Most conventional systemic and biologic agents for the treatment of psoriasis carry FDA-approved labeling indicating that patients with moderate to severe disease are the appropriate candidates for these medications. The label for adalimumab (Humira, Abbot) specifies that patients eligible for adalimumab should be those who are candidates for systemic therapy or phototherapy, and those for whom other systemic therapies are medically less appropriate. The label for infliximab (Remicade, Centocor) specifies that infliximab is appropriate for patients with severe psoriasis who are candidates for systemic therapy or for whom other systemic therapies are medically less appropriate. Unfortunately, the distinction between mild, moderate, and severe psoriasis is undefined by the FDA, which renders the labeling difficult to interpret.
The National Psoriasis Foundation (NPF) treatment guidelines are more practical. Patients are divided into two classes: those for whom topical therapy is appropriate and those for whom "other" treatment is warranted. For patients with mild psoriasis, topical therapy is adequate. However, if patients do not achieve sufficient improvement with an appropriate trial of topical treatment, physicians may consider other forms of therapy, such as phototherapy, conventional systemic therapy, or biologic therapy. This decision should be based on a host of individual factors, including the patient's medical history, proximity to clinic, and availability during business hours (if phototherapy or infliximab is being considered), and insurance coverage.
One of the most important things to consider when selecting a biologic is that the treatment should not only be successful at treating the disease, but also conducive to the patient's lifestyle and social circumstances. For example, while we might find NB-UVB light treatments effective, many patients cannot commit to traveling to the office three times a week for 12 weeks. Unfortunately, approximately 30 percent of patients who receive light treatments do not have remission. Patients who do not respond to phototherapy, cannot make it to the clinic, or who have psoriatic arthritis, may receive the best treatment from a systemic or biologic agent.
The focus of this article will be on the decision to use biologics, recognizing that other systemic treatment options exist and may in some cases be preferrable for individual patients. Given the number of potential considerations for use of biologics, making sense of the overall process of treatment can be difficult. Ahead, we will examine the variety of factors influencing physicians' decisions to prescribe biologics and review the treatment process step-by-step, in an effort to help streamline the process.
Initial History and Physical Examination
Before considering treatment options, physicians should acquire a thorough history of present illness. This history should document the duration of disease, exacerbating or mitigating factors, and response to and tolerability of previous therapies. When possible, physicians should elicit information about the duration and dosage of prior therapies to determine if trials of prior therapy have been adequate. Reich and Mroweitz have recently published treatment guidelines on the appropriate use of different anti-psoriasis treatments and have concluded that treatment courses of up to 16 weeks, at adequate dosages, serve as a sufficient trial for treatments such as methotrexate.1
A focused set of questions may help guide the choice of therapy with the optimal benefit-risk balance for that patient. For example, ask about symptoms consistent with psoriatic arthritis, including the presence of joint pain or back pain, stiffness (particularly morning stiffness in the hands or feet that improves with use), and fatigue. Symptoms of psoriatic arthritis-associated enthesitis may include heel pain, pain on the bottoms of the feet, or buttock pain (if the patient suffers from inflammation at insertion of the Achilles tendon, plantar fasciitis; or inflammation at ligamentous insertions into pelvic bones, respectively). The presence of such symptoms, especially if unimproved with NSAIDs, inclines us to favor prescribing agents that have demonstrated efficacy and safety for psoriatic arthritis, such as TNF-antagonists.
There is a paucity of information on the use of biologic agents in patients with a history of internal malignancies, as such patients were excluded from clinical trials of these agents. Because a large observational study of patients with rheumatoid arthritis treated with TNF-antagonists detected an increased risk for melanoma skin cancer,2 a history of melanoma skin cancer is a relative contraindication for prescribing TNF-antagonists. In light of concerns about TNF-antagonist therapy and increased risk of reactivation of latent tuberculosis or exacerbation of active tuberculosis, screening for history of TB in all prospective patients for immunosuppressive agents is advised. Therefore, patients under consideration for a TNF-antagonist therapy should first have a purified protein derivative (PPD).
Although there are lab-based tests for latent TB (Quantiferon Gold), the sensitivity and specificity of these tests have not been studied in patients initiating anti-TNF therapy. There is no evidence that these can be used to supplant the "gold standard" for latent TB testing: the PPD test. The justification for collecting PPD is that the sensitivity of PPD alone in detecting latent TB is 90 percent but would be expected to improve with dual testing. Chest X-rays are not standard but may be quite useful.
There is no evidence suggesting that efalizumab (Raptiva, Genentech) or alefacept (Amevive, Astellas) treatment increases the risk of TB reactivation. The presence of signs suggestive of active TB, i.e. cough, weight loss, fever, would necessitate discontinuation of treatment and checking a PPD, and depending on the outcome referral to an infectious disease consultant until the case is further evaluated.
Some case reports have described exacerbation of hepatitis B in patients treated with TNF-antagonists, which may warrant a screening in some cases. Such screening is not widey recommended but may be considered.
