As more is learned about the disease, physicians must now consider life-threatening comorbidities such as cardiovascular disease, as well as the risks of the treatments, making the dilemma of choosing appropriate therapy even more complex. Psoriasis is a chronic, inflammatory, multi-system disease affecting 1% to 3% of the world’s population.1 Psoriasis is characterized by pruritic and sometimes painful, hyperkeratotic skin lesions that can occur on any region of the body. The overall mortality attributed to psoriasis is low, but the morbidity can be devastating.2 It is well known that psoriasis substantially reduces health-related quality of life, with impact on physical and mental functioning comparable to other chronic diseases such as cancer, heart disease, diabetes, arthritis and depression. 3 In the last decade, we have become increasingly aware that psoriasis patients have an increased prevalence of obesity, malignancy, cardiovascular disease, metabolic syndrome and other immune-mediated inflammatory diseases. 4, 5
Background
New Findings on Comorbidities Previously, it was thought that the increased risk of these comorbidities was attributable to behavior-related factors such as obesity and smoking, which were thought to be provoked by the psychosocial burden of disease. 6 However, research now suggests that it is the underlying chronic inflammatory nature of psoriasis that is responsible for the development of some comorbidities, including cardiovascular disease. 4, 6-8 In addition to the risk of cardiovascular disease and other immune-mediated inflammatory diseases, several studies have demonstrated that psoriasis is also associated with an increased risk of malignancy. 8-12 It is well established that psoriasis patients are at increased risk for head and neck cancer, solid tumors (liver, pancreas, lung, breast, kidney), and non-melanoma skin cancer. 7,8,13 Lymphomas have also been recognized as a significant comorbidity associated with psoriasis. 5,7,8 The etiology for the increased risk is unknown, and could be attributed to the disease itself and abnormal immune activation, 8 certain immunosuppressive therapies, or lifestyle factors, such as alcohol consumption or smoking. 7 Comorbidities must be taken in to account during treatment planning and surveillance, particularly when topical psoriatic therapy fails and systemic therapy must be initiated. Weighing the Risks and Benefits of Full Range of Options Treatment options for psoriasis have traditionally been chosen on disease severity. 8 First-line therapy includes topical therapy with topical corticosteroids, vitamin D analogues, tars, retinoids and emollients. Despite major advances, these creams, ointments, lotions and other various vehicles can be awkward, leading to poor compliance. Furthermore, when psoriasis is extensive or recalcitrant to topical therapy, topical therapy becomes impractical. Additionally, these topical therapies do not address the underlying inflammatory mechanism of the disease and its associated comorbidities, while some systemic therapies target these underlying inflammatory processes. 8 While some therapies decrease the risk of comorbidities, others may exacerbate them or increase the risk, making the data less straightforward. For example, psoralen ultraviolet therapy (PUVA) increases the risk of skin cancer, retinoids the risk of hyperlipidemia, cyclosporine the risk of renal problems, and methotrexate (MTX) the risk of hepatotoxicity. 14 Moreover, some immunosuppressive therapies — including the newer biologic therapies — have increased risk of lymphoma. There have been very few trials comparing the efficacy and safety of biologic therapy versus traditional systemic therapy for the treatment of psoriasis. Therefore, it is important for the clinician to evaluate treatment risks and benefits of each individual therapy for a given patient. An ideal psoriasis therapy would gain initial and rapid control of the disease, reducing the size and severity of plaque lesion. Because psoriasis is a life-long disease and is associated with a plethora of comorbidities, this therapy would also achieve and maintain long-term remission while minimizing adverse events (AEs) of treatment and improve quality of life while reducing the risk of comorbid disease. 15 Traditional systemic therapies such as MTX, cyclosporine, retinoids and psoralen ultraviolet therapy, may be effective and well tolerated for a short duration, but are associated with serious end-organ toxicities that limit their long-term use. 14,16,17 Newer biologic therapies more specifically target the immune factors responsible for psoriasis, potentially yielding greater efficacy with fewer and less severe toxicities. 14,18,19 Interpreting Data on Biologics The biologics currently FDA-approved for the treatment of psoriasis include anti-TNF agents etanercept, adalimumab and infliximab, the T-cell modulators alefacept, and the anti-IL 12/23 ustekinumab. Efficacy and safety of these biologics have been evaluated in many clinical trials for psoriasis patients, but over a short period of time (generally 12 to 24 weeks). 20 Although these treatments are relatively new to the management of psoriasis, many have been used for years in other diseases, including rheumatoid arthritis and Crohn’s disease. Long-term safety data are available from the treatment of these diseases, and it is often from this data that dermatologists extrapolate their safety in psoriasis. 21 Potential safety concerns regarding the use of biologics include a general dampening of the immune system, leading to reactivation of tuberculosis, development of opportunistic infections, malignancies, demyelinating diseases and congestive heart failure. 1,22,23 Safety outcomes are analyzed separately from efficacy, so uncovering real-practice clinical benefit from published data is not always straightforward. 24 Early clinical trials demonstrating efficacy of these biologics were limited to 12 to 16 weeks. 25 Because of the chronic nature of psoriasis therapy, questions regarding the long-term safety of these drugs remain. 23 Recent studies have examined safety and efficacy in maintenance therapy with little increase in serious adverse events. 25 However, no one will forget that efalizumab, a T-cell inhibitor previously approved in 2003 for the treatment of moderate-to-severe psoriasis that had initially shown great efficacy with a very good safety profile, was withdrawn from the market in 2009 after it was found to increase the risk of progressive multifocal leukoencephalopathy (PML), a rare and often fatal opportunistic demyelinating disorder. 26,27 Therefore, great caution remains with the use of biologic therapies in the long-term. This paper will help to address the risks and benefits of individual biologic therapies from the current literature.
