Chapter 234. Immunobiologicals, Cytokines, and Growth Factors in Dermatology

Immunobiologicals are compounds synthesized in living organisms that exhibit immune modulatory properties. They consist of recombinant cytokines, growth factors, antibody-based agents, and fusion proteins. Those with dermatologic indications are discussed in this chapter and are listed in Table 234-1. Fig. 234-1 illustrates the molecular targets of these compounds. Fig. 234-2 depicts the cellular events that mediate cutaneous inflammation and identifies the molecular interactions affected by specific immunobiological agents.

Cytokines are low-molecular-weight polypeptides that exhibit paracrine and/or autocrine activity in the mediation of immune responses. They may act as growth factors by inducing the proliferation of specific immune cell populations. A particular cytokine may also influence the production of other cytokines and the behavior of cellular populations that express its receptor. Over the past two decades, recombinant cytokines have proven to be invaluable for the treatment of conditions in which immunologic aberrations exist or among which some clinical benefit might be derived from augmentation or suppression of the host immune response.

Recombinant Interferons

(See also Chapters 231 and 235)

Interferon-α

IFN-α is a Type I interferon produced by plasmacytoid dendritic cells. It enhances cell-mediated cytotoxicity against viral disease and malignancy by increasing MHC I expression by antigen-presenting cells, stimulating NK cell activity, promoting the development of Th1 cells, and suppressing the production of Th2 cytokines.1,2

Recombinant IFN-α may be administered as a subcutaneous or intramuscular injection and has been utilized for a broad range of dermatologic conditions that include cutaneous T-cell lymphoma, melanoma, nonmelanoma skin cancer, Kaposi sarcoma, Behcet disease, hemangiomas, condyloma acuminatum, verruca vulgaris, and keloids.3 A pegylated form (containing polyethylene glycol) of this compound is currently available which has a longer half-life and increased patient tolerability.2 Prior to the availability of pegylated IFN-α, treatment was typically administered 3×/week with dosing dependent upon the condition being treated and patient response to therapy. Pegylated IFN-α may be administered once weekly with a steady state plasma level achieved within 5–9 weeks.4

There is extensive experience using IFN-α for the treatment of cutaneous T-cell lymphoma (CTCL). Objective clinical responses have been noted among 50%–75% of CTCL (Stage Ia–IVa) patients treated with different IFN-α dosing regimens.5 Typically, it is administered subcutaneously at a starting dose of 1.5–3.0 million units three times per week. When combined with other immunodulatory therapies, high clinical responses have been achieved among patients with Sézary syndrome.6

The most common side effect associated with IFN-α therapy is “flu-like” symptoms characterized by fever, sweats, chills, myalgias, and arthralgias. These symptoms typically resolve over the first ten days of therapy and can be managed with acetaminophen. Patients may also experience injection site reactions. Other associated side effects include fatigue, depression, weight loss, photosensitivity, peripheral neuropathy, psychosis, hypothyroidism, and sexual dysfunction.2,7 Laboratory abnormalities include elevated hepatic transaminases and leukopenia. Liver function tests and a complete blood count should be evaluated every 1 to 2 weeks upon initiation of therapy, or with any increase in dosing.2

IFN-α is contraindicated for use in patients with a known hypersensitivity to the drug or any of its components. Relative contraindications include a history of cardiovascular disease, renal disease, hepatic disease, central nervous system disorders, and/or preexisting mental illness. IFN-α is a pregnancy category C medication with unknown safety during lactation. Multiple case reports have suggested that IFN-α may induce, exacerbate, or unmask autoimmune disorders including immune-mediated thyroid disease, anemia, thrombocytopenia, sarcoidosis, and connective tissue disorders. IFN-α should be used with caution among patients with CD8+ CTCL, as multiple cases of disease progression have been reported in this setting.8–10 This finding may be explained by the inherent ability of Th1 cytokines to augment CD8+ T-cell activity.

Interferon-γ

IFN-γ is a cytokine produced by Th1 lymphocytes. Similar to IFN-α, it enhances cell-mediated cytotoxicity and suppresses Th2 cytokine production. IFN-γ has also been shown to enhance MHC 2 expression and interleukin 12 (IL12) production by antigen-presenting cells. In the dermatologic setting, it is reported to exhibit clinical efficacy in the management of chronic granulomatous disease and CTCL.

Children with chronic granulomatous disease treated with IFN-γ exhibited a significant reduction in the frequency of infections and associated hospitalizations.11 This has been attributed to its ability to partially correct defects in oxidative metabolism and promote superoxide release, thus enhancing phagocytes’ ability to combat infection.12

Studies regarding the use of IFN-γ in the treatment of CTCL are limited. Partial clinical responses have been reported among patients treated with IFN-γ during all stages of disease.13 This has been attributed, in part, to its ability to suppress the production of Th2 cytokines by malignant cells.14 Thus, IFN-γ offers an alternative therapeutic option for patients who may not tolerate or respond to IFN-α therapy secondary to the formation of neutralizing antibodies, cognitive dysfunction and/or fatigue—which are more frequently associated with IFN-α therapy.15

IFN-γ is administered via intravenous, intramuscular, and subcutaneous routes. The recommended dosing for children with chronic granulomatous disease is 50 μg/m2 three times a week for life.16 We have utilized IFN-γ doses ranging from 50–100 μg three times a week for the treatment of adult CTCL patients.2

Adverse effects associated with IFN-γ are similar to those reported for IFN-α and include flulike symptoms, elevated hepatic transaminases, leukopenia, and thrombocytopenia. IFN-γ is a pregnancy category C medication with unknown safety during lactation. Its contraindications are similar to those reported for FN-α.

Recombinant Interleukins and Growth Factors

Interleukin 2

Interleukin 2 (IL2) is a Th1 cytokine with antitumor activity produced by CD4+ lymphocytes in response to activation by antigen-presenting cells. IL2 has been shown to promote the proliferation and maintenance of helper T-cell populations. In addition, it has been shown to enhance both natural killer cell cytotoxicity and lymphokine-activated cell activity.17 In the dermatologic setting, recombinant human IL2 has been used for the treatment of melanoma.

