Etanercept for psoriasis: two case reports

Psoriasis is a chronic inflammatory skin disorder. Recent advances in the understanding of its immunological basis have led to its redefinition as being T-cell mediated. New biological agents have been developed as effective selective target therapies and promise to be an alternative to conventional systemic medications. Etanercept is a recombinant human protein recently approved for psoriatic arthritis treatment that has activity against tumor necrosis factor-alpha (TNF-alpha). It is composed of the human TNF receptor linked to the Fc portion of human IgG1. TNF-alpha seems to play a key role in the pathogenesis of psoriasis and psoriatic arthritis. Therefore, etanercept TNF antagonism is an effective approach for severe psoriasis. We describe two case reports of severe recalcitrant psoriasis, also with arthritis, that showed a remarkable improvement with etanercept, with no adverse events.     

Targeting tumor necrosis factor-alpha in the therapy of psoriasis

Tumor necrosis factor-alpha (TNF-alpha) plays a fundamental role in the initiation and persistence of skin inflammation in psoriasis. The best evidence of the essential activity of this cytokine in the pathogenesis of psoriasis came from the observation that selective TNF-alpha blockers are dramatically effective in the therapy of this disease. The TNF-alpha inhibitors, infliximab and etanercept, have been employed with success in moderate to severe psoriasis and in psoriatic arthritis in randomized controlled trials. Anti-TNF-alpha biologicals induce rapid disease resolution and long-lasting remission, suggesting that they may alter the natural course of the disease. Further studies are warranted to more precisely establish the biological bases of the action of anti-TNF-alpha agents, better define which subgroup of patients can benefit most from this treatment, and the modalities of combination therapy with other antipsoriatic agents. Many other TNF-alpha inhibitors have been developed but none of them has been yet used in the therapy of psoriasis. Major limitations to the use of selective TNF-alpha blockers include the reactivation of latent tuberculosis, the risk of opportunistic infections, the development of specific antibodies, which is associated with a reduced duration of response to treatment, and the high cost.     

Pulmonary sarcoidosis associated with etanercept therapy

We present a case of probable pulmonary sarcoidosis associated with the use of etanercept for psoriatic arthritis. Other cases of etanercept-induced granulomas and skin sarcoidosis were recently published in the medical literature, but we found only one case that involved lung sarcoidosis during etanercept therapy. We describe a 40-year-old man who was receiving etanercept for severe psoriatic arthritis and was admitted to the hospital with dyspnea and subfebrile illness several months after the start of treatment. His diagnosis was consistent exclusively with sarcoidosis. The patient's symptoms improved when etanercept was discontinued, but they did not resolve completely. Treatment with prednisone 40 mg led to complete improvement of his pulmonary disease. Etanercept therapy can induce or exacerbate sarcoidosis. The disease disappears when etanercept is discontinued, although treatment with corticosteroids is sometimes required, as in our patient. Use of the Naranjo adverse drug reaction probability scale revealed a probable likelihood (score of 6) that the adverse reaction was related to etanercept. The association of etanercept with sarcoidosis is still a rare finding. This case highlights the importance of monitoring and possibly discontinuing the drug when sarcoidosis is suspected. Patients should be monitored during and after etanercept therapy for manifestations suggesting sarcoidosis, and we recommend patients receive baseline chest radiography at the start of therapy with follow-up of respiratory symptoms.     

TNF-alpha and apoptosis: implications for the pathogenesis and treatment of psoriasis

TNF-alpha is a key cytokine in innate immune responses and is increased in psoriatic lesions. TNF-alpha has many effects, ranging from inflammation to apoptosis. These effects are reviewed to better understand the role of TNF-alpha as it relates to the pathogenesis and treatment of psoriasis. TNF-alpha increases production of pro-inflammatory molecules (e.g. IL-1, IL-6, IL-8, NF-kappa B, vasoactive intestinal peptide) and adhesion molecules (e.g. intercellular adhesion molecule-1, P-selectin, E-selectin). TNF-alpha promotes apoptosis through binding to the TNF-receptor 1; however, psoriatic lesions are hyperproliferative despite an increase in TNF-alpha. This paradox is partially explained as NF-kappa B activation seems to inhibit TNF-alpha-induced apoptosis. The importance of TNF-alpha and apoptosis in psoriasis is shown through the review of clinical trials using anti-TNF-alpha immunobiologics (e.g. etanercept, infliximab) and apoptosis-inducing treatments that result in clinical improvement of the disease.     