Evidence for Individual TNF inhibitors
Infliximab is a chimeric (mouse-human) monoclonal antibody against TNF-α that was initially approved for use in the treatment of rheumatoid arthritis and Crohn’s disease. Infliximab is administered as an intravenous (IV) infusion, and in one randomized, controlled trial, 73% to 82% of patients receiving infliximab had an improvement in PASI score of at least 75%, compared with 18% of placebo-treated patients. 28 Since regimens for treatment of rheumatoid arthritis and Crohn’s disease are similar to the treatment regimen for psoriasis, it is plausible to extrapolate the safety data from these trials. 14 A number of adverse events have been reported with infliximab, the most common being infusion-related reactions and immunogenicity. 20 Nineteen percent of patients in clinical trials reported infusion-related reactions including headache, fever or chills, chest pain, hypo- and hypertension, dyspnea and injection-site reactions. 18,29,30 Given the common occurrence of these reactions, it is recommended that patients are monitored for approximately 2 hours after the infusion. Generally, these reactions are mild and easily managed, and rarely lead to discontinuation of treatment. 14 Etanercept is a TNF-α inhibitor approved in the United States and Europe for the treatment of psoriasis. Etanercept is a human dimeric fusion protein administered twice-weekly for the first 3 months and weekly thereafter, by subcutaneous injection. Unlike infliximab, etanercept is administered at home and monitoring is not required before or during treatment. During placebo-controlled trials, etanercept has shown efficacy in patients with moderate-to-severe psoriasis in 12-week studies as well as in maintenance studies. Following 48 weeks’ treatment with etanercept 25 mg twice weekly, 67% and 38% of patients achieved PASI-50 and PASI-75, respectively. 31 Etanercept has been evaluated for up to 144 weeks and was well tolerated with no increase in adverse events with increased weeks on treatment. 25,32 The most common adverse events in controlled trials were mild-to-moderate injection site reactions, including redness, itching, pain and swelling. These occurred in approximately 37% of patients receiving etanercept and rarely led to discontinuation of the drug. 14 Weight gain was also reported in some trials among etanercept-treated patients. 20 Rarely, pancytopenia was also seen (Enbrel package insert). Adalimumab, a fully human recombinant IgG1 monoclonal anti-TNF-α antibody, has been evaluated for up to 120 weeks in psoriatic arthritis and 60 weeks in psoriasis. 25 Adalimumab is approved at 40 mg dosing weekly and every-other-week. The Comparative Study of Humira versus MTX versus Placebo in Psoriasis Patients (CHAMPION) showed adalimumab was associated with a greater and more rapid reduction of psoriasis symptoms compared with MTX. 33 The most common adverse effects — noted in this study and others — were upper respiratory infections and nasopharyngitis. 1 Others included hypersensitivity, anaphylaxis, rashes, nausea, headache and abdominal pain. Few rare and serious adverse events included infections, malignancy, cerebrovascular events, osteoarthritis, kidney stones and coronary artery disease. 34 Patients followed for 1 to 2 years did not show increased rates of adverse events compared to patients at 12 weeks. 25,35
Evidence on TNF Therapies as a Group
Link to Lymphomas There have been several case reports of lymphoma or lymphoproliferative disorder (LPD) developing specifically in psoriasis patients on biologic therapies. 5,36-42 Nine of the 12 patients were receiving one biologic agent at the time of diagnosis, and the remaining three were receiving two biologic agents concomitantly. The most common type of lymphoma was cutaneous T-cell lymphoma (CTCL) (4/10), and the other types were unspecified B-cell non-Hodgkins lymphoma, one lymphoproliferative disease, one Epstein-Barr virus positive large B-cell lymphoma, one Hodgkin’s lymphoma, and one gastric mucosa-associated lymphoid tissue lymphoma. 5 In many cases, patients have been on previous immunosuppressive therapies in the past, many of which can potentially increase the risk of lymphoma. Also complicating the picture is that severe psoriasis also poses an inherent risk of malignancy. Furthermore, in several of these cases, lymphoma could have been present prior to initiating biologic therapy, but the treatment could have allowed the lymphoma cells to grow rapidly, rather than the drug causing the lymphoma. 5 These case reports allow for safety signal detection, but because lymphoma is rare to begin with, larger studies are needed to yield more information regarding the risk of lymphoma from biologic therapies. In one meta-analysis of anti-TNF antibody therapies in 2006, Bongartz et al found an increased risk of serious infections and a dose-dependent increase in the risk of malignancies in patients with rheumatoid arthritis treated with anti-TNF therapy. 43 The most common malignancy was non-melanoma skin cancer, and the second most common malignancy was lymphoma. This data, however, has been highly criticized. One problem was that this review excluded etanercept. Moreover, included trials were not adjusted for different duration of exposure to therapy, disease activity, and previous and concomitant DMARD therapies. Another large observational cohort study conducted in 2007 included 19,562 patients with 89,710 patient-years of follow-up. This study examined rheumatoid arthritis (RA) patients who received anti-TNF therapy compared to those who did not, and found that the probability of lymphoma was the same for both groups. 44, 45 In 2009 in a follow-up to the previous study, Bongartz et al completed another meta-analysis, this time including etanercept. In this analysis, they did not find a statistically significant increase in the risk of malignancy in etanercept-treated RA patients. 46 The authors also examined the effect of exposure duration and dose and found no statistically significant impact on the results. 5 These results were consistent with other published trials and meta-analyses of RCT data. 20,34,47 Finally, Leombruno et al analyzed data from 18 RCTs for the TNF agents involving more than 8,000 RA patients and found no significant increase in the risk of lymphoma at recommended dose of the anti-TNF agents. They did show higher risk of serious infections at higher doses of adalimumab and infliximab, but risk of death, SAE and overall malignancy were not increased. 48 Link to Infections All of the TNF inhibitors are associated with immunosuppression by nature of their pathophysiology. Reports of serious infections, including reactivation of tuberculosis, have been associated with all three of the TNF inhibitors mentioned above. 14 In general, no apparent differences have been observed between the infection rates for each of this class of medications. 49 Demyelinating disorders, including multiple sclerosis (MS), have also been reported in association with the TNF inhibitors. 50 TNF inhibitors have also been shown to exacerbate congestive heart failure (CHF) as well as contribute to new onset CHF. 51 However, the rate of new onset cardiovascular disease is lower in patients treated with TNF inhibitors compared with other patients with RA, suggesting that TNF blockade may have a beneficial effect on arteriosclerosis. 52 A German group conducted a risk-benefit assessment of treating rheumatoid arthritis with biologics based on registry data on mortality and found that the death rate in TNF-inhibitor-treated patients is higher than in the general population but lower than that in the control group of patients with RA. Furthermore, when TNF inhibitors were given for the usual indication, they found mortality is actually reduced compared to conventional therapy. 53 This finding was affirmed by another group who found that TNF inhibitors were found to be associated with a reduced mortality in women with RA, but not in men with RA. 52
Evidence for T-cell Inhibitors
Alefacept, a human, dimeric fusion protein, was one of the first biologics approved by the FDA in 2003. 54 Alefacept is made up of the terminal portion of leukocyte function associated antigen-3 (LFA-3), and reduces T-cell activation and depletes the number of active T cells. Alefacept is administered intramuscularly once a week for 12 weeks, followed by a 12-week treatment-free period. 14 Using a dosage of 15 mg weekly, PASI 75 scores at week 12 were found to be between 21% to 35%.54-56 Alefacept has demonstrated long psoriasis remission times in patients treated for up to 60 weeks, 25 and is generally well tolerated. The most common side effects include headache and upper respiratory infections. 57 The main safety concern is the induction of dose-dependent lymphopenia. 58 As a result, alefacept is contraindicated in patients with a low CD4+ T-cell count, and regular monitoring of lymphocytes is required during treatment. Other minor adverse include chills after induction of treatment, 59 and mild injection-site reactions. 60 In 2009, another T-cell modulator efalizumab was withdrawn from the European and U.S. markets after being linked to progressive multifocal leukoencephalopathy (PML). 17 This drug had shown great clinical efficacy but the company deemed the risks of PML outweighed the benefits and voluntarily pulled the drug from the market.
