The development of biologic agents in the management of cutaneous disorders has become firmly established worldwide. Biologic agents have been defined as those that can only be produced by living systems and are protein-based therapies. These therapies include monoclonal antibodies, soluble receptors, or cytokines designed to modulate the human immunologic response. Since the approval of alefacept (Amevive, Astellas) in 2003, biologic agents have had the biggest impact on psoriasis management. It has been demonstrated that psoriasis can have a significant impact on the quality of life of patients and produce significant disability.1,2 Prior to the development of biologic therapy, many patients with moderate to severe psoriasis were frustrated with their management and often gave up on treatment. 1 The advancement of biologic therapy in the treatment of psoriasis was demonstrated to be of significant benefit in improving moderate to severe cutaneous disease, controlling psoriatic arthritis, and producing a significant improvement in the quality of life of psoriatic patients. With greater insights into the immunologic pathogenesis of psoriasis, newer therapies have been developed with impressive results.
Despite these impressive therapeutic advances, biologic agents are a focus of increasing concern for their potential side effects. The US Food and Drug Administration (FDA) has issued warnings about serious infections, neurologic complications, malignancies, and death.3,4,5 A voluntary removal from the market of efalizumab (Raptiva, formerly Genentech, Inc.) by the manufacturer due to reported cases of progressive multifocal leukoencephalopathy (PML) was a stark reminder of the potential unforeseen side effects of these agents over time.6 The cost of administering biologic agents is very high in an economic environment burdened by the already staggering cost of health care delivery.
The use of biologic agents in the management of psoriasis has demonstrated the significant benefit that these drugs can have in the management of challenging and debilitating diseases. With a greater appreciation and further discovery of immunologic factors in the pathogenesis of cutaneous diseases, physicians and researchers will develop newer biologic agents for specific immunologic targets involved in cutaneous disease. An area of need for further study is the impact of biologic therapy on psoriasis related comorbidities, such as cardiovascular disease and progressive destructive arthritis. Genomic assessments of therapeutic responses to the biologic agents in the treatment of cutaneous disorders may provide future insights into the best management practice for dermatologic diseases with biologic agents.7 Biologic agents are only at the threshold of greater advancement in the management of cutaneous disease.
Biologics in the Management of Psoriasis
The management of patients with moderate to severe psoriasis using conventional treatments failed to meet the needs of many of these patients. Conventional therapies demonstrated limited efficacy, cumulative toxicities, and patient inconvenience. A survey by the National Psoriasis Foundation in 1998, prior to the biologics, indicated that patients with moderate to severe psoriasis were not adequately treated. Among patients with severe psoriasis, 78 percent were frustrated with treatment, and 32 percent felt their treatment was not aggressive enough.1 Since the approval of the first biologic agent (alefacept) specifically for the treatment of cutaneous psoriasis in 2003, many biologic agents have been approved by the FDA for the treatment of cutaneous psoriasis and psoriatic arthritis. In contrast to the broad-acting conventional systemic therapies for psoriasis, the biologic agents have very selective targeted immunologic actions.
The understanding of the pathogenesis of psoriasis shifted from a disorder of keratinocyte proliferation to a disorder of Th1 and Th17 cell-mediated activity. Psoriasis is a chronic immune disorder mediated by T-cells that impact the skin and joints. Biologic agents in the treatment of psoriasis can be categorized as agents that inhibit T-cells, inhibit tumor necrosis factor factor alpha, and that target interleukin 12 and interleukin 23.8 These specific mechanisms of action can impact efficacy, safety, and duration of therapeutic benefit.
