Key Points
Question
Is a skin eruption that develops during hydroxychloroquine sulfate use associated with autoantibodies in dermatomyositis?
Findings
In this cohort study of 111 patients with dermatomyositis treated with hydroxychloroquine, 23 experienced an associated adverse cutaneous event. Of those with a skin eruption, 7 had anti–small ubiquitinlike modifier 1 activating enzyme autoantibodies vs 7 of 88 patients without a skin eruption; in contrast, none of those with a skin eruption had anti–melanoma differentiation-associated gene 5 autoantibodies vs 15 of those without a skin eruption, and associations were significant in multivariable models.
Meaning
Patients with dermatomyositis with anti-small ubiquitinlike modifier 1 activating enzyme autoantibodies appear to be at increased risk of developing a hydroxychloroquine-associated skin eruption, and this may be the result of differences in disease mechanism among autoantibody subsets.
Abstract
Importance
Hydroxychloroquine sulfate is a commonly used medication for patients with dermatomyositis and has been associated with a uniquely elevated risk of adverse cutaneous reactions in this population. No studies to date have examined whether certain subsets of patients with dermatomyositis are at increased risk of experiencing a hydroxychloroquine-associated skin eruption.
Objective
To identify disease features that increase the risk of hydroxychloroquine-associated skin eruption in adults with dermatomyositis.
Design, Setting, and Participants
A retrospective cohort study was conducted in the outpatient dermatology clinic at a tertiary academic referral center. All adults with dermatomyositis (age >18 years) who started receiving hydroxychloroquine between July 1, 1990, and September 13, 2016, were eligible for the analysis. Patients were considered to have a hydroxychloroquine-associated skin eruption if a skin eruption had developed within their first 4 weeks of treatment and resolved with discontinuation of hydroxychloroquine therapy.
Exposures
One or more doses of hydroxychloroquine.
Main Outcomes and Measures
The associations between autoantibodies (against transcription intermediary factor 1γ [TIF-1γ], nucleosome-remodeling deacetylase complex [Mi-2], nuclear matrix protein [NXP-2], small ubiquitinlike modifier 1 activating enzyme [SAE-1/2], melanoma differentiation-associated gene 5 [MDA-5], histidyl–transfer RNA synthetase [Jo-1], Ku, and signal recognition particles) and cutaneous adverse reactions to hydroxychloroquine in patients with dermatomyositis.
Results
A total of 111 patients met the inclusion criteria, and 23 (20.7%) developed a hydroxychloroquine-associated skin eruption (20 [87.0%] were women with a mean [SD] age of 49 [14] years at diagnosis). Skin eruptions were approximately 3 times more common in patients with anti–SAE-1/2 autoantibodies (7 of 14 [50.0%]) compared with those without the autoantibody (16 of 97 [16.5%]). In contrast, none of 15 patients with anti–MDA-5 autoantibodies had a skin eruption vs 23 of 96 (24.0%) of those without the autoantibody. In exact logistic regressions adjusted for age, race/ethnicity, sex, amyopathic status, anti–Ro52 status, and dermatomyositis-associated cancer, the presence of anti–SAE-1/2 autoantibodies was significantly associated with a hydroxychloroquine-associated skin eruption (odds ratio [OR], 8.43; 95% CI, 1.98-49.19; P = .003) and presence of anti–MDA-5 autoantibodies was significantly negatively associated with a hydroxychloroquine-associated skin eruption (OR, 0.06; 95% CI, 0.0004-0.52; P = .006). No other autoantibodies were significantly positively or negatively associated with a hydroxychloroquine-associated skin eruption.
Conclusions and Relevance
Adverse skin reactions to hydroxychloroquine are relatively common in a US cohort of patients with dermatomyositis. Our data suggest that pathophysiologic differences exist between autoantibody subsets in dermatomyositis.
