Topical tacrolimus for atopic dermatitis.

BACKGROUND: Atopic dermatitis (AD) (or atopic eczema) is a chronic inflammatory skin condition that affects children and adults and has an important impact on quality of life. Topical corticosteroids (TCS) are the first-line therapy for this condition; however, they can be associated with significant adverse effects when used chronically. Tacrolimus ointment (in its 2 manufactured strengths of 0.1% and 0.03%) might be an alternative treatment. Tacrolimus, together with pimecrolimus, are drugs called topical calcineurin inhibitors (TCIs). OBJECTIVES: To assess the efficacy and safety of topical tacrolimus for moderate and severe atopic dermatitis compared with other active treatments. SEARCH METHODS: We searched the following databases up to 3 June 2015: the Cochrane Skin Group Specialised Register, CENTRAL in the Cochrane Library (Issue 5, 2015), MEDLINE (from 1946), EMBASE (from 1974), LILACS (from 1982), and the Global Resource of Eczema Trials (GREAT database). We searched six trials registers and checked the bibliographies of included studies for further references to relevant trials. We contacted specialists in the field for unpublished data.A separate search for adverse effects of topical tacrolimus was undertaken in MEDLINE and EMBASE on 30 July 2013. We also scrutinised the U.S. Food and Drug Administration (FDA) websites for adverse effects information. SELECTION CRITERIA: All randomised controlled trials (RCTs) of participants with moderate to severe atopic dermatitis (both children and adults) using topical tacrolimus at any dose, course duration, and follow-up time compared with other active treatments. DATA COLLECTION AND ANALYSIS: Two authors independently screened and examined the full text of selected studies for compliance with eligibility criteria, risk of bias, and data extraction. Our three prespecified primary outcomes were physician's assessment, participant's self-assessment of improvement, and adverse effects. Our secondary outcomes included assessment of improvement of the disease by validated or objective measures, such as SCORAD (SCORing Atopic Dermatitis), the EASI (Eczema Area and Severity Index), and BSA (Body Surface Area) scores. MAIN RESULTS: We included 20 studies, with 5885 participants. The variability of drug doses, outcomes, and follow-up periods made it difficult to carry out meta-analyses.A single trial showed that tacrolimus 0.1% was better than low-potency TCS by the physician's assessment (risk ratio (RR) 3.09, 95% confidence interval (CI) 2.14 to 4.45, 1 study, n = 371, moderate-quality evidence). It was also marginally better than low-potency TCS on face and neck areas and moderate-potency TCS on the trunk and extremities by the physician's assessment (RR 1.32, 95% CI 1.17 to 1.49, 1 study, n = 972, moderate level of evidence) and for some of the secondary outcomes. Compared with pimecrolimus 1%, people treated with tacrolimus were almost twice as likely to improve by the physician's assessment (RR 1.80, 95% CI 1.34 to 2.42, 2 studies, n = 506, moderate quality of evidence). Compared with the lower concentration of 0.03%, the tacrolimus 0.1% formulation reduced the risk of not having an improvement by 18% as evaluated by the physician's assessment (RR 0.82, 95% CI 0.72 to 0.92, 6 studies, n = 1640, high-quality evidence). Tacrolimus 0.1% compared with moderate-to-potent TCS showed no difference by the physician's assessment, and 2 secondary outcomes (1 study, 377 participants) and a marginal benefit favouring tacrolimus 0.1% was found by the participant's assessment (RR 1.21, 95% CI 1.13 to 1.29, 1 study, n = 974, low quality of evidence) and SCORAD.Based on data from 2 trials, tacrolimus 0.03% was superior to mild TCS for the physician's assessment (RR 2.58, 95% CI 1.96 to 3.38, 2 studies, n = 790, moderate-quality evidence) and the participant's self-assessment (RR 1.64, 95% CI 1.41 to 1.90, 1 study, n = 416, moderate quality of evidence). One trial showed moderate benefit of tacrolimus 0.03% compared with pimecrolimus 1% on the physician's assessment (RR 1.42, 95% CI 1.02 to 1.98, 1 study, n = 139, low-quality evidence), but the effects were equivocal when evaluating BSA. In the comparison of tacrolimus 0.03% with moderate-to-potent corticosteroids, no difference was found in most of the outcomes measured (including physician's and participant's assessment and also for the secondary outcomes), but in two studies, a marginal benefit favouring the corticosteroid group was found for the EASI and BSA scores.Burning was more frequent in those using calcineurin inhibitors than those using corticosteroid tacrolimus 0.03% (RR 2.48, 95% CI 1.96 to 3.14, 5 studies, 1883 participants, high-quality evidence), but no difference was found for skin infections. Symptoms observed were mild and transient. The comparison between the two calcineurin inhibitors (pimecrolimus and tacrolimus) showed the same overall incidence of adverse events, but with a small difference in the frequency of local effects.Serious adverse events were rare; occurred in both the tacrolimus and corticosteroid groups; and in most cases, were considered to be unrelated to the treatment. No cases of lymphoma were noted in the included studies nor in the non-comparative studies. Cases were only noted in spontaneous reports, cohorts, and case-control studies. Systemic absorption was rarely detectable, only in low levels, and this decreased with time. Exception is made for diseases with severe barrier defects, such as Netherton's syndrome, lamellar ichthyosis, and a few others, with case reports of a higher absorption. We evaluated clinical trials; case reports; and in vivo, in vitro, and animal studies; and didn't find any evidence that topical tacrolimus could cause skin atrophy. AUTHORS' CONCLUSIONS: Tacrolimus 0.1% was better than low-potency corticosteroids, pimecrolimus 1%, and tacrolimus 0.03%. Results were equivocal when comparing both dose formulations to moderate-to-potent corticosteroids. Tacrolimus 0.03% was superior to mild corticosteroids and pimecrolimus. Both tacrolimus formulations seemed to be safe, and no evidence was found to support the possible increased risk of malignancies or skin atrophy with their use. The reliability and strength of the evidence was limited by the lack of data; thus, findings of this review should be interpreted with caution. We did not evaluate costs.

