Biologics in Practice: Adherence to Biologic Therapy in Psoriasis
Although adherence to treatment with biologic agents is greater than with other traditional treatments for psoriasis, a better understanding of adherence behaviors will be valuable in improving treatment outcomes.
The treatment of patients with psoriasis can be difficult due to the recurring and remitting nature of the disease and the need for persistent, long-term therapy. Adherence to traditional treatment regimens is poor and results in suboptimal treatment outcomes. As biologic agents like tumor necrosis factor-alpha (TNF-α) inhibitors and ustekinumab (anti-IL-12 /23) become more widely used in the treatment of psoriasis and psoriatic arthritis, adherence rates, factors affecting adherence and methods of improving adherence all need to be explored.
Adherence to treatment with biologic agents is greater than with other traditional treatments for psoriasis. While not the most accurate means of measuring adherence, self-reported adherence rates were highest for biologics, followed by oral medications, phototherapy and topical agents.1 Persistence to therapy (retention/survival rates) of biologics use can be assessed by analyzing administrative claims. In a study of pharmacy records of Medicaid patients, Bhosle et al found a 66% adherence rate to TNF-α inhibitors (considerably higher than the adherence rate seen with topicals), with no difference in adherence between which anti-TNF-α was prescribed.2 Other studies have found 1-year survival rates for patients with psoriatic arthritis were 45%-70% and 2-year survival rates were 57% for anti-TNF agents, with a median drug survival of 2.9 years.3,4 Pauses in therapy and discontinuation are common, but 40% restart anti-TNF therapy.4 Persistence with biologic therapy in rheumatologic diseases has been more extensively characterized than in psoriasis patients with reported rates of adherence between 38%-84% (1-year survival rates 68%-84%, 2-year survival rates 58%-66%, 3-year survival rates 58%-75%, and 4-year survival rates 38%-56%), median drug survival of 37 months, and no concurrence of data to support better adherence to one anti-TNF agent over another, regardless of intravenous or subcutaneous of administration.5-11
Developing Reliable Adherence Monitoring Systems
Measuring adherence to any treatment can be difficult. Persistence defined by administrative claims is the more commonly used method of measuring adherence to biologic therapy.12 With biologic therapy, traditional means of monitoring and measuring adherence cannot be utilized, as there are no medication bottles. Counting injector devices, akin to pill counts, is not readily feasible. Self-reported adherence through questionnaires or medication diaries is not reliable.13,14 The use of electronic monitoring systems is a reliable way to measure adherence and would provide additional information important to biologic therapy such as dosing frequency and dosage intervals and thus may be optimal.15 In ulcerative colitis and Crohn’s disease, measuring anti-TNF levels and detecting antibodies to anti-TNF agents have provided insight into whether patients will respond to biologic therapy and may ultimately be a means of measuring adherence to treatment of biologic agents in psoriasis and other dermatologic or rheumatologic diseases.16,17 The cost of this method would not likely be feasible for general use in all patents on biologics, but may provide a means of confirming adherence in patients who fail treatment. Having a way to accurately measure adherence is crucial to evaluating poor response to treatment.
Examining Issues that Contribute to Non-Adherence
Non-adherence to biologics is multifactorial. As with adherence to any treatment regime, patient education, physician-patient relationship, efficacy and cost all play a role. Drug inefficacy represented the largest single reason for discontinuing treatment (55.8%) in patients using anti-TNF agents for rheumatoid arthritis (RA).11 Similar to vehicle preference affecting adherence with topical therapy,18 patient preferences in terms of intravenous versus subcutaneous administration likely have a role in adherence to biologics. Patients with inflammatory bowel disease and RA surveyed on their preference of administration preferred an intravenous (IV) over self-injected subcutaneous (SC) route of administration.19,20 For those choosing IV, the most common reason cited was an aversion to the idea of self-injecting, and for those who chose SC, the most common reason given was the convenience of treating at home.19 Cost is a known factor in adherence, whether it is treating psoriasis or any chronic health problem.21 Patients on biologics therapy for rheumatoid arthritis with higher out-of-pocket expenses had decreased adherence.22
Patients with longstanding psoriasis often employ self-management techniques to treating their disease. Ersser et al found that patient attitudes toward self management in the treatment of psoriasis included feeling like they are the best people to deal with their disease and having a one size doesn’t fit all attitude. Many utilize trial and error techniques and have developed their own medication regimes.23 While self-management may not be ideal, it is a reality in the treatment of chronic skin diseases and, therefore, may be an important factor in better educating patients. Self-managing is likely a factor in adherence to biologics. Patients may be hesitant to give themselves a “painful” injection at times when they feel their disease is well controlled.
Cost, again, may play a role here. Patients are aware of the high cost of treatment with biologics and many may have had difficulty with insurance coverage or may have had to apply for a financial assistance program to cover the cost. When their disease improves with biologic therapy, they may save doses for future flares as a means of cost saving. This can be assessed by asking patients, “Are you keeping the extra syringes you’ve accumulated refrigerated like you are supposed to?” If the patient says yes, then we know they are accumulating extras and not taking the medication per the prescribed schedule.