It is appropriate to question patients about a history of severe congestive heart failure and demyelinating disease. Patients with these conditions were excluded from studies of TNF-antagonists, and evidence suggests that TNF antagonist therapy may increase the risk of exacerbation of these conditions.
We also recommend routinely obtaining a CBC chemistry panel.
Making the Decision
When the choice is made to pursue biologic therapy for moderate to severe psoriasis, generally four agents can be used effectively, each with its own advantages and drawbacks. They are etanercept (Enbrel, Amgen Wyeth), adalimumab, alefacept, and efalizumab. In contrast to some clinicians, we tend not to include infliximab in this group because of increasing data suggesting the prevalence of infusion and allergic reactions. There may be a general loss of efficacy over time associated with TNF-antagonists, but a recent study showed that using infliximab in conjunction with methotrexate maintained response.5
Deciding between these four agents will depend on what physicians and patients seek from treatment. For example, alefacept is not known for strong efficacy—with only about 21 percent of patients achieving PASI 75—but remission periods may last up to six months or longer.6 Additionally, alefacept has a strong safety profile, with no increased risk of TB, CHF, demyelinating diseases, or other diseases.6 These factors may be more attractive depending on the patient, which is why it's important for physicians to consult with patients before deciding on a treatment.
For patients who would rather visit the office less frequently, efalizumab, etanercept, or adalimumab may be more appropriate. Of these three agents, adalimumab likely has the best efficacy profile.7 An additional benefit of adalimumab is that patients only need to take it every other week subcutaneously. Etanercept and efalizumab, on the other hand, should be taken at least once a week. Adalimumab also has a favorable efficacy profile, however, it's important to keep in mind that it has relatively less long-term safety data in psoriasis.
Also worth noting is that etanercept has been in development since 1992, with more than half a million people having received it during that time. It may require more frequent treatments—sometimes up to twice per week—but its safety profile is relatively strong.8 Efalizumab doesn't appear to hold up as well in comparison to etanercept and adalimumab, both in terms of safety and efficacy. Recently, two patients out of 400 receiving efalizumab over the age of 65 died from progressive multifocal leukoencephalopathy.9 This study has confirmed some recent speculation about risks associated with long-term efalizumab use. Its use may be declining relative to other agents.
Follow-Up and Screening
After starting patients on biologic therapy, careful and frequent follow-up is important to ensure they are responding optimally and to make proper adjustments where necessary. We recommend follow-up visits every three months for the first year, and then every six months thereafter is generally satisfactory. These visits involve thorough physical examination and a complicated review of symptoms. These sessions provide ample opportunity to assess the efficacy of the treatment. Since PASI evaluations are more suited as a clinical research tool, we believe it's best to make a physicians global assessment (PGA) of the patient's degree of involvement (e.g., mild, moderate, severe), which should capture the elements of approximate percentage body surface area (BSA) involvement, erythema, induration, and scaling on a scale of 0 to 4. This is a personal preference, amd use of BSA scores to monitor progress is still standard.
It is important to probe the patient's history, particularly looking at how specific dimensions of the patient's life ( i.e. work, school, home life, sleep, itching, etc.) are affected by residual psoriasis and vice versa.
In most cases, you would expect to see satisfactory response to treatment (such as a global assessment of minimal disease) within 24 weeks of starting therapy (i.e., by the second follow-up visit). If this does not occur, it may be wise to start thinking about adjusting therapy. Some patients will also lose response to biologics over time, which should prompt an adjustment to therapy, as well. Under these scenarios, physicians should assess how compliant their patients are with following their injections schedules.
Working to optimize patients' concomitant topical therapy can be beneficial, as well. Physicians may consider adding concomitant low-dose methotrexate, such as 5-15mg per week (though the use of methotrexate in combination with biologics for psoriasis is off-label). You could also add NB-UVB. For patients who fail to respond to this approach or who have adverse effects or problems with intolerance of their biologic therapies, to consider switching to a different biologic is warranted.
Though etanercept, infliximab, and adalimumab are all TNF-antagonists, patients who fail to respond to one of these agents may respond to a different TNF antagonist. If patients don't respond to a second TNF-antagonist, physicians may consider a switch to a T-cell agent, unless the patient has concomitant psoriatic arthritis. Patients who don't respond or who lose response to a T-cell agent may achieve a positive response when they switch to a TNF-antagonist.
Rigorous follow-up is also necessary to ensure that patients are not experiencing serious treatment-related adverse events. The principal concern in monitoring safety during follow-up is to vigilantly survey for serious infections, including serious opportunistic infections (e.g. tuberculosis and histoplasmosis) and malignancy (e.g. lymphoma). To varying degrees, the risk for these infections exists for all the biologics (and for traditional systemic agents like methotrexate or cyclosporine). Although the risk for most of these conditions is quite low, physicians should query patients for symptoms and to document these queries at each follow-up visit. In addition, ask about any unexplained weight loss, fevers, night sweats, fatigue, general malaise, or coughing. For patients with any of these symptoms, we recommend inquiring about their duration, severity, whether they are worsening, and also about recent travel history (to screen for possible coccidioidomycosis or histoplasmosis).
