Myopathy: Selected Tests

Number: 0862

Policy

Aetna considers measurement of autoantibodies against 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (anti-HMGCR antibody testing) medically necessary to diagnose statin-associated autoimmune myopathy in statin-exposed persons with myalgias and elevated creatnine kinase (greater than 10 times the upper limit of normal) that persist for two months (or less if symptoms progress) after discontinuation of statins.

Aetna considers the following tests (not an all-inclusive list) experimental and investigational because their effectiveness has not been established:

• ADSSL1 mutations testing for diagnosis distal myopathy
• Home medical diagnostic tests (e.g., food allergy and intolerance testing, heavy metal/lead poisoning testing, and water testing) for the diagnosis of familial visceral myopathy
• Low-dose computed tomography for monitoring progression and regression of calcifications in juvenile idiopathic inflammatory myopathy
• Measurement of antinuclear matrix protein 2 antibody (anti-NXP2 Ab) for immune-mediated necrotizing myopathy
• Measurement of skeletal muscle ClC-1 expression for evaluation of statin myopathy
• Myoglobinuria Test Panel
• Pyrophosphate muscle scan in the evaluation of myalgia and myositis.

For SLCO1B1 testing for statin-induced myopathy, see CPB 0140 - Genetic Testing.

For myositis antibody panel, see CPB 0866 - Rheumatic Diseases: Selected Tests.

Background

Myalgia is muscular pain or tenderness. Muscle pain can also involve ligaments, tendons and fascia, the soft tissues that connect muscles, bones and organs together. Myositis is an inflammation or swelling of the muscles and may be caused by injury, infection or an autoimmune disorder.

Pyrophosphate Muscle Scan

The pyrophosphate muscle scan or scintigraphy, is a nuclear imaging technique evaluating the uptake of technetium-99m pyrophosphate to reflect muscle viability and activity. According to Rider and colleagues, 2002, several types of scintigraphy have been used to image the muscles of patients with idiopathic inflammatory myopathies, including antimyosin, ^99mtechnetium pyrophosphate, and ⁶⁷gallium, each demonstrating uptake in inflamed, but not atrophied, muscles. The clinical usefulness of scintigraphy in the assessment of myositis is not clear.

The Myoglobinuria Test Panel

The Myoglobinuria Test Panel is used for individuals with exercise intolerance related weakness, pain, cramping and idiopathic myoglobulinuria. The test, using muscle tissue, detects specific enzymes related to metabolic function. Diseases tested for include Phosphofructokinase deficiency (PFK), McArdle's disease, Tarui's disease, Phosphoglycerate kinase deficiency (PGK), Phosphoglycerate mutase deficiency (PGAM), Lactate Dehydrogenase deficiency (LDH), Glycogen, Phosphorylase A+ total deficiency (Ph), Phosphorylase B kinase deficiency (PhK), Carnitine Palmitoyltransferase 2 deficiency (CPT2) and Myoadenylate Deaminase deficiency (MAD). The Myoglobinuria Test Panel is a proprietary test of Athena Diagnostics. There is no clinical evidence to support the use of the Myoglobinuria Test Panel.

Home Medical Diagnostic Tests for Familial Visceral Myopathy

Familial visceral myopathy is a rare condition in which the duodenum is dilated and the muscles don't function normally; thus, affecting the movement of digestive waste material through the intestines. The symptoms of familial visceral myopathy are similar to that caused by an intestinal obstruction. However, there is a lack of evidence regarding the effectiveness of home testing (e.g., food allergy and intolerance testing, heavy metal/lead poisoning testing, and water testing) for the diagnosis of familial visceral myopathy.

