraepidermal neutrophilic pustules and parakeratosis. Radiographic examination of the hands revealed diffuse osteoporosis and small areas of bone resorbtion without any joint involvement. Repeated biological evaluations showed increased leukocyte counts ranging from 10,000 to 19,000/mm³ (N: 4,300-10,600/mm³) with a neutrophilic fraction ranging between 76 and 87.5% (N: 42-75%). Increased SER and CRP values were also repeatedly recorded. Liver and renal functions were normal.

Initial treatments with topical corticosteroids (clobetasol propionate 0.05%, betamethasone dipropionate 0.05%, clobetasone butyrate 0.05%) were interrupted due to the lack of efficacy. Local and total body PUVA-therapy also failed to improve ACH. No clinical response was noted with oral methylprednisolone, neither of the general symptoms nor of the acropustulosis. After three administrations systemic methotrexate (25 mg/wk) was followed by severe toxic pneumopathy, slowly reversible after treatment was interrupted. Low dose methotrexate (initially 5 mg/wk, subsequently increased to 20 mg/wk) yielded only a partial response of the acrodermatitis. The lesions flaredup within 2 days after each methotrexate intake, particularly when the doses exceeded 15 mg/wk. Etretinate at a dose of 75 mg daily initially improved ACH. Thereafter, the disease became progressively refractory to etretinate. Cyclosporin A therapy, at the dose of 3 mg/kg was rapidly hampered by the development of uncontrolled and drug-resistant hypertension, that forced us to withhold this treatment. A treatment combining methotrexate (15 mg/day) and etretinate (50 mg) initially brought good clinical results but the disease subsequently became resistant to such combined treatment. Acitretin treatment at a dose of 40 mg/day was abandoned after 5 weeks due to prominent cutaneous side-effets and to the lack of efficacy on ACH. Minocycline, at 100 mg daily, was also abandoned in absence of clinical efficacy after a 6-week trial. A severe episode of generalized eruption invoked the necessity for hospitalization and topical tar therapy cleared the generalized pustular eruption, without any effect on the ACH. Subsequently, a 200 mg/day DDS treatment was initiated. Blood controls indicated the absence of methemoglobulinemia and G6PD deficiency. During DDS therapy, methemoglobulinemia remained in an acceptable range (4-10%) without any clinical manifestation (Fig. 2). Hemolysis remained stable at 12.7 g/dL (N: 13-18 g/dL), associated with compensatory reticulocytosis at 15.3% (N: 0.2-2%). The previous hyperleukocytosis returned to normal. Every attempt to reduce the DDS dose below 150 mg/day or to interrupt the drug intake was rapidly followed by recurrences. The appropriate maintenance DDS dose for optimal clinical efficacy was 150 mg daily. Local corticosteroids were interrupted and replaced by emollients. The patient remains symptom free after a 3-month follow up.

Discussion

The treatment of ACH remains difficult and often disappointing. Many therapies have been attempted with only partial remissions and rapid recurrences upon treatment interruption or dose reduction. No clear-cut therapeutic management guideline exists for ACH. Etretinate
(50-75 mg/day) [8], methotrexate (10-25 mg/wk) [9], acitretin (0.5 mg/kg daily) [10], corticosteroids (triamcinolone 40-60 mg/day with subsequent tapering) [11], colchicine (1-2 mg/day), cyclosporin A (3-5 mg/kg/day) [12], minocycline (100-200 mg/day), PUVA and rePUVA therapy have been advocated as systemic treatments. Topical treatments, including corticosteroids, tar, anthralin, mechlorethamine [13], fluorouracil [14], and intralesional injections of triamcinolone, do not provide satisfying results. Topical calcipotriol has been documented to significantly improve ACH [15, 16]. It is important not to lose sight of discomfort and serious complications linked to many of these therapies. The present case report illustrates some limitations in obtaining a remission in ACH using these therapeutic modalities.

Beside its antibacterial properties, DDS has remarkable anti-inflammatory capacities, in particular targeting neutrophils [3]. It has been demonstrated that DDS inhibits the adherence of neutrophils to basement membrane zone antibody in a dose-dependent manner [17]. The inhibition by DDS of neutrophilic infiltration in neutrophilic dermatoses may be mediated by a suppression of leukocyte integrin function [18]. The use of DDS in ACH has seldom been documented [4, 5]. However, considering the prominent neutrophilic involvement in ACH, DDS constitutes a reasonable therapeutic option. The present case highlights the remarkable clinical response of ACH to DDS in a patient. Chance seems to be an unlikely explanation of the results. Hence, we underline the usefulness of DDS in drug-resistant ACH. Another clear lesson from the clinical observation is that there exists strong evidence that ACH and its associated generalized pustular eruption may respond distinctively to various treatments. There needs to be further debate about the pathogenic unicity of neutrophilic dermatoses and whether any therapeutic effect is specifically limited to certain subgroups. It has certainly been, and will continue to be, necessary in many of these dermatoses to accept less than the ideal therapeutic outcomes.

REFERENCES

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