Cytokine-based therapy in psoriasis.

Psoriasis and psoriatic arthritis are chronic inflammatory diseases of unknown etiology, affecting 2-3% of the world population. Initially, psoriasis was thought to be a hyper-proliferation disorder of keratinocytes only, but as time passed, the role of immune system became more evident and now both diseases are considered autoimmune disorders. In last few years, the discovery of interleukin (IL)-23/Th17 axis in pathophysiology of psoriatic diseases shifts the cytokine paradigm from Th1 to Th17 cytokines, focused mainly on IL-17 and IL-22. Therapeutic experiences strongly support the use of cytokine antagonists as an important modality in the treatment of psoriatic arthritis and plaque psoriasis. Studies examining these therapeutic agents which target different steps of the psoriatic inflammatory cascade have also shown significant efficacy. The relatively new IL-23/Th17 axis in psoriatic diseases got more importance with the success of ustekinumab, a new monoclonal antibody against IL-12 and IL-23. In IL-17 and IL-22 knock-out and transgenic mouse models, it has been found that recombinant IL-23 fails to produce epidermal hyperplasia which resembles psoriasis. Also, some success in animal models of psoriasis was found with anti IL-17A and anti IL-22. More studies are needed to validate the efficacy and safety of these cytokine antagonists in psoriatic diseases. Using a historical perspective and a chess game as an analogy, the main objective of this review is to summarize the central role of some of these cytokines in psoriasis pathophysiology and to develop a strategic approach to new therapeutic weapons within the armamentarium of psoriasis treatment.

An inflammatory reaction surrounding molluscum contagiosum as possible manifestation of immune reconstitution inflammatory syndrome in HIV infection.

Highly active antiretroviral therapy can restore specific immune responses and control of microorganism infections in human immunodeficiency virus-positive patients. This immune recovery may cause an inflammatory reaction to microbial and autoimmune antigens known as immune reconstitution inflammatory syndrome. We describe a clinical case with an intense inflammatory response surrounding molluscum contagiosum after highly active antiretroviral therapy. The clinical and laboratory findings suggested that the reaction was due to immune reconstitution inflammatory syndrome occurring during a period of immune recovery in a child with acquired immune deficiency syndrome.

Targeting IL-23: insights into the pathogenesis and the treatment of psoriasis.

Therapeutic experience strongly supports the use of TNF antagonists as important modalities in the treatment of psoriatic arthritis and plaque psoriasis. Studies with anti-IL-12/23 therapeutic agents, which act in different steps of the psoriatic inflammatory cascade, have also shown demonstrable efficacy. Here, we discuss this approach and its potential within the armamentarium for the treatment of psoriasis. Evidences that the selective blocking of IL-23 may be effective and safe therapy are also addressed.

Laboratorial atopy markers in children with human immunodeficiency virus.

Changes in immune system functions are one of the most important consequences of human immunodeficiency virus (HIV) infection. Studies have reported a higher prevalence of disease mediated by immunological hypersensitivity mechanisms in HIV-positive patients. This study aims to observe how immunological changes in HIV-infected children interfere in atopy determinants. Fifty-seven HIV-positive children were studied between June 2004-August 2005 to evaluate the possible modifications in atopy diagnosis from prick test environmental allergen reactivity. Patients were subjected to two evaluations: on both occasions, atopic and non-atopic groups were correlated with immunological (CD4+ and CD8+ lymphocyte concentrations and serum levels of IgA, IgM, IgG and IgE) and viral parameters (HIV viral load). The percent atopy was 20.05 in the first and 29.82 in the second evaluation and atopy was diagnosed in patients without immunosuppression or with moderate immunosuppression. Six patients changed from a negative to a positive atopy profile. One patient with a decreased CD4+ T lymphocyte concentration failed to demonstrate prick test positivity between evaluations. Multivariate analysis showed that the variables associated with atopy diagnosis included a personal history of allergic diseases as well as elevated IgE for age and elevated IgE levels. Atopy development in HIV-infected children seems to be modulated by genetic and environmental factors as well as immunological condition.

Laboratorial atopy markers in children with human immunodeficiency virus

Changes in immune system functions are one of the most important consequences of human immunodeficiency virus (HIV) infection. Studies have reported a higher prevalence of disease mediated by immunological hypersensitivity mechanisms in HIV-positive patients. This study aims to observe how immunological changes in HIV-infected children interfere in atopy determinants. Fifty-seven HIV-positive children were studied between June 2004-August 2005 to evaluate the possible modifications in atopy diagnosis from prick test environmental allergen reactivity. Patients were subjected to two evaluations: on both occasions, atopic and non-atopic groups were correlated with immunological (CD4+ and CD8+ lymphocyte concentrations and serum levels of IgA, IgM, IgG and IgE) and viral parameters (HIV viral load). The percent atopy was 20.05 in the first and 29.82 in the second evaluation and atopy was diagnosed in patients without immunosuppression or with moderate immunosuppression. Six patients changed from a negative to a positive atopy profile. One patient with a decreased CD4+ T lymphocyte concentration failed to demonstrate prick test positivity between evaluations. Multivariate analysis showed that the variables associated with atopy diagnosis included a personal history of allergic diseases as well as elevated IgE for age and elevated IgE levels. Atopy development in HIV-infected children seems to be modulated by genetic and environmental factors as well as immunological condition.

