Safety and Tolerability of Tumor Necrosis Factor-α Inhibitors in Psoriasis: A Narrative Review

Tumor necrosis factor (TNF)-α inhibitors are an alternative to oral systemic therapies for psoriasis. Data regarding the safety of TNF-α inhibitors from randomized clinical trials may not fully reflect the effects on the clinic patient population receiving the therapy, but other sources of information are available. We performed a literature review to assess the safety and tolerability of the treatment of moderate-to-severe plaque psoriasis with TNF-α inhibitors. A literature search was conducted using PubMed for articles dating from January 2000 to October 2013. Randomized controlled, cohort, open-label, and observational studies were included, as well as case reports and letters to the editor. Articles found on PubMed describing the safety of anti-TNF-α therapy in psoriasis patients were included, while studies highlighting interleukin (IL)-12 and IL-23 inhibitors were excluded, as were non-English articles. In total, 58 articles were included in the review. TNF-α inhibitors exhibit both efficacy and tolerability in patients with moderate-to-severe plaque psoriasis. Adverse effects associated with these medications are not common and can be minimized with routine clinical monitoring and patient education. While the risk of severe adverse events is low, the lack of very large, long-term, randomized safety trials limits the ability to fully define the safety of these agents. TNF-α inhibitors have a good efficacy/safety ratio for use in patients with moderate-to-severe psoriasis. Serious adverse effects are not common, and common injection-site reactions are usually manageable. The benefits of TNF-α inhibitors outweigh the risks for moderate-to-severe psoriasis; however, there are potential adverse effects and the patient populations at highest risk include the elderly and those with a history of malignancy.     

Is It Possible to Discontinue Tumor Necrosis Factor Antagonists after Psoriasis Remission?

Tumor necrosis factor (TNF) antagonists are highly effective treatments for psoriasis. These agents provide the opportunity to improve disease activity and achieve clinical remission. Despite its efficacy, long-term use of biologics is associated with high financial costs and possibly life-threatening adverse events. Recently, there has been an increasing interest in discontinuing TNF antagonists in patients with psoriasis who have achieved a positive clinical response. However, there is a paucity of data and clinical guidelines concerning the cessation TNF antagonists in psoriasis treatment. Several factors, including cost, subsequent treatment efficacy, relative risks, and tolerability, should be considered before the decision is made to discontinue TNF antagonists. Well-designed clinical trials are necessary to identify factors that may trigger disease exacerbation after medication discontinuation in order to recognize the potential disadvantages of discontinuing treatment in patients who are previously successfully managed on TNF antagonists.     

A Case of Tumor Necrosis Factor-�� Inhibitors-induced Pustular Psoriasis

Anti-tumor necrosis factor (TNF)-α agents promise better disease control for the treatment of ankylosing spondylitis resistant to classical disease-modifying treatments. Etanercept, a recombinant human TNF receptor fusion protein, is used to treat a variety of TNF-α-mediated diseases by inhibiting the biological activity of TNF-α. We experienced a case of pustular psoriasis in a 32-year-old man during anti-TNF-α therapy with etanercept. He had a history of ankylosing spondylitis for 2 years. Two years after treatment of etanercept, erythematous pustules developed on his palms and soles. He had no previous history of pustular psoriasis. The skin lesion improved as the etanercept therapy was stopped, but pustular skin eruption recurred as adalimumab, a different TNF-α inhibitor, was administered to manage his ankylosing spondylitis. Several TNF-α inhibitors have different molecular structures, but these inhibitors might have a similar potency to induce pustular psoriasis from this case.     

The Role of Tumor Necrosis Factor-α in the Pathogenesis of Vitiligo

Vitiligo is an acquired immune disorder of the skin characterized by the presence of white depigmented macules. Its immunopathogenesis is not completely understood, but inflammatory alterations in the skin microenvironment, and particularly increased expression of the cytokine tumor necrosis factor-α (TNFα), are thought to be essential regulators of melanocyte dysfunction and death. In this article we review the evidence that implicates TNFα in the pathogenesis of vitiligo, including studies on serum and tissue levels of TNFα, TNFα gene polymorphisms, in vitro studies, and therapeutic trials using TNFα inhibitors. TNFα emerges as a complex mediator with apparently conflicting roles in vitiligo.     

