Biologics in Practice: How Effective Are Biologics?
Biologic immunomodulators are custom-engineered proteins synthesized from the products of living organisms that target specific cytokines or immune cells. Their therapeutic exclusiveness results in a limited side effect profile compared to traditional systemic immunosuppressive agents. Although psoriasis remains the only condition in dermatology for which the use of biologic immunomodulators has been approved by the FDA, these drugs have been used with success in the treatment of several inflammatory conditions. This article reviews the effectiveness of biologics used for skin diseases and compares their efficacy with each other and with other immunosuppressive drugs.
Biologics and Their Efficacy in Dermatology
Biologic agents in dermatology can be divided into the following categories: a) monoclonal antibodies (mAbs), b) fusion proteins and c) recombinant cytokines and interleukins. Monoclonal antibodies (ending in –mab) can be further classified as chimeric (ending in –ximab), humanized (ending in –zumab), or human (ending in –umab). Chimeric mAbs are composed of variable region from donor mouse mAb grafted onto acceptor human antibody. Humanized mAbs contain complementarity determining region (CDR) segments from variable region of donor mouse grafted onto acceptor human variable region. Human mAbs are entirely human sequences. Although all three types can induce the formation of anti-drug antibodies, murine–human chimeric proteins like infliximab may be the most immunogenic.1,2
Currently, the two classes of biologics FDA-approved to treat psoriasis and psoriatic arthritis are tumor necrosis factor-alpha (TNF-α) inhibitors and anti-interleukin (IL)-12/IL-23 therapies.
TNF-α is released from T cells, keratinocytes, macrophages, mast cells and dermal dendrocytes. It is present in two biologically active forms, soluble TNF and transmembrane TNF.3 Both forms have the capacity to bind to membrane receptors that are expressed on the surfaces of many cells in the immune cascade. This promotes increased secretion of cytokines and further perpetuates the inflammatory cascade involved in the pathogenesis of some autoimmune diseases, including psoriasis. TNF-α causes hyperproliferation of keratinocytes, vascular changes, inflammation and subsequent tissue damage in psoriasis and psoriatic arthritis.4 TNF-α inhibitors have been used for the treatment of psoriasis with success. The three TNF-α inhibitors currently FDA-approved for the treatment of psoriasis and psoriatic arthritis are infliximab, adalimumab and etanercept. Golimumab is the most recently added drug to this class and is currently approved for psoriatic arthritis.
Infliximab. Infliximab is a chimeric IgG1 monoclonal antibody composed of a murine-derived variable region and a human-derived constant region.5 It targets and neutralizes both soluble TNF-α and membrane-bound TNF-α. By binding to membrane-bound TNF-α on the surface of TNF-α-producing cells, it causes apoptosis, complement-dependent lysis and antibody dependent cellular cytotoxicity of the cells, thus expanding the mechanisms by which it may modulate the immune processes seen in psoriasis. Particularly, by binding the membrane-bound TNF-α on dentritic cells, infliximab impairs the ability to activate T cells and perpetuate the inflammatory cascade.6 Infliximab is FDA-approved for psoriasis, psoriatic arthritis, Crohn’s disease, ulcerative colitis, rheumatoid arthritis and ankylosing spondylitis.
For psoriasis, the most effective dose of infliximab has been 5 mg/kg at weeks 0, 2 and 6, followed by maintenance injections every 8 weeks, with 79% of patients achieving 75% or more reduction in the Psoriasis Area and Severity Index (PASI-75) at 12 weeks, 82% at 24 weeks and 77% of patients at week 66.7,8 The onset of infliximab effectiveness occurs within the first 2 to 4 weeks of treatment and reaches maximum benefit by week 10 in the majority of patients.9
There have been a few reports describing the successful use of infliximab in patients affected by severe pustular psoriasis. These responses are rapid, with dramatic improvement of pustules and erythema within days after the first injection of infliximab.10-12 Infliximab is more efficacious than methotrexate in patients with moderate-to-severe plaque psoriasis and more efficacious than azathioprine in patients with Crohn’s disease.13,14
Neutralizing antibodies develop in 20% to 60% of patients receiving infliximab.15,16 Interestingly, higher doses of infliximab are progressively less immunogenic and concomitant use of infliximab with methotrexate seems to reduce the formation of anti-drug antibodies.17-19 Clinically, a loss in therapeutic effectiveness may be noted in patients who develop anti-infliximab antibodies.20,21 Specifically, concentrations of anti-infliximab antibodies at greater than or equal to 8.0 μg/ml predict a shorter duration of therapeutic effect (35 days vs. 71 days) and a higher risk of infusion reactions.22
Adalimumab. Adalimumab is a recombinant human IgG1 monoclonal antibody that targets both membrane-bound TNF-α and soluble TNF-α.23 It has similar binding properties to infliximab and induces apoptosis, complement-dependent lysis and antibody-dependent cellular cytotoxicty in TNF-α-producing cells.24 Adalimumab is FDA-approved for psoriasis, psoriatic arthritis, rheumatoid arthritis, Crohn’s disease, juvenile rheumatoid arthritis and ankylosing spondylitis.