Several studies have reported durable clinical responses among melanoma patients treated with IL2 therapy. This finding led to the FDA approval of this medication for the treatment of patients with metastatic disease. In early studies, high dose intravenous IL2 therapy (600,000–720,000 IU/kg) led to a 15% to 20% overall response among melanoma patients, with 4% to 6% achieving a complete clinical response.18–20 Unfortunately, prolonged responses are only achieved by a minority of patients. Over the past two decades, IL2 has been combined with other treatment modalities in an attempt to enhance clinical response rates and overall survival among melanoma patients.21

Adverse effects associated with infused IL2 include fever, chills, hypotension, thrombocytopenia, vascular leak syndrome, pulmonary edema, cardiac arrhythmias, renal compromise, and exfoliative erythroderma.2,3 IL2 is contraindicated for use in patients with a known hypersensitivity to the drug or any of its components. It is also contraindicated for patients with a history of an abnormal thallium stress test, abnormal pulmonary function tests, or organ allograft transplantation. IL2 is a pregnancy category C medication with unknown safety during lactation.

Interleukin 1 Receptor Antagonist

Interleukin 1 (IL1) is a proinflammatory cytokine produced by monocytes/macrophages that are involved in the recruitment of leukocytes to inflamed tissue, the generation of acute phase reactants, activation of osteoclast activity, induction of collagenase production by chondrocytes, and fever induction. In combination with other inflammatory cytokines, IL1 has been implicated in the pathogenesis of conditions that include rheumatoid arthritis and neonatal-onset multisystem inflammatory disease (NOMID).

The potentially damaging effects of prolonged IL1-α and/or IL1-β exposure are normally balanced by a naturally produced interleukin-1 receptor antagonist (IL1ra), which counters the effects of excessive IL1 exposure. If this protective mechanism is overcome, tissue damage may ensue. Anakinra is a recombinant IL1ra that was approved by the Food and Drugs Administration (FDA) in 2001 for the treatment of moderate-to-severe rheumatoid arthritis among adult patients who failed to respond to other antirheumatic drugs. It binds to the IL1 Type 1 receptor and competitively inhibits IL1 binding. The interaction between anakinra and the IL1 receptor does not activate the IL1 receptor accessory protein, thus no signal transduction cascade ensues.

Aside from adult rheumatoid arthritis, anakinra has been reported to exhibit clinical efficacy in the management of other inflammatory conditions, including Still disease, polyarticular juvenile rheumatoid arthritis, Muckle-Wells syndrome, and NOMID. This is a chronic inflammatory condition which presents during early childhood with a constellation of clinical findings that include an urticarial cutaneous eruption, central nervous system abnormalities, and bone deformities. A recent study to address the efficacy of anakinra in the management of NOMID reported a rapid clinical response to daily injections (1–2 mg/kg) with all patients achieving marked clearing of their cutaneous disease.22 A small study to address the long-term safety and efficacy of anakinra among NOMID patients reported sustained clinical improvement for 26–42 months (the duration of follow-up) with no adverse events aside from mild injection-site reactions.23

Clinical trials have suggested a small increased risk for infection among anakinra treated patients. Thus, treatment should not be initiated among patients with an active infection. The use of this drug in combination with TNF-inhibitor therapy should be avoided. Anakinra is contraindicated among patients with known allergies to Escherichia coli-derived proteins. The most common side effect associated with treatment is injection site reaction.

Granulocyte-Macrophage Colony-Stimulating Factor

Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a growth factor that induces the proliferation of myeloid precursors and is involved in the proliferation, differentiation, and migration of dendritic cells.24 In the dermatologic setting, GM-CSF has been reported to exhibit efficacy as a wound-healing agent by promoting the proliferation of keratinocytes in the setting of ulcerated, diseased skin.25,26 It has also been utilized as an antitumor agent in the treatment of melanoma and CTCL.

Regression of in-transit melanoma and cutaneous metastases have been reported with the administration of intralesional recombinant GM-CSF.27,28 A phase II trial in which GM-CSF was administered to postsurgical, clinically disease-free, stage III or IV melanoma patients reported enhanced survival among treated patients compared to matched historical controls.29 It has also been used as an adjuvant in combination with other treatment modalities for the treatment of melanoma.30,31

GM-CSF has been shown to induce the differentiation and proliferation of antigen-presenting cells,32 and may contribute toward disease improvement in CTCL through its ability to replete antigen-presenting cell populations, which are reduced in Sézary syndrome patients. Recombinant human GM-CSF has been used as adjuvant therapy in the treatment of patients with Sézary syndrome. Clinical improvement was reported in a patient treated with an aerosolized form of the medicine.33 Recombinant human GM-CSF dosing for the treatment of dermatologic disease has not been standardized. GM-CSF was used in combination with other immune modulating therapies for the treatment of Sézary syndrome leading to enhanced clinical responses in a non-placebo controlled study.6 Associated side effects include fatigue, myalgia, injection site reactions, and generalized cutaneous reactions. GM-CSF is contraindicated for use in patients with a known hypersensitivity to the drug or any of its components. Administration of this drug concurrently with chemotherapy is not recommended, as some combinations may increase myelosuppression. GM-CSF is a pregnancy category C medication with unknown safety during lactation.

Recombinant Human Platelet-Derived Growth Factor

(See also Chapter 235)

Platelet-derived growth factor (PDGF) is a peptide produced by platelets, macrophages, neutrophils, and smooth muscle cells that has proven to be of clinical benefit for the management of chronic wounds. It consists of two polypeptide chains (A and B) that form dimers linked by disulfide bonds. The PDGF-BB homodimer has been shown to promote granulation tissue formation, wound angiogenesis, re-epithelialization, and the proliferation of fibroblasts and smooth muscle cells in the cutaneous microenvironment. It is currently the only growth factor approved by the FDA for the treatment of diabetic foot ulcers.

