Expert opinion on management of moderate-to-severe atopic dermatitis in Qatar.

Atopic dermatitis (AD), a chronic-relapsing inflammatory skin disorder, manifests with intense itching and eczematous lesions impairing quality of life. A heterogeneous population, and regional clinical practices for treating AD warrant the development of guidelines in Qatar. Therefore, guidelines for the management of moderate-to-severe AD in Qatar have been developed and discussed. Experts, including dermatologists and immunologists, used the Delphi technique for developing guidelines. Consensus was defined as ≥75% agreement or disagreement. AD is highly prevalent in primary and tertiary dermatology centers. AD-associated foot eczema and psoriasiform eczema are more frequent in Qatar than in Europe or USA. SCORing Atopic Dermatitis Index quantifies disease severity and itch. Dermatology Life Quality Index assesses the quality of life. Atopic Dermatitis Control Tool assesses long-term disease control. Moderate-severe AD benefits from new topicals like Janus-kinase-inhibitors or PDE4-inhibitors combined with phototherapy. Currently approved systemic agents are dupilumab, baricitinib, abrocitinib, and upadacitinib. New anti-IL-13 and anti-IL-31 therapies will soon be available. Patient education, allergy testing, and comorbidity consideration are critical in the management of AD. The expert panel established a comprehensive and pragmatic approach to managing moderate-to-severe AD, thereby assisting clinical decision-making for healthcare professionals in Qatar.

Light-based therapies in the management of rosacea: a systematic review with meta-analysis.

BACKGROUND: The current scenario and position of laser and light-based therapies (LLBT) in the therapeutic rosacea scheme are lacking evidence-based recommendations and comparisons on efficacy and tolerability among different devices. This article aimed to systematically compare the efficacy, acceptability, and tolerability of the pulsed dye laser (PDL) versus other devices. METHOD: A literature search was conducted in March 2020. Four domains were analyzed throughout the following six outcomes: Spectrophotometer erythema index and percentage of reduction for background erythema, telangiectasia grading scale for telangiectasias, visual analog scale for pain, and physician's assessment and patient's satisfaction for treatment success. RESULTS: Our search yielded 423 potentially relevant studies. After removing the excluded and duplicated records, 12 records were assessed for eligibility in the meta-analysis. Erythema (RR:0.38 95%CI: -0.20-0.95), telangiectasias (RR:0.54 95%CI: -0.87-1.94), and the treatment success throughout the physician's assessment (RR:1.23 95%CI: 0.74-2.04) and the patient's satisfaction (RR:1.15 95%CI: 0.73-1.82) were not significantly different between pulsed dye laser and other LLBT. In the pain domain, PDL was as painful as other LLBT (RR:-0.23 95%CI: -0.96-0.49) but more painful than neodymium: yttrium-aluminum-garnet laser (RR:0.84 95%CI: 0.53-1.14) and less than intense pulsed light (RR:-1.18 95%CI: -1.56-0.80). CONCLUSION: This work based on previously published literature demonstrates that the quality of evidence to support any recommendation on LLBT in rosacea is low-to-moderate. Among all the available devices, PDL holds the most robust evidence, although in the meta-analysis the effectiveness was comparable to other LLBT, such as neodymium: yttrium-aluminum-garnet laser (Nd-YAG) or IPL.

Comparative appraisal with meta-analysis of erbium vs. CO2 lasers for atrophic acne scars.

Recent advances in laser technology allowed the development of systems that improve texture, appearance and pliability of skin in acne scars (AS). Currently, comprehensive comparative studies on the efficacy of the most commonly used fractional systems in AS are lacking. Thus, the aim of this work was to appraise and compare the clinical response to erbium versus CO2 lasers in AS in the form of a meta-analysis. The databases MEDLINE, EMBASE, Cochrane library were searched. Main clinical outcomes were investigator-reported scar improvement and participant-reported scar improvement. Five studies were included in this meta-analysis. Scar improvement was similar for both types of laser in terms of investigator-reported scar improvement (RR: 0.60 95 % CI: 0.35-1.02) and participant-reported scar improvement (RR: 0.99 95 % CI: 0.79-1.25). A sensitivity analysis that excluded studies with high risk of bias found the CO2 lasers to be superior to the erbium lasers (RR: 0.47 95 % CI: 0.24-0.93): However, the subgroup analysis showed the CO2 laser not to be significantly different from either the non-ablative erbium (RR: 0.65 95 % CI: 0.34-1.24) or the ablative erbium laser (RR: 0.60 95 % CI: 0.35-1.02). The CO2 laser produced a slightly greater clinical response compared to the erbium lasers based on the physician's assessment. Overall, the two devices do not differ largely in terms of efficacy but may be complementary, with each resurfacing laser better suited for different clinical tasks.