The FDA-approved standard dosing regimen for adalimumab is an initial dose of 80 mg at week 0 that is followed by 40 mg every other week starting at week 1. However, the most effective dosage for adalimumab has been 40 mg every week, with 80% of patients achieving PASI-75 at 12 weeks comparing to 53% to 70% of patients who were on adalimumab 40 mg every other week. At 60 weeks, 56% of patients on adalimumab 40 mg every other week and 64% of patients on adalimumab 40 mg weekly achieved PASI-75.25,26
Adalimumab is more effective than cyclosporine in the treatment of psoriatic arthritis but not for psoriatic skin lesions. Combination therapy with adalimumab and cyclosporine has been more effective than monotherapy with adalimumab or cyclosporine for both joint inflammation and skin lesions.27
In one study, 11% of patients developed antibodies to adalimumab, which led to significantly diminished PASI response rates compared with patients who did not develop antibodies. Anti- adalimumab antibody-positive patients had greater rates of infection and injection-site reactions.28
Etanercept. Etanercept is a recombinant fusion protein composed of the cell surface TNF-α receptor fused to the Fc portion of IgG1. This complex binds both the soluble and transmembrane forms of TNF.29 Unlike infliximab and adalimumab, etanercept does not appear to fix complement, even though it contains the Fc portion of IgG1 and thus is unlikely to promote complement-dependent lysis and antibody-dependent cell-mediated cytotoxicty of TNF-producing cells.21 Etanercept is FDA-approved for psoriasis, psoriatic arthritis, rheumatoid arthritis and ankylosing spondylitis.
The most effective dose of etanercept has been 50 mg twice weekly, with 49% of psoriasis patients achieving PASI-75 at 12 weeks and 59% of patients achieving PASI-75 at 24 weeks. Lower doses have lower efficacy.30,31 Continued long-term treatment has been reported with success. At 96 weeks, 51% of patients with psoriasis on etanercept had achieved PASI-75. Etanercept antibodies are non-neutralizing and had no effect on efficacy.32
Golimumab. Golimumab is a human IgG1 monoclonal antibody with a structure similar to adalimumab. It binds to both soluble and transmembrane forms of TNF-α.23 Golimumab is FDA-approved for rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis.
The most effective dose of golimumab has been 100 mg every 4 weeks, with 58% of patients with psoriasis achieving PASI-75 at 14 weeks and 66% of patients achieving PASI-75 at 24 weeks. Lower doses have lower efficacy on skin lesions but not on arthrithis.33
Certolizumab. Certolizumab pegol is an anti-TNF-α agent with a unique structure. It is composed of a single Fab′ of human anti-TNF-α antibody conjugated with a polyethylene glycol molecule.34 It lacks an Fc′ portion and therefore does not induce antibody-dependent cellular cytotoxicity, complement activation or apoptosis in T cells or macrophages. It can bind to soluble and membrane-bound TNF-α. Certolizumab is FDA-approved for rheumatoid arthritis and Crohn’s disease.
The most effective dose of certolizumab has been 400 mg every other week, with 83% of patients with psoriasis achieving PASI-75 at 12 weeks.35
The discovery of the important roles of IL-23 and Th17 cells in psoriasis pathogenesis led to the development of therapeutic agents targeting this pathway.36 The only inhibitor of IL-23/Th17 pathway currently FDA-approved for the treatment of psoriasis is ustekinumab.
Ustekinumab. Ustekinumab is a fully human monoclonal antibody directed against the common p40 subunit of IL-12 and IL-23, inflammatory cytokines that are thought to be important in the pathogenesis of psoriasis. While IL-23 promotes the Th17 pathway, IL-12 perpetuates the Th1 pathway.25 Therefore, ustekinumab prevents the differentiation of naïve T cells into Th17 and Th1 cells.26 Ustekinumab is approved for moderate-to-severe plaque psoriasis.
The most effective dose of ustekinumab has been 90 mg at weeks 0 and 4 and every 12 weeks thereafter, with 76% of patients with psoriasis achieving PASI-75 at 12 weeks and 78% of patients achieving PASI-75 at 28 weeks. Increasing the dose to 90 mg every 8 weeks in non-responders has resulted in better control, compared to continuing to receive 90 mg every 12 weeks.37 A majority of patients (83%) who have an initial good response to therapy maintain the good response up to 3 years on treatment.38
Briakinumab. Like ustekinumab, briakinumab is a fully human monoclonal antibody directed against the common p40 subunit of IL-12 and IL-23. At week 12, 24 and 52, 81%, 82% and 66% of patients with psoriasis could achieve PASI-75, respectively, at a dose of 200 mg at weeks 0 and 4 and 100 mg at week 8 and every 4 weeks thereafter.39,40 Briakinumab at this dose has been more effective than etanercept 50 mg twice weekly for psoriasis and also more effective than methotrexate at a dose of 5 to 25 mg weekly.41,42,43
Th17 cells secrete a number of pro-inflammatory cytokines, including interleukin-17.44,45 Specific inhibition of interleukin-17 represents another therapeutic approach against psoriasis.