Lipodystrophy in the patient with HIV: social, psychological, and treatment considerations.

Approximately 1.3 million people in the United States and an estimated 33.2 million worldwide are infected with HIV. In the past, HIV/AIDS was considered to be uniformly fatal. With the introduction of highly active antiretroviral therapy (HAART), HIV has become a chronic, manageable disease in countries that are able to provide this therapy. The preservation of lives has not been without complications. In these patients, metabolic and stereotypical body disfiguring fat changes have emerged and have been lumped under the term lipodystrophy. Lipoatrophy and fat accumulation are generally thought to be separate yet overlapping phenomena. The prevalence rates for lipoatrophy may be as high as 25% to 38%; estimates for fat accumulation vary widely (from 14%-63%). Far from being "purely cosmetic," these fat changes can have a profoundly negative social and psychological impact, causing patients to feel disfigured, isolated, and stigmatized. Further, lipodystrophy may also negatively impact compliance with HAART. While there is evidence that the use of new HIV medications can prevent the development of these fat changes, many patients already manifest fat abnormalities; switching HAART, especially after lipodystrophy has progressed, offers only limited benefit. In addition, many resource-poor nations continue to rely on older HAART out of necessity. Because of this, methods are needed to address disfiguring body shape changes. The authors review the prevalence of lipoatrophy and lipohypertrophy, focusing on the impact on patients as well as reviewing available treatment options.

Cutaneous manifestations of HIV in the era of highly active antiretroviral therapy: an institutional urban clinic experience.

BACKGROUND: Widespread introduction of highly active antiretroviral therapy (HAART) in the mid 1990s has altered the presentation of the cutaneous manifestations associated with HIV infection. OBJECTIVE: Our purpose was to evaluate the use of HAART on the prevalence and spectrum of cutaneous manifestations in HIV-infected patients. METHODS: A study of the initial visits of 897 HIV-infected patients at an urban dermatology clinic between 1996 and 2002 was performed. RESULTS: Folliculitis was the most common cutaneous disorder identified. Patients with CD4-positive cell counts less than 200 cells/mm3 had an increased prevalence of folliculitis and prurigo nodularis, whereas those with HIV viral loads higher than 55,000 copies/mL had a higher prevalence of idiopathic pruritus and candidiasis. Patients not receiving HAART had increased rates of folliculitis and prurigo nodularis. Patients receiving HAART had increased rates of photosensitivity and molluscum contagiosum. LIMITATIONS: This was a cross-sectional study in which temporality was unable to be determined. CONCLUSION: With ongoing therapeutic advancements, the cutaneous manifestations associated with HIV infection will continue to evolve.