Evidence for Anti IL-12/23
Ustekinumab is a human monoclonal antibody that targets the p40 subunit of IL 12 and IL 23 and is the newest biologic approved for psoriasis on the U.S. market. PHOENIX 1 and 2 trials demonstrated excellent efficacy with ustekinumab 45 mg or 90 mg subcutaneous injection at weeks 0 and 4, and then every 12 weeks. 19 At week 12, 66.7% of the 45mg group and 75.7% in the 90 mg group had PASI 75. 17 Adverse events in Phase I and II studies were generally mild and included headaches, abdominal pain, arthralgias and common cold symptoms. 19, 61 The adverse events did not appear to be dose-related, were not significantly different for patients treated with placebo or either of the ustekinumab doses, and were not considered serious. 19 Some serious adverse events included infections, myocardial infarctions, a cerebrovascular accident, non-melanoma skin cancer and prostate cancer. There are very few trials comparing different biologic therapies to each other. In the ACCEPT trial, ustekinumab was studied head-to-head against etanercept for the treatment of moderate-to-severe plaque psoriasis. The primary endpoint of the trial was the percentage of patients achieving a PASI 75 at week 12. 68% and 74% of patients receiving ustekinumab 45 mg or 90 mg, respectively, achieved a PASI 75, compared with 57% of patients receiving etanercept 50 mg SC twice weekly for 12 weeks. Additionally, PASI 90 was observed in 36% and 45% of patients in these respective ustekinumab groups versus 23% of etanercept-treated patients. 19,62 In general, ustekinumab and etanercept were well tolerated with comparable rates of adverse events. The safety profiles of the various anti-TNF agents have also not been studied head-to-head. Gerloni et al reported a nearly equal rate of AEs among infliximab-treated patients and etanercept-treated patients, but nearly twice as many infliximab-treated patients as etanercept-treated patients discontinued their medication because of an AE. 49 This finding was corroborated in other studies, which might best be described as a difference in the tolerability of these medications. For instance, Brunasso et al found that more patients responded to infliximab, but long-term tolerability was higher for etanercept and adalimumab. 20 Patient tolerance to a specific drug is an important factor and should be taken in to consideration along with efficacy and safety when determining which drug to choose for a given patient. Compared to the T-cell inhibitor adalimumab, and the anti-IL 12/23 ustekinumab, the TNF inhibitors have been most extensively studied because of their broad application to a variety of diseases. It is generally assumed that because the biologic agents more specifically target the inflammatory cytokines responsible for psoriasis, these agents have better safety profiles compared to traditional therapies that globally suppress the immune system and can lead to organ toxicity, infections and cancer. However, we know that patients with severe psoriasis are more likely to develop malignancies because of their inherent disease. 14 As noted earlier, there is published data that both confirms and denies an increased risk of malignancy with biologic agents. Data from case reports, observational studies, RCTs and meta-analyses have generally indicated a favorable risk profile of the anti-TNFs with respect to lymphoma. 5 However, the risks associated with any of the biologics must be weighed against the benefits in a specific patient. Reich et al attempted to develop a standardized, risk-benefit algorithm, measured at the patient level, to examine results from the CHAMPION trial. They found that adalimumab was associated with four times as many AE-free response days, and demonstrated a superior benefit-risk profile. 33 They advocated using a standardized risk-benefit algorithm to allow clinicians to more accurately review the risks (safety and tolerability) versus the benefits (efficacy) of the various treatments, to better serve their patient. 33 Despite the fact that it is often difficult to ascertain a true risk given the many possible confounding variables, including disease duration, severity, previous treatments and lifestyle, it seems that with appropriate screening for serious infections, demyelinating diseases, and heart disease, any one of these biologics may prove to have an acceptable benefit to risk ratio for a given patient.
Proceeding Cautiously
Data published over the last decade demonstrate the improved efficacy of biologic therapies for psoriasis over conventional drugs. The medications appear safe and effective, and in the long-term have shown no increase in adverse events in published extension studies. However, lymphoma or other malignancies may not be detected until years after the initiation of therapy. 63 Furthermore, the interaction of these drugs with other medications may not yet be elucidated. Therefore, the long-term safety and efficacy of continuous treatment in real-life settings is not known. There is no standardized algorithm yet to aid the clinician in which biologic, if any, is appropriate. For each patient, the physician should review the event rates reported for a wide set of AEs from disparate RCTs, consider the individual patient and his/her comorbidities, and the risk-benefit evidence. Finally, applying the recommended screening before and during biological treatment helps to minimize adverse events related to therapy. 64-66 As we continue, well-designed prospective cohort studies in patients with moderate to severe psoriasis are needed to assess the complex relationship among psoriasis, comorbidities, cancer risk, and medications. Dr Frankel is a clinical dermatopharmacology fellow in the Department of Dermatology at Mount Sinai Medical Center, New York, NY. Dr. Goldenberg is Assistant Professor of Dermatology and Pathology, Medical Director of the Dermatology Faculty Practice, Mount Sinai School of Medicine in New York. He is Board Certified in Dermatology and Dermatopathology. Disclosures: The authors have no conflicts of interest with any material found in this article.
As more is learned about the disease, physicians must now consider life-threatening comorbidities such as cardiovascular disease, as well as the risks of the treatments, making the dilemma of choosing appropriate therapy even more complex. Psoriasis is a chronic, inflammatory, multi-system disease affecting 1% to 3% of the world’s population.1 Psoriasis is characterized by pruritic and sometimes painful, hyperkeratotic skin lesions that can occur on any region of the body. The overall mortality attributed to psoriasis is low, but the morbidity can be devastating.2 It is well known that psoriasis substantially reduces health-related quality of life, with impact on physical and mental functioning comparable to other chronic diseases such as cancer, heart disease, diabetes, arthritis and depression. 3 In the last decade, we have become increasingly aware that psoriasis patients have an increased prevalence of obesity, malignancy, cardiovascular disease, metabolic syndrome and other immune-mediated inflammatory diseases. 4, 5
Background
New Findings on Comorbidities Previously, it was thought that the increased risk of these comorbidities was attributable to behavior-related factors such as obesity and smoking, which were thought to be provoked by the psychosocial burden of disease. 6 However, research now suggests that it is the underlying chronic inflammatory nature of psoriasis that is responsible for the development of some comorbidities, including cardiovascular disease. 4, 6-8 In addition to the risk of cardiovascular disease and other immune-mediated inflammatory diseases, several studies have demonstrated that psoriasis is also associated with an increased risk of malignancy. 8-12 It is well established that psoriasis patients are at increased risk for head and neck cancer, solid tumors (liver, pancreas, lung, breast, kidney), and non-melanoma skin cancer. 7,8,13 Lymphomas have also been recognized as a significant comorbidity associated with psoriasis. 5,7,8 The etiology for the increased risk is unknown, and could be attributed to the disease itself and abnormal immune activation, 8 certain immunosuppressive therapies, or lifestyle factors, such as alcohol consumption or smoking. 7 Comorbidities must be taken in to account during treatment planning and surveillance, particularly when topical psoriatic therapy fails and systemic therapy must be initiated. Weighing the Risks and Benefits of Full Range of Options Treatment options for psoriasis have traditionally been chosen on disease severity. 8 First-line therapy includes topical therapy with topical corticosteroids, vitamin D analogues, tars, retinoids and emollients. Despite major advances, these creams, ointments, lotions and other various vehicles can be awkward, leading to poor compliance. Furthermore, when psoriasis is extensive or recalcitrant to topical therapy, topical therapy becomes impractical. Additionally, these topical therapies do not address the underlying inflammatory mechanism of the disease and its associated comorbidities, while some systemic therapies target these underlying inflammatory processes. 8 While some therapies decrease the risk of comorbidities, others may exacerbate them or increase the risk, making the data less straightforward. For example, psoralen ultraviolet therapy (PUVA) increases the risk of skin cancer, retinoids the risk of hyperlipidemia, cyclosporine the risk of renal problems, and methotrexate (MTX) the risk of hepatotoxicity. 14 Moreover, some immunosuppressive therapies — including the newer biologic therapies — have increased risk of lymphoma. There have been very few trials comparing the efficacy and safety of biologic therapy versus traditional systemic therapy for the treatment of psoriasis. Therefore, it is important for the clinician to evaluate treatment risks and benefits of each individual therapy for a given patient. An ideal psoriasis therapy would gain initial and rapid control of the disease, reducing the size and severity of plaque lesion. Because psoriasis is a life-long disease and is associated with a plethora of comorbidities, this therapy would also achieve and maintain long-term remission while minimizing adverse events (AEs) of treatment and improve quality of life while reducing the risk of comorbid disease. 15 Traditional systemic therapies such as MTX, cyclosporine, retinoids and psoralen ultraviolet therapy, may be effective and well tolerated for a short duration, but are associated with serious end-organ toxicities that limit their long-term use. 14,16,17 Newer biologic therapies more specifically target the immune factors responsible for psoriasis, potentially yielding greater efficacy with fewer and less severe toxicities. 14,18,19 Interpreting Data on Biologics The biologics currently FDA-approved for the treatment of psoriasis include anti-TNF agents etanercept, adalimumab and infliximab, the T-cell modulators alefacept, and the anti-IL 12/23 ustekinumab. Efficacy and safety of these biologics have been evaluated in many clinical trials for psoriasis patients, but over a short period of time (generally 12 to 24 weeks). 20 Although these treatments are relatively new to the management of psoriasis, many have been used for years in other diseases, including rheumatoid arthritis and Crohn’s disease. Long-term safety data are available from the treatment of these diseases, and it is often from this data that dermatologists extrapolate their safety in psoriasis. 21 Potential safety concerns regarding the use of biologics include a general dampening of the immune system, leading to reactivation of tuberculosis, development of opportunistic infections, malignancies, demyelinating diseases and congestive heart failure. 1,22,23 Safety outcomes are analyzed separately from efficacy, so uncovering real-practice clinical benefit from published data is not always straightforward. 24 Early clinical trials demonstrating efficacy of these biologics were limited to 12 to 16 weeks. 25 Because of the chronic nature of psoriasis therapy, questions regarding the long-term safety of these drugs remain. 23 Recent studies have examined safety and efficacy in maintenance therapy with little increase in serious adverse events. 25 However, no one will forget that efalizumab, a T-cell inhibitor previously approved in 2003 for the treatment of moderate-to-severe psoriasis that had initially shown great efficacy with a very good safety profile, was withdrawn from the market in 2009 after it was found to increase the risk of progressive multifocal leukoencephalopathy (PML), a rare and often fatal opportunistic demyelinating disorder. 26,27 Therefore, great caution remains with the use of biologic therapies in the long-term. This paper will help to address the risks and benefits of individual biologic therapies from the current literature.
Evidence for Individual TNF inhibitors
Infliximab is a chimeric (mouse-human) monoclonal antibody against TNF-α that was initially approved for use in the treatment of rheumatoid arthritis and Crohn’s disease. Infliximab is administered as an intravenous (IV) infusion, and in one randomized, controlled trial, 73% to 82% of patients receiving infliximab had an improvement in PASI score of at least 75%, compared with 18% of placebo-treated patients. 28 Since regimens for treatment of rheumatoid arthritis and Crohn’s disease are similar to the treatment regimen for psoriasis, it is plausible to extrapolate the safety data from these trials. 14 A number of adverse events have been reported with infliximab, the most common being infusion-related reactions and immunogenicity. 20 Nineteen percent of patients in clinical trials reported infusion-related reactions including headache, fever or chills, chest pain, hypo- and hypertension, dyspnea and injection-site reactions. 18,29,30 Given the common occurrence of these reactions, it is recommended that patients are monitored for approximately 2 hours after the infusion. Generally, these reactions are mild and easily managed, and rarely lead to discontinuation of treatment. 14 Etanercept is a TNF-α inhibitor approved in the United States and Europe for the treatment of psoriasis. Etanercept is a human dimeric fusion protein administered twice-weekly for the first 3 months and weekly thereafter, by subcutaneous injection. Unlike infliximab, etanercept is administered at home and monitoring is not required before or during treatment. During placebo-controlled trials, etanercept has shown efficacy in patients with moderate-to-severe psoriasis in 12-week studies as well as in maintenance studies. Following 48 weeks’ treatment with etanercept 25 mg twice weekly, 67% and 38% of patients achieved PASI-50 and PASI-75, respectively. 31 Etanercept has been evaluated for up to 144 weeks and was well tolerated with no increase in adverse events with increased weeks on treatment. 25,32 The most common adverse events in controlled trials were mild-to-moderate injection site reactions, including redness, itching, pain and swelling. These occurred in approximately 37% of patients receiving etanercept and rarely led to discontinuation of the drug. 14 Weight gain was also reported in some trials among etanercept-treated patients. 20 Rarely, pancytopenia was also seen (Enbrel package insert). Adalimumab, a fully human recombinant IgG1 monoclonal anti-TNF-α antibody, has been evaluated for up to 120 weeks in psoriatic arthritis and 60 weeks in psoriasis. 25 Adalimumab is approved at 40 mg dosing weekly and every-other-week. The Comparative Study of Humira versus MTX versus Placebo in Psoriasis Patients (CHAMPION) showed adalimumab was associated with a greater and more rapid reduction of psoriasis symptoms compared with MTX. 33 The most common adverse effects — noted in this study and others — were upper respiratory infections and nasopharyngitis. 1 Others included hypersensitivity, anaphylaxis, rashes, nausea, headache and abdominal pain. Few rare and serious adverse events included infections, malignancy, cerebrovascular events, osteoarthritis, kidney stones and coronary artery disease. 34 Patients followed for 1 to 2 years did not show increased rates of adverse events compared to patients at 12 weeks. 25,35
Evidence on TNF Therapies as a Group
Link to Lymphomas There have been several case reports of lymphoma or lymphoproliferative disorder (LPD) developing specifically in psoriasis patients on biologic therapies. 5,36-42 Nine of the 12 patients were receiving one biologic agent at the time of diagnosis, and the remaining three were receiving two biologic agents concomitantly. The most common type of lymphoma was cutaneous T-cell lymphoma (CTCL) (4/10), and the other types were unspecified B-cell non-Hodgkins lymphoma, one lymphoproliferative disease, one Epstein-Barr virus positive large B-cell lymphoma, one Hodgkin’s lymphoma, and one gastric mucosa-associated lymphoid tissue lymphoma. 5 In many cases, patients have been on previous immunosuppressive therapies in the past, many of which can potentially increase the risk of lymphoma. Also complicating the picture is that severe psoriasis also poses an inherent risk of malignancy. Furthermore, in several of these cases, lymphoma could have been present prior to initiating biologic therapy, but the treatment could have allowed the lymphoma cells to grow rapidly, rather than the drug causing the lymphoma. 5 These case reports allow for safety signal detection, but because lymphoma is rare to begin with, larger studies are needed to yield more information regarding the risk of lymphoma from biologic therapies. In one meta-analysis of anti-TNF antibody therapies in 2006, Bongartz et al found an increased risk of serious infections and a dose-dependent increase in the risk of malignancies in patients with rheumatoid arthritis treated with anti-TNF therapy. 43 The most common malignancy was non-melanoma skin cancer, and the second most common malignancy was lymphoma. This data, however, has been highly criticized. One problem was that this review excluded etanercept. Moreover, included trials were not adjusted for different duration of exposure to therapy, disease activity, and previous and concomitant DMARD therapies. Another large observational cohort study conducted in 2007 included 19,562 patients with 89,710 patient-years of follow-up. This study examined rheumatoid arthritis (RA) patients who received anti-TNF therapy compared to those who did not, and found that the probability of lymphoma was the same for both groups. 44, 45 In 2009 in a follow-up to the previous study, Bongartz et al completed another meta-analysis, this time including etanercept. In this analysis, they did not find a statistically significant increase in the risk of malignancy in etanercept-treated RA patients. 46 The authors also examined the effect of exposure duration and dose and found no statistically significant impact on the results. 5 These results were consistent with other published trials and meta-analyses of RCT data. 20,34,47 Finally, Leombruno et al analyzed data from 18 RCTs for the TNF agents involving more than 8,000 RA patients and found no significant increase in the risk of lymphoma at recommended dose of the anti-TNF agents. They did show higher risk of serious infections at higher doses of adalimumab and infliximab, but risk of death, SAE and overall malignancy were not increased. 48 Link to Infections All of the TNF inhibitors are associated with immunosuppression by nature of their pathophysiology. Reports of serious infections, including reactivation of tuberculosis, have been associated with all three of the TNF inhibitors mentioned above. 14 In general, no apparent differences have been observed between the infection rates for each of this class of medications. 49 Demyelinating disorders, including multiple sclerosis (MS), have also been reported in association with the TNF inhibitors. 50 TNF inhibitors have also been shown to exacerbate congestive heart failure (CHF) as well as contribute to new onset CHF. 51 However, the rate of new onset cardiovascular disease is lower in patients treated with TNF inhibitors compared with other patients with RA, suggesting that TNF blockade may have a beneficial effect on arteriosclerosis. 52 A German group conducted a risk-benefit assessment of treating rheumatoid arthritis with biologics based on registry data on mortality and found that the death rate in TNF-inhibitor-treated patients is higher than in the general population but lower than that in the control group of patients with RA. Furthermore, when TNF inhibitors were given for the usual indication, they found mortality is actually reduced compared to conventional therapy. 53 This finding was affirmed by another group who found that TNF inhibitors were found to be associated with a reduced mortality in women with RA, but not in men with RA. 52
Evidence for T-cell Inhibitors
Alefacept, a human, dimeric fusion protein, was one of the first biologics approved by the FDA in 2003. 54 Alefacept is made up of the terminal portion of leukocyte function associated antigen-3 (LFA-3), and reduces T-cell activation and depletes the number of active T cells. Alefacept is administered intramuscularly once a week for 12 weeks, followed by a 12-week treatment-free period. 14 Using a dosage of 15 mg weekly, PASI 75 scores at week 12 were found to be between 21% to 35%.54-56 Alefacept has demonstrated long psoriasis remission times in patients treated for up to 60 weeks, 25 and is generally well tolerated. The most common side effects include headache and upper respiratory infections. 57 The main safety concern is the induction of dose-dependent lymphopenia. 58 As a result, alefacept is contraindicated in patients with a low CD4+ T-cell count, and regular monitoring of lymphocytes is required during treatment. Other minor adverse include chills after induction of treatment, 59 and mild injection-site reactions. 60 In 2009, another T-cell modulator efalizumab was withdrawn from the European and U.S. markets after being linked to progressive multifocal leukoencephalopathy (PML). 17 This drug had shown great clinical efficacy but the company deemed the risks of PML outweighed the benefits and voluntarily pulled the drug from the market.
Evidence for Anti IL-12/23
Ustekinumab is a human monoclonal antibody that targets the p40 subunit of IL 12 and IL 23 and is the newest biologic approved for psoriasis on the U.S. market. PHOENIX 1 and 2 trials demonstrated excellent efficacy with ustekinumab 45 mg or 90 mg subcutaneous injection at weeks 0 and 4, and then every 12 weeks. 19 At week 12, 66.7% of the 45mg group and 75.7% in the 90 mg group had PASI 75. 17 Adverse events in Phase I and II studies were generally mild and included headaches, abdominal pain, arthralgias and common cold symptoms. 19, 61 The adverse events did not appear to be dose-related, were not significantly different for patients treated with placebo or either of the ustekinumab doses, and were not considered serious. 19 Some serious adverse events included infections, myocardial infarctions, a cerebrovascular accident, non-melanoma skin cancer and prostate cancer. There are very few trials comparing different biologic therapies to each other. In the ACCEPT trial, ustekinumab was studied head-to-head against etanercept for the treatment of moderate-to-severe plaque psoriasis. The primary endpoint of the trial was the percentage of patients achieving a PASI 75 at week 12. 68% and 74% of patients receiving ustekinumab 45 mg or 90 mg, respectively, achieved a PASI 75, compared with 57% of patients receiving etanercept 50 mg SC twice weekly for 12 weeks. Additionally, PASI 90 was observed in 36% and 45% of patients in these respective ustekinumab groups versus 23% of etanercept-treated patients. 19,62 In general, ustekinumab and etanercept were well tolerated with comparable rates of adverse events. The safety profiles of the various anti-TNF agents have also not been studied head-to-head. Gerloni et al reported a nearly equal rate of AEs among infliximab-treated patients and etanercept-treated patients, but nearly twice as many infliximab-treated patients as etanercept-treated patients discontinued their medication because of an AE. 49 This finding was corroborated in other studies, which might best be described as a difference in the tolerability of these medications. For instance, Brunasso et al found that more patients responded to infliximab, but long-term tolerability was higher for etanercept and adalimumab. 20 Patient tolerance to a specific drug is an important factor and should be taken in to consideration along with efficacy and safety when determining which drug to choose for a given patient. Compared to the T-cell inhibitor adalimumab, and the anti-IL 12/23 ustekinumab, the TNF inhibitors have been most extensively studied because of their broad application to a variety of diseases. It is generally assumed that because the biologic agents more specifically target the inflammatory cytokines responsible for psoriasis, these agents have better safety profiles compared to traditional therapies that globally suppress the immune system and can lead to organ toxicity, infections and cancer. However, we know that patients with severe psoriasis are more likely to develop malignancies because of their inherent disease. 14 As noted earlier, there is published data that both confirms and denies an increased risk of malignancy with biologic agents. Data from case reports, observational studies, RCTs and meta-analyses have generally indicated a favorable risk profile of the anti-TNFs with respect to lymphoma. 5 However, the risks associated with any of the biologics must be weighed against the benefits in a specific patient. Reich et al attempted to develop a standardized, risk-benefit algorithm, measured at the patient level, to examine results from the CHAMPION trial. They found that adalimumab was associated with four times as many AE-free response days, and demonstrated a superior benefit-risk profile. 33 They advocated using a standardized risk-benefit algorithm to allow clinicians to more accurately review the risks (safety and tolerability) versus the benefits (efficacy) of the various treatments, to better serve their patient. 33 Despite the fact that it is often difficult to ascertain a true risk given the many possible confounding variables, including disease duration, severity, previous treatments and lifestyle, it seems that with appropriate screening for serious infections, demyelinating diseases, and heart disease, any one of these biologics may prove to have an acceptable benefit to risk ratio for a given patient.
Proceeding Cautiously
Data published over the last decade demonstrate the improved efficacy of biologic therapies for psoriasis over conventional drugs. The medications appear safe and effective, and in the long-term have shown no increase in adverse events in published extension studies. However, lymphoma or other malignancies may not be detected until years after the initiation of therapy. 63 Furthermore, the interaction of these drugs with other medications may not yet be elucidated. Therefore, the long-term safety and efficacy of continuous treatment in real-life settings is not known. There is no standardized algorithm yet to aid the clinician in which biologic, if any, is appropriate. For each patient, the physician should review the event rates reported for a wide set of AEs from disparate RCTs, consider the individual patient and his/her comorbidities, and the risk-benefit evidence. Finally, applying the recommended screening before and during biological treatment helps to minimize adverse events related to therapy. 64-66 As we continue, well-designed prospective cohort studies in patients with moderate to severe psoriasis are needed to assess the complex relationship among psoriasis, comorbidities, cancer risk, and medications. Dr Frankel is a clinical dermatopharmacology fellow in the Department of Dermatology at Mount Sinai Medical Center, New York, NY. Dr. Goldenberg is Assistant Professor of Dermatology and Pathology, Medical Director of the Dermatology Faculty Practice, Mount Sinai School of Medicine in New York. He is Board Certified in Dermatology and Dermatopathology. Disclosures: The authors have no conflicts of interest with any material found in this article.
As more is learned about the disease, physicians must now consider life-threatening comorbidities such as cardiovascular disease, as well as the risks of the treatments, making the dilemma of choosing appropriate therapy even more complex. Psoriasis is a chronic, inflammatory, multi-system disease affecting 1% to 3% of the world’s population.1 Psoriasis is characterized by pruritic and sometimes painful, hyperkeratotic skin lesions that can occur on any region of the body. The overall mortality attributed to psoriasis is low, but the morbidity can be devastating.2 It is well known that psoriasis substantially reduces health-related quality of life, with impact on physical and mental functioning comparable to other chronic diseases such as cancer, heart disease, diabetes, arthritis and depression. 3 In the last decade, we have become increasingly aware that psoriasis patients have an increased prevalence of obesity, malignancy, cardiovascular disease, metabolic syndrome and other immune-mediated inflammatory diseases. 4, 5
Background
New Findings on Comorbidities Previously, it was thought that the increased risk of these comorbidities was attributable to behavior-related factors such as obesity and smoking, which were thought to be provoked by the psychosocial burden of disease. 6 However, research now suggests that it is the underlying chronic inflammatory nature of psoriasis that is responsible for the development of some comorbidities, including cardiovascular disease. 4, 6-8 In addition to the risk of cardiovascular disease and other immune-mediated inflammatory diseases, several studies have demonstrated that psoriasis is also associated with an increased risk of malignancy. 8-12 It is well established that psoriasis patients are at increased risk for head and neck cancer, solid tumors (liver, pancreas, lung, breast, kidney), and non-melanoma skin cancer. 7,8,13 Lymphomas have also been recognized as a significant comorbidity associated with psoriasis. 5,7,8 The etiology for the increased risk is unknown, and could be attributed to the disease itself and abnormal immune activation, 8 certain immunosuppressive therapies, or lifestyle factors, such as alcohol consumption or smoking. 7 Comorbidities must be taken in to account during treatment planning and surveillance, particularly when topical psoriatic therapy fails and systemic therapy must be initiated. Weighing the Risks and Benefits of Full Range of Options Treatment options for psoriasis have traditionally been chosen on disease severity. 8 First-line therapy includes topical therapy with topical corticosteroids, vitamin D analogues, tars, retinoids and emollients. Despite major advances, these creams, ointments, lotions and other various vehicles can be awkward, leading to poor compliance. Furthermore, when psoriasis is extensive or recalcitrant to topical therapy, topical therapy becomes impractical. Additionally, these topical therapies do not address the underlying inflammatory mechanism of the disease and its associated comorbidities, while some systemic therapies target these underlying inflammatory processes. 8 While some therapies decrease the risk of comorbidities, others may exacerbate them or increase the risk, making the data less straightforward. For example, psoralen ultraviolet therapy (PUVA) increases the risk of skin cancer, retinoids the risk of hyperlipidemia, cyclosporine the risk of renal problems, and methotrexate (MTX) the risk of hepatotoxicity. 14 Moreover, some immunosuppressive therapies — including the newer biologic therapies — have increased risk of lymphoma. There have been very few trials comparing the efficacy and safety of biologic therapy versus traditional systemic therapy for the treatment of psoriasis. Therefore, it is important for the clinician to evaluate treatment risks and benefits of each individual therapy for a given patient. An ideal psoriasis therapy would gain initial and rapid control of the disease, reducing the size and severity of plaque lesion. Because psoriasis is a life-long disease and is associated with a plethora of comorbidities, this therapy would also achieve and maintain long-term remission while minimizing adverse events (AEs) of treatment and improve quality of life while reducing the risk of comorbid disease. 15 Traditional systemic therapies such as MTX, cyclosporine, retinoids and psoralen ultraviolet therapy, may be effective and well tolerated for a short duration, but are associated with serious end-organ toxicities that limit their long-term use. 14,16,17 Newer biologic therapies more specifically target the immune factors responsible for psoriasis, potentially yielding greater efficacy with fewer and less severe toxicities. 14,18,19 Interpreting Data on Biologics The biologics currently FDA-approved for the treatment of psoriasis include anti-TNF agents etanercept, adalimumab and infliximab, the T-cell modulators alefacept, and the anti-IL 12/23 ustekinumab. Efficacy and safety of these biologics have been evaluated in many clinical trials for psoriasis patients, but over a short period of time (generally 12 to 24 weeks). 20 Although these treatments are relatively new to the management of psoriasis, many have been used for years in other diseases, including rheumatoid arthritis and Crohn’s disease. Long-term safety data are available from the treatment of these diseases, and it is often from this data that dermatologists extrapolate their safety in psoriasis. 21 Potential safety concerns regarding the use of biologics include a general dampening of the immune system, leading to reactivation of tuberculosis, development of opportunistic infections, malignancies, demyelinating diseases and congestive heart failure. 1,22,23 Safety outcomes are analyzed separately from efficacy, so uncovering real-practice clinical benefit from published data is not always straightforward. 24 Early clinical trials demonstrating efficacy of these biologics were limited to 12 to 16 weeks. 25 Because of the chronic nature of psoriasis therapy, questions regarding the long-term safety of these drugs remain. 23 Recent studies have examined safety and efficacy in maintenance therapy with little increase in serious adverse events. 25 However, no one will forget that efalizumab, a T-cell inhibitor previously approved in 2003 for the treatment of moderate-to-severe psoriasis that had initially shown great efficacy with a very good safety profile, was withdrawn from the market in 2009 after it was found to increase the risk of progressive multifocal leukoencephalopathy (PML), a rare and often fatal opportunistic demyelinating disorder. 26,27 Therefore, great caution remains with the use of biologic therapies in the long-term. This paper will help to address the risks and benefits of individual biologic therapies from the current literature.