Several randomized control studies have reported the efficacy of PDGF-BB for the treatment of pressure ulcers and lower extremity ulcers in diabetic patients. A phase III study reported significant efficacy of PDGF-BB in the time required to achieve complete wound closure for the treatment of chronic diabetic neuropathic ulcers of the lower extremities.34 This multicenter, double-blind, placebo-controlled study reported a 43% increase in the incidence of wound closure, and a 32% reduction in the time required to achieve complete wound closure compared to patients receiving a placebo gel. When combined with good wound care, daily application of PDGF has been found to substantially improve time to healing of chronic diabetic neuropathic foot ulcers.35

PDGF-BB (100 μg/g) is distributed as a topical gel that should be applied daily and refrigerated when not in use. Studies addressing the safety of recombinant human PDGF-BB found no increased risk for cardiovascular, respiratory, musculoskeletal, or central nervous system disorders among patients with lower extremity diabetic neuropathic ulcers treated with topical PDGF-BB compared to patients treated with placebo or general ulcer care.36 Patients receiving PDGF-BB therapy did not develop neutralizing antibodies to the drug, nor did they exhibit an increase in mortality relative to placebo. Cutaneous eruptions have been reported but are uncommon. Recombinant PDGF-BB is contraindicated for use in patients with a known hypersensitivity to the drug or any of its components. It also should not be applied to sites affected by cutaneous neoplastic disease. PDGF-BB is a pregnancy Category C medication with unknown safety during lactation. In 2008, a black box warning was added to the safety labeling of this drug as it was associated with an increase in cancer mortality among patients treated with three or more tubes (15 g/tube) of the gel.

Advances in immunobiology have led to our ability to synthesize antibodies that target specific cytokines and cell surface receptors. By utilizing them to interrupt specific signaling cascades, we have been able to manipulate immune responses through the activation or suppression of pathways mediating inflammation, tolerance, and antitumor immunity. The structural nature of a recombinant antibody can be determined by the suffix associated with its name [-ximab: chimeric monoclonal antibody (a hybrid antibody consisting of human and murine antibody components), -zumab: humanized monoclonal antibody, -umab: human monoclonal antibody, -cept: antibody fusion protein that mimics immunoglobulin].

Antibodies Against Cytokines

(See Chapter 11)

Antitumor Necrosis Factor

Antitumor necrosis factor-α (anti-TNF-α) is a cytokine that has been linked to the pathogenesis of psoriasis and other inflammatory conditions including psoriatic arthritis, rheumatoid arthritis, and inflammatory bowel disease. It is produced by multiple cell types in the skin (keratinocytes, Langerhans cells, and dermal mast cells),37 which are believed to contribute to the pathogenesis of inflammatory dermatoses (see Fig. 234-2). TNF triggers its effects by binding to its p55 and p75 receptors expressed primarily on the surface of keratinocytes, neutrophils, endothelial cells, and fibroblasts. In combination with other proinflammatory cytokines, it is believed to be involved in the recruitment of immune cells to the cutaneous microenvironment.38 TNF may also contribute to both the inhibition of keratinocyte apoptosis and the induction of keratinocyte proliferation in psoriasis.39,40

Psoriasis is a chronic inflammatory condition of the skin that affects over 2% of the adult population.41 Elevated levels of TNF-α have been detected in the cutaneous lesions of psoriasis patients.42 Murine studies support a role for TNF-α in the activation and proliferation of lymphocytes, which induce psoriatic lesions.43 Elevated TNF-α levels have also been reported in patient serum and has been shown to correlate with disease activity.44,45

Three biologics, which inhibit TNF-α are approved for psoriasis: (1) infliximab, (2) adalimumab, and (3) etanercept. Infliximab and adalimumab are antibody-based therapeutics, whereas, etanercept is a fusion protein. Although all three drugs inhibit TNF-α, they are structurally different and have unique pharmacodynamic and pharmacokinetic profiles. Given their shared molecular target, certain of their properties will be discussed together as a “class” for comparative purposes in this section. Etanercept will be reviewed in more detail in the Section “Fusion Proteins.”

Infliximab and adalimumab bind to both soluble and membrane-bound TNF, whereas etanercept binds primarily to soluble TNF.46 Infliximab and adalimumab also have a greater propensity to induce lymphocyte apoptosis compared to etanercept, as they can lyse cells with membrane-bound TNF through complement activation and/or antibody-dependent, cell-mediated cytotoxicity.47 Given its inability to effectively associate with membrane-bound TNF, etanercept is incapable of activating complement-mediated apoptotic pathways. In terms of pharmacokinetics, the subcutaneous administration of adalimumab and etanercept yields smooth and uniform concentration time profiles at steady state, whereas the intravenous dosing of infliximab results in very high peak-to-trough ratios.48 Infliximab binds TNF quickly and irreversibly, whereas etanercept sheds about 50% of soluble TNF within 10 minutes of binding.47 The pharmacodynamic, pharmacokinetic, and structural differences between TNF inhibitors may result in differing safety and efficacy profiles. While infliximab appears to be more efficacious than etanercept in the management of autoimmune granulomatous diseases such as Crohn disease, sarcoidosis, and granulomatosis with polyangiitis (Wegener's); its use47 has been associated with a higher risk of granulomatous infections.49

Indications

Etancercept, infliximab, and adalimumab are FDA approved for the treatment of moderate/severe plaque-stage psoriasis and psoriatic arthritis. Additionally, etanercept is FDA approved for rheumatoid arthritis, ankylosing spondylitis, and juvenile rheumatoid arthritis; infliximab is approved for rheumatoid arthritis, Crohn disease, ulcerative colitis, and ankylosing spondylitis; and adalimumab is approved for rheumatoid arthritis, juvenile idiopathic arthritis, ankylosing spondylitis, and Crohn disease. Other TNF inhibitors, without dermatologic indications, have also been approved by the FDA and include golimumab (for the treatment of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis) and certolizumab pegol (for the treatment of Crohn disease and rheumatoid arthritis).