Cutaneous drug reactions associated with newer antiretroviral agents.

Skin is the most commonly affected organ in patients with HIV, and the incidence of cutaneous adverse reactions in persons infected with HIV versus those who are not infected is significantly higher. Cutaneous drug reactions contribute to increased morbidity and are often the cause of treatment nonadherence. Undoubtedly, the widespread use of highly active antiretroviral therapy has had a positive effect on the natural course of the disease; however, advances in HIV therapy will continue to increase the potential for cutaneous eruptions, further complicating the evaluation of skin manifestations that are so common in this disease. Distinguishing between cutaneous drug reactions and other cutaneous diseases associated with HIV infection can be challenging. Nevertheless, it is important for clinicians to be knowledgeable about the clinical characteristics and presentations of these reactions and to determine whether drug discontinuation is indicated.

DNA methylation in anal intraepithelial lesions and anal squamous cell carcinoma.

PURPOSE: Anal intraepithelial neoplasia is associated with human papillomavirus infection and may progress to invasive squamous cell carcinoma (SCC), which is increasing in immunocompromised patients. We hypothesize that anal intraepithelial neoplasia is associated with abnormal DNA methylation and that detection of these events may be used to improve screening programs. EXPERIMENTAL DESIGN: Seventy-six patients were identified who underwent anal cytology screening and subsequent biopsy at our institution between 1999 and 2004. The specimens from these patients included 184 anal biopsies [normal, n = 57; low-grade squamous intraepithelial lesion (LSIL), n = 74; high-grade squamous intraepithelial lesion (HSIL), n = 41; and invasive SCC, n = 12] and 37 residual liquid-based anal cytology specimens (normal, n = 11; LSIL, n = 12; HSIL, n = 14). The methylation status of the following genes was determined for each biopsy and cytology sample using real-time methylation-specific PCR: HIC1, RASSF1, RARB, CDKN2A, p14, TP73, APC, MLH1, MGMT, DAPK1, and IGSF4. RESULTS: Methylation-specific PCR analysis of biopsy samples revealed that DNA methylation was more common in SCC and HSIL than LSIL and normal mucosa. Specifically, methylation of IGSF4 and DAPK1 was prevalent in SCC (75% and 75% of cases, respectively) and HSIL (59% and 71%, respectively) but was absent in LSIL and normal biopsy samples. Methylation profiles of cytologic samples were similar to those found in the biopsy samples. CONCLUSIONS: Aberrant DNA methylation is a frequent event in anal HSIL and SCC. Methylation of IGSF4 and DAPK1 is specific for HSIL and SCC, and may serve as a useful molecular biomarker.

Management options for facial lipoatrophy.

Lipoatrophy of the face, limbs, buttocks, and other subcutaneous tissue is increasingly recognized in HIV-infected patients. Although the pathogenesis of lipoatrophy and its association with metabolic abnormalities are becoming better understood with intense research efforts, there are very few treatment options, and the appearance of facial lipoatrophy can be devastating to patients. Treatment strategies include antiretroviral substitution, medications, and dermatologic and surgical interventions. Switching the HAART regimen produces only a modest effect. There are conflicting and generally disappointing data on the benefit of medications such as rosiglitazone. Surgical and dermatologic procedures are available for treatment of facial lipoatrophy, and several facial fillers have gained popularity as a means to restore the facial contour. Most are expensive, require multiple visits, and can produce scars. Temporary fillers require ongoing reapplication, and permanent fillers may sag if lipoatrophy progresses. All require a pure compound and expert technique and can be prohibitively expensive because these procedures are not generally covered by insurance. Prevention and early recognition of lipoatrophy and proper selection or early modification of antiretroviral treatment remain the best options.

Clinical and epidemiologic characterization of photosensitivity in HIV-positive individuals.

