ABSTRACT
Sunscreens have been around for more than 70 years. Designed originally to protect against sunburn, recognition of the various harmful effects of ultraviolet (UV) radiation has broadened the use of sunscreens. The addition of effective UVA sunscreen agents has enabled claims beyond protection against sunburn to include prevention of idiopathic photodermatosis, actinic keratoses, skin cancer, and photoaging. This article will review some of the recent advances in photoprotection, including the development of sunscreen formulations offering higher and broader protection against solar radiation.

Key Words:
sunscreens, photoprotection, ultraviolet A, ultraviolet B, UVA, UVB, sun protection factor, SPF

Protection Against Ultraviolet A (UVA) Radiation

Rating UVA Protection

The almost universal use of the sun protection factor (SPF) has lured many consumers into thinking that a higher SPF means a better sunscreen. Because SPF is mostly an indicator of UVB protection, it is difficult for consumers and physicians to compare the UVA protection afforded by sunscreens.¹ For many years, some countries have been using UVA labeling systems that can provide guidance on both UVA and UVB protection that is offered by sunscreens. Other countries, like the US and Canada, have been slower to introduce guidelines for UVA protection labeling.

Modifications to Sunscreen Labeling

The US FDA recently proposed inclusion of a 4 star grading system in conjunction with a descriptor (i.e., low, medium, high, and highest) to rate UVA protection.2 This star rating system will depend on results of both in vitro and in vivo UVA testing. According to the agency, UVA ratings would be based on 2 tests: one would measure the sunscreen’s ability to reduce UVA penetration and the second would measure the product’s ability to prevent tanning. The test that yields the lowest level of UVA protection would determine the number of stars that the sunscreen would receive. This will help consumers and physicians identify the level of UVA protection provided by the different sunscreens. Other modifications include making minor changes to UVB testing procedures to improve accuracy, increasing the maximum sunburn protection factor from SPF 30+ to SPF 50+, and sanctioning the use of new combinations of active ingredients.²

Avobenzone and Photostability

Protection against UVA radiation was revolutionized by the introduction of butyl methoxydibenzoylmethane (avobenzone) in the late 1980s and early 1990s. This was the first organic sunscreen agent that provided some protection for mid- to long-range UVA rays. However, the degradation of some UVA filters, such as avobenzone, by sunlight, prompted the need to stabilize the formulation in order to prevent the loss of efficacy. Upon absorption of UV radiation, the avobenzone molecule can transform into a molecule that no longer absorbs UVA radiation. In formulations where avobenzone is not photostable, UVA protection decreases with the time spent under the sun. This has been shown to occur after as little as 60-90 minutes of sun exposure.³


A number of different companies have developed systems to stabilize avobenzone in the final formulations. For example, a combination of avobenzone and 2-ethylhexyl ester (octocrylene) has been shown to achieve a photostable product.4 The addition of diethylhexyl 2,6-naphthalate also makes avobenzone photostable.⁵ The combination of diethylhexyl 2,6-naphthalatate, avobenzone and oxybenzone is known under the commercial name of Helioplex™ and it is present in UltraSheer® and Age Shield® sunscreens (Neutrogena®/Johnson & Johnson). The addition of
Tinosorb S® (Ciba Specialty Chemicals) has also been shown to photostabilize avobenzone.⁶ Confirmation of avobenzone’s photostability in a given formulation is difficult unless the sunscreen’s chemical stability has been studied and the results are published in a peer reviewed journal. In the absence of such studies, physicians can get indirect evidence of the photostability of a given formulation from UVA protection factor determination with methods such as persistent pigment darkening (PPD).

PPD evaluates pigmentation present at 2 hours after the end of exposure to different UVA fluences. Because UVA exposures for these methods are rather lengthy, a sunscreen formulation with unstable avobenzone will have a lower protection factor than a similar formulation with stabilized avobenzone.

Recently Introduced Organic UVA Sunscreen Agents

A number of UVA sunscreen agents have been introduced in the past few years. Unfortunately, their availability varies widely from country to country. For example, in the US and Canada, sunscreen agents are considered to be drugs. Sunscreen manufacturers must therefore submit a new drug application when they want to incorporate a new agent into a formulation. This explains why ecamsule (terephthalylidene dicamphor sulphonic acid [Mexoryl SX™, L’Oréal]) was only recently introduced in the US in 2006, whereas, this agent has been available in most other regions of the globe for more than 10 years. Mexoryl SX™ is a photostable chemical sunscreen agent that offers mid-range UVA protection.7 When combined with avobenzone, UVA protection is enhanced. Sunscreen products that contain Mexoryl SX™, and are available in the US, include Anthelios SX™ Daily Moisturizing Cream (SPF 15), Anthelios™ 15 Sunscreen Cream (SPF 15) and Anthelios SX™ 40 Sunscreen Cream (SPF 40, to be introduced in 2008).

Dometrizole trisiloxane (Mexoryl XL™) is another recently introduced organic sunscreen agent offering mid-range UVA protection. The addition of Mexoryl XL™ to Mexoryl SX™ has been shown to increase UVA protection in a synergistic manner, which may be attributable to its 2 phase component. Mexoryl XL™ was introduced in Canada in 2006. It has not yet been approved in the US, but has been available worldwide for many years in different sunscreens made by L’Oréal. In Canada, Mexoryl XL™ can be found in sunscreens sold under different brands including Anthelios™, Ombrelle™, Vichy™ and Biotherm™ (L’Oréal).