SLCO1B1 Testing for Statin-Related Myopathy

Hou and colleagues (2015) noted that statin-related myopathy (SRM) is an important adverse effect of statin which is classically unpredictable. The evidence of association between solute carrier organic anion transporter 1B1 (SLCO1B1) gene T521C polymorphism and statin-related myopathy risk remained controversial.  These investigators examined this genetic association.  Databases of PubMed, Embase, Chinese Biomedical Literature Database (CBM), China National Knowledge Infrastructure (CNKI), Chinese Scientific Journals Database, and Wanfang Data were searched until June 17, 2015.  Case-control studies investigating the association between SLCO1B1 gene T521C polymorphism and SRM risk were included.  The Newcastle-Ottawa Scale (NOS) was used for assessing the quality of included studies.  Data were pooled by odds ratios (ORs) and their 95 % confidence intervals (CIs).  A total of 9 studies with 1,360 cases and 3,082 controls were included.  Cases of SRM were found to be significantly associated with the variant C allele (TC + CC versus TT: OR = 2.09, 95 % CI: 1.27 to 3.43, p = 0.003; C versus T: OR = 2.10, 95 % CI:  1.43 to 3.09, p < 0.001), especially when SRM was defined as an elevation of creatine kinase (CK) greater than 10 times the upper limit of normal (ULN) or rhabdomyolysis (TC + CC versus TT: OR = 3.83, 95 % CI:  1.41 to 10.39, p = 0.008; C versus T: OR = 2.94, 95 % CI:  1.47 to 5.89, p = 0.002).  When stratified by statin type, the association was significant in individuals receiving simvastatin (TC + CC versus TT: OR = 3.09, 95 % CI: 1.64 to 5.85, p = 0.001; C versus T: OR = 3.00, 95 % CI:  1.38 to 6.49, p = 0.005), but not in those receiving atorvastatin (TC + CC versus TT: OR = 1.31, 95 % CI:  0.74 to 2.30, p = 0.35; C versus T: OR = 1.33, 95 % CI:  0.57 to 3.12, p = 0.52).  The authors concluded that the available evidence suggested that SLCO1B1 gene T521C polymorphism is associated with an increased risk of SRM, especially in individuals receiving simvastatin.  Thus, a genetic test before initiation of statins may be meaningful for personalizing the treatment.

Hubacek and associates (2015) stated that gene SLCO1B1, encoding solute organic anionic transport polypeptide OATP1B1, belongs to the group of candidates potentially influencing statin treatment safety. OATP1B1 regulates (not only) the hepatic uptake of statins.  Its genetic variation was described as an important predictor of SRM in a cohort of patients treated with a maximum dose of simvastatin.  However, the impact of SLCO1B1 gene polymorphism on this risk in patients treated with other statins or lower doses of simvastatin needs to be assessed.  Therefore, these researchers performed the present study.  SLCO1B1 tagging rs4363657 polymorphism was analyzed in 2 groups of patients with dyslipidemia (treated with simvastatin or atorvastatin, 10 or 20 mg per day), subgroup with statin-induced myalgia (n = 286), and subgroup (n = 707) without myalgia/myopathy, and in 2,301 population controls without lipid-lowering treatment.  Frequency of the individual genotypes in patients with myalgia/myopathy (TT = 62.3 %, CT = 34.5 %, CC = 2.8 %) did not significantly differ (both p values over 0.19) from that in patients without muscle symptoms (TT = 61.4 %, CT = 32.9 %, CC = 5.7 %) or from the population controls (TT = 63.9 %, CT = 32.5 %, CC = 3.6 %).  Null results were also obtained for the dominant and recessive models of the analysis.  The authors concluded that in Czech patients treated with low statin doses, there is no association between SLCO1B1 gene polymorphism and risk of myalgia/myopathy.

ADSSL1 Mutations Testing for Diagnosis of Distal Myopathy

Park and colleagues (2017) examined the clinical manifestation in Korean patients with ADSSL1 mutations.  These researchers developed a targeted panel of 16 distal-myopathy genes and recruited a total of 12 patients with genetically undetermined distal myopathy.  They found 4 (33 %) with ADSSL1 mutations and 1 (8 %) with GNE mutations.  ADSSL1 mutations consisted of c.910G>A, c.1048delA and c.1220T>C mutations.  Patients with ADSSL1 mutations demonstrated distal muscle weakness in adolescence, followed by quadriceps muscle weakness in the early 30s.  All patients had mild facial weakness and 2 patients complained of easy fatigue while eating and chewing.  Vastus lateralis muscle biopsies revealed non-specific chronic myopathic features with a few nemaline rods.  Whole body muscle MR imaging showed more fatty replacement in the distal limb and tongue muscles than in the proximal limb and axial muscles.  The authors concluded that the findings of this study showed that ADSSL1 myopathy was not rare among distal myopathy patients of Korean origin, and expanded the clinical and genetic spectrum.  They suggested that the screening test of ADSSL1 gene should be considered for the diagnosis of distal myopathy.  These preliminary findings need to be validated in well-designed studies with larger sample size and different ethnic groups.

