Statins produce rhabdomyolysis through two distinct mechanisms - one is a direct toxic effect on muscles, and the other is the induction of autoantibodies to the enzyme HMGCR.
In 24%–45% of patients, antibodies against 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) are present in serum. Statin use is one potential trigger of HMGCR IMNM. Mixed evidence also suggests that HMGCR IMNM may be paraneoplastic. In other cases, the trigger is unknown.
CK levels.
For CK, the following sex-and age-adjusted upper limits of normal as described by George et al (M. D. George, N. K. McGill, and J. F. Baker, “Creatine Kinase in the U.S. Population: Impact of Demographics, Comorbidities, and Body Composition on the Normal Range,” Medicine 95, no. 33 (2016): e4344). is used:
White male 312 U/L, White female 188
Black male 712, Black female 323
Hispanic male 394, Hispanic female 207
Asian male 378, and Asian female 162
The direct toxic effect is non-immune self-limited statin related myotoxicity is common than the autoimmune (statin associated autoimmune myopathy) occurs in approximately 2 to 5 in every 100,000 statin users. It often occurs when there is a change in dose of a statin or when another drug that alters the metabolism of the statin, such as cytochrome P-450 3A4 inhibitor, is added to the regimen. It typically occurs <12 weeks of statin exposure. Patients usually complain of myalgias in the thighs and calves in ~25% of patients. Resolve <2 week after discontinuation. ~1/2 of patients tolerate a different statin with recurrence. Risk factors are old age, Asian descent, heavy exercise, low BMI, excess alcohol, low vitamin D, DM, thyroid dysfunction, renal or liver disease, and exposure to interacting drugs.
Also referred to anti-HMCR-ab associated necrotizing myopathy, as this entity can be seen with associated statin exposure. It has insidious onset and a protracted course. It can resemble classic inflammatory myopathies, including polymyositis, dermatomyositis, and then necrotizing autoimmune myopathies that arise from autoantibodies to the signal recognition particle or other muscle nucleic-acid or protein targets. Discontinuation of the statin does not improve the condition. The drug must be stopped and patients should not be rechallenged with any form of statin. Check anti-HMGCR-abs; usually high titers (reference rage, <20). A muscle biopsy could be performed. MRI, US, or EMG guidance may be used to enhance the likelihood of selecting an affected area of muscle. NCS are usually normal, EMG would show marked abnormal spontaneous activity indicating muscle membrane irritability. With activation of voluntary motor units a myopathic pattern is seen (short-duration, reduced amplitude, polyphasic and early recruitment of motor units.
Histopathology: The muscle histopathology in immune-mediated necrotizing myopathy is characterized by the presence of necrosis of muscle fibers or regeneration with a paucity of (if any) lymphocytic infiltrates. Although major histocompatibility complex class-1 upregulation, myofiber degeneration, necrosis, and macrophage infiltration can be seen in immune-mediated necrotizing myopathy (features similar to dermatomyositis), perivascular inflammation and perifascicular atrophy do not occur. There is mild variation in fiber size, with a few angulated and atrophic fibers. The endomysial regions show a slight increase in cellularity and a few degenerated fibers and nuclear bags. Immunohistochemical staining for CD68 (macrophage marker) shows mild macrophage infiltrate. There is usually no lymphocytic inflammation on immunohistochemical staining. PAS, ORO, and ATPase stains are normal. Macrophages are the most common type of inflammatory cell to be seen on muscle biopsy in patients with anti-HMCR-ab subtype of IMNM (NAM.
Treatment: In most patients, the disease is refractory to treatment with glucocorticoids alone. Therefore, recommended induction regiments typically consist of glucocorticoids and one or more disease-modifying antirheumatic drugs, which in mild-to-moderate cases include methotrexate, IVIg, rituximab, azathioprine, or mycophenolate mofetil. In severe or refractory disease IVIg and rituximab is used. IVIg is used successfully as monotherapy in some patients and is emerging as a first-line treatment. Younger patients have a worse prognosis than older patients and may benefit from aggressive treatment.
Prednisone 60 - 70 mg PO daily, IVIG 2 gm/kg over 2 days or 0.4 g/kg/day x 5 days, and/or rituxumab.
Maintenance IVIG q3-4 weeks, prednisone slow taper (usually over a year), rituximab.
Physical therapy has to be intensive and is the key component in recovery of patients with SAAM.
In patients with SAAM, the risk of cancer may be increased, albeit less than those with DM. Age-appropriate cancer screening should be performed.
An association has been established between statin induced myopathy and variations in the SLCO1B1 gene.