The successful use of etanercept in combination therapy for treatment of acrodermatitis continua of hallopeau

Acrodermatitis continua of Hallopeau (ACH) is a rare form of pustular psoriasis which poses a challenge to treat and causes considerable pain and suffering for those afflicted. Tumor necrosis factor-alpha (TNF-alpha) is a pro-inflammatory cytokine involved in the pathogenesis of ACH and other forms of psoriasis. Inhibition of TNF-alpha has been shown to provide benefit in such inflammatory conditions as rheumatoid arthritis, psoriatic arthritis, and, most recently, plaque psoriasis. In this report, we present the case of a 65-year-old man with a 9-year history of recalcitrant ACH who demonstrated significant and sustained clinical improvement when etanercept, a competitive inhibitor of TNF-alpha, was added to his treatment regimen of acitretin and topical corticosteroids over a 12-week period.     

The evaluation of psoriasis therapy with biologics leads to a revision of the current view of the pathogenesis of this disorder

Psoriasis is a common chronic, recurring skin disease that is characterised by typical macroscopic and microscopic skin alterations. It is widely accepted that the immune system plays an important role in the pathogenesis of this disorder. Since the early 1990s, the dominant role of a subpopulation of T cells, so-called T1 cells, and their prominent cytokine IFN-gamma has been assumed in the pathogenesis of psoriasis. Surprisingly, the comparison of the therapeutic success of treatments with recombinant proteins directed against defined immunological structures shows that those that directly affect T cells (alefacept, efalizumab, Hu-max-CD4, OKTcdr4a) were clearly less effective than those targeting TNF-alpha (etanercept, adalimumab, infliximab). For this reason, the authors critically re-evaluated the view of psoriasis pathogenesis and postulate that in the majority of patients the T1 cells do not play a dominant role in the clinical, visible stage of this disease.     

Puerto Rico psoriasis study group: efficacy and safety of etanercept

BACKGROUND:Although major advances in the understanding of its pathogenesis have been achieved, psoriasis remains an incurable disease. In April 2004, etanercept, an antagonist of TNF-alpha, was approved by the Food and Drug Administration for the treatment of chronic, moderate to severe plaque psoriasis in adults. In this study we intend to document the efficacy and further establish the safety profile of etanercept for the treatment of moderate to severe psoriasis in our population and compare our data to the Leonardi et al study published in 2003. METHODS: A total of 26 patients were followed for a period of 24 weeks. Subjects were administered 25 mg of etanercept subcutaneously twice weekly for 24 weeks. Patients were seen every 4 weeks to measure clinical improvement by means of the psoriasis area and severity index (PASI) scores. Development of side effects was also assessed. RESULTS: Ninety-two percent of the patients had an improvement of greater than 50% in their PASI score, with 79% of these patients with a PASI improvement of 75% or greater. Adverse events were uncommon and none required the permanent discontinuation of treatment. CONCLUSION: Treatment with etanercept was well-tolerated and resulted in significant sustained improvement of psoriasis throughout a period of 24 weeks. Our data strongly correlates with the findings reported by Leonardi et al in 2003.     

