Although some drug eruptions have histologic patterns that make them easily diagnosed, in most patients histology is ‘‘non-specific’’ or ‘‘non-diagnostic’’. In a study published in the December issue of the Journal of the American Academy of Dermatology the authors have made a revision of the of cutaneous drug eruptions diagnosed over a 5-year period. A total of 104 cases were included in the study. In 83% of the cases, the suspected drug or drugs could be narrowed to 3 or fewer. The two most frequent classes of drug associated with the appearance of a rash were antibiotics (45%) and antiepileptics (15%). 94% of the rashes were morbiliform. Most of the biopsies (80%) showed superficial dermal inflammatory infiltrates in a combined perivascular and interstitial pattern. There were interface changes in 53% of the biopsies. The inflammatory infiltrates was composed of lymphocytes only in 32% of the cases, lymphocytes and eosinophils in 29% of the cases, lymphocytes and neutrophils in 10% of the cases, and lymphocytes, neutrophils and eosinophils in 21% of the cases. Therefore, 50% of the cases contained eosinophils in the infiltrate. In summary, the finding of superficial infiltrates with or without interface changes, with the presence of eosinophils is the most frequent histologic pattern observed in morbilliform drug eruptions. (more…)

In the November issue of Nature Medicine, a group of researchers from the United States and Belgium have found that there is an imbalanced vascular endothelial growth factor (VEGF) receptor 1 (VEGFR1) and VEGF receptor 2 (VEGFR2) function in hemangiomas that could be one of the implicated mechanisms underlying endothelial cell growth in these tumors. In normal endothelial cells VEGF usually binds to VEGFR1 with higher affinity than to VEGFR2. VEGFR1 would act as a regulator of VEGF levels and would decrease VEGFR2 activity on endothelial cells. By contrast, the endothelial cells in hemangiomas have mutations in several genes and this results in the expression of several aberrant proteins complexes (that contain beta-1 integrin, mutated VEGFR2, and TEM8 among others).These aberrant protein complexes in turn decrease the activity of nuclear factor of activated T cells (NFAT), and this results in turn in that much less VEGFR1 is expressed on these cells. As VEGFR1 is a regulator of VEGF levels, then there is more VEGF that is going to bind to VEGFR2, resulting in an increased endothelial cell growth.

All these findings suggest that antibodies directed against the VEGF, inhibitors of VEGFR2 tyrosine kinase or other agents inhibiting the different components of these signaling pathway (VEGFR2, TEM8, beta1 integrin and NFAT) could be used in the future as promising target-directed therapies for hemangiomas. (more…)

They studied a patient that had remained free of melanoma 10 years after the infusion of a clone of tumor-infiltrating lymphocytes (TIL). These T-cells cells are obtained from the tumor of a patient with late-stage melanoma. They are cultured in vivo, expanded in sufficient numbers, and then infused to different melanoma patients. In this patient the researchers found that the T-cell line recognized a specific antigen that could be found in all melanoma cell lines and, to a lower extent, melanocytes. They named this protein MELOE-1 (melanoma-over expressed antigen-1).

Subsequently, they found that 5 out of 9 patients treated with TILs that did not had relapse had been infused with TILs that contained MELOE-1–specific T cells. In contrast none of the 21 patients treated with TILs who relapsed had been infused with MELOE-1–specific T cells.

These interesting findings suggest that MELOE-1 can be a promising antigenic target for immunotherapy of melanoma in the near future. (more…)

The gene on chromosome 20p11 has not been identified but it is probable that it harbors an androgen-independent pathway in androgenetic alopecia that may be the target of future therapies. (more…)

Recently, selective inhibitors of intracellular tyrosine kinases have been evaluated as novel antifibrotic approaches. Imatinib mesylate (Gleevec, Novartis) is a small molecule tyrosine kinase inhibitor that blocks two major pro-fibrotic pathways activated in fiibrosing conditions by inhibiting two important tyrosine kinases: c-Abl, a downstream signal in the TGF-beta and PDGF pathways, and the PDGF receptors. Experimental studies have shown that imatinib inhibits collagen synthesis, prevents experimental fibrosis induced by bleomycin, and i by a reduction in thenhibits the proliferation of normal and scleroderma fibroblasts.

Several case reports suggesting the efficacy of this drug in systemic sclerosis, sclerodermatous graft-versus-host disease, and nephrogenic systemic fibrosis have been published in the last few months. For this reason several clinical trials have been started and we will have to wait for these results to know if we are entering in a promising new era of anti-fibrotic therapies.

1. Sfikakis PP, Gorgoulis VG, Katsiari CG, Evangelou K, Kostopoulos C, Black CM. Imatinib for the treatment of refractory, diffuse systemic sclerosis. Rheumatology (Oxford). 2008; 47:735-7.