A genomewide scan yielded a single strong association of myopathy with the rs4363657 single-nucleotide polymorphism (SNP) located within SLCO1B1 on chromosome 12 (P=4×10−9). SLCO1B1 encodes the organic anion–transporting polypeptide OATP1B1, which has been shown to regulate the hepatic uptake of statins. The presence of this common variant to SLCO1B1 results in a significantly decreased ability to take up statins by the liver, less effectiveness of the statin in lowering ‘bad’ LDL cholesterol levels, higher blood levels after dosing, and an increased risk of myopathy. Studies show that people who have inherited one or two copies of a specific SLCO1B1 variant are up to 4.5-fold and 17-fold increased risk respectively for developing significant myopathy due to statins. Among patients taking 20 to 40 mg of simvastatin daily (or standard doses of other statins), the incidence of myopathy is typically low, only about 1 per 10,000 patients per year. In contrast, the risk of myopathy is increased in patients who take 80 mg of simvastatin daily (and some other high-dose statin regimens), as well as in those who are also receiving certain other drugs (e.g., cyclosporine and amiodarone). Hence, the use of those drugs in subjects who are taking such high doses of statins and who have the C allele of the rs4149056 polymorphism may produce particularly high risks of myopathy
SLCO1B1 Genotype Predicts Ability to Metabolize Statins, especially simvastatin. This is a pharmacogenomics test for the SLCO1B1 *5 (c.521T>C, p.V174A; rs4149056) allele. Presence of the *5 allele is associated with an increased risk for simvastatin-associated myopathy. In this case the amino acid valine at position 174 is replaced with the amino acid alanine (written as V174A or SLCO1B1*5). The protein produced from this version of the SLCO1B1 gene is less able to transport compounds into the liver, which leads to elevated levels of the compounds in the body. When statins are not efficiently transported into the liver, they build up in the body, and can cause a condition known as statin-induced myopathy. This condition causes fatigue, pain, tenderness, weakness, and cramping in muscles. People with the V174A polymorphism who take statin drugs have an increased risk of developing statin-induced myopathy.
DRB1*11:01 as a risk factor for anti–HMG-CoA reductase myopathy. DRB1*11:01 has been found in 70% of patients with anti–HMG-CoA reductase antibodies, but only in 15% of the general population, and may play a role in presenting the relevant HMG-CoA reductase peptides with exposure to statins that trigger an immune response.
Rosuvastatin is the statin to use in patients with myopathy with myalgia. Although all statins can cause myalgia and myopathy, most patients with self-limited statin myopathy can tolerate rosuvastatin at a low dose administered on alternate days.
Pravastatin is a statin which is not metabolized by the hepatic P450 enzyme system via CYP3A4 isozyme, so would not be susceptible to drug-drug interaction with verapamil, and risk of myopathy is less.
It would be advisable to change the statin to fluvastatin or rosuvastatin. In the PRIMO study the incidence of statin-induced muscle pain and cramps was found to be 5 % for fluvastatin, 10.9% for pravastatin, 14.9% for atorvastatin, and 18.2% for simvastatin. Alternative, Rosuvastatin, alternate day regimen or twice a week can be used.
Avoid drug interaction that can trigger statin-induced symptoms: erythromycin, clarithromycin, anti-fungal, CCB, vitamin E, grapefruit, red yeast rice (contains monacolin K which is chemically identical to lovastatin). If symptoms continue with these changes, then a 6 week drug holiday from all lipid lowering agents and monitor for symptoms. If symptoms abate, then low dose statin may be reintroduced
In addition to statin exposure, mixed evidence suggests that cancer may be a risk factor for HMGCR-positive IMNM, particularly in patients over 50 years of age. Some studies found 2.8–9.1 times the risk of cancer in patients with HMGCR IMNM within the period of 3 years before to 3 years after the diagnosis of IMNM, after controlling for age and sex.
In patients with a history of statin exposure, we advise against restarting any type of statin. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors can be used an alternative cholesterol lowering agent to statins in these patients without the risk of causing disease relapse.
Some sources also suggest taking a dietary history and advising against consuming foods or supplements that are natural HMGCR inhibitors (e.g., oyster and shiitake mushrooms, red yeast rice) as they may continue to drive the disease process.
Drugs Associated With an Increased Risk of Statin Muscle Toxicity
Amiodarone
Azole antifungals
Calcium channel blockers
Colchicine
Cyclosporine
Ezetimibe
Fibrates (eg, gemfibrozil)
Niacin
Protease inhibitors
Rapamycin
Sirolimus
Excessive intake of grapefruit juice
Treatment regimen for myositis:
IVIG can be used in the treatment of refractory myositis.
IVIG 2 g/kg over 5 days (0.4 g/kg/day x 5 days) in combination with prednisone 60 mg PO QAM after meal and assess response. This treatment is induction therapy and can be maintained until patient is back to normal strength or until improvement in strength has reached a plateau. Following this a rapid taper of prednisone by 5 to 10 mg every 2 weeks can be initiated. Once the dose is reduced to 20 mg every other day, taper by 5 mg every 2 weeks. If steroids are needed long-term pulsed dose steroids (IV Solumedrol) 1 g may be used, monthly.