Bemotrizinol and bisoctrizole (Tinosorb S® and Tinosorb M®
respectively, Ciba Specialty Chemicals) are organic compounds that also provide broad-spectrum UV protection. Tinosorb S® has been shown to increase photostability of avobenzone.6 Tinosorb S® and Tinosorb M® are mid-range photostable sunscreen agents that have been used in Europe for many years, but they are not yet approved in the US. These UV filters have recently been introduced in Canada and are formulated in Minesol® SPF 60 products (RoC®/Johnson & Johnson).

Protection Against Visible Light

The effect of visible light on the skin has received very little attention, compared with UV radiation. The role of visible light, viewed as both physiologic and pathologic phenomena, and its effects on the skin are probably less important than the role of UV radiation. However, visible light sensitivity is an important phenomenon in diseases such as porphyria, solar urticaria, and other idiopathic photodermatoses, such as polymorphous light eruption. Patients who undergo photodynamic therapy treatments also become sensitive to visible light for a few days because of the accompanying topical medications, such as aminolevulinic acid and methylaminolevulinate, or for a few weeks due to systemic agents like porfimer sodium. A recent study by Mahmoud, et al. suggested that visible light exposure can increase pigmentation in patients with skin phototype IV to VI.8 Protection against visible light might be important for darker skinned patients who have pigmentary disorders such as post-inflammatory hyperpigmentation and melasma. Further research on the effects of visible light is definitely needed.

Organic sunscreen agents usually offer no protection against visible light, as their absorption spectrum is limited to UVB and UVA wavebands. Inorganic sunscreen agents, such as iron oxide, titanium dioxide, and zinc oxide can offer some visible light protection. However, the spectral protection of these agents varies according to their particle size. Larger particles of titanium dioxide and zinc oxide can protect in the visible range. Earlier formulations containing physical blocking agents tended to leave a white/pasty film on the skin, but with the advent of smaller-sized particles, modern physical sunscreens have made improvements in their effect on cosmetic appearance. Iron oxide is another physical UV blocking agent; however, it has the unique advantage of being closer to the natural skin color of phototype II and III individuals. The difference in visible light protection afforded by high SPF sunscreens with inorganic sunscreen agents was illustrated in a recent study that compared 2 inorganic sunscreens containing titanium dioxide, zinc oxide, and iron oxide for their ability to protect against blue light sensitivity induced by aminolevulinic acid application.9 The sunscreen containing 3.2% iron oxide (Avène Compact, Pierre Fabre Dermo-Cosmétique) offered a protection factor of 22:1 (i.e., the ratio of the lower blue light fluence that induced erythema on sunscreen protected skin to the lower blue light fluence that induced erythema on skin that was unprotected). Whereas the sunscreen with a lower concentration of 0.3% iron oxide offered only a protection factor of 2:1.

Systemic Absorption of Sunscreening Agents

Until recently, systemic exposure to sunscreen agents had also received relatively little attention in the medical literature. Agents such as benzophenones and octyl-methoxycinnamate can be detected in plasma and urine after topical application of sunscreen products.10 Unfortunately, most of these studies were conducted with non-commercial sunscreen formulations or were performed at significantly higher doses than what the average consumer uses. Additional research is definitely needed to explore the absorption of active agents contained in commercial sunscreens used under normal conditions. Furthermore, studies assessing the risks (or benefits) of systemic absorption of various sunscreen agents in adults, children, and pregnant women are also warranted.

Sunlight, Vitamin D and Sunscreens

Over the past few years there has been considerable media coverage about the influence of vitamin D and sun exposure on various diseases, including different types of cancer. The incidence of and mortality from many cancers have been reported to be reduced with decreasing latitude.11 Holick hypothesized that this reduction is related to higher vitamin D production from increased sun exposure.11 Vitamin D synthesis is a UVB phenomenon and sunscreens are usually very effective in protecting against UVB. Few prospective studies on the role of vitamin D and sun exposure in cancer prevention have been published. Additional studies are necessary to address issues such as the optimal amount of vitamin D needed to have beneficial effects and the role of oral vitamin D intake versus vitamin D synthesis following sun exposure.

Sun avoidance and the adequate use of high SPF and high UVA protection sunscreens on all exposed skin areas may still be appropriate for a kidney transplant patient who already has had multiple invasive squamous cell carcinomas. However, the situation is different for a healthy phototype IV indoor worker living in Canada who has no personal or familial history of skin cancer and takes part in no outdoor activities. Based on the current retrospective and prospective studies, physicians should individualize the sun protection advice that they give to their patients and discuss whether additional benefits can be derived from oral vitamin D supplementation. The Canadian Cancer Society issued a statement in 2007 recommending that Canadian adults should consider taking 1000 IU of vitamin D daily. This was based on evidence suggesting that vitamin D could reduce the risks of breast, colorectal, and prostate cancers.

Conclusion

Many sunscreens now offer very good broad-spectrum protection in both the UVA and UVB ranges. In many countries, changes in labeling guidelines will make it easier for consumers and physicians to evaluate the level of UVA protection afforded by sunscreens. However, further research is needed in many areas including the role of visible light, the risks of systemic absorption of sunscreen agents, and the role of vitamin D and sun exposure in preventing cancers and other diseases.

References

1. Bissonnette R, Allas S, Moyal D, et al. Comparison of UVA protection afforded by high sun protection factor sunscreens. J Am Acad Dermatol 43(6):1036-8 (2000 Dec).
2. Department of Health and Human Services, Food and Drug Administration. Federal Register, 21 CRF Parts 347 and 353 Sunscreen Drug Products for Over-the-Counter Human Use; Proposed Amendment of Final Monograph; Proposed Rule. Vol. 72, No. 165 (2007 August 27).
3. Gonzalez H, Tarras-Wahlberg N, Stromdahl B, et al. Photostability of commercial sunscreens upon sun exposure and irradiation by ultraviolet lamps. BMC Dermatol 7:1 (2007).
4. Gaspar LR, Maia Campos PM. Evaluation of the photostability of different UV filter combinations in a sunscreen. Int J Pharm 307(2):123-8 (2006 Jan 13).
5. Cole C, Chu M, Finkey MB, et al. Comparison of photoprotection efficacy and photostability of broad spectrum sunscreens. Presented at: The 64th Annual Meeting of the American Academy of Dermatology; San Francisco, CA; March 3-7, 2006. Poster #P2617.
6. Chatelain E, Gabard B. Photostabilization of butyl methoxydibenzoylmethane (Avobenzone) and ethylhexyl methoxycinnamate by bis-ethylhexyloxyphenol methoxyphenyl triazine (Tinosorb S), a new UV broadband filter. Photochem Photobiol 74(3):401-6 (2001 Sep).
7. Moyal D. Prevention of ultraviolet-induced skin pigmentation. Photodermatol Photoimmunol Photomed 2004;20(5):243-7 (2004 Oct).
8. Mahmoud BH, Hexsel C, Lim H, et al. Impact of long wavelength UVA and visible light on melanocompetent skin. Presented at: The 66th Annual Meeting of the American Academy of Dermatology; San Antonio, TX; February 1-5, 2008. Poster #P2420.
9. Bissonnette R, Nigen S, Bolduc C, et al. Protection afforded by sunscreens containing inorganic sunscreening agents against blue light sensitivity induced by aminolevulinic acid. Dermatol Surg. In press 2008.
10. Janjua NR, Kongshoj B, Andersson AM, et al. Sunscreens in human plasma and urine after repeated whole-body topical application. J Eur Acad Dermatol Venereol 22(4):456-61 (2008 Apr).
11. Holick MF. Vitamin D deficiency. N Engl J Med 357(3):266-81 (2007 Jul 19).

Innovaderm Research, Montreal, Quebec, Canada

ABSTRACT

Etanercept has recently been approved for the treatment of moderate-to-severe plaque psoriasis at a dose of 50mg twice per week for 12 weeks followed by a maintenance dose of 50mg once weekly thereafter. Clinical studies have shown excellent efficacy and a good safety profile in patients with psoriasis. Extensive information on etanercept safety is available as this biological agent has been used for many years for other indications such as rheumatoid arthritis, and psoriatic arthritis.

Key Words:
etanercept, plaque psoriasis, Enbrel®, psoriatic arthritis

Etanercept (Enbrel®, Amgen/Wyeth Pharmaceuticals) is a fusion protein with affinity for soluble tumor necrosis factor alpha (TNF-a) and has been US FDA approved for the treatment of rheumatoid arthritis (RA) since 1998. This biologic treatment is currently approved in several countries, including recent approval in Canada, for the treatment of moderate-to-severe plaque psoriasis. The approved dosage for treatment of psoriasis is 50mg subcutaneous (SC) twice per week for 3 months followed by 50mg once per week thereafter. This dosage regimen is different from the dose commonly used to treat RA, which is 25mg SC twice weekly.

Current Therapies for Psoriasis

Current treatment options for mild psoriasis include topical treatments such as calcipotriol, corticosteroids, and tar. For patients with more severe or extensive disease, phototherapy, including narrow band UVB and PUVA, has been shown to be very effective. Patients with severe and/or extensive disease, disease unresponsive to topical treatment and phototherapy, or disease that has a severe impact on quality of life, such as hand or foot involvement, are usually candidates for systemic therapy.

The three most frequently used oral medications for psoriasis in North America are methotrexate, acitretin, and cyclosporine. Biologics are a new therapeutics class for the treatment of psoriasis, and three agents are currently approved in the US and Canada for the treatment of psoriasis: alefacept (Amevive®, Biogen Idec), efalizumab (Raptiva®, Serono and Genentech/Xoma), and etanercept (Enbrel®, Amgen/Wyeth Pharaceuticals). This article will review safety and efficacy of etanercept in the treatment of moderate-to-severe plaque psoriasis.

Efficacy of Etanercept in the Treatment of Psoriasis

PASI (Psoriasis area severity index) is the primary endpoint used in studies assessing the efficacy of biologics for the treatment of psoriasis. PASI takes into account the extent of the disease, as well as the severity of erythema, scaling, and thickness in different body areas affected by psoriasis. Clinical improvement in biologics trials for psoriasis is usually reported as PASI-50 or PASI-75. A PASI-75 represents an improvement in the PASI score of at least 75% as compared with baseline (i.e., before the biologic was administered). Etanercept at a dose of 50mg SC twice per week has been shown to induce a PASI-75 response in 49% of patients after 12 weeks.^1,2 Papp, et al. reduced the dose to 25mg twice per week for an additional 12 weeks and found that the percentage of patients exhibiting a PASI-75 response increased to 54%.2 In this study, 23% of patients lost their PASI-75 response when the etanercept dose was lowered to 25mg twice weekly; however, only 3% of these patients lost their PASI-50 response.² Despite lowering the dose after 12 weeks, 32% of patients who did not reached PASI-75 at week 12 reached PASI-75 at week 24.² Studies conducted with 25mg of etanercept twice weekly for 6 months (the last 3 months being open-label) demonstrated that 42%-44% of patients reached PASI-75 at week 24.^1,2

Studies were also conducted where etanercept was stopped after 3 months of continuous treatment to determine if this would lead to a rebound phenomenon, as this can be seen with other systemic agents used to treat psoriasis. Rebound was defined as an increase in PASI of at least 25% compared with baseline, or an erythrodermic, pustular, or severe inflammatory flare within 12 weeks of treatment cessation. Of the 409 patients studied, only one etanercept treated patient presented with an increase of PASI of more than 25% above baseline.3 This patient received a lower starting dose of etanercept (i.e., 25 mg weekly.) No cases or erythrodermic or pustular psoriasis were reported, suggesting that etanercept can be safely stopped.

