Retrospective study on the association of human herpesvirus reactivation with severe DRESS: A description of blood and skin reactivations.

BACKGROUND: Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) is a severe adverse event (mortality of 10%). Its pathophysiology involves herpesviruses, particularly HHV-6, but the exact mechanisms are still poorly understood. OBJECTIVE: To describe severe cases of DRESS and especially their association with herpesvirus reactivation. METHODS: This study was a multicentre case series conducted between 2007 and 2021 at five University Hospital Centres in France. The study included patients who had severe DRESS, which was defined as death, transfer to the intensive care unit (ICU), or severe damage to internal organs. We excluded patients without blood PCR sample, without a drug formally attributed or with RegiSCAR score < 6. We collected data on severity, causative drug, associated visceral damage and results of viral blood PCRs. HHV-6 reactivation was studied in skin biopsies by detection of small non-coding transcripts (HHV-6 miR-aU14) and a late viral protein (GP82/105). RESULTS: Fifty-two patients were included (29 female, median age 62, interquartile range (IQR) [37;72]). Eight patients (15%) died, 13 (27%) were admitted to ICU. Most patients (n = 34; 65%) had multisystem involvement: most frequent was liver (n = 46; 88%), then renal failure (n = 24; 46%). Forty patients (77%) had at least one blood viral reactivation among HHV-6, EBV or CMV, of which 21 (53%) had at least two. Median time of blood HHV-6 reactivation was 24 days (IQR [20;35]). HHV-6 reactivation was demonstrated in 15 out of 20 skin biopsies, with a median time of 11 days [9;17]. CONCLUSIONS: We confirmed the high rate of HHV-6 reactivation in severe DRESS and demonstrated cutaneous HHV-6 reactivation using small non-coding transcripts (HHV-6 miR-aU14), which preceded viral PCR positivity in blood. These results suggest that HHV-6 reactivation during DRESS may start in skin. Furthermore, search for miR-aU14 in skin biopsy could become a useful diagnostic tool for early detection of HHV-6 reactivation.

Severe cutaneous adverse reactions due to inappropriate medication use.

BACKGROUND: The proportion of severe cutaneous adverse reactions (SCARs) that could be avoided if medication use was consistent with good medical practice is unknown. OBJECTIVES: To estimate the proportion of SCARs related to inappropriate medication use. METHODS: We carried out a retrospective study of all validated SCARs collected in a French registry between 2003 and 2016. For each case, all plausible drugs suspected of inducing SCARs (i.e. not just the drug regarded as 'the most probable') were considered with regard to (i) prescription for an inappropriate indication, (ii) unintentional rechallenge despite a previous allergy to the drug or (iii) self-medication with prescription medicines. RESULTS: In total, 602 cases were included in the analyses. Antibiotics, anticonvulsants and allopurinol were the drugs most frequently involved, accounting for more than 50% of all cases. All suspected medications were considered to have been appropriately used for 417 of the 602 individuals included in the study population [69·3%, 95% confidence interval (CI) 65·6-73·0] and inappropriately used for 144 individuals (23·9%, 95% CI 20·5-27·3). These inappropriate uses were due mainly to prescriptions for an inappropriate indication (65·8%, 95% CI 58·4-73·2) or unintentional rechallenge (20·9%, 95% CI 14·6-27·2). Allopurinol and co-trimoxazole were the drugs most frequently involved in inappropriate indications. Antibiotics were the largest group involved in unintentional rechallenge. Nonsteroidal anti-inflammatory drugs, available on prescription, were most frequently involved in inappropriate self-medication. CONCLUSIONS: Our results underline the need for respecting the appropriate indication for drugs in order to reduce the incidence of SCARs. Reducing unintentional rechallenge also seems to be a necessary preventive measure.

[Macroglobulinosis cutis revealing Waldenström macroglobulinemia]. / Une maladie de Waldenström révélée par une macroglobulinemia cutis.

Waldenström macroglobulinemia is defined by a bone marrow lymphoplasmacytic infiltration associated with serum IgM monoclonal gammopathy. Specific properties of the IgM gammopathy induce the main clinical manifestations revealing the disease: hyperviscosity syndrome, autoimmune peripheral neuropathy, cryoglobulinemia or hemolysis, and exceptional skin deposit such as macroglobulinosis cutis that we here report. Physicians should be aware of these clinical manifestations to avoid diagnostic delay.

[Guidelines for the management of nilotinib (Tasigna)-induced side effects in chronic myelogenous leukemia: recommendations of French Intergroup of CML (Fi-LMC group)]. / Recommandations du groupe Fi-LMC pour la gestion des effets indésirables du traitement par nilotinib (Tasigna) au cours de la leucémie myéloïde chronique.

