Neutropenia and cutaneous lesions secondary to propafenone

ARTICLE

Auteur(s) : Nuno Couto¹, Márcia Ferreira², Ernestina Reis¹

¹Medicine Department, Hospital Geral de S. António, Largo Abel Salazar, 4099-001 Porto, Portugal
²Dermatology and Venerology Department, Hospital Geral de S. António, Porto, Portugal

accepté le 25 Février 2009

In this article, the authors present the concomitant occurrence of two rare secondary effects of propafenone, a second line anti-arrhythmic drug. These secondary effects have previously been described separately. Agranulocytosis is defined as a profound decrease of granulocyte numbers in circulating blood, resulting in a neutrophil count < 0.5/μL. In the majority of patients, the neutrophil count is < 0.1/μL. Patients with such severe neutropenia, particularly elderly patients, are likely to experience life-threatening and sometimes fatal infections. For the most part, agranulocytosis results from exposure to drugs (idiosyncratic drug-induced agranulocytosis), and either the drug itself or a metabolite may be causative [1]. Neutropenia is a well known side effect of propafenone since its introduction in the market and a lupus erythematosus-like syndrome has also been previously reported [2]. In this case we present a concomitant occurrence of two secondary effects in the same patient.

Case report

On physical examination there were multiple non-scaling erythematosus papules that became confluent, forming non-indurated plaques, some of which had a delicate central scale and hypopigmentation. The lesions were preferentially distributed over the V-area of the neck, upper trunk and extensor surfaces of the upper extremities (figure 1). On the dorsal aspect of the fingers there was a diffuse desquamation grossly sparing the proximal knuckles. The face, lower extremities and mucosae were spared. The patient had no fever and there was no palpable adenomegaly or organomegaly.

Laboratory parameters showed a severe neutropenia (leucocytes: 870/μL; neutrophils: 0/μL, haemoglobin: 10.4 g/dL; platelets 163,000/μL). The bone marrow smear had a normal cellularity with a predominance of immature cells (promyelocytes and myelocytes). Serological and immunological studies (antinuclear, anti-Ro, anti-La, anti ds-DNA and anti-histone antibody quantifications) showed no significant changes. A urine smear was normal. In the skin biopsy, a focal hydropic degeneration of the epidermal basal layer, accompanied by a superficial and perivascular infiltrate of lymphocytes and plasmocytes, was found. In the papillary dermis, slight mucin deposition was observed (figure 2). These aspects are compatible with a lupus erythematosus skin reaction. Histological results associated to the clinical lesions were consistent with a drug-induced subacute cutaneous erythematous lupus and the haematological events could also be a consequence of propafenone.

All her medication was suspended and G-CSF was initiated. There was a steady recovery of the neutrophil count (after three days) and the cutaneous lesions gradually disappeared in one week. After complete recovery, the initial medication was sequentially reintroduced with the exception of propafenone. After six months of follow-up the patient was asymptomatic, atrial fibrillation and arterial hypertension were controlled, there were no cutaneous lesions and laboratory parameters, including hemogram and immunological studies, were normal.

Discussion

Drug metabolites acting as haptens could also explain the cutaneous lesions. Drug-induced sub-acute lupus erythematous usually presents as psoriasiform or annular lesions, which may be clinically and histologically indistinguishable from the idiopathic form of the disease, and sometimes even anti-Ro and anti-La antibodies are found (70% of cases) [5]. This condition is associated with a great variety of drugs, including anti-arrhythmics like procainamide (an anti-arrhythmic of the same group as propafenone). A SCLE associated to propafenone has already been reported [3].

In this case, the distribution of lesions (preferentially on photo-exposed areas), the absence of mucosal involvement and the rapid improvement without scarring, associated to the histological pattern, enabled us to diagnose SCLE. The absence of typical auto-antibodies does not exclude SCLE, since in approximately 30% of cases immunological tests are negative. Differential diagnoses must, however, be done with several delayed adverse skin reactions to drugs, such as erythema multiforme and lichenoid reactions. The association of clinical and histological features and the rapid resolution make SCLE the more plausible diagnostic.

In similar reactions, Barbara Reed et al. supported a cytotoxic reaction against epidermal and dermal cells as the main mechanism leading to the cutaneous lesions and speculated that the same process was responsible for the haematological reaction [6]. Another theory raises the possibility of a reaction mediated by auto-antibodies that may remain detectable for months, even when the dermatological symptoms resolve within four to six weeks after drug withdrawal [7]. In this case, the last theory seems unlikely since there were no identifiable auto-antibodies and because of the rapid recovery (skin and blood symptoms) after the discontinuation of the drug.

The clinical case presented shows that cutaneous and haematological responses can occur in a patient prescribed with propafenone. The two circumstances in the same individual is extremely rare. Starkebaum and colleagues [8] completed a revision of secondary effects of anti-arrhythmic drugs and reported two cases of concomitant procainamide-lupus like reaction and agranulocytosis. Although the lupus erythematosus reaction is benign and disappears with the discontinuation of the imputable drug, agranulocytosis is a life-threatening condition that demands special medical attention.

Acknowledgements

References

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