Alefacept is a fully human LFA-3/IgG1 fusion protein that targets CD2. This results in inhibition of Tcell activation and induces selective apoptosis of memory T-cells (CD45RO+).9 Because it selectively targets CD2, which is expressed on CD45RO+ memory Tcells, alefacept inhibits only the pathogenic effector memory T-cells.10 This selective immunomodulatory effect provides alefacept with one of the best safety profiles among the biologics in the treatment of psoriasis. Alefacept is administered as a 15mg intramuscular injection every week for 12 weeks, followed by a 12 week drug-free interval. If clinically indicated, the 12- week treatment course can be repeated.11 It is the only biologic agent that has demonstrated potentially remitive effects, with some patients receiving over one year of remission following a 12-week treatment course. Improvement with alefacept is slow, and maximal benefit usually occurs several weeks after the last injection. A majority of patients do not reach a PASI 75.12 In a randomized, double-blind placebo-controlled phase III trial, 33 percent of patients treated with 15mg weekly for 12 weeks achieved 75 percent improvement in PASI scores at some point during treatment or 12 weeks of follow up.13
Efalizumab is a recombinant humanized monoclonal IgG antibody directed against alpha subunit of CD11a of LFA-1, found in the surface of T-cells. This results in a blockage of LFA-1 mediated T-cell adhesion. 14 Although approved by the FDA for the treatment of cutaneous psoriasis in 2003, it was withdrawn by the manufacturer due to long-term safety concerns for PML.15
The tumor necrosis factor-α (TNF-α) biologic agents have represented a major advancement in the treatment of cutaneous psoriasis and psoriatic arthritis. TNF-α plays an important role in inflammation and is an end-stage product of the inflammatory cytokine cascade.16 TNF-α levels are increased in the serum and cutaneous plaques of patients with active psoriasis and joints of patients with psoriatic arthritis. 17,18 TNF blockade has resulted in significant improvement in cutaneous disease and psoriatic arthritis. Infliximab (Remicade, Centocor Ortho Biotec, Inc.), adalimumab (Humira, Abbott Laboratories) and etanercept (Enbrel, Amgen Corp.) are all FDA approved for the treatment of psoriasis and psoriatic arthritis. Golimumab (Simponi,Centocor Ortho Biotec, Inc.) is approved for the treatment of psoriatic arthritis only. All of these agents have demonstrated significant clinical efficacy in the management of psoriatic arthritis and cutaneous psoriasis.
Etanercept is a receptor antibody fusion protein that binds soluble TNF-α and lymphotoxin. It was approved by the FDA in 1998 for rheumatoid arthritis, in 2002 for psoriatic arthritis, and in 2004 for the treatment of moderate to severe plaque psoriasis. The recommended dosing regimen for etanercept is 50mg subcutaneously twice a week for 12 weeks, followed by 50mg subcutaneously once per week.19 Many clinical trials have demonstrated the efficacy of etanercept in the treatment of chronic moderate to severe plaque psoriasis. A phase III, double-blind, placebo controlled, randomized trial evaluated the long-term efficacy of etanercept for up to 96 weeks for moderate to severe psoriasis. At week 12, 47 percent of etanercept- treated patients achieved a PASI 75 response and 52 percent at week 96.20 Because etanercept has been on the market since 1998 when it was approved for rheumatoid arthritis, physicians may feel more comfortable prescribing this biologic because of long-term safety data, compared to newer agents with shorter safety observation periods.