Nilotinib (Tasigna) is a second-generation BCR-ABL kinase inhibitor, recently introduced and used for the treatment of chronic or accelerated phase CML patients, intolerant or resistant to imatinib. This treatment represents and important step forward for the disease control of such patients but can lead to side effects, sometimes serious, which can limit its optimal use. We propose here some guidelines that might be of help in daily practice, in order to manage properly these side effects.

Cytokine imbalance with increased production of interferon-alpha in psoriasiform eruptions associated with antitumour necrosis factor-alpha treatments.

BACKGROUND: Psoriasiform eruptions occur in association with antitumour necrosis factor (TNF)-alpha treatments in autoinflammatory diseases. The major reported clinical presentation is palmoplantar pustulosis, sometimes accompanied with plaque-like psoriasis. In some reports, histological findings suggest psoriasis whereas others favour a lichenoid drug reaction. We present a case series with a comprehensive clinical, histopathological and immunohistochemical study. OBJECTIVES: To investigate the mechanism involved in psoriasiform eruptions in patients receiving anti-TNF-alpha inhibitors. METHODS: Between July 2004 and May 2008, 13 patients with psoriasiform eruptions arising under anti-TNF-alpha treatment were enrolled in the study. Punch biopsy specimens of lesions were processed for standard and immunohistochemical analyses using antibodies against CD3, CD4, CD8, CD20, CD1a, KP1, CXCR3, CXCL9, Tia1 and MxA, which is specifically induced by type I interferons (IFNs). Additionally, we analysed biopsies from lesional skin of patients with cutaneous discoid lupus erythematosus, lichen planus and psoriasis. Control biopsies were taken from unaffected skin. RESULTS: All patients developed psoriasiform plaques on the body accompanied with palmoplantar keratoderma or pustulosis in three patients. Histological and immunohistochemical findings showed a psoriasiform pattern with focal lichenoid and spongiotic features. We detected strong production of the MxA protein in inflammatory cells, indicating involvement of type I IFNs, and the expression was higher than in control psoriasis samples. Expression of MxA was closely associated with the recruitment of CXCR3+ lymphocytes in the skin bearing markers of cytotoxic capacity. CONCLUSIONS: Results support the hypothesis that psoriasiform eruptions are a new model of drug reaction characterized by an increased expression of type I IFNs induced by anti-TNF-alpha.

[Primary cutaneous cryptococcosis in HIV-seronegative subjects]. / Cryptococcoses cutanées primitives chez des sujets séronégatifs pour le VIH.

BACKGROUND: Primary cutaneous cryptococcosis is an uncommon clinical entity characterized by direct skin inoculation without systemic involvement. We report four cases of this affection in HIV-negative patients seen between 1990 and 1999 in Nantes Dermatological Clinic. CASE REPORTS: Patients mean age was seventy. Three patients had recent exposure to soil or birds, and two remembered a trauma before the lesion appeared. In three cases the lesion was on the hand. In two cases the lesion was an ulcerated nodule, in another an abscess and in the last a cellulitis. Two subjects were treated by fludarabin and systemic corticosteroids for respectively chronic lymphocytic leukemia and Waldenstrom's macroglobulinemia. The third had a CD4 lymphopenia. Cultural examination confirmed the diagnosis. Treatment, with fluconazole in 3 cases and ketoconazole and itraconazole in 1 case, resulted in healing of the skin lesion in a few months. DISCUSSION: Recognition of primary cutaneous cryptococcosis as a clinical entity has long been debated. An altered immunological status is an important factor for developing this disease. There is often a clear history of trauma or exposure to soil or birds preceding the development of the lesion. Clinically it often looks like a papule or an ulcerated nodule. The lesion is confined to the skin without systemic involvement. The prognosis is excellent thanks to the use of oral antifungal imidazoles.

Randomised comparison of thalidomide versus placebo in toxic epidermal necrolysis.

BACKGROUND: Toxic epidermal necrolysis (TEN) is associated with a 30% death rate. Tumour necrosis factor alpha (TNF-alpha) has been implicated in the pathogenesis of TEN. Thalidomide is a potent inhibitor of TNF-alpha action. We did a double-blind, randomised, placebo-controlled study of thalidomide in TEN. METHODS: The patients received a 5-day course of thalidomide 400 mg daily or placebo. The main endpoint was the progression of skin detachment after day 7. Secondary endpoints were the severity of the disease, evaluated with the simplified acute physiology score (SAPS), and the mortality. TNF-alpha and interleukin 6 were measured. FINDINGS: The study was stopped because there was excess mortality in the thalidomide group--ten of 12 patients died compared with three of ten in the placebo group (Fisher's exact test with Katz's approximation, relative risk=2.78, p=0.03). After adjustment for SAPS, mortality remained significantly higher in the thalidomide group than in the placebo group (exact logistic regression mid-p=0.007; 95% CI for odds ratio 2.7 to infinity). Plasma TNF-alpha concentration was higher in the thalidomide group than the placebo group on day 2, though the difference was not significant (Wilcoxon rank-sum test p=0.07). INTERPRETATION: Even though few patients were included, our data suggest that thalidomide is detrimental in TEN, possibly because of a paradoxical enhancement of TNF-alpha production.

[Thrombotic microangiopathies in HIV infection: 4 cases]. / Microangiopathies thrombotiques au cours de l'infection à VIH: quatre observations.

Thrombotic microangiopathy (TMA) has been rarely described in HIV-infected patients. We report four cases of TMA during HIV infection and we analyse clinical, biological, etiologic, therapeutic and evolutive aspects of these four cases. Initial symptomatology is non specific and diagnosis is often delayed. Peripheric thrombopenia with haemolytic anemia and renal failure must be suggestive of the diagnosis. TMA can be present at any stage of HIV infection. Physiopathological mechanism of TMA during HIV infection remains unclear. These cases lead to suspect the role of opportunistic infections, neoplasia or HIV directly by endothelial injury or indirectly by cytokines secretion. Therapy of TMA is not different from non-HIV patients. Improvement with treatment must be obtained but long-term prognosis remains poor in account of HIV infection.

[Lichenoid eruption induced by gold salts. An autonomous eruption]. / Toxidermie lichenoïde induite par les sels d'or. Autonomisation d'une éruption.

INTRODUCTION: We report a severe lichenoid drug eruption due to gold salts which relapsed 8 months after the cessation of chrysotherapy. CASE REPORT: A 56 year old man, 3 months after the beginning of a gold sodium propanol sulfonate therapy, developed a polymorphous eruption with violin papules on the trunk, eczematous lesions on the limbs and erosive stomatitis. Gold salts were definitively withdrawn. We saw the patient four months after gold therapy cessation: the eruption remained and diagnosis of severe drug cutaneo-mucous lichenoid eruption was done. We saw thereafter the patient again, 8 months after gold therapy cessation: the eruption had relapsed, more intense. DISCUSSION: We suggest that lichenoid eruption, first caused by gold salts, has become autonomous.

Keratinocyte T6 antigen expression after PUVA therapy.

We report T6 antigen expression on keratinocytes in 11 cutaneous T lymphomas treated by PUVA therapy. This staining was absent before treatment. T6 reactivity was strictly limited to cell membrane. The nature of this expression is discussed, and it is suggested that it could be attributed to a passive diffusion from Langerhans's cells.

Cutaneous immunological studies in diagnosis of acute graft-versus-host disease.

A comparative study of the healthy skin of patients who had undergone bone marrow grafting and not developed graft-versus-host disease (GVHD) and of patients with cutaneous lesions of acute GVHD has been carried out. The aim of this study was to assess the diagnostic value of cutaneous immunopathology in the diagnosis of acute GVHD. A double-labelling immunofluorescence technique was used with a panel of monoclonal antibodies. The results showed a lack of specificity for GVHD in the distribution of Langerhans cells, but confirmed the diagnostic value of HLA-DR staining of epidermal keratinocytes. Cellular polymorphism of the T cell infiltrate in the dermis was observed (T helpers 40% and T suppressors 20%). The expression of the 55-57 Kd keratin polypeptide and of bullous pemphigoid antigen showed modification during acute GVHD while that of pemphigus antigen remained unchanged.

[Value of correlated immunofluorescence and immunoperoxidase study of monoclonal markers in 2 adult cases of histiocytosis X]. / Intérêt de l'étude corrélée par immunofluorescence et immunoperoxydase des marqueurs monoclonaux dans deux observations d'histiocytose X de l'adulte.

Two cases of adult histiocytosis X have been studied using monoclonal antibodies on skin sections by two techniques: indirect immunofluorescence and immunoperoxidase. This study confirm: --that histiocytosis X express two specific antigens Ia and T6, --the relations between Langerhans cell and histiocytosis X. Especially, it suggests that histiocytosis X cell would be a dedifferentiated cell with receptors OKT4 and OKT10.