Any patient symptomatology consistent with a serious infection should prompt you to refer the patient immediately to their internists or family physicians and to suspend biologic treatment until they get a clean bill of health. Additionally, regular age-appropriate vaccinations while patients are on biologics are also useful. Live, attenuated vaccines are contraindicated during biologic therapy, but non-live vaccines can be administered. There may be no clinically relevant diminution of the efficacy of these vaccines with biologic therapy, though this has not been clearly established. It may be optimal for the patient to receive vaccines prior to initiating therapy with biologic agents.
Increased risk of malignancy, especially lymphoma, has been attributed to use of some of the biologic therapies. To a large degree, the general review of health described above should capture symptoms associated with onset of lymphoma or other internal malignancy. Patients should maintain relationships with their primary care physicians and undergo age- and gender-specific cancer screenings, as well. Because immunosuppressive therapies are associated with concerns about development of demyelinating disorders, physicians should question patients about possible symptoms of these during follow-up. They should ask about new-onset tingling in fingers or toes, sudden changes in visual field (to screen for optic neuritis), and new problems with balance. For any patient who may have a new-onset demyelinating disorder, we recommend arranging an immediate neurology consultation and consider suspending anti-TNF therapy in the interim, or alternatively switching to a T-cell agent. Some physicians have also reported cases of carpal tunnel syndrome with this surveillance, but no cases of bona fide demyelinating disorder.
Screening for new onset joint pains or morning stiffness is also essential. For patients on T-cell agents, the motivation is two-fold: First, arthralgias are a described adverse event associated with efalizumab.9 Second, if patients have new-onset psoriatic arthritis, they might benefit by switching to anti-TNF antagonist therapy. Patients already receiving TNF-antagonist therapy primarily for their psoriasis who experience new-onset or worsening symptoms consistent with psoriatic arthritis may be switched to a different TNF-antagonist therapy; methotrexate may be added as well.
Finally, physicians should be sure to ask patients how they are tolerating injections and if there are any signs of injection site reactions. Reinforcing the need to rotate sites of injections and clarification about injection technique can help reduce the potential for pain and swelling. In rare cases, severe injection-site reactions may necessitate switching from one biologic to another.
Collecting CBC and chemistry panels at follow-up visits can be important. With alefacept, monitoring T-cells is necessary, as dropping CB4 T-cell count below 250/microliter should prompt suspension of weekly injections until the T-cell count recovers. Also, rare cases of thrombocytopenia and of hematologic dyscrasias with efalizumab and the TNF-antagonists have been described.9 Therefore, physicians may wish to ask about this possibility during follow-up visits by asking about signs of pallor, easy bruising, or bleeding. Also, physicians should check blood concentrations every month for three months and then every three months thereafter. CB4 concentrations should be checked at zero weeks, two weeks, and four weeks. If CB4 levels are greater than 600 at week four, they likely do not need to be checked again.
We advocate annual checking of PPD and chest X-rays for all patients, especially because anyone who is PPD-negative at baseline carries the risk of conversion to latent tuberculosis following contact with someone with tuberculosis. There is no other way to detect conversion without repeated PPD screening. Anecdotal evidence suggests receiving biologic therapy does not interfere with the sensitivity of the PPD test status results.
A Collaborative Future
As indicated above, follow-up for psoriasis patients on biologics is more complex and can be considerably more time-consuming than, for example, follow-up of a basal cell carcinoma patient. This will continue to change as the spectrum of biologic therapies keeps growing. For example, the addition of IL-12/23 antibodies may create a new branch to the therapeutic armamentarium. Phase III clinical trials have suggested that the efficacy of these molecules is superior to currently available biologics, but it's important to note that they have only been used in approximately 7,500 people.
Once approved by the FDA, IL-12/23 inhibitors may first be employed in those patients who have not responded to the currently available agents. Some patients with body surface area of 60 percent improve by 70 percent within two weeks of the first injection.10 There's hope among some practitioners that these agents can be first line in the management of "crisis" psoriasis, i.e. psoriasis that is rapidly flaring as well as exfoliative erythroderma secondary to psoriasis, for which cyclosporine or infliximab are currently used; these older agents are administered more frequently.
When discussing treatment options with patients, you'll find that patients have different needs and will likely require different approaches to treatment. Some patients may want the drug that works "the best" and is administered "the least often." But, "best" and "least" must be measured against the quantitative safety of these agents in that they do not, as of yet, have the test of time.
Selecting biologics and administering therapy is ultimately a collaborative process in which the patient is involved every step of the way. For biologic therapy to be successful, physicians need to make the most informed decisions based on evidence as well as the needs of the patient. Just as psoriasis manifests differently in each case, patients come to your practice with different concerns. Therefore, treatment approaches will not always be the same. Physicians should keep this in mind as the repertoire of psoriasis treatments continues expanding.
Martin Okun, MD, PhD contributed to this article. Dr. Okun is a full-time employee of Abbott Laboratories, the manufacturer of Humira.
Dr. Bagel is on the speakers bureau for Abbott Labs, Genentech, Astellas, Amgen, Stiefel, and Warner-Chilcott.
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