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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
 
Arch Dermatol. Author manuscript; available in PMC 2012 November 1.
Published in final edited form as:
PMCID: PMC3282057
NIHMSID: NIHMS319717

Response to Antimalarials in Cutaneous Lupus Erythematosus A Prospective Analysis

Aileen Y. Chang, BA,1,2 Evan W. Piette, BS,1,2 Kristen P. Foering, BS,1,2,3 Thomas R. Tenhave, PhD, MPH,4 Joyce Okawa, RN,1,2 and Victoria P. Werth, MD1,2

Abstract

Objective

To demonstrate response to antimalarials in patients with cutaneous lupus erythematosus using activity scores from the Cutaneous Lupus Erythematosus Disease Area and Severity Index, a validated outcome measure.

Design

Prospective, longitudinal cohort study.

Setting

University cutaneous autoimmune disease clinic.

Participants

One hundred twenty-eight patients with cutaneous lupus erythematosus who presented from January 2007-July 2010 and had at least 2 visits with activity scores.

Main Outcome Measures

Response defined by 4-point or 20% decrease in activity score. Response to initiation determined with score before treatment and first visit at least 2 months after treatment. Response to continuation determined with score at first visit and most recent visit on treatment.

Results

Of 11 patients initiated on hydroxychloroquine, 55% were responders with a decrease in median (interquartile range) activity score from 8.0 (3.5-13) to 3.0 (1.8-7.3) (p=0.03). Of 15 patients who had failed hydroxychloroquine, 67% were responders to initiation of hydroxychloroquine-quinacrine, with a decrease in median (interquartile range) activity score from 6.0 (4.8-8.3) to 3.0 (0.75-5.0) (p=0.004). Nine out of 21 patients (43%) continued on hydroxychloroquine and 9 out of 21 patients (43%) continued on hydroxychloroquine-quinacrine were responders with a decrease in median (interquartile range) activity score from 6.0 (1.5-9.5) to 1.0 (0-4.5) (p=0.009) and 8.5 (4.25-17.5) to 5.0 (0.5-11.5) (p=0.01), respectively.

Conclusion

The use of quinacrine with hydroxychloroquine is associated with response in patients who fail hydroxychloroquine monotherapy. Further reduction in disease activity can be associated with continuation of antimalarials.

Introduction

Antimalarial drugs have been in use for the treatment of cutaneous lupus erythematosus (CLE) since 1894, when the use of quinine was reported to be beneficial in lupus erythematosus (LE)1. During World War II, British physicians observed that soldiers with rheumatoid arthritis and systemic lupus erythematosus (SLE) improved while taking quinacrine, a synthetic derivative of quinine2. Following Page’s landmark 1951 paper3, various reports over the next ten years confirmed the efficacy of antimalarials in treating LE4. Antimalarials are now considered first-line systemic therapy in CLE5, 6. Several mechanisms have been proposed to explain the therapeutic benefit of antimalarials in CLE: suppression of antigen presentation, inhibition of prostaglandin and cytokine synthesis, lysosomal stabilization, inhibition of toll-like receptor signaling, and photoprotective properties7, 8.

Currently, the antimalarials used to treat CLE include hydroxychloroquine, chloroquine, and quinacrine6. There have been 2 randomized controlled trials demonstrating improvement in patients taking hydroxychloroquine or chloroquine, though neither were placebo-controlled9, 10. These data are supported by numerous case reports and case series11. Although quinacrine was the first synthetic antimalarial reported as beneficial in treating LE, its use declined as hydroxychloroquine was felt to be safer and with fewer side effects12. Only in the past 20 years has there been a renewed interest in quinacrine12. Response to quinacrine, in combination with either hydroxychloroquine or chloroquine, has been documented in the treatment of CLE with response determined by clinical criteria and an unvalidated use of a CLE-specific outcome measure13-15. It has also been documented in the treatment of SLE with a SLE-specific outcome measure16.