Anti-HMGCR Testing for Evaluation of Statin Myopathy

Mammen, et al. (2016) stated that autoantibodies against HMG-CoA reductase, the pharmacologic target of statins, are found predominantly in biopsy specimens from patients with necrotizing myopathy and much less frequently in specimens from patients with other muscle conditions. The author explained that these autoantibodies are associated with statin exposure. In patients who have myopathy after statin exposure, a positive test for anti–HMG-CoA reductase autoantibodies strongly supports the diagnosis of an autoimmune process. In antibody-negative patients, alternative diagnoses should be considered.

Ge et al (2015) determined the prevalence of anti-3-hydroxyl-3- methylglutaryl coenzyme A reductase (anti-HMGCR) antibodies in Chinese patients with idiopathic inflammatory myopathies (IIMs), and analyzed the clinical features of the antibody-positive IIM patients.  The presence of anti-HMGCR antibodies was detected in 405 patients with IIMs, 90 healthy controls, and 221 patients with other rheumatic diseases by using an ELISA kit.  Clinical data from anti-HMGCR antibody-positive and -negative patients were compared.  Long-term follow-up of the anti-HMGCR antibody-positive patients was conducted to evaluate the role of anti-HMGCR antibody in IIM disease prognosis.  Of the 405 IIM patients, 22 (5.4 %) were found to carry the anti-HMGCR antibody.  These IIM patients were predominantly female (73 %), and only 3 anti-HMGCR antibody-positive patients with IIM were exposure to statins.  Most patients experienced progressive onset, and presented with muscular weakness.  Dysphagia was observed in 50 % of the patients (p < 0.01), and 15 % of these patients experienced the complication of interstitial lung disease (ILD) (p > 0.05).  Mean creatine kinase (CK) levels were higher in antibody-positive patients than in antibody-negative patients (p < 0.05).  Muscle biopsies were available from 12 anti-HMGCR antibody-positive patients, 8 who experienced myofiber necrosis and showed very little or no evidence of inflammatory cell infiltrates in their muscle biopsies.  Of the 11 patients who were followed-up 2.5 to 29 months, 73 % experienced improvement after treatment.  A cross-sectional study showed that anti-HMGCR antibody levels were significantly associated with CK levels (r = 0.486, p = 0.026) as well as with Myositis Disease Activity Assessment (MYOACT) scores (r = -0.67, p = 0.003) during the initial visit.  However, changes in serum anti-HMGCR antibody levels did not correlate with changes in CK levels, Manual Muscle Testing 8 (MMT-8) scores or MYOACT scores in long-term follow-up.  The authors concluded that the major clinical features of anti-HMGCR antibody-positive Chinese IIM patients were muscle weakness and dysphagia, which were seen in patients with and without statin exposure.  This subtype of patients were responsive to immunosuppressive treatment and received good prognoses after treatment, but serum levels of the anti-HMGCR antibody do not correlate with disease activity.

Bergua et al (2016) noted that immune-mediated necrotizing myopathy (IMNM) is a newly identified subgroup of idiopathic inflammatory myopathies.  It is defined as a rare and severe disease, with symmetrical and proximal muscle weakness and a characteristic histology.  An autoimmune aspect of IMNM is suggested by its association with autoantibodies directed against signal recognition particle (SRP) and 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) in the majority of patients.  Statin use is strongly associated with anti-HMGCR-positive IMNM.  The pathophysiological mechanisms of this disease are still poorly understood, and as a result, no therapeutic strategy has been validated to date.  These investigators provided an overview of the current knowledge about epidemiology, clinical features, and pathophysiology of IMNM, as well as treatment strategies.  The authors concluded that IMNM is a subject of widespread interest, with quick and meaningful advances being made.  In recent years, huge progress has been made in terms of diagnosis and patient management.  However, the understanding of pathophysiological mechanisms and treatment strategies still requires further investigation.