How extensively self-management or other factors contributing to non-adherence affect treatment outcomes is difficult to assess. Discontinuing and then reinstating treatment with etanercept in psoriatic patients has a response rate similar to that of initial treatment and mean time to relapse after discontinuing treatment was 3 months.24 Relapses after interruption in treatment, changes in morphology of psoriasis, and adverse affects were not observed. Similarly, both continuous and interrupted etanercept therapy were effective in psoriasis,25 though greater improvements were seen with continuous treatment with anti-TNF agents and anti-IL 12/23 over interrupted treatment.25,26 These findings, along with good physician-patient communication and patient education, may support the use of interrupted biologic therapy, whether it is a result of self-management, drug holidays, or other factors affecting adherence in patients where disease is well controlled. Still, most efficacy data on psoriasis supports adherence and continuous use of biologic agents as necessary for maintenance and control of disease.26
Examining Issues Contributing to Good Adherence
Factors contributing to improved adherence with biologics compared to other treatment options are also important to emphasize. Inconvenience of applying messy topicals and frequent dosing of traditional therapies are not factors with biologic agents. Less frequent dosing of medications may lead to greater adherence in some settings.27 Etanercept is injected once to twice weekly and has the most frequent dosing schedule of the biologics agents, while ustekinumab is dosed the least frequently, once every 3 months. Overall, patients on injectable biologics place importance on efficiency and convenience of therapy and are highly satisfied with their treatment,28 and patient satisfaction leads to better adherence.
While adherence may be greater with biologics than other treatments for psoriasis, non-adherence is still suboptimal and results in poor treatment outcomes and higher healthcare costs. There is no one thing that will improve adherence. A variety of factors need to be considered, the most important of which is the physician-patient relationship. Patients fear drugs and are not typically trusting of drug companies. Patients’ willingness to take medication is supported by the trust and faith they place in their physicians. Taking the time to establish a strong, trusting relationship between the patient and the physician may be an important key to success, albeit one that has not been extensively explored.
Educating patients about their disease, informing them of treatment options and discussing treatment expectations and adverse effects is crucial. In fact, patients are seeking more information.23,29 This is especially important in regard to biologics agents, where patients in most cases will be unfamiliar will subcutaneous injections. The more education and training the patient receives on how to self-inject, the more comfortable the patient will be with treatment and the more likely he or she will be to adhere. It is especially important that patients are educated on common side effects such as injection site reactions and are knowledgeable about how to proceed if such a reaction occurs so as to not unnecessarily interrupt treatment.
Biologics do come with serious side effect profiles and black box warnings that can be scary for patients. Taking time to thoroughly educate patients on these potential adverse effects may lead to better adherence. Using resources from the National Psoriasis Foundation can be helpful in this regard. The authors use the Foundation’s Overview of Treatment brochure to give patients information about all their options; the Foundation also has Fact Sheets that provide more detail for each of the biologic agents (and non-biologic systemic treatments) approved as psoriasis treatments.30,31 These materials are reviewed by psoriasis experts, provide high-quality information and are available to both patients and physicians on the Foundation’s website at www.psoriasis.org. Electronic versions of these materials can be accessed and downloaded at no cost.
Putting the risks of biologics into perspective is not easy. Patients may hear of a risk of lymphoma and think it is a 50:50 “I will get it or not” risk. Graphical illustrations to show the level of risk have been recommended and may be helpful for clarifying risk to patients.32
Developing Tools to Increase Adherence
Many successful techniques to improve adherence have been studied in chronic skin diseases that could be applied to the use of biologics. Patients receiving daily text messages providing reminders and educational tools had better adherence compared to control group as well as improved disease severity in terms of Psoriasis Area Severity Index (PASI), Self-Administered Psoriasis Area Severity Index (SAPASI), body surface area (BSA), Physician Global Assessment (PGA), and Dermatology Life Quality Index (DLQI).33 Increasing the frequency of office visits improves adherence to topical treatment in psoriasis and acne.34,35 A similar effect may apply to the use of biologics, though more frequent office visits are not always feasible for the physician or the patient. Currently, ustekinumab is required to be administered by a healthcare professional and is generally given at the time of an office visit. Whether this results in improved adherence has yet to be reported, although reports on adherence with infliximab in the treatment of RA, also administered by a healthcare professional, has been inconclusive, with both better and worse adherence reported.7-11
Reports of adherence to biologic therapy in psoriasis are limited in the literature. Most studies of adherence, including studies of adherence rates and factors affecting adherence, are from the study of rheumatologic diseases, which are helpful but do not necessarily translate equally to the treatment of psoriasis. Biologic agents are quickly becoming a standard of care option in psoriasis treatment and further studies examining adherence behaviors will be valuable in improving treatment outcome.
Dr. Sandoval 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 at Wake Forest University School of Medicine.
Disclosure: The Center for Dermatology Research is supported by an unrestricted educational grant from Galderma Laboratories, L.P.
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/Valeant, Pharmaderm, Ortho Pharmaceuticals, Aventis Pharmaceuticals, Roche Dermatology, 3M, Bristol Myers Squibb, Stiefel/GlaxoSmithKline, Novartis, Medicis, Leo, HanAll Pharmaceuticals, Celgene, Basilea, and Anacor and has received stock options from Photomedex.
Dr. Sandoval has no conflicts to disclose.