Minocycline-induced cutaneous polyarteritis nodosa with antineutrophil cytoplasmic antibodies

ARTICLE

Auteur(s) : Fabien PELLETIER, Eve PUZENAT, Dominique BLANC, Brigitte FAIVRE, Philippe HUMBERT, François AUBIN

Department of Dermatology, University Hospital, 2 Place Saint-Jacques, 25030 Besançon Cedex, France

Observation

A 23-year-old female was examined in January 2002 for pigmented lesions of the lower limbs. Her history showed acne vulgaris treated by minocycline (Minocyne^®50) for 24 months. She also presented with Raynaud’s phenomenon and started a new treatment (Fluoxetine and Bromazepam) for depressive symptoms one month previously. In October 2000, when the patient had been taking minocycline for 24 months, various skin lesions appeared: sub-cutaneous nodular lesions on the knees and livedo reticularis over the thighs and legs. These lesions were associated with reticular hyperpigmentation which appeared first on the legs, then the thighs. Treatment by cyclines was then spontaneously withdrawn by the patient who did not report it to the physician. At that time, a fortuitous blood test showed inflammatory syndrome (C-reactive protein: 44 mg/l). The nodular lesions disappeared quickly, but the pigmented lesions and livedo persisted (figure 1). Since then, the patient’s various biological tests had shown an inflammatory syndrome (elevated erythrocytes sedimentation rate: 44 mm, and C-reactive protein: 22 mg/l). On admission to hospital, the patient’s general condition was stable, without weight loss nor arthralgia and the neurological examination was normal. Blood tests showed microcytic anemia (10.9 g/dl), with iron deficiency (serum ferritin: 15 ng/ml) owing to heavy menstruation. Kidney functions and 24 hour proteinuria were both normal. The search for antinuclear antibodies was slightly positive (1/80) with negative anti-histone antibodies. Perinuclear antineutrophil cytoplasmic antibodies (pANCA) were positive (1/320) by indirect immunofluorescence detection. Specific enzyme-linked immunosorbent assay (ELISA) for ANCA was significantly positive for myeloperoxydase (MPO) but not for proteinase 3. Antiphospholipid antibodies, cryoglobulinemia as well as cold agglutinins were negative. Hepatitis B serology showed an efficient immunity (anti-HBs antibodies > 500 UI/l) and hepatitis C serology was negative. Parvovirus B19 serology suggested a past immunisation. The class I HLA phenotype was A2, B18, B42 and the class II phenotype was DRB1*01,*11, and DQB1*05, *03. Biopsy of the livedo showed a focal involvement of a medium-sized artery including fibrinoid necrosis and peri-vascular inflammatory infiltrate (figure 2). Chest x-rays and abdominal-pelvic ultrasonography were normal. Renal Doppler sonography did not show any micro-aneurysms or renal artery stenosis. Electromyography was normal. Cutaneous PAN was diagnosed in view of livedo reticularis, vasculitis of the medium-sized vessels, inflammatory syndrome and absence of visceral involvement. The severity prognosis index of PAN was 0 [1]. According to the imputability criteria of Begaud et al. [2], intrinsic imputability of minocycline was possible (I2: chronological criteria = C2 and semiological criteria = S2), while the extrinsic imputability was B2. Treatment with prednisone was prescribed (0.5 mg/kg/day during a month, and then decrease in two months). This treatment allowed the complete disappearance of the livedo and the attenuation of the pigmented lesions within three months. Biological inflammatory syndrome was normalized within the first month. Neither the livedo, nor the biological inflammatory syndrome recurred nine months after prednisone withdrawal. At this date pANCA were also negative.

