N. Franck

Drug-induced Hypersensitivity Syndrome: Clinical and Biologic Disease Patterns in 24 Patients

Drug-induced hypersensitivity syndrome (DIHS), also called drug rash with eosinophilia and systemic symptoms (DRESS), is a severe reaction usually characterized by fever, rash, and multiorgan failure, occurring 1-8 weeks after drug introduction. It is an immune-mediated reaction involving macrophage and T-lymphocyte activation and cytokine release, although no consensus has been reached as to its etiology. The skin, hematopoietic system, and liver are frequently involved. DIHS can mimic severe sepsis, viral infection, adult-onset Still disease (AOSD), or lymphoproliferation. We describe 24 consecutive patients with DIHS who were hospitalized between September 2004 and March 2008. Criteria for inclusion in this observational study were suspected drug reaction, eosinophilia ≥500/&mgr;L and/or atypical lymphocytes, involvement of at least 2 organs (skin being 1 of them), with suggestive chronology and exclusion of other diagnoses. Our cohort of 12 women and 12 men had a median age of 49 years (range, 22-82 yr), and 11 had skin phototype V or VI. Patients with mild or no rash were immunocompromised (7/24)- defined as treatment with prednisone (≥10 mg/d) and another immunosuppressant drug, or human immunodeficiency virus infection. All patients were febrile (>38 °C), 14 had localized or generalized edema, 7 had pharyngitis, 8 had lymphadenopathy, 22 had hepatitis, 4 had nephritis, 2 had noninfectious and nonlithiasic angiocholitis or cholecystitis. Ten patients were hypotensive, 5 of whom had associated laboratory signs and/or imaging findings suggestive of acute myocardial dysfunction. Half of the patients had hemogram abnormalities, including eosinophilia. Nine DIHS patients fulfilled the Fautrel criteria for AOSD diagnosis, including glycosylated ferritin <20% in 4/11, with or without laboratory characteristics of hemophagocytosis. Twenty DIHS episodes occurred during the less sunny months of October to March. We determined 25-hydroxyvitamin D3 (25[OH]D3) levels in 18 patients and found that 9 patients had vitamin D deficiency (<25 nmol/L or <10 &mgr;g/L) and 5 had vitamin D insufficiency (25-50 nmol/L). Moreover, 25(OH)D3 levels were inversely correlated with ferritin values. After culprit-drug withdrawal, outcomes were favorable for all patients, including those with cardiac abnormalities under slow tapering of glucocorticoids. We recommend looking for the frequent but underdiagnosed hypersensitivity myocarditis with noninvasive diagnostic tools, such as N-terminal probrain natriuretic peptide, and promptly withdrawing the culprit drug and starting glucocorticoids. Vitamin D deficiency might be a DIHS risk or severity factor, especially for patients with high skin phototype and during the winter. Because DIHS clinical and laboratory patterns share similarities with AOSD and hemophagocytosis, DIHS should be included in their differential diagnoses. Abbreviations: 25(OH)D3 = 25-hydroxyvitamin D3, AOSD = adult-onset Still disease, CRP = C-reactive protein, DIHS = drug-induced hypersensitivity syndrome, DRESS = drug rash with eosinophilia and systemic symptoms, EBV = Epstein-Barr virus, HHV6 = human herpesvirus 6, HIV = human immunodeficiency virus, IL = interleukin, LDH = lactate dehydrogenase, MRI = magnetic resonance imaging, N = upper limit of normal, NT-proBNP = N-terminal-probrain natriuretic peptide, SMX-TMP = sulfamethoxazole-trimethoprim, Th1-type = T-helper type 1.

Heterogeneity of skin manifestations in patients with Carney complex.

BACKGROUND Carney complex is an autosomal dominant endocrine disorder associated with skin involvement. OBJECTIVE To describe the dermatological signs of patients diagnosed with Carney complex (CNC) or primary pigmented adrenocortical nodular disease (PPNAD). METHODS We conducted a prospective, single-center descriptive study of inpatients and outpatients at a university hospital endocrinology department. Sixteen patients from 14 families diagnosed with CNC or PPNAD were prospectively included in the study between September 2003 and March 2006. Data collected were age at enrollment; sex; Fitzpatrick skin phototype; the presence, location, and density of classic CNC skin lesions--lentigines, freckles, blue nevi, cutaneous myxoma--and other non-disease-specific skin lesions. Histopathologic analysis was carried out in cases in which the lesions were thought to be degenerative or to confirm the diagnosis. Patients were systematically assessed for endocrine and visceral involvement and genotyped for the PRKAR1A gene. RESULTS Twelve patients had lentiginosis (75%), 7 patients had blue nevi (43%), and 5 patients had cutaneous myxoma (31%). Patients could be classified into 3 groups based on skin signs: patients with no prominent skin lesions (n = 3), patients with skin lesions that could not be directly linked to CNC (n = 4), and patients with cutaneous lesions suggestive of CNC (n = 9). We found a correlation between dermatological and endocrine signs in 3 groups of patients: patients with few lesions, patients with an intermediate phenotype, and patients with both many endocrine signs and dermatological signs. LIMITATIONS The classification proposed in our study should be validated on more patients. CONCLUSIONS Skin manifestations are heterogeneous in patients with CNC, and skin phenotype seems to be correlated with endocrine phenotype.

Epidermodysplasia verruciformis in human immunodeficiency virus-infected patients: a marker of human papillomavirus-related disorders not affected by antiretroviral therapy.

BACKGROUND Skin eruptions resembling epidermodysplasia verruciformis (EV) are rarely observed in immunocompromised patients. We focused on the epidemiologic, clinical, virologic, and immunologic features of EV in human immunodeficiency virus (HIV)-positive patients. OBSERVATIONS We studied 11 HIV-positive patients (6 men and 5 women) with clinical and histological features of EV observed at our department. The median age at HIV diagnosis was 27 years. At the onset of eruption, the median age was 40 years and the median CD4 T-cell count was 170/μL. Clinical presentation included flat warts (n = 11), pityriasis versicolor-like macules (n = 5), and lichenoid papules (n = 3) on sun-exposed skin. Detection and typing of cutaneous human papillomavirus (HPV) were carried out in 8 cases and always revealed β-HPV infection, including oncogenic HPV-5 or 8 (n = 6). Mucosal HPV-related diseases were present in 7 cases. Histories of skin cancer and lymphoproliferative disorder were recorded in 3 and 4 patients, respectively, including 2 fatal cases. Skin eruption was never improved by highly active antiretroviral therapy (HAART). In 2 cases, EV was associated with an immune reconstitution syndrome. The present series is the largest with a complete characterization. A review of similar cases was carried out. CONCLUSION Despite effective HAART, HIV-infected patients with EV require a prolonged and careful follow-up to detect mucosal HPV-related diseases, lymphoproliferative disorders, and skin cancers.

Epidermolysis bullosa acquisita following bullous pemphigoid, successfully treated with the anti-CD20 monoclonal antibody rituximab

Epidermolysis bullosa acquisita is a rare autoimmune subepidermal blistering disease, often resisting current treatments, especially systemic corticosteroids. We report a patient having a bullous pemphigoid who relapsed with clinical and immunological features of inflammatory epidermolysis bullosa acquisita. An anti-CD20 monoclonal antibody (rituximab) was proposed because of resistance to high-dose steroids and other immunosuppressive agents. The disease dramatically improved within a few weeks following rituximab infusion allowing the decrease in steroid therapy. Our case illustrates also the possible evolution from bullous pemphigoid to epidermolysis bullosa acquisita that should be suspected when clinical atypia occurs or in case of corticosteroid resistance.

Spiny Follicular Hyperkeratosis Eruption: A New Cutaneous Adverse Effect of Sorafenib

TO THE EDITOR: Sorafenib is an inhibitor of angiogenesis approved by the European Medicines Agency and US Food and Drug Administration and widely used for the treatment of metastatic renal cell carcinoma and hepatocarcinoma. This oral multikinase inhibitor has a large spectrum of activity on various targets, including vascular endothelial growth factor (VEGF) receptor (VEGFR) 2 and VEGFR3, platelet-derived growth factor receptor, Fms-like tyrosine kinase 3, c-kit, and RAF-1 kinase pathway. Antitumoral activity has been also demonstrated in preclinical studies for various tumors including melanoma, non–small-cell lung cancer, and thyroid cancer. In two large pivotal trials and a daily practice report, cutaneous adverse events were frequently reported (70%) and comprised hand-foot skin reaction (30%), rash and desquamation (40%), subungual splinter hemorrhages (40%), alopecia (27%), slow beard growth, stomatitis and cheilitis, xerosis, hyperkeratosis of the nipples, and eruptive cysts. As observed in a phase I trial, dose interruption, dose reduction, and treatment discontinuation were mostly a result of dermatologic adverse effects. Physiopathology is unclear, and emerging toxicities are reported in clinical practice, such as eruptive nevus or keratoacanthomas and squamous cell carcinomas. Here, we report a new sorafenib-induced cutaneous adverse effect, highlighted by a multidisciplinary team around the patients’ treatment. Between March and November 2008, patients were prospectively included in a cohort with a multidisciplinary approach of toxicity induced by antiangiogenesis inhibitors in Cochin and Tenon Hospitals in France. All patients signed inform consent and were observed by a multidisciplinary team including oncologists, dermatologists, pathologists, and pharmacists in a hospitalized care unit (Centre d’Etudes et de Recours sur les Inhibiteurs de l’Angiogenèse). Past dermatologic history and drug interactions were assessed at first visit before intake of sorafenib. Clinical examinations and plasma concentration measurement of sorafenib were performed at baseline and every 2 weeks for 2 months and then once a month until the discontinuation of treatment. Dermatologic adverse events were reported and graded according to the National Cancer Institute Common Terminology Criteria of Adverse Events (version 3). The sorafenib plasma concentration was assayed by high-performance liquid chromatography and quantified by area under the curve with Bayesian pharmacokinetic modeling. Area under the concentration-time curve from 0 to 12 hours of sorafenib was calculated using a Bayesian estimator specifically developed in our institution for sorafenib. Beside the already known cutaneous adverse events, relevant or unusual dermatologic events were characterized with pictures and skin biopsy. Patients were treated for skin adverse events according to international guidelines. Forty-three patients (30 men and 13 women) with a median age of 61 years (range, 31 to 81 years) without past dermatologic history were treated with sorafenib for several cancers including hepatocarcinoma (n 12, 27%), metastatic cutaneous melanoma (n 11, 26%), renal carcinoma (n 6, 14%), thyroid carcinoma (n 7, 16%), neuroendocrine tumor (n 3, 7%), choroid melanoma (n 2, 5%), and fibrolamellar hepatocarcinoma (n 2, 5%). Previous oncologic treatments included cytotoxic chemotherapy (n 13, 30%) and the angiogenesis inhibitors sunitinib (n 8, 19%) and bevacizumab (n 1). Most patients had initial good performance status (Eastern Cooperative Oncology Group performance status of 0 to 1, n 32, 74%). The median time of sorafenib treatment was 171 days (range, 5 to 534 days). Patient demographics clinical and histopathologic characteristics are listed in Table 1. After sorafenib intake, nine patients (21%) experienced an asymptomatic white spiny follicular hyperkeratosis (SFH) located on the face, scalp, upper trunk, and, less frequently, upper arms, but always sparing the palms and soles. Each spiny lesion was approximately 0.5 to 1 mm in diameter and up to 5 mm high. Four of nine patients had pathology analysis. For two patients, a biopsy of a white spiny keratotic projection on the abdomen showed a spike-like orthoparakeratotic column filling the infundibulum and protruding above the surface; a sparse lymphocytic infiltrate was present in the adjacent dermis without lichenoid alteration (Fig 1). The surrounding epidermis was normal. The SFH appeared a median of 82 days (range, 9 to164 days) after treatment began and disappeared after a median of 98 days (range, 4 to 168 days). No patient required specific topical treatment or dose interruption. Four patients experienced treatment discontinuation for extradermatologic adverse effects with disappearance of the eruption after 5 to 7 days. A rechallenge with sorafenib for two of the patients was followed by reappearance of the SFH. The residual plasma concentration of sorafenib was assessed in eight patients, and three patients had a high level (area under the concentration-time curve 65 mg/L h). A comparison between patients with SFH and the main cohort revealed no statistical association of SFH with grade 2 or 3 hand-foot skin reaction (seven patients [77%] v 21 patients [61%], respectively; P .37) or alopecia (three patients [33%] v eight patients [23.5%], respectively; P .68). This type of eruption has been described under several names, including spiny follicular keratoderma, hyperkeratotic spicules, filiform hyperkeratosis, parakeratotic horns, and follicular hyperkeratosis. Facial hyperkeratotic spicule eruption was reported in association with monoclonal gammopathy and linked to cutaneous deposits of the monoclonal immunoglobulins and was also reported in association with viral particles in a patient with lymphoma. Filiform palmoplantar hyperkeratosis, which is clinically close to this pattern, was reported in familial and sporadic forms but rarely in association with malignant diseases (renal, breast, and rectal carcinomas and melanoma) and exceptionally with chronic renal failure, hypovitaminosis A, and Crohn’s disease. In the patients described here, palms and soles were spared by the eruption, corresponding to type IIb Zarour et al classification. JOURNAL OF CLINICAL ONCOLOGY C O R R E S P O N D E N C E VOLUME 28 NUMBER 31 NOVEMBER 1 2010