There are few studies that systemically evaluate the use of medications, including antimalarials, in treating CLE17. The purpose of this study was to demonstrate prospectively the response to antimalarial monotherapy and combination therapy in a cohort of CLE patients using the Cutaneous Lupus Disease Area & Severity Index (CLASI), a disease-specific outcome measure.

Methods

Identification of Patients

This is a prospective, longitudinal cohort study of CLE patients. Using our ongoing database of LE patients with skin manifestations18, we identified 212 patients with CLE or SLE with non-specific lupus skin disease who were enrolled in the database between January 5, 2007 and July 9, 2010. We included patients with a diagnosis of chronic (CCLE), subacute (SCLE), and acute CLE (ACLE) subtypes, based on the modified Gilliam classification19. We also included patients diagnosed with SLE, based on American College of Rheumatology revised criteria20. We excluded patients with non-specific lupus skin findings, bullous ACLE (blisters are not captured by the CLASI), or unclear medication history (e.g. medications taken intermittently). Figure 1 demonstrates how we identified patients for this study.

Figure 1
Identification of the 128 patients

Of the remaining 128 CLE patients, we identified those who were initiated and/or continued on the following antimalarial therapies: hydroxychloroquine, hydroxychloroquine-quinacrine, chloroquine, and chloroquine-quinacrine. We excluded patients who were taking concomitant non-antimalarial immunomodulators, such as dapsone and thalidomide, or concomitant immunosuppressives, such as corticosteroids, methotrexate, mycophenolate, azathioprine, cyclophosphamide, cyclosporine, and rituximab. We included patients using concomitant topical or intralesional medications.

This study was approved by our Institutional Review Board (IRB). All subjects were enrolled after having signed the IRB-approved written informed consent and the Health Insurance Portability and Accountability Act (HIPAA) authorization.

Treatment Protocol

Hydroxychloroquine was dosed at 200mg to 400mg per day, based on ideal body weight. Chloroquine was dosed at 250mg per day for five to seven days a week, determined by ideal body weight. Quinacrine was dosed at 100mg per day. In our clinic, we use an algorithmic approach for antimalarial therapy6. If a patient fails first-line hydroxychloroquine, we add quinacrine. If the patient has previously failed hydroxychloroquine-quinacrine or does not have access to a compounding pharmacy, we consider the use of chloroquine. We use chloroquine-quinacrine if the patient fails hydroxychloroquine-quinacrine or chloroquine.

Cutaneous Lupus Erythematosus Disease Area Severity Index (CLASI)

The CLASI is a validated clinical tool that quantifies disease activity and damage in patients with CLE. The activity score is based on the degree of erythema, scale, mucous membrane lesions, and non-scarring alopecia21. The CLASI has been shown to have good content validity, as well as inter-rater and intra-rater reliability. Since its development, the CLASI has been used in several studies that have examined all subsets of CLE13, 22-27.

Recent work has demonstrated that a 4-point or 20% decrease in CLASI activity score is the most specific criterion for classifying patients as responders or non-responders and represents the minimal clinically important change28. Responders are patients who have improved. Non-responders are patients who have not improved, defined as either unchanged or worsened. Disease severity is defined by the following CLASI activity score criteria: mild 0-9, moderate 10-20, severe 21-7028. In calculating percent change, if the baseline CLASI activity score (i.e. the denominator value) was zero, 0.5 points were added to each score to allow the percent change to be calculated. This is consistent with previous methods28.

Treatment Response Analysis

For analysis of response to treatment initiation, we compared the CLASI activity score obtained at the visit before initiation of therapy with the score obtained at the first follow-up visit after initiation. The first follow-up visit occurred at least 2 months following initiation, based on clinical practice and data indicating that antimalarials may take up to 2 months to demonstrate benefit6. Based on the change and percent change in CLASI score between the visit prior to initiation and the first follow-up visit after initiation, patients were categorized into responders (improved) or non-responders (unchanged or worsened) using the criteria of 4-point or 20% decrease in CLASI activity score28.