BACKGROUND: An increased prevalence and severity of cutaneous photosensitivity has been recognized in association with human immunodeficiency virus (HIV) infection. However, this disorder remains poorly characterized in terms of its epidemiology, predisposing factors, clinical, and environmental associations. METHODS: To define the risk factors associated with the presence of photosensitivity among HIV-positive individuals, a cross-sectional study of 631 primary patient visits to an urban HIV Dermatology clinic between January 1997 and August 2001, inclusive, was conducted. A multivariate model was fit to estimate adjusted odds ratios for risk factors associated with photosensitivity diagnosis. Subsequently, a case-series of the patients with photosensitivity was reported. RESULTS: The overall prevalence of photosensitivity was 5.4%, while African-Americans (AA) exhibited a prevalence of 7.3%. In the multivariate model, using highly active anti-retroviral therapy (HAART) (OR=2.82, 95% CI: 1.13, 7.03) and being AA (OR=6.68, 95% CI: 1.56, 28.65) significantly increased the odds of photosensitivity. Patients with photosensitivity were more likely to present during periods of higher ultraviolet (UV) index (P=0.08). Two distinct clinical morphologies were noted: lichenoid and non-lichenoid, eczematous. Sub-morphologies in the non-lichenoid group were suggestive of differences in immunologic profile and estimated UV exposure. CONCLUSION: Photosensitivity associated with HIV infection is an increasingly recognized dermatologic condition with a heterogeneous clinical presentation. AA ethnicity and HAART were independent indicators for the diagnosis of photosensitivity, whereas CD4+ and UV exposure had non-significant associations. The subtleties in these and other clinical variables may directly aid in the recognition and diagnosis of this poorly characterized disorder.

Disseminated cutaneous acanthamebiasis: a case report and review of the literature.

The genus Acanthamoeba includes species of free-living soil and water ameba that have been implicated in a small number of human diseases. Acanthamoeba species have been identified as the etiologic agents in 2 well-defined clinical entities, amebic keratitis and granulomatous amebic encephalitis (GAE). Less commonly, Acanthamoeba species have been identified as the cause of disseminated disease in debilitated and immunocompromised patients. Cutaneous acanthamebiasis, often a reflection of disseminated disease, is an increasingly recognized infection since the emergence of acquired immunodeficiency syndrome (AIDS) and the use of immunosuppressive drugs. The disease portends a poor prognosis and is uniformly fatal if the infection involves the central nervous system (CNS). We describe a patient with advanced AIDS who presented with disseminated cutaneous lesions, headache, and photophobia, and in whom a diagnosis of cutaneous acanthamebiasis was made based on the results of a skin biopsy. A multidrug therapeutic regimen was begun that included sulfadiazine; the patient responded favorably to treatment. This paper also reviews 36 previously reported cases of cutaneous acanthamebiasis with delineation of clinical, diagnostic, histologic, and prognostic features, as well as discusses treatment options.

Dermatologic diagnoses in the perianal area.

Perianal dermatosis can encompass lesions from benign eczematous processes to advanced malignancies. It is important for the colorectal surgeon to be able to distinguish common problems from more serious pathology. This article covers nonsexually transmitted diseases occurring in the intergluteal fold and perianal region. These include inflammatory dermatoses, bacterial and fungal infections, and other disease processes.

The histopathology of folliculitis in HIV-infected patients.

BACKGROUND: Cutaneous disease referable to human immunodeficiency virus (HIV) infection has become less common with the advent of widespread administration of antiretroviral medications, particularly the protease inhibitors. Pruritic eruptions that fall into the general categorization of folliculitis continue to be problematic. METHODS: In this report, we describe 33 skin biopsy samples prospectively obtained of follicular papules and pustules from 33 HIV-infected individuals with the clinical diagnosis of HIV-related folliculitis. RESULTS: The histopathologic findings were stratified as follows: (i) acute folliculitis with bacteria and/or yeast (n = 9); (ii) lymphocytic perifolliculitis (n = 7); (iii) eosinophilic folliculitis (n = 5); (iv) perifolliculitis with mixed inflammation (n = 11); (v) follicular rupture with predominant granulomatous inflammation (n = 1). Demodex organisms were found in 10 specimens scattered among these categories. CONCLUSIONS: The histopathology of folliculitis in HIV-infected patients is protean. No single factor could be identified as the cause, making targeted antibacterial or antifungal therapy unlikely to be successful across a wide range of patients.