Eleni Sotiriou1, Aikaterini Patsatsi1, Christina Tsorova1, Elisabeth Lazaridou1 and Dimitrios Sotiriadis2

1First Dermatologic Clinic and 2Second Dermatologic Clinic, Aristotle University of Thessaloniki, Greece

Febrile ulceronecrotic Mucha-Habermann disease is a severe variant of pityriasis lichenoides et varioliformis acuta characterized by the sudden onset of ulceronecrotic skin lesions and associated with high fever and systemic symptoms. We report here a case of a 20-year-old woman in whom the disease started as pityriasis lichenoides et varioliformis acuta and evolved to febrile ulceronecrotic Mucha-Habermann disease. Almost 90% of the body surface was involved, together with high fever and malaise. Steroids alone proved to be an insufficient therapeutic procedure. The remission achieved was attributed to the use of methotrexate. To our knowledge, only 39 cases of febrile ulceronecrotic Mucha-Habermann disease have been reported in the literature to date. Key words: febrile ulceronecrotic Mucha-Ηabermann disease; pityriasis lichenoides and varioliformis acuta.

(Accepted December 17, 2007.)

Acta Derm Venereol 2008; 88: 350–355

Dimitrios Sotiriadis, 12, Steph Tatti str, GR-54622 Thessaloniki, Greece. E-mail: iros@med.auth.gr

Febrile ulceronecrotic Mucha-Habermann disease (FUMHD) is a severe variant of pityriasis lichenoides et varioliformis acuta (PLEVA), first described by Degos et al. in 1966 (1). To the best of our knowledge, 39 cases of FUMHD have so far been reported in the literature in English (1–36). We describe here a 20-year-old woman with FUMHD who was treated successfully with methotrexate and we review all cases reported in the literature.

Case report

The patient was a 20-year-old woman with FUMHD. The disease started as classic PLEVA with the abrupt onset of a polymorphic pruritic skin eruption comprising scattered erythematous, purpuric papules and vesicles on the trunk and extremities. The condition was misdiagnosed as chickenpox and treated with acyclovir, antibiotics and topical steroids by general practitioners.

However, the skin lesions consecutively disseminated. One week later, in October 2006, when she was referred to our hospital more than 90% of her body surface was involved, leaving the patient susceptible to bacterial infections (Fig. 1).

No personal or family history of dermatological diseases was reported. She denied receiving any medications, she had no sexual contact and no drug or food allergies.

Physical examination revealed a generalized skin eruption comprising necrotic papules and pustules with thick haemorrhagic crusts, round erosions and ulcers from several millimetres to several centimetres in diameter. The lesions presented in different evolutionary stages. There was extensive and extremely painful skin necrosis with a purulent exudate over flexural sites such as the neck, axilla, antecubital, umbilical and inguinal areas. A small number of pustules and tense bullae were present on the palms and soles. Oral mucosa was also involved, with painful fissures located on the dorsal surface of the tongue. The patient had high fever (39.5°C) with chills, malaise and myalgia.

Routine laboratory tests showed elevated erythrocyte sedimentation rate, increased levels of C-reactive protein and a normochromic-normocytic anaemia. Serology for hepatitis B virus, hepatitis C virus, HIV, Epstein-Barr virus (EBV), cytomegalovirus, varicella-zoster virus, human herpes virus 6,7,8, as well as Treponema pallidum haemagglutination test were negative. Serology for herpes simplex virus was negative for IgM but positive for IgG, suggesting a past infection. Skin cultures detected Staphylococcus epidermidis and Pseudomonas aeruginosa.

Histology of a cutaneous lesion of her right forearm revealed basket-weave hyperkeratosis with a few nuclear fragments derived from polymorphonuclear cells, focal parakeratosis and preservation of the granular layer (Fig. 2). In the malpigian layer there were areas of spongiosis accompanied by exocytosis of lymphocytes. The dermis showed a perivascular lymphocytic infiltrate without evidence of vasculitis.

Initial treatment with oral corticosteroids (prednisolone 40 mg/day) for 4 days proved insufficient to halt disease progression. Intravenous administration of ticarcillin-clavulanic acid 5.2 g 3 times a day and cloxacillin 1.5 g 4 times a day was based on skin cultures. Despite the above treatment new skin lesions appeared. Intravenous methotrexate was initiated on a weekly regimen of 15 mg together with folic acid with a simultaneous decrease in prednisolone to 20 mg per day. The patient also received supportive care including a high-calorie parenteral diet, as well as meticulous nursing care with topical mupirocin, whirlpool and sodium permanganate baths.

The patient showed a dramatic response within 10 days; she became afebrile and her general condition improved significantly. No new lesions appeared, with progressive re-epithelization of the existing ones. Administration of methotrexate and prednisolone lasted 2 months.

Relapse occurred 7 months after the original eruption and new papulosquamous lesions developed at the lateral sides of the neck, the infra-mammary area and peri-umbilically with the formation of erosions and ulcers at the axillary and popliteal fossa. Methotrexate per os was restarted, albeit at a lower dosage (10 mg/week), coupled with prednisolone 20 mg/day. The skin condition started to improve after 5 days, so the prednisolone was subsequently tapered off until discontinuation.

