The n e w e ng l a n d j o u r na l of m e dic i n e

Case Records of the Massachusetts General Hospital

Founded by Richard C. Cabot

Eric S. Rosenberg, M.D., Editor
Virginia M. Pierce, M.D., David M. Dudzinski, M.D., Meridale V. Baggett, M.D.,
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Case 22-2019: A 65-Year-Old Woman

with Weakness, Dark Urine, and Dysphagia
Mason W. Freeman, M.D., Ajay K. Singh, M.D., Amanda C. Guidon, M.D.,
Sheila L. Arvikar, M.D., Robert H. Goldstein, M.D., Ph.D.,
and Nathan F. Clement, M.D.​​

Pr e sen tat ion of C a se

Dr. Doll L. Golden (Medicine): A 65-year-old woman was admitted to this hospital From the Departments of Medicine (M.W.F.,
because of falls, weakness, dark urine, and difficulty swallowing. S.L.A., R.H.G.), Radiology (A.K.S.), Neu‑
rology (A.C.G.), and Pathology (N.F.C.),
Approximately 35 years before the current admission, the patient underwent Massachusetts General Hospital, and the
staged male-to-female sex reassignment surgery at another hospital, with orchiec- Departments of Medicine (M.W.F., S.L.A.,
tomy, penectomy, and urethral fixation, followed by scrotoplasty and vaginal R.H.G.), Radiology (A.K.S.), Neurology
(A.C.G.), and Pathology (N.F.C.), Harvard
construction. Estrogen therapy was prescribed. Medical School — both in Boston.
Seventeen months before the current admission, a friend found the patient on
N Engl J Med 2019;381:275-83.
the floor of her apartment, unable to speak or to move her face, arm, or leg on DOI: 10.1056/NEJMcpc1900589
the left side. Emergency medical services took the patient to a second hospital, Copyright © 2019 Massachusetts Medical Society.

where computed tomographic (CT) angiography reportedly revealed changes con-

sistent with ischemic stroke in the territory of the right middle cerebral artery. Six
hours later, the patient was transferred to this hospital. Examination revealed
aphasia and weakness of the face, arm, and leg on the left side.
Dr. Ajay K. Singh: CT angiography performed at the second hospital had shown
a lack of opacification of the right middle cerebral artery. On the same day, mag-
netic resonance imaging (MRI) of the head and magnetic resonance angiography
performed at this hospital (Fig. 1A) confirmed the presence of acute ischemic
stroke in the territory of the right middle cerebral artery. There was occlusion of
the right middle cerebral artery, which had caused acute infarction of the right
supramarginal gyrus, angular gyrus, insula, corona radiata, and putamen, with
small hemorrhages in the corona radiata and putamen. Diffusion-weighted MRI
(Fig. 1B) revealed restricted diffusion in the territory of the right middle cerebral
artery.
Dr. Golden: Transthoracic echocardiography revealed a left ventricular ejection
fraction of 32% and dilatation of the left atrium and left ventricle, without intra-
cardiac thrombus, valvular disease, or intracardiac shunting. Cardiac MRI revealed

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 The n e w e ng l a n d j o u r na l of m e dic i n e

A B

C D

Figure 1. Initial Neuroimaging Studies.

Seventeen months before the current admission, time‑of‑flight magnetic resonance angiography was performed;
an image shows nonvisualization of the right internal carotid artery and some of the right M2 branches (Panel A,
arrow). Diffusion‑weighted MRI was also performed; an image shows restricted diffusion in the territory of the right
middle cerebral artery (Panel B, arrowheads), including the right caudate body and corona radiata (Panel B, arrow).
At the time of the current admission, CT of the head was performed without the administration of intravenous
contrast material; images show evidence of the previous infarcts in the territory of the right middle cerebral artery
(Panel C, arrow) and right external capsule (Panel D, arrowheads).

