T-Cell–Targeting Biological Therapies for Psoriasis

Although alefacept was the first biological therapy approved in the United States in January 2003 for the treatment of adult patients with moderate to severe chronic plaque psoriasis, it was later withdrawn from the market by the manufacturer in 2011 (see Table 1 ). Alefacept is a recombinant dimeric fusion protein that consists of the extracellular CD2-binding portion of the human LFA-3 linked to the Fc (hinge, CH2 and CH3 domains) portion of human immunoglobulin G1 (IgG1). LFA-3 binds to the CD2 receptor located on memory-effector T lymphocytes, thus inhibiting these cells and thereby limiting the propagation of the inflammatory response. Alefacept was dosed either intramuscularly (15 mg) or intravenously (IV, 7.5 mg) in a regimen of 12 weekly injections. Although the proportional response to alefacept was fairly limited, a subset of patients (∼20%) did achieve a high response with significant duration of 2.0 to 3.5 months and occasionally up to 1 year as defined by maintenance of psoriasis area and severity index (PASI)-75. This responder cohort exhibited unique patterns of gene regulation in response to alefacept, characterized by the suppression of the genes for T-cell receptors as well as the CD2 and CD3 costimulatory molecules. Thus, optimal response to alefacept (and indeed other biological therapies) may depend on the differential classification of responder patients based on pretreatment gene expression analysis.

Efalizumab is a recombinant humanized IgG1 monoclonal antibody that binds to human CD11a, a subunit of LFA-1, which is expressed on all leukocytes. Mechanistically, efalizumab inhibits the binding of LFA-1 to intercellular adhesion molecule-1, which inhibits T-cell activation, adhesion, and migration to sites of inflammation, including psoriatic skin. To support the registration of efalizumab in 2003 (see Table 1 ), 4 randomized controlled studies were performed in adults with chronic, stable, plaque psoriasis. Patients received doses of 1 mg/kg or 2 mg/kg or placebo administered once a week for 12 weeks. The proportion of patients who achieved a PASI-75 response ranged from 22% to 39% across the 4 clinical trials. During the clinical program, the use of efalizumab was associated with various adverse events (AEs) that included serious infections, malignancy, immunosuppression, and, notably, thrombocytopenia, hemolytic anemia, as well as a characteristic worsening of psoriasis in some patients. With increasing temporal exposure to efalizumab, progressive multifocal leukoencephalopathy (PML) was observed in 3 patients who had exposure greater than 3 years. These events ultimately resulted in the voluntary withdrawal of efalizumab from the market in 2009.

Ustekinumab is the most recent biological therapy to join the armamentarium against psoriasis gaining registration in both the United States and the European Union in 2009 (see Table 1 ). Ustekinumab is a fully human monoclonal antibody that specifically binds to the p40 protein subunit, which is a component of the cytokines IL-12 and IL-23. In so doing, ustekinumab inhibits human IL-12 and IL-23 from binding to its cognate receptor on natural killer (NK) and T cells, IL-12Rβ1/β2 for IL-12 and IL-12Rβ1/23R for IL-23. IL-12 and IL-23 are naturally occurring cytokines that are involved in inflammatory and immune responses, such as natural killer cell activation and CD4+ T-cell differentiation and activation. Overexpression of IL-12 and IL-23 has been documented in psoriasis lesions, and the levels of these cytokines may correlate with disease severity. Two randomized controlled clinical trials that included more than 2000 subjects supported the registration of ustekinumab in psoriasis. Subjects were randomized to placebo, 45 mg or 90 mg of ustekinumab and received subcutaneous doses at Weeks 0, 4, and 16. At the week 12 primary end point, the proportion of subjects who experienced an improvement in PASI-75 ranged from 66% to 76% (see Table 2 ). Although subjects who weighed 100 kg or less responded similarly to either the 45- or 90-mg dose, those subjects who weighed greater than 100 kg experienced higher response rates with the 90-mg dose (68%–71% PASI-75) relative to the 45-mg dose (49%–54% PASI-75). Through the 52-week treatment regimen, 89% subjects who displayed a 75% improvement in their psoriasis retained the response with continued dosing. The results demonstrate the validity of targeting IL-12/23 in psoriasis and also contribute additional insights as to the role of these cytokines in psoriasis pathophysiology. The most notable precautions related to the use of ustekinumab were observed to include serious infections, malignancies, anaphylaxis, and reversible posterior leukoencephalopathy syndrome. Emerging long-term data on the safety of ustekinumab are reviewed in subsequent paragraphs.

Tumor Necrosis Factor-α–Targeting Biological Therapies for Psoriasis

The TNF class of biologics (etanercept, infliximab, and adalimumab) appeared following the initial registration of both alefacept and efalizumab (see Table 1 ). Targeting TNF-α in psoriasis was based on the identification of elevated levels of the cytokine in psoriatic skin lesions and in the blood of patients with psoriasis. Retrospectively, it can be asserted that anti–TNF-α therapies have shown remarkable efficacy in treating psoriatic skin lesions, enthesitis, dactylitis, as well as joint pain and, importantly, the capacity to inhibit radiographic progression of joint damage. Etanercept, the first of the registered TNF biological agents, is a soluble form of the p75 TNF receptor, stabilized by the attachment of the human IgG1 Fc region, which competes with the natural cell-surface TNF receptor for the relevant ligand. Etanercept mediates its function through the binding of either TNF-α or TNF-β (lymphotoxin alpha) thereby inactivating the targeted cytokines. This effect dampens systemic inflammation through altered neutrophil migration as well as dendritic cell and T-cell maturation. Today, etanercept is typically provided to patients as a single-use prefilled syringe or as a single-use autoinjector for subcutaneous administration. The US Food and Drug Administration (FDA)–approved initial dosage for etanercept in psoriasis of 50 mg twice weekly for 12 weeks is higher than that in the other FDA-approved indications for etanercept (25 mg twice weekly for 12 weeks). In contrast, the European Medicines Agency–approved dose of etanercept is consistent with the other indications at 25 mg twice weekly for 12 weeks. Maintenance doses of 50 mg weekly are recommended similarly in the United States and the European Union. The pivotal trials evaluated etanercept in 2 well-controlled clinical trials that included more than 1200 patients. At the primary end points, the proportion of patients achieving a PASI-75 was 46% (study 1) and 47% (study 2) for patients receiving 50 mg twice weekly (see Table 2 ). For those patients who received 25 mg twice weekly, the proportion of PASI-75 responders was 32% in each study. Responses with etanercept were evaluated through 24 weeks wherein improvement continued up to 59% PASI-75 responders for those patients on 50 mg twice weekly and 44% PASI-75 responders for those on 25 mg twice weekly. However, loss of response was observed in patients who experienced a decrease in dose from 50 mg to 25 mg at week 12, with only 70 out of 91 (77%) maintaining a PASI-75 response at week 24. The most serious precautions relevant to etanercept are typical of the TNF class as a whole and include infections (including tuberculosis), malignancies (including lymphoma), anaphylaxis, pancytopenia, aplastic anemia, demyelinating disease, and the development of lupuslike syndrome or autoimmune hepatitis. In addition, it has been reported that mostly mild injection site reactions can occur in approximately 37% of patients.

Infliximab is a chimeric monoclonal antibody with specificity for both soluble and membrane-bound forms of TNF-α and, in that regard, has a more restricted specificity versus etancercept. Infliximab potentially inhibits a variety of functions, including induction of proinflammatory cytokines (eg, IL-1, IL-6), enhancement of leukocyte migration and expression of adhesion molecules by endothelial cells and leukocytes, activation of neutrophil and eosinophil functional activity, induction of acute phase reactants, and tissue degrading enzymes produced by synoviocytes and/or chondrocytes. Because infliximab can bind to cell-associated TNF-α that has already bound to its cognate receptor, it also induces apoptosis resulting in cell lysis, which is thought to be one of the mechanisms of action of this therapy. Infliximab was studied in 2 phase 3 trials that included 1213 patients with moderate to severe psoriasis. Patients were dosed by IV infusion with either 3 mg/kg or 5 mg/kg at weeks 0, 2, and 6, followed by a maintenance dosing regimen at every 8 weeks. At the week 10 primary end point, the proportion of patients who achieved a PASI-75 response was 70% for the 3-mg/kg dose versus 75% to 80% for the 5-mg/kg dose (see Table 2 ). The infliximab trials also demonstrated a reduction in response over time, similar to the other biological therapies, with only 61% of those that demonstrated a PASI-75 improvement at week 10 being maintained at week 52. Nevertheless, it is recognized that few dermatologists have infusion centers or use IV-administered infliximab relative to other biologics that are subcutaneously injected. The most serious precautions related to infliximab therapy include serious infections (including tuberculosis), invasive fungal infections, malignancies (including lymphoma), hepatitis B virus reactivation, hypersensitivity, cytopenia, hepatotoxicity, heart failure, demyelinating disease, and lupuslike syndrome. Because infliximab is IV administered, infusion-related reactions are a concern for approximately 16% of patients, although these tend to be mostly mild, with less than 1% considered serious, and can be managed with appropriate medications and infusion rate adjustments.

Adalimumab is a fully human monoclonal antibody with specificity for TNF-α, thus blocking the interaction of TNF-α with the cell-surface TNF receptors. Like infliximab, adalimumab binds to both soluble and receptor-bound TNF, which can result in cell lysis in the presence of complement. The safety and efficacy of adalimumab was evaluated in 2 randomized and controlled trials that included 1696 subjects with moderate to severe chronic plaque psoriasis. Patients received subcutaneously injected adalimumab at an initial dose of 80 mg at week 0 followed by 40-mg doses every other week thereafter. The proportion of patients who achieved a PASI-75 from baseline to week 16, the primary end point of the trials, was 71% and 78% for studies 1 and 2, respectively (see Table 2 ). The proportion of subjects who maintained a PASI-75 response from week 33 through week 52 was 79% of those who reached PASI-75 at week 16. Like most fixed-dose drugs, a lesser response was observed in heavy patients (>125 kg). Interestingly, 43% of the week 16 PASI-75 responders maintained a PASI-75 response at week 52 even with placebo treatment from week 33 onward, possibly indicating an impact on the natural history of disease in a subset of patients. The most serious precautions related to the use of adalimumab are similar to the other TNF-biologic class members, etanercept and infliximab. Consequently, they include serious infections, invasive fungal infections, malignancies, anaphylaxis or serious allergic reactions, hepatitis B virus reactivation, pancytopenia, heart failure, lupuslike syndrome, and demyelinating disease. The most common adverse reactions related to the use of adalimumab are infections (eg, upper respiratory, sinusitis), injection site reactions, headache, and rash.

A fourth potential member of the TNF class remains in development for psoriasis. Certolizumab pegol (CZP) is a pegylated anti-TNF agent that is composed of a TNF-α–targeting Fab’ portion of an antibody that has been pegylated to preserve stability of the therapy. CZP has been studied in a controlled phase 2 trial of 176 patients with moderate to severe psoriasis. Patients received either placebo or 400 mg CZP at week 0 followed by placebo or CZP (200 or 400 mg) every other week dosed subcutaneously through week 10. At the week 12 primary end point for the study, 75% and 83% of patients in the 200-mg and 400-mg groups, respectively, achieved PASI-75 versus only 7% of those who received placebo. Serious AEs (SAEs) occurred in 3%, 5%, and 2% of CZP 200-mg, CZP 400-mg, and placebo patients, respectively.

Long-term Safety Studies

Ustekinumab has now been evaluated for 5 years in 800 patients (517 of whom completed the study) demonstrating a stable clinical response and safety profile that are conducive to the chronic management of psoriasis. Patients were initially randomized to either placebo or ustekinumab (45 mg or 90 mg) at weeks 0 and 4 and every 12 weeks thereafter. However, partial responders were permitted to adjust their dosing interval to every 8 weeks. The clinical response was generally maintained through week 244 with a PASI-75 achieved in 63.4% and 72.0% patients receiving the 45-mg and 90-mg doses, respectively. Concomitant with such clinical responses, improvements in HRQOL as measured by the Dermatology Life Quality Index (DLQI) were also consistently maintained through the 5-year trial evaluation period. Moreover, immunogenicity rates remained low through year 5, with antibodies to ustekinumab detected in only 5.2% of patients. The extended trial was calculated to span 3104 patient-years of follow-up, with rates of overall AEs, SAEs, serious infections, malignancies, and major adverse cardiovascular events that were generally consistent over time and comparable between doses. Notably, the cumulative rates of overall AEs, AEs leading to discontinuation, SAEs, infections, malignancies, and major adverse cardiac event (MACE) were generally comparable between patients receiving ustekinumab 45 and 90 mg, suggesting no dose effect. There were 32 serious infections reported in 30 patients, 14 reports of nonmelanoma skin cancers, and 15 reports of other malignancies. Also, there were 10 cases of MACE (8 in the 45-mg group and 2 in the 90-mg group) that occurred in patients with at least 3 established cardiovascular risk factors. Thus, through 5 years of continuous treatment, ustekinumab maintained a stable effectiveness and safety profile in patients with psoriasis that was consistent with the observations seen in the shorter-term pivotal trials used for product registration. These results help dermatologists determine the likelihood of treatment success in patients with psoriasis who may be candidates for biological therapies, such as ustekinumab. Thus, the results confirm that ustekinumab is an effective and well-tolerated therapeutic regimen that is appropriate for long-term management of patients with moderate to severe psoriasis.

