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\begin{document}

\title{An Atorvastatin-induced positive anti-HMGCR immune-mediated necrotizing
myopathy case}



\author[1]{Nattanicha Chaisrimaneepan}%
\author[1]{Jerapas Thongpiya}%
\author[1]{Pitchaporn  Yingchoncharoen}%
\author[1]{Sakditad Saowapa}%
\affil[1]{Texas Tech University Health Sciences Center}%


\vspace{-1em}



  
  \date{June 09, 2024}


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\textbf{Introduction}

Statin belongs to a medication class of 3-hydroxy-3-methylglutaryl
coenzyme A reductase (HMGCR) inhibitor. It is the most significant drug
used for lipid-lowering and cardiovascular disease
prevention\textsuperscript{1}. A wide range of statin myopathy has been
reported including myalgia, myopathy, myositis, or rhabdomyolysis.
Statin-induced immune-mediated necrotizing myopathy (IMNM) is a
relatively rare side effect with an incidence of 2 or 3 of every 100,000
patients taking statins\textsuperscript{2}. Many different findings help
differentiate toxic non-inflammatory effects from immune-mediated
myopathy due to statins\textsuperscript{1}. We report a case of
statin-induced IMNM with oropharyngeal involvement.

\textbf{Case description}

A 56-year-old man with a past medical history of hypertension, and
hyperlipidemia, presented with progressive generalized weakness for 4
months. He had been on atorvastatin 40 mg daily for a few months before
the symptoms started. Atorvastatin was discontinued when he started
having weakness, which started with the slowing of his gait and
increased fatigue; and then, progressed to aching shoulders. He noticed
difficulty standing from a squatting position and later from a seated
position.

Despite stopping Atorvastatin, his symptoms continued to progress to the
point he was bed-bound, unable to roll on the bed without assistance. He
also complained of dysphagia which led to unintentional 60-pound weight
loss since the onset of his symptoms. Physical examination was notable
for generalized muscle wasting, proximal muscle weakness grade I-II/V,
and distal group grade III-IV/V on both upper and lower extremities.

\textbf{Methods:}

Blood chemistries were significant for elevated creatine kinase (CK) at
4,050 IU/L, c-reactive protein (CRP) at 13.8 mg/dl, erythrocyte
sedimentation rate (ESR) at 130 mm/hr, and elevated aldolase at 24
units/L. Liver enzymes were mildly elevated (AST 199 and ALT 119).
Creatinine level was low at 0.3 mg/dl. ANA was negative; C3 was normal
while C4 was slightly high. Table 1 summarizes the laboratory. The
thyroid function test was normal. Workup for idiopathic inflammatory
myopathy was negative including anti-Jo-1(Table 2). MRI of both lower
extremities with STIR demonstrated diffuse myositis of the left and
right thigh likely related to drug-induced myopathy but other infectious
or inflammatory myopathies cannot be excluded(figure 1.1-1.2). No
significant muscular fatty atrophy was observed on the MRI (figure
2.1-2.2).

Table 1 Summarization of laboratory during hospitalization.\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
\textbf{Lab} & \textbf{Normal range} & \textbf{On admission} &
\textbf{At discharge}\tabularnewline
ESR & 0-20 mm/hr & 130 & 45\tabularnewline
CRP & 0.0-0.5 mg/dl & 13.8 & 0.4\tabularnewline
Creatinine kinase & 26-308 IU/L & 4,050 & 660\tabularnewline
AST & 5-37 IU/L & 199 & 81\tabularnewline
ALT & 5-41 IU/L & 119 & 111\tabularnewline
Aldolase & [?] 8.1 unit/L & 24 & -\tabularnewline
C3 & 90-180 mg/dl & 179 & -\tabularnewline
C4 & 10-40 mg/dl & 57 & -\tabularnewline
\bottomrule
\end{longtable}

Table 2 Myositis profile\selectlanguage{english}
\begin{longtable}[]{@{}ll@{}}
\toprule
\textbf{Myositis profile} & \textbf{Result}\tabularnewline
MI-2 Autoantibodies & NOT DETECTED\tabularnewline
PL-7 Autoantibodies & NOT DETECTED\tabularnewline
PL-12 Autoantibodies & NOT DETECTED\tabularnewline
Ku Autoantibodies & NOT DETECTED\tabularnewline
EJ Autoantibodies & NOT DETECTED\tabularnewline
OJ Autoantibodies & NOT DETECTED\tabularnewline
SRP Autoantibodies & NOT DETECTED\tabularnewline
JO-1 Autoantibodies & \textless{}1.0 (negative)\tabularnewline
\bottomrule
\end{longtable}

A muscle biopsy of his right upper thigh was performed and later
revealed many necrotic and regenerating fibers indicating an active
myopathy. Small collections of mononuclear cells were present at
perivascular sites in the perimysium and a few mononuclear cells were
present at the endomysium surrounding necrotic or regenerating fibers.
The biopsy findings could represent necrotizing autoimmune myopathy.
Regarding the patient's clinical correlation, anti-body against HMGCR
was tested, which returned positive at 139.3 CU. The patient was
diagnosed with statin-induced immune-mediated necrotizing myopathy.

\textbf{Results}

He received combination therapy with intravenous immunoglobulin (IVIG)
1g/kg/day for 2 days, methylprednisolone IV high dose up to 500mg every
12 hours and tapering to oral prednisone 60 mg daily, and mycophenolate
mofetil titration up to 1,500mg oral twice a day. He was discharged to
an inpatient rehabilitation facility with oral prednisone and
mycophenolate mofetil. His CK level at discharge was 660 IU/L.

