[Omalizumab for the treatment of chronic urticaria: Real-life findings]. / Traitement de l'urticaire chronique par omalizumab : données en vie réelle.

OBJECTIVE: Assessment of the efficacy and safety of omalizumab in chronic urticaria refractory to conventional treatment (H1-antihistamines at high dosage and montelukast) in real-life practice. PATIENTS AND METHODS: A retrospective, descriptive, single-centre study was performed of the data for all patients presenting refractory chronic spontaneous urticaria or inducible urticaria and receiving omalizumab (300mg every four weeks) from November 2012 to June 2016. RESULTS: In all, 23 patients were included. Omalizumab led to complete or significant remission in 19 patients (83%) with chronic urticaria, with remission in 9 patients (47%) occurring within 72hours of the first injection. One patient had a partial response and 3 (13%) showed no response. Only 2 patients (9%) in complete remission stopped their treatment at 1 and 3 years. 52% of patients presented non-serious adverse events, which in one case resulted in treatment withdrawal. CONCLUSION: Omalizumab exhibited good real-life efficacy in a small series of chronic urticaria patients in France.

Immediate hypersensitivity to iodinated contrast media: diagnostic accuracy of skin tests and intravenous provocation test with low dose.

BACKGROUND: The diagnosis of HSR to iodinated contrast media (ICM) is challenging based on clinical history and skin tests. OBJECTIVE: This study evaluates the negative predictive value (NPV) of skin tests and intravenous provocation test (IPT) with low-dose ICM in patients with suspected immediate hypersensitivity reaction (HSR) to ICM. METHODS: Thirty-seven patients with suspected immediate hypersensitivity reaction to ICM were included retrospectively. Skin tests and a single-blind placebo-controlled intravenous provocation test (IPT) with low-dose iodinated contrast media (ICM) were performed. RESULTS: Skin tests with ICM were positive in five cases (one skin prick test and five intradermal test). Thirty-six patients were challenged successfully by IPT, and only one patient had a positive challenge result, with a grade I reaction by the Ring and Messmer classification. Ten of 23 patients followed up by telephone were re-exposed to a negative tested ICM during radiologic examination; two experienced a grade I immediate reaction. CONCLUSIONS & CLINICAL RELEVANCE: For immediate hypersensitivity reaction to ICM, the NPV for skin tests and IPT with low dose was 80% (95% CI 44-97%).

PDGFRB mutants found in patients with familial infantile myofibromatosis or overgrowth syndrome are oncogenic and sensitive to imatinib.

Recently, germline and somatic heterozygous mutations in the platelet-derived growth factor receptor ß (PDGFRB) have been associated with familial infantile myofibromatosis (IM), which is characterized by soft tissue tumors, and overgrowth syndrome, a disease that predisposes to cancer. These mutations have not been functionally characterized. In the present study, the activity of three PDGFRB mutants associated with familial IM (R561C, P660T and N666K) and one PDGFRB mutant found in patients with overgrowth syndrome (P584R) was tested in various models. The P660T mutant showed no difference with the wild-type receptor, suggesting that it might represent a polymorphic variant unrelated to the disease. By contrast, the three other mutants were constitutively active and able to transform NIH3T3 and Ba/F3 cells to different extents. In particular, the germline mutant identified in overgrowth syndrome, P584R, was a stronger oncogene than the germline R561C mutant associated with myofibromatosis. The distinct phenotypes associated with these two mutations could be related to this difference of potency. Importantly, all activated mutants were sensitive to tyrosine kinase inhibitors such as imatinib, nilotinib and ponatinib. In conclusion, the PDGFRB mutations previously identified in familial IM and overgrowth syndrome activate the receptor in the absence of ligand, supporting the hypothesis that these mutations cause the diseases. Moreover, imatinib seems to be a promising treatment for patients carrying these mutations. To our knowledge, these are the first confirmed gain-of-function point mutations of PDGFRB in human cancer.

[Bullous rash around a peritoneal dialysis catheter exit site]. / Éruption bulleuse péri-ombilicale autour d'un cathéter de dialyse péritonéale.

