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Table 1.  
Characteristics and Treatments of 73 Patients With Antimalarial-Refractory CLE
Characteristics and Treatments of 73 Patients With Antimalarial-Refractory CLE
Table 2.  
Treatment Outcomes in Patients With Antimalarial-Refractory CLE
Treatment Outcomes in Patients With Antimalarial-Refractory CLE
1.
Hejazi  EZ, Werth  VP.  Cutaneous lupus erythematosus: an update on pathogenesis, diagnosis and treatment.  Am J Clin Dermatol. 2016;17(2):135-146.PubMedGoogle ScholarCrossref
2.
Ruzicka  T, Sommerburg  C, Goerz  G, Kind  P, Mensing  H.  Treatment of cutaneous lupus erythematosus with acitretin and hydroxychloroquine.  Br J Dermatol. 1992;127(5):513-518.PubMedGoogle ScholarCrossref
3.
Moghadam-Kia  S, Chilek  K, Gaines  E,  et al.  Cross-sectional analysis of a collaborative Web-based database for lupus erythematosus-associated skin lesions: prospective enrollment of 114 patients.  Arch Dermatol. 2009;145(3):255-260.PubMedGoogle ScholarCrossref
4.
Chasset  F, Francès  C, Barete  S, Amoura  Z, Arnaud  L.  Influence of smoking on the efficacy of antimalarials in cutaneous lupus: a meta-analysis of the literature.  J Am Acad Dermatol. 2015;72(4):634-639.PubMedGoogle ScholarCrossref
5.
Chasset  F, Arnaud  L, Costedoat-Chalumeau  N, Zahr  N, Bessis  D, Francès  C.  The effect of increasing the dose of hydroxychloroquine (HCQ) in patients with refractory cutaneous lupus erythematosus (CLE): An open-label prospective pilot study.  J Am Acad Dermatol. 2016;74(4):693-9.e3.PubMedGoogle ScholarCrossref
6.
Husein-ElAhmed  H, Callejas-Rubio  JL, Rios-Fernandez  R, Ortego-Centeno  N.  Refractory subacute cutaneous lupus erythematous responding to a single course of belimumab: a new anti-BLyS human monoclonal antibody.  Indian J Dermatol Venereol Leprol. 2014;80(5):477-478.PubMedGoogle ScholarCrossref
Research Letter
September 2017

Characteristics and Alternative Treatment Outcomes of Antimalarial-Refractory Cutaneous Lupus Erythematosus

Author Affiliations
  • 1Ronald O. Perelman Department of Dermatology, New York University Langone Medical Center, New York, New York
  • 2Department of Dermatology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
JAMA Dermatol. 2017;153(9):937-939. doi:10.1001/jamadermatol.2017.1160

Cutaneous lupus erythematosus (CLE) is an autoimmune skin disease associated with substantial morbidity.1 Although antimalarial therapy is considered to be first-line systemic treatment, as many as 50% of patients have recalcitrant disease.2 Alternative therapies have been investigated for antimalarial-refractory CLE, but the existing literature is limited to small studies without comparative treatment data.1 We therefore sought to evaluate the characteristics and treatments of antimalarial-refractory CLE.

Methods

We performed a query-based search of medical records from New York University Langone Medical Center, New York; Bellevue Hospital Center, New York, New York; Brigham and Women’s Hospital, Boston, Massachusetts; and Massachusetts General Hospital, Boston, to identify patients with antimalarial-refractory CLE from January 1, 2000, through December 31, 2015. Antimalarial-refractory disease was defined as no clinical response (CR) (no improvement in erythema, scaling, and alopecia) or partial CR (<50% improvement) to standard doses of at least 1 antimalarial therapy for at least 3 months. Deidentified clinical and treatment data were extracted, and categorical variables were compared using 2-tailed χ2 tests with Bonferroni post hoc analysis (P ≤ .05). This study was approved by the institutional review boards of all participating institutions.

Results

We identified 73 patients with antimalarial-refractory CLE (11 men [15%] and 62 women [85%]; mean [SD] age, 42 [11] years) (Table 1). Of these, nearly all (72 of 73) were treated with hydroxychloroquine sulfate whereas the remaining patient was initially treated with chloroquine phosphate. Twenty of 35 patients with discoid lupus erythematosus (57%) had involvement above and below the neck (generalized discoid lupus erythematosus). Twenty of 64 patients (31%) with data available were active smokers. Concomitant systemic lupus erythematosus (SLE) was present in 22 of the 54 patients (41%) with chronic CLE.

Fifty-five of 72 patients (76%) received an alternative antimalarial (chloroquine or quinacrine). Substantial CR (≥50% improvement) was seen in 15 of 33 patients (45%) receiving chloroquine and 10 of 19 (53%) receiving quinacrine (8 in combination with hydroxychloroquine, 1 with chloroquine, and 1 as monotherapy) (Table 2). Thalidomide led to substantial CR in 10 of 11 patients (91%), followed by methotrexate sodium in 10 of 19 (53%), dapsone in 8 of 18 (44%), belimumab in 6 of 16 (38%), mycophenolate mofetil hydrochloride in 9 of 25 (36%), and azathioprine sodium in 3 of 12 (25%). Thalidomide had the highest rate of adverse effects (11 of 13 [85%]), with neuropathy occurring in 6 of these (54%).