Mycosis Fungoides–Type Cutaneous T-Cell Lymphoma and Neutrophilic Dermatosis

OBJECTIVES To delineate the natural history of pityriasis rosea in black children and to compare our findings with those of the American, European, and African literature on pityriasis rosea. Textbook and journal article descriptions of pityriasis rosea usually offer information about the presentation and clinical course of this condition in white patients. DESIGN Prospective observational study. SETTING The general pediatric clinic, adolescent clinic, and emergency department of Childrens Hospital of Michigan, Detroit, from June 2003 through May 2005. PATIENTS We followed up 50 black children with pityriasis rosea from the time of diagnosis through follow-up visits at 1, 2, and 4 weeks. Detailed observations were made and digital photographs taken at each visit. MAIN OUTCOME MEASURES Duration of illness and pigmentary sequelae. RESULTS Similarities with the medical literature were found regarding season of onset and prevalence of pruritus and of a herald patch. Our patients had more frequent facial involvement (30%) and more scalp lesions (8%) than usually described in white populations. One third had papular lesions. The disease resolved in nearly one half of patients within 2 weeks. Residual hyperpigmentation was seen in 48% of patients. Hypopigmentation developed in 29% of patients with purely papular or papulovesicular lesions. CONCLUSIONS Pityriasis rosea in black children differs in several ways from textbook descriptions. Physicians may use this information to better counsel patients about the course and potential sequelae of this condition.

Fanconi Syndrome Induced by Vemurafenib: A New Renal Adverse Event

lyzing group A streptococci, notably without prior drug intake. Again, intraoral pustules were observed. During this episode, clinical and histologic findings were consistent with GPP.1 The patient recalled a similar episode 20 years before with a generalized pustular eruption with systemic symptoms without prior drug intake. The patient was given oral clarithromycin (500 mg twice daily) for his throat infection and 2 infusions with infliximab (5 mg/kg of body weight), which resulted in rapid clearance of the lesions.

Sarcoidosis in Patients Treated with Vemurafenib for Metastatic Melanoma: A Paradoxical Autoimmune Activation

Background: Vemurafenib, a BRAF inhibitor, is a first-line treatment for inoperable melanoma. Sarcoidosis has never been reported in patients on vemurafenib. Objectives: We describe 5 cases of sarcoidosis in patients treated with vemurafenib. Methods: Seventy patients receiving vemurafenib for a BRAF-mutated inoperable stage III or IV melanoma were treated in our centre. Results: Five patients (7.1%) developed sarcoidosis or a sarcoid-like reaction on vemurafenib; 4 patients had cutaneous signs and 3 had extracutaneous disorders (bilateral hilar lymph nodes, uveitis). Histological analysis of skin lesions revealed epithelioid granulomas without necrosis, consistent with sarcoidosis. Angiotensin-converting enzyme levels were high in 2 patients. Cutaneous and ophthalmological lesions rapidly disappeared on topical corticosteroid treatment without the cessation of vemurafenib treatment. Complete remission of melanoma was observed in 3 patients and partial remission was observed in another. Conclusion: BRAF inhibitors probably have immune system-enhancing effects and should therefore be recognized as potential inducers of sarcoidosis.

