- Email: [email protected]
Statin-Induced Anti-HMGCR-Associated Myopathy
JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
VOL. 68, NO. 2, 2016
ª 2016 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION
ISSN 0735-1097/$36.00
PUBLISHED BY ELSEVIER
Letters Statin-Induced Anti-HMGCR-Associated Myopathy
Within our longitudinal cohort, we identified 58
anti-HMGCR–positive
statin-exposed
myositis
patients and 37 comparator myositis patients who were exposed to a statin and were anti-HMGCR negative. All patients met the Bohan and Peter criteria for PM or DM (3,4). Of note, the Bohan and
In addition to self-limited myotoxicity, statins have
Peter criteria do not distinguish PM or DM from
recently been shown to trigger an immune-mediated
IMNM by muscle biopsy characteristics; thus, all
necrotizing myopathy (IMNM), which is distin-
patients in the IMNM category meet the Bohan and
guished from polymyositis (PM) and dermatomyositis
Peter definition for PM.
(DM) by the absence of primary inflammation on
The average duration of follow-up was 29 months
muscle biopsy. Previously, we have shown that pa-
(range from 0 to 100 months). Anti-HMGCR–positive
tients with statin-associated necrotizing myopathy
patients were slightly older (mean age 59.9 vs. 55.4
3-hydroxy-3-
years, p ¼ 0.025), and there was a trend for women to
methylglutaryl-CoA reductase (HMGCR), the phar-
be more likely to have anti-HMGCR antibodies (52%
express
an
autoantibody
targeting
macological target of statins (1,2). We conducted a
vs. 35%, p ¼ 0.113). They had a higher prevalence of
case-control study to characterize the comorbidities
non-steroid–induced type 2 diabetes (47% vs. 17%,
and detailed individual statin history and to investi-
p ¼ 0.003). All patients with diabetes were taking oral
gate the possible clinical associations that could
hypoglycemic agents and/or insulin.
contribute to the development of anti-HMGCR– positive myopathy in statin-treated patients.
Anti-HMGCR–positive patients had higher median creatine kinase values at the time of diagnosis (6,800 vs. 1,990 IU/l, p < 0.001). They also had lesser median hip flexor strength at presentation (14.5 vs. 18 on a
F I G U R E 1 Multiple Regression Analysis of Variables Potentially Associated
20-point scale, p ¼ 0.005), but interestingly, median arm
With Statin-Induced Anti-HMGCR Myopathy (n ¼ 69)
abduction
strength
was
not
significantly
different (18 vs. 20 on a 20-point scale, p ¼ 0.21) (The method used for scoring the muscle strength has
* Atorvastatin
been described elsewhere [5]). Dysphagia was also more frequently reported by anti-HMGCR–negative patients (60% vs. 40%, p ¼ 0.059).
Simvastatin
The interval from statin start date to 2014, the year of data review, did not differ between anti-HMGCR–
*
positive (mean 11 years before 2014, SD 6) and anti-
Type 2 DM
HMGCR–negative patients (mean 10 years before 2014, SD 5, p ¼ 0.65). The median duration of statin Age at diagnosis
therapy before the onset of muscle symptoms was 38 months in anti-HMGCR–positive patients. More patients in the anti-HMGCR–positive group were
Female
exposed to atorvastatin (86% vs. 43%, p < 0.001). 0
50
100
Odds Ratio
The vertical orange line ¼ 1; the blue dots indicate the odds ratio; the horizontal black lines indicate 95% confidence interval; the asterisk indicates p < 0.05. The plot shows the odds
Twenty-four patients, with equal frequency in both groups, had a history of treatment with multiple statins/combination therapy. In order to identify whether individual statins were associated with antiHMGCR myopathy, in the multiple regression anal-
ratios of variables associated with statin-induced anti-HMGCR myopathy. Rosuvastatin
ysis,
was designated as the base category for comparing the statins. DM ¼ diabetes mellitus.
regarding the exact dose of statins were available for
these
patients
were
excluded.
The
data
only 27 patients. However, there was no significant
JACC VOL. 68, NO. 2, 2016
Letters
JULY 12, 2016:234–9
difference in the proportion of patients who underwent high-intensity statin therapy in the 2 groups
Andrew L. Mammen, MD, PhD *Lisa Christopher-Stine, MD, MPH
(38% and 27% of anti-HMGCR-positive and -negative
*Division of Rheumatology
patients, respectively, p ¼ 0.69). Given the limited
Johns Hopkins University School of Medicine
sample, no conclusions regarding the association of
5200 Eastern Avenue, MFL Center Tower Suite 4500
statin intensity and anti-HMGCR–associated myop-
Baltimore, Maryland 21224
athy could be made.
E-mail: [email protected]
We employed multiple regression analysis for the analysis of 69 patients who had been treated with a single statin to identify independent variables that may be associated with the risk for the development of anti-HMGCR myopathy in statin-exposed patients. After adjusting for age and sex, type 2 diabetes mellitus and atorvastatin use (vs. rosuvastatin and simvastatin) were significantly associated with anti-HMGCR myopathy (odds ratio [OR]: 15.6, p ¼ 0.006, and OR: 14.3, p ¼ 0.005, respectively; both with notably wide confidence intervals) (Figure 1). In addition, we repeated the analysis with all participants and individual statins entered into the model as dichotomous variables. Again, atorvastatin and type 2 diabetes remained significant independent predictors of anti-HMGCR–associated myopathy (OR: 7.4, p ¼ 0.001, and OR: 3.8, p ¼ 0.023, respectively). Notably, the median duration of statin therapy before
the
onset of
muscle
symptoms
in
the
anti-HMGCR–positive group was 38 months. This finding suggests that long-term exposure to statins is likely required to trigger an autoimmune response in most cases (85% >6 months). Therefore, medical
http://dx.doi.org/10.1016/j.jacc.2016.04.037 Please note: This work was funded by the Huayi and Siuling Zhang Discovery Fund. The Johns Hopkins Rheumatic Disease Research Core Center, where the serum samples were processed and stored, is supported by NIH grant P30-AR-053503. Dr. Christopher-Stine has received personal fees from Walgreens, Novartis, Idera Pharmaceuticals, Ono Pharma UK, Marathon Pharmaceuticals, Medimmune/AstraZeneca, and Mallinckrodt; is a consultant for Medimmune, Optioncare, and Mallinckrodt; is on the advisory boards of Mallinckrodt and Novartis; and has intellectual property interest in the HMGCR assay licensed to Inova Diagnostics. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Drs. Basharat and Lahouti contributed equally to this work.
REFERENCES 1. Christopher-Stine L, Casciola-Rosen LA, Hong G, et al. A novel autoantibody recognizing 200-kd and 100-kd proteins is associated with an immune-mediated necrotizing myopathy. Arthritis Rheum 2010;62: 2757–66. 2. Mammen AL, Chung T, Christopher-Stine L, et al. Autoantibodies against 3-hydroxy-3-methylglutaryl-coenzyme A reductase in patients with statin-associated autoimmune myopathy. Arthritis Rheum 2011;63: 713–21. 3. Bohan A, Peter JB. Polymyositis and dermatomyositis (first of two parts). N Engl J Med 1975;292:344–7. 4. Bohan A, Peter JB. Polymyositis and dermatomyositis (second of two parts). N Engl J Med 1975;292:403–7. 5. Werner JL, Christopher-Stine L, Ghazarian SR, et al. Antibody levels correlate with creatine kinase levels and strength in anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase-associated autoimmune myopathy. Arthritis Rheum 2012;64:4087–93.
providers should be aware that statin-induced antiHMGCR myopathy may occur even after several years of continuous uneventful statin exposure. Our results indicate that statin-exposed patients with anti-HMGCR antibodies have severe skeletal muscle manifestations, specifically, hip flexor muscle weakness at presentation. In addition, type 2 diabetes mellitus and atorvastatin may be associated with a higher risk of development of this myopathy.
Effects of Prasugrel Versus Clopidogrel on Coronary Microvascular Function in Patients Undergoing Elective PCI
This study was exploratory with small numbers of patients. Further studies are needed to better characterize the risk factors for statin-induced antiHMGCR–associated myopathy. Pari Basharat, MD Arash H. Lahouti, MD Julie J. Paik, MD, MHS Jemima Albayda, MD Iago Pinal-Fernandez, MD, PhD Tanmayee Bichile, MD Thomas E. Lloyd, MD, PhD Sonye K. Danoff, MD, PhD Livia Casciola-Rosen, PhD
Microvascular impairment has been reported in patients on clopidogrel undergoing elective percutaneous coronary intervention (PCI) (1). The related potential mechanisms might include the high residual platelet reactivity observed in a substantial proportion of these patients pretreated with clopidogrel at the time of PCI (2,3). Alternatively, microvascular constriction could occur possibly as consequence of transient endothelial dysfunction related to impaired platelet response to clopidogrel (4). It is unknown whether prasugrel might exert a protective effect on microcirculation during elective PCI in patients with
235
VOL. 68, NO. 2, 2016
ª 2016 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION
ISSN 0735-1097/$36.00
PUBLISHED BY ELSEVIER
Letters Statin-Induced Anti-HMGCR-Associated Myopathy
Within our longitudinal cohort, we identified 58
anti-HMGCR–positive
statin-exposed
myositis
patients and 37 comparator myositis patients who were exposed to a statin and were anti-HMGCR negative. All patients met the Bohan and Peter criteria for PM or DM (3,4). Of note, the Bohan and
In addition to self-limited myotoxicity, statins have
Peter criteria do not distinguish PM or DM from
recently been shown to trigger an immune-mediated
IMNM by muscle biopsy characteristics; thus, all
necrotizing myopathy (IMNM), which is distin-
patients in the IMNM category meet the Bohan and
guished from polymyositis (PM) and dermatomyositis
Peter definition for PM.