At present, almost a year after the patient’s initial presentation, she remains on methotrexate 10 mg weekly. Her general condition is excellent apart from the significant hyperpigmentation and the varioliform-atrophic hypopigmented scars at the sites of previous ulcerations (Fig. 3) Discussion

FUMHD occurs more frequently in children, adolescents or young adults than in older subjects (29). It exhibits a male predominance (male:female ratio 27:14). The mean age of patients in the reported cases is 27.4 years (range 4–82); 30 of the 40 patients reported were younger than 35 years at the time of presentation (Table I).

The disease may either start with a mild form of skin changes consistent with PLEVA that evolve later to large coalescent ulceronecrotic lesions, or it may have an acute onset with large papulonecrotic and haemorrhagic lesions all over the body (28). The ulcerated lesions often become secondarily infected and tend to heal with hypertrophic scars (23). Oral, genital and conjunctival mucosae can be affected (37). The disease is associated with high fever; up to 40ºC. Associated systemic manifestations in the reported cases include gastrointestinal (1, 6, 15, 26, 27, 31, 34, 36), neurological (1) and pulmonary involvement (4, 12, 31, 32, 34), cardiomyopathy (3, 8), rheumatological manifestations (9, 20), megaloblastic anaemia (6, 12, 26), pancytopaenia (28) and diffuse intravascular coagulation (31).

The reported mortality rate of FUMHD is approximately 20% (9 of 40 patients). There have, so far, been no child fatalities (27). Considering the fact that the mortality rate in children (0–14 years) is zero, this rate in adult raises to 33.3%. A comparison between adult and paediatric cases shows a more favourable outcome in children (24). In fact, fatal cases were confined to persons older than 40 years, until 2004–05 when Cozzio et al. (28) and Aytekin et al. (30) reported cases of 26–27-year-old females with fatal outcome.

In the cases with fatal outcome death was attributed to pulmonary thromboembolism (8, 34), pneumonia (12), cardiac arrest (15), sepsis (18, 28, 30, 34), hypovolemic shock (27) and massive thrombosis of the superior mesenteric artery (34).

The aetiology of PLEVA remains controversial. A hypersensitivity reaction to an infectious agent is suggested to be the main cause (1, 6, 20, 38). Many different infectious agents, such as EBV (22, 24, 39), adenovirus (4), and cytomegalovirus (20) have been implicated in the pathogenesis of the disease, but there has been no consistent finding so far. In a case described by Yanaba et al. (23), a predominantly CD8+ lymphocyte infiltrate around the dermis and into the epidermis might suggest cytotoxic attack of lymphocytes to altered epidermal antigens, perhaps induced by an unknown infectious agent.

Recent studies have demonstrated PLEVA to be a benign disorder of activated T-cell lymphocytes. Dereure et al. (40) concluded that the disease exists within a spectrum of clonal T-cell cutaneous lymphocytic disorders, while Weinberg et al. (41) found that 57% of their specimens demonstrated monoclonal T-cell receptor gene rearrangements. These findings lead to the conclusion that PLEVA is a benign clonal T-cell disorder. Additional evidence to this hypothesis was presented by Magro et al. (42). Cases with fatal course revealed clonal TCR rearrangement, but it remains unclear whether TCR clonality stands for the predominance of a pre-neoplastic lymphocyte clone or if it represents a clonal cytotoxic T-lymphocyte reaction against a supposed intracellular pathogen (33).

Histopathological findings in most of the presented cases include the typical features of PLEVA and different grades of leukocytoclastic vasculitis (1–38)

Several treatment modalities have been described, but no definite therapy can be recommended for all patients at present (23, 32). All reported patients received multiple drugs including systemic steroids, methotrexate, antibiotics, psoralen + ultraviolet A (PUVA), ultraviolet B (UVB), unspecified ultraviolet receptor, acyclovir, immunoglobulins and 4,4-diaminodiphenylsulphone (DDS) (see Table I). The effectiveness of these treatment modalities is difficult to assess as they failed to achieve remission in patients with eventually fatal outcome.

Therapeutic efficacy of systemic steroids is highly controversial. Twenty-seven of 40 patients (including the present case) were treated with steroids, but the only positive effect was reported by Degos et al. (1). Methotrexate has been used in 15 patients with FUMHD (including ours). It induced rapid remissions and was successful in cases that did not respond to other therapeutic measures. Four patients died despite methotrexate therapy, but this might be attributed to its late institution (8, 15, 28).

Successful treatment with a short course of oral cyclosporine in 2 cases of an 8-year-old boy and a girl of the same age has been reported (31, 35), as well as a case that required debridement of necrotic skin and placement of epidermal autografts (23). Treatment with tumour necrosis factor (TNF)-a inhibitors might represent a first-line option in future cases, as elevated levels of serum TNF-a have been reported in FUMHD cases (29). Furthermore, intensive care, treatment of superinfection and maintenance of the patient’s general condition is required.

In conclusion, considering the severity of this disease, which can be fatal, it is of great importance to make the diagnosis at an early stage, to commence treatment as soon as possible, to monitor patients closely and, if necessary, to transfer them to intensive care.

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