BACKGROUND: Cutaneous eruption around a peritoneal dialysis (PD) catheter exit site is a rare complication. Herein we report a case of bullous eruption; we discuss the diagnostic approach and the related therapeutic implications. PATIENTS AND METHODS: A 63-year-old man presented a bullous periumbilical eruption two months after initiation of PD. Cultures of laboratory samples ruled out an infectious origin and systemic corticosteroids initiated at 0.5mg/kg for suspected eosinophilic peritonitis produced significant improvement of the cutaneous eruption. Recurrence of the bullous eruption was observed upon dose-reduction of the corticosteroid. Skin histology showed a clinical picture of eczema and direct immunofluorescence was negative. Patch testing was carried out using the European Standard Battery comprising antiseptic, cosmetic and plastic series; a semi-open test was performed with the dressing used for PD, and ROAT was carried out on the povidone iodine (Betadine™) 10% used for topical care during PD. The patch testing and ROAT were positive (++), confirming contact dermatitis due to Betadine™. The eruption totally disappeared on substitution of Betadine™ by chlorhexidine for topical antisepsis of the PD catheter, thus enabling PD to be continued rather than instituting hemodialysis. DISCUSSION: Allergic contact dermatitis around a PD catheter is a rare and little-known complication. In the present case, ROAT testing showed sensitization to Betadine™ and enabled an alternative antisepsis solution to be found, allowing PD to be continued.

Persistent STAT5 activation in myeloid neoplasms recruits p53 into gene regulation.

STAT (Signal Transducer and Activator of Transcription) transcription factors are constitutively activated in most hematopoietic cancers. We previously identified a target gene, LPP/miR-28 (LIM domain containing preferred translocation partner in lipoma), induced by constitutive activation of STAT5, but not by transient cytokine-activated STAT5. miR-28 exerts negative effects on thrombopoietin receptor signaling and platelet formation. Here, we demonstrate that, in transformed hematopoietic cells, STAT5 and p53 must be synergistically bound to chromatin for induction of LPP/miR-28 transcription. Genome-wide association studies show that both STAT5 and p53 are co-localized on the chromatin at 463 genomic positions in proximal promoters. Chromatin binding of p53 is dependent on persistent STAT5 activation at these proximal promoters. The transcriptional activity of selected promoters bound by STAT5 and p53 was significantly changed upon STAT5 or p53 inhibition. Abnormal expression of several STAT5-p53 target genes (LEP, ATP5J, GTF2A2, VEGFC, NPY1R and NPY5R) is frequently detected in platelets of myeloproliferative neoplasm (MPN) patients, but not in platelets from healthy controls. In conclusion, persistently active STAT5 can recruit normal p53, like in the case of MPN cells, but also p53 mutants, such as p53 M133K in human erythroleukemia cells, leading to pathologic gene expression that differs from canonical STAT5 or p53 transcriptional programs.

[A study of 19 cases of allergy to heparins with positive skin testing]. / Étude de 19 cas d'allergie aux héparines prouvée par des tests cutanés.

BACKGROUND: Allergic hypersensitivity to unfractioned or low-molecular-weight heparins is uncommon but is known, and in particular the most common form is localized dermatitis, although such cases have seldom turned into maculopapular exanthema. Since cross-reactions with other heparins are frequent, identification of therapeutic alternatives is essential. PATIENTS AND METHODS: This retrospective study included patients referred to the Department of Dermatology and Allergology at Tenon Hospital between 2000 and 2012 with suspicion of allergy to unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH) and sensitized to at least one heparin (i.e. positive skin tests to at least one heparin). The heparins and hirudins used were tested in the forearm by means of intradermal skin tests. All patients were contacted in 2012 to establish whether they had used some form of heparin since the cutaneous allergy tests. RESULTS: Nineteen patients had at least one positive skin test for heparin; 1 patient had presented anaphylactic shock, while 18 others had presented localized eczema (12) or generalized dermatitis (6). The heparin most often responsible for these adverse reactions was enoxaparin (13/19). An LMWH was responsible in most cases (18 vs. 1 with UFH). Of these 18 patients, 16 also presented positive skin tests for UFH, 9 for synthetic heparinoid and 1 for hirudin. 11/19 patients were tested for fondaparinux (a synthetic pentasaccharid) and all had negative skin tests. 5/7 patients with negative skin tests had taken fondaparinux without any visible reaction, whereas 2 who also tested negative experienced localized eruption at the injection site. DISCUSSION: Our results underline the greater frequency of delayed hypersensitivity reactions compared with immediate reactions to heparins. Skin tests can help to identify substitution molecules. Fondaparinux might be an alternative but certain diagnosis relies on rechallenge.

Cutaneous adverse drug reaction to oral acetazolamide and skin tests.