(DM) by the absence of primary inflammation on
The average duration of follow-up was 29 months
muscle biopsy. Previously, we have shown that pa-
(range from 0 to 100 months). Anti-HMGCR–positive
tients with statin-associated necrotizing myopathy
patients were slightly older (mean age 59.9 vs. 55.4
3-hydroxy-3-
years, p ¼ 0.025), and there was a trend for women to
methylglutaryl-CoA reductase (HMGCR), the phar-
be more likely to have anti-HMGCR antibodies (52%
express
an
autoantibody
targeting
macological target of statins (1,2). We conducted a
vs. 35%, p ¼ 0.113). They had a higher prevalence of
case-control study to characterize the comorbidities
non-steroid–induced type 2 diabetes (47% vs. 17%,
and detailed individual statin history and to investi-
p ¼ 0.003). All patients with diabetes were taking oral
gate the possible clinical associations that could
hypoglycemic agents and/or insulin.
contribute to the development of anti-HMGCR– positive myopathy in statin-treated patients.
Anti-HMGCR–positive patients had higher median creatine kinase values at the time of diagnosis (6,800 vs. 1,990 IU/l, p < 0.001). They also had lesser median hip flexor strength at presentation (14.5 vs. 18 on a
F I G U R E 1 Multiple Regression Analysis of Variables Potentially Associated
20-point scale, p ¼ 0.005), but interestingly, median arm
With Statin-Induced Anti-HMGCR Myopathy (n ¼ 69)
abduction
strength
was
not
significantly
different (18 vs. 20 on a 20-point scale, p ¼ 0.21) (The method used for scoring the muscle strength has
* Atorvastatin
been described elsewhere [5]). Dysphagia was also more frequently reported by anti-HMGCR–negative patients (60% vs. 40%, p ¼ 0.059).
Simvastatin
The interval from statin start date to 2014, the year of data review, did not differ between anti-HMGCR–
*
positive (mean 11 years before 2014, SD 6) and anti-
Type 2 DM
HMGCR–negative patients (mean 10 years before 2014, SD 5, p ¼ 0.65). The median duration of statin Age at diagnosis
therapy before the onset of muscle symptoms was 38 months in anti-HMGCR–positive patients. More patients in the anti-HMGCR–positive group were
Female
exposed to atorvastatin (86% vs. 43%, p < 0.001). 0
50
100
Odds Ratio
The vertical orange line ¼ 1; the blue dots indicate the odds ratio; the horizontal black lines indicate 95% confidence interval; the asterisk indicates p < 0.05. The plot shows the odds
Twenty-four patients, with equal frequency in both groups, had a history of treatment with multiple statins/combination therapy. In order to identify whether individual statins were associated with antiHMGCR myopathy, in the multiple regression anal-
ratios of variables associated with statin-induced anti-HMGCR myopathy. Rosuvastatin
ysis,
was designated as the base category for comparing the statins. DM ¼ diabetes mellitus.
regarding the exact dose of statins were available for
these
patients
were
excluded.
The
data
only 27 patients. However, there was no significant
JACC VOL. 68, NO. 2, 2016
Letters
JULY 12, 2016:234–9
difference in the proportion of patients who underwent high-intensity statin therapy in the 2 groups
Andrew L. Mammen, MD, PhD *Lisa Christopher-Stine, MD, MPH
(38% and 27% of anti-HMGCR-positive and -negative
*Division of Rheumatology
patients, respectively, p ¼ 0.69). Given the limited
Johns Hopkins University School of Medicine
sample, no conclusions regarding the association of
5200 Eastern Avenue, MFL Center Tower Suite 4500
statin intensity and anti-HMGCR–associated myop-
Baltimore, Maryland 21224
athy could be made.