This cohort study examines myositis-specific autoantibodies observed during hydroxychloroquine therapy in patients with dermatomyositis to determine whether certain subsets of patients are more likely to experience a skin eruption.
Introduction
Hydroxychloroquine sulfate is a common and effective treatment for dermatomyositis skin disease,1,2 but it has been associated with acute cutaneous eruptions in up to 31% of patients.3 Variations in disease pathogenesis among patients with different autoantibodies (transcription intermediary factor 1γ [TIF-1γ], nucleosome-remodeling deacetylase complex [Mi-2], nuclear matrix protein [NXP-2], small ubiquitinlike modifier 1 activating enzyme [SAE-1/2], melanoma differentiation-associated gene 5 [MDA-5], histidyl-transfer RNA [tRNA] synthetase [Jo-1], Ku, and signal recognition particles) may be contributing to both heterogeneous clinical phenotypes and variable response to hydroxychloroquine. Our aim was to investigate the association between dermatomyositis autoantibodies and risk of developing a skin eruption in patients with dermatomyositis who were receiving hydroxychloroquine.
Methods
Patient Population
The study population (N=111) consisted of adults with dermatomyositis (age >18 years) who started receiving hydroxychloroquine between July 1, 1990, and September 13, 2016. Dermatomyositis was diagnosed using Bohan and Peter criteria4,5 or, for clinically amyopathic patients, Sontheimer criteria.6 The Stanford University Institutional Review Board approved collection of plasma samples and clinical information, and all participants provided written and oral informed consent. There was no financial compensation.
Patients were identified through our prospectively enrolled dermatomyositis database and considered for analysis if they received 1 or more doses of hydroxychloroquine sulfate and had 4 or more weeks of follow-up after beginning treatment. A hydroxychloroquine-associated skin eruption was defined as a skin eruption beginning within the first 4 weeks of hydroxychloroquine treatment and resolving after discontinuation of hydroxychloroquine therapy. Information about hydroxychloroquine dose, treatment dates, skin eruption dates, concomitant dermatomyositis medications (ie, methotrexate, mycophenolate mofetil, azathioprine, leflunomide, intravenous immunoglobulin, and prednisone), skin eruption morphologic characteristics, and subsequent treatment with chloroquine or quinacrine was collected from the medical records. Concomitant dermatomyositis medications were defined as medications used simultaneously with initiation of hydroxychloroquine treatment, or, for intravenous immunoglobulin, received within 2 months. Six patients were contacted to confirm the interval between initiation of hydroxychloroquine treatment and skin eruption. Dermatomyositis-associated cancer was defined as any malignancy diagnosed within 5 years of dermatomyositis onset.
Skin Activity Assessment
The Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI) was used to quantify skin disease activity.7 CDASI scores collected between initiation of hydroxychloroquine treatment and January 3, 2017, were included. Clinical remission was defined as a CDASI activity score of 5 or lower, excluding periungual score, no ulcers, and no individual erythema score greater than 1, as previously described.8
Dermatomyositis-Autoantibody Detection
Antibodies against TIF-1γ, Mi-2, NXP-2, SAE-1/2, and MDA-5 were assayed as previously described.9 Antibodies against Jo-1, Ro52, threonyl-tRNA synthetase (PL-7), alanyl-tRNA synthetase (PL-12), isoleucyl-tRNA synthetase (OJ), glycyl-tRNA synthetase (EJ), Ku, and signal recognition particles were assayed using the autoimmune inflammatory myopathies 16 Ag line immunoassays (EUROLine; Euroimmun).
Statistical Analysis
Unpaired, 2-tailed t tests or Wilcoxon rank sum tests were used to compare continuous variables and P ≤ .05 was considered statistically significant. Fisher exact or χ2 tests were used to compare categorical variables. The associations between autoantibodies and hydroxychloroquine-associated skin eruption were investigated using exact logistic regressions. Adjustments were made for age, race/ethnicity, sex, amyopathic status, anti–Ro52 status, and dermatomyositis-associated cancer. GraphPad Prism, version 7.0 (GraphPad Software), and RStudio, version 1.0.143, were used for statistical tests and http://clincalc.com/stats/convertor.aspx was used to convert odds ratios (ORs) to risk ratios.