Case reports and small case series suggest potential efficacy of TNF-α inhibitors for the management of numerous inflammatory dermatologic conditions that include apthous stomatitis, Behcet disease, cicatricial pemphigoid, dermatomyositis, eosinophilic fasciitis, hidradenitis suppurativa (HS), multicentric reticulohistiocytosis, necrobiosis lipoidica diabeticorum, pityriasis rubra pilaris, pyoderma gangrenosum, sarcoidosis, scleroderma, Sneddon-Wilkinson syndrome, and SAPHO (synovitis, acne, pustulosis, hyperostosis, and osteitis) syndrome.50 A phase 2, randomized, placebo-controlled trial conducted at a single institution reported a higher response rate among HS patients treated with infliximab (5 mg/kg on weeks 0, 2, and 6) compared to placebo. More specifically, a greater percentage of infliximab-treated patients achieved a >50% reduction in baseline HS Severity Index (HSSI) score at week 8 compared to placebo.51 In addition, 60% of infliximab-treated patients achieved a 25% to 50% reduction in HSSI compared to 6% of placebo.

Initiating Therapy and Monitoring

TNF inhibitors have been the most extensively studied class of biologics and therefore they have detailed and relatively robust safety data compared to other biologics. TNF inhibitors are immunosuppressive, and therefore, patients should be carefully screened for signs and symptoms of malignancy and infection prior to initiating therapy as well as during the course of treatment. Product labeling and published guidelines recommend screening for latent tuberculosis infection with a tuberculin skin test prior to initiating therapy with etanercept, infliximab, and adalimumab.52 A whole blood test, such as QuantiFERON-TB gold or T-SPOT.TB assay, is an alternative screening method that offers higher specificity and comparable sensitivity to the traditional tuberculin skin test. It is particularly useful among BCG-vaccinated individuals who are more likely to exhibit a false-positive PPD reaction. TNF inhibitors should be used with caution in patients with a history of congestive heart failure—infliximab at doses >5 mg/kg is contraindicated in patients with moderate-to-severe congestive heart failure.

Infliximab may be associated with liver function test abnormalities, which, in rare cases, have led to hepatic failure. Additionally, TNF inhibitors have been associated with reactivation of hepatitis B in patients who are chronic carriers. Some of these cases have been fatal; therefore, one should consider monitoring liver function tests during TNF therapy and screening at-risk patients for hepatitis B. Small cases series suggest that TNF inhibitors can be used safely in patients with Hepatitis B when lamivudine is given concurrently. Larger studies, however, will be necessary to further substantiate these findings.53 No exacerbation of liver disease has been reported among hepatitis C-positive patients receiving TNF inhibitor therapy. In fact, it has been suggested that TNF inhibitor therapy may contribute toward improving clinical outcomes among this patient population given their potential to suppress TNF-induced hepatic inflammation and fibrosis.54,55 A recent multicenter study addressing the efficacy of etanercept in the treatment of alcoholic hepatitis reported increased mortality among patients with moderate-to-severe disease after 6 months of therapy; thus, the use of TNF inhibitors in this setting should be avoided if possible.56

Risks, Precautions, and Complications

Infection

TNF inhibitors are associated with serious infections including pneumonia, sepsis, tuberculosis, histoplasmosis, coccidioidomycosis, and other invasive fungal infections, thus accounting for the black box warning for infection. Product labeling also indicates that for patients who have resided in regions where histoplasmosis and coccidioidomycosis are endemic, the risks and benefits of TNF inhibitor therapy should be carefully considered. A recent meta-analysis of rheumatoid arthritis patients treated with infliximab or adalimumab in randomized controlled trials suggested that use of these agents result in one excess serious infection for every 59 patients treated for a period of 3–12 months.57 Use of etanercept with anakinra has been associated with an increased risk of serious infections, and therefore, it is recommended that anakinra not be used concurrently with any TNF inhibitor. One prospective study reported an increased incidence of herpes zoster among rheumatoid arthritis patients treated with anti-TNF monoclonal antibodies (adalimumab, infliximab) compared to conventional disease-modifying antirheumatic drugs (DMARDs).58 A meta-analysis addressing the risk of serious infections (infection requiring antibiotic treatment and/or hospitalization) among rheumatoid arthritis patients treated with adalimumab and infliximab reported a significantly increased risk for such infections compared to placebo.57 Another meta-analysis addressing the risk of serious infections among RA patients treated with adalimumab, etanercept, or infliximab, with and without adjustment for exposure, reported no increased risk of serious infection at manufacturer recommended doses, however, there was a two-fold increased risk of serious infection among patients treated with higher doses (two to three times the recommended dose).59

Malignancy

A black box warning for malignancy was added to the product labeling of TNF inhibitors after cases of lymphoma and other malignancies were reported among adult and pediatric patients. A meta-analysis [data from 9 randomized controlled trials (RCTs)] of 3,493 RA patients treated with adalimumab or infliximab demonstrated an increased risk of solid organ malignancies.57 This increased risk proved to be dose dependent. Nonmelanoma skin cancers accounted for the majority of reported malignancies followed by lymphoma in this study. Infliximab has been associated with aggressive hepatosplenic T-cell lymphomas in postmarketing surveillance of patients with Crohn disease treated with concomitant azathioprine or 6-mercaptopurine. Additionally, aggressive cutaneous T-cell lymphomas have been reported in patients receiving TNF inhibitors.60 A meta-analysis integrating data from 18 randomized control trials, involving 8,808 RA subjects, reported no increased risk for lymphoma, nonmelanoma skin cancer, and melanoma among patients treated with adalimumab, etanercept, and infliximab.59

A comprehensive review of the literature addressing the risk of lymphoma among patients receiving biologic therapy suggests the use of such agents to be safe with respect to lymphoma risk among those treated for a limited time (up to 4 years).61 A meta-analysis addressing the risk of malignancies among rheumatoid arthritis patients reported a higher point estimate of malignancy among etanercept-treated patients compared to placebo, however, the results were not statistically significant.62 Current data are insufficient to definitively rule out an increased risk of lymphoma, or causal relationship between biologic therapies and lymphoma. The largest observational study to date suggests a slightly higher risk of lymphoma associated with adalimumab and infliximab compared to etanercept in the French population.63

It remains unclear whether the excess risk of lymphoma reported in observational studies is due to the TNF inhibitor or the severity of the underlying disease (e.g., rheumatoid arthritis), which itself may portend a greater risk of lymphoma. Psoriasis patients may also have an increased risk of lymphoma, independent of biologic therapy and therefore additional studies will be necessary to determine if long-term exposure to biologics impacts lymphoma risk in psoriasis patients.64

Neurological Events

TNF inhibitors have been associated with rare cases of new onset demyelinating disease and with exacerbation of clinical and radiologic findings in patients with a history of demyelinating disease (e.g., multiple sclerosis).