Laser and light-based therapies in the management of rosacea: an updated systematic review.

Unlike other rosacea therapies which need daily takings or applications over long periods, the edge of lasers and light-based therapies (LLBT) is the limited number of sessions to achieve improvement. The proper selection of the adequate physical device in accordance with the patients' skin features and rosacea-related signs and symptoms should be considered and the management with physical sources should be updated as new data become available. This article reviews and discusses the current use of lasers and light-based therapies in rosacea with reference to all the available literature.This systematic review demonstrates the quality of evidence to support any recommendation on LLBT in rosacea is low-to-moderate. Among all the available devices, PDL holds the most robust evidence. Treatments options should be tailored for each specific clinical scenario as it is unlike that single modality results in complete resolution. Platforms that include two or more devices and combined therapies with topical agents are suitable and they warrant further investigations.

Efficacy of topical ivermectin and impact on quality of life in patients with papulopustular rosacea: A systematic review and meta-analysis.

Rosacea is a chronic dermatosis which affects negatively patients' quality of life (QoL). There is shortage of high-quality evidence comparing the efficacy of ivermectin cream (IVM) 1% with other available topical choices. Besides, the well-documented impaired of self-esteem and stigmatization of rosacea patients make essential to address which treatment provides the greatest psychological and social benefit. Our objective is to critically review and appraise the efficacy of IVM 1% in PPR and the impact in patients' QoL against other options. We carried out a literature search from PubMed, MEDLINE, EMBASE, Cochrane, and clinicaltrials.gov using the following descriptors: "rosacea" AND "ivermectin." Efficacy was assessed with the Investigator Global Assessment (IGA), and the impact on QoL was based on the DLQI score. Six studies from four published articles were included. The meta-analysis estimated that more participants achieved "success" (IGA ≤ 1) and "complete clearance" (IGA = 0) with IVM1%. The overall effect estimate for IGA ≤ 1 was: 1.56 [1.23-1.97], whereas for IGA = 0, it was: 1.72 [1.40-2.11]. The rate of participants achieving lower DLQI score, and thus, better QoL was with IVM 1%. The overall effect estimate was: 1.71 [1.34-2.18] at week 16# and 1.64 [1.38-1.94] at week 52#. This meta-analysis confirms IVM 1% cream as the most effective topical treatment and it satisfies the impairment of social life with sustained better QoL. Further studies extending this period of remission are warranted, as well as researches about the potential application of this agent combined with other agents. KEY POINTS: Question: What is the current efficacy of ivermectin versus other choices in papulopustular rosacea and its impact on patients' quality of life? Findings: In this meta-analysis, ivermectin showed higher efficacy than metronidazol, azelaic acid, and placebo measured by Investigator Global Assessment. Parallely, the DLQI score highlighted that this agent was more beneficious in both short and long-term. Meaning: This meta-analysis gives strong evidence that ivermectin is the most effective topical treatment. Besides, this agent provides the greatest psychological benefit as it satisfies the stigmatization of rosacea patients as well as the impairment of social and working life with a sustained better QoL above other alternatives.

Evaluation of cationic channel TRPV2 as a novel biomarker and therapeutic target in Leukemia-Implications concerning the resolution of pulmonary inflammation.

Patients treated during leukemia face the risk of complications including pulmonary dysfunction that may result from infiltration of leukemic blast cells (LBCs) into lung parenchyma and interstitium. In LBCs, we demonstrated that transient receptor potential vanilloid type 2 channel (TRPV2), reputed for its role in inflammatory processes, exhibited oncogenic activity associated with alteration of its molecular expression profile. TRPV2 was overexpressed in LBCs compared to normal human peripheral blood mononuclear cells (PBMCs). Additionally, functional full length isoform and nonfunctional short form pore-less variant of TRPV2 protein were up-regulated and down-regulated respectively in LBCs. However, the opposite was found in PBMCs. TRPV2 silencing or pharmacological targeting by Tranilast (TL) or SKF96365 (SKF) triggered caspace-mediated apoptosis and cell cycle arrest. TL and SKF inhibited chemotactic peptide fMLP-induced response linked to TRPV2 Ca2+ activity, and down-regulated expression of surface marker CD38 involved in leukemia and lung airway inflammation. Challenging lung airway epithelial cells (AECs) with LBCs decreased (by more than 50%) transepithelial resistance (TER) denoting barrier function alteration. Importantly, TL prevented such loss in TER. Therefore, TRPV2 merits further exploration as a pharmacodynamic biomarker for leukemia patients (with pulmonary inflammation) who might be suitable for a novel [adjuvant] therapeutic strategy based on TL.