Infections associated with tumor necrosis factor-alpha antagonists

Tumor necrosis factor-alpha (TNF-alpha) is a proinflammatory cytokine involved in a wide range of important physiologic processes. This cytokine has a pathologic role in some diseases, and TNF-alpha antagonists are effective in treating inflammatory conditions. Given the putative role of TNF-alpha in host defense against tuberculosis and other infections, the risk of infection with TNF-alpha antagonists is a concern. Therefore, we searched the literature for reports of tuberculosis and other infections associated with TNF-alpha-antagonist therapy. Although tuberculosis was rarely reported in randomized clinical comparisons of these antagonists, case reports and submissions to the MedWatch program of the United States Food and Drug Administration have been numerous. Most instances were associated with infliximab, but etanercept and adalimumab may also be associated with an increased risk of tuberculosis. Histoplasmosis, listeriosis, aspergillosis, coccidioidomycosis, and candidiasis have been associated with TNF-alpha antagonists, but the causative relationship is not clear. Potential recipients of these drugs should be rigorously screened with skin testing, detailed questioning about recent travel and potential tuberculosis exposure, assessment for symptoms such as cough and weight loss, and chest radiography to minimize their risk of acquiring or reactivating tuberculosis. As with other immunosuppressant drugs, TNF-alpha antagonists should not be given to patients with active infection.     

Longitudinal analysis of the use of etanercept versus infliximab determined from medical chart audit

OBJECTIVE: To describe the dosing of etanercept and infliximab for the treatment of rheumatoid arthritis (RA). METHODS: Adult patients with a diagnosis of RA who were treated with either etanercept or infliximab between 1999 and 2002 were selected from 16 rheumatology practices in the western and southeastern United States. Patients with a terminal illness or those receiving a tumor necrosis factor (TNF)-alpha inhibitor for an indication other than RA were excluded. Data were collected through a review of the patient medical records. Data collected on each patient included demographics, concurrent disease-modifying antirheumatic drug therapy, TNF-alpha inhibitor dose, frequency, duration of TNF-alpha inhibitor therapy, and discontinuation of TNF-alpha inhibitor therapy. RESULTS: A total of 244 patients were included in the evaluation (etanercept only [n=128; 52%], infliximab only [n=89; 36%], both [n=27; 11%]). The mean age of these patients was 55.1+/-13.3 years, 54.9+/-13.5 years, and 52.8+/-14.0 years, respectively; the mean duration of RA was 13.3 +/- 8.8 years, 13.4+/-8.0 years, and 14.0 +/- 9.9 years, respectively. Female patients constituted 70% of the sample. Health maintenance organization insurance was the most common form of medical insurance (45.8%), followed by Medicare (22.3%). The mean duration of follow-up for etanercept and infliximab treatment was 29.3+/-14.1 months and 14.8+/-6.9 months, respectively. Among patients who were still receiving therapy at the time of review, the mean initial and last etanercept doses were 25.0 mg versus 25.8 mg (P=0.16); the mean initial and last infliximab doses were 3.38 mg/kg versus 4.51 mg/kg (P<0.001). CONCLUSION: The dosing of etanercept and infliximab therapy was consistent with the approved labeling of both medications.     

Leukaemic transformation in patients with haematological disease receiving tumour necrosis factor inhibitors

In recent years, there has been an increase in the use of tumour necrosis factor (TNF) inhibitors as treatment for several inflammatory conditions. However, the question of whether TNF inhibitors increase the risk of malignancies (including lymphoma and leukaemia) in these diseases remains controversial. Despite this concern, anti-TNF therapy is being used experimentally in the management of haematological patients with risk of leukaemic transformation such as myeloproliferative neoplasms. We report here the first ever reported case of blastic transformation in a patient with myelofibrosis under etanercept treatment for a severe hidradenitis suppurativa. Although etanercept provided a sustained partial response of the skin disease, the patient developed an acute myeloid leukaemia after 27 months on exclusively etanercept therapy. According to the Dynamic International Prognostic Scoring System-plus score, the patient had a low risk for leukaemic transformation. We discuss here the potential of TNF inhibitors to increase the already elevated risk of leukaemic transformation of these haematological diseases.     

Etanercept: a review of its use in the management of ankylosing spondylitis and psoriatic arthritis

Etanercept (Enbrel), a recombinant, dimeric, soluble tumour necrosis factor (TNF) receptor protein, is approved in various countries for the treatment of adult patients with ankylosing spondylitis or psoriatic arthritis.Monotherapy with subcutaneous etanercept 25mg twice weekly or 50mg once weekly was effective and generally well tolerated in patients with ankylosing spondylitis or psoriatic arthritis participating in several large, well designed clinical studies. Treatment with etanercept was more effective than placebo in reducing disease activity and improving health-related quality of life (HR-QOL) in both patient populations, and in delaying structural disease progression in patients with psoriatic arthritis. The beneficial response to etanercept achieved with shorter-term treatment was sustained in studies of up to 4 years' total duration. Randomised, well designed, head-to-head comparisons, including pharmacoeconomic analyses, with other anti-TNF biological modulators are required to accurately position etanercept and fully establish its cost effectiveness. In the meantime, etanercept is a valuable treatment option for patients with ankylosing spondylitis or psoriatic arthritis who are suitable candidates for therapy.     

Etanercept in rheumatoid arthritis

Etanercept (Enbrel, Immunex Corporation, Seattle, Washington, USA) is a new biological disease-modifying antirheumatic drug (DMARD) for the treatment of active rheumatoid arthritis (RA). It is one of two TNF-alpha blockers to be licensed for the treatment of active RA and is classified as a recombinant human soluble TNF receptor. The drug competitively inhibits the binding of TNF to cell surface receptors and thus renders TNF biologically inactive. In doing so, etanercept inhibits the pro-inflammatory effects of TNF and results in a reduction of joint inflammation in patients with RA. Etanercept has shown a statistically significant reduction in swollen and inflamed joint counts, biochemical markers such as erythrocyte sedimentation rate and C-reactive protein and shown significant improvements in quality of life measures (HAQ and global assessment scores) in all studies. In early disease, etanercept has shown a reduction in joint space narrowing equal to methotrexate (MTX) and a reduction in the appearance of new erosions significantly better than MTX after 1 year of treatment. Etanercept has a rapid onset of action which is significantly faster than standard DMARDs. Etanercept was well-tolerated in clinical trials. The commonest side effects were injection site reactions and upper respiratory tract infections. Etanercept therapy has resulted in serious infections in some patients and should be used with caution in any patient with a history of recurring infections or with disease states that may predispose to infections. In summary, etanercept is an effective and well-tolerated agent that is a significant breakthrough in the treatment of this disabling condition.     

Tumor necrosis factor alpha in ulcerative colitis and diverticular disease associated colitis

Conventional treatment of moderate-severe ulcerative colitis (UC) has resulted in only a limited therapeutic benefit. Advancing knowledge of UC pathogenesis and recent advances in biotechnology have led to the development of biological agents that selectively target individual inflammatory pathways. In particular, the role of tumor necrosis factor alpha (TNF-alpha) in UC pathogenesis has been clarified by serological and immunohistochemical studies in humans and by experimental models. Clinical efficacy of anti-TNF-alpha therapy with infliximab has been assessed in two large controlled trials, showing a good compromise between therapeutic gain and safety. The aim of this review is to provide an insight into the role of TNF-alpha and anti-TNF-alpha therapy in patients with UC and diverticular disease associated colitis.     

Fulfilling an unmet need in psoriasis : do biologicals hold the key to improved tolerability?