Focal Rituximab-Induced Edematous Reaction at Primary Cutaneous Follicle Center Lymphoma Lesions: Case Report and Literature Review

Primary cutaneous follicle center lymphoma (PCFCL) is the most common cutaneous B cell lymphoma. It is most often indolent and responds well to rituximab. We present a case of transient rituximab-induced edematous lesions located exclusively on tumor papules in a patient treated for PCFCL. Based on this observation and on a review of the literature, we discuss the mechanism of this edematous reaction which does not seem to be allergic. Indeed, this focal reaction observed solely during the first infusion of rituximab is more likely linked with local cytokine release induced by B cell lysis in the skin. This reaction is neither unusual nor severe and should not lead to an interruption of rituximab.

Morphoea (localized scleroderma): baseline body surface involvement and antinuclear antibody may have a prognostic value

Morphoea (localized scleroderma) is a group of idiopathic dermatoses characterized by soft-tissue thickening. Life expectancy in patients with morphoea is similar to that in the general population. Very few large studies provide baseline and follow-up clinical data on morphoea in adult patients. There are no consensus guidelines on the appropriate management of morphoea. Our aim was to appraise the internal organ involvement and biological abnormalities in morphoea, and to determine whether blood tests and radiological explorations are warranted. We conducted a retrospective descriptive study of 35 cases of morphoea [15 plaque morphoea (42.9%), 15 generalized morphoea (42.9%) and 4 linear morphoea (11.4% and 1 eosinophilic fasciitis (2.9))] referred to our dermatology department between 1997 and 2007. Morphoea was classified according to the criteria of Peterson et al. Clinical, immunological and follow-up data were systematically collected. The mean ± SD age at disease onset was 42.9 ± 20.5 years. Delay to diagnosis tended to be shorter in plaque (21.6 months), than in generalized (48.1 months) and linear morphoea (71.3 months). Most patients had three cutaneous lesions or more (n = 25; 71.4%). Linear morphoea presented in all four cases (100%) as a unique skin lesion. Most of the patients (24; 68.6%) had bilateral lesions. Eleven patients (31.4%) had at least one lesion > 100 mm in size. The limbs were spared in all 4 patients with linear morphoea, and in most of the patients with plaque morphoea (13 ⁄ 15, 86.7%), compared with only 7 of 15 patients (46.7%) with generalized morphoea (7 ⁄ 15, P < 0.02). There were no patients with acrosclerosis. Two patients (one with proximal linear morphoea of the lower limb and one with eosinophilic fasciitis) had considerable functional impairment. Extracutaneous clinical signs were rare: Raynaud s phenomenon (n = 1), arthralgia (n = 5) and gastrooesophageal reflux (n = 2). Of 32 tested patients, 12 (37.5%) had antinuclear antibodies (ANA), with a median titre of 1 : 160 and a range of 80–1280), including 2 (6.3%) with anti-DNA antibodies. None had antitopoisomerase I, anticentromere or antihistidyl-tRNA synthetase antibodies. Of 28 tested patients, 2 (7.1%) had positive serology results for Borrelia. One patient had positive IgM serology and received amoxicillin 1.5 g ⁄ day for 3 weeks without response. Another patient had positive IgG and negative IgM serology, but did not receive antibiotics. Of 13 tested patients, none had decreased total lung capacity or forced expiratory volume in 1 second, and 1 had a mild and asymptomatic decreased lung diffusing capacity, which was rated as not related to the scleroderma after computed tomography of the lung. After a mean follow-up of 29 months, stability or improvement of the lesions were seen in 63% of the patients. Worsening was significantly associated with generalized morphoea as the initial presentation (46.7% vs. 15.4%, P < 0.05) and with positive baseline ANA (50.0% vs. 21.1%, P < 0.05). Our study confirms the scarcity of vascular and internal organ involvement and supports the nosological partition between morphoea and systemic sclerosis. We advocate that the term systemic sclerosis should replace the confusing term systemic scleroderma , to avoid misconception among doctors and patients. Morphoea exposes patients to aesthetic and functional impairment, but is rarely life-threatening. Laboratory investigations should be sparsely prescribed and clinically orientated, as they seldom modify the clinical management. The prognostic significance of baseline body surface involvement and ANA deserves further appraisal.