We found a significant difference among the groups in terms of substantial CR (P = .04). Based on Bonferroni post hoc analysis, only thalidomide was significantly associated with substantial response (P = .003). Patients with CLE without SLE were significantly more likely to have a substantial CR to an alternative antimalarial therapy or nonantimalarial therapy compared with patients with both CLE and SLE (44 of 76 treatment regimens [58%] vs 41 of 103 [40%]; P = .02).

Discussion

To our knowledge, this retrospective study represents the first to analyze the characteristics and treatments of patients with antimalarial-refractory CLE. Generalized DLE was highly prevalent in our cohort, suggesting that this feature predicts treatment resistance.3 Concordant with previous studies, active tobacco use was highly prevalent in our cohort.4 Furthermore, SLE was present in 22 of 54 patients with refractory chronic CLE (41%) (Table 1), suggesting that concurrent SLE may represent a risk factor for recalcitrance to antimalarials.

Only 55 patients in our cohort (76%) received an alternative or additional antimalarial after hydroxychloroquine treatment failed, suggesting that second-line antimalarials may be underused in recalcitrant CLE.5 Although some evidence suggests that antimalarial metabolism varies among individuals and response may vary according to serum drug and metabolite levels, antimalarial drug level assays are not widely available and were not recorded in our study participants.1

Of nonantimalarial treatments, thalidomide and methotrexate were the most effective options. Although thalidomide had the highest rate (85%) of adverse effects, it was the only therapy significantly associated with a substantial response. Belimumab and mycophenolate mofetil demonstrated similar efficacy. This study is the largest, to our knowledge, to report on CLE outcomes using belimumab.6

Limitations of our study include its retrospective design, lack of use of a validated CLE index given the years of data acquisition, and the potential for patients with concomitant SLE to have received therapies for systemic disease. Nevertheless, this study represents the first, to our knowledge, to describe disease characteristics and systemic treatment outcomes in aggregate for antimalarial-refractory CLE.

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Article Information

Corresponding Author: Alisa N. Femia, MD, Ronald O. Perelman Department of Dermatology, New York University Langone Medical Center, 240 E 38th St, 11th Floor, New York, NY 10016 (alisa.femia@nyumc.org).

Accepted for Publication: March 18, 2017.

Published Online: June 21, 2017. doi:10.1001/jamadermatol.2017.1160

Author Contributions: Drs Fruchter and Kurtzman are co-first authors. Dr Vleugels and Femia are co-senior authors. Dr Fruchter and Kurtzman had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Fruchter, Kurtzman, Patel, Franks, Vleugels, Femia.

Acquisition, analysis, or interpretation of data: Fruchter, Kurtzman, Merola, Franks, Vleugels, Femia.

Drafting of the manuscript: Fruchter, Kurtzman, Franks, Vleugels.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Fruchter, Kurtzman.

Administrative, technical, or material support: Merola, Franks.

Study supervision: Franks, Vleugels, Femia.

Conflict of Interest Disclosures: Dr Merola reports acting as a consultant/advisor for Biogen IDEC, AbbVie, Amgen, Eli Lilly and Company, Novartis, Pfizer, Janssen, UCB, Kiniksa, Momenta, Mallinckrodt, Sumumed, and Science 37; serving as a speaker for AbbVie; working as an investigator for Biogen IDEC and Pfizer; receiving grant support from Biogen IDEC; and having a licensed outcome measure for AbbVie. No other disclosures were reported.

References
1.
Hejazi  EZ, Werth  VP.  Cutaneous lupus erythematosus: an update on pathogenesis, diagnosis and treatment.  Am J Clin Dermatol. 2016;17(2):135-146.PubMedGoogle ScholarCrossref
2.
Ruzicka  T, Sommerburg  C, Goerz  G, Kind  P, Mensing  H.  Treatment of cutaneous lupus erythematosus with acitretin and hydroxychloroquine.  Br J Dermatol. 1992;127(5):513-518.PubMedGoogle ScholarCrossref
3.
Moghadam-Kia  S, Chilek  K, Gaines  E,  et al.  Cross-sectional analysis of a collaborative Web-based database for lupus erythematosus-associated skin lesions: prospective enrollment of 114 patients.  Arch Dermatol. 2009;145(3):255-260.PubMedGoogle ScholarCrossref
4.
Chasset  F, Francès  C, Barete  S, Amoura  Z, Arnaud  L.  Influence of smoking on the efficacy of antimalarials in cutaneous lupus: a meta-analysis of the literature.  J Am Acad Dermatol. 2015;72(4):634-639.PubMedGoogle ScholarCrossref
5.
Chasset  F, Arnaud  L, Costedoat-Chalumeau  N, Zahr  N, Bessis  D, Francès  C.  The effect of increasing the dose of hydroxychloroquine (HCQ) in patients with refractory cutaneous lupus erythematosus (CLE): An open-label prospective pilot study.  J Am Acad Dermatol. 2016;74(4):693-9.e3.PubMedGoogle ScholarCrossref
6.
Husein-ElAhmed  H, Callejas-Rubio  JL, Rios-Fernandez  R, Ortego-Centeno  N.  Refractory subacute cutaneous lupus erythematous responding to a single course of belimumab: a new anti-BLyS human monoclonal antibody.  Indian J Dermatol Venereol Leprol. 2014;80(5):477-478.PubMedGoogle ScholarCrossref
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