2. van Daele PL, Dik WA, Thio HB, van Hal PT, van Laar JA, Hooijkaas H, van Hagen
PM. Is imatinib mesylate a promising drug in systemic sclerosis? Arthritis Rheum 2008; 58:2549-52.

3. Magro L, Catteau B, Coiteux V, Bruno B, Jouet JP, Yakoub-Agha I. Efficacy of imatinib mesylate in the treatment of refractory sclerodermatous chronic GVHD.
Bone Marrow Transplant. 2008 Sep 1. [Epub ahead of print]

4. Moreno-Romero JA, Fernández-Avilés F, Carreras E, Rovira M, Martínez C, Mascaró JM Jr. Imatinib as a potential treatment for sclerodermatous chronic graft-vs-host disease. Arch Dermatol 2008; 144:1106-9.

5. Kay J, High WA. Imatinib mesylate treatment of nephrogenic systemic fibrosis.
Arthritis Rheum. 2008; 58:2543-8.

In a recent study published in the Archives of Disease in Childhood, a group of Swedish investigators have found that introducing fish in the diet of babies before they are nine months old may cut their risk of developing AD.

The investigators followed the children from a cohort of 8176 families, who were sent a questionnaire about diet and home environment when the children were six months of age. These families were then sent another questionnaire when the child was twelve months of age. 4941 families completed the two questionnaires. The prevalence of eczema was13% at six months, and 20% at twelve month.

Genetic factors were found to be the most important risk factor for developing eczema, as having either the mother or a sibling with eczema doubled the risk of a child to develop eczema. Breast feeding, the age at which dairy products were introduced, and the presence of a furry pet in the home had no detectable influence on eczema. Interestingly, the introduction of fish into the diet before nine months diminished the risk of developing eczema by 25 percent compared with children who never ate it. There was no link with the amount of fish or type of fish. Although one explanation might be that fish is rich in omega-3 fatty acids, the investigators found no differences between children who ate white fish, and those who ate other types of fish richer in omega-3. (more…)

This medical board recommends to screen for TB by using tuberculin skin tests all patients before initiating any of the TNF antagonists. In additio these authors recommend that this also should be done ton any patient before initiating any immunosuppressive medication (such as methotrexate, cyclosporine, alefaceft, or efalizumab). This would not be needed for topical therapies or phototherapy.

Tuberculin skin tests are considered positive if there is an induration equal or greater than 5 mm at 48 hours. Some person might have false negative tests due and in Europe anergy testing and ‘‘booster’’ tuberculin tests are recommended, but this is not the current practice in the United States. The wholeblood interferon-g release There are more sensitive and specific assays based in whole-blood interferon-gamma release. These can be positive in individuals with latent TB whose tuberculin skin tests are negative, or help to diagnose a latent TB in patients with a history of BCG vaccination (where a positive tuberculin skin test is the rule). However these assays are not widely available.

When these tests are positive and an active TB has been ruled out (by chest radiograph), TB infection prophylaxis with 9 months of isoniazid (preferred) or 4 months ryphampycin has to be started. Treatment with TNF antagonists should be initiated only after 1-2 months ot prophylaxis has been done. (more…)

Therefore NMSC may be a clinical marker of cancer risk. This may be due to an inadequate ability to repair DNA, or alternatively, ultraviolet radiation exposure that causes NMSC may induce some degree of immunosuppression resulting in an increased risk for internal cancers, as well as of NMSC. (more…)

They observed that the relative risk (compared with placebo) of PASI 75 achievement was, respectively, 4, 7, 12 and 19 for maintenance doses of alefacept, efalizumab, etanercept and infliximab. In addition, they calculated that the number needed to treat to obtain at least a patient with a PASI 75 improvement was 8 for alefacept, 4 for efalizumab, 3 for etanercept, and 2 for infliximab. Therefore they found that the efficacy of these treatments was in decreasing order of rank: infliximab, etanercept, efalizumab and alefacept. The authors stress that these were not head to head trials, and therefore future studies will add more information on these data of efficacy.

