Consider drugs as a cause or an exacerbating factor in patients diagnosed with subacute cutaneous lupus erythematosus!
Authors: Jeffrey P. Callen
Journal: British Journal of Dermatology (2012)

I recently saw a patient with ‘recalcitrant’ subacute cutaneous lupus erythematosus (SCLE) whose initial disease was felt to be related to the use of either hydrochlorothiazide or lisinopril. Both drugs had been stopped in late 2010, and her disease improved and therapy was being reduced. However, she was noted to be hypertensive and in early 2011 she was started on amlodipine therapy. Throughout the next 15 months doses of prednisone, mycophenolate mofetil, hydroxychloroquine, quinacrine and methotrexate were administered with little ability to control her disease when the prednisone dosage was below roughly 20 mg per day. What can we learn from this case, and how does the current article1 in this issue of the Journal inform us? The first description of SCLE probably predates the 1979 publication by Sontheimer et al.2 which coined the term and allowed dermatologists to classify patients correctly with nonscarring, nonatrophy-producing skin lesions. Early studies made no mention of drugs as a cause or an exacerbating factor; however in 1985, Reed et al.3 reported five patients with SCLE that was temporally related to the use of hydrochlorothiazide. This led to an explosion of reports in which thiazide diuretics were implicated; then reports began to appear linking calcium channel blockers to this phenomenon,4 and eventually to the inclusion of terbinafine5 and several chemotherapeutic agents.6 Now over 100 individual drugs have been linked to this phenomenon. Another seminal observation is that of Srivastava et al.7 in which they examined patients known to have anti-Ro (SS-A) antibodies. This group found that 15 of their 70 patients (21%) had new drugs prescribed within 6 months preceding a diagnosis of SCLE. It is presumed that their patients had SCLE, but some may have had other types of CLE. They noted that many of their cases were linked to antihypertensive agents or cardiovascular drugs, but none were linked to terbinafine. Most authorities agree that other than the presence of a drug that might cause or exacerbate SCLE, there is little clinical or histopathological difference in patients with drug-induced SCLE compared with those in whom a drug is not implicated.8 The current study in this Journal links the presence of a drug with the diagnosis of SCLE in roughly 33% of the patients with SCLE.1 This is a rate that is higher than any previously reported. In addition, these authors did not note a statistically significant association between thiazides, calcium channel blockers or other cardiovascular drugs, a presumed cause of roughly one-third of patients from previous reports.9 However, they did note a significant risk for terbinafine, proton pump inhibitors, tumor necrosis factor (TNF)-α antagonists and antiepileptic therapies. Aside from terbinafine, which at present accounts for more cases in the world’s literature than any other single agent, the other agents that were significantly associated with the development of SCLE have only been sporadically mentioned. Further, TNF antagonists have been linked to both CLE and to systemic LE (SLE) and perhaps in this report some patients with skin findings of SLE were incorrectly diagnosed as having SCLE. Lastly, lack of an association with diuretics and antihypertensive agents remains a mystery, but perhaps is explained by many of these agents potentially having a delay longer than 6 months in the onset of the toxic reaction. Despite this finding, we need to recognize that all of these drugs are only rarely associated with SCLE development or exacerbation and should not be withheld due to the fear that SCLE might develop or be exacerbated. What is unique to this study is the early use of ICD-10 as a coding system (this is not yet being utilized in the U.S.A.) which allows the separation of various types of CLE, and the use of databases that cover > 80% of the population of Sweden (the National Patient Register and the Prescribed Drug Register). Possible issues with the data collection in this study are the use of nonvalidated diagnosis for SCLE; this is an issue that is often clinically important as I have seen multiple patients who are incorrectly diagnosed as SCLE who have been properly diagnosed as dermatomyositis, and there are occasional debates at conferences over whether an individual patient is best diagnosed as chronic CLE or as SCLE. In addition, the authors selected only newly diagnosed patients with SCLE instead of including those in whom a drug caused an exacerbation of a previously quiescent process. In many of my reports that link SCLE to drugs, we have included patients with known SCLE or Sjögren syndrome whose cutaneous disease was exacerbated by a newly prescribed drug in addition to those whose disease was new onset.5, 6 However, the authors did allow inclusion of patients known to have SLE prior to the diagnosis of SCLE, but they do not mention whether any patients had Sjögren syndrome prior to the onset of SCLE. Only one control had a prior diagnosis of SLE and no additional control patient developed SLE. However, eliminating those with a prior diagnosis of SLE did not change the results noted. Let us now turn back to the patient described at the beginning of this editorial. Firstly, she probably would not have been counted in this study when the first drugs were recognized as possible offending agents as they had been utilized for > 6 months. In addition, she would not have been included when it was likely that the amlodipine was an exacerbating factor as her CLE diagnosis predated the use of the second exacerbating drug, a phenomenon that I have noted in several patients, but that has only been previously reported once.10 The bottom line is that we should be alert to drugs as a cause or as a factor that causes relapse of SCLE. Further, we need to consider the newer agents found to be linked to SCLE that were noted in this study, but also not forget the traditionally noted agents that have been described in open observational studies. Also, just because one agent has exacerbated the disease, it does not exclude other drugs, even ones not chemically related, being involved in the exacerbation of the disease. Recognition of this phenomenon is important, as had my patient been recognized, she would have avoided large doses of prednisone and various immunosuppressive agents. Lastly, neither the current study, nor previous observations are able to inform us whether the disease is induced by the drug or awakened; however, the consideration of drugs in the induction or worsening of SCLE and their cessation will result in improved clinical outcome. None declared.