Psoriasis is a chronic inflammatory disease of the skin affecting approximately 2% of the world's population. Traditional systemic treatments, including methotrexate, ciclosporin, psoralen plus UVA (PUVA), oral retinoids and fumaric acid esters, are widely used for severe disease and are effective in the short term. Severe psoriasis is a chronic disease and patients and physicians have expressed concerns about possible harm from organ toxicity, such as skin cancer (PUVA), hyperlipidaemia (retinoids), renal (ciclosporin) or hepatotoxicity (methotrexate). Long-term monitoring is required and may not detect early organ damage. The pathophysiology of psoriasis remains to be clarified, but advances toward the understanding of the immunological basis of psoriasis have uncovered the involvement of immunological pathways; for example, the role of tumour necrosis factor (TNF)-alpha, T cell proliferation and T cell activation, and migration to the epidermis. This advancement in knowledge combined with developments in recombinant technologies has led to the development of target-specific therapies. Biological agents are defined as proteins that can be extracted from animal tissue or produced via recombinant DNA technologies and possess pharmacological activity. Adalimumab, alefacept, infliximab, efalizumab and etanercept are examples of biological agents currently used for the treatment of psoriasis. Some of these are also therapy for other autoimmune conditions, such as rheumatoid arthritis and Crohn's disease. These biological agents are effective in psoriasis but raise new safety concerns. Information on the safety of biological agents in conditions such as rheumatoid arthritis and Crohn's disease can not be directly extrapolated to psoriasis. An increased incidence of lymphomas has been postulated to be associated with etanercept, infliximab and adalimumab; serious infections, such as tuberculosis, have also been reported with these three biologicals, all of which target TNF-alpha. Demyelinating disorders, such as multiple sclerosis, have been reported with some biologicals as has congestive heart failure. Alefacept, because of its mechanism of action of lowering the number of active T cells, is associated with low T cell counts. Efalizumab has been associated with thrombocytopenia and haemolytic anaemia. Data on the safety of >2.5 years' continuous treatment with efalizumab are reassuring and a valuable beginning to understanding the role and risk of harm of long-term therapy for a chronic disease. Longer follow-up studies and safety databases, for each of the biologicals used in psoriasis, are needed to ensure both prolonged efficacy and minimal risk of harm.     

Septic shock and community-acquired pneumonia associated with etanercept therapy

OBJECTIVE: To report a case of septic shock and community-acquired pneumonia in a patient with psoriatic arthritis receiving treatment with etanercept. PATIENT DETAILS: A 65-year-old woman diagnosed as having psoriatic arthritis had received treatment with etanercept. Chest X-ray studies were normal and the tuberculin skin test was negative. Two months after etanercept therapy, the patient presented to our emergency department with fever, cough, chest pain and generalized weakness. Chest radiography revealed a right pulmonary infiltrate. Her condition rapidly deteriorated and she went into shock with a further drop in her blood pressure, tachycardia and tachypnea. She was intubated, mechanically ventilated and was treated with fluids, cardioversion and amiodarone. Empiric therapy with levofloxacin, amikacin and cefepime were initiated. In the urinalysis, the result of a rapid test for Streptococcus pneumoniae was positive. Etanercept treatment was suspended due to a possible adverse reaction associated with this drug. At the start of therapy her clinical condition improved slowly. On Day 28, the patient was afebrile and she was discharged from the intensive care unit. DISCUSSION: Most of the infections associated with etanercept therapy have been reported in patients with rheumatoid arthritis. Based on our observations, etanercept was the possible offender in the development of septic shock and respiratory failure in community-acquired pneumonia. There was a temporal relationship between exposure to the drug and onset of symptoms. Etanercept was the only drug administered before the septic shock developed. Based on the Naranjo algorithm, the adverse reaction could be considered possible. CONCLUSION: Patients initiated on etanercept should be counseled and receive appropriate screening before drug initiation. All febrile and newly occurring concomitant illnesses should be promptly evaluated. General practitioners should discontinue etanercept treatment and institute prompt and aggressive intervention if infection develops.     

Tumor necrosis factor alpha promoter polymorphisms at position -308 in Taiwanese chronic hepatitis C patients treated with interferon-alpha

A G-to-A polymorphic sequence at position -308 in the tumor necrosis factor alpha promoter (TNF308.2) might be associated with disease susceptibilities. To investigate the association between -308 TNF-alpha variants and pathogenesis of hepatitis C virus (HCV) infection and response to interferon-alpha (IFN-alpha) treatment for chronic hepatitis C (CHC), -308 TNF-alpha genotypes were determined in 100 unrelated Taiwanese CHC patients treated with IFN-alpha and in 100 unrelated healthy subjects. The distribution of -308 TNF-alpha genotypes did not differ between CHC patients and controls. Age, sex, HCV genotype, and the necroinflammatory activity of liver histopathology did not differ among CHC patients with different -308 TNF-alpha genotypes. Although pretreatment HCV RNA serum levels, aminotransferase and the rate of severe fibrosis decreased with the copy number of TNF308.2, the difference did not reach significance. We failed to demonstrate any association between -308 TNF-alpha promoter polymorphisms and response to IFN therapy, which was inversely correlated to liver cirrhosis, pretreatment serum HCV RNA levels and genotype 1b by using multivariate analysis. In conclusion, our findings suggest that -308 TNF-alpha promoter polymorphisms do not play a direct role in the susceptibility and pathogenesis of HCV infection, and in the response to interferon-alpha therapy for CHC.     