Results
Characteristics of Patients
A total of 111 patients with dermatomyositis who were receiving hydroxychloroquine composed our study group; of these, 23 (20.7%) developed a hydroxychloroquine-associated skin eruption (20 [87.0%] were women with a mean [SD] age of 49 [14] years at diagnosis) (Table 1). Patients who developed the skin eruption were less likely to have anti–MDA-5 autoantibodies (0 vs 15 [17.0%]; P = .04) and more likely to have anti–SAE-1/2 autoantibodies (7 [30.4%] vs 7 [8.0%]; P = .009). There were no significant differences in concomitant medications between those who did and did not develop a hydroxychloroquine-associated skin eruption. However, patients who developed a skin eruption were more likely to be receiving only hydroxychloroquine compared with patients who did not develop a skin eruption (11 [47.8%] vs 25 [28.4%]; P = .09), although the difference did not reach statistical significance. Most patients who developed a hydroxychloroquine-associated skin eruption (17 [73.9%]) developed it within 2 weeks of starting hydroxychloroquine. None of the other variables was significantly associated with developing a hydroxychloroquine-associated skin eruption.
Table 1. Characteristics of Study Population.
| Variable | No. (%) | P Value | |
|---|---|---|---|
| Hydroxychloroquine Skin Eruption (n = 23) | No Hydroxychloroquine Skin Eruption (n = 88) | ||
| Sex | |||
| Men | 3 (13.0) | 19 (21.6) | .56 |
| Women | 20 (87.0) | 69 (78.4) | |
| Age at diagnosis, mean (SD), y | 49 (14) | 50 (14) | .77 |
| Race/ethnicity | |||
| White | 18 (78.2) | 53 (60.2) | .22 |
| Asian | 2 (8.7) | 11 (12.5) | .73 |
| Pacific Islander | 0 | 3 (3.4) | >.99 |
| African American | 0 | 2 (2.3) | >.99 |
| Hispanic/Latino | 3 (13.0) | 19 (21.6) | .40 |
| DM-associated cancer | 1 (4.3) | 11 (12.5) | .45 |
| Clinically amyopathic | 8 (34.8) | 19 (21.6) | .27 |
| Autoantibodies | |||
| Anti–TIF-1γ | 11 (47.8) | 40 (45.5) | >.99 |
| Anti–MDA-5 | 0 | 15 (17.0) | .04a |
| Anti–SAE-1/2 | 7 (30.4) | 7 (8.0) | .009a |
| Anti–NXP-2 | 3 (13.0) | 6 (6.8) | .39 |
| Anti–Mi-2 | 1 (4.3) | 7 (8.0) | >.99 |
| Anti–Ku | 0 | 7 (8.0) | .34 |
| Anti–SRP | 0 | 5 (5.7) | .58 |
| Anti–Jo-1 | 0 | 4 (4.5) | .58 |
| Anti–PL-12 | 0 | 3 (3.4) | >.99 |
| Anti–PL-7 | 0 | 2 (2.3) | >.99 |
| Anti–OJ | 0 | 1 (1.1) | >.99 |
| Anti–EJ | 0 | 0 | >.99 |
| Anti–Ro52 | 6 (26.1) | 21 (23.9) | .79 |
| Concomitant medicationsb | |||
| Prednisone | 10 (43.5) | 48 (54.5) | .36 |
| Methotrexate | 3 (13.0) | 18 (20.5) | .56 |
| Mycophenolate mofetil | 1 (4.3) | 10 (11.4) | .45 |
| Azathioprine | 2 (8.7) | 6 (6.8) | .67 |
| IVIG | 2 (8.7) | 4 (4.5) | .60 |
| None | 11 (47.8) | 25 (28.4) | .09 |
| Unknown | 1 (4.3) | 5 (5.7) | >.99 |
Abbreviations: DM, dermatomyositis; EJ, glycyl-transfer RNA (tRNA) synthetase; IVIG, intravenous immunoglobulin; Jo-1, histidyl-tRNA synthetase; MDA-5, melanoma differentiation-associated gene 5; Mi-2, nucleosome-remodeling deacetylase complex; NXP-2, nuclear matrix protein; OJ, isoleucyl-tRNA synthetase; PL-7, threonyl-tRNA synthetase; PL-12, alanyl-tRNA synthetase; SAE1/2, small ubiquitinlike modifier 1 activating enzyme; SRP, signal recognition particle; TIF-1γ, transcription intermediary factor 1γ.