Musset et al (2016) noted that in an effort to find naturally occurring substances that reduce cholesterol by inhibiting HMGCR, statins were first discovered by Endo in 1972.  With the widespread prescription and use of statins to decrease morbidity from myocardial infarction and stroke, it was noted that approximately 5 % of all statin users experienced muscle pain and weakness during treatment.  In a smaller proportion of patients, the myopathy progressed to severe morbidity marked by proximal weakness and severe muscle wasting.  Remarkably, Mammen and colleagues were the first to discover that the molecular target of statins, HMGCR, is an autoantibody target in patients that develop an IMNM.  These observations have been confirmed in a number of studies but, until today, a multi-center, international study of IMNM, related idiopathic inflammatory myopathies (IIM), other auto-inflammatory conditions and controls has not been published.  Accordingly, an international, multi-center study investigated the utility of anti-HMGCR antibodies in the diagnosis of statin-associated IMNM in comparison to different forms of IIM and controls.  This study included samples from patients with different forms of IIM (n = 1,250) and patients with other diseases (n = 656) that were collected from 12 sites and tested for anti-HMGCR antibodies by ELISA.  This study confirmed that anti-HMGCR autoantibodies, when found in conjunction with statin use, characterize a subset of IIM who are older and have necrosis on muscle biopsy.  The authors concluded that these data indicated that testing for anti-HMGCR antibodies is important in the differential diagnosis of IIM and might be considered for future classification criteria.

Pinal-Fernandez and Mammen (2016) described the spectrum of clinical, histological, and serological features in patients with IMNMs.  Autoantibodies recognizing the SRP or HMGCR define 2 unique subtypes of necrotizing myositis patient with distinct clinical features.  For example, the major histocompatibility class II human leukocyte antigen allele DRB111:01 is a strong immuno-genetic risk factor for developing anti-HMGCR autoantibodies whereas B5001 and DQA10104 are over-represented in patients with anti-SRP autoantibodies.  Furthermore, statin exposure is a risk factor only for anti-HMGCR autoantibodies.  And while skeletal muscle involvement is predominant in most patients with both autoantibodies, lung involvement appeared in approximately 20 % of anti-SRP-positive patients but is more rare in anti-HMGCR-positive patients.  Of note, approximately 20 % of anti-SRP and anti-HMGCR positive patients have significant lymphocytic infiltrates on muscle biopsy and thus would not be formally categorized as having IMNM; aside from this, these patients are clinically indistinguishable from other patients with the same autoantibody profile.  The authors concluded that anti-SRP and anti-HMGCR autoantibodies define unique populations of IMNM patients.  It may be more appropriate to subtype myositis patients based on these autoantibodies than on their muscle biopsy features.

In a cross-sectional, multi-center study, Hudson et al (2016) examined the frequency of autoantibodies to HMGCR in systemic sclerosis (SSc) and associations with inflammatory myositis and statin exposure.  A total of 306 subjects from the Canadian Scleroderma Research Group cohort who had complete data on statin exposure and serology for anti-HMGCR antibodies assayed by an addressable laser bead immunoassay (ALBIA) were included in this study. Descriptive statistics were used to summarize the baseline characteristics of the patients and to compare subjects with and without anti-HMGCR antibodies.  Four (1.3 %) subjects had anti-HMGCR antibodies.  None of the subjects with anti-HMGCR antibodies titers had a history of an inflammatory myositis or overlap with polymyositis/dermatomyositis, compared to 8.6 % and 2.0 % of those without anti-HMGCR antibodies, respectively.  In addition, none of the subjects with anti-HMGCR antibodies had past or current exposure to statins compared to 12 % of those with negative titers.  Anti-HMGCR antibodies are rare in SSc and are not associated with inflammatory myopathy or statin exposure.  The authors concluded that anti-HMGCR antibodies are unlikely to play a major role in inflammatory myopathy in SSc and anti-HMGCR antibodies can be present in subjects without exposure to statins.  Moreover, they stated that larger studies are needed to confirm these preliminary observations. 

