Phototherapy, psoriasis, and the age of biologics
Conflicts of interest:
Over 10 years have passed since the first approval of a biologic agent for the treatment of psoriasis. No one can argue that the arrival of this entirely new, highly effective class of medications has not forever changed the therapeutic landscape for psoriasis. Traditional treatments such as phototherapy, however, remain both viable and effective therapies, both as standalone treatments and in combination with biologics. In general, synergistic effects are noted for combinations utilizing phototherapy; however, the long-term impact of these combinations on skin cancer development has yet to be fully determined. Increasing financial pressures for cost-effective therapies augment the appeal of phototherapy and other traditional treatments as compared with the more costly biologics. Phototherapy also remains strong outside the realm of psoriasis, in the management of atopic dermatitis, vitiligo, and cutaneous T-cell lymphoma, among other conditions. Phototherapy will remain a cornerstone in the management of psoriasis as well as nonpsoriatic skin conditions, as its efficacy is well known, its financial cost is reasonable, it is readily compatible with other therapeutics, and its utility is historically proven.
The advent of biologic therapy added a new rung to the therapeutic ladder for psoriasis. Many predicted the decline of more traditional therapies, including phototherapy, with the concomitant rise of the biologics. The role of dermatologists in the treatment of psoriasis was also called into question. Anyone could give an injection, so was it possible other specialties could stake a greater claim in psoriasis management? Could psoriasis treatment leave the specialty of dermatology? And what would be the role of phototherapy in this new order?
Fifteen years have passed since 1998, when infliximab was approved for Crohn's disease and etanercept was approved for rheumatoid arthritis. With off-label use in the intervening years, etanercept was the first biologic approved for psoriasis, in 2002. Today, psoriasis remains a problem, plaguing 2% of the US population, and dermatologists have maintained their role as experts in the diagnosis and treatment of this chronic disease. Furthermore, beyond psoriasis the role of phototherapy in dermatology continues to be strong. In the age of biologics for the treatment of psoriasis, phototherapy should not, must not, and will not become obsolete. Here is why.
The basic principle underlying phototherapy is exposure of the skin to ultraviolet (UV) radiation on a regular basis to treat skin diseases. At present, there are four phototherapy modalities used in dermatology: ultraviolet B (UVB), ultraviolet A plus psoralen (PUVA), ultraviolet A1 (UVA1), and the excimer laser/excimer lamp.
The sun's UVB spectrum includes a broad range of wavelengths from 290 to 320 nm, and originally, artificial sources of UVB emitted the entire range of wavelengths. UVB radiation is the most biologically active. As of the present, narrowband sources have become the most commonly used for UVB therapy, emitting UV radiation at the specific wavelength range of 311–312 nm. This more focused range has proven to be the most beneficial component of natural sunlight for treating psoriasis and other skin diseases. These disorders include atopic dermatitis, vitiligo, pruritus, parapsoriasis, cutaneous T-cell lymphoma (CTCL), and polymorphous light eruption (PMLE).
The UVA radiation emitted by the sun (320–400 nm) is less biologically active than UVB. Psoralens, a group of naturally occurring phototoxic compounds, absorb light photons and then go on to interact with cell function via photochemical reactions. Psoralens maximally absorb at particular wavelengths in vivo, including the UVA spectrum, and the administration of psoralens followed by exposure to broadband UVA radiation (PUVA) is used as therapy for a wide variety of dermatoses. As a therapy, PUVA is used for psoriasis, vitiligo, CTCL, atopic dermatitis, lichen planus, morphea, graft-versus-host disease (GVHD), and other indications. PUVA can also be utilized in a preventative manner for PMLE, solar urticaria, chronic actinic dermatitis, and pruritus, among others [1-3].
The UVA spectrum is further subdivided into UVA2 (320–340 nm) and UVA1 (340–400 nm). Long-wave UVA1 is in clinical use as monotherapy for atopic dermatitis, a variety of sclerosing disorders including morphea and scleroderma, and sclerodermoid GVHD. Without the erythema-producing wavelengths in the UVA2 spectrum, higher UV doses can be administered, and the longer wavelengths penetrate deeper into the skin .