Briakinumab.

BACKGROUND: Psoriasis is a chronic, autoimmune, T-cell mediated, inflammatory disease. An improved understanding of the pathogenesis of the autoimmune response has led to the development of targeted biologic therapies. Briakinumab is a human monocolonal antibody that blocks the activity of the cytokines IL-12 and IL-23. Immune dysregulation has been implicated in multiple inflammatory disorders and briakinumab has been investigated for the treatment of psoriasis, rheumatoid arthritis, inflammatory bowel disease, and multiple sclerosis. OBJECTIVES: This review focuses on briakinumab and its use in chronic plaque-type psoriasis. METHODS: A literature review was performed, searching Medline and the clinicaltrials.gov database for all articles with the keywords ABT-874, IL-12/IL-23 and psoriasis. CONCLUSIONS: Although limited by small sample sizes, length of follow-up, and a lack of direct comparisons with other psoriasis treatments, initial data regarding the safety and efficacy of briakinumab for the treatment of psoriasis is promising. Ongoing Phase III trials may provide additional information regarding the relative efficacy and safety of briakinumab.

Infectious and inflammatory skin diseases in children with HIV infection and their relation with the immune status--evaluation of 127 patients.

Human immunodeficiency virus infection causes changes in the immune system and disease evolution can be partially measured by levels of T CD4(+) lymphocytes. Knowledge of the chronology of skin disease in relationship to the immune status of the patient may help understand the pathogenesis of AIDS. One hundred twenty-seven children were prospectively evaluated for skin diseases and their relationship to immune status. Immunodeficiency in human immunodeficiency virus-infected children was correlated with infectious dermatoses whereas normal CD4(+) T lymphocyte levels was correlated with diseases mediated by hypersensitivity mechanisms.

Molecular diagnosis of leishmaniosis in the Paraná state of southern Brazil.

The objective of the present study was to establish a polymerase chain reaction (PCR) technique for the diagnosis of cutaneous and mucocutaneous leishmaniosis from autochthonous cases in the state of Paraná in southern Brazil as well as imported cases. We sought to determine its utility and accuracy compared with smears and present culture methods. To standardize PCR samples, skin and mucosal punch biopsies from human lesions were performed on patients living in different regions of the Paraná state (76 cases) and other endemic areas of Brazil and Argentina (7 cases). For PCR standardization, two pairs of primers (MP1L/MP3H and B1/B2) were utilized for amplification of the conserved sequences in the minicircle of kinetoplast DNA (kDNA) for the Leishmania braziliensis complex. Two other primer pairs (b1/b2 and a1/a2) were species-specific for L. (V.) braziliensis and L. (V.) amazonensis, respectively. After differential diagnosis, eight patients had clinical diagnosis of the cutaneous ulcer changed to others pathologies such as syphilis, baso-cellular carcinoma, varicose ulcer, ecthyma and paracoccidioidomycosis. Of the 75 patients with cutaneous (CL) and mucocutaneous (MCL) lesions who provided samples, 47 (46 CL + 1 MCL) were diagnosed with leishmaniosis by smear and 57 (52 LC + 5 MCL) were diagnosed by culture methods. In contrast, our PCR technique presented higher accuracy when compared to the direct examination and culture of parasites. PCR is applicable both for CL where all 61 lesions were diagnosed, and MCL where 12 of 14 lesions were diagnosed. This molecular biology technique is also a faster and more specific diagnostic method compared with present parasitological procedures.

Comparative study of histopathological and immunohistochemical findings in skin biopsies from patients with psoriasis before and after treatment with acitretin.