Ixekizumab. Ixekizumab is a humanized IgG4 monoclonal antibody that neutralizes interleukin-17. Patients with psoriasis receiving subcutaneous injections of 75 mg of ixekizumab at 0, 2, 4, 8, 12, and 16 weeks achieved 83% PASI-75 at 12 weeks with sustained response through 20 weeks.46
Anti-T cell Agents/T-cell Blockers
T cells play an essential role in the pathogenesis of psoriasis. Two anti-T-cell drugs have showed promise, but one (efalizumab) was discontinued as more data on its long-term safety became available, and the other (alefacept) was voluntarily discontinued by the manufacturer. Currently, there is no drug of this type on the market.
Anti-B cell Agents
Rituximab. Rituximab is a chimeric monoclonal antibody to CD20, which induces depletion of B cells. It is currently approved for the treatment of CD20+ B-cell malignancies, rheumatoid arthritis, Wegener’s granulomatosis and microscopic polyangiitis.
CD20 is a B-cell-specific antigen expressed on the surface of B lymphocytes throughout differentiation from the pre-B cell to the mature B-cell stage, but not on plasma cells or stem cells.47,48 Because plasma cells and hematopoietic precursors are spared, immunoglobulin levels do not fall dramatically. The B-cell count decreases and remains undetectable until day 180 in most patients. B cells typically begin to return to the circulation after 6 months of therapy.49,50 No major changes in T cells or natural killer cells or in T-cell cytokine production are detected after rituximab treatment.51
Although there have been no randomized controlled trials of rituximab in dermatologic disease, case reports describe its successful use in the treatment of pemphigus vulgaris, paraneoplastic pemphigus, epidermolysis bullosa acquisita, cutaneous B-cell lymphoma, dermatomyositis and graft-versus-host disease.52-58
Rituximab (two infusions of 0.5 g to 1 g at an interval of 2 weeks) has been used for patients with severe, long-standing pemphigus vulgaris or pemphigus foliaceus due to conventional therapy resistance or major complications after steroid therapy. Complete remission has been achieved in 53-86% of patients.59,60
Three review articles have studied the effects of biologics in psoriasis.9,61,62Figure 1 shows the efficacy of biologic drugs used for the treatment of moderate to severe psoriasis.
Long-term Efficacy of Biologics in Dermatology
Infliximab, adalimumab and etanercept have been evaluated for psoriasis for up to 60 to 96 weeks. In these studies, more than 50% of patients achieved PASI-75 on long-term follow-up. Although no study had a placebo group beyond 12 weeks, one study comparing the effects of low- and high-dose adalimumab in psoriasis for 60 weeks showed better results with the higher dose.25 Another study evaluating infliximab for psoriasis showed that, at week 50, PASI responses were better maintained with continuous high dose compared with intermittent or low-dose therapy.20 Most studies evaluating long-term effects of the biologics show lower PASI responses after one year compared to weeks 12 to 20.63 Although one reason may be the appearance of anti-drug antibodies, another reason is drop-outs who are considered failures in intent-to-treat studies.
Biologics have revolutionized the treatment of many autoimmune diseases by offering therapeutic selectivity and restricting immune suppression to specific targeted pathways. Some seem to have higher efficacies and lower risk/benefit ratios compared to conventional immunosuppressant drugs. While TNF-α inhibitors and anti-T cell agents have been the main biologic therapeutic approaches for psoriasis, the appearance of newer classes of drugs and availability of data regarding safety are going to change our therapeutic plans regarding psoriasis and other inflammatory skin diseases. Although there are mixed levels of evidence for the long-term efficacy of biologics, these medications do appear to be effective long-term for patients with psoriasis.
Dr. Taheri is with the Center for Dermatology Research and the Department of Dermatology at Wake Forest University School of Medicine in Winston-Salem, NC.
Dr. Feldman is with the Center for Dermatology Research and the Departments of Dermatology, Pathology and Public Health Sciences in Winston-Salem, NC.
Disclosure: The Center for Dermatology Research is supported by an unrestricted educational grant from Galderma Laboratories, L.P.
Dr. Taheri has no conflicts to disclose.
Dr. Feldman is a consultant and speaker for Galderma, Stiefel, GlaxoSmithKline, Abbott Labs, Warner Chilcott, Janssen, Amgen, Photomedex, Genentech, BiogenIdec and Bristol Myers Squibb. Dr. Feldman has received grants from Galderma, Astellas, Abbott Labs, Warner Chilcott, Janssen, Amgen, Photomedex, Genentech, BiogenIdec, Coria, Pharmaderm, Ortho Pharmaceuticals, Aventis Pharmaceuticals, Roche Dermatology, 3M, Bristol Myers Squibb, Stiefel, GlaxoSmithKline and Novartis and has received stock options from Photomedex.