Jean-Jacques Guilhou

Efficacy of Daflon 500 mg in Venous Leg Ulcer Healing: A Double-Blind, Randomized, Controlled Versus Placebo Trial in 107 Patients

The objective of this study was to evaluate the efficacy of Daflon® 500 mg (Dios)* in venous ulcers. A multicenter, double-blind, randomized, controlled versus placebo (Plac) trial was conducted, with stratification according to the size of ulcer (≤ 10 cm and > 10 cm). The protocol called for a two-month treatment with Dios (one tablet = 450 mg micronized purified Diosmin) or a placebo, two tablets/day, in addition to compression therapy. Evaluations were performed every fifteen days, from DO to D60. The primary endpoint, in accordance with Alexander House group requirements were: percentage of patients with complete ulcer healing, ie, comparison between Dios and Plac group at D60, and comparison of survival curves in each group between DO and D60 (log rank test). Secondary endpoints included ulcer surface area assessed by computerized plani metric measurements, qualitative evaluation of ulcers, and symptoms. The patients were 105 men and women ranging in age from eighteen to eighty-five years, with standard compression stocking, who were undergoing standardized local care of ulcer and had no significant arterial disease (ankle/arm systolic pressure index > 0.8). Fifty-three patients received Dios, and 52 received Plac. The 2 groups were well matched for age (m ±1 SD = seventy-one ±eleven years), gender, ulcer size, and associated disorders. Among patients with ulcer size ≤ 10 cm (Dios = 44, Plac = 47) a significantly larger number of patients had a complete ulcer healing at two months in the Dios group (n = 14) in comparison with the Plac group (n = 6) (32% vs 13%, P = 0.028) with a signifi cantly shorter time duration of healing (P = 0.037). No difference was shown for the secondary criteria, except for sensation of heavy legs (P = 0.039) and a less atonic aspect of ulcer (P = 0.030) in favor of Dios. Among the 14 patients with ulcer size > 10 cm (Dios = 9, Plac = 5), subjected to a descriptive analysis only, no ulcer healed. This study showed that a two-month course of Daflon 500 mg at a daily dose of two tablets, in addition to conventional treatment, is of benefit in patients with venous ulcer ≤ 10 cm by accelerating complete healing.

Diffuse inflammatory lesions in patients treated with interferon alfa and ribavirin for hepatitis C: a series of 20 patients

Summary Background  Cutaneous side‐effects of treatment with interferon alfa or interferon alfa plus ribavirin in patients with hepatitis C have already been reported but they are mostly local with inflammation and, much less frequently, necrosis at the injection points. By contrast, very few data are available with regard to distant skin reactions, particularly inflammatory lesions on other parts of the body.

New concepts in the pathogenesis of psoriasis.

The pathogenesis of psoriasis has stimulated many studies. We suggested in 1972 that immunological factors could explain the biochemical abnormalities ofthe psoriatic lesion (Rimbaud et al., 1972b) and subsequently at the 1975 French National Dermatological Society Meeting we proposed an immunobiochemical theory (Guilhou & Meynadicr, 1976). In the light of numerous recent immunological, biochemical and ultrastnictural investigations we can try to integrate all these findings, going step by step from the main epidermal feature (cellular proliferation) to the initial events ofthe pathogenesis of psoriasis (Fig. i).

A new endogenous retroviral sequence is expressed in skin of patients with psoriasis.

Background  The origin of psoriasis, a chronic inflammatory skin disease involving keratinocyte proliferation, immune disturbances and complex inheritance, remains unknown. Human endogenous retroviruses (HERVs) are part of the normal human genome and their participation in the pathogenesis of various human diseases with complex genetic traits has been proposed. A possible role of HERVs in the induction of psoriasis was suggested many years ago. However, to date no study has searched for HERV expression in psoriasis.

Decreased expression of Fas (APO-1/CD95) on peripheral blood CD4+ T lymphocytes in cutaneous T-cell lymphomas

Background The usually protracted and indolent course of cutaneous T‐cell lymphoma (CTCL) is consistent with an accumulation of lymphocytes rather than being a true proliferative disorder, perhaps as the result of defective lymphocyte apoptosis. Fas (CD95) is the main signalling membrane molecule involved in postactivation T‐lymphocyte apoptosis.

Treatment of Old World Cutaneous Leishmaniasis by Pentamidine Isethionate

Background: Pentavalent antimonial derivatives (PAD), especially meglumine antimoniate (Glucantime®), are usually considered as the first-line drugs for Old World leishmaniasis, but their potential toxicity and the number of required injection, either intralesional or intramuscular, prompt to search for alternative treatments. Objective: To evaluate the efficiency and tolerance of pentamidine isethionate in Old World leishmaniasis. Methods: An open pilot study included 11 patients from two regional academic centers, with varied parasitological forms of Old World leishmaniasis, treated with three strictly intramuscular injections of 4 mg/kg of base-pentamidine every other day. Results: Tolerance was good overal, and 8/11 (73%) of patients responded well with a quick healing of their lesions, little scarring and no relapse. Conclusion: Pentamidine isethionate is a safe and effective first-line treatment for Old World leishmaniasis. Larger-scale prospective studies comparing several dosage regimens of pentamidine and pentamidine isethionate to PAD are warranted.