When dealing with safety the authors found that there was a statistically significant increased risk of adverse events (compared with placebo) with alefacept (9% more), efalizumab (15% more), and infliximab (18% more). Common adverse events with with alefaceft were pharyngitis, chills and headache. Severe adverse events were uncommon, but they found coronary artery disorder (n = 4), cellulitis (n = 3) and myocardial infarction (n = 3). For efaluzimab they found that common adverse events were headaches, infection and chills. Severe adverse events from efaluzimab reported in FDA reviews included hospitalization for psoriasis flare (n = 17), serious infection (n = 7), and thrombocytopenia (n = 5). Etanercept common adverse events included injection-site reaction, headache and upper respiratory tract infection. The most common severe adverse events in etanercept treated patients were malignancy (n = 10), serious infection (n = 4) and worsening psoriasis (n = 3). Infliximab common adverse events were upper respiratory tract infection, headache, increased hepatic enzymes and infection. Some of the most common severe adverse events reported with infliximab were malignancy (n = 12), serious infection (n = 6), serious infusion reaction (n = 4) and lupus-like syndrome (n = 4). The authors calculated that the number needed to harm (this is the total number of patients that had to be treated to get any adverse event) was 15 for alefacept, 9 for efalizumab, 46 for etanercept, and 9 for infliximab. Therefore they found that the safety of these treatments was in decreasing order of rank: etanercept, alefacept, efalizumab, and infliximab.

Limitations of this study include that it has been done on a short term treatment basis (most are only 12 weeks), and that there is a short follow-up for adverse events (10–30 weeks). It is based on clinical trials and does not fully reflect ‘real life’ treatments.

(more…)

To explore the potential association between the risks of developing psoriasis for the first time with the intake of beta-blockers or other antihypertensive drugs a group from Switzerland performed a large case-control study that was recently published in the British Journal of Dermatology. The authors used a large database from general practitioners in the U.K. They identified 36.702 patients who had been diagnosed of psoriasis for the first time between 1994 and 2005, and used the same number of matched controls. They assessed the exposure history for beta-blockers, angiotensin-converting enzyme inhibitors, angiotensin II antagonists, calcium channel blockers, diuretics or clonidine.

The authors found that there was no increased risk of psoriasis among patients that used any of the antihypertensive medications. In relation to beta-blokers they found that current long-term use of these medications was associated with a relative risk estimate of 1,10 (95% CI 1,01–1,20). So, in conclusion this large study does not support that the use of beta-blocker may induce the development or trigger psoriasis. (more…)

The investigators (from several centers across the US) studied a cohort of 463 men aged 18-40, who reported having sex with a woman in the preceding year. These men completed a questionnaire, and were sampled for HPV DNA on genital and anal skin using PCR based techniques. When HPV was detected further genotyping was done.

241 of the men were excluded (if they acknowledged having had sex with men or had not been asked or had refused to answer questions about it.or did not answer the question). Of the 222 men that were finally included in the study anal HPV infection was found in 24.8% (n=55). Of these 55 men, 29.1% (n=16) had only an anal infection while most of them (70.9%, n= 39) had both an anal and another anatomical site (or semen) infection. Only nine men had warts (reported by clinician) at any site, and none had visible lesions at anal sites. Oncogenic HPV were found in 5.9% of men with anal infection, but in men with anal canal infection this rate rose up to 33.3%.

Risk factors associated with anal HPVinfection were the lifetime number of female sex partners and the frequency of sex with females during the preceding month.

In summary the data from this study show that about one in four heterosexual men can be infected by HPV and, that in many cases, these can be of the oncogenic subtypes. These data are important because many physicians do not consider anal HPV infection an important issue in heterosexual men or in men non-infected by the HIV. (more…)

The patient was a 52 year old man with melanoma who had lung and abdominal metastases that had not responded to high-dose interferon-alpha, interleukin-2, and local excision. T cells were extacted from the patient’s blood and co-cultured in vitro with autologous dendritic cells primed to recognize one melanoma antigen called NY-ESO-1. A CD4-positive T-cell clone specific for NY-ESO-1 was isolated and grown in vitro. The expanded cells were infused to the patient, who developed transient lymphopenia, low-grade fever, and myalgia for 3 days. Two months after the infusion the patient was disease-free, and is disease free after two years of follow-up. (more…)

Psoriasis Vulgaris Lesions Contain Discrete Populations of Th1 and Th17 T Cells

Lowes MA, et al

Journal of Investigative Dermatology 2008; 128:1207–1211.

The importance of T helper 17 (Th17) cells in inflammation and autoimmunity is now being appreciated. We analyzed psoriasis skin lesions and peripheral blood for the presence of IL-17-producing T cells. We localized Th17 cells predominantly to the dermis of psoriasis skin lesions, confirmed that IL-17 mRNA increased with disease activity, and demonstrated that IL-17 mRNA expression normalized with cyclosporine therapy. IL-22 mRNA expression mirrored IL-17 and both were downregulated in parallel with keratin 16. Th17 cells are a discrete population, separate from Th1 cells (which are also in psoriasis lesions), and Th2 cells. Our findings suggest that psoriasis is a mixed Th1 and Th17 inflammatory environment. Th17 cells may be proximal regulators of psoriatic skin inflammation, and warrant further attention as therapeutic targets.