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 Case Records of the Massachuset ts Gener al Hospital
late gadolinium enhancement in a linear pattern
in the subepicardial and midwall areas, spanning
multiple coronary distributions, a finding that
is most consistent with previous myocarditis. A
cardioembolic mechanism of stroke was suspect-
ed; estrogen therapy was stopped, and aspirin,
atorvastatin, and furosemide were started. Six
weeks later, residual weakness of the left bicep
and hip flexor persisted; warfarin was started.
Six months before the current admission, the
patient presented to this hospital with a fall and
worsening of weakness on the left side, which
followed 2 weeks of coryza, nonproductive cough,
dyspnea on exertion, and edema of the legs.
Imaging studies were obtained.
Dr. Singh: Magnetic resonance angiography and
CT angiography revealed changes consistent with
chronic infarcts in the territory of the right
middle cerebral artery but no acute infarction.
Ultrasonography of the legs and CT performed
with a pulmonary-embolism protocol after the
administration of intravenous contrast material
were negative for thrombus.
Dr. Golden: Transthoracic echocardiography re-
vealed a left ventricular ejection fraction of 31%,
and coronary angiography revealed normal coro-
nary arteries. A device for cardiac resynchroni-
zation therapy was implanted.
The dyspnea on exertion improved, but then
3 months before the current admission, insidious
progressive generalized weakness and fatigue
developed. The patient noted that basic daily
activities, such as getting dressed, were “burden-
some” and caused “exhaustion.” Two weeks be-
fore the current admission, she had difficulty
swallowing a communion wafer at church, and
later that night, she had difficulty swallowing
solids and liquids. Dysphagia persisted; she ate
soft foods such as bread and peanut butter and
would cough after sipping liquids. Weakness
increased, and she had muscle pains; she had
difficulty hanging up coats, standing up from a
seated position (which led her to use her arms
to pull herself up), putting on shoes and socks,
and lifting her leg to get into a car. One week
before the current admission, she had a mechan-
ical fall in which her legs felt weak and “gave
out.” She fell onto her left side and was on the
ground for approximately 15 minutes. She was
evaluated by emergency medical services but was
not taken to the hospital. Four days later, she
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noted darkening of her urine, and a friend
thought she had a transient episode of slurred
speech. After friends noticed other episodes of
slurred speech and the patient had further pro-
gression of weakness, she was brought to the
emergency department of this hospital.
A review of systems revealed urinary urgency,
bowel movements with soft stool every 2 to 3 days,
and chronic mild pruritus on the back. The pa-
tient reported that she had had early satiety and
overall disinterest in food since the stroke, and
she had lost 24 kg. She reported no fevers, chills,
night sweats, vision changes, diplopia, difficulty
hearing, ataxia, numbness, headache, dyspnea,
wheezing, orthopnea, odynophagia, dysuria, nau-
sea, vomiting, new rash, or bruising.
The patient’s medical history included hyper-
tension, nonischemic cardiomyopathy, glaucoma,
ileus (which had led to sigmoidoscopy and intes-
tinal decompression), colonic polyps (which had
led to polypectomy), and degenerative disease of
the cervical spine. Medications included aspirin,
apixaban, atorvastatin, furosemide, hydralazine,
isosorbide dinitrate, metoprolol succinate, spirono­
lactone, docusate, and omeprazole, as well as
latanoprost and timolol eye drops. Angiotensin-
converting–enzyme inhibitors had caused angio-
edema, and heparin had caused immune throm-
bocytopenia. The patient had not recently
traveled outside New England; she lived alone
and worked as an administrator. She walked
with a cane at baseline. She did not use alcohol,
tobacco, over-the-counter or herbal medications,
or illicit substances. Her father had died of myo-
cardial infarction at 79 years of age, her mother
had hypertension and osteoarthritis that had led
to a hip replacement, her brother had received a
diagnosis of prostate cancer when he was in his
50s, and her sister had sarcoidosis.
The patient appeared thin and had mild dysar-
thria. The temperature was 37.4°C, the pulse 67
beats per minute, the blood pressure 98/54 mm Hg,
the respiratory rate 16 breaths per minute, and
the oxygen saturation 97% while she was breath-
ing ambient air. The abdomen was protuberant
but soft and nontender. Neurologic examination
was notable for reduced strength in the upper
arms, with 4/5 strength in the left deltoid, triceps,
and biceps and 4+/5 strength in the same muscle
groups on the right side. Grip strength was 4+/5