BACKGROUND: Acitretin has been shown to be effective for psoriasis treatment. Its mechanism of action is not completely understood, and there are few studies focusing on histological and immunohistochemical differences before and after treatment of psoriasis with acitretin. METHODS: This is a prospective study of 17 patients with plaque psoriasis treated with acitretin for 4 months with biopsies taken before and after therapy. Histological features and immunohistochemical reactions to cytokeratin (CK) 10, CK16, CK19, Ki67 and CD1a were evaluated and compared. RESULTS: There were nine men and eight women with median age of 47 years. Epidermal thickness, CK16 positivity, Ki67 and CD1a-positive cell index reduced after treatment (p < 0.01). Suprapapillary plate thickness stayed the same (p > 0.05) although the epidermal/suprapapillary thickness ratio was significantly higher before treatment (p < 0.01). CK10 positivity was lower and a thicker basal cell layer was seen in the epidermis before treatment (p < 0.01). CK19 was negative in all cases. CONCLUSIONS: Acitretin therapy improved histological and immunohistochemical features typical of psoriasis. In psoriasis, suprapapillary plates are not thin, but the epidermal/suprapapillary thickness ratio is increased. Basal cell layer is expanded in psoriasis. Langerhans' cells were less frequent after treatment, and that finding has to be investigated further to determine its role in acitretin mechanism of action.

Fatos e mitos sobre imunomoduladores / Facts and myths about immunomodulators

O objetivo deste artigo é discutir alguns fatos dos imunomoduladores modernos que podem ser úteis para o dermatologista clínico. Outro objetivo importante é o de dissipar mitos que possam ter impacto negativo no uso dessas drogas pelo clínico. O foco inicial está em imunomoduladores estimuladores que podem conduzir à acentuação da resposta normal das células imunocompetentes. Para tanto, diversos aspectos associados à regulação do sistema imune e às vias regulatórias das células do sistema imune são mencionados. Discutem-se a regulação aberrante e seu impacto no sistema imune e examina-se a classe de drogas imunossupressoras que têm sua função bem estabelecida. Diversas drogas não foram mencionadas. A razão para isso é o foco do artigo que pretende cobrir os fatos bem estabelecidos ou os mitos que as novas evidências científicas modificaram. Com esse padrão em mente, é provável que exista uma quantidade considerável de similaridade nos conceitos, uma vez que descrevem drogas imunomoduladoras. Nesse contexto, a intenção de fornecer novas perspectivas de como o sistema imune pode ser modulado por essas drogas supera esse problema.

The objective of this article is to discuss some facts of modern immunomodulators that might be useful for clinical dermatology. Moreover, it aims to dispel myths that might have a negative impact on the use of such drugs by clinicians. The primary focus is on immunomodulators that stimulate and may enhance the normal response of immunocompetent cells. Therefore, several aspects associated to immune system regulation, and regulatory pathways of immune cells are also mentioned. Furthermore, aberrant regulation is discussed in the context of immunomodulator use and the impact this has on the immune system. This review also examines the class of immunosuppressive drugs and their wellestablished function. Several drugs were not mentioned since the article focuses on well accepted facts or myths that new scientific evidences have changed. With that in mind, it is likely that there is a considerable amount of similarity in concepts, given that they describe immunomodulating drugs. In this context, the intention to provide important insight into how the immune system can be modulated by theses drugs surpasses this problem.

Acne vulgar: estudo piloto de avaliação do uso oral de ácidos graxos essenciais por meio de análises clínica, digital e histopatológica / Acne vulgaris: a pilot study to assess an oral treatment with essential fatty acids using clinical, digital, and pathological analyses

FUNDAMENTOS: A relação entre acne vulgar, alimentação e terapia com ácidos graxos essenciais é desconhecida, embora esses elementos tenham papel importante na fisiopatogenia dessa dermatose. OBJETIVO: Verificar a resposta clínica da acne vulgar com o uso de ácidos graxos essenciais e quais os melhores métodos de avaliação do tratamento. MÉTODOS: Trinta e um voluntários, dos quais 16 (51,6 por cento) receberam esquema oral rico em ácidos graxos essenciais e 15 receberam placebo (48,4 por cento). Foram utilizadas análises clínica, de auto-avaliação, digital e histológica para avaliação. RESULTADOS: Não houve diferença nas notas subjetivas (p=0,419) e na análise digital (p=0,2187) entre os gupos placebo e produto; houve sugestão de melhora com o uso do produto, pela histopatologia (p=0,087), sem significância pelo teste do qui-quadrado (= 4,878); ausência de correlação estatística entre a análise digital e a nota subjetiva dos voluntários (p=0,127), entre a nota subjetiva e a resposta histopatológica (p=0,438); houve, porém, relação entre a análise histopatológica e a digital (p=0,012). CONCLUSÕES: 1) Para se avaliar o benefício clínico deve-se realizar um estudo com amostra maior; 2) a auto-avaliação do voluntário e a análise digital não puderam discernir o melhor padrão terapêutico para acne vulgar, se medicamento ou placebo; 3) a associação histopatologia-análise digital parece ser a melhor forma de avaliação da qualidade da resposta clínica dessa terapêutica; 4) a histopatolgia parece ser o método mais sensível para avaliar essa modalidade terapêutica.

BACKGROUND: The relation among acne vulgaris, foods and treatment with essential fatty acids is unknown; however essential fatty acids are important in the pathophysiology of acne vulgaris. OBJECTIVES: To verify the clinical response of acne vulgaris with essential fatty acids and to establish the best methods to assess therapy. METHODS: Thirty-one volunteers took part in the study; in that, 16 (51.6 percent) received a product rich in essential fatty acids and 15 (48.4 percent) received a placebo. Clinical examination, volunteer's self-evaluation (subjective score), digital image and pathological evaluation were performed before and after treatment. RESULTS: There was no difference in the subjective score (p=0.419) and digital analysis (p=0.2187) between the product and placebo groups; there was a suggestive sign of improvement based on the pathological examination (p=0.087) but the chi-squared test showed no significance (¼2= 4.878); there was no statistical correlation between digital analysis and subjective score (p=0.127), between the subjective score and pathological examination (p=0.438). However, pathological and digital analyses showed correlation (p=0.012). CONCLUSIONS: 1) further studies with larger samples should be used to evaluate the clinical benefit; 2) self-evaluation and digital analysis were not sufficient to indicate the best therapeutic standard - product or placebo - for acne vulgaris; 3) the correlation between digital and pathological analyses seems to be the best form to assess quality of this therapy; 4) pathological examination seems to be the most sensitive method to evaluate this therapeutic regimen.

Objective evaluation of skin prick test reactions using digital photography.

BACKGROUND: The skin prick test has been used worldwide to determine IgE-mediated hypersensitivity. However, the most current method to record this reaction has problems with accuracy and precision. OBJECTIVE: To demonstrate a new approach to measure the skin prick reaction and its kinetics with precision. METHODS: The skin prick test was induced using histamine or Dermatophagoides pteronyssinus antigen in 80 volunteers aged 4 and 67 years who had different skin colors. Digital photographs were obtained at 0, 3, 5, 10, 15 and 20 min. The mean wheal and erythema area as well as the erythema intensity were determined using Adobe Photoshop software. The accuracy and precision of this approach were also evaluated. RESULTS: The digital photographic analysis measured the wheal and erythema sizes independent of the antigen or skin color with precision. In addition, a new variable of this test, the skin erythema intensity, could be determined objectively using the chromaticity of reflected light. CONCLUSIONS: Digital photographic analysis is a precise and objective method to evaluate the skin prick test reaction, which can be used independent of the patient's skin color in clinical or research settings.

Papel das células T reguladoras no desenvolvimento de dermatoses / Role of regulatory T cells in the development of skin diseases

Células T, em particular as células T CD4+, têm sido associadas a muitos aspectos das doenças de pele. A evidência atual sugere, porém, que o papel dos linfócitos T CD4+ no desenvolvimento de inflamação cutânea excede o de ativador pró-inflamatório das células T de ação que dirigem a resposta imune. Subtipos de células T com capacidade reguladora, tais como Tregs CD4+CD25+high, têm sido identificadas. Observações recentes sugerem que em algumas doenças da pele a função dessas células está modificada. Portanto, o desenvolvimento e a função de Tregs na dermatologia são atualmente um tópico atraente devido a sua importância no controle da resposta do sistema imune contra tumores e doenças infecciosas, bem como inibindo o desenvolvimento de auto-imunidade e alergia. Assim, mecanismos reguladores defeituosos podem permitir a quebra da tolerância imune periférica seguida por inflamação crônica e doença. Detalham-se as anormalidades funcionais e a contribuição de diferentes subtipos de células T reguladoras no desenvolvimento de doenças dermatológicas nesta revisão. Acentuam-se os possíveis alvos terapêuticos e as modificações dos T reguladores causados por imunomoduladores usados no campo da dermatologia.

Flow cytometry assay for intracellular rabies virus detection.

Following previous studies reporting microbiological diagnosis by flow cytometry, the possibility of using this method was examined to monitor infection of susceptible cell lines by a fixed rabies virus strain (Pasteur Virus strain-PV) or a wild rabies virus strain (WRS). Suspensions of BHK-21 and C6 cells were infected with viruses and a time course of virus infection was established. Sequentially, at several time points, infected and control uninfected cells were fixed, permeabilized, and stained with a rabies virus-specific antibody conjugate. This was achieved by resuspending cells in a solution containing p-formaldehyde in FACS lysis fluid, which allowed the detection of intracellular virus with flourescein-coupled antibodies by flow cytometry. A Becton Dickinson FACSCalibur flow cytometer was used to analyze the percentage of cells infected and the kinetics of the infection process was determined. As early as 12 h after inoculation with both rabies virus strains, significant levels (P<0.01) of infection (from 4.7 to 7.1%) were detected by flow cytometry. The maximum level of infection was obtained at 48 h in C6 cells (88%) with both viruses. The advantages of this method for examination of intracellular virus infection are discussed.