For analysis of response to treatment continuation, we compared the CLASI activity score obtained at the first visit on the therapy with the score obtained at the most recent visit on the therapy and categorized patients into responders or non-responders. If patients had been initiated on treatment while in the study, we also looked at their initial responsiveness to the treatment.

Not all patients initiated on a treatment were included in the continuation of treatment analysis for several reasons: lost to follow-up (defined as no visit in over a year), follow-up visit had not occurred yet, or medication change. Likewise, not all patients included in the continuation of treatment analysis were included in the initiation of treatment analysis, as some patients were started on treatment prior to enrollment in the database.

Statistical Analysis

CLASI scores and change in CLASI scores were not normally distributed. Age and duration between visits were normally distributed. The Mann-Whitney test was performed for comparison of change in CLASI scores between responders and non-responders within each treatment group, when the total sample size was at least 829. The Wilcoxon signed rank test was performed for comparison of CLASI scores between visits for all patients, responders, and non-responders within each treatment group. We did not adjust for multiple comparisons because this analysis was exploratory. With this strategy, we avoided being too conservative and hence missing important exploratory findings30. Between responders and non-responders within each treatment group, student’s t-test was performed for comparison of age and Fisher’s exact test was performed for comparison of sex and smokers. Stata 11.0 (StataCorp LP, College Station, Texas) was used for data analysis. GraphPad Prism 5.0 (GraphPad Software Inc., La Jolla, California) was used for data analysis and making graphs.

Results

Patient Characteristics

Characteristics of patients initiated on each therapy, as well as comparisons between responders and non-responders, can be found in Table 1. Similar statistics for patients continued on each therapy can be found in Table 2.

Table 1
Characteristics of responders and non-responders with initiation of treatment.
Table 2
Characteristics of responders and non-responders with continuation of treatment.

Initiation of hydroxychloroquine monotherapy

Eleven patients, representing 8.6% (11/128) of the study population, were initiated on hydroxychloroquine while enrolled in the database. These patients had failed topical/intralesional treatments or had been on no treatment.

Six patients (6/11) were responders, with a decrease in median (interquartile range) CLASI activity score from 8.0 (3.5-13) to 3.0 (1.8-7.3) from initiation to the first follow-up visit (p=0.03) (Figure 2A). Five patients (5/11) were non-responders, with an increase in median (interquartile range) CLASI score from 3.0 (1.5-6.5) to 5.0 (4.5-8.0) from initiation to the first follow-up visit (p=0.10) (Figure 2B).

Figure 2Figure 2
Hydroxychloroquine initiation at month 0

Continuation of hydroxychloroquine monotherapy

Twenty-one patients, representing 16% (21/128) of the study population, had at least two consecutive visits on hydroxychloroquine. Two-thirds had been on hydroxychloroquine for over 12 months.

Nine patients (9/21) were responders with continuation of hydroxychloroquine over a mean (interquartile range) duration of 9.2 (3.3-13) months (Figure 3A). Twelve patients (12/21) were non-responders with continuation of hydroxychloroquine over a mean (interquartile range) duration of 14 (2.8-26) months (Figure 3A). Of these 12 patients, 5 required the addition of quinacrine. Continuation data for patients initiated on hydroxychloroquine while enrolled in the database is shown in Figure 2A-B.

Figure 3Figure 3
Continuation of hydroxychloroquine

Initiation of Hydroxychloroquine-quinacrine therapy

Fifteen patients, representing 12% (15/128) of the study population, were initiated on hydroxychloroquine-quinacrine while enrolled in the database. These patients were either currently taking hydroxychloroquine or had failed hydroxychloroquine in the past.