Collectively, the use of TNF biologics has been found to reduce the risk for myocardial infarction (MI) in patients with psoriasis. Wu and colleagues performed a retrospective cohort study spanning 6 years between 2004 and 2010 to investigate the impact of anti-TNF therapy on MI. The cohort included patients who had received diagnoses of psoriasis or PsA. The study population of Kaiser Permanente Southern California health system included a total of 8845 patients composed of 1673 patients who received a TNF-inhibitor for at least 2 months (TNF-inhibitor cohort), 2097 who were TNF-inhibitor naive and received other systemic agents or phototherapy (oral/phototherapy cohort), and 5075 who were not treated with TNF-inhibitors, other systemic therapies, or phototherapy (topical cohort). The collective cohort was observed for a median of 4.3 years translating into 42,424 patient-years of follow-up. The entire cohort experienced 221 episodes (2.5%) of incident MI, for an overall rate of 5.21 per 1000 patient-years. The incident rates of MI for the TNF-inhibitor, oral/phototherapy, and topical cohorts were 3.05, 3.85, and 6.73 per 1000 patient-years, respectively ( P <.001). After adjusting for MI risk factors, the TNF-inhibitor cohort had a 50% lower hazard of MI compared with the topical cohort (adjusted hazard ratio, 0.50; 95% confidence interval). Future and more comprehensive research in this area is still needed to better define the potential of TNF therapy in reducing the risk of major adverse cardiovascular events in patients with systemic inflammatory conditions.

Etanercept has been studied in open-label extensions of controlled trials for up to 4 years. In the 108 patients that completed the treatment regimen, the incidence of SAEs (infections, malignancies, or cardiovascular events) did not increase over time. The numbers of AEs per 100 patient-years of treatment were measured at 96.9 for infections and 0.9 for serious infections, the latter of which included bronchitis, cellulitis, fasciitis, diverticulitis, enteritis, and viral meningitis. The most common infections in the study were nasopharyngitis (26.1 events per 100 patient-years) and upper respiratory tract infections (14.9 events per 100 patient-years). There were no reports of opportunistic infections or tuberculosis reactivation. The rate for malignancies was found to be similar to that in the general population, and the rate did not increase with continued exposure to etanercept. Nineteen malignancies were reported through the study, with 6 nonmelanoma skin cancers and 5 nonskin malignancies being reported as serious. However, no cases of malignant melanoma or lymphoma were reported. Several cardiovascular events were reported in the study, but these did not correlate with etanercept dose of time on therapy. The adjusted event rates were 2.8 per 100 patient-years for cardiovascular events and 1.7 per 100 patient-years for serious cardiovascular events, the latter of which included 2 MIs and 1 congestive heart failure that were considered possibly related to etanercept use. Consequently, these studies support the long-term safety for the use of etanercept in patients with chronic plaque psoriasis.

Infliximab has been studied for more than 5 years in specific populations with psoriasis. This controlled trial that included 54 Japanese patients observed the safety of infliximab for 78 weeks. SAEs were reported in 6 patients and consisted of infections (herpes zoster) and malignancies (adenoma). The most common AEs reported were nasopharyngitis (50%), back pain (16%), tinea pedis (12%), arthralgia (12%), headache (10%), and abnormal liver function tests in 10% of patients. This study supports the safety of infliximab in the psoriasis population over the long-term and demonstrates that infliximab is generally well tolerated for periods of up to 78 weeks.

Beyond the 52-week pivotal trials in psoriasis, adalimumab has been studied in patients with psoriasis continuously treated for more than 3 years. The study consists of an open-label extension to the REVEAL controlled clinical trial in which patients received doses of either 40 mg every other week for those that indicated a PASI-75 response or 40 mg weekly for those patients who failed to achieve PASI-50 relative to their enrollment baseline scores. The data indicated that the AE profile for adalimumab as a result of this 3-year open-label extension was consistent with that observed in the initial controlled portion of the REVEAL trial. Indeed the rate of AEs declined through the study period with 245 events per 100 patient-years as compared with the 399 events per 100 patient-years observed in the original REVEAL trial. Similarly, the rate of patient discontinuation on therapy declined with increasing exposure to adalimumab. There were no reported cases of tuberculosis, lupuslike syndrome, or demyelinating disorders in the extension study. Additionally, the rates of infections, malignancies, and cardiovascular events were similar between the long-term extension study and the controlled REVEAL trial. The data, therefore, support the stable safety profile of long-term adalimumab use in patients with moderate to severe psoriasis.