Autoimmunity

TNF inhibitors may be associated with the development of antinuclear antibodies and antidouble-stranded DNA antibodies compared to placebo, the clinical significance of which is unknown. Rarely, TNF inhibitors have been associated with lupus-like syndromes and vasculitis.

Immunizations

TNF inhibitors may lower the titer response to immunizations; however, the clinical significance of this observation is unknown. Most patients with psoriatic arthritis receiving etanercept were able to mount effective B-cell immune responses to pneumococcal polysaccharide vaccine. Live vaccines should not be used in patients taking TNF inhibitors.

Hematologic Events

Rare cases of serious hematologic events have been associated with TNF inhibitors.

Other Events

Cases of worsening congestive heart failure, in addition to new onset cases, have been reported. Psoriasiform eruptions, both pustular and plaque-like, have also been reported among patients treated with TNF inhibitors. The onset of this paradoxical reaction may occur anywhere from one month to several years after initiation of therapy. The majority of cases have been reported among RA patients and have been primarily pustular in nature.65,66 Discontinuation of the medication and initiation of oral immunosuppressants (methotrexate, cyclosporine, prednisone) +/− topical steroid therapy has led to clinical improvement/resolution of the lesions.

Pregnancy and Lactation

TNF inhibitors are pregnancy category-B medications with unknown safety during lactation.

Infliximab

Infliximab is a 149-kDa monoclonal chimeric antibody that consists of a murine antigen-binding region with specificity for human TNF-α fused to a human IgG1 constant region. A phase III, double-blind, placebo-controlled trial in patients with psoriasis reported that 80% of patients treated with infliximab (5 mg/kg) achieved a PASI 75 at week 10, whereas, at week 50, 61% of patients achieved a PASI 75.67 This decrease in response over time has been reported in other clinical settings as well. When utilized as a monotherapy for Crohn disease, a shorter duration of response and higher risk for infusion reactions has been attributed to the formation of antibodies against infliximab.68

By nature of its chimeric structure, infliximab may be targeted by the host immune system if the murine portion of its structure is identified as foreign.69 Neutralizing antibodies generated against infliximab have also been reported among patients treated for rheumatoid arthritis and psoriasis.67,70 Strategies to decrease the formation of neutralizing antibodies include use of concomitant immunosuppressive medications (e.g., methotrexate), and regular (as opposed to intermittent) dosing of the drug. Infliximab is also associated with the development of ANA and antidouble-stranded DNA antibodies, the clinical significance of which is unknown. (See Section “Anti-TNF-α“ for greater detail on indications, initiating, and monitoring therapy, risks, precautions, and complications.)

Infliximab is administered intravenously as a 5-mg/kg dose over 2–3 hours on weeks 0, 2, 6, and every 8 weeks thereafter. Infliximab has a serum half-life of ∼9 days. Through its ability to neutralize both membrane-bound and soluble TNF-α, infliximab is believed to decrease cutaneous inflammation and promote keratinocyte differentiation in psoriatic plaques. In-vitro studies also suggest that infliximab may promote disease improvement through an ability to induce apoptosis of lesional keratinocytes.71

Although infliximab has demonstrated marked clearing of psoriasis, several recent reports have suggested the potential for infliximab to induce or exacerbate psoriatic disease via unknown mechanisms.72

Adalimumab

Adalimumab is a fully human 148-kDa monoclonal antibody against TNF-α. Similar to infliximab, it inhibits TNF-α signaling by binding to both soluble and membrane-bound forms. Adalimumab is administered as a subcutaneous injection with a serum half-life of 10–20 days. Psoriasis patients receive an 80-mg dose at week 0, followed by a 40-mg dose 1 week later and then every other week thereafter.

The short- and long-term efficacy of adalimumab has been evaluated among 1,212 patients with moderate-to-severe chronic plaque psoriasis in a phase III randomized, double-blind, placebo controlled trial.73 After 16 weeks of treatment, 71% of adalimumab-treated patients achieved a PASI 75 compared to 7% of placebo. At week 33, adalimuab-treated patients who had achieved a PASI 75 were rerandomized 1:1 to continue receiving adalimumab or placebo through week 52. Among these patients, 5% of those who continued to receive adalimumab experienced a loss of adequate response (i.e., a <50% improvement in PASI response relative to baseline) compared to 28% of patients who were rerandomized to placebo. These findings, in combination with the results of the open-label extension study of this trial, support the notion that continuous therapy may be necessary to achieve sustained clinical responses among patients.73 A randomized trial comparing the efficacy and safety of adalimumab to methotrexate reported the superior efficacy of adalimumab after 16-weeks of therapy.74 More specifically, 80% of the adalimumab group achieved PASI 75 compared to 36% and 19% of the methotrexate and placebo groups, respectively. Two severe adverse events were reported in each treatment group.

Antibody formation against adalimumab has also been reported. One study addressing the clinical implications of this phenomenon found that psoriasis patients with low serum adalimumab trough concentrations, secondary to antibody formation, were more likely to exhibit a lack or loss of response to treatment compared to patients with higher trough concentrations.75 Injection site reactions occur with adalimumab, however, they are generally mild and self-limited. (See Section “Anti-TNF-α“ for greater detail on indications, initiating, and monitoring therapy, risks, precautions, and complications.)