Statistically significant at P ≤ .05.
Medications patients were taking at the time of initiation of hydroxychloroquine treatment.
Hydroxychloroquine dosing information was available for 97 patients. Ninety-three patients were receiving 200 to 400 mg/d and 4 were receiving 400 to 800 mg/d. None of the patients taking more than 400 mg/d developed a hydroxychloroquine-associated skin eruption.
There was a variety of hydroxychloroquine-associated skin eruption morphologies, including dermatomyositis flare (n = 5) and photosensitive skin eruption (n = 2). Most of the remaining patients had nonspecific, diffuse, erythematous, and pruritic cutaneous eruptions. We investigated the systemic symptoms associated with hydroxychloroquine-associated skin eruption: increased muscle weakness (n = 3), peripheral edema (n = 2), and gastrointestinal tract symptoms (n = 2).
Five patients who developed a hydroxychloroquine-associated skin eruption were subsequently treated with chloroquine and 2 were subsequently treated with both chloroquine and quinacrine; none developed a cutaneous reaction with these antimalarial agents. One patient was rechallenged with hydroxychloroquine and, although she did not have another adverse cutaneous event, she developed biopsy-proven hydroxychloroquine muscle toxicity.
Autoantibodies and Hydroxychloroquine-Associated Skin Eruptions
The association between autoantibodies and hydroxychloroquine-associated skin eruption was investigated using multivariable exact logistic regressions (Table 2). In adjusted analyses, having anti–MDA-5 autoantibodies was significantly negatively associated with hydroxychloroquine-associated skin eruption (OR, 0.06; 95% CI, 0.0004-0.52; P = .006) and having anti–SAE-1/2 autoantibodies was significantly associated with hydroxychloroquine-associated skin eruption (OR, 8.43; 95% CI, 1.98-49.19; P = .006). These ORs correspond to risk ratios of 0.077 (approximately 13-fold decrease in risk) and 3.79 (approximately 4-fold increase in risk), but the 95% CIs are wide.
Table 2. Unadjusted and Adjusted Exact Logistic Regression Results.
| Autoantibody | Unadjusted OR (95% CI) | P Value | Adjusted OR (95% CI)a | P Value |
|---|---|---|---|---|
| Anti–Mi-2 | 0.72 (0.07-3.58) | .72 | 0.84 (0.08-4.56) | .85 |
| Anti–TIF-1γ | 1.1 (0.44-2.73) | .83 | 1.16 (0.43-3.15) | .76 |
| Anti–SAE1/2 | 4.94 (1.56-15.82) | .007b | 8.43 (1.98-49.19) | .003b |
| Anti–NXP-2 | 2.17 (0.48-8.38) | .29 | 3.33 (0.67-16.90) | .13 |
| Anti–MDA-5 | 0.1 (0.0008-0.80) | .03b | 0.06 (0.0004-0.52) | .006b |
| Anti–Ku | 0.23 (0.002-2.02) | .23 | 0.29 (0.002-2.84) | .34 |
| Anti–SRP | 0.32 (0.002-3.02) | .38 | 0.37 (0.003-3.85) | .47 |
| Anti–Jo-1 | 0.40 (0.003-3.96) | .50 | 0.40 (0.002-5.56) | .53 |
Abbreviations: Jo-1, histidyl-tRNA synthetase; MDA-5, melanoma differentiation-associated gene 5; Mi-2, nucleosome-remodeling deacetylase complex; NXP-2, nuclear matrix protein; OR, odds ratio; SAE1/2, small ubiquitinlike modifier 1 activating enzyme; SRP, signal recognition particle; TIF-1γ, transcription intermediary factor 1γ.