Shovman et al (2017) stated that anti-HMGCR antibodies represent a characteristic serological feature of statin-exposed and statin-unexposed patients with IMNM.  These researchers evaluated anti-HMGCR antibodies in patients with suspected IMNM following statin exposure and patients with other autoimmune rheumatic diseases.  They examined the presence of anti-HMGCR autoantibodies in sera samples from 13 statin-exposed patients who were suspected of having IMNM, 38 patients with different inflammatory and autoimmune rheumatic diseases and 29 healthy subjects.  The autoantibodies were evaluated by 2 assays: a new chemiluminescence QUANTA Flash HMGCR kit utilizing BIO-FLASH system and QUANTA Lite® HMGCR ELISA kit; 12 samples from patients with suspicion for IMNM were found positive for anti-HMGCR antibodies by both assays.  Only 1 of the 13 samples that were found positive by ELISA was negative by CIA.  A very good qualitative correlation (κ = 0.95; 95 % confidence interval [CI]: 0.85 to 1.0) and quantitative agreement (Spearman's rho 0.87; p value < 0.0001; 95 % CI: 0.62 to 0.96) were found between these 2 assays.  All samples from healthy subjects and from the disease-controlled patient cohort were negative for anti-HMGCR antibodies.  In comparison with ELISA results, the CIA exhibited high sensitivity and specificity values of 92.3 and 100 %, respectively.  Receiver operating characteristic analysis for CIA and ELISA yielded area under the curve values of 0.99.  The authors concluded that the presence of anti-HMGCR antibodies may be a useful biomarker of IMNM in statin-exposed patients.

Low-Dose Computed Tomography for Monitoring Progression and Regression of Calcifications in Juvenile Idiopathic Inflammatory Myopathy

Calcinosis is a well-recognized complication in patients with juvenile inflammatory myopathy. Ibarra and colleagues (2016) stated that dystrophic calcifications may occur in patients with juvenile idiopathic inflammatory myopathy (JIIM) as well as other connective tissue and metabolic diseases, but a reliable method of measuring the volume of these calcifications has not been established.  In a pilot study, these researchers determined the feasibility of low-dose, limited-slice, computed tomography (CT) to measure objectively in-situ calcification volumes in patients with JIIM over time.  A total of 10 JIIM patients (8 juvenile dermatomyositis [JDM], 2 overlap syndrome) with calcifications were prospectively recruited over a 2-year period to undergo 2 limited, low-dose, 4-slice CT scans.  Calculation of the volume of calcifications used a CT post-processing work-station.  Additional patient data included: Disease Activity Scores (DAS), Childhood Myositis Assessment Scale (CMAS), myositis specific antibodies (MSA), and the tumor necrosis factor-alpha (TNFα)-308 promoter region A/G polymorphism.  Statistical analysis utilized the Pearson correlation coefficient, the paired t-test and descriptive statistics.  Subjects ( mean age of 14.54 ± 4.54 years) had a duration of untreated disease of 8.68 ± 5.65 months, MSA status: U1RNP (n = 1), PM-Scl (n = 1), Ro (n = 1, 4 indeterminate), p155/140 (n = 2), MJ (n = 3), Mi-2 indeterminate (n = 1), negative (n = 3); 4/8 JDM (50 %) were TNF-α-308 A+.  Overall, the calcification volumes tended to decrease from the 1st to the 2nd CT study by 0.5 cm3 (from 2.79 ± 1.98 cm3 to 2.29 ± 2.25 cm3).  The average effective radiation dose was 0.007 ± 0.002, 0.010 ± 0.005, and 0.245 mSv for the upper extremity, lower extremity and chest, respectively (compared to a standard chest x-ray -- 0.02mSV effective dosage).  The authors concluded that

1. the limited low-dose CT technique provided objective data about volume of the calcifications in JIIM;
2. measuring the volume of calcifications in an extremity was associated with minimal radiation exposure; and
3. this method may be useful to evaluate the effectiveness of therapies for JIIM dystrophic calcification. 