The management of moderate to severe psoriasis in children and adolescents is very challenging. Etanercept was demonstrated to be safe and efficacious in children and adolescents with moderate to severe psoriasis. In a double-blind, placebo controlled clinical trial involving 211 patients between four and 17 years of age, patients were randomized to 0.8mg/kg of etanercept weekly or placebo. A PASI 75 response was obtained at 12 weeks in 57 percent of etanercept-treated patients compared to 11 percent of patients treated with placebo.21
Infliximab is an anti-TNF-α chimeric monoclonal IgG1 antibody that binds soluble TNF-α and binds trans membrane TNF-α. It received FDA approval in 2006 and is indicated for the treatment of adult patients with chronic severe (i.e., extensive and/or disabling) plaque psoriasis who are candidates for systemic therapy and when other systemic therapies are medically less appropriate.22 It forms stable complexes with TNF and has more rapid clinical response compared to etanercept.23 Infliximab's relatively rapid onset of action is advantageous for patients with rapid worsening of psoriasis, pustular psoriasis, erythrodermic psoriasis, and patients who need rapid clearing for socio-economic reasons. As with other TNF inhibitors, infliximab has been associated with concerns for possible development of neutralizing antibodies in a minority of patients that may reduce efficacy of treatment over time.24 The degree of clinical response to infliximab has been impressive in clinical trials. In a double-blind study of 378 patients with moderate to severe psoriasis, infliximab was administered in 5mg/kg infusions at weeks 0, 2, 6, and every eight weeks versus placebo. At week 10, 80 percent of patients receiving infliximab compared to three percent of placebo patients obtained a PASI 75 response.25
Adalimumab is a fully human monoclonal IgG1 antibody against TNF-α. Adalimumab received approval by the FDA for the treatment of moderate to severe psoriasis in 2008, after previous approval for psoriatic arthritis. After an initial 80mg subcutaneous loading dose, the drug is administered 40mg subcutaneously every other week. In the REVEAL trial, a double-blind, placebo-controlled, Phase III trial, adalimumab 40mg every other week for 15 weeks achieved a PASI 75 response in 71 percent of patients compared to seven percent of placebo controls.26
Although the monoclonal TNF blockers may produce higher degrees of clearing and more rapid response than etanercept, there may be greater concerns for infections. All TNF blockers have been associated with life-threatening infections, reactivation of tuberculosis, invasive fungal infections, demyelinating disorders, and worsening of CHF. A baseline PPD skin test is recommended before starting any TNF blockers due to concerns for latent tuberculosis.8,27
The discovery that the Th17 pathway plays an important role in psoriasis development as well as Th1 has been an important scientific advance in biologic development. Ustekinumab (Stelara, Centocor Ortho Biotec, Inc.) is a fully human monoclonal antibody that binds with high affinity and specificity to the p40 protein subunit of the human cytokines interleukin (IL)-12 and IL-23. This inhibits the bioactivity of IL-12 and IL-23 by preventing these cytokines from binding to their receptor proteins.28 IL-12 and IL-23 are heterodimeric cytokines that share a common p40 protein subunit that is linked to a p35 subunit on IL- 12 and p19 subunit on IL-23.29
It is suspected that IL-12 and IL-23 play a significant role in the pathogenesis of psoriasis.30
In the double-blind Phoenix 2 study, patients were injected subcutaneously with ustekinumab with 45mg or 90mg at baseline, four weeks, and then every 12 weeks. Of the patients who received 45mg, 66.7 percent achieved a PASI 75 at 12 weeks, compared to 75.7 percent of those patients administered 90mg.31
ABT-874 (Abbott) is a human monoclonal antibody that also targets the p40 subunit of IL-12 and IL-23. This drug has not yet been approved by the FDA. In a phase II, double-blind, placebo-controlled study, 180 patients were randomized to five different dose regimens or placebo for psoriasis. Patients were randomized to receive ABT-874 200mg subcutaneously one dose, 100mg subcutaneously every other week for 12 weeks, 200mg subcutaneously every week for four weeks, 200mg subcutaneously every other week for 12 weeks, 200mg subcutaneously weekly for 12 weeks, or placebo. The drug showed a high level of efficacy. At 12 weeks, 63 percent of patients receiving one dose of 200mg achieved a PASI 75 response. Also noted at 12 weeks, 93 percent of the 100mg everyother- week, 90 percent of the 200mg every week for four weeks, 93 percent of the 200mg every-otherweek, and 90 percent of the 200mg every week achieved a PASI 75.32
Ustekinumab and etanercept were compared in a head-to-head trial measuring efficacy. The ACCEPT study randomly assigned 903 patients with moderate to severe psoriasis to receive subcutaneous injections of either 45 or 90mg of ustekinumab at weeks 0 and 4 or high-dose etanercept 50mg twice weekly for 12 weeks. The primary endpoint was the proportion of patients with at least a PASI 75 percent improvement. A PASI 75 percent improvement at week 12 was noted in 67.5 percent of patients who received 45mg of ustekinumab and 73.8 percent of patients who received 90mg of ustekinumab. In comparison, 56.8 percent of those who received etanercept reached a PASI 75 at 12 weeks. Of interest, among those patients who did not reach a PASI 75 response with etanercept, 48.9 percent had at least 75 percent improvement within 12 weeks after crossover to ustekinumab. The clinical response to ustekinumab was less in the study for those who previously failed etanercept as initial therapy in comparison to those without previous etanercept therapy. This raises the question of whether patients who fail TNF inhibitors may be a subset of more therapeutically challenging patients.33 In general, patients were less likely to respond to ustekinumab if they were overweight, had psoriatic arthritis, and failed previous biologics.
Broad genomic assessments of therapeutic responses to biologic agents in the treatment of cutaneous disorders is an exciting new area of drug management. Patients who were enrolled in the ACCEPT study were evaluated for their genomic response to etanercept and ustekinumab.7 Skin biopsies were obtained in a subset of patients at baseline, week 1 and week 12. Microassay analyses compared nonlesional skin to lesional skin at baseline. Patients who achieved a PASI 75 response to each agent had significant changes in approximately 4,000 transcripts, compared to untreated lesions. This indicated a significant resolution of pathologic gene circuits. Of interest, the top 10 genes downregulated at week 12 by ustekinumab overlapped with nine or the top 10 genes downregulated by etanercept at week 12, however, only two of the top 10 genes upregulated overlapped. The genes specifically upregulated by ustekinumab included a number of keratin genes demonstrating the specific effect of ustekinumab on keratonocytes, compared to etanercept.7
The Impact of Biologics on Co-morbid Conditions
Evolving scientific data support the possible association of specific co-morbid conditions with psoriasis. The direct link between skin changes of psoriasis and these co-morbid conditions remains unclear but may be related in part to systemic inflammation. Biologic agents have the potential to reduce systemic inflammation, but their impact on these co-morbidities is unknown and in need of study.
There is an increased prevalence of metabolic syndrome in patients with moderate to severe psoriasis34 and cardiovascular disease.35 In a population-based cohort study from the General Practice Research Database in the United Kingdom, patients with severe psoriasis had an adjusted relative risk of myocardial infarction of 7.08, compared to 1.54 with mild psoriasis. The risk of myocardial infarction was especially high in younger patients with severe psoriasis. At age 30, a patient with severe psoriasis had a hazard ratio of MI of 3.10.36
It is not known what the impact of biologic therapy will be in coronary artery disease in patients with severe psoriasis due to reduction in systemic inflammation. It is known that patients with severe rheumatoid arthritis have a higher incidence of cardiovascular disease. One study suggested that the risk of developing cardiovascular disease is lower in patients with rheumatoid arthritis who are treated with TNF inhibitors.37 Another British study indicated that improvement in coronary heart disease was limited to those patients who had a clinical response to treatment. 38 The impact of biologic therapy on the risk of cardiovascular disease in patients with severe psoriasis is an important area for future study.