Anti-Interleukin 12/Interleukin 23

Ustekinumab is a human IgG1k monoclonal antibody that is FDA approved for the treatment of moderate-to-severe plaque psoriasis. Ustekinumab targets the p40 subunit of IL12 and interleukin 23 (IL23). These cytokines are involved in the activation of natural killer cells and the differentiation of naive CD4+ T-cells into Th1 and Th17 effector cells. Upon activation, Th17 cells secrete multiple cytokines, including interleukin 17 (IL17) and interleukin 22 (IL22). IL22 has been shown to contribute to the epithelial dysregulation and abnormal proliferation of keratinocytes characteristic of psoriasis and has been strongly implicated in its pathogenesis. High levels of p40 mRNA have been detected in psoriatic plaques; whereas, a notable reduction in its expression has been reported in clinically improved lesions after treatment.76

Several studies have addressed the efficacy and safety of ustekinumab for the treatment of patients with moderate-to-severe psoriasis. A phase III, double-blind, placebo-controlled trial found that 66.7% of patients receiving ustekinumab 45 mg (at weeks 0, 4, and every 12 weeks thereafter) achieved a PASI 75 by week 12, compared to 75.7% of patients receiving ustekinumab 90 mg, and 3.7% placebo.77 A study comparing ustekinumab to the TNF inhibitor etanercept among patients with moderate-to-severe psoriasis reported superior efficacy of ustekinumab at a dose of 45 or 90 mg (at weeks 0 and 4) compared to etanercept at a dose of 50 mg twice weekly over a 12 week period.78 A PASI 75 was achieved by 73.8% and 67.5% of ustekinumab treated patients at doses of 45 mg and 90 mg, respectively, compared to the etanercept treatment group, among whom 56.8% achieved a PASI 75 at week 12 (p ≤0.01). A higher incidence of injection site reactions was reported among the etanercept treatment group; otherwise, the proportion of adverse events was comparable between the two treatment groups.

Indications

Ustekinumab was approved by the FDA in 2009 for the treatment of adult patients with moderate-to-severe plaque psoriasis who are candidates for systemic and/or phototherapy.

Initiating Therapy and Monitoring

Ustekinumab should only be administered by a healthcare provider. Dosing of the medication is weight based. Patients under 100 kg receive an initial 45-mg SC dose, which is repeated 4 weeks later. Subsequent dosing is administered every 12 weeks. Patients weighing over 100 kg receive a 90-mg dose with the same aforementioned dosing schedule. The serum half-life for ustekinumab has been reported to range from 14.9 +/− 4.6 days to 45.6 +/− 80.2 days according to the package insert. Ustekinumab is a pregnancy category-B medication with unknown safety during lactation.

Risks, Precautions, and Complications

The most commonly reported adverse events associated with ustekinumab were nasopharyngitis, upper respiratory tract infections, headache, and fatigue. Injection site reactions have also been reported but are less common.

Given its immunosuppressive properties, ustekinumab may increase one's risk for infection and certain cancers. Studies among patients with an inherited deficiency of IL12/IL23 have shown an increased risk for viral and bacterial infections (Salmonella and mycobacterial).79–81 Thus, prospective patients should be screened for tuberculosis prior to initiating therapy. Ustekinumab should not be administered to patients with active or latent tuberculosis until they have undergone treatment. The BCG vaccine should be avoided for at least one year before, during, or after treatment with ustekinumab.

One case of reversible posterior leukoencephalopathy syndrome (RPLS) was reported among patients treated with ustekinumab during its clinical development. RPLS is a noninfectious syndrome characterized by headache, visual changes, seizures, and confusion. It has multiple ascribed etiologies including hypertension, electrolyte abnormalities, and a reaction to medications. Patients should be monitored for RPLS symptoms during the course of therapy. Live vaccines are contraindicated during treatment. The safety and efficacy of ustekinumab beyond 2 years of therapy remains undetermined. Large long-term studies of ustekinumab will be necessary in order to define the risk of cancer and serious infections with this novel agent.

Antibodies Against Cell Surface Receptors

Efalizumab

Efalizumab is a recombinant humanized monoclonal IgG1 antibody against the α-subunit of the leukocyte function-associated antigen 1 [LFA-1, CD11a (Fig. 234-1)]. LFA-1 is a member of the β-2 integrin family and is involved in lymphocyte activation, enhanced cytotoxic T-cell function, and the trafficking of lymphocytes to the skin (see Fig. 234-2). In both short- and long-term studies, efalizumab has exhibited efficacy in the treatment of patients with moderate-to-severe psoriasis. Efalizumab was withdrawn from the United States market in April 2009 after three cases of progressive multifocal leukonencephalopathy (PML) were reported among patients receiving the drug. PML is a rare, life-threatening infection that is most prevalent among immunosuppressed individuals. It is caused by the JC virus, a typically harmless virus among immunocompetent individuals.

Rituximab

Rituximab is a humanized chimeric monoclonal antibody against CD20, a cell surface protein expressed by mature and pre-B cells. It has been shown to induce the depletion of B-cells in vivo. CD20 expression is lost during the differentiation of B-cells to plasma cells. Aside from playing a crucial role in antibody production, B-cells may also serve as antigen presenting cells and have been shown to provide costimulatory signals, which promote CD4+ T-cell expansion and effector cell function.82

Rituximab is FDA approved for the treatment of patients with moderate-to-severe rheumatoid arthritis and for the treatment of relapsed or chemorefractory (low-grade or follicular) CD20+ non-Hodgkin B-cell lymphomas and has been shown to transiently reduce the population of CD20+ cells in the circulation.83 This effect is achieved by its ability to enhance antibody and complement-mediated cytotoxicity, and promote the apoptosis of malignant CD20+ cells.84 Aside from its role in the treatment of lymphoma and rheumatoid arthritis, rituximab has been increasingly used off-label for the management of other autoimmune diseases. More specifically, reports have suggested its efficacy for the treatment of paraneoplastic and refractory pemphigus, autoimmune hemolytic anemia, granulomatosis with polyangiitis (Wegener's) hypocomplementemic urticarial vasculitis, systemic lupus erythematosus (SLE), cutaneous B-cell lymphoma, chronic graft-versus-host disease, and epidermolysis bullosa acquisita.

