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.

Erythema multiforme associated with anti-plakin antibodies: a multicentric retrospective case series.

BACKGROUND: Erythema multiforme (EM) is a muco-cutaneous inflammatory disease mainly triggered by herpes simplex virus (HSV) recurrences. Association of EM and circulating auto-antibodies against plakins (anti-PLK-Abs [EM-PLK+]) has been reported. However, little is known about this subset of EM. OBJECTIVES: We aimed to describe the clinical and immunological features and response to treatment of EM-PLK+. METHODS: We conducted a retrospective multicentric study of EM-PLK+ selected from the database of the immunological laboratory of Bichat hospital, Paris, France, from January 2009 to December 2020. Anti-PLK-Abs were detected in ≥1 immunological tests: immunofluorescence assay, immunoblotting and/or ELISA. Patients with alternative diagnoses were excluded. RESULTS: We included 29 patients (16 women, median age 25 [range 2-58] years). EM-PLK+ were mostly major (EM with ≥2 mucosal involvements; n = 24, 83%) and relapsing (≥2 flares; n = 23, 79%). Cutaneous lesions were target (n = 13, 54%) and target-like lesions (n = 9, 38%) with usual topography (acral, n = 19, 79%; limbs, n = 21, 88%). Mucosal lesions affected the mouth (n = 27, 96%) and genitalia (n = 19, 68%), with a median of 2 [range 0-5] mucous membranes. EM-PLK+ were suspected as certain or possible postherpetic (EM-HSV) in 19 cases (65.5%); no triggering factors were detected in 9 (31%) patients. Desmoplakin-I/II Abs were the most frequent anti-PLK-Abs (n = 20, 69%); envoplakin and periplakin Abs were detected in 11 and 9 cases. Relapsing EM-PLK+ (n = 23) were still active (≥1 flare within 6 months) in 13 (57%) patients despite immunosuppressive therapy (n = 8, 62%). Antiviral drugs were ineffective in preventing relapse in 15/16 (94%) EM-HSV. CONCLUSION: The rationale for anti-PLK-Ab detection in EM is not elucidated. More systematic research of anti-PLK-Abs is warranted to better understand whether this association reflects humoral immune activity in a subset of EM or is fortuitous, related to an epitope spreading process. However, EM-PLK+ seems to be associated with major and relapsing subtypes, and difficult-to-treat cases.

Treatment of Eosinophilic Annular Erythema: Retrospective multicenter study and literature review.

BACKGROUND: Eosinophilic annular erythema (EAE) is a rare eosinophil-related skin disease which typically manifests with annular erythematous plaques and severe pruritus. Besides the diagnosis, the treatment of EAE is challenging since relevant published data are sparse. METHODS: The aim of this study was to assess the underlying diseases, treatments and outcomes of patients with EAE. To this end, we conducted a retrospective multicenter study and a systematic review of the MEDLINE database. RESULTS: We included 18 patients with EAE followed in 8 centers. The MEDLINE database search yielded 37 relevant publications reporting 55 cases of EAE with 106 treatment sequences. The most common and efficient treatments included topical or systemic corticosteroids, hydroxychloroquine and dapsone. In refractory patients, a combination of systemic corticosteroids with hydroxychloroquine was associated with 88% of complete clinical response. DISCUSSION: To improve the management of EAE patients, we discuss the following treatment strategy: in topical steroid-resistant patients, hydroxychloroquine can be given as first-line systemic treatment. Dapsone, hydroxychloroquine or systemic corticosteroids are second-line options to consider. Last, monoclonal antibodies or JAK inhibitors targeting type 2 inflammation could represent promising last-resort options in refractory patients.

[Dermatomyositis-like syndrome revealing statin-induced necrotizing autoimmune myopathy with anti-HMGCR antibodies]. / Myopathie nécrosante auto-immune à anticorps anti-HMGCR induite par les statines et révélée par un tableau évocateur de dermatomyosite.

BACKGROUND: Statin-induced necrotizing autoimmune myopathy (NAM) has been recently characterized. Herein we report an accurate description of the clinical and histological characteristics of cutaneous rash associated with NAM. PATIENTS AND METHODS: A 61-year-old woman presented a skin rash involving the face, the chest and the back of the hands with heliotropic distribution coupled with proximal symmetrical muscle weakness. Rosuvastatin had been introduced 8 months earlier. Creatinine kinase levels were dramatically raised. Screening for lupus and dermatomyositis antibodies were negative. The cutaneous histology was consistent with neutrophilic lupus while a muscle biopsy revealed no inflammation but showed necrotic and regenerative myofibres. Finally, antibodies directed against 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) were found at high levels (1658UA/ml vs. normal<13.0UA/ml), resulting in diagnosis of necrotizing autoimmune myopathy (NAM). Intensive immunosuppressive therapy resulted in excellent improvement. DISCUSSION: NAM is a severe acquired autoimmune myopathy characterised by severe proximal weakness and specific positive antibodies (anti-HMGCR or anti-signal recognition particle). It is classically associated with statin use. Some extra-muscular symptoms have been described in previous studies. We report the third accurate description of cutaneous rash associated with statin-induced NAM involving HMGCR antibodies. The skin rash was evocative of connective tissue disease and our diagnosis was based on immunology and muscle histology. CONCLUSION: Dermatologists must be able to recognise this rare entity of "pseudo-dermatomyositis" and then discontinue statin intake if present and carry out further investigations consisting of muscle biopsy and serological tests.

