On December 2012, a 29-year-old woman presented to our observation for facial cutaneous rash that had appeared about 10 months earlier. She had only a past history of allergy to penicillin. Medical history was unremarkable until February 2012, when was made her a diagnosis of impaired glucose tolerance (IGT), insulin-resistance (evaluated by hyperinsulinemic euglycemic clamp) and subclinical hypothyroidism. For this reasons after we obtained the written informed consent, she started metformin (500 mg/12 h), used off-label, plus levothyroxine (50 μg/die). Two days after the beginning of this treatment she noticed intense pruritus and burning in the center of the face. In about 1 month her skin rash worsened in severity and the eruption involved the whole face (except for orbicularis oculi), in particular malar areas and forehead like a butterfly with papules and teleangectasies (see Figure 1). During this time she was not taking any pharmacological or herbal products except for metformin and levothyroxine. Firstly a dermatologist diagnosed a rosacea and prescribed both minocycline and metronidazole for 1 month, without any benefit. The persistence of symptoms induced a new clinical examination and another dermatologist hypothesized a probable subacute cutaneous lupus like-syndrome and treated with cetirizine, vitamin E, total-block sunscreens and lincomicine, without clinical effects. A new dermatologist diagnosed a probable toxic mixoedema thyroid-based disease, so deflazacort (30 mg/day for 1 month) was started with a transient moderate improvement of symptoms that reappeared when the therapy was finished.
On December 02nd 2012, the patient forgot to take the metformin treatment and she noted a moderate improvement of pruritus, and due to this empiric experience she went to our observation. On admission clinical examination revealed the presence of erythema with papular eruption involving cheeks, glabella, perioral zone, until scalp and mandibular area. There was no involvement of neck, ears, shoulders, groin, thighs or knees. She was overweight (Body Mass Index = 28 kg/m2) and cardiopulmonary, abdominal, ophthalmologic systems were unremarkable. Laboratory findings (i.e. blood cells count, immunoglobulins, C3, C4, C-reactive protein, glucose, insulin, serum protein electrophoresis and urinalysis) were in normal range. Both an extensive autoimmune tests (i.e. antinuclear antineutrophil cytoplasmic, anti-Ro/SSA antibodies, anti double stranded-DNA antibodies cryoglobulins, rheumatoid factor) and infective serological screening (i.e. hepatitis B, C, helicobacter pylori) were negative too. A nailfold capillaroscopy showed a pattern of regular disposition of the capillary loops along with the nailbed.
In order to evaluate the association between metformin and facial rash, we re-administered metformin with an impairment of skin manifestation. According to the Naranjo probability scale [10], we documented a probable association (Naranjo Score 7/13) between facial rush and metformin administration. Metformin was stopped with a progressive remission of exanthema in about 1 month (Figures 2 and 3).
Type 2 diabetes mellitus is a serious and costly disease and the Diabetes Prevention Program Research Group demonstrated that treatment with metformin is able to reduce the incidence of diabetes in subjects with such risk factors including impaired glucose tolerance [11] and/or to reduce the insulin-resistance [12]. In agreement with these studies, after we advise the patient regarding the treatment and obtained the written informed consent, an off-label treatment with metformin was started. Metformin has been used clinically for many years with good safety profile, and rarely induces skin ADRs [6]. However, Salem and coworkers [7], described a leukocytosis vasculitis with purpuric necrotizing eruption in lower legs in a young woman during metformin’s treatment.
