Over the last years, biologic therapies have emerged in the treatment of psoriasis. T lymphocytes and several cytokines responsible for the inflammation in psoriasis are the target of these molecules. One of these cytokines is tumor necrosis factor (TNF), a key molecule in several inflammatory and immune responses that can be blocked by fusion proteins such as etanercept (Enbrel), or monoclonal antibodies such as infliximab (Remicade) or adalimumab (Humira). Anti-TNF agents are considered immunosuppressants, and there are concerns and precautions that have to be kept in mind in patients treated with them. There is an increased risk of some opportunistic infections (such as latent tuberculosis), and there is also a concern that there may be an increased risk of cancers with the long-term use of these drugs.

In a recent study published in the October issue of Arthritis and Rheumatism, a group of Swedish researchers analyzed data from 6,366 rheumatoid arthritis patients who started treatment with either infliximab, adalimumab, or etanercept between January 1999 and July 2006. This group was compared with other groups of patients: 61,160 not taking any medication, 4,015 taking methotrexate, and 4,105 taking combinations of disease-modifying anti-rheumatic drugs (but not anti-TNF agents). The authors found a total of 240 first primary cancers occurred among 6,366 patients treated with anti-TNF agents. Among the anti-TNF naïve patients the authors found 4,244 cancers in patients who did not have a history of cancer at start of the study. The relative risk was 1.00 (95% confidence interval, 0.87-1.17). This relative risk remained unchanged for those taking immunosuppressant drugs for up to six years. The authors conclude that the overall cancer risk was the same for rheumatoid arthritis patients on immunosuppressant therapies and those not taking medications for the disease. These results are interesting for dermatologist as they may also be applicable to patients with psoriasis treated with anti-TNF agents. (more…)

The introduction of the new biological therapies have revolutionized the treatment of patients with several inflammatory diseases (such as rheumatoid arthritis, inflammatory bowel disease, and psoriasis) biological therapies inflammatory bowel disease. While these therapies have proven efficacy, they are not without significant side effects due to their actions on the immune system, increasing the possibility of the patients to develop several types of infections and neoplasms.

Among the most effective in treating psoriasis are several drugs that target the cytokine protein TNF, such as infliximab, adalimumab, and etanercept. These drugs have collectively been called anti-TNF therapies, and one of the main concerns (with the monoclonal antibodies against TNF, infliximab and adalimumab, in particular) is that these patients have a higher incidence of tuberculosis than the general population. This makes mandatory to perform latent tuberculosis screening in patients with psoriasis who are planned to be treated with these drugs.

In a recent study published in the May 2009 issue of the Journal of Clinical Investigation, a group of German researchers investigated the immune cells of patients with rheumatoid arthritis before and after treatment with infliximab to try and identify the mechanisms underlying the association between anti-TNF therapy and tuberculosis. The authors found that anti-TNF therapy reduced lymphocyte expression of perforin and granulysin, two components of the T cell-mediated antimicrobial response to intracellular pathogens. They found that subset of effector memory CD8+ T cells characterized by the expression of the protein CD45RA expressed the highest levels of granulysin. The authors called these CD8+CCR7–CD45RA+ effector memory T cells “TEMRA cells”.

TEMRA cells were found to lyse Mycobacterium tuberculosis and infected macrophages, and mediate an antimicrobial attack against M. tuberculosis. They also express membrane TNF and bind to anti-TNF antibodies. During the first 2 weeks of treatment with infliximab TEMRA cells decreased by an average of 29%. Moreover, monocytes isolated from patients and infected with M. tuberculosis showed that peripheral blood mononuclear cells limited bacterial growth more efficiently before than during infliximab therapy. When peripheral blood mononuclear cells from infliximab-treated patients were replenished with autologous TEMRA cells their ability to limit M. tuberculosis growth was restored.

The authors conclude that the loss of this immune cell subset provides a mechanism to explain the reactivation of latent tuberculosis infection in patients treated with infliximab. (more…)

Nail involvement is a very frequent event in psoriasis, and in some patients it may be the only sign of psoriasis. It manifests as pitting, salmon patches, onycholysis, nail thickening, and nail bed hyperkeratosis. Although nail psoriasis is common, there are not many treatments that have been proven to be effective in this condition. In a recent study from Italy published in the Archives of Dermatology, Tosti and coworkers have found low-dose acitretin to be very effective in isolated nail psoriasis. They treated 36 patients with moderate to severe nail psoriasis with 0.2 to 0.3 milligrams of acitretin per kilogram for 6 months. Patients were evaluated using the Nail Psoriasis Severity Index (NAPSI), with higher NAPSI scores indicating more severely affected nails. They found that the mean percentage of reduction of the NAPSI score and of a modified NAPSI score were 41 percent and 50 percent, respectively. Nine patients (25 percent) had complete or almost complete clearing, 9 (25 percent) had a moderate improvement, 12 (33 percent) had mild improvement and 6 (11 percent) had no improvement. There was a 46% reduction of the NAPSI score for the target nail after 20 weeks of acitretin. These results are similar to those found with other agents, such as biologic therapies. In previous studies it has been found that with infliximab there is a NAPSI reduction of 57% at 24 weeks, and with adalimumab there is a NAPSI reduction of 69% at 20 weeks. This study suggests that low-dose acitretin could be considered as a first-line therapy for nail psoriasis. (more…)

Tumor necrosis factor (TNF) antagonists (infliximab, etanercept, and adalimumab) are new medications that have proven to be very effective in the treatment of psoriasis. However all these medications have been implicated in an increased rate of tuberculosis (TB) infection, th to reactivation of latent TB infection. For this reason screening for latent of active or latent TB has been recommended in these patients. In a recent publication at the Journal of the American Academy of Dermatology the medical board of the National Psoriasis Foundation (a patient-driven non-profit organization form the United States) has made a consensus statement based on an extensive review of the literature.

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…)

Several new biological agents have been introduced for the treatment of psoriasis in the last few years. These include alefaceft, efalizumab, and the anti-TNF agents etanercept, infliximab, and adalimumab. In a recent paper from Brimhall et al published in the August issue of the British Journal of Dermatology, the authors performed a metha-analysis on the safety and efficacy of all these agents (except adalumimab, that was not approved for this indication when the study was done). They searched for randomized, controlled, double-blind, monotherapy trials that had been done until July 2006 , and finally selected 16 studies including 7931 patients (5454 treatment and 2477 placebo patients): 3 trials of alefacept (n = 1289), 5 trials of efalizumab (n = 3130), 4 trials of etanercept (n = 2017) and 4 trials of infliximab (n = 1495).

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.

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