HFE mutations and transferrin receptor polymorphism analysis in porphyria cutanea tarda: a prospective study of 36 cases from southern France

Background  Porphyria cutanea tarda (PCT) is associated in most cases with iron overload, which may participate in decreased activity of uroporphyrinogen decarboxylase in the liver. The aetiology of this iron overload remains unknown; however, it has been demonstrated that mutations of HFE, the genetic haemochromatosis gene, might be present in a significant proportion of Anglo‐Saxon and Italian patients. Furthermore, transferrin receptor polymorphism may influence the affinity of this receptor to its ligand with a subsequent increase of cellular iron absorption and storage.

The proto-oncogene c- fos increases the sensitivity of keratinocytes to apoptosis

In human skin, most studies have suggested a role of c-fos or c-fos related genes in keratinocyte differentiation. The aim of our work was to more directly address this question by transfecting more or less differentiated keratinocyte cell lines (A431 and HaCaT) with constitutive expression vectors for c-Fos or c-Fos+c-Jun. Our results showed that c-Fos expression decreased keratinocyte growth, yet addition of c-Jun seemed to revert this c-Fos induced growth inhibition. Whereas no obvious differentiation program was turned on by c-Fos or c-Fos+c-Jun expression in our tissular model, apoptotic figures were observed and confirmed by in situ DNA fragmentation studies. These results do not rule out a role of c-Fos in keratinocyte differentiation but may indicate that the cell lines we used have reached an irreversible state of transformation so that they no longer respond to differentiation signals and rather die from apoptosis. These data add further evidence in favor of a role of c-Fos in epidermal homeostasis.

Straight hair associated with interferon-alfa plus ribavirin in hepatitis C infection.

SIR, Interferon alfa (IFN-a) therapy is highly effective in patients with chronic myelogenous leukaemia and other malignant diseases. Most side-effects, such as chills, malaise, myalgia and fatigue, are transient and tend to disappear with ongoing therapy, while others, such as anorexia, neurological and mood disorders, are dose-related and need dose adjustment or withdrawal of IFN-a. Induction of immunemediated disease, including thyroid disease, rheumatoid arthritis, systemic lupus erythematosus, vasculitis, thrombocytopenia, autoimmune haemolytic anaemia, and insulin-dependent diabetes mellitus, has also been described. Moreover, other immunological entities, such as myasthenia gravis, vitiligo, lichen planus, Henoch–Schönlein purpura and Sjögren syndrome, have been reported after IFN-a therapy for chronic viral hepatitis or multiple sclerosis (MS). Here, we report on the first case of systemic sclerosis (SSc) developing after therapy with IFN-a for chronic myelogenous leukaemia. In October 1998, a 52-year-old-woman without a personal or a familiar history of autoimmune disease, was diagnosed as having chronic myelogenous leukaemia, with a karyotype 46,XX,t(9;22), bcr ⁄ abl positive in all the metaphases. She was given hydroxyurea 20 mg kg day for 2 months and then IFN-a 2a to a maximum daily dose of 10 · 10 U. In June 1999, cytogenic evaluation showed a normalization of the karyotype in up to 33% of metaphases. Meanwhile, treatment was reduced to 6 · 10 U day for the appraisal of arthralgias, ataxia and depression. In June 2000 a further evaluation revealed the loss of efficacy of therapy (Ph chromosome positive in all the analysable metaphases). In the same period, the patient experienced fever, dyspnoea and oedema of the extremities. Laboratory findings were normal, except for an increased erythrocyte sedimentation rate (ESR, 50 mm in the first hour). Chest X-ray and computed tomography (CT) of the lung demonstrated the presence of pulmonary vascular congestion. Cardiac function, evaluated by electrocardiogram and Doppler echocardiography, was normal. The possible diagnosis of congestive heart failure was discarded and the patient’s symptoms were ascribed to a leak capillary syndrome secondary to interferon therapy; interferon therapy was interrupted. Peripheral oedema and respiratory symptoms improved on treatment with diuretics. Nevertheless, 3 months later, in November 2000 she experienced dyspnoea, oedema of both the upper and lower limbs and progressive skin thickening of the hands and wrists. A further echocardiographic evaluation revealed a normal ejection fraction (70%) and minimal tricuspid regurgitation with increased pulmonary artery pressure (34 mmHg). CT of the chest showed a picture of diffuse parenchymal and interstitial fibrosis with multiple areas of ground-glass attenuation. Pulmonary function tests demonstrated the presence of reduced volumes with an impaired diffusion capacity for carbon monoxide (DLCO, 46% predicted). Oesophagogastroduodenoscopy showed a total absence of peristalsis. Laboratory examination indicated: elevated ESR (80 mm in the first hour), impaired renal function (creatinine, 1Æ8 mg dL) with mild proteinuria (72 mg 24 h) and positive antisclero-70 antibodies. Her complete major histocompatibility phenotype was HLA-DRB1*11; 07, DQA*05;0201, DQB*03;02, A28, A24, B35, B13, Bw4, Bw6, Cw4. Capillaroscopy findings were consistent with scleroderma, showing multiple microhaemorrhages, dilation, distortion and rarefaction of capillaries. No skin biopsy was performed. A diagnosis of localized SSc was put forward, according to LeRoy et al. The patient was given loop diuretics, cyclophosphamide 100 mg day, prostanoids (iloprost, 2 ng kg min for 8 h for five consecutive days and then thrice monthly), steroids (methylprednisolone 750 mg intravenously for 3 days and then prednisone 25 mg day). In the following months the patient’s clinical condition improved, scleroedema decreased, the skin thickening partially receded and the signs of alveolitis were no longer detectable at a further CT evaluation of the lung (October 2001). Therapy has been gradually tapered and the patient is now receiving cyclophosphamide 50 mg day, prednisone 12Æ5 mg day, iloprost 2 ng kg min for 8 h every 3 weeks and hydroxyurea 10 mg kg on every alternate day. The patient’s main clinical and laboratory findings, before and after 10 months of therapy, are summarized in Table 1. Several authors showed that IFN-a therapy for malignancies, chronic viral hepatitis or MS may trigger the formation of autoantibodies directed toward various substrates, such as thyroid, platelets, erythrocytes, pancreas, parietal cells and nuclei. Their occurrence is sometimes, but not necessarily, coupled with the onset or the exacerbation of autoimmune diseases. In most cases endocrine disorders are described, but rheumatic and collagen–vascular diseases have been observed as well. Nevertheless, to date, no reports of SSc after interferon therapy have been made. However, Wandl et al. noticed that patients who develop antinuclear antibodies may experience Raynaud’s phenomenon, one of the diagnostic findings in SSc. Moreover, Black et al. pointed out that IFN-a therapy in the treatment of scleroderma may be deleterious, exacerbating life-threatening symptoms and precipitating the lung deterioration. As far as our patient is concerned, the laboratory findings, typical vascular alterations and ⁄ or clinical signs of autoimmunity are ascribable to interferon therapy. The patient had neither a personal nor a familiar history of autoimmunity, and a clear temporal relation between IFN-a administration and the occurrence of initial symptoms can be seen. Besides, she did receive IFN-a continuously for approximately 2 years. Fattovich et al. indeed noticed that de novo immuneBritish Journal of Dermatology 2002; 147: 385–410.