Topical Ivermectin 10 mg/g and Oral Doxycycline 40 mg Modified-Release: Current Evidence on the Complementary Use of Anti-Inflammatory Rosacea Treatments.

Rosacea is a common, chronic inflammatory skin disease that can present with a variety of signs and symptoms. The potentially simultaneous occurrence of different signs and symptoms is due to different underlying inflammatory pathways, emphasizing the need for complementary treatment approaches. Topical ivermectin cream (10 mg/g) and systemic, oral anti-inflammatory doxycycline (40 mg modified-release) are both approved for the treatment of papulopustular rosacea (PPR). Whether or not a combined therapeutic approach may be more beneficial than monotherapy for patients with PPR remains to be tested. Here, we summarize underlying inflammatory pathways implicated in rosacea and clarify the impact of these two agents on selective pathways during inflammation, due to specific characteristics of their individual mechanisms of action (MoA). Based on the complementary MoA of doxycycline modified-release and ivermectin, a scientific rationale for a combined therapy targeting inflammatory lesions in rosacea is given. We propose that topical ivermectin cream is a promising new candidate as first-line treatment to target the inflammatory lesions of rosacea, which can be used in combination with systemic doxycycline modified-release to provide an optimal treatment approach considering all inflammatory pathways involved in PPR. Funding Galderma.

Psychoneuroimmunology of psychological stress and atopic dermatitis: pathophysiologic and therapeutic updates.

Atopic dermatitis is a chronic inflammatory skin disease characterized by impaired epidermal barrier function, inflammatory infiltration, extensive pruritus and a clinical course defined by symptomatic flares and remissions. The mechanisms of disease exacerbation are still poorly understood. Clinical occurrence of atopic dermatitis is often associated with psychological stress. In response to stress, upregulation of neuropeptide mediators in the brain, endocrine organs, and peripheral nervous system directly affect immune and resident cells in the skin. Lesional and non-lesional skin of patients with atopic dermatitis demonstrates increased mast cells and mast cell-nerve fiber contacts. In the setting of stress, sensory nerves release neuromediators that regulate inflammatory and immune responses, as well as barrier function. Progress towards elucidating these neuroimmune connections will refine our understanding of how emotional stress influences atopic dermatitis. Moreover, psychopharmacologic agents that modulate neuronal receptors or the amplification circuits of inflammation are attractive options for the treatment of not only atopic dermatitis, but also other stress-mediated inflammatory skin diseases.

Pruritus and renal failure.

Patients with renal failure, usually end-stage renal disease (ESRD), commonly are afflicted by severe pruritus. The pathogenesis of ESRD pruritus is unknown, but improving the quality of dialysis can reduce the prevalence and severity of ESRD pruritus. Topical and systemic agents as well as broadband ultraviolet phototherapy can be extremely beneficial. Gabapentin has been recently discovered as an effective agent for the patient with ESRD pruritus. Kappa opiate agonists are promising new therapeutic options.

Management of itch in atopic dermatitis.

Atopic dermatitis is a common, pruritic, inflammatory skin disorder. Chronic, localized, or even generalized pruritus is the diagnostic hallmark of atopic dermatitis, and its management remains a challenge for physicians. The threshold for itch and alloknesis is markedly reduced in these patients, and infections can promote exacerbation and thereby increase the itch. Modern management consists of anti-inflammatory, occasionally antiseptic, as well as antipruritic therapies to address the epidermal barrier as well as immunomodulation or infection. Mild forms of atopic dermatitis may be controlled with topical therapies, but moderate-to-severe forms often require a combination of systemic treatments consisting of antipruritic and immunosuppressive drugs, phototherapy, and topical compounds. In addition, patient education and a therapeutic regimen to help the patient cope with the itch and eczema are important adjuvant strategies for optimized long-term management. This review highlights various topical, systemic, and complementary and alternative therapies, as well as provide a therapeutic ladder for optimized long-term control of itch in atopic dermatitis.

Pruritus: management algorithms and experimental therapies.

Pruritus (itch) is a major symptom in many dermatologic as well as systemic diseases and has a dramatic impact on the quality of life in these patients. The symptom of itch has to be treated on the basis of its pathophysiology and its underlying disease. In daily practice, a "quick" diagnosis of the underlying disease is often difficult, although a rapid relief of the itch is desired. We often treat patients on the basis of the symptomatology. A rational therapeutic ladder for a symptomatic therapy is useful until the final diagnosis has been confirmed. There are probably many subtypes of pruritus, just as there are many diseases that cause itch. The pathophysiology in many subtypes of pruritus is still poorly understood, hindering a rapid and targeted treatment strategy. An extensive diagnostic workup is often required to determine the final cause(s) of the itch. Thus, in daily life, physicians often start with a more or less rational therapeutic strategy to combat the debilitating itch. We present possible therapeutic ladders that form the basis for effective therapeutic itch strategies in various diseases. On the basis of our current knowledge about the different pathophysiologies of itch, on clinical trials or case reports, and our own clinical experience, we aim to present therapeutic ladders for the rapid as well as long-term management of itch. Finally, we summarize current exciting developments of experimental strategies in itch research and in clinical development for itch therapy.

Successful treatment of generalized eruptive histiocytoma with PUVA.

Generalized eruptive histiocytoma (GEH) is a rare benign skin disease mainly affecting adults which belongs to the family of non-Langerhans-cell histiocytoses. A 32-year-old Caucasian woman developed disseminated, monomorphic papules of the trunk after a common cold with sinusitis. Mucous membranes, palms and soles were spared. She also suffered from arthralgia without fever or night sweats. After one month, the patient noticed progression of the reddish papules involving the trunk, extremities and face. Clinical as well as histological examination and immunohistochemistry led to the diagnosis of GEH. The clinical examination and laboratory testing were normal, except for eosinophilia in the peripheral blood and bone marrow. No neoplastic diseases were found during thorough examinations. Systemic PUVA therapy produced rapid regression of the skin lesions. After 10 treatments the lesions began to regress leaving slight papules and multiple brown hyperpigmentations. The lesions resolved completely after 20 PUVA treatments. No relapses occurred. Systemic PUVA therapy represents a promising option for the treatment of GEH.

Recycling and resensitization of the neurokinin 1 receptor. Influence of agonist concentration and Rab GTPases.

Substance P (SP) induces endocytosis and recycling of the neurokinin 1 receptor (NK1R) in endothelial cells and spinal neurons at sites of inflammation and pain, and it is thus important to understand the mechanism and function of receptor trafficking. We investigated how the SP concentration affects NK1R trafficking and determined the role of Rab GTPases in trafficking. NK1R trafficking was markedly influenced by the SP concentration. High SP (10 nM) induced translocation of the NK1R and beta-arrestin 1 to perinuclear sorting endosomes containing Rab5a, where NK1R remained for >60 min. Low SP (1 nM) induced translocation of the NK1R to early endosomes located immediately beneath the plasma membrane that also contained Rab5a and beta-arrestin 1, followed by rapid recycling of the NK1R. Overexpression of Rab5a promoted NK1R translocation to perinuclear sorting endosomes, whereas the GTP binding-deficient mutant Rab5aS34N caused retention of the NK1R in superficial early endosomes. NK1R translocated from superficial early endosomes to recycling endosomes containing Rab4a and Rab11a, and Rab11aS25N inhibited NK1R recycling. Rapid NK1R recycling coincided with resensitization of SP-induced Ca2+ mobilization and with the return of surface SP binding sites. Resensitization was minimally affected by inhibition of vacuolar H(+)-ATPase and phosphatases but was markedly suppressed by disruption of Rab4a and Rab11a. Thus, whereas beta-arrestins mediate NK1R endocytosis, Rab5a regulates translocation between early and sorting endosomes, and Rab4a and Rab11a regulate trafficking through recycling endosomes. We have thus identified a new function of Rab5a as a control protein for directing concentration-dependent trafficking of the NK1R into different intracellular compartments and obtained evidence that Rab4a and Rab11a contribute to G-protein-coupled receptor recycling from early endosomes.