Monochromatic 308-nm UV radiation can be produced either in a coherent form by a xenon chloride excimer laser or in a noncoherent form by an excimer lamp . These devices can be used to treat localized skin diseases such as psoriasis, vitiligo, and eczema – some of the same indications as for conventional UVB phototherapy. These handheld delivery systems allow for quick, focused delivery of therapeutic UVB radiation to limited areas of affected skin.
When used to treat psoriasis, as well as other skin diseases, phototherapy's mechanism of action is based on several categories of action, including (1) alteration of the cytokine profile, (2) induction of apoptosis, and (3) promotion of immunosuppression . Furthermore, the side-effect profile of phototherapy is well known, both short-term and long-term. While the clinical response, i.e., control and/or clearance of psoriasis, may take several months to be attained, the efficacy is predictable, and the response rate is well known. UVB has a reported efficacy of 40% to 80%, as measured by attainment of 75% improvement in the Psoriasis Area and Severity Index (PASI-75) from baseline. Efficacy, as measured by the PASI-75, is reported in over 80% of patients undergoing PUVA therapy . In addition, phototherapy generally lacks systemic toxicity, and there are few to no pharmacologic interactions. For these reasons, phototherapy holds a strong position as a first-line treatment for moderate to severe psoriasis.
Biologic therapy in dermatology
Psoriasis is the major indication for which biologics are utilized in dermatology. Targeting specific steps in the pathogenesis of psoriasis, the biologics alter the natural history of the disease. The immune system is targeted based on our understanding of where an abnormal immune response contributes to psoriasis.
Several biologic agents are approved for psoriasis and/or psoriatic arthritis, including adalimumab, etanercept, and infliximab, all of which act on tumor necrosis factor α (TNF-α). The interleukin-12/23 (IL-12/23) pathway is inhibited by ustekinumab, and alefacept targets and blocks T cells [8, 9]. With regard to efficacy, estimates of PASI-75 scores range from 20% with alefacept to 66% with ustekinumab and between 40% and 80% with the TNF-α antagonists .
Administered by either injection or infusion, these therapies have advantages and disadvantages over phototherapy and the traditional systemic agents . Issues ranging from financial considerations to patient safety are being raised as the medical community learns more about the long-term effects of these agents. Known risks of these agents include immunosuppression and malignancy, both lymphoproliferative and cutaneous . Safety concerns in regard to the possible association of anti-IL-12/23 biologic agents, such as ustekinumab, and major adverse cardiovascular events (MACEs) have been raised [12-14]. Further work is needed in this area to clarify any increased risk of MACE with the anti-IL-12/23 agents, especially in light of the increased baseline risk for cardiovascular events in the psoriatic population. The chronic Th1-mediated inflammation characteristic of psoriasis is also at the center of the atherosclerotic plaque. There is an independent association between psoriasis and coronary artery disease and stroke [15-17].
Pediatric psoriasis patients represent a segment of the psoriatic population for whom biologics are used but are not officially FDA-approved. The anti-TNF agents are cleared for pediatric use, but only for rheumatologic and gastroenterologic indications. This subset of psoriatic patients may not be able to obtain insurance coverage for biologics; hence, phototherapy remains a mainstay of treatment for moderate to severe disease.
Combination therapy in psoriasis
When dealing with moderate (3–10% of body surface area) and severe (> 10% of body surface area) psoriasis, combination is the rule rather than the exception. The most simple combinations blend topicals with phototherapy or systemic medications, and the combinations grow ever more complex as more agents are added to the mix. New combinations are the natural result of the arrival of the biologics as new therapeutic choices.
When phototherapy is combined with biologics, among the first and most logical concerns is the potential for increase in skin cancers. Lessons learned from the association with skin cancer of combined cyclosporine and phototherapy highlight the risk of combined immunosuppression and UV radiation . While the biologics appear to be less immunosuppressive than cyclosporine, treatment with biologics alone has demonstrated a risk of skin cancer [11, 19]. On the positive side, the mechanisms by which phototherapy and biologics work are entirely different, and from a therapeutic perspective, the hope remains for an additive and/or synergistic benefit [20-22].
There are a growing number of reports in the literature addressing the efficacy of combination therapy in psoriasis. As expected, the combinations include phototherapy in conjunction with topicals, systemic agents, and biologics as well. Overall, as would be anticipated, combination therapy yields faster clearance and/or better results than a single modality of treatment [20, 22, 23].