Discussion

Minocycline is a second generation semi-synthetic antibiotic of the tetracycline group. It has been commercialized since 1972. In addition to its anti-microbial activity with a spectrum similar to the other cyclines, minocycline has anti-inflammatory and anti-fibrotic properties [3]. However, many side-effects induced by minocycline have been reported. Digestive disorders (nausea, vomiting, diarrhoea) are the most frequent. Vestibular symptoms like vertigo or ataxia are often described during the first days of the treatment. Benign intracranial hypertension is a rare but often reported side-effect of minocycline [4]. Various mucous or cutaneous hyperpigmentations were also reported. The most severe reactions are systemic including hypersensitivity reactions (DRESS syndrome [5], pneumonitis, nephropathy, and hepatitis), serum sickness-like reaction, and auto-immune disorders (systemic lupus erythematosus, hepatitis and arthritis) [6-9].
Our case report is original mainly because of the occurrence of cutaneous PAN during a treatment by minocycline, but also because of the positivity of pANCA that are usually absent in cutaneous PAN [10]. To our knowledge, only four cases of minocycline-induced cutaneous PAN have been reported [11-13]. The average treatment by minocycline was over a 35-month period, with a minimum of 9 months [13] and a maximum of 65 months [11], whereas our patient was treated over a 24-month period. Three patients showed livedo reticularis of the lower limbs and sub-cutaneous nodules without systemic symptoms (like our patient). One patient had livedo only, together with fever, myalgia and arthralgia [12]. As soon as the treatment was stopped and after a short oral corticotherapy, a rapid regression of the clinical features was observed in the four patients. But, in one patient, the sub-cutaneous nodules reappeared one month later [11]. In our patient, the course was different since on drug withdrawal, a complete regression of the sub-cutaneous nodules was observed within a few weeks. However, livedo, reticular hyperpigmentation of the lower limbs and biological inflammatory syndrome persisted and required general corticotherapy over several months to resolve completely.
Our observation is also remarkable due to the presence of anti-myeloperoxydase ANCA at a high rate. Indeed, the presence of ANCA in “classical” PAN is rare (less than 10%), and even more in cutaneous PAN [14]. These antibodies are more often pANCA. pANCA are also frequent in microscopic polyangeitis (75%) [15], Churg-Strauss syndrome (50 to 60%) [16] and in some glomerulonephritis. Anti neutrophil cytoplasmic auto-antibodies (characteristically cytoplasmic with anti-proteinase 3 specificity) or cANCA are of considerable help for the diagnosis of Wegener’s granulomatosis because these antibodies are present in 90% of cases [17]. Previous authors reported the role played by minocycline in the appearance of these antibodies. Other drugs (propylthiouracil, hydralazine, penicillamine) can generate vasculitis with positive pANCA [18-22]. Among the 78 cases of lupus induced by minocycline so far published, anti-histones antibodies were found in less than 25% of cases, whereas they are supposed to be usually present in 95% of the cases of drug-induced lupus [7]. In addition, among all the patients suffering from minocycline-induced lupus and/or auto-immune hepatitis, 85% of the patients tested (about one third) had paradoxically positive pANCA [7]. Several hypotheses have been suggested to explain the presence of ANCA in the autoimmune disorders induced by minocycline. Jiang et al. [23] have demonstrated that minocycline is transformed into a reactive hydroxyled product by the enzymatic action of myeloperoxydase from neutrophils or hepatocytes. These reactive products then form complexes with myeloperoxydase that act like haptens inducing an auto-immune response. The capacity of minocycline to serve as myeloperoxydase substrates in vitro was associated with the ability to induce lupus in vivo [23]. Furthermore, in a series of 14 patients with minocycline-induced lupus associated with pANCA, Dunphy et al. [24] demonstrated that the major histocompatibility complex (MHC) class II typing was HLA-DQB1 allele encoding for tyrosine at position 30 of the first domain in all patients. However, this was not observed in our patient. The authors suggested that the ANCA production is genetically induced by a MHC class II-restricted T cell clone in response to epitopes constituted from the native drug or modified by myeloperoxydase [24]. As a consequence, the ANCA could constitute a useful marker of a risk to develop autoimmune disorders during a treatment by minocycline in genetically susceptible subjects. < 

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