In the same study etanercept was reintroduced when the disease relapsed, and the PASI-75 response was assessed following retreatment. The percentage of patients achieving a PASI-75 response was the same after retreatment as that seen in patients who received etanercept for the first time.³ These studies suggest that etanercept can be stopped and reinitiated without the induction of rebound or loss of clinical response.

Etanercept has also been shown to reduce the signs and symptoms of psoriatic arthritis and has been approved in the US since June 2002 and in Canada since Jan 2004 for this indication.⁴ Etanercept should be considered as a treatment option in patients with both plaque psoriasis and active psoriatic arthritis.

Mechanism of Action

Etanercept binds soluble TNF-a, thus preventing its interaction with TNF-a cell surface receptors. This inhibits the effects of TNF-a in the skin, such as the release of proinflammatory cytokines by keratinocytes and lymphocytes, as well as the increase in expression of adhesion molecules on endothelial cells. This mechanism seems to differ from some of the other TNF-a antagonists that have an affinity for soluble as well as membrane bound TNF therefore enabling cell lysis following interaction with TNF-a.^5,6

Adverse Events

The current information on etanercept safety comes from clinical studies conducted in patients with various diseases such as psoriasis, psoriatic arthritis, RA, ankylosing spondylitis, and juvenile arthritis as well as from post-marketing experience. To date it is estimated that more than 337,000 patients worldwide, including over 74,000 patients with psoriasis, have received etanercept. Clinical studies are ideal to study the incidence and severity of frequent side-effects but are usually not powerful enough to assess less frequent adverse events. For example, clinical studies conducted with etanercept have given precise information on injection site reactions but cannot adequately assess the incidence of less frequent events such as serious infections.

The most commonly reported adverse event is injection site reactions, which occurred in 14%-20% of patients in psoriasis studies.¹ These are characterized by erythema and edema at injection sites and are usually mild.

Serious infections, sometimes resulting in death, have been reported in patients treated with all anti-TNFa agents including etanercept. In patients with psoriasis who participated in placebo-controlled studies, the number of serious infections per patient per year was similar in patients treated with placebo and patients treated with etanercept.^1,2 In an ongoing long-term, open-label study of patients treated with etanercept for RA, there was no increase in serious infections.⁷ There were 1272 patients with either early RA or long-standing RA enrolled in this trial, with some having received continuous etanercept for more than 8 years. The rate of serious infections did not increase over time, and there was no significant difference between what had been observed in the etanercept group vs. the placebo-treated patients, as well as cohorts of patients with RA. The exact role of etanercept in these serious infections is currently unknown.

Cases of demyelinating disorders have been reported in patients treated with anti-TNFa, including etanercept. A study conducted in the past with another anti-TNFa agent (lenercept), used to treat patients with multiple sclerosis, was stopped because of worsening of the disease under study.⁸ Cases of new onset multiple sclerosis, exacerbation of established multiple sclerosis, as well as optic neuritis and myelitis have been reported in patients treated with anti-TNFa agents, including etanercept.⁹ Some of these cases were reversible upon cessation of etanercept whereas others were not. In an ongoing long-term, open-label study in patients with RA, two cases of MS were reported.⁷ The causality of etanercept in these events as well as the exact risk of demyelinating disease with etanercept is unknown.

Patients with active tuberculosis should not be initiated on anti-TNFa agents. Cases of reactivation of latent TB have been reported with anti-TNFa agents, including etanercept, infliximab and adalimumab.¹⁰ Most cases were reported from patients treated with anti-TNFa antibodies as opposed to the etanercept fusion protein. The current US and Canadian monographs do not require TB screening before initiating etanercept,^9,11 but many physicians currently prefer to perform a purified protein derivative of Mycobacterium tuberculosis (PPD) skin test and/or a chest X-ray. This should at least be considered for patients at higher risk of TB including patients coming from countries where TB is more frequent.

Clinical trials with etanercept, including a long-term, open-label RA trial, have not shown that patients are at higher risk of solid tumors.⁷ Cases of lymphoma were reported in patients treated with etanercept.⁷ In a long-term, open-label RA study, four cases of lymphoma were reported in patients with early RA and 7 cases in patients with long-standing RA when the expected number, based on the SEER database, were 0.8 and 1.1, respectively.⁷ These data should be interpreted with caution as patients with RA are at higher risk of developing lymphoma, and the risk increases with severity of the disease.^12,13 It is currently unknown if the lymphoma cases seen in etanercept treated patients represent the fact that severe patients with RA are more at risk of lymphoma than the general population, or if etanercept has a role in the genesis of lymphomas. Interestingly patients with psoriasis (not treated with biologics) have also been reported to have an increased risk of lymphoma.¹⁴

Cases of an increase in pre-existing as well as new onset congestive heart failure (CHF) have been reported.⁹ The role of etanercept in these cases is unknown. Two clinical trials that were designed to assess the safety and efficacy of etanercept in the treatment of CHF were stopped because of lack of efficacy.⁹

Cases of an increase in liver enzymes, as well as cases of liver failure, have been reported in post-marketing experience in patients taking etanercept.¹⁵ It is difficult to assess the relationship of these adverse events to etanercept, as many of these cases occurred in patients taking concomitant hepatotoxic medications or in patients who were previously exposed to hepatotoxic drugs like methotrexate. Health Canada recently sent out a Dear Healthcare Professional letter reporting very rare cases of hepatitis B virus (HBV) in patients receiving biologic agents, including etanercept.¹⁶ Other side-effects reported with etanercept include an increase in antinuclear antibody (ANA) and anti-dsDNA (double-stranded) antibody sometimes associated with lupus-like symptoms, as well as rare cases of neutropenia, leucopenia, thrombopenia, anemia, or pancytopenia.⁹

Conclusion

Etanercept is a biological agent that has shown excellent efficacy for the treatment of psoriasis. As opposed to other biologics previously approved for psoriasis, etanercept has been extensively used in rheumatology both in adults and in children.

The current information on safety is based on more than 337,000 patients treated with the product and includes a long-term, open-label study in patients with rheumatoid arthritis where patients have been on continuous therapy for as long as 8 years.

References

1. Leonardi CL, Powers JL, Matheson RT, et al. Etanercept as monotherapy in patients with psoriasis. N Engl J Med 349(21):2014-22 (2003).
2. Papp KA, Tyring S, Lahfa M, et al. A global phase III randomized controlled trial of etanercept in psoriasis: safety, efficacy, and effect of dose reduction. Br J Dermatol 152(6):1304-12 (2005).
3. Gottlieb AB, Gordon KB, Wang AT, Jahreis A. Etanercept can safely be withdrawn from patients with psoriasis and re-establishes disease control on retreatment. Poster presented at the American Academy of Dermatology Meeting (2005).
4. Mease PJ, Kivitz AJ, Burch FX, et al. Etanercept treatment of psoriatic arthritis: safety, efficacy, and effect on disease progression. Arthritis Rheum 50(7):2264-72 (2004).
5. Van den Brande JM, Braat H, van den Brink GR, et al. Infliximab but not etanercept induces apoptosis in lamina propria T-lymphocytes from patients with Crohn’s disease. Gastroenterology 124(7):1774-85 (2003).
6. Shen C, Maerten P, Geboes K, Van Assche G, Rutgeerts P, Ceuppens JL. Infliximab induces apoptosis of monocytes and T lymphocytes in a human-mouse chimeric model. Clin Immunol 115(3):250-9 (2005).
7. Weinblatt ME, Genovese MC, Moreland LW, et al. Efficacy and safety of over 8 years of etanercept (Enbrel) therapy in North American patients with early and long-standing rheumatoid arthritis. Arthritis & Rheumatism 52(9 (Supplement)):S541 (2005).
8. TNF neutralization in MS: results of a randomized, placebo-controlled multicenter study. The Lenercept Multiple Sclerosis Study Group and The University of British Columbia MS/MRI Analysis Group. Neurology 53(3):457-65 (1999).
9. Enbrel® Canadian product monograph. Amgen/Wyeth Pharmaceuticals.
10. Rychly DJ, DiPiro JT. Infections associated with tumor necrosis factor-alpha antagonists. Pharmacotherapy 25(9):1181-92 (2005 Sep).
11. Enbrel® US Product Monograph. Amgen/Wyeth Pharmaceuticals.
12. Thomas E, Brewster DH, Black RJ,Macfarlane GJ. Risk of malignancy among patients with rheumatic conditions. Int J Cancer 88(3):497-502 (2000).
13. Baecklund E, Ekbom A, Sparen P, Feltelius N, Klareskog L. Disease activity and risk of lymphoma in patients with rheumatoid arthritis: nested case-control study. BMJ 317(7152):180-1 (1998).
14. Hannuksela-Svahn A, Pukkala E, Laara E, Poikolainen K,Karvonen J. Psoriasis, its treatment, and cancer in a cohort of Finnish patients. J Invest Dermatol 114(3):587-90 (2000).
15. Cannon GW, Strand V, Scarazzini L, Holden WL. Comparison of adverse event reporting rates for etancercept, infliximab, leflunomide and methotrexate between September 1998 and June 2003. Arthristis Rheum 50(Suppl 9):S56. Abstract 1469 (2004).
16. Dear Healthcare Professional Letter from HPB Canada (2006 Jan 18).

ABSTRACT

Polymorphous light eruption (PLE) and solar urticaria (SU) are two photodermatoses that are induced by ultraviolet radiation and sometimes by visible light. This article will review the various means of preventing PLE and SU with an emphasis on the role of sunscreens.

Key Words:
PLE, polymorphous light eruption, solar urticaria

Polymorphous Light Eruption

Polymorphous light eruption is a common photodermatosis with a prevalence as high as 10-20% in Caucasian populations.^1,2 Photo-provocation studies have shown that the eruption is triggered by UVA in most patients, although in certain patients UVB alone can trigger the eruption.^3-5 In a recent series of 110 patients, PLE could be photoinduced with visible light in 23 patients who were also sensitive to UVB and UVA. The clinical significance of visible light sensitivity in these patients is unknown.⁶

Because PLE is a self-limited disease that spontaneously resolves when exposure to triggering light is stopped, the focus is centered on prevention. Sun protection and sun avoidance are central for PLE prevention. The level of photoprotection necessary to avoid the development of the eruption varies from patient to patient. For most patients with mild disease, avoidance of intense sun exposure, especially in the winter or early spring is sufficient to prevent the eruption. However, for some patients, seeking the shade and avoidance of intense sun exposure is not enough. Sunscreens have been recommended for these patients even though efficacy of earlier sunscreens has been low, probably because of their limited UVA protection.⁷

Sunscreen for the Treatment of PLE

We recently compared the efficacy of two high SPF sunscreens for the prevention of indoor PLE generated by metal halide lamps.⁸ The two sunscreens compared were Coppertone® 45 which contains only oxybenzone for UVA protection and Anthelios® L, which contains Mexoryl SX, Parsol® 1789 and titanium dioxide (TiO₂) for UVA protection. UVA protection by oxybenzone is limited to short-wave UVA. Anthelios® L prevented PLE in all patients, whereas Coppertone® 45 was able to prevent PLE in only 3 patients out of the 23 who completed the study.

To further explore UVAprotection afforded by sunscreens we compared the ability of 6 sunscreens with SPF of 21 or more to prevent pigmentation induced 2 hours after artificial UV exposure.⁹ The sunscreens compared were: Anthelios® L 60, Bain de Soleil® 25, Coppertone® 45, Hawaiian Tropic® 50, Presun® 21 and Presun® 30. In order of decreasing efficacy the best sunscreens for UVA protection were Anthelios® L, Presun® 30, PreSun® 21, Bain de Soleil® 25, Coppertone® 45 and Hawaian Tropic® 50. In this study the two sunscreens that afforded the highest UVA protection contained Parsol® 1789, which has a maximal absorption at 358nm. Anthelios® L also contained Mexoryl SX for UVA protection, which has a maximal absorption at 345nm. The two sunscreens containing physical agents only (i.e., PreSun® 21 and Bain de Soleil® 25) were not as efficient for UVA protection, which could be related to the fact that the spectral protection of micronized titanium dioxide (TiO₂) decreases with increasing UVAwavelength.¹⁰ This study confirmed that SPF, a measure of UVB protection, is not indicative of UVA protection provided by sunscreens. It also illustrates how difficult it is to select a sunscreen with broadspectrum and high UVA protection, since SPF is the only indicator of UV protection on sunscreen labels in North America.

Photostability is another important parameter to consider when selecting a sunscreen that provides good UVA protection. Parsol® 1789 is known to be photounstable in certain preparations.¹¹ Unfortunately, it is not possible to know if a sunscreen is photostable only by looking at the label, because there is no information on this subject on labels in North America.

Prophylactic Treatments

Prophylactic treatments with UVA, UVB or PUVA therapy can prevent PLE in certain patients.^12,13 Although PUVA therapy is effective, its use has to be weighed against the risks of squamous cell carcinoma and melanoma.¹⁴Atopical formulation containing the antioxidants tocopheryl acetate, ferulic acid and α-glycosylrutin was reported to prevent the development and reduce the severity of indoor PLE in certain patients,¹⁵ suggesting that the role of antioxidants in sunscreen formulations deserves further study.

Solar Urticaria

Solar urticaria (SU) is photodermatosis characterized by urticarial papules and plaques appearing typically after 5-10 minutes of sun exposure, with spontaneous disappearance after a few hours of sun avoidance. The spectrum of solar urticaria induction varies according to patients and can include UVA, UVB as well as visible light. Visible light alone can induce SU,^16,17 and a recent Japanese series reported that as many as 60% of patients were sensitive to visible light.¹⁸

SU and Sunscreens

SU is a problem as far as sunscreens are concerned, because the protection afforded by sunscreens in the visible range is not very good. The absorption spectrum of chemical sunscreen agents is limited to the UV range of the solar spectrum. Although opaque nonmicronized physical agents may reduce visible light transmission, patients are reluctant to use opaque sunscreens. An in vitro spectroscopic study suggested that sunscreens with iron oxide offer a better protection against visible light than titanium dioxide or zinc oxide.¹⁹ RVPaque® is a sunscreen containing 1.7% of iron oxide.¹⁹ The disadvantage of iron oxide is that it gives a red-brown colour to sunscreens. Dihydroxyacetone can also protect against the lower portion of the visible spectrum.²⁰ Many sunless tanning lotions contain dihydroxyacetone. With the current developments in the field of photodynamic therapy, which consists of administering drugs that make patients sensitive to visible light, there is renewed interest in the development of sunscreens that offer better protection in the visible range.

Table 1: Six sunscreens with SPF ratings >21 in order of decreasing efficacy tested to
prevent pigmentation induced 2 hours after artificial UV exposure.⁹

Other Treatments for SU

Antihistamines can be valuable for SU, but their use is often disappointing for patients with severe disease. Other treatments that have been used with limited success include UVB, narrow band UVB and PUVA therapy.^21,22 Plasmapheresis has been used in selected cases with success.²³ This approach is useful for patients, in which it is possible to induce urticarial plaques following in vitro irradiation of their own serum, suggesting that the improvement could be related to removal of the antigen by plasmapheresis. Interestingly, this modality has been shown to induce remissions of more than a year in certain patients.

Conclusion

In conclusion, PLE and solar urticaria can be prevented in most patients by decreasing their amount of sun exposure and by using an adequate sunscreen. As UVA is mainly involved in the induction of both diseases, the sunscreen used should contain broad as well as high UVA protection.

References

1. Morison WL, Stern RS. Polymorphous light eruption: a common reaction uncommonly recognized. Acta Dermato-Venereologica 62(3):237-40 (1982).
2. Ros AM, Wennersten G. Current aspects of polymorphous light eruptions in Sweden. Photo-Dermatol 3(5):298-302 (1986).
3. Holzle E, Plewig G, Hofmann C, Roser-Maass E. Polymorphous light eruption. Experimental reproduction of skin lesions. J Ame Acad Dermatol 7(1):111-25 (1982).
4. Ortel B, Tanew A, Wolff K, Honigsmann H. Polymorphous light eruption: action spectrum and photoprotection. J Ame Acad Dermatol 14(5 Pt 1):748-53 (1986).
5. Miyamoto C. Polymorphous light eruption: successful reproduction of skin lesions, including papulovesicular light eruption, with ultraviolet B. Photo- Dermatol 6(2):69-79 (1989).
6. Boonstra HE, van Weelden H, Toonstra J, van Vloten WA. Polymorphous light eruption: Aclinical, photobiologic, and follow-up study of 110 patients. J Am Acad Dermatol 42(2 Pt 1):199-207 (2000 Feb).
7. Farr PM, Diffey BL. Effect of a sunscreen in photosensitive patients [letter]. Lancet 1(8646):1087-8 (1989).
8. Allas S, Lui H, Moyal D, Bissonnette R. Comparison of the ability of 2 sunscreens to protect against polymorphous light eruption induced by a UVA/ UV-B metal halide lamp [letter]. Arch Dermatol 135(11):1421-2 (1999).
9. Bissonnette R, Allas S, Moyal D, Provost N. Comparison of UVA protection afforded by high sun protection factor sunscreens. J Am Acad Dermatol 43(6):1036-8 (2000 Dec).
10. Mitchnick MA, Fairhurst D, Pinnell SR. Microfine zinc oxide (Z-cote) as a photostable UVA/UVB sunblock agent. J Am Acad Dermatol 1999;40(1):85-90.
11. Diffey BL, Stokes RP, Forestier S, Mazilier C, Rougier A. Suncare product photostability: a key parameter for a more realistic in vitro efficacy evaluation. Eur J Dermatol 7(April-May 1997):226-8 (1997).
12. Berg M, Ros AM, Berne B. Ultraviolet Aphototherapy and trimethylpsoralen UVAphotochemotherapy in polymorphous light eruption–a controlled study. Photodermatol, Photoimmunol & Photomedicine 10(4):139-43 (1994).
13. Murphy GM, Logan RA, Lovell CR, Morris RW, Hawk JL, Magnus IA. Prophylactic PUVA and UVB therapy in polymorphic light eruption–a controlled trial. Br J Dermatol 116(4):531-8 (1987).
14. Stern RS, Nichols KT, Vakeva LH. Malignant melanoma in patients treated for psoriasis with methoxsalen (psoralen) and ultraviolet A radiation (PUVA). The PUVA Follow-Up Study [see comments]. N Engl J Med 336(15):1041-5 (1997).
15. Hadshiew I, Stab F, Untiedt S, Bohnsack K, Rippke F, Holzle E. Effects of topically applied antioxidants in experimentally provoked polymorphous light eruption. Dermatology 195(4):362-8 (1997).
16. Ryckaert S, Roelandts R. Solar urticaria. Areport of 25 cases and difficulties in phototesting. Arch Dermatol 34(1):71-4 (1998).
17. Armstrong RB. Solar urticaria. Dermatologic Clinics 4(2):253-9 (1986).
18. Uetsu N, Miyauchi-Hashimoto H, Okamoto H, Horio T. The clinical and photoibological characteristics of solar urticaria in 40 patients. Br J Dermatol (142):32-38 (2000).
19. Kaye ET, Levin JA, Blank IH, Arndt KA, Anderson RR. Efficiency of opaque photoprotective agents in the visible light range [see comments]. Arch Dermatol 127(3):351-5 (1991).
20. Rice EG. Dihydroxyacetone naphthoquinone protection against photosensitivity. Dermatologica 153(1):38-43 (1976).
21. Parrish JA, Jaenicke KF, Morison WL, Momtaz K, Shea C. Solar urticaria: treatment with PUVA and mediator inhibitors. Br J Dermatol 106(5):575- 80 (1982).
22. Collins P, Ferguson J. Narrow-band UVB (TL-01) phototherapy: an effective preventative treatment for the photodermatoses. Br J Dermatol 132(6):956-63 (1995).
23. Bissonnette R, Buskard N, McLean DI, Lui H. Treatment of refractory solar urticaria with plasma exchange. J Cutan Med Surg 3(5):236-8 (1999).

ABSTRACT
Sunscreens have been in use for nearly 70 years. Originally designed to protect against sunburn, enable longer sun exposure and promote tanning, sunscreens are now often promoted as a method for preventing skin cancer and skin aging. Although there is experimental evidence in animals suggesting that used adequately, sunscreens can prevent skin cancer, no prospective study has shown a decrease in incidence of skin cancer in sunscreen users, and sunburn prophylaxis is currently the only FDA-approved use of sunscreens. Preliminary studies suggest that new-generation sunscreens could prevent photodermatoses like polymorphous light eruption.¹

Key Words:
Sunscreen, UVB, UVA, Photodegradation, SPF

The regular and adequate use of sunscreens, avoiding the sun around mid-day, staying in the shade, wearing hats with brims which can shade the head, face and neck, and wearing clothes made from tightly woven fabrics, are all important factors that could prevent the deleterious effects of sunlight.

Table 1 lists some sunscreen agents available with their corresponding spectral photoprotection. Chemical agents protect by absorbing light, whereas physical agents act mainly by reflecting and scattering light. The recent development of micronized preparations of physical agents has improved the cosmetic acceptability of physical sunscreens. We will review some key factors to consider when selecting a sunscreen and will compare some commercially available sunscreens, including new sunscreens made recently available in North America (Table 2).

TABLE 1: Protection wavebands of sunscreens 2,3

TABLE 2: Comparison of Some Sunscreens Available in North America
a Could prevent polymorphous light eruption¹
b Contains no chemical sunscreen

Factors to consider when selecting a sunscreen

UVB protection

UVB (290-320nm) is the most erythemogenic solar radiation reaching the surface of the earth. It is also a potent skin carcinogen in animal studies. Sun Protection Factor (SPF) indicates the degree of protection against UVB induced erythema. It is measured in the laboratory by applying 2 mg/cm² of sunscreen to the skin of volunteers and irradiating with an artificial light source. Studies have shown that people use an average of 0.5 to 1mg/cm² of sunscreen,^4,5 and that the SPF may overestimate the actual protection against sunlight.⁶ The real protection against sun-induced erythema of a self-applied SPF 15 sunscreen is thus lower than 15, probably not much more than half this figure. By applying a sunscreen with a SPF of 30 or higher, most people should get a SPF protection equivalent to at least 15. UVB also induces immunosuppression, which in animal studies is not totally prevented by sunscreens.^7,8 One consequence of high SPF sunscreens is that, by preventing sunburn, some people may stay under the sun for long periods of time and thus receive high total daily UVA exposures.

UVA protection

In animal models, UVA (320-400 nm) has been implicated in skin sagging, skin cancer and immunosuppression. UVA protection is now offered in most sunscreens, but unfortunately the labels usually provide no indication of the level or wavelengths of UVA protection. Most UVA protecting sunscreen agents only offer protection against short wave UVA (Table 1). Relative protection against long wave UVA can be achieved by Avobenzone (Parsol 1789), and physical agents. Mexoryl SX is a new sunscreen agent with maximal absorption in the mid-UVA that also offers some UVB protection. Spectral protection, including UVA protection, from micronized physical agents varies according to the size of the micronized particles, with smaller particles providing more UVB and less UVA protection.⁹

Children

Sun exposure in the first 20 years of life is a strong determinant for the risk of skin cancer.¹⁰ Therefore sun protection throughout childhood and teenage years is probably crucial to preventing such carcinogenesis. Direct sun exposure should probably be minimized in children, and if they must spend periods of time outside during the day, physical blockers such as clothing should be used; failing that, sunscreens. Sprays and gels should be used with caution in young children as they can irritate the skin and exacerbate atopic dermatitis. Sunscreens are not recommended for use in children less than 6-12 months of age in order to discourage unnecessary sun exposure. However, there is no strong reason to suggest that sunscreens are harmful in this age group.

Substantivity

Substantivity is the ability of a sunscreen to resist its removal by physical means such as sweating or contact with water. If the SPF of a sunscreen stays unchanged after 40 minutes of contact with water, it is said to be water resistant, whereas if it stays unchanged for 80 minutes or more, it is said to be waterproof. Thus a person staying outside in a pool for six hours may wish to reapply a waterproof sunscreen at least four times to ensure that the SPF remains unchanged. Some manufacturers state the actual time their product remains waterproof, and products which are waterproof for six hours or more should be used if prolonged exposure to water or prolonged sweating is anticipated.

Allergic potential

The prevalence of allergic reactions to sunscreens is low and most reactions reported by patients are of the irritant type. PABA and its derivatives, benzophenone and fragrances are among the most allergenic ingredients in sunscreens, explaining why many commercial products no longer contain PABA. Physical sunscreen agents do not cause allergic contact dermatitis.

Photodegradation

Certain sunscreen agents like avobenzone (Parsol 1789) have been shown to isomerize and lose part of their sun protection properties when exposed to light, whereas others like the newer agent Mexoryl-SX are especially photostable.¹¹ In vitro studies have shown that certain sunscreen formulations can lose more than half their SPF value after one hour of artificial light exposure, suggesting that photodegradation is an important factor to consider when evaluating sunscreens.¹² In vivo studies are needed comparing the photostability of sunscreens to both UVA and UVB.

References

1. Moyal D, Binet O. Polymorphous light eruption: Its reproduction and prevention by sunscreens. In: Lowe NJ, Shaath NA, Pathak MA, eds. Sunscreens development, evaluation, and regulatory aspects. New York: Marcel Dekker, 1997: 611-617.
2. Drug information for the health care professional. USP DI. Taunton: Rand McNally, 1997: 2713-2729.
3. Shaath NA. Evolution of modern sunscreen chemicals. In: Lowe NJ, Shaath NA, Pathak MA, eds. Sunscreens development, evaluation, and regulatory aspects.New York: Marcel Dekker, 1997: 3 – 33 .
4. Stender IM, Andersen JL, Wulf HC. Sun exposure and sunscreen use among sunbathers in Denmark. Acta Dermato-Venereologica 1996; 76: 31-3.
5. Bech-Tomsen N, Wulf HC. Sunbather’s application of sunscreen is probably inadequate to obtain the sun protection factor assigned to the preparation. Photodermatol Photoimmunol Photomed 1992/1993; 9: 242-244.
6. Sayre RM, Kollias N, Ley RD et al. Changing the risk spectrum of injury and the performance of sunscreen products throughout the day. Photodermatol Photoimmunol Photomed 1994; 10: 148-153.
7. Wolf P, Yarosh DB, Kripke ML. Effects of sunscreens and a DNA excision repair enzyme on ultraviolet radiation-induced inflammation, immune suppression, and cyclobutane pyrimidine dimer formation in mice. J Invest Dermatol 1993; 101: 523-527.
8. Walker SL, Young AR. Sunscreens offer the same UVB protection factors for inflammation and immunosuppression in the mouse. J Invest Dermatol 1997; 108: 133-138.
9. Anderson MW, Hewitt JP, Spruce SR. Broad-spectrum physical sunscreens: Titanium dioxide and zinc oxide. In: Lowe NJ, Shaath NA, Pathak MA, eds. Sunscreens development, evaluation, and regulatory aspects. New York: Marcel Dekker, 1997: 353-397.
10. Gallagher RP, Hill GB, Bajdik CD et al. Sunlight exposure, pigmentary factors, and risk of nonmelanocytic skin cancer. I. Basal cell carcinoma. Arch Dermatol 1995; 131: 157-163.
11. Deflandre A, Lang G. Photostability assessment of sunscreens. Benzylidene camphor and bibenzoylmethane derivatives. Int J Cosmetic Sci 1988; 10: 53-62.
12. Diffey BL, Stokes RP, Forestier S. et al. Suncare product photostability: a key parameter for a more realistic in vitro efficacy evaluation. Eur J Dermatol 1997; 7: 226-228.