Ten patients (10/15) were responders, with a decrease in median (interquartile range) CLASI activity score from 6.0 (4.8-8.3) to 3.0 (0.75-5.0) from initiation to the first follow-up visit (p=0.004) (Figure 4A). Five patients (5/15) were non-responders, with a decrease in median (interquartile range) CLASI activity score from 9.0 (3.5-24) to 8.0 (3-23) from initiation to the first follow-up visit (p=0.27) (Figure 4B).

Figure 4Figure 4
Hydroxychloroquine-quinacrine (HCQ-Qn) initiation at month 0

Continuation of hydroxychloroquine-quinacrine therapy

Twenty-one patients, representing 16% (21/128) of the study population, had at least two consecutive visits on hydroxychloroquine-quinacrine. Twenty-five percent of patients had been on hydroxychloroquine-quinacrine for over 12 months.

Nine patients (9/21) were responders with continuation of hydroxychloroquine-quinacrine over a mean (interquartile range) duration of 9.0 (4.0-13) months (Figure 3B). Twelve patients (12/21) were non-responders with continuation of hydroxychloroquine-quinacrine over a mean (interquartile range) duration of 15 (7.6-21) months (Figure 3B). Of these 12 patients, 3 patients required a medication change, either switching from hydroxychloroquine-quinacrine to chloroquine-quinacrine or adding an immunosuppressive. Continuation data for patients initiated on hydroxychloroquine-quinacrine while enrolled in the database is shown in Figure 4A-B.

Initiation of chloroquine monotherapy

Three patients, representing 2.3% (3/128) of the study population, were initiated on chloroquine while enrolled in the database. All had failed hydroxychloroquine, and one had also failed hydroxychloroquine-quinacrine therapy. All three patients were responders (Table 1).

Continuation of chloroquine monotherapy

Three patients, representing 2.3% (3/128) of the study population, had at least two consecutive visits on chloroquine. All were non-responders with continuation of chloroquine over a mean (interquartile range) duration of 15 (6.1-30) months (Table 2). Two patients required the addition of quinacrine.

Initiation of chloroquine-quinacrine therapy

Six patients, representing 4.7% (6/128) of the study population, were initiated on chloroquine-quinacrine while enrolled in the database. All had failed hydroxychloroquine and hydroxychloroquine-quinacrine therapy. Two patients (2/6) were responders (Table 1).

Continuation of chloroquine-quinacrine therapy

Five patients, representing 3.9% (5/128) of the study population, had at least two consecutive visits on chloroquine-quinacrine. One patient (1/5) was a responder with continuation of chloroquine-quinacrine over 12 months (Table 2). Four patients (4/5) were non-responders with continuation of chloroquine-quinacrine therapy over a mean (interquartile range) duration of 18 (3.4-35) months. Of these 4 patients, 1 required the addition of thalidomide.

Discussion

Our prospective analysis presents evidence of response to antimalarials, without concomitant immunosuppressive or immunomodulator use, in a CLE population seen at an academic referral center.

In our patients initiated on hydroxychloroquine, about half demonstrated improvement at their first follow-up visit. Our response rate is similar to that of a multicenter randomized controlled trial comparing hydroxychloroquine to acetretin, in which 50% of CLE patients on hydroxychloroquine improved at 8 weeks based on clinical parameters10. In the discoid LE population, response to antimalarials has been cited to occur in 95% of patients and response to hydroxychloroquine in 70%11, 31, though the latter was studied in a non-referral dermatological setting. This suggests that our referral population is more antimalarial-resistant than the non-referral population18.

In patients who failed hydroxychloroquine, we detected a significant reduction in CLASI activity scores with initiation of hydroxychloroquine-quinacrine, which supports Cavazzana et al’s work that demonstrated improvement with hydroxychloroquine-quinacrine therapy by using an unvalidated method of retrospectively assigning CLASI scores13. Additionally, for non-responders at the first follow-up visit following initiation of hydroxychloroquine-quinacrine, we found a decrease in CLASI activity scores for almost all patients, despite their not meeting response criteria. For those with further follow-up, a continued decrease in scores was observed (Figure 4B). Also, patients with consistently mild disease while taking hydroxychloroquine demonstrated response with the addition of quinacrine (Figure 4A), suggesting that adding quinacrine could be helpful in mild patients who desire improvement.