Tumor Necrosis Factor-α Inhibitor-Induced Psoriasis or Psoriasiform Exanthemata

Tumor necrosis factor-alpha (TNFalpha) inhibition is effective in the treatment of moderate-to-severe psoriasis. We report on 120 patients from the literature including six new patients (three women and three men) who developed pustular lesions during treatment with TNFalpha inhibitors. We identified 72 women and 36 men (several papers did not specify the gender of patients) with an age range of 13-78 years (mean 42.3 years). The primary diagnoses were rheumatoid arthritis (n = 61), ankylosing spondylitis (n = 21), psoriasis (n = 10), Crohn disease (n = 8), SAPHO (synovitis acne pustulosis hyperostosis osteitis) syndrome (n = 3), psoriatic arthritis (n = 2), and other diagnoses (n = 15). Psoriasis (except palmoplantar pustular type) was the most common adverse effect during anti-TNFalpha treatment (n = 73), followed by palmoplantar pustular psoriasis (n = 37) and psoriasis of the nail (n = 6), sometimes combined in the same patient. Palmoplantar pustulosis and psoriasiform exanthema was the diagnosis in ten patients each. A positive personal history of psoriasis was recorded in 25 patients. A positive family history was noted in eight patients. No data about personal (n = 7) or family history (n = 46) were available in a number of patients. Newly induced psoriasis was diagnosed in 74 patients whereas an exacerbation or aggravation of a pre-existing psoriasis was noted in another 25 patients. All three TNFalpha inhibitors available on the market were involved: infliximab (63 patients), etanercept (37 patients), and adalimumab (26 patients). Several patients were treated with more than a single TFNalpha inhibitor. The timing of cutaneous adverse effects (psoriasis and psoriasiform rash) varied considerably among patients, ranging from after a single application to a delayed response of up to 63 months after initiation of treatment. The mean time to appearance of the cutaneous adverse effect for all TNFalpha inhibitors was 9.5 months. Cessation of the responsible TNFalpha inhibitor was carried out in 47 patients either alone or in association with adjuvant anti-psoriatic therapy (mostly topical). This resulted in complete remission in 21 patients, partial remission in 20 patients, and stable disease in another three patients; in the other three patients, the outcome was not reported. TNFalpha inhibition was continued in 47 patients but anti-psoriatic adjuvant therapy was introduced. The outcome in this group was complete remission in 22 patients, partial remission in 25 patients, and stable disease in 2 patients. The response rate (complete remission plus partial remission) was 93.2% and 95.9%, respectively, in each group. In six patients, switching from one TNFalpha inhibitor to another one immediately after cutaneous adverse effects occurred resulted in an improvement in five patients. In nine patients, a second TNFalpha inhibitor was initiated after a break in TNFalpha inhibition. The response to a second or third drug in these patients was mixed. The underlying pathomechanisms of induction of psoriasis or psoriasiform exanthemata by TNFalpha inhibitors remain elusive but there is reason to assume that induction of such adverse events has more than one pathophysiology.     

Dermatological Side Effects of Epidermal Growth Factor Receptor Inhibitors: ‘PRIDE’ Complex

Epidermal growth factor receptor (EGFR) inhibitor therapy has become the standard treatment for non-small cell lung cancer and head neck malignancy. This class of drug comprises EGFR inhibitors (erlotinib and gefitinib) and monoclonal antibody (cetuximab). Use of this class of drugs has been associated frequently with dermatological side effects termed as PRIDE complex–Papulopustules and/or paronychia, Regulatory abnormalities of hair growth, Itching, Dryness due to EGFR inhibitors. We hereby report the cutaneous side effects of EGFR inhibitor therapy in 15 patients of lung and head/neck cancer. The major clinical findings being acneiform eruption and severe xerosis of skin. Management of these dermatological adverse effects rarely requires discontinuation of targeted therapy and can be managed symptomatically.     

Effect of photodynamic treatment on the secretion of tumor necrosis factor α by human vascular endothelial cells

Objective To measure the changes in levels of tumor necrosis factor α(TNF-α) secreted by human endothelial cells EC-304 after hematoporphyrin monomethyl ether-photodynamic treatment (HMME-PDT),and to explore the relationship between cytokines and inflammation initiation after management of nevus flammeus with photodynamic therapy.Methods EC-304 cells were cultured in 6-well plates,and classified into 4 groups:HMME-PDT group pretreated with HMME followed by irradiation with laser,HMME control group treated with HMME only,laser control group irradiated with laser only,and blank control group without any treatment.Culture supematants of EC-304 cells were collected from HMME-PDT group at 12,24 and 48 hours after the irradiation,and from the other three groups at the same time points.The supernatant TNF-α level was measured with enzyme linked immunosorbent assay (ELISA).Results The difference was statistically significant in the supernatant TNF-α level between different time points in each group (F=62.276.P<0.01) and between the 4 groups at each time point (F=11.538,P<0.01).Multiple comparison analysis showed that HMME-PDT group differed significantly from the other 3 control groups in the supernatant TNF-αlevel at each time point (all P<0.01),while no significant difierence was observed among the other three control groups at any time point (all P>0.05).Conclusion HMME-PDT promotes the secretion of TNF-α by EC-304 cells.     

Effect of photodynamic treatment on the secretion of tumor necrosis factor α by human vascular endothelial cells

Objective To measure the changes in levels of tumor necrosis factor α(TNF-α) secreted by human endothelial cells EC-304 after hematoporphyrin monomethyl ether-photodynamic treatment (HMME-PDT),and to explore the relationship between cytokines and inflammation initiation after management of nevus flammeus with photodynamic therapy.Methods EC-304 cells were cultured in 6-well plates,and classified into 4 groups:HMME-PDT group pretreated with HMME followed by irradiation with laser,HMME control group treated with HMME only,laser control group irradiated with laser only,and blank control group without any treatment.Culture supematants of EC-304 cells were collected from HMME-PDT group at 12,24 and 48 hours after the irradiation,and from the other three groups at the same time points.The supernatant TNF-α level was measured with enzyme linked immunosorbent assay (ELISA).Results The difference was statistically significant in the supernatant TNF-α level between different time points in each group (F=62.276.P<0.01) and between the 4 groups at each time point (F=11.538,P<0.01).Multiple comparison analysis showed that HMME-PDT group differed significantly from the other 3 control groups in the supernatant TNF-αlevel at each time point (all P<0.01),while no significant difierence was observed among the other three control groups at any time point (all P>0.05).Conclusion HMME-PDT promotes the secretion of TNF-α by EC-304 cells.