Combinations of phototherapy and biologics examined in the literature include narrowband UVB plus etanercept , narrowband UVB plus ustekinumab , narrowband UVB plus adalimumab , and narrowband UVB plus alefacept [27, 28]. Notably, however, in at least one study, the results of treatment with narrowband UVB alone were comparable with those of a combination of narrowband and alefacept . Recent work presents evidence that the combination of etanercept and narrowband UVB has a synergistic effect on plaque psoriasis; however, only a small group of patients (2.5% of the study population) ultimately required the combination. This small subset of patients did not attain adequate response with either treatment as monotherapy and finally cleared with the combination treatment .
While on the whole these studies suggest that combinations of biologic therapy and phototherapy provide viable, feasible, and promising therapeutic avenues, caution must still be exercised, as long-term safety data on these combinations are not available. Clinicians must still have a significant respect for the potential for promotion of malignant neoplasms and/or immunosuppression [29, 30]. Cost, too, is a reality and must be factored into the equation.
Furthermore, all patients and their respective diseases are unique, and consequently not every patient responds to every therapeutic modality. For many, phototherapy works wonders, while for others, only marginal improvement in their disease is noted. Likewise, biologic therapies may yield tremendous psoriasis clearance for some, yet inevitably a subset of patients treated with any given biologic will note little change in their skin. When comparing PASI-75 scores among therapies, it quickly becomes evident that while all therapies are efficacious, none are perfect. As with any treatment, there will be a group of ‘nonresponders’ or ‘minimal responders’, and frequently it is these patients who require a combination or rotation of therapies. From the diversity of responses, we can learn more about psoriasis the disease as well as about approaches to designing optimal and effective therapeutic strategies.
Phototherapy outside psoriasis
As mentioned in previous sections, in addition to their role in treating psoriasis, the various modalities of phototherapy are integral in the treatment of nonpsoriatic disease as well . Numerous inflammatory skin conditions respond to phototherapy. For moderate to severe atopic dermatitis, narrowband UVB is effective, frequently used in combination with topical treatment regimens . PUVA and UVA1 are also effective; however, narrowband UVB's safety and efficacy profile make narrowband the first line among phototherapy options. As an adjunct to topical therapy, especially when involving a cosmetically sensitive area, vitiligo can be treated with phototherapy. Modalities utilized in vitiligo include PUVA, narrowband UVB, and 308-nm excimer laser . Malignancies including cutaneous T-cell lymphoma, especially in their early stages, can be treated with skin-directed therapy, including phototherapy . Other skin diseases that may be treated with phototherapy include GVHD, sclerosing skin disorders, granuloma annulare, chronic urticaria, pityriasis lichenoides, PMLE, other photodermatoses, and pruritus (itch).
Economics and cost are realities of medicine in the present day, and psoriasis therapies are no exception. Several recent pharmacoeconomic analyses addressed this issue in severe psoriasis and concluded that phototherapy and methotrexate are the most cost-effective therapies [7, 35]. One study estimates a greater than 10-fold difference in cost when comparing biologics to older, traditional treatments, including phototherapy . When considering quality-of-life data and the improvement in quality of life a given therapy provides, the cost of phototherapy was the lowest . Studies such as these confirm the inherently obvious – biologics are more costly and are driving the rising costs of psoriasis therapy.
Phototherapy remains a viable and strong part of the dermatologist's tool kit for psoriasis therapy. The arrival and addition of the biologics to the therapeutic milieu has increased awareness of the disease through advertising and marketing as well as patient research on the Internet. Not all psoriasis patients are candidates for treatment with biologics, nor are all of these individuals willing to accept the biologics' risk profile. Overall, phototherapy maintains an excellent benefit-versus-risk profile when compared with systemic therapy. In moderate to severe pediatric psoriasis, there are fewer FDA-approved therapeutic choices; hence, phototherapy continues to play a key role in treatment options for this subset of patients as well. Its utility in treating nonpsoriatic disease as an adjunct and/or first-line therapy remains strong. These facts alone will maintain phototherapy as a workable, practical, and safe choice for providers and patients alike. The appeal of phototherapy is timeless.
Combination therapy has long been a reality in psoriasis, and with each new biologic, new possibilities for combinations are created. In particular, it is the expertise of the dermatologist in psoriasis, phototherapy, and biologics that ensures that psoriasis treatment will remain in dermatology and phototherapy will shine on.