[Eruptive disseminated superficial porokeratosis associated with acute hepatitis E]. / Porokératose éruptive superficielle disséminée associée à une hépatite virale E aiguë.

BACKGROUND: Porokeratosis (PK) is a rare form of dermatosis characterized by a keratinization disorder of unknown etiology. Herein we describe the first case associated with hepatitis E virus infection. PATIENTS AND METHODS: A 69-year-old patient with colorectal cancer treated with radiation and chemotherapy followed by surgery in April 2017 presented two months later with jaundice associated with annular keratotic lesions of the skin with a raised border. Blood tests revealed elevated liver enzymes and hyperbilirubinemia. Viral hepatitis E was diagnosed based on serology and viral PCR after other aetiologies such as obstruction, auto-immune disease and other viruses (HAV, HBV, HCV, HSV, HIV, EBV and CMV) had been ruled out. A skin biopsy showed a cornoid lamella. Disseminated superficial porokeratosis associated with hepatitis E infection was then diagnosed. DISCUSSION: The mechanism of PK is unknown and probably involves a combination of different factors. PK has been described in patients with treatment-induced immunosuppression, solid cancer or AIDS, sometimes promoted by HCV viral infection, but never with concomitant HEV infection. A combination of immunosuppression induced by radio-chemotherapy and HEV infection could have prompted the development of PK in our patient. CONCLUSION: We report the first case of eruptive disseminated superficial porokeratosis associated with hepatitis E infection. The exact role of hepatitis E infection in the development of PK is still unclear.

Claudin-1, miR-122 and apolipoprotein E transductions improve the permissivity of SNU-182, SNU-398 and SNU-449 hepatoma cells to hepatitis C virus.

Hepatitis C virus (HCV) is a human hepatotropic virus, but many hepatoma cell lines are not permissive to this virus. In a previous study, we observed that SNU-182, SNU-398 and SNU-449 hepatoma cell lines were nonpermissive to HCV. To understand the nonpermissivity, we evaluated the ability of each cell line to support the different steps of HCV life cycle (entry, replication and production of infectious particles). Using retroviral pseudoparticles pseudotyped with HCV envelope proteins and recombinant HCV produced in cell culture, we observed that low level or absence of claudin-1 (CLDN1) expression limited the viral entry process in SNU-182 and SNU-398 cells, respectively. Our results also showed that supplementation of the three cell lines with miR-122 partly restored the replication of a JFH1 HCV replicon. Finally, we observed that expression of apolipoprotein E (ApoE) was very low or undetectable in the three cell lines and that its ectopic expression permits the production of infectious viral particles in SNU-182 and SNU-398 cells but not in SNU-449 cells. Nevertheless, the supplementation of SNU-182, SNU-398 and SNU-449 cells with CLDN1, miR-122 and ApoE was not sufficient to render these cells as permissive as HuH-7 cells. Thus, these cell lines could serve as cell culture models for functional studies on the role of CLDN1, miR-122 and ApoE in HCV life cycle but also for the identification of new restriction and/or dependency host factors essential for HCV infection.

[What's new in dermatological treatment?] / Quoi de neuf en thérapeutique dermatologique?

The therapeutic revolution in the management of inflammatory dermatoses is under way. The therapeutic arsenal is expanding in the field of psoriasis, including biologics (TNF blockers, anti-IL12/IL23, anti-IL17, and anti-IL23 antibodies), new small molecules (tyrosine kinase inhibitor), and a new biologic for generalized pustular psoriasis (anti-IL36 receptor). New biologics will be soon available in the field of atopic dermatitis in addition to anti-IL4/IL13 antibodies. New targeted treatments of pruritus are also coming (biologics and small molecules). A first randomized placebo-controlled trial has confirmed the interest of JAK inhibitors in alopecia areata. These molecules seem to be also promising in dermatomyositis. Another therapeutic revolution will be technological with the development of new therapeutic agents: small interfering RNA. Recent clinical trials confirmed their efficacy in hereditary amyloidosis.

A new tool to quantify the geometrical characteristics of facial skin pores. Changes with age and a making-up procedure in Caucasian women.