Caution, however, should be taken before initiating therapy with rituximab for off-label use. Two cases of PML were reported to the FDA in 2006 involving patients who received rituximab for the treatment of SLE.85 Recent reports have also noted marked progression of Kaposi sarcoma among patients treated for autoimmune hemolytic anemia and Castleman disease.86,87

In a case series of patients receiving rituximab for autoimmune bullous disorders (pemphigus vulgaris, bullous pemphigoid, and mucous membrane pemphigus), severe adverse reactions were noted in three of seven patients.88 These reactions, which consisted of serious infections, enteropathy, and pulmonary embolism, were believed to be associated with concurrent high-dose adjuvant immunosuppression and underlying malignancy among the affected individuals. In a study involving 11 patients with refractory pemphigus vulgaris treated with rituximab and intravenous immune globulin, no infections or other clinically significant adverse effects were noted.89 Additionally, no severe adverse effects were reported in case series and open-label studies among patients treated with intralesional and/or intravenous rituximab for cutaneous B-cell lymphoma and dermatomyositis.90 A study addressing the safety of rituximab for the treatment of diffuse cutaneous systemic sclerosis (among 15 patients) reported mild infusion reactions (affecting 46% of patients), urinary tract infection and a dental abscess affecting a single patient, and one case of prostate cancer at six month follow-up.91

Indications

Rituximab is FDA approved for the treatment of CD20+ non-Hodgkin's B-cell lymphomas and moderate-to-severe rheumatoid arthritis.

Initiating Therapy and Monitoring

No specific dosing regimen has been established for the off-label use of this medicine in the dermatologic setting. Rituximab is usually administered at a standard dose of 375-mg/m2 body surface area at weekly intervals. Premedication with acetaminophen and antihistamines should be considered to decrease the risk for infusion reactions. Monitoring of blood cell counts and serum antibody levels may be pursued every 2–3 months while on therapy. A rapid depletion of CD20+ B-cells occurs after treatment and may last from 2–6 months before recovery. Live vaccines should not be administered to patients prior to and during therapy.

Rituximab is a pregnancy category C medication with unknown safety during lactation.

Risks, Precautions, and Complications

Reported adverse effects associated with rituximab therapy include fatal infusion reactions, vasculitis, hepatitis B reactivation, tumor lysis syndrome, renal toxicity, severe mucocutaneous reactions, cardiac arrhythmias/angina and bowel obstruction/perforation. Cases of PML have been reported among patients with lymphoid malignancies and SLE treated with rituximab.92

Alefacept

Alefacept is a bioengineered protein consisting of the human IgG1 antibody Fc region fused to the first extracellular domain of human lymphocyte function-associated antigen-3 (LFA-3). LFA-3 is a member of the immunoglobulin superfamily and is expressed on the surface of antigen presenting cells. It normally binds to CD2 which is preferentially expressed on the surface of effector/memory T-cells, an interaction that plays an important role in the activation of T-cells in response to antigen. Alefacept is believed to prevent the activation of T-cells by blocking this interaction.93 In addition, it may induce the apoptosis of memory T-cells via binding of its IgG1 portion to the CD16 receptor of natural killer cells.94

Indications

Alefacept was the first biologic agent FDA approved for the treatment of psoriasis in 2003. Studies have evaluated the efficacy of both intravenous and intramuscular dosing (7.5-mg IV qwk and 15-mg IM qwk), however, only the IM form is commercially available at this time. A randomized, placebo-controlled phase III trial of adult patients with chronic plaque psoriasis involving at least 10% body surface area was performed to address the efficacy and safety of alefacept therapy (15-mg IM qwk) for 12 weeks.95 PASI 75 responses were achieved by 21% of treated patients. Among this group, 71% maintained at least a PASI 50 in the 12-week follow-up period. No opportunistic infections or disease rebound was noted during this time.

Reports of off-label use of alefacept in the treatment of other inflammatory dermatoses such as graft versus host disease, lichen planus and alopecia areata have been published.96,97 A randomized, double-blind, placebo-controlled study found alefacept to be ineffective for the treatment of patients with severe alopecia areata.98 Alefacept has shown promise in the treatment of psoriatic arthritis as a monotherapy and in combination with methotrexate.99,100

Initiating Therapy and Monitoring

Alefacept is contraindicated in patients with HIV infection and should not be used in patients with a CD4+ T lymphocyte count that is below normal. On the basis of published studies and manufacturer recommendations, alefacept treatment is typically initiated as a 15-mg intramuscular dose administered on a weekly basis for 12 weeks, followed by a 12-week period of nontreatment observation. The serum half-life of alefacept is approximately 12 days. Improved efficacy may be achieved by increasing the initial treatment course to 16 weeks.101 Phase III clinical trials have shown increased efficacy of alefacept after successive courses of treatment (up to five courses) with no observed compromise in safety or tolerability.102,103

Upon initiation of therapy, CD4 and CD8 T-cell counts should be monitored every 2 weeks and treatment should be withheld if the CD4 count drops below 250 cells/μL; counts should then be monitored weekly. If the CD4 count remains below 250 for over 4 weeks, treatment should be discontinued. In general, alefacept should not be initiated in patients with low CD4 counts or an active infection within 2 weeks of therapy. Treatment of patients with a history of a prior malignancy should be pursued with caution.

Alefacept is a pregnancy category B medication with unknown safety during lactation.

Risks, Precautions, and Complications

Alefacept is well tolerated with a limited side effect profile. Pooled data from randomized controlled trials revealed a low incidence of malignancy among treated patients, which was similar to untreated patients. Abnormalities in liver function tests were more frequent compared to placebo, and serious liver reactions have been reported in postmarketing studies. No correlation between CD4+T-cell counts and infection has been reported. CD4+ T-cell mediated antibody titer responses to external antigens appear to remain intact after treatment.104 Large, long-term follow up studies will be necessary to determine if the immunosuppressive properties of alefacept increase the risk of serious infections and malignancies.

Etancercept

Etanercept is a fusion protein consisting of the human TNF type II receptor linked to a human IgG1 Fc region, already briefly discussed with the anti-TNF agents. It blocks the effects of TNF-α by binding to it in the circulation, thus preventing it from associating with its cell surface receptor. In a double-blind, placebo-controlled study, 49% of psoriatic patients treated with high-dose etanercept (50 mg twice weekly) for 12 weeks achieved at least a PASI 75, whereas only 4% of patients in the placebo group attained this result.105 Continued clinical improvement was noted in the subsequent weeks with 59% of high-dose etanercept-treated patients achieving PASI 75.