Evidence for Individual TNF inhibitors
Infliximab is a chimeric (mouse-human) monoclonal antibody against TNF-α that was initially approved for use in the treatment of rheumatoid arthritis and Crohn’s disease. Infliximab is administered as an intravenous (IV) infusion, and in one randomized, controlled trial, 73% to 82% of patients receiving infliximab had an improvement in PASI score of at least 75%, compared with 18% of placebo-treated patients. 28 Since regimens for treatment of rheumatoid arthritis and Crohn’s disease are similar to the treatment regimen for psoriasis, it is plausible to extrapolate the safety data from these trials. 14 A number of adverse events have been reported with infliximab, the most common being infusion-related reactions and immunogenicity. 20 Nineteen percent of patients in clinical trials reported infusion-related reactions including headache, fever or chills, chest pain, hypo- and hypertension, dyspnea and injection-site reactions. 18,29,30 Given the common occurrence of these reactions, it is recommended that patients are monitored for approximately 2 hours after the infusion. Generally, these reactions are mild and easily managed, and rarely lead to discontinuation of treatment. 14 Etanercept is a TNF-α inhibitor approved in the United States and Europe for the treatment of psoriasis. Etanercept is a human dimeric fusion protein administered twice-weekly for the first 3 months and weekly thereafter, by subcutaneous injection. Unlike infliximab, etanercept is administered at home and monitoring is not required before or during treatment. During placebo-controlled trials, etanercept has shown efficacy in patients with moderate-to-severe psoriasis in 12-week studies as well as in maintenance studies. Following 48 weeks’ treatment with etanercept 25 mg twice weekly, 67% and 38% of patients achieved PASI-50 and PASI-75, respectively. 31 Etanercept has been evaluated for up to 144 weeks and was well tolerated with no increase in adverse events with increased weeks on treatment. 25,32 The most common adverse events in controlled trials were mild-to-moderate injection site reactions, including redness, itching, pain and swelling. These occurred in approximately 37% of patients receiving etanercept and rarely led to discontinuation of the drug. 14 Weight gain was also reported in some trials among etanercept-treated patients. 20 Rarely, pancytopenia was also seen (Enbrel package insert). Adalimumab, a fully human recombinant IgG1 monoclonal anti-TNF-α antibody, has been evaluated for up to 120 weeks in psoriatic arthritis and 60 weeks in psoriasis. 25 Adalimumab is approved at 40 mg dosing weekly and every-other-week. The Comparative Study of Humira versus MTX versus Placebo in Psoriasis Patients (CHAMPION) showed adalimumab was associated with a greater and more rapid reduction of psoriasis symptoms compared with MTX. 33 The most common adverse effects — noted in this study and others — were upper respiratory infections and nasopharyngitis. 1 Others included hypersensitivity, anaphylaxis, rashes, nausea, headache and abdominal pain. Few rare and serious adverse events included infections, malignancy, cerebrovascular events, osteoarthritis, kidney stones and coronary artery disease. 34 Patients followed for 1 to 2 years did not show increased rates of adverse events compared to patients at 12 weeks. 25,35
Evidence on TNF Therapies as a Group
Link to Lymphomas There have been several case reports of lymphoma or lymphoproliferative disorder (LPD) developing specifically in psoriasis patients on biologic therapies. 5,36-42 Nine of the 12 patients were receiving one biologic agent at the time of diagnosis, and the remaining three were receiving two biologic agents concomitantly. The most common type of lymphoma was cutaneous T-cell lymphoma (CTCL) (4/10), and the other types were unspecified B-cell non-Hodgkins lymphoma, one lymphoproliferative disease, one Epstein-Barr virus positive large B-cell lymphoma, one Hodgkin’s lymphoma, and one gastric mucosa-associated lymphoid tissue lymphoma. 5 In many cases, patients have been on previous immunosuppressive therapies in the past, many of which can potentially increase the risk of lymphoma. Also complicating the picture is that severe psoriasis also poses an inherent risk of malignancy. Furthermore, in several of these cases, lymphoma could have been present prior to initiating biologic therapy, but the treatment could have allowed the lymphoma cells to grow rapidly, rather than the drug causing the lymphoma. 5 These case reports allow for safety signal detection, but because lymphoma is rare to begin with, larger studies are needed to yield more information regarding the risk of lymphoma from biologic therapies. In one meta-analysis of anti-TNF antibody therapies in 2006, Bongartz et al found an increased risk of serious infections and a dose-dependent increase in the risk of malignancies in patients with rheumatoid arthritis treated with anti-TNF therapy. 43 The most common malignancy was non-melanoma skin cancer, and the second most common malignancy was lymphoma. This data, however, has been highly criticized. One problem was that this review excluded etanercept. Moreover, included trials were not adjusted for different duration of exposure to therapy, disease activity, and previous and concomitant DMARD therapies. Another large observational cohort study conducted in 2007 included 19,562 patients with 89,710 patient-years of follow-up. This study examined rheumatoid arthritis (RA) patients who received anti-TNF therapy compared to those who did not, and found that the probability of lymphoma was the same for both groups. 44, 45 In 2009 in a follow-up to the previous study, Bongartz et al completed another meta-analysis, this time including etanercept. In this analysis, they did not find a statistically significant increase in the risk of malignancy in etanercept-treated RA patients. 46 The authors also examined the effect of exposure duration and dose and found no statistically significant impact on the results. 5 These results were consistent with other published trials and meta-analyses of RCT data. 20,34,47 Finally, Leombruno et al analyzed data from 18 RCTs for the TNF agents involving more than 8,000 RA patients and found no significant increase in the risk of lymphoma at recommended dose of the anti-TNF agents. They did show higher risk of serious infections at higher doses of adalimumab and infliximab, but risk of death, SAE and overall malignancy were not increased. 48 Link to Infections All of the TNF inhibitors are associated with immunosuppression by nature of their pathophysiology. Reports of serious infections, including reactivation of tuberculosis, have been associated with all three of the TNF inhibitors mentioned above. 14 In general, no apparent differences have been observed between the infection rates for each of this class of medications. 49 Demyelinating disorders, including multiple sclerosis (MS), have also been reported in association with the TNF inhibitors. 50 TNF inhibitors have also been shown to exacerbate congestive heart failure (CHF) as well as contribute to new onset CHF. 51 However, the rate of new onset cardiovascular disease is lower in patients treated with TNF inhibitors compared with other patients with RA, suggesting that TNF blockade may have a beneficial effect on arteriosclerosis. 52 A German group conducted a risk-benefit assessment of treating rheumatoid arthritis with biologics based on registry data on mortality and found that the death rate in TNF-inhibitor-treated patients is higher than in the general population but lower than that in the control group of patients with RA. Furthermore, when TNF inhibitors were given for the usual indication, they found mortality is actually reduced compared to conventional therapy. 53 This finding was affirmed by another group who found that TNF inhibitors were found to be associated with a reduced mortality in women with RA, but not in men with RA. 52
Evidence for T-cell Inhibitors
Alefacept, a human, dimeric fusion protein, was one of the first biologics approved by the FDA in 2003. 54 Alefacept is made up of the terminal portion of leukocyte function associated antigen-3 (LFA-3), and reduces T-cell activation and depletes the number of active T cells. Alefacept is administered intramuscularly once a week for 12 weeks, followed by a 12-week treatment-free period. 14 Using a dosage of 15 mg weekly, PASI 75 scores at week 12 were found to be between 21% to 35%.54-56 Alefacept has demonstrated long psoriasis remission times in patients treated for up to 60 weeks, 25 and is generally well tolerated. The most common side effects include headache and upper respiratory infections. 57 The main safety concern is the induction of dose-dependent lymphopenia. 58 As a result, alefacept is contraindicated in patients with a low CD4+ T-cell count, and regular monitoring of lymphocytes is required during treatment. Other minor adverse include chills after induction of treatment, 59 and mild injection-site reactions. 60 In 2009, another T-cell modulator efalizumab was withdrawn from the European and U.S. markets after being linked to progressive multifocal leukoencephalopathy (PML). 17 This drug had shown great clinical efficacy but the company deemed the risks of PML outweighed the benefits and voluntarily pulled the drug from the market.