BACKGROUND: Few cases of cutaneous adverse drug reactions (CADR) to oral acetazolamide, a non-antimicrobial sulfonamide, have been previously reported, and the interest of acetazolamide skin tests has never been studied. OBJECTIVES: We report a series of ten patients with oral acetazolamide CADR and skin tests. PATIENTS AND METHODS: The files of ten patients with CADR secondary to oral acetazolamide prescribed for cataract surgery in most cases referred between 2001 and 2011 in four French dermatology and allergy departments were retrospectively reviewed. Skin tests with acetazolamide were performed in nine patients and twelve controls. Other sulfonamides were tested in five of ten patients. RESULTS: Seven patients developed maculopapular exanthema and four had acute generalized exanthematous pustulosis. Patch tests were positive for 8/9 patients, prick tests for 2/4 and intradermal tests for 3/3. Patch and prick or intradermal test results were concordant in 2/3 positive subjects. Patch tests for other sulfonamides were negative, as were patch tests in controls. CONCLUSIONS: We report the largest series of CADR to oral acetazolamide (maculopapular exanthema or acute generalized exanthematous pustulosis). A drug eruption after cataract surgery should be investigated for accountability of acetazolamide. In view of this retrospective study, skin tests and particularly intradermal tests appear to be an important contribution to demonstrate accountability.

Continuous subcutaneous insulin infusion allows tolerance induction and diabetes treatment in a type 1 diabetic child with insulin allergy.

AIM: Insulin allergy is a rare but serious and challenging condition in patients with type 1 diabetes (T1D). This is a case report of an 8-year-old boy with T1D and an allergy to insulin. CASE REPORT: Three months after being diagnosed with T1D, the patient developed progressive skin reactions to insulin, characterized by small 1.5-cm pruritic wheals at injection sites that persisted for several days. Seven months after diagnosis, he experienced two episodes of generalized urticaria with systemic symptoms that were seen within a few seconds of insulin injection. Examination revealed lipoatrophy of the thighs. Intradermal skin tests were positive for protamine, glargine and lispro. The patient was started on a continuous subcutaneous insulin infusion (CSII) tolerance induction protocol, consisting of a very low basal rate that was progressively increased, with the first bolus given under medical supervision, and was well tolerated for 4 months. After this period of time, the skin wheals reappeared, localized to the infusion sites, but without urticaria or any other generalized reactions. Intradermal skin tests were repeated and were again positive. Serum insulin-specific IgE measured 30 months after the first allergic reactions were positive. After 3 years, pump therapy is ongoing and blood glucose control has remained relatively good (HbA1c 7.6%). CONCLUSION: In T1D children with insulin allergy, CSII can successfully be used to both induce insulin tolerance and allow diabetes insulin therapy, although insulin desensitization cannot always be fully achieved. The induction protocol was easily manageable partly due to the "honeymoon" period that the patient was still in, but it should nonetheless be used even when the patient has higher insulin requirements.

Five cases of contact dermatitis to a trendy pet.

Skin contact with animal hair may induce contact urticaria (syndrome) or protein contact dermatitis. We report here 5 cases of dermatitis due to contact with ferrets kept as pets. The nature of the skin lesions, i.e. eczematous dermatitis, as well as the history of our 5 cases point to protein contact dermatitis. Further studies are requested to confirm this hypothesis and to identify the mechanisms and allergens. Physicians must be aware of the possibility of contact dermatitis with ferrets, especially when the patient has no previous history of atopic dermatitis and presents dermatitis of the neck, arm and around mouth.

[Contact urticaria induced by hydrolyzed wheat proteins in cosmetics]. / Urticaire de contact aux hydrolysats de protéines de blé contenus dans des cosmétiques.

BACKGROUND: Hydrolyzed wheat protein, produced by hydrolysis of gluten, is used in certain cosmetics and foods as emulsifiers and stabilizers. It can induce contact urticaria to cosmetics and/or anaphylaxis to food via an immunologic mechanism. PATIENTS AND METHODS: A 28-year-old female beautician presented recurrent contact urticaria, initially on the hands and then more diffused, immediately after applying cosmetics of the same brand containing hydrolyzed wheat protein. Skin tests were positive with the cosmetics and with the hydrolyzed wheat protein contained therein. A 34-year-old woman presented four episodes of generalized urticaria after eating industrially prepared foods. She had also experienced contact urticaria with cosmetics. Skin tests with hydrolyzed wheat protein were positive. For both patients, withdrawal of cosmetics and foods containing hydrolyzed wheat protein led to the regression of symptoms. They were both tolerant to traditional wheat products, such as bread and pastries. DISCUSSION: Although contact urticaria to hydrolyzed wheat protein is rarely described, it must be understood since treatment by eradication of this product is simple and because contact urticaria may precede food allergy. Patients are tolerant to products containing unmodified wheat protein.

[Indications for rapid readout skin tests]. / Tests cutanés à lecture immédiate : indications.

Rapid readout skin tests are indicated in the investigation of antigens involved immediate reactions, whether or not IgE-mediated. They are thus indicated in the exploration of some immediate reactions in allergology-dermatology reactions such as immunological contact urticaria (latex allergy for example) and protein contact dermatitis.

Genetic differences in omega-gliadins involved in two different immediate food hypersensitivities to wheat.

BACKGROUND: Anti-gliadin IgE are expressed in patients with food allergy associated to skin immediate hypersensitivity to hydrolyzed wheat proteins (IHHWP). It is not known if they react with omega5-gliadins, the major allergens in wheat dependant exercise-induced food anaphylaxis (WDEIA), encoded on wheat chromosomes 1B. METHODS: Unmodified gliadins from 14 wheat varieties expressing most of the 1B omega-gliadin alleles, were immunoprobed after SDS-PAGE and blotting, with four sera from patients with IHHWP, and two with WDEIA. Gliadins reacting with IgE were visualized using chemiluminescence and identified according to their mobility and typical SDS-PAGE pattern. The resulting signal was also measured to compare their IgE reactivity. RESULTS: IHHWP and WDEIA sera exhibited distinct patterns of reactivity. IgE of patients with IHHWP reacted mainly with all omega-gliadins alleles and one gamma-gliadin encoded respectively on chromosomes 1D and 1B, but not with any omega5-gliadins alleles as for WDEIA. A few other reactive alleles of omega-gliadins were encoded on chromosomes 1A. Unassigned additional bands of the whole gliadin pattern were also reactive. The four patients with IHHWP exhibited almost the same pattern of reactivity. Main differences concerned band reactivity which modulated the overall reactivity of each wheat variety. CONCLUSIONS: The IgE epitopes involved in IHHWP and WDEIA are different. This suggests that the protein state and the route of exposure to very similar gluten structures, probably orientate the pattern of epitope reactivity and the wheat food allergy manifestations.

The Src tyrosine kinase Hck is required for Tel-Abl- but not for Tel-Jak2-induced cell transformation.

Tel-Abl and Tel-Jak2 are fusion proteins associated with human haematologic neoplasms. They possess constitutive tyrosine kinase activity and activate common downstream signalling pathways like Stat-5, PI3-K/Akt, Ras/MapK and NF-kappaB. In this study, we showed the specific requirement of Src family members for the Tel-Abl-mediated cell growth, activation of Stat5, PI3-K/Akt and Ras/MapK while dispensable for Tel-Jak2. Hck was found strongly phosphorylated in Tel-Abl-expressing Ba/F3 cells and sensitive to imatinib mesylate treatment, providing evidence that Hck is a target of Tel-Abl tyrosine kinase activity. Overexpression of a kinase dead form of Hck inhibits the proliferation of Ba/F3 cells expressing Tel-Abl as the phosphorylation of Akt and Erk1/2. These results argue for an important role of Hck in Tel-Abl oncogenic signalling.

Head and neck atopic dermatitis and malassezia-furfur-specific IgE antibodies.

BACKGROUND: Atopic dermatitis of the head and neck (HNAD) has been recognized as a separate entity. Malassezia furfur, a lipophilic yeast, is considered to be a pathogenic allergen in this form of atopic dermatitis. OBJECTIVE: The purpose of this study was to determine the level of IgE anti-M.-furfur antibodies and their relation to the severity of the disease. METHODS: IgE anti-M.-furfur antibodies were assayed in 106 patients with HNAD. Controls included 25 patients with non-HNAD, 20 with nonatopic dermatitis and 16 with seborrheic dermatitis (including 4 with AIDS). RESULTS: There was a highly significant correlation between the level of anti-M.-furfur IgE and clinical severity. Furthermore, there was a significant but smaller correlation between total IgE and clinical severity. In patients with HNAD, total IgE was higher amongst men. CONCLUSION: IgE anti-M.-furfur antibodies are a good and specific marker for HNAD. IgE M. furfur levels are strongly correlated with the severity of the disease.