Methotrexate, azathioprine, mycophenolate mofetil, and rituximab are other ISTs that can be used in addition to maintenance IVIg. These ISTs are often needed to suppress the autoimmune process that drives the disease. IVIg by itself although good for induction therapy does not make the immune disorder go away.
Continue PPI or start H2 blockers.
Low sodium, low-carbohydrate, high protein diet to avoid excessive weight gain, while on steroids.
QuantiFERON-TB Gold Plus test.
Bactrim for pneumocystis prophylaxis.
Baseline DEXA scan.
Calcium supplementation of 1 g/day and vitamin D 800 IU/day for prophylaxis against steroid-induced osteopenia.
Monitoring electrolytes and replacement of potassium PRN.
Monitoring blood glucose
Monitoring blood pressure
Ophthalmology evaluation to check for glaucoma and cataracts.
Monitor response based on objective clinical examination, and myopathy questionnaire score.
Monitor serum CK levels. Remission is nicely associated with normalizing CK and EMG.
Necrotizing myopathy panel (Mayo): anti-HMGCR-ab and anti-SRP.
Myositis-Specific Antibodies. They are highly specific for patients with PM, DM, anti-synthetase syndrome, necrotizing myositis, and overlap syndromes: Anti-Jo-1, Anti-PL-12, Anti-PL-7, Anti-OJ, Anti-EJ, Anti-SRP (part of necrotizing myopathy panel), Anti-Mi-2, Anti-TIF-1gamma/TIF-1alpha, Anti-MDA5, Anti-NXP-2 (MJ).
Anti-AChr-ab (MG eval).
Muscle biopsy can be considered following MRI of upper limbs to check for signal changes to obtain better yield.
Physical Therapy.
Effectiveness and Safety of IVIG for the Treatment of HMGCR Immune-Mediated Necrotizing Myopathy
Muscle & Nerve, 2025; 71:392–397
https://doi.org/10.1002/mus.28333
ABSTRACT
Introduction/Aims: Immune-mediated necrotizing myopathy (IMNM) is an autoimmune myopathy. We aimed to compare clinical outcomes in patients with antibodies against 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) treated on immunotherapy regimens with and without maintenance intravenous immunoglobulin (IVIG). The secondary aim was to assess outcomes in a subset that received IVIG monotherapy.
Methods: This was a retrospective longitudinal cohort study. Multivariate logistic regression was used to analyze the association between IVIG and the probability of reaching normal creatine kinase (CK) and normal/near-normal proximal muscle strength at 3-and 6-month follow-ups.
In patients treated with IVIG monotherapy, changes in CK and strength were analyzed using Wilcoxon signed rank tests.
Results: Patients treated with IVIG (n = 40) had higher odds of CK normalization at 6 months (OR 9.44, 95% CI 1.19–74.89, p = 0.03) although not at 3 months (p = 0.08) compared to patients not treated with IVIG (n = 13). Increased odds of normal/near-normal proximal muscle strength was not observed at 3 months (p = 0.14) or 6 months (p = 0.35). Subgroup analysis of patients on IVIG monotherapy (n = 15) showed a median CK reduction of 84.5% at 3 months (p < 0.001) and 95.7% at 6 months (p < 0.001). CK normalized in 40% by 6 months. Proximal muscle strength improved at 3 months (p = 0.003) and 6 months (p = 0.008). 76.9% had normal/near-normal proximal strength by 6 months.
Discussion: Patients treated with immunotherapy regimens that included IVIG were more likely to reach normal CK at 6 months. Maintenance IVIG monotherapy also induced marked improvements in CK and strength. IVIG monotherapy can be an effective first-line treatment for HMGCR IMNM
At 6 months, patients on maintenance IVIG (with or without other immunotherapy) were more likely to have normal CK after adjusting for potential confounders.
Normalization of CK reflects cessation of disease activity (myonecrosis) in IMNM.
Improvement in clinical strength lags behind CK decline. Another potential explanation is that patients who received IVIG may have had more muscle fibrosis and fatty replacement at baseline.
Normalization of clinical strength requires not only cessation of myonecrosis but also myoregeneration, which may be limited if there has already been extensive fatty replacement prior to immunotherapy.
As recovery of strength can be limited by permanent damage that occurs prior to starting therapy, normalization of CK may be a better indicator of treatment controlling the active disease process. While CK can also pseudo-normalize with extensive muscle damage that leaves few myocytes as sources of CK, this is unlikely to explain the CK normalization observed in this study as none of these patients had worsening clinical weakness, which might be expected with CK pseudo-normalization.
Patients on treatment regimens containing IVIG are able to tolerate lower doses of corticosteroids sooner.
Although the 2016 European Neuromuscular Centre guidelines recommends starting IVIG concurrently or within 1 month of starting corticosteroids depending on disease severity and response to steroids, other publications suggested that IVIG may also be effective as monotherapy.
If a clear trajectory of improvement is not observed by 6 months, additional or alternative