Evidence for Anti IL-12/23
Ustekinumab is a human monoclonal antibody that targets the p40 subunit of IL 12 and IL 23 and is the newest biologic approved for psoriasis on the U.S. market. PHOENIX 1 and 2 trials demonstrated excellent efficacy with ustekinumab 45 mg or 90 mg subcutaneous injection at weeks 0 and 4, and then every 12 weeks. 19 At week 12, 66.7% of the 45mg group and 75.7% in the 90 mg group had PASI 75. 17 Adverse events in Phase I and II studies were generally mild and included headaches, abdominal pain, arthralgias and common cold symptoms. 19, 61 The adverse events did not appear to be dose-related, were not significantly different for patients treated with placebo or either of the ustekinumab doses, and were not considered serious. 19 Some serious adverse events included infections, myocardial infarctions, a cerebrovascular accident, non-melanoma skin cancer and prostate cancer. There are very few trials comparing different biologic therapies to each other. In the ACCEPT trial, ustekinumab was studied head-to-head against etanercept for the treatment of moderate-to-severe plaque psoriasis. The primary endpoint of the trial was the percentage of patients achieving a PASI 75 at week 12. 68% and 74% of patients receiving ustekinumab 45 mg or 90 mg, respectively, achieved a PASI 75, compared with 57% of patients receiving etanercept 50 mg SC twice weekly for 12 weeks. Additionally, PASI 90 was observed in 36% and 45% of patients in these respective ustekinumab groups versus 23% of etanercept-treated patients. 19,62 In general, ustekinumab and etanercept were well tolerated with comparable rates of adverse events. The safety profiles of the various anti-TNF agents have also not been studied head-to-head. Gerloni et al reported a nearly equal rate of AEs among infliximab-treated patients and etanercept-treated patients, but nearly twice as many infliximab-treated patients as etanercept-treated patients discontinued their medication because of an AE. 49 This finding was corroborated in other studies, which might best be described as a difference in the tolerability of these medications. For instance, Brunasso et al found that more patients responded to infliximab, but long-term tolerability was higher for etanercept and adalimumab. 20 Patient tolerance to a specific drug is an important factor and should be taken in to consideration along with efficacy and safety when determining which drug to choose for a given patient. Compared to the T-cell inhibitor adalimumab, and the anti-IL 12/23 ustekinumab, the TNF inhibitors have been most extensively studied because of their broad application to a variety of diseases. It is generally assumed that because the biologic agents more specifically target the inflammatory cytokines responsible for psoriasis, these agents have better safety profiles compared to traditional therapies that globally suppress the immune system and can lead to organ toxicity, infections and cancer. However, we know that patients with severe psoriasis are more likely to develop malignancies because of their inherent disease. 14 As noted earlier, there is published data that both confirms and denies an increased risk of malignancy with biologic agents. Data from case reports, observational studies, RCTs and meta-analyses have generally indicated a favorable risk profile of the anti-TNFs with respect to lymphoma. 5 However, the risks associated with any of the biologics must be weighed against the benefits in a specific patient. Reich et al attempted to develop a standardized, risk-benefit algorithm, measured at the patient level, to examine results from the CHAMPION trial. They found that adalimumab was associated with four times as many AE-free response days, and demonstrated a superior benefit-risk profile. 33 They advocated using a standardized risk-benefit algorithm to allow clinicians to more accurately review the risks (safety and tolerability) versus the benefits (efficacy) of the various treatments, to better serve their patient. 33 Despite the fact that it is often difficult to ascertain a true risk given the many possible confounding variables, including disease duration, severity, previous treatments and lifestyle, it seems that with appropriate screening for serious infections, demyelinating diseases, and heart disease, any one of these biologics may prove to have an acceptable benefit to risk ratio for a given patient.
Proceeding Cautiously
Data published over the last decade demonstrate the improved efficacy of biologic therapies for psoriasis over conventional drugs. The medications appear safe and effective, and in the long-term have shown no increase in adverse events in published extension studies. However, lymphoma or other malignancies may not be detected until years after the initiation of therapy. 63 Furthermore, the interaction of these drugs with other medications may not yet be elucidated. Therefore, the long-term safety and efficacy of continuous treatment in real-life settings is not known. There is no standardized algorithm yet to aid the clinician in which biologic, if any, is appropriate. For each patient, the physician should review the event rates reported for a wide set of AEs from disparate RCTs, consider the individual patient and his/her comorbidities, and the risk-benefit evidence. Finally, applying the recommended screening before and during biological treatment helps to minimize adverse events related to therapy. 64-66 As we continue, well-designed prospective cohort studies in patients with moderate to severe psoriasis are needed to assess the complex relationship among psoriasis, comorbidities, cancer risk, and medications. Dr Frankel is a clinical dermatopharmacology fellow in the Department of Dermatology at Mount Sinai Medical Center, New York, NY. Dr. Goldenberg is Assistant Professor of Dermatology and Pathology, Medical Director of the Dermatology Faculty Practice, Mount Sinai School of Medicine in New York. He is Board Certified in Dermatology and Dermatopathology. Disclosures: The authors have no conflicts of interest with any material found in this article.