ANCA-associated vasculitis: new options beyond steroids and cytotoxic drugs

Small vessel vasculitic syndromes--Wegener's granulomatosis, microscopic polyangiitis and renal limited vasculitis (which are associated with circulating antineutrophil cytoplasmic autoantibodies)--are an important cause of renal failure. Present immunosuppressive regimens that are based on cyclophosphamide have significantly increased survival rates. However, these treatments are toxic, increase the risk of infection and do not cure disease. Therefore, newer approaches are required. Understanding disease pathogenesis has allowed rational use for newer therapies such as rituximab, which depletes B cells. Unfortunately, blockade of promising targets such as TNF-alpha, which was thought to be a pivotal cytokine in inflammation, has not shown benefit in a randomised controlled trial. Better understanding of the pathogenesis of the disease is the key to the development of novel targeted therapies, which are urgently required to improve patient prognosis. Gene therapy with targeted delivery of specific proteins is an exciting future prospect.     

The evaluation of psoriasis therapy with biologics leads to a revision of the current view of the pathogenesis of this disorder

Psoriasis is a common chronic, recurring skin disease that is characterised by typical macroscopic and microscopic skin alterations. It is widely accepted that the immune system plays an important role in the pathogenesis of this disorder. Since the early 1990s, the dominant role of a subpopulation of T cells, so-called T1 cells, and their prominent cytokine IFN-γ has been assumed in the pathogenesis of psoriasis. Surprisingly, the comparison of the therapeutic success of treatments with recombinant proteins directed against defined immunological structures shows that those that directly affect T cells (alefacept, efalizumab, Hu-max-CD4, OKTcdr4a) were clearly less effective than those targeting TNF-α (etanercept, adalimumab, infliximab). For this reason, the authors critically re-evaluated the view of psoriasis pathogenesis and postulate that in the majority of patients the T1 cells do not play a dominant role in the clinical, visible stage of this disease.     

Tumour necrosis factor-alpha blockade: a new era for effective management of rheumatoid arthritis

Tumour necrosis factor (TNF)-alpha inhibitors have emerged as a new treatment option for rheumatoid arthritis (RA). The scientific rationale for targeting TNF-alpha in RA derives from extensive work in the laboratory, showing the importance of this pro-inflammatory cytokine as a mediator of joint inflammation. Proof of principle has now been firmly established in clinical trials where TNF-alpha inhibitors have been shown to decrease the signs and symptoms of joint inflammation and slow radiological progression of joint damage. Presently, the two TNF-alpha inhibitors available for use in RA are etanercept and infliximab. Etanercept is a soluble TNF receptor: Fc fusion protein that competes with the endogenous TNF receptors for TNF-alpha binding. Infliximab is a chimeric anti-TNF-alpha monoclonal antibody, which also binds with high affinity to soluble TNF-alpha. Etanercept and infliximab will be rapidly incorporated into current treatment paradigms, which call for early and intensive treatment of RA using disease-modifying antirheumatic drugs (DMARDs), such as methotrexate, sulfasalazine and hydroxychloroquine. A major drawback to the widespread use of these biologics is their high costs. Some patients with limited financial means may be denied access to these effective anti-inflammatory agents. Moreover, long-term experience with TNF-alpha inhibitor therapy has been limited and concerns linger about the possibility that etanercept and infliximab may cause unforeseen side effects or increase the risk for opportunistic infection. Despite these caveats, TNF-alpha inhibitors represent a major advance for the treatment of RA and will likely spawn new indications for anti-TNF-alpha therapy and the development of novel therapeutic compounds with similar biological activity.