Forty percent of patients continued on either hydroxychloroquine or hydroxychloroquine-quinacrine demonstrated response with continuation of their respective antimalarial therapy. One out of 5 initial non-responders to hydroxychloroquine and 2 out of 5 initial non-responders to hydroxychloroquine-quinacrine were responders with continuation of their respective antimalarial therapy (Figure 2B, ,4B).4B). These data support the recommendation of continuing patients on antimalarial therapy beyond 2 months, even if they do not initially demonstrate improvement6.

Two previous papers have addressed the use of chloroquine-quinacrine combination therapy. Feldmann et al found skin lesions improved significantly or cleared totally in all SCLE and one-half of chronic LE patients14. Lipsker et al found that three-quarters of DLE, all SCLE, and all DLE/SCLE patients demonstrated complete or greater than 50% clearance of lesions15. Our response rate is not as high as those reported in these two studies, which may be a reflection of differences in antimalarial use. None of the patients in these two studies had been on a trial of hydroxychloroquine-quinacrine before starting chloroquine-quinacrine, which is in contrast to our patients who had all failed hydroxychloroquine-quinacrine in the past.

There are several limitations to our study. As a result of both small sample size and a wide range of CLE subtypes, we could not draw any conclusions regarding differences in treatment response based on CLE subtype. Larger studies are necessary to evaluate response to antimalarials and any differences across CLE subtypes. In using both change and percent change criteria to determine response28, it became apparent that percent change may not be as meaningful with very low (e.g. 0, 1) and high CLASI scores. Studies to evaluate the use of the CLASI across disease severity subtypes would be helpful in determining when change or percent change is most appropriate to use. Additionally, when the criteria for response were determined, high specificity was favored to minimize the misclassification of patients as responders who did not experience a true clinical improvement28. As such, the sensitivity is lower, increasing the number of patients classified as non-responders who did experience a true clinical improvement. Lastly, in our referral population, we see a wide variety of CLE subtypes18 and are more likely see treatment-resistant patients. Although this selection bias limits the generalizability of our results, it allows us to better characterize treatment response in an antimalarial-resistant population and understand which patients will benefit from immunosuppressives, immunomodulators, or investigational therapies.

Overall, this prospective study provides evidence supporting the use of hydroxychloroquine-quinacrine for treating CLE patients who do not respond to hydroxychloroquine. It also demonstrates that continuing patients on hydroxychloroquine or hydroxychloroquine-quinacrine can be beneficial, even in the absence of initial response.

Acknowledgments

We would like to thank Dr. Lynne Taylor (Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania, Philadelphia, PA, USA) for her help with statistical analysis.

Funding/Support: This work was supported by the National Institutes of Health, including NIH K24-AR 18 02207 (Werth), and a grant from the Doris Duke Charitable Foundation to the University of Pennsylvania School of Medicine to fund Clinical Research Fellow Ms. Chang.

Footnotes

Author Contributions: Ms. Chang and Dr. Werth had full access to all of 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: Chang and Werth. Acquisition of data: Chang, Piette, Foering, Okawa, and Werth. Analysis and interpretation of data: Chang, Piette, Foering, Tenhave, and Werth. Drafting of the manuscript: Chang. Critical revision of the manuscript for important intellectual content: Chang, Piette, Foering, Tenhave, Okawa, and Werth. Statistical analysis: Chang and Tenhave. Obtained funding: Chang and Werth. Administrative, technical, or material support: Chang, Foering, Piette, Okawa, and Werth. Study supervision: Werth.

Financial Disclosure: None reported.

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