Adjusted for age, race/ethnicity, sex, amyopathic status, anti–Ro52 status, and dermatomyositis-associated cancer.
Statistically significant at P ≤ .05.
Cutaneous Outcomes
We investigated the association between hydroxychloroquine-associated skin eruption and cutaneous outcomes. Twenty-one patients who developed a hydroxychloroquine-associated skin eruption had CDASI scores available, a median of 3 (interquartile range [IQR], 1-7), each with a median follow-up of 40 months (IQR, 14-68) after exposure to hydroxychloroquine. Seventy-three patients who did not develop a hydroxychloroquine-associated skin eruption had CDASI scores available, a median of 3 (IQR, 1-6), each with a median (IQR, 19-74) follow-up of 51 months after exposure to hydroxychloroquine. The percentage who achieved clinical remission of skin disease was not significantly different between those who did and did not develop a hydroxychloroquine-associated skin eruption (62% vs 41%; P = .14).
Discussion
We found that 20.7% of patients with dermatomyositis developed a hydroxychloroquine-associated skin eruption, with anti–MDA-5 autoantibodies associated with significantly decreased risk and anti–SAE-1/2 autoantibodies associated with significantly increased risk. Hydroxychloroquine is a common dermatomyositis medication with the potential to alleviate and exacerbate the burden of skin disease.1,2,3 Our findings, which highlight specific patient groups at increased and decreased risk of developing a hydroxychloroquine-associated skin eruption, may help with treatment management.
Many patients experienced acute worsening of their dermatomyositis-associated skin disease after hydroxychloroquine exposure. The mechanism of action of antimalarial agents in dermatomyositis remains unclear. Antimalarial agents interfere with endosomal trafficking, lysosome acidification and fusion, and autophagy, which inhibits antigen presentation and causes apoptosis of memory T cells.10 Recent data demonstrate that hydroxychloroquine blocks nucleic acid–sensing pathways that lead to induction of interferon (IFN) (along with interleukin-6 and tumor necrosis factor-α) associated with active dermatomyositis.11,12,13 Specifically, hydroxychloroquine has been shown to inhibit Toll-like receptor 7/9 signaling and, more recently, the cGAS-STING (cyclic guanosine monophosphate-adenosine monophosphate synthase-stimulator of interferon genes) pathway that leads to production of IFN-α and IFN-β, respectively.14,15 MDA-5 is the only dermatomyositis autoantigen known to function as a direct nucleic acid sensor that is involved in IFN induction, and patients with anti–MDA-5 autoantibodies are less likely to develop a hydroxychloroquine-associated skin eruption. It is conceivable that the different effects of hydroxychloroquine are the result of variable roles for specific nucleic acid–sensing pathways between autoantibody subsets.
Limitations
This study has limitations. We were limited by information available in the medical record, and there is the possibility of recall bias among contacted patients. We were often unable to clearly differentiate between a hypersensitivity-type drug reaction and acute worsening of dermatomyositis skin disease.
Conclusions
In a US cohort of adults with dermatomyositis, patients with anti–SAE-1/2 autoantibodies were at an increased risk of developing a hydroxychloroquine-associated skin eruption and patients with anti–MDA-5 autoantibodies were at a decreased risk of developing a hydroxychloroquine-associated skin eruption. These data may guide further studies on mechanisms of disease across dermatomyositis autoantibody subsets.
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