bilaterally. There was reduced strength in the
277
 The n e w e ng l a n d j o u r na l
legs, with 5−/5 hip flexion bilaterally and 5−/5
knee extension and flexion on the left side. Ankle
dorsiflexion and plantar flexion were normal
bilaterally. There was slight pronator drift on the
left side. Reflexes were 1+ and symmetric through-
out. The gait was wide-based and described as
“cautious”; the Romberg sign was absent. There
was 1+ edema of the lower legs, which was
slightly greater on the left side than on the right
side. Results of the remainder of the examina-
tion — including tests of cranial-nerve function,
sensation to light touch and pinprick, and coor-
dination and evaluations of the neck, chest, and
abdomen — were normal and consistent with
results obtained during previous gender-affirma-
tion procedures.
The white-cell, differential, and platelet counts
and levels of hemoglobin, magnesium, globulin,
bilirubin, alkaline phosphatase, thyrotropin, and
antinuclear antibodies were normal, as were the
results of urine and blood toxicology screenings.
Other laboratory test results are shown in Table 1.
Dr. Singh: CT of the head performed without
the administration of intravenous contrast mate-
rial (Fig. 1C and 1D) revealed no new infarction
or hemorrhage. Ultrasonography of the lower legs
was negative for thrombus.
Dr. Golden: Intravenous normal saline was ad-
ministered, and the patient was admitted to this
hospital.
Diagnostic tests were performed.
Differ en t i a l Di agnosis
Dr. Mason W. Freeman: This 65-year-old woman
with a history of nonischemic cardiomyopathy
and embolic stroke affecting the left side of her
body presented with chronic progressive weak-
ness and fatigue, along with dysphagia. Her my-
algia was associated with worsening weakness
of her arm and leg muscles and with a loss of
core muscle strength. Several days before the
current admission to this hospital, she noticed
that her urine was dark, and she had an episode
of slurred speech. Physical examination con-
firmed the presence of diffuse muscle weakness,
but she could still walk with an unsteady gait,
was able to lift her arms and legs against grav-
ity and some resistance, and had mild dysarthria
with no evidence of cranial-nerve deficits, cogni-
tive impairment, or sensory loss. Imaging stud-
ies showed no evidence of a new stroke or intra-
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of m e dic i n e
cranial abnormalities other than the previous
infarcts in the territory of the right middle cere-
bral artery. Her laboratory findings were all unre-
markable except for a markedly increased creatine
kinase level of 20,793 U per liter and more mod-
est but still substantial elevations of the alanine
aminotransferase and aspartate aminotransfer-
ase levels. Markers of inflammation, including
the erythrocyte sedimentation rate and C-reactive
protein level, were within the normal range, as
were results of renal-function tests.
Rhabdomyolysis
The patient’s muscle weakness and pain com-
bined with the presence of dark urine and a
clinically significant elevation of the blood cre-
atine kinase level are most consistent with a diag-
nosis of rhabdomyolysis. Although rhabdomyol-
ysis is relatively easy to diagnose, the underlying
cause of the muscle breakdown is less straight-
forward to identify. Most cases of rhabdomyoly-
sis in the United States are caused by trauma
(due to crush injury), prolonged immobilization
or confinement, or less commonly, postsurgical
ischemia.1 The patient’s fall that occurred the
week before admission does not appear to have
been a clinically significant traumatic episode
and would not account for the much longer pro-
drome of muscle weakness that is described in
her medical history. Extreme muscle activity
caused by voluntary protracted exercise or invol-
untary stimuli, such as seizures or tetany, is not
described. The laboratory findings are not con-
sistent with a major metabolic disturbance that
could cause myopathy, such as hypocalcemia, hy-
pophosphatemia, hyponatremia, hypokalemia, or
hypothyroidism. The patient’s age and the ap-
parent absence of muscle problems before the
current illness also make any of the inborn
metabolic deficiency syndromes that affect glyco-
genolysis, glycolysis, or lipid metabolism unlikely.
The paucity of specific symptoms other than
muscle weakness and the absence of fever, of an
abnormal white-cell count, and of elevated in-
flammatory markers (e.g., a high erythrocyte
sedimentation rate and C-reactive protein level)
make an infectious cause of rhabdomyolysis un-
likely.
The remaining major causes of rhabdomyoly-
sis include drug- or toxin-induced muscle injury,
as well as chronic inflammatory or necrotizing
myopathies. Neuroleptic malignant syndrome,
 Case Records of the Massachuset ts Gener al Hospital

malignant hyperthermia, and serotonin syndromes Table 1. Laboratory Data.*

can be ruled out by the absence of any history of
exposure to drugs that produce these condi- Reference Range, On Admission,
Variable Adults† This Hospital
tions. Similarly, there is no history suggestive of
any recreational drug use, ingestion of heavy Blood
metals, or exposure to snake or insect venoms. Sodium (mmol/liter) 135–145 140
The patient was receiving one drug that is an un- Potassium (mmol/liter) 3.4–5.0 3.2
common cause of rhabdomyolysis, the 3-hydroxy-
Chloride (mmol/liter) 100–108 97
3-methylglutaryl coenzyme A reductase (HMGCR)
Carbon dioxide (mmol/liter) 23–32 28
inhibitor atorvastatin. Statins can produce rhab-
domyolysis through two distinct mechanisms — Urea nitrogen (mg/dl) 8–25 11
one is a direct toxic effect on muscles, and the Creatinine (mg/dl) 0.60–1.50 0.66
other is the induction of autoantibodies to the Glucose (mg/dl) 70–110 98
enzyme HMGCR. The direct toxic mechanism ap- Phosphorus (mg/dl) 2.6–4.5 3.0
pears to be more common than the autoimmune
Calcium (mg/dl) 8.5–10.5 9.6
mechanism, occurring in approximately 2 to 5 in
Total protein (g/dl) 6.0–8.3 7.5
every 100,000 statin users. Statin-associated toxic
myopathy often occurs when there is a change in Albumin (g/dl) 3.3–5.0 3.8
the dose of the statin or when another drug that Alanine aminotransferase (U/liter) 7–33 360
alters the metabolism of the statin, such as a Aspartate aminotransferase (U/liter) 9–32 813
cytochrome P-450 3A4 inhibitor, is added to the Creatine kinase (U/liter) 40–150 20,793
patient’s regimen.2
N-terminal pro–B-type natriuretic <900 2091
­peptide (pg/ml)
Statin-Associated Autoimmune Myopathy
Folate (ng/ml) >4.7 7.1
Statin-associated autoimmune myopathy typically
Vitamin B12 (pg/ml) >250 421
has an insidious onset and a protracted course.3-5
In patients with statin-associated autoimmune Erythrocyte sedimentation rate (mm/hr) 0–20 10
or toxic myopathy, the drug must be stopped to C-reactive protein (mg/liter) <8.0 3.0
enable recovery; however, patients with the auto- Urine
immune syndrome typically do not recover with Color Yellow Amber
cessation of the drug alone, whereas patients Clarity Clear Slightly cloudy
with the toxic syndrome often do. Thus, if a
pH 5.0–9.0 5.0
patient’s condition does not improve substan-
tially within 1 or 2 weeks after statin withdrawal, Specific gravity 1.001–1.035 1.035
the autoimmune cause must be considered. A key Glucose Negative Negative
diagnostic test is the detection of autoantibodies Ketones Negative Trace
that target HMGCR. Statin-associated autoim- Leukocyte esterase Negative Negative
mune myopathy can resemble classic inflamma-
Nitrite Negative Negative
tory myopathies, including polymyositis, dermato-
Blood Negative 3+
myositis, and the necrotizing autoimmune
myopathies that arise from autoantibodies to the Protein Negative 2+
signal recognition particle or to other muscle Erythrocytes (per high-power field) 0–2 0–2
nucleic-acid or protein targets.6 Leukocytes (per high-power field) <10 3–5
Because the patient had a protracted course
of muscle weakness and did not have a change * To convert the values for urea nitrogen to millimoles per liter, multiply by 0.357.
To convert the values for creatinine to micromoles per liter, multiply by 88.4.
in the statin dose or introduction of a drug that To convert the values for glucose to millimoles per liter, multiply by 0.05551. To
would be likely to produce an important drug– convert the values for phosphorus to millimoles per liter, multiply by 0.3229.
drug interaction at the time of the onset of To convert the values for calcium to millimoles per liter, multiply by 0.250.
† Reference values are affected by many variables, including the patient popu­
muscle-injury symptoms, I favor the diagnosis of lation and the laboratory methods used. The ranges used at Massachusetts
autoimmune myopathy rather than a direct toxic General Hospital are for adults who are not pregnant and do not have medi‑
effect of the statin. Withdrawal of the statin cal conditions that could affect the results. They may therefore not be appro‑
priate for all patients.
could be done, followed by a period of watchful

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 The n e w e ng l a n d j o u r na l
waiting. Alternatively, a muscle biopsy could be
performed immediately and blood could be tested
for the detection of autoantibodies to HMGCR.
Since I think a direct toxic effect of the statin is
an unlikely diagnosis in this patient and the
diagnosis is more likely to be statin-associated
autoimmune myopathy or another inflammatory
myopathy, I would perform a muscle biopsy, per-
haps with MRI guidance to enhance the likeli-
hood of selecting an affected area of muscle.
Although the patient could have polymyositis or
one of the other necrotizing autoimmune myopa-
thies, I suspect that the biopsy specimen would
show few signs of inflammation and that a blood
test would identify an elevated level of auto­
antibodies to HMGCR, confirming the diagnosis
of statin-associated autoimmune myopathy.
Dr . M a son W. Fr eem a n’s
Di agnosis
Statin-associated autoimmune myopathy.
Neurol o gic Te s t ing
Dr. Amanda C. Guidon: Because this patient had
rhabdomyolysis, we performed electrodiagnostic
studies to further investigate whether she had an
underlying myopathy or myositis, which may have
conferred a predisposition to rhabdomyolysis. In
patients with isolated rhabdomyolysis, the results
of nerve-conduction studies are typically normal
and recordings from needle electromyography of
muscle are either normal or show subtle features
suggestive of myopathy.7 The presence of marked
abnormal spontaneous activity or of motor-unit
potentials that appear substantially abnormal
(with low amplitude, short duration, polyphasia,
and early recruitment) suggests an underlying
muscle disorder.8 Recruitment is the orderly ac-
tivation of more motor units as effort increases.
In this patient, the results of nerve-conduc-
tion studies were essentially normal, as we had
expected. We then performed electromyography
of muscle groups that were weak in the patient
(including biceps and quadriceps, which could be
targets for biopsy) to further understand whether
myopathy explained the weakness and to delineate
the pattern of involvement. At rest, there was
abnormal spontaneous activity, which indicated
muscle-membrane irritability. With activation,
there were short-duration motor-unit potentials
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of m e dic i n e
with and without reduced amplitude, polyphasia,
and early recruitment.
In this patient, the pattern of abnormality on
electrodiagnostic studies suggested an underly-
ing “irritable myopathy.” Possible causes of irri-
table myopathy include inflammatory, dystrophic,
and toxic or necrotic myopathies, as well as
congenital and metabolic disorders.8 Additional
diagnostic blood testing and muscle biopsy were
performed.
Pathol o gic a l Discussion
Dr. Nathan F. Clement: The patient’s blood was sent
to a reference laboratory to be tested for auto-
antibodies to HMGCR by means of an enzyme-
linked immunosorbent assay, a test that is 94 to
95% sensitive and 99 to 100% specific.9,10 The
autoantibody titer was more than 200 IU per
milliliter (reference range, <20), which is strong
evidence for statin-associated myopathy.
After the antibody test, a biopsy of the right
biceps was performed. Microscopic examination
of the biopsy specimen revealed mild variation
in fiber size, with a few angulated and atrophic
fibers. The endomysial regions showed a slight
increase in cellularity and a few degenerated fi-
bers and nuclear bags but showed no evidence of
necrosis (Fig. 2A). Immunohistochemical stain-
ing for CD68 showed a mild macrophage infil-
trate (Fig. 2B). There was no lymphocytic in-
flammation on immunohistochemical staining.
Periodic acid–Schiff, oil red O, and ATPase stains
showed normal findings. Overall, the findings
were notable for the presence of a macrophage
infiltrate and the absence of necrosis.
Although evidence of necrosis would be ex-
pected in this scenario, it is not unusual for this
finding to be absent on muscle biopsy.11 The
absence of this finding probably reflects sam-
pling of a less-involved area of muscle. Macro-
phages are the most common type of inflamma-
tory cell to be seen on muscle biopsy in patients
with statin-associated autoimmune myopathy. In
one study, all 18 patients with myopathy associ-
ated with autoantibodies to HMGCR had macro-
phage infiltrates on muscle biopsy.12 Overall, the
findings in this patient — including the high
titer of autoantibodies to HGMCR and the pres-
ence of a macrophage infiltrate on muscle biopsy
— confirm the diagnosis of statin-associated
myopathy.
 Case Records of the Massachuset ts Gener al Hospital

Discussion of M a nagemen t readmitted to this hospital with exacerbation of

heart failure. One month later, IVIG was added
Statin-Associated Myopathy to her regimen since she had continued weak-
Dr. Sheila L. Arvikar: As mentioned previously, ness and a rising creatine kinase level while she
statins should be discontinued immediately in was receiving prednisone (40 mg daily). After 2
patients with suspected statin-associated myopa- months of IVIG treatment, the creatine kinase
thy. However, improvement after statin discon- level normalized. She continued to receive a
tinuation alone is rarely seen in patients with slowly tapering course of prednisone with ritux-
statin-associated autoimmune myopathy, unlike imab and monthly IVIG, as well as to undergo
in those with statin-associated toxic myopathy.
Most patients with statin-associated autoimmune
A
myopathy receive immunosuppression, often with
multiple therapeutic agents. The HMGCR pro-
tein is highly expressed in regenerating muscle
cells, providing a robust source of autoantigen
to perpetuate autoimmune responses even after
statins are discontinued.4 Statin-associated auto-
immune myopathy can be refractory and more
severe than other inflammatory myopathies,
and muscle atrophy can develop rapidly. Aggres-
sive immunosuppression at the onset may pre-
vent long-term disability.
Data from randomized clinical trials to guide
the management of statin-associated autoim-
mune myopathy are limited. In most patients,
the disease is refractory to treatment with gluco-
corticoids alone. Therefore, recommended induc-
tion regimens typically consist of glucocorticoids
B
and one or more disease-modifying antirheu-
matic drugs,9 which in mild-to-moderate cases
may include methotrexate, intravenous immune
globulin (IVIG), rituximab, azathioprine, or my-
cophenolate mofetil. In severe or refractory dis-
ease, IVIG and rituximab are used. IVIG has
been used successfully as monotherapy in some
patients and is emerging as a first-line treat-
ment.13 Finally, patient factors are considered.
Younger patients have a worse prognosis than
older patients and may benefit from aggressive
treatment.14 This patient received treatment with
prednisone (starting at 70 mg daily) and ritux-
imab instead of IVIG, given her history of throm-
boembolic disease and congestive heart failure,
which can be exacerbated by IVIG treatment. In
patients with statin-associated autoimmune my- Figure 2. Muscle-Biopsy Specimen.
opathy, the risk of cancer may be increased, albeit A muscle‑biopsy specimen (Panel A) shows mild varia‑
less than in those with dermatomyositis.4 At tion in fiber size, with a few atrophic fibers, degenerated
fibers, and nuclear bags (top inset, arrow) and increased
minimum, age-appropriate cancer screening
endomysial cellularity (bottom inset, arrows). No necro‑
should be performed. In this case, the results of sis is present. Immunohistochemical staining for CD68
prostate-cancer screening, mammography, and (Panel B) shows that the increased endomysial cellu‑
colonoscopy were unremarkable. larity is due to macrophage infiltration (inset, arrows).
Two weeks after discharge, the patient was

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 The n e w e ng l a n d j o u r na l of m e dic i n e

Table 2. Four Principles of Gender-Affirming Care.

Principle Description Example

Ask rather than assume.
Validate the patient’s gender identity.
See mistakes as opportunities to learn.
Remember that anatomy does not define
the patient.
Ask patients about their sexual orientation,
gender identity, and preferred name and
pronouns.
Mirror the language that the patient uses.
If you make a mistake with a patient, acknowl‑ “I’m sorry that I used ‘he’ instead of ‘they.’
edge it, apologize, and try to move on
­together.
Provide care related to the anatomy that is
present but still validate the patient’s
­gender identity.
“Hi, I’m Dr. Goldstein. I use ‘he’ and ‘him’
for pronouns. What’s your name and what
pronouns do you use?”
I’ll try my best to use the correct pro‑
nouns, and please let me know if I make
a mistake.”
Only 25% of transgender people have had a
gender-affirming procedure. For trans­
gender men who retain breast tissue and
a cervix, mammography and cervical
Papanicolaou (Pap) testing remain im­
portant cancer-screening methods.

intensive physical therapy, which is a key compo-
nent in the recovery of patients with statin-asso-
ciated myopathy.
Dr. Mark A. Matza (Medicine): Now, 2 years
after the initial hospitalization, the patient is
doing remarkably well. Her strength and swal-
lowing ability rapidly returned to her poststroke
baseline levels. The creatine kinase level has re-
mained within the normal range. The level of
autoantibodies to HMGCR has markedly de-
clined. Prednisone was tapered slowly over a
period of 1 year. IVIG infusions were discon-
tinued after 1 year. The final rituximab dose was
given 16 months after the initial dose. Her
strength, muscle enzyme levels, and inflamma-
tory markers have all remained stable. She has
remained in very good spirits.
A physician: Would you ever rechallenge this
patient with a statin?
Dr. Arvikar: Rechallenging patients who have
statin-associated autoimmune myopathy has not
been successful and is not recommended.
A physician: Did this person’s cross-sex hormone
therapy play a role in causing the disease or affect
the selection of and response to treatment?
Dr. Freeman: In a review of 12 cases of statin-
associated autoimmune myopathy,5 exactly half
the patients were female, so I do not know of
any evidence that suggests a difference between
sexes in risk. It seems unlikely that the patient’s
sex reassignment surgery or hormonal treatments
contributed to the development of myopathy.
A physician: Are there any additional lessons
we can learn from this case with respect to
gender-affirming care?
Dr. Robert H. Goldstein: This case provides an
opportunity to emphasize the importance of
gender-affirming care for transgender and gen-
der-diverse patients. Transgender is an umbrella
term that is often used to identify a person whose
gender identity and sex assigned at birth do not
correspond. Some people use the term gender
nonbinary or gender diverse, acknowledging
that gender identity and gender expression are
on a continuous spectrum rather than reflecting
a binary classification.
Nearly 1 in every 300 people in the United
States identifies as transgender or gender diverse,
and many struggle to gain access to gender-
affirming care.15,16 This includes routine health
care that is not related to gender identity, as well
as transition-related care. Barriers to care involve
socioeconomic factors (e.g., unemployment, low
annual income, or a lack of insurance coverage),
as well as health care–specific factors (e.g., patient
mistreatment by a health care provider, provider
discomfort, or provider inexperience).17,18 Per-
ceived discrimination in the health care setting
prevents transgender and gender-diverse people
from receiving medical care. When transgender
people fear discrimination in the health care
setting, they are less likely to seek primary care,
urgent care, or emergency services.19 Respecting
the four principles shown in Table 2 will help in
the delivery of effective and affirming care for
the transgender and gender-diverse community.
A nat omic a l Di agnosis
Statin-associated autoimmune myopathy.

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 Case Records of the Massachuset ts Gener al Hospital

This case was presented at the Medical Case Conference. potential conflict of interest relevant to this article was re-
Dr. Guidon reports receiving advisory board fees from Alex- ported.
ion Pharmaceuticals, consulting fees from Momenta Pharma- Disclosure forms provided by the authors are available with
ceuticals, and clinical trial support from Ra Pharma. No other the full text of this article at NEJM.org.

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