E-mail: [email protected]
We employed multiple regression analysis for the analysis of 69 patients who had been treated with a single statin to identify independent variables that may be associated with the risk for the development of anti-HMGCR myopathy in statin-exposed patients. After adjusting for age and sex, type 2 diabetes mellitus and atorvastatin use (vs. rosuvastatin and simvastatin) were significantly associated with anti-HMGCR myopathy (odds ratio [OR]: 15.6, p ¼ 0.006, and OR: 14.3, p ¼ 0.005, respectively; both with notably wide confidence intervals) (Figure 1). In addition, we repeated the analysis with all participants and individual statins entered into the model as dichotomous variables. Again, atorvastatin and type 2 diabetes remained significant independent predictors of anti-HMGCR–associated myopathy (OR: 7.4, p ¼ 0.001, and OR: 3.8, p ¼ 0.023, respectively). Notably, the median duration of statin therapy before
the
onset of
muscle
symptoms
in
the
anti-HMGCR–positive group was 38 months. This finding suggests that long-term exposure to statins is likely required to trigger an autoimmune response in most cases (85% >6 months). Therefore, medical
http://dx.doi.org/10.1016/j.jacc.2016.04.037 Please note: This work was funded by the Huayi and Siuling Zhang Discovery Fund. The Johns Hopkins Rheumatic Disease Research Core Center, where the serum samples were processed and stored, is supported by NIH grant P30-AR-053503. Dr. Christopher-Stine has received personal fees from Walgreens, Novartis, Idera Pharmaceuticals, Ono Pharma UK, Marathon Pharmaceuticals, Medimmune/AstraZeneca, and Mallinckrodt; is a consultant for Medimmune, Optioncare, and Mallinckrodt; is on the advisory boards of Mallinckrodt and Novartis; and has intellectual property interest in the HMGCR assay licensed to Inova Diagnostics. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Drs. Basharat and Lahouti contributed equally to this work.
REFERENCES 1. Christopher-Stine L, Casciola-Rosen LA, Hong G, et al. A novel autoantibody recognizing 200-kd and 100-kd proteins is associated with an immune-mediated necrotizing myopathy. Arthritis Rheum 2010;62: 2757–66. 2. Mammen AL, Chung T, Christopher-Stine L, et al. Autoantibodies against 3-hydroxy-3-methylglutaryl-coenzyme A reductase in patients with statin-associated autoimmune myopathy. Arthritis Rheum 2011;63: 713–21. 3. Bohan A, Peter JB. Polymyositis and dermatomyositis (first of two parts). N Engl J Med 1975;292:344–7. 4. Bohan A, Peter JB. Polymyositis and dermatomyositis (second of two parts). N Engl J Med 1975;292:403–7. 5. Werner JL, Christopher-Stine L, Ghazarian SR, et al. Antibody levels correlate with creatine kinase levels and strength in anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase-associated autoimmune myopathy. Arthritis Rheum 2012;64:4087–93.
providers should be aware that statin-induced antiHMGCR myopathy may occur even after several years of continuous uneventful statin exposure. Our results indicate that statin-exposed patients with anti-HMGCR antibodies have severe skeletal muscle manifestations, specifically, hip flexor muscle weakness at presentation. In addition, type 2 diabetes mellitus and atorvastatin may be associated with a higher risk of development of this myopathy.
Effects of Prasugrel Versus Clopidogrel on Coronary Microvascular Function in Patients Undergoing Elective PCI
This study was exploratory with small numbers of patients. Further studies are needed to better characterize the risk factors for statin-induced antiHMGCR–associated myopathy. Pari Basharat, MD Arash H. Lahouti, MD Julie J. Paik, MD, MHS Jemima Albayda, MD Iago Pinal-Fernandez, MD, PhD Tanmayee Bichile, MD Thomas E. Lloyd, MD, PhD Sonye K. Danoff, MD, PhD Livia Casciola-Rosen, PhD
Microvascular impairment has been reported in patients on clopidogrel undergoing elective percutaneous coronary intervention (PCI) (1). The related potential mechanisms might include the high residual platelet reactivity observed in a substantial proportion of these patients pretreated with clopidogrel at the time of PCI (2,3). Alternatively, microvascular constriction could occur possibly as consequence of transient endothelial dysfunction related to impaired platelet response to clopidogrel (4). It is unknown whether prasugrel might exert a protective effect on microcirculation during elective PCI in patients with
235