The Use of Biologics Beyond Psoriasis
Physicians are beginning to treat diseases other than psoriasis with biologic therapies, although currently off-label. Most of the reports in the literature have been case reports or clinical trials with small numbers of patients, which make efficacy and side-effects difficult to appreciate. Use of anti-TNF-α therapies has been reported in sarcoidosis, hidradenitis suppurativa, cicatricial pemphigoid, Behcet's disease, pyoderma gangrenosum, multicentric reticulohistiocytosis, apthous stomatitis, SAPHO syndrome, Sneddon- Wilkinson disease, pityriasis rubra pilaris, eosinophilic fascitis, panniculitis, necrobiosis lipoidica diabeticorum, dermatomyositis, and scleroderma.39 Alefacept was reported to be an effective therapy for steroid resistant graft versus host disease (GVHD), but some patients developed CMV reactivation.40 Treatment-refractory lichen planus was effectively treated in two patients with alefacept.41 Alefacept has also been reported in the treatment of alopecia areata. A course of alefacept produced improvement in four patients with severe alopecia areata in one case series.42 In a prospective open-label study of nine adult patients with moderate to severe atopic dermatitis, only two of nine patients treated with alefacept had significant improvement at 18 weeks.43 Prior to its voluntary removal from the market, in some small studies efalizumab was reported to be beneficial for atopic dermatitis in children and adults.44,45
Sarcoidosis is one condition that has shown promising results when treated with biologic agents. Sarcoidosis is a chronic granulomatous disease in which TNF-α appears to play a major role.46 In a review of treatment outcomes in 54 patients with lupus pernio, infliximab appeared superior to systemic corticosteroids. Infliximab infusion achieved resolution or near resolution in 77 percent of patients, compared to 29 percent with corticosteroids. 47 Etanercept, even used in high dosage, may be less effective for the treatment of cutaneous sarcoidosis than the monoclonal antibodies infliximab and adalimumab.48
The use of TNF-α blockers in the management of refractory hidradenitis suppurativa (HS) has been promising. In a systematic review of the medical literature evaluating TNF-α blockers in the treatment of hidradenitis suppurativa, a total of 105 patients were identified.49 Most case reports and series reported treatment with infliximab (52/105). A positive treatment outcome was reported in 90/105 cases, but only 15/105 cases had long-term remission. A long-term study of 10 patients with hidradenitis suppurativa treated with a single course of infliximab infusions at 0, 2, and 6 weeks demonstrated improvement in all patients.50 Adalimumab has been demonstrated to be useful in a dose of 40mg every other week.51 A prospective clinical trial of open-label etanercept demonstrated minimal evidence of significant clinical benefit in the treatment of hidradenitis suppurativa with 50mg of etanercept subcutaneously weekly.52
On the Threshold
In summary, the biologics have become firmly established as important therapeutic agents in the management of moderate to severe psoriasis. A significant positive impact on disability and quality of life has been clearly demonstrated for psoriasis patients. Despite their significant clinical advances, there has been increasing concern for serious side effects resulting in serious infections, malignancies, and death. The voluntary removal of efalizumab from the market due to PML complications developing after three years of therapy demonstrated the concern for serious unforeseen side effects occurring years after a biologic treatment is initiated. Due to concerns for unforeseen side effects of biologics over time and the evolution of biologic agents with new mechanisms of action that lack long-term safety data, many physicians may continue to embrace older established agents. As our understanding of the immunology of cutaneous diseases advances, potential biologic targets for other cutaneous disorders will be identified. A need for future study should focus on the impact of biologic therapy on altering relevant co-morbidities associated with cutaneous disorders, such as psoriasis. We are on the threshold of more significant advances in the treatment of cutaneous disease with biologic agents.
Dr. Bechtel is on the Speaker's Bureau for Centocor, Amgen, and Abbott.
The use of biologic agents in the management of psoriasis has demonstrated the significant benefit that these drugs can have in the management of challenging and debilitating diseases. In contrast to broad-acting conventional systemic therapies, biologic agents have very selective targeted immunologic actions. Biologic agents in the treatment of psoriasis can be categorized as agents that inhibit T-cells, inhibit TNF-alpha, and that target IL-12 and IL-23. Evolving scientific data support the possible association of specific co-morbid conditions with psoriasis; Biologic agents have the potential to reduce systemic inflammation, but their impact on co-morbidities is unknown.