At the 3-month outpatient follow-up, prednisone had been tapered and
discontinued but he remained on mycophenolate mofetil. The patient was
able to walk and had significant improvement in oropharyngeal
dysfunction.

\textbf{Discussion}

Immune-mediated necrotizing myopathy (IMNM) can be caused by cancer,
viral infection, connective tissue diseases, and medications, especially
statin, anti-HMGCR, and anti-SRP autoantibodies, resulting in skeletal
muscle injury\textsuperscript{3}. Antibodies against HMGCR, the statins
target, are found more often in patients with necrotizing myopathy with
statin exposure; thus, the positive antibody supports the autoimmune
process\textsuperscript{2}. There have been many proposed mechanisms for
the pathogenesis underlying the statin-induced IMNM; however, the true
mechanism is not well understood \textsuperscript{2,4}.

Anti-HMGCR IMNM presents clinically as a subacute or chronic progressive
symmetrical proximal muscle weakness. Dysphagia, like our patient,
occurs in approximately one-third of patients. Muscle weakness persists
despite discontinuing statins and CK levels, usually exceeding 10 times
the upper normal limit\textsuperscript{1,2}. Extramacular manifestations
like those of dermatomyositis can be present\textsuperscript{5}.
However, malignancy-associated anti-HMGCR IMNM was unclear; there was no
statistically significant relation\textsuperscript{6,7}.

Musculoskeletal MRI and EMG can be done prior to antibody assay or
muscle biopsy. EMG usually shows signs of irritable myopathic patterns
but is not possible to differentiate the type of inflammatory myositis.
MRI with STIR sequence in statin-induced IMNM demonstrates diffuse and
symmetrical muscle edema and signs of fibro-adipose tissue
replacement\textsuperscript{2,3}. A report by Mammen proposed an
algorithm for evaluating potential cases of statin-associated autoimmune
myopathy\textsuperscript{2}. The presence of muscle necrosis and
regeneration with sparse inflammatory infiltrates on muscle biopsy are
the prominent histologic features\textsuperscript{2}.

There is no definite cutoff point on how long after taking statins
patients would develop IMNM---it can range from months to
years\textsuperscript{8}. In our case, the patient developed weakness a
few months after statin initiation and continued to deteriorate even
after statin discontinuation. Compared to other statins, atorvastatin
was more frequently reported to be a cause of statin-induced IMNM,
likely due to its high lipophilic property resulting in better
penetration to peripheral and liver tissues\textsuperscript{9}. Symptoms
are milder at onset 50-60 years old while younger patients appear to be
more severe and, regardless of statin use, are more recalcitrant to
treatment.\textsuperscript{7}

Serum levels of the anti-HMGCR antibody are correlated with creatinine
kinase and inversely associated with the degree of muscle
weakness\textsuperscript{7,10.} However, anti-HMGCR titers remain
positive even in the remission of the disease and CK level normalizes.
Together with being a more expensive test, there is no need to monitor
anti-HMGCR levels practically\textsuperscript{7}.

No definite guideline has been available on how long a patient should be
on the treatment. The first step is to discontinue statins. Unlike
self-limited forms of statin myopathy, statin-induced IMNM very rarely
improves spontaneously after stopping statins. Only a few reported
statin-induced IMNM patients with positive anti-HMGCR antibodies
spontaneously resolved\textsuperscript{2}. The most common therapy is
prednisolone combined with at least another agent like methotrexate,
azathioprine, or mycophenolate mofetil\textsuperscript{5,6,8}. IVIg or
rituximab can be added to support the treatment but preferentially
IVIG\textsuperscript{3,11,12} Our case, the patient received triple
therapy which comprises IVIg, systemic corticosteroids, and a
non-steroidal immunosuppressant, which has been described as in the
literature\textsuperscript{2,5}. Symptom resolution time was
approximately twelve months and might take longer in females at 16
months\textsuperscript{9}. Most of the patients responded well to
immunosuppressive treatment. Symptoms monitoring is required following
tapering doses of immunosuppressants due to the autoimmunity which may
cause disease relapse.

Statins are contraindicated in this group of patients. To substitute the
need for statins, aside from fenofibrate or ezetimibe, proprotein
convertase subtilisin/kexin type 9 (PCSK9) inhibitors can be used and
are safe in patients with anti-HMGCR myopathy\textsuperscript{9}.

\textbf{Conclusion}

A patient presenting with ongoing symmetrical muscle weakness after
statin discontinuation with elevated CK levels should have anti-HMG-CoA
reductase antibodies checked. Together with positive anti-HMGCR and
supporting evidence of MRI or muscle biopsy consistent with necrotizing
myopathy, the diagnosis of statin-induced IMNM is highly suspicious.
This should lead to the initiation of immunosuppressive therapy and
long-term follow-up.

\textbf{AUTHOR CONTRIBUTIONS}

Nattanicha Chaisrimaneepan:~Resources; writing -- original draft;
writing -- review and editing.

Jerapas Thongpiya: Conceptualization; resources; writing-original draft;
supervisation

Pitchaporn Yingchoncharoen: validation

Sakditad Saowapa: Validation

\textbf{ACKNOWLEDGEMENT}

Not applicable

\textbf{FUNDING INFORMATION}

The authors did not receive financial support for the research,
authorship, and/or publication of this article.

\textbf{CONFLICT OF INTEREST STATEMENT}

There are no conflicts of interest to declare.

\textbf{CONSENT}

Verbal and written consent was obtained from the patient to publish this
case.

\textbf{References}

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\tightlist
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\end{enumerate}\selectlanguage{english}
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