Localized urticaria pigmentosa Triggered by Mesotherapy

Mesotherapy is a treatment consisting of subcutaneous microinjections of a drug or a cocktail of drugs at sites of the body with medical or aesthetic problems. Rare cutaneous side effects have been previously reported, including immediate or delayed ‘allergic’ reactions to the administered drugs [1–3] or skin infections mostly caused by Mycobacterium sp. [3]. We report herein a new side effect consisting of an urticaria-pigmentosa-like eruption located at the sites of the injections. A 31-year-old woman without a relevant medical background or history of drug reactions was referred for the evaluation of asymptomatic red brownish macules with moderate pruritus, present for more than 18 months. These lesions were scattered on the external sides of the thighs and buttocks and strictly confined to the sites of previous subcutaneous injections for anticellulite treatment. The treatment consisted of a unique session of almost 50 subcutaneous injections (total dose of 3 ml) of a drug mixture including procaine and medicinal plants (Hamamelis and Memilotus). All the skin lesions appeared progressively 2–3 weeks after the treatment session and had remained stable since. The patient had previously received the same treatment once a year during 3 years without any side effect. Cutaneous examination revealed about 50 red brownish macules of a few millimeters in diameter, located in a roughly symmetrical pattern on the external sides of the buttocks and thighs (fig. 1). Darier’s sign was positive. A solitary brown macule was noted also on the right shoulder, where no treatment had been done. The clinical examination was otherwise unremarkable. Two biopsies from lesional and normal skin of the buttock showed the same histological pattern, consisting of an infiltrate composed mostly of mast cells in the upper dermis, mainly located around blood vessels. Positive toluidine blue staining and CD 117 immunostaining (fig. 2) confirmed the presence of increased numbers of mast cells in both specimens. The results of routine blood tests and urinalysis were within normal limits. The plasma histamine level and the tryptase serum level were raised within 1.5and 3-fold, respectively. Chest X-ray, abdominal ultrasonography and osteodensitometry were normal. The patient was treated with medium-potency topical corticosteroid cream applied once a day for a few weeks with partial improvement. Fig. 1. Numerous brownish macules of the buttocks and the thighs on the sites of subcutaneous microinjections for anticellulite treatment.