Enjoying the Summer Dr. Fernandez

ENJOYING THE SUMMER WITH LUPUS ERY THEMATOSUS

Anthony P. Fernandez, MD, PhD

The onset of summer often triggers mixed emotions in patients with lupus erythematosus (LE). On the one hand, there is a desire to enjoy beautiful weather and participate in outdoor activities with family and friends. On the other hand, concern that sun exposure will trigger disease flares and/or new LE manifestations can cause significant anxiety. An understanding of how sunlight (ultraviolet radiation, or UVR) can precipitate or aggravate LE, in addition to strategies to mitigate risk of excess UVR exposure, can optimize the enjoyment of summer months for LE patients.

Photosensitivity represents a hallmark symptom of LE and often manifests as cutaneous lupus erythematosus (CLE), which may occur as the sole manifestation of LE or as one manifestation of systemic LE (SLE). In fact, the skin represents the second most common organ involved in SLE1. Photosensitivity can also lead to symptoms of fatigue, joint pain, or even onset of lupus nephritis in SLE patients exposed to excess UVR2,3.

Importantly, there has been significant progress in understanding how excess sun exposure contributes to the onset/aggravation of LE. It is thought that the accumulation of apoptotic (dying) cells is fundamental to the pathogenesis of both SLE and CLE4. Research suggests that, in a background of LE immune system dysfunction, sun/UVR exposure leads to pathologic accumulation of apoptotic cells in the skin5. Under normal conditions, immune system cells efficiently clear apoptotic cells. However, LE patients demonstrate impaired or delayed clearance of apoptotic cells in the skin, leading to the accumulation of UVR-induced cellular debris. This debris includes intracellular, DNA-containing nuclear material that promotes the formation of LE autoantibodies and activates cells to secrete interferon (IFN)-α, a key molecule involved in LE inflammation6. Excess sun/UVR exposure also triggers production of other pro-inflammatory molecules known to be involved in LE inflammation and onset of various LE symptoms and physical manifestations7 .

With this in mind, it is important for patients with LE to balance enjoyment of the outdoors during summer months with adequate sun/UVR protection. Several important points are critical to understand in order to accomplish this balance. First, it is important to recognize that the threshold sun/UVR dose needed to trigger LE flares is lower than that of a sunburn8. So recognizing the amount of sun exposure one can personally tolerate without

getting sunburned is important. Furthermore, it is suggested that subsequent exposures to UVR following an initial UVR-induced LE flare result in a significantly higher frequency of UVR-induced eruptions6,9. Thus, meticulous sun/UVR protection is especially important for LE patients who have already had an initial UVR-induced flare.

So what can LE patients do to adequately protect themselves from excess sun/UVR exposure aside from simply avoiding it by staying indoors? An obvious strategy is to apply sunscreen regularly. Studies have suggested that sunscreens can effectively protect most LE patients against harmful amounts of UVR, including those patients who have previously developed UVR-induced skin lesions10. Clinical evidence also suggests that consistent sunscreen protection in patients with SLE is associated with significantly better systemic outcomes, such as less frequent renal involvement and decreased need for immunosuppressive treatment9,11. LE patients should also do their best to avoid and/or protect themselves from mid-day sun exposure (approximately 10AM to 3PM), when UVR is strongest and has the most potential for causing harm to the skin. Finally, LE patients should also recognize that sun/UVR exposure through windows at home or during long car rides might lead to precipitation of LE inflammation. Therefore, CLE and SLE patients should wear sunscreen in the summer even when only exposed to UVR through car/ home windows.

Using appropriate types of sunscreen in adequate amounts is key to achieving UVR protection. In a vehicle-controlled, randomized, comparative double-blind study, it was demonstrated that use of a broad-spectrum sunscreen with high UVB and UVA protection factor can prevent skin lesions in patients with photosensitive CLE12. The American Academy of Dermatology recommends at least 30 mL of sunscreen with a high sun protection factor (SPF 50) to cover exposed skin to achieve the goal concentration of 2 mg/ cm211. This translates to ~1 ounce of sunscreen, or enough to fill a shot glass, to cover all skin not covered by clothing13. Remembering this is especially important for LE patients, as studies suggest in the real-world patients often apply only 25–50% of this recommended sunscreen amount13,14. Moreover, LE patients should remember to apply sunscreen daily, as research supports sunscreen usage typically decreases significantly on overcast days despite the UV index being >6 (dangerous levels)15 . Sunscreen should be applied at least 20 to 30 minutes before sun exposure, and repeat applications should occur every 2 hours when outdoors. Currently, there are no studies that have specifically evaluated the effectiveness of sun-protective clothing for preventing UVR-induced, LE skin lesions16 . However, results of studies in the general population suggest wearing such clothing is likely effective and should be encouraged.

An unintentional effect of intense sun protection can be development of vitamin D deficiency. Usually, sun exposure to the skin provides sufficient vitamin D in healthy individuals. However, in a recent study of CLE patients, 25-hydroxyvitamin D levels were significantly lower among sun avoiders and daily sunscreen users17. Therefore, dietary supplementation with at least 400 IU per day of vitamin D3 (cholecalciferol) is recommended in all LE patients who actively avoid sun exposure and frequently use sunscreens.

When daily sunscreen and/or sun-protective clothing is ineffective, antimalarial medications may be helpful for LE patients. Antimalarials protect against UV light absorption and inhibit development of CLE lesions18 . Currently, antimalarials are considered first-line systemic treatment for CLE. There are 3 antimalarials that have traditionally been used to treat CLE: hydroxychloroquine (HCQ), chloroquine (CQ), and quinacrine. Several studies have recently explored optimal use of antimalarials for CLE. In one study, researchers examined the effectiveness of switching antimalarials after patients either (1) failed to respond or (2) had an adverse reaction to a first antimalarial19 . This study found >50% of patients responded to a second antimalarial after failing the first, although response to the second agent seemed to decrease with time. Additionally, 69% of patients exposed to a second antimalarial agent after having an adverse reaction to the first agent tolerated it without incident, and 80% of patients who tolerated the second antimalarial agent responded positively to it. Additional studies suggest adding quinacrine to either HCQ or CQ can also be a useful and safe strategy for up to two-thirds of patients who fail either medication as monotherapy20,21. Consideration of the above strategies when needed can potentially prevent LE patients

from exposure to more toxic immunosuppressive medications to control active disease.

One caveat to the use of antimalarials is that quinacrine is not currently manufactured by any company. Quinacrine has the advantage of not being associated with retinal toxicity, unlike HCQ and CQ. Studies have also suggested quinacrine may be a stronger anti-inflammatory agent than HCQ or CQ23,24. Although quinacrine was previously obtainable from India and compounded into capsules readily by most compounding pharmacies, this ceased in 2019 when the US Food and Drug Administration (FDA) placed an import alert on an international manufacturer22. Thus, finding ways to bring quinacrine back to a clinical setting or finding alternative medications for LE patients is important.

In summary, excess sun/UVR exposure can be detrimental to LE patients. However, understanding and implementing various sun protection strategies, including sun avoidance, sunscreen application, sun protective clothing, and antimalarial medications can protect LE patients from UVR’s harmful effects. In turn, these strategies can ease anxiety and help LE patients enjoy the unique events and aspects of summer that make it an exciting time of year. References 1. Obermoser G, Sontheimer RD, Zelger B. Overview of common, rare and atypical manifestations of cutaneous lupus erythematosus and histopathological correlates. Lupus 2010;19(9):1050–70. 2. Kim A, Chong BF. Photosensitivity in cutaneous lupus erythematosus. Photodermatol Photoimmunol Photomed 2013; 29: 4–11. 3. Schmidt E, Tony HP, Brocker EB, Kneitz C. Sun-induced lifethreatening lupus nephritis. Ann N Y Acad Sci 2007;1108: 35-40. 4. Kuhn A, Wenzel J, Bijl M. Lupus erythematosus revisited. Semin Immunopathol 2016;38:97–112. 5. Scholtissek B, Zahn S, Maier J, et al. Immunostimulatory endogenous nucleic acids drive the lesional inflammation in cutaneous lupus erythematosus. J Invest Dermatol 2017;137:1484–92. 6. Kuhn A, Wenzel J, Weyd H. Photosensitivity, apoptosis, and cytokines in the pathogenesis of lupus erythematosus: a critical review. Clin Rev Allergy Immunol 2014; 47: 148–162. 7. Robinson ES, Werth VP. The role of cytokines in the pathogenesis of cutaneous lupus erythematosus. Cytokine 2015; 73: 326–334. 8. Obermoser G, Zelger B. Triple need for photoprotection in lupus erythematosus. Lupus 2008; 17: 525–527. 9. Ruland V, Haust M, Stilling RM, Amler S, Ruzicka T, Kuhn A. Updated analysis of standardised photoprovocation in patients with cutaneous lupus erythematosus. Arthritis Care Res 2013; 65: 767–776. 10. Herzinger T, Plewig G, Rocken M. Use of sunscreens to protect against ultraviolet-induced lupus erythematosus. Arthritis Rheum 2004; 50: 3045–3046. 11. Kuhn A, Ruland V, Bonsmann G. Cutaneous lupus erythematosus: update of therapeutic options part I. J Am Acad Dermatol 2011; 65: e179–193. 12. Kuhn A, Gensch K, Haust M, Meuth AM, Boyer F, Dupuy P, Lehmann P, Metze D, Ruzicka T. Photoprotective effects of a broad-spectrum sunscreen in ultraviolet-induced cutaneous lupus erythematosus: a randomized, vehicle-controlled, double-blind study. J Am Acad Dermatol. 2011 Jan;64(1):37-48. 13. Sunscreen FAQs (aad.org). Accessed August 7, 2021. 14. Mancuso JB, Maruthi R, Wang SQ, Lim HW. Sunscreens: an update. Am J Clin Dermatol 2017; 18: 643–650. 15. Wood M, Raisanen T, Polcari I. Observational study of free public sunscreen dispenser use at a major US outdoor event. J Am Acad Dermatol 2017; 77: 164–166. 16. Vilá LM, Mayor AM, Valentín AH, Rodríguez SI, Reyes ML, Acosta E, Vilá S. Association of sunlight exposure and photoprotection measures with clinical outcome in systemic lupus erythematosus. P R Health Sci J. 1999 Jun;18(2):89-94. 17. Cusack C, Danby C, Fallon JC, Ho WL, Murray B, Brady J, O’Kelly P, Ambrose N, Kearns G, Murphy GM. Photoprotective behaviour and sunscreen use: impact on vitamin D levels in cutaneous lupus erythematosus. Photodermatol Photoimmunol Photomed. 2008 Oct;24(5):260-7. 18. Tang C, Godfrey T, Stawell R, Nikpour M. Hydroxychloroquine in lupus: emerging evidence supporting multiple beneficial effects. Intern Med J 2012; 42: 968–978. 19. Chasset F, Arnaud L, Jachiet M, Monfort JB, Bouaziz JD, Cordoliani F, Bagot M, Barbaud A, Francès C. Changing antimalarial agents after inefficacy or intolerance in patients with cutaneous lupus erythematosus: A multicenter observational study. J Am Acad Dermatol. 2018 Jan;78(1):107-114.e1. 20. Chang AY, Piette EW, Foering KP, Tenhave TR, Okawa J, Werth VP. Response to antimalarial agents in cutaneous lupus erythematosus: a prospective analysis. Arch Dermatol. 2011 Nov;147(11):1261-7. 21. Chasset F, Bouaziz JD, Costedoat-Chalumeau N, Francès C, Arnaud L. Efficacy and comparison of antimalarials in cutaneous lupus erythematosus subtypes: a systematic review and meta-analysis. Br J Dermatol. 2017 Jul;177(1):188-196. 22. Yan D, Borucki R, Sontheimer RD, Werth VP. Candidate drug replacements for quinacrine in cutaneous lupus erythematosus. Lupus Sci Med. 2020 Oct;7(1):e000430. 23. Wallace DJ. The use of quinacrine (Atabrine) in rheumatic diseases: a reexamination. Semin Arthritis Rheum. 1989 May;18(4):282-96. 24. Alves P, Bashir MM, Wysocka M, Zeidi M, Feng R, Werth VP. Quinacrine Suppresses Tumor Necrosis Factor-α and IFN-α in Dermatomyositis and Cutaneous Lupus Erythematosus. J Investig Dermatol Symp Proc. 2017 Oct;18(2):S57-S63.