In a study addressing the efficacy of etanercept for the treatment of children and adolescent patients with moderate-to-severe plaque psoriasis, patients were randomly assigned to a double-blind trial of weekly subcutaneous etanercept (0.8 mg/kg to a maximum of 50 mg) or placebo.106 After 12 weeks, 57% of patients receiving etanercept achieved a PASI 75 compared to 11% of placebo (p<0.001). Over the following 24 weeks, both groups received open-label etanercept. Four serious adverse events were reported (three infections and one ovarian cyst removal). Overall, etanercept may offer a relatively safe and efficacious treatment option for pediatric patients with advanced plaque psoriasis.

For adults, etancercept is initiated at a dose of 50-mg SC 2×/week for 12 weeks, then reduced to 50-mg qwk (or 25-mg SC twice weekly). The median time to relapse after discontinuation of therapy after 6 months is estimated at 70–91 days.107 The serum half life of etancercept is between 4 and 25 hours. Injection site reactions may occur with etanercept; however, they are generally mild and self-limited. (See Section “Anti-TNF-α“ for greater detail on indications, initiating and monitoring therapy, risks, precautions, and complications.)

Denileukin Diftitox

Denileukin diftitox (DAB389-IL2) is a ligand-toxin fusion protein consisting of a fragment of diphtheria toxinfused to interleukin-2 (IL2). DAB389-IL2 is believed to associate with malignant cells expressing the high-affinity IL2 receptor. Upon binding to the receptor, it is internalized within endosomes, where its ADP-ribosyltransferase region is cleaved and translocated into the cytoplasm. In the cytoplasm, it interrupts protein synthesis, eventually leading to apoptosis of the affected cell.

CD25 represents the α-chain of the IL2 receptor. It serves both as a marker for activated T-cells, as well as for a unique population of CD4+ T-cells that express the transcription factor, FoxP3, called regulatory T-cells (CD4+CD25+FoxP3+). Naturally occurring regulatory T-cells exhibit immunosuppressive properties and have been shown to play an important role in the induction of immune tolerance. Murine melanoma models indicate a role for regulatory T-cells in suppressing antitumor immunity.108 In addition, the in-vivo use of anti-CD25 specific antibody was shown to deplete regulatory T-cell populations and enhance tumor regression in the murine system.109 Because of its ability to deplete CD25+ T-cells, DAB389-IL2 may contribute to antitumor immunity by eliminating regulatory T-cells in addition to malignant cells that express the CD25 component of the IL2 receptor.

A recent study examining the ability of DAB389-IL2 to eliminate regulatory T lymphocytes among human patients with metastatic melanoma revealed neither any significant change in Foxp3 levels nor objective clinical response among treated patients.110 Studies of other human malignancies in which large populations of regulatory T cells were present exhibited a notable reduction in circulating regulatory T-cells and enhanced effector T-cell activation in response to DAB389-IL2.111 Thus, the ability of DAB389-IL2 to eliminate regulatory T cells and enhance antitumor immunity in human malignancies requires further study. In addition, its effects on CD25+ nonregulatory effector T-cells, which also play an important role in antitumor immunity, is under investigation.

In a phase III double-blind, placebo-controlled study, patients with advanced or refractory cutaneous T-cell lymphoma were randomized to receive DAB389-IL2 by infusion at doses of 9μg/kg/day or 18μg/kg/day.112 All patients had failed at least one prior therapy (the median number of prior therapies was five) and were shown to have at least 20% CD25 expression among tumor cells in the skin. Treatment was administered for 5 consecutive days and was repeated every 3 weeks for up to eight treatment cycles. Intent to treat analysis revealed a 30% clinical response rate among all treated patients, characterized by a 50% reduction in tumor burden. Ten percent of patients achieved a complete clinical response characterized by no evidence of cutaneous disease. The majority of patients exhibited a clinical response within the first three treatment cycles. The durability of response was higher among complete responders with a median of 9 months. The median duration of response among partial responders was 4 months. No statistically significant difference in response was noted between the two dosing groups. Another study reported a direct correlation between CD25 expression by lesional skin in CTCL patients and response to DAB289-IL2. More specifically, 78.5% of patients with high CD25 expression, which correlated with advanced CTCL, exhibited a clinical response to DAB289-IL2, in comparison to only 20% of patients with low-to-undetectable CD25 expression.113

DAB389-IL2 is FDA approved for the treatment of cutaneous T-cell lymphoma in which the malignant cell population expresses the CD25 receptor. Studies have reported clinical efficacy with the use of DAB289-IL2 in the treatment of patients with moderate-to-severe plaque psoriasis; however, it is not approved for this indication.114,115

Initiating Therapy and Monitoring

DAB389-IL2 is administered intravenously over at least 15 minutes. Doses at 9 μg/kg/day and 18 μg/kg/day have been utilized for the treatment of cutaneous T-cell lymphoma.

DAB389-IL2 is a pregnancy category C medication with unknown safety during lactation.

Risks, Precautions, and Complications

Infusion-reactions represent the most common adverse effect associated with DAB389-IL2 treatment and may be characterized by fever, hypotension, arthralgias, dyspnea, rash, and chest/back tightness. DAB389-IL2 has also been associated with flu-like symptoms, a reversible transaminitis, vascular leak syndrome, and a morbilliform cutaneous eruption. DAB389-IL2 is contraindicated among patients with a known hypersensitivity to any of its components.

In this chapter, we have discussed a number of biologic agents currently available for the management of dermatologic disease. Large, prospective, long-term, follow-up studies will be necessary to fully discern the safety of these agents. As we have discussed, targeting of the immune system with biologics may result in an increased risk for serious infections and malignancies. The emergence of PML among patients treated with efalizumab, 5 years after its approval, highlights the need for ongoing pharmacovigilance of novel therapeutic agents.

Immunobiologics require complex and expensive manufacturing processes, which may ultimately limit their utilization. Because these drugs generally exhibit reduced efficacy over time, long-term disease control remains a challenge for many patients. As we further characterize the immunopathogenesis of cutaneous disease, new potential targets may be identified, thus improving our ability to manage conditions that may otherwise be poorly responsive to current therapeutic modalities.