This pilot study had 2 main drawbacks:

1. small sample size (n = 10), and
2. the lack of information to provide validation of this method (intra- and inter-rater reliability, validity, responsiveness). 

European consensus guidelines on juvenile dermatomyositis (Enders, et al., 2017) recommends actively looking for calcinosis by manual palpation, with the use of plain radiographs where needed. The guidelines state that CT has been found to have no additional benefit over radiographs for detecting calcinosis.

Measurement of Skeletal Muscle ClC-1 Expression for Evaluation of Statin Myopathy

Camerino and colleagues (2017) noted that statin therapy may induce skeletal muscle damage ranging from myalgia to severe rhabdomyolysis.  Their previous pre-clinical studies showed that statin treatment in rats involves the reduction of skeletal muscle ClC-1 chloride channel expression and related chloride conductance (gCl).  An increase of the activity of protein kinase C theta (PKC theta) isoform, able to inactivate ClC-1, may contribute to destabilize sarcolemma excitability.  These effects can be detrimental for muscle function leading to drug-induced myopathy.  In a pilot study, these researchers studied the causes of statin-induced muscle side effects in patients in an attempt to identify biological markers useful to prevent and counteract statin-induced muscle damage.  These investigators examined 10 patients, who experienced myalgia and hyper-CK-emia after starting statin therapy compared to 9 non-myopathic subjects not using lipid-lowering drugs.  Western Blot (WB) analysis showed a 40 % reduction of ClC-1 protein and increased expression of phosphorylated PKC in muscle biopsies of statin-treated patients with respect to untreated subjects, independently from their age and statin type.  Real-time polymerase chain reaction (PCR) analysis showed that despite reduction of the protein, the ClC-1 mRNA was not significantly changed, suggesting post-transcriptional modification.  The mRNA expression of a series of genes was also evaluated.  MuRF-1 was increased in accordance with muscle atrophy, MEF-2, calcineurin (CN) and GLUT-4 transporter were reduced, suggesting altered transcription, alteration of glucose homeostasis and energy deficit.  Accordingly, the phosphorylated form of AMPK, measured by WB, was increased, suggesting cytoprotective process activation.  In parallel, mRNA expression of Notch-1, involved in muscle cell proliferation, was highly expressed in statin-treated patients, indicating active regeneration.  Also, PGC-1-alpha and isocitrate-dehydrogenase increased expression together with increased activity of mitochondrial citrate-synthase, measured by spectrophotometric assay, suggesting mitochondrial biogenesis.  Thus, the reduction of ClC-1 protein and consequent sarcolemma hyper-excitability together with energy deficiency appeared to be among the most important alterations to be associated with statin-related risk of myopathy in humans.  The authors concluded that it may be important to avoid statin treatment in pathologies characterized by energy deficit and chloride channel malfunction.  They stated that the findings of this pilot study validated the measure of ClC-1 expression as a reliable clinical test for assessing statin-dependent risk of myopathy.

Table: CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+":
CPT codes covered if selection criteria are met:
83520	Immunoassay for analyte other than infectious agent antibody or infectious agent antigen; quantitative, not otherwise specified [Measurement of autoantibodies against 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (anti-HMGCR antibody testing)]
CPT codes not covered for indications listed in the CPB:
Low- dose computed tomography, measurement of antinuclear matrix protein 2 antibody (anti-NXP2 Ab) - no specific code:
83615	Lactate dehydrogenase (LD), (LDH)
84311	Spectrophotometry, analyte not elsewhere specified
HCPCS codes not covered for indications listed in the CPB:
A9538	Technetium Tc-99m pyrophosphate, diagnostic, per study dose, up to 25 millicuries
ICD-10 codes covered if selection criteria are met:
G72.0	Drug-induced myopathy
ICD-10 codes not covered for indications listed in the CPB (not all inclusive) :
G71.00 - G71.09	Muscular dystrophy
G72.49	Other inflammatory and immune myopathies, not elsewhere classified [Immune-mediated necrotizing myopathy]
G72.89	Other specified myopathies [juvenile idiopathic inflammatory myopathy]
M60.000 - M60.9	Myositis
M79.10 - M79.18	Myalgia
M79.7	Fibromyalgia

The above policy is based on the following references: