SKIN January 2018 Volume 2 Issue 1 Copyright 2018 The National Society for Cutaneous Medicine 59 BRIEF ARTICLES Capecitabine-induced subacute cutaneous lupus erythematosus in a patient with systemic lupus erythematosus Alyx Rosen MD a , Evan Darwin BS a , Jennifer N. Choi MD b a University of Miami Miller School of Medicine, Department of Dermatology and Cutaneous Surgery, Miami, FL b Northwestern University Feinberg School of Medicine Department of Dermatology, Chicago, IL Drug-induced subacute cutaneous lupus erythematosus (DI-SCLE) is characterized by histopathological and immunopathological features of typical SCLE that are induced by a drug, dissipate with the drug’s removal, and recur with re- exposure to the agent. 1 Capecitabine is a fluoropyrimidine chemotherapy prodrug of 5- fluorouracil (5-FU) used for the treatment of metastatic breast and colorectal cancers. 2 Dermatologic conditions commonly associated with capecitabine include palmar-plantar erythrodysesthesia, photoeruption, dermatitis, leopard-like vitiligo, erythematous rash, and onycholysis. 3 Here we present a case of DI-SCLE in association with capecitabine in the setting of known systemic lupus erythematosus (SLE). A 68-year-old female with colon adenocarcinoma presented to the dermatology clinic with a photosensitive rash without pain or pruritus on her upper body that began eight weeks after initiating capecitabine therapy. Her past medical history was significant for SLE diagnosed 16 years prior, which was well-controlled with hydroxychloroquine. The patient denied a history of skin lesions with her lupus. On examination, the patient had several 0.5-2 ABSTRACT Capecitabine is a fluoropyrimidine chemotherapy prodrug of 5-fluorouracil (5-FU) used in the treatment of metastatic breast and colorectal cancers. Drug-induced subacute cutaneous lupus erythematosus (DI-SCLE) is a rare side effect of capecitabine therapy, with eight cases previously reported. We report a case of DI-SCLE in a patient with a documented history of systemic lupus erythematosus (SLE). This is the second documented case of DI-SCLE in a patient with a past medical history of SLE, and provides evidence that there may be an increased risk of DI-SCLE in these patients. Further research should examine whether patients with SLE are at greater risk for this adverse event. INTRODUCTION CASE REPORT SKIN January 2018 Volume 2 Issue 1 Copyright 2018 The National Society for Cutaneous Medicine 60 cm thin pink annular scaly papules and plaques on her forearms, posterior neck, and anterior chest in a photodistribution [Fig. 1]. Patchy scarring alopecia was noted on the scalp, along with several 0.5-1 cm pink scaly papules and plaques on her upper cutaneous lip and bilateral cheeks. The oral mucosa was clear. Review of systems revealed no associated systemic symptoms, such as fevers, fatigue, arthralgias, chest pain, or neurologic symptoms. A biopsy was obtained from the patient’s left forearm. Histopathology showed an interface lymphocytic infiltrate with basal vacuolar changes and necrotic keratinocytes, telangiectasias with a perivascular lymphocytic infiltrate, and dermal edema. The patient’s laboratory values showed a positive ANA titer of 1:640 and an anti-dsDNA antibody level of 498, up from 396 immediately prior to starting capecitabine. C3 complement levels fell from 79 to 66, and C4 dropped from 14 to 10. She was weakly positive for anti- SSA/Ro, anti-Smith, and anti-histone antibodies; however, baseline levels of these antibodies were not performed prior to capecitabine therapy. All other laboratory data were unremarkable. The patient was prescribed triamcinolone 0.1% cream twice daily and strict sun protection. Due to her symptoms and histologic and laboratory results, she was diagnosed with DI-SCLE and capecitabine was discontinued. At two-week follow-up, the rash had significantly improved, with decreased erythema and scaling of the lesions. Two months after drug discontinuation, the rash had completely resolved [Fig. 2]. Four months after drug discontinuation, the patient’s ANA titer fell to 1:320. Figure 1. Annular scaly pink papules and plaques on the bilateral forearms. Figure 2. Resolution of rash two months after drug discontinuation. SKIN January 2018 Volume 2 Issue 1 Copyright 2018 The National Society for Cutaneous Medicine 61 DI-SCLE from capecitabine therapy is rare. In addition to our patient, eight other cases of capecitabine-induced SCLE have been reported [Table 1]. While the antibody profile varied slightly between cases, every patient had an elevated ANA and positive anti-SSA/Ro antibodies, and most demonstrated negative anti-histone and anti- dsDNA autoantibodies. 1-8 One other patient also had a history of SLE, making this the second case of DI-SCLE from capecitabine in the setting of underlying SLE and highlighting a potential association. 6 Additionally, no other cases of DI-SCLE from other chemotherapies in patients with underlying SLE have been described; however, cases of idiopathic SCLE exacerbated by either docetaxel or doxorubicin have been reported. 9-10 The patients in these cases had well-controlled disease and positive serology for anti- SSA/Ro antibodies prior to the onset of chemotherapy, and their skin rash resolved with cessation of the causative drug. 9-10 Table 1. Cases of Subacute Cutaneous Lupus Erythematosus from Capecitabine Author and year Age/sex ANA Anti- dsDNA Anti- Ro/SSA Anti- histone Medical History of SLE or other rheumatic disease Weger et al. 2008 3 77/female + - + - No Fernandes et al. 2009 7 49/female + 1:640 - + + No Floristan et al. 2009 8 66/female Before therapy 1:160 After therapy: 1:1280 Not reported + - Seronegative polyarthritis with occasional positive ANA Kindem et al. 2013 2 78/female + 1:640 - + - No Ko et al. 2013 1 72/female + >1:2560 - + - No Fongue et al. 2014 6 50/female Not reported Not reported + Not reported SLE Kim et al. 2016 5 67/female + >1:320 - + - No Li et al. 2016 4 74/female + 1:1000 - + - No Our case 2017 68/female + 1:640 + + + SLE DISCUSSION SKIN January 2018 Volume 2 Issue 1 Copyright 2018 The National Society for Cutaneous Medicine 62 One possible explanation for DI-SCLE in association with SLE is the presence of preexisting anti-SSA/Ro antibodies in SLE patients, which may be a risk factor for the development of SCLE in the correct setting, such as exposure to a chemotherapeutic agent. A large multicenter cohort study demonstrated that 32% of childhood-onset SLE patients had positive anti-SSA/Ro antibodies. 11 Additionally, 5-FU may translocate SSA/Ro antigens to the surface of keratinocytes, leading to lupus-like eruptions and possibly higher rates of SCLE in patients with underlying SLE and elevated autoantibodies. 11,12 Alternatively, one case showed a patient who developed DI-SCLE from capecitabine that did not recur with subsequent administration of 5-FU. 5 This suggests a novel pathophysiology for the induction of SCLE from capecitabine that is distinct from 5-FU, although the mechanism is still unclear. While the pathophysiology of DI-SCLE requires further investigation, it is also important to differentiate DI-SCLE from other diagnoses such as DI-SLE or a flare of underlying SLE. DI-SCLE is distinguished from DI-SLE by its clinical characteristics and immunologic profile. DI-SCLE will typically present as a skin rash and patients have positive anti-SSA/Ro antibodies. 2 The cutaneous lesions of DI-SCLE classically present as generalized annular polycyclic or papulosquamous plaques. 3 Conversely, DI- SLE patients present more often with systemic symptoms, such as arthralgias and serositis, than with a skin rash and can have anti-histone antibodies. 2 DI-SCLE is distinguishable from a flare of underlying SLE based on the disease time course. If the rash begins with onset of the drug, subsides with the drug’s cessation, and recurs with re-exposure, it is likely DI- SCLE. Additionally, if the new rash is substantively different from the patient’s typical SLE presentation, then the presence of the rash in the setting of a new drug exposure most likely represents a drug adverse event. Our patient presented with a new-onset rash that was clinically, immunologically, and histopathologically consistent with SCLE several weeks after starting capecitabine therapy while on oral hydroxychloroquine therapy for her SLE. Her rash improved with topical steroids and ultimately resolved with cessation of capecitabine. No systemic symptoms suggestive of an SLE flare occurred simultaneously. In conclusion, this case highlights an occurrence of DI-SCLE secondary to capecitabine therapy in a patient with SLE. This is the second case of a patient on capecitabine that developed DI-SCLE with a documented history of SLE and raises concern that SLE in the setting of capecitabine or possibly other chemotherapeutic agents may predispose patients to this reaction. Patients receiving capecitabine should be monitored for the development of SCLE during treatment, with clinicians having a low threshold to perform a skin biopsy and laboratory work-up for possible SCLE if a patient develops new pink scaly papules in a photodistributed pattern. More research should be undertaken to determine the pathophysiology of DI-SCLE in patients with underlying SLE. SKIN January 2018 Volume 2 Issue 1 Copyright 2018 The National Society for Cutaneous Medicine 63 Conflict of Interest Disclosures: none. Funding: none. Corresponding Author: Jennifer N. Choi, MD 676 N. St. Clair Street, Arkes Family Pavilion Suite 1600 Chicago, Illinois 60611-2997 312-921-6097 Jennifer.choi@northwestern.edu References: 1. Ko JH, Hsieh CI, Chou CY, Wang KH. Capecitabine-induced subacute cutaneous lupus erythematosus: report of a case with positive rechallenge test. The Journal of dermatology. 2013;40(11):939-940. 2. Kindem S, Llombart B, Requena C, et al. Subacute cutaneous lupus erythematosus after treatment with capecitabine. The Journal of dermatology. 2013;40(1):75-76. 3. Weger W, Kranke B, Gerger A, Salmhofer W, Aberer E. Occurrence of subacute cutaneous lupus erythematosus after treatment with fluorouracil and capecitabine. J Am Acad Dermatol. 2008;59(2 Suppl 1):S4-6. 4. Li Z, Jiang N, Xu Y. The concurrence of subacute cutaneous lupus erythematosus and hand-foot syndrome in a patient undergoing capecitabine chemotherapy. The Australasian journal of dermatology. 2016;57(1):e14-16. 5. Kim WI, Kim JM, Kim GW, et al. Subacute cutaneous lupus erythematosus induced by capecitabine: 5-FU was innocent. Journal of the European Academy of Dermatology and Venereology : JEADV. 2016;30(11):e163- e164. 6. Fongue J, Meunier B, Lardet D, et al. Capecitabine-induced subacute cutaneous lupus: a case report. Annales de dermatologie et de venereologie. 2014;141(10):593-597. 7. Fernandes NF, Rosenbach M, Elenitsas R, Kist JM. Subacute cutaneous lupus erythematosus associated with capecitabine monotherapy. Archives of dermatology. 2009;145(3):340-341. 8. Floristan U, Feltes RA, Sendagorta E, et al. Subacute cutaneous lupus erythematosus induced by capecitabine. Clinical and experimental dermatology. 2009;34(7):e328- 329. 9. Marchetti MA, Noland MM, Dillon PM, Greer KE. Taxane associated subacute cutaneous lupus erythematosus. Dermatology online journal. 2013;19(8):19259. 10. Lebeau S, Tambe S, Sallam MA, et al. Docetaxel-induced relapse of subacute cutaneous lupus erythematosus and chilblain lupus. Journal der Deutschen Dermatologischen Gesellschaft : JDDG. 2013;11(9):871-874. 11. Novak GV, Marques M, Balbi V, et al. Anti- RO/SSA and anti-La/SSB antibodies: Association with mild lupus manifestations in 645 childhood-onset systemic lupus erythematosus. Autoimmunity reviews. 2017;16(2):132-135. 12. Adachi A, Nagai H, Horikawa T. Anti- SSA/Ro antibody as a risk factor for fluorouracil-induced drug eruptions showing acral erythema and discoid- lupus-erythematosus-like lesions. Dermatology (Basel, Switzerland). 2007;214(1):85-88.