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* From the Department of Medicine and Pediatrics (Drs. Liebhaber and Wright), UCLA School of Medicine, Los Angeles, CA; Department of Medicine (Drs. Gelberg and Kupperman), USC School of Medicine, Los Angeles, CA; and Santa Barbara Medical Foundation Clinic (Dr. Dyer), Santa Barbara, CA.
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Abstract |
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 TOP Abstract Materials and MethodsResultsDiscussionReferences |
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Key Words: HMG-CoA reductase inhibitors • hypersensitivity • pneumonitis • statin
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Materials and Methods |
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TOPAbstractMaterials and MethodsResultsDiscussionReferences |
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Results |
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Patient 2
A 69-year-old woman who is an ex-smoker with a history of
hypertension and type II diabetes mellitus was referred to the clinic
for an evaluation of a cough. She had been taking pravastatin, 20 mg to
40 mg daily, for 6 years. Additional medications included glyburide,
oxaprozin, conjugated estrogen, medroxyprogesterone, levothyroxine,
chlorpheniramine, ipratropium, albuterol, and triamcinolone. Her chest
radiograph and sinus CT scan were negative. She was given IM
methylprednisolone acetate, 160 mg, and methylprednisolone sodium
succinate, 125 mg, and she was told to take pseudoephedrine and
beclomethasone nasal spray. One week later she was better, and
spirometry showed mild obstruction. Loratidine was then added to her
medications. One month later, her symptoms worsened, and she was
prescribed ranitidine for suspected reflux esophagitis. Her spirometry
and barium swallow were normal. She became much worse 6 weeks later,
and she was started on prednisone, 60 mg daily. She improved briefly,
and her dosage of prednisone was lowered to 40 mg daily. But she
subsequently began to cough despite her daily doses of prednisone. A
repeat chest radiograph and sinus CT scan were normal. However, a
high-resolution CT (HRCT) scan showed evidence of alveolitis with
ground-glass haziness (Fig 1
,
top). Her ESR measured 101 mm/h, and her
angiotensin-converting enzyme test, ANA test, antineutrophilic
cytoplasmic antibody test, hypersensitivity assay for common antigens,
mycoplasma titers, chlamydia titers, and quantitative immunoglobulins
were normal. Also, her diffusing capacity was markedly reduced. The
prednisone was stopped. Her open-lung biopsy was consistent with
hypersensitivity pneumonitis (Fig 2
). The pravastatin was then stopped, and her cough resolved 2
weeks later. A follow-up HRCT scan (Fig 1 , bottom) 7 weeks
after the first one showed complete resolution of her alveolitis.
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Patient 4
A 66-year-old man had a six-vessel bypass for severe coronary
artery disease with left ventricular dysfunction. Lovastatin, 20 mg
daily, was given for moderately severe lipid abnormalities. Additional
medication included nifedipine, lisinopril,
hydrochlorothizide/triamterene, and aspirin. Four years later, the
patient complained of fatigability, somnolence, and joint pain. His
sedimentation rate measured 32 mm/h and increased to 72 mm/h, with a
positive ANA at 1:160 nucleolar pattern. His shortness of breath
continued despite the increase in his dosage of dexamethasone to 1 mg
daily and his use of bronchodilators. His symptoms of dyspnea and
muscle and joint pain gradually resolved over 2 months only after
lovastatin was discontinued.
Patient 5
A 76-year-old woman with ischemic heart disease and aortic valve
disease had an aortic valve replacement along with coronary artery
bypass surgery. The patient was started on lovastatin, 20 mg daily, and
1 year later began to complain of muscle aches. Her creatine
phosphokinase and sedimentation rate were normal. Two years later, she
developed joint pain and then developed psoriasis. Despite nonsteroidal
anti-inflammatory therapy, steroids, and methotrexate, she developed
dyspnea. Inhaled steroids and bronchodilators were prescribed. She also
developed back pain and depression. She then had a small myocardial
infarction and a failed left internal mammary artery graft. Lovastatin
was discontinued, and she had a gradual improvement of her dyspnea,
arthralgia, myalgias, and back pain over a 2-month period.
Patient 6
An 80-year-old woman with severe coronary artery disease and
hypercholesterolemia had been treated with simvastatin, 10 mg daily,
for 3 years. She began having exertional dyspnea that did not appear to
be related to her coronary artery disease. Her sedimentation rate
gradually increased from 13 to 89 mm/h over 15 months. Simvastatin was
discontinued, and her exertional dyspnea improved with an associated
decrease in the sedimentation rate to 23 mm/h over the subsequent 3
weeks.
Patient 7
A 49-year-old man with hypercholesterolemia was treated with
pravastatin, 40 mg daily, for 4 years. During this period, he had
generalized itching and urticaria, along with swelling of his fingers
and feet. His ANA test was positive at 1:80 and had a speckled pattern.
The sedimentation rate, anti-DNA, and microsomal antibodies were
normal. He was treated with cetirazine, 10 mg daily. Pravastatin was
discontinued, and the itching and swelling gradually resolved over the
subsequent month.
Patient 8
A 77-year-old woman was treated with pravastatin, 10 mg daily, for
3 years. During this period, she had generalized itching with
urticaria. Her ANA test was positive at 1:160 homogeneous with strong
cytoplasmic staining, and her sedimentation rate measured 54 mm/h.
Additional medications included propranolol. Her symptoms cleared 1
month after discontinuing the pravastatin, and her sedimentation rate
decreased to 48 mm/h.
Patient 9
A 53-year-old man with a history of coronary angioplasty and
rotational atherectomy developed angioedema of the eyelids and a
sensation of airway closing within 6 months of beginning to take
pravastatin, 40 mg daily. He took diphenhydramine for relief.
Additional medications included isosorbide mononitrate, diltiazem,
aspirin, alprazolam, and multivitamins. His serum complement, complete
blood count, sedimentation rate, and ANA test were normal. His symptoms
gradually resolved 30 days after discontinuing the pravastatin.
Patient 10
A 73-year-old man with hypercholesterolemia developed intense
pruritis and urticaria after taking pravastatin 20 mg daily for 3
years. His sedimentation rate was normal. However, the ANA test was
positive at 1:80. His rash resolved 12 days after discontinuing
pravastatin.
Table 1 summarizes the clinical characteristics of the reported 10 patients.
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Discussion |
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TOPAbstractMaterials and MethodsResultsDiscussionReferences |
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The metabolism of statin medications is quite complex and still not completely understood. Lovastatin, simvastatin, and atorvastatin are metabolized by the cytochrome P-450 system, resulting in primarily hydroxylated metabolites.7 In contrast, pravastatin is not metabolized by the cytochrome system and is unique because it has a sulfated metabolite.8 The role that metabolites of statin medications have in causing manifestations of hypersensitivity is unclear. HMG-CoA reductase inhibitors have been reported to cause a lupus-like syndrome similar to that caused by medications such as procainamide and quinidine.9 ,10 However, the metabolism of statins is different from that of procainamide and quinidine.11 The mechanism of a lupus-like syndrome associated with statins is also unknown, and, therefore, any similarity with other drugs causing similar reactions is unknown as well. Simvastatin not only caused a lupus-like syndrome, but it also resulted in death in at least one patient previously reported in the literature.9
It is important for clinicians to recognize these manifestations of hypersensitivity because they have not been commonly associated with these medications. Our patients experienced symptoms that were insidious in onset and were frequently delayed for years, with delays lasting 6 months to 6 years. After we saw a few such patients experiencing urticaria, our suspicions heightened. Clinicians may attribute cough and dyspnea to other causes. However, we feel that when a careful search fails to find a cause for complaints in patients taking these medications, HMG-CoA inhibitors should be considered as a possible cause.
The finding of hypersensitivity pneumonitis in case 2 has been suggested by two previous reports.3 ,4 Our case and the previously reported case of simvastatin-associated lung disease4 are similar in that both deal with normal chest radiographs and yet very abnormal HRCTs. As such, a normal chest radiograph should not preclude clinical suspicion of disease caused by these medications. Our case differs from the two previously reported cases of statin-associated lung disease because our patient survived and had an earlier stage of lung injury. The findings on HRCT were very graphic and unexpected. The rapid improvement in the HRCT after withdrawal of the statin medication dramatically highlights the response we have typically seen in our patients. With the report of these three cases, we feel that hypersensitivity pneumonitis and interstitial pneumonitis should be considered in any patient taking a statin medication with unexplained dyspnea.
Case 3 was probably the most dramatic because of the severe left ventricular dysfunction, which improved markedly after withdrawal of the statin medication. In this instance, the effects of the statin medication were potentially fatal. Likewise, we are unaware of any similarly reported effect of statin medication on cardiac function.
In summary, we report 10 patients who developed hypersensitivity-type reactions after taking statin medications for extended periods of time. In all instances, symptoms improved rapidly after withdrawal of the medications. Additionally, we report a case of biopsy-proven hypersensitivity pneumonitis secondary to an HMG-CoA inhibitor. We feel it is important for clinicians to recognize early symptoms of statin drug hypersensitivity because they are potentially life-threatening.
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Footnotes |
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Received for publication April 7, 1998. Accepted for publication July 31, 1998.
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This article has been cited by other articles:
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  J-M. Naccache, M. Kambouchner, F. Girard, M. Antoine, A. Parrot, J. Piquet, M. Brauner, and D. Valeyre Relapse of respiratory insufficiency one year after organising pneumonia Eur. Respir. J., December 1, 2004; 24(6): 1062 - 1065. [Full Text] [PDF]
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 K. LeBlanc and M. T. Brophy Simvastatin Ann Intern Med, June 17, 2003; 138(12): W-53 - W-53. [Full Text] [PDF]
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S. Lantuejoul, E. Brambilla, C. Brambilla, and G. Devouassoux Statin-induced fibrotic nonspecific interstitial pneumonia Eur. Respir. J., March 1, 2002; 19(3): 577 - 580. [Abstract] [Full Text] [PDF]
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