BACKGROUND: Facial skin pores (FSP) are common and benign signs that generate frequent esthetic concerns or complaints. Despite their worldwide prevalence, related literature remains scarce. Hence, a new device has been developed and applied to validating studies, aiming at best describing FSP as they are self-perceived, i.e. their anatomic features, their possible alterations with age and their appearance after application of a make-up product. METHODS: Dermascore+® is an imaging device dedicated to a direct observation and acquisition of various characteristics of the skin surface. Images are captured under a high magnification and under different lighting configurations, to highlight the skin relief, based upon parallel polarized images. Dedicated software allows FSP to being detected and their morphological parameters to being extracted and computed. By measuring each detected FSP in a given region of interest, a statistically significant impact of both age and an applied cosmetic product upon their morphological features can be observed and quantified. RESULTS: Although the size and density of FSP are not affected by aging, their shape becomes elongated. A few tested make up products show variable effects that closely correlate with visual assessments made by trained estheticians. CONCLUSION: The shape of FSP present on cheeks shows age-related changes, toward a more elongated aspect, likely linked to a progressively altered (more isotropic) skin surface micro-relief. The new tool Dermascore+® allows foundations to being rapidly differentiated and screened according to their variable effects upon the visual appearance through instrumental, objective depiction of FSP.

[Acute generalized exanthematous pustulosis induced by phloroglucinol]. / Pustulose exanthématique aiguë généralisée induite par le phloroglucinol (Spasfon®).

BACKGROUND: Acute generalized exanthematous pustulosis (AGEP) is a severe drug eruption. We report herein the first case of AGEP induced by phloroglucinol (Spasfon®). PATIENTS AND METHODS: A 27-year-old pregnant woman developed a febrile exanthematous pustulosis eruption three days after treatment with intravenous phloroglucinol and paracetamol for nephritic colic. She had no previous history of psoriasis. The laboratory workup showed hyperleukocytosis with neutrophilia. A cytobacteriological sample of the pustules was negative. Skin biopsy revealed marked neutrophilic and leukocytoclastic vasculitis. Reintroduction of phloroglucinol after delivery resulted in the same clinical symptoms within a few hours of intake. A diagnosis of phloroglucinol-induced AGEP was made on the basis of intrinsic imputability of I4 (S3 C3) using the imputability criteria of Begaud et al. The outcome was favorable after withdrawal of the drug. DISCUSSION: To the best of our knowledge, this is the first case of phloroglucinol-induced AGEP confirmed by reintroduction of the drug.

[Keratoacanthomas on recent tattoos: Two cases]. / Kératoacanthomes sur tatouages récents : deux cas.

BACKGROUND: Increasing numbers of reports of rapidly arising, isolated or eruptive keratoacanthomas (KA) and squamous cell carcinomas (CSC) on the red part of tattoos tend to suggest a non-fortuitous link with the procedure. We report herein two different presentations of KAs on tattoos: one patient with multiple eruptive KAs on sun-exposed areas of a recent red tattoo and another with a solitary lesion on a recent tattoo. We discuss the issues related to the distinction between KAs and CSCs in this particular context. PATIENTS AND METHODS: Case No. 1: A 55-year-old heavily tattooed man presented multiple round keratotic verrucous-like lesions restricted to a red tattoo. The tattoo had been performed by a professional tattooist in summer 2016, a week before the onset of the symptoms. The patient did not protect a part of his tattoo from sun-exposure during the healing phase and lesions developed only on the sun-exposed tattooed parts. In January 2017, he consulted with about ten lesions. The histologic study by shaving of a lesion militated in favor of a CSC, KA type. The physical examination was unremarkable. He had no previous history of skin cancer. Two weeks later, most of the lesions regressed spontaneously. Based on the clinical history and progression of the lesions, a diagnosis was made of eruptive KA on a red tattoo. Residual lesions were treated by cryotherapy or excision. Case No. 2: A 72-year-old woman developed a 1-cm painful dome-shaped nodule with a central crust three weeks after tattooing. Full excision confirmed the diagnosis of KA. DISCUSSION: To date, we have found 31 case reports and series (17 men, median age: 50.5 years) of KA and CSC on tattoos. Lesions usually develop rapidly after completion of the tattoo, after between one week and several months. Exceptional cases have been described in old tattoos. Red tattoo ink is most commonly the culprit. The main difficulty lies in distinguishing between KA and CSC. Nowadays pathologists agree that a KA should be considered as a variant of CSC. Eruptive forms of KA present a peculiar situation. They may sometimes be inherited, and KA on recent traumatized areas or drug-induced have been described. Like other authors, we believe that cases of CSC on red tattoos belong rather to the KA type. The physiopathogenesis of tattoo-associated eruptive KA and CSC is not clearly understood, but could be multifactorial, involving: the trauma induced by tattooing, local inflammatory reaction, a component of the red ink, external factors such UV exposure, and a possible genetic predisposition. Rapidly arising KA and eruptive KA on top of recent (red) tattoos are not fortuitous. The lesions should be excised and the patient monitored. Additional studies on tumor specimens are warranted to identify the possible causative agents in tattoo ink that may be responsible for such reactions.

Rituximab, a new treatment for difficult-to-treat chronic erythema multiforme major? Five cases.

BACKGROUND: Erythema multiforme major (EMM) is an inflammatory disease affecting skin and mucosae, often triggered by infection with Herpes simplex virus. Some patients have a chronic disease associated with antidesmoplakin autoantibodies, but the pathophysiology remains to be elucidated. First-line treatment is antiviral therapy. With treatment failure or in patients without herpes-triggered disease, thalidomide is effective but has neurological side-effects. Alternatives (dapsone, immunosuppressant agents) are not codified. For many patients, systemic steroids use is chronic. The immunosuppressant drug rituximab (RTX) may be effective. OBJECTIVES: We report five cases of severe chronic EMM treated with rituximab (RTX). METHODS: Five patients with severe chronic EMM for 9-20 years received RTX after failure or side-effects of several treatments, especially antiviral therapy and thalidomide. All had chronic use of steroids. Four patients had antidesmoplakin autoantibodies. RESULTS: Four patients experienced complete or quasi-complete remission of EMM with withdrawal of steroids and one patient partial remission, for 3-11 months. Disease relapsed in all patients, and three received a second cycle of RTX with shorter duration of efficacy. Two patients received a third cycle, one without efficacy. CONCLUSION: The use of RTX for many autoimmune diseases, especially pemphigus, is increasing. Chronic EMM, especially EMM associated to antidesmoplakin autoantibodies, is an inflammatory disease in which the role of B cells is not well understood. However, we report a favourable benefit of RTX treatment for months in five patients with severe disease. RTX could be a therapeutic option in severe, difficult-to-treat EMM.

[Cutaneous manifestations of sarcoidosis]. / Manifestations cutanées de la sarcoïdose.

Sarcoidosis is a systemic granulomatous disorder of unknown aetiology. Its dermatological manifestations are extremely polymorphous. They are normally classed as either specific lesions, comprising granulomas, which are generally chronic, or non-specific lesions, principally acute erythema nodosum. These signs are seen in around 25% of sarcoidosis patients. The disease may be heralded by a skin disorder. Diagnosis of cutaneous sarcoidosis provides the clinician with three problems: screening for a visceral site of the disease, determination of the prognosis, and long-term management with regular monitoring coupled with suitable therapy in the event of cosmetic or functional impairment.

Hypochromic vitiligo: delineation of a new entity.

BACKGROUND: Hypochromic vitiligo is a rare entity that has been reported only twice under the term 'vitiligo minor', with an absence of clear delineation. OBJECTIVES: To delineate hypochromic vitiligo through a case series of patients with typical bilateral hypopigmented lesions affecting the face and trunk. METHODS: This is a retrospective multicentric evaluation study conducted in eight departments of dermatology in France, Belgium, Senegal and Saudi Arabia. RESULTS: Twenty-four cases of hypochromic vitiligo were identified. Fourteen were men and 10 women. The mean age at diagnosis was 35·4 years (range 8-66). Strikingly, all patients were dark skinned, with skin types V and VI. The pattern of distribution was highly similar in most of the patients (18 of 24), with involvement of the face and neck area predominating on seborrhoeic areas associated with multiple isolated hypopigmented macules involving predominantly the scalp. The retrospective nature of this study is its main limitation. CONCLUSIONS: Hypochromic vitiligo is not yet part of a conventional classification. The disease seems to be limited to individuals with dark skin types. Hypopigmented seborrhoeic face and neck involvement associated with hypopigmented macules of the trunk and scalp is the hallmark of the disease.

[Sirolimus-induced lymphedema in a kidney-transplant recipient: Partial recovery after changeover to tacrolimus]. / Lymphœdème induit par le sirolimus chez une greffée rénale : amélioration après remplacement par le tacrolimus.

BACKGROUND: Lymphedema induced by mTOR inhibitors is a side-effect rarely reported to date. PATIENTS AND METHODS: Long-lasting bilateral lower-limb lymphedema with left predominance developed in a 71-year-old stable renal transplant recipient after 40 months of sirolimus treatment. Although no change in lymphedema was observed after 21 months despite dosage reduced, it improved markedly after changeover to tacrolimus. DISCUSSION: Regardless of the individual drug, mTOR inhibitors can cause lymphedema. This effect may be countered through substitution with tacrolimus. CONCLUSION: Physicians should be aware of lymphedema as a side-effect of mTOR inhibitors. It can be improved by substitution with tacrolimus. However, early withdrawal of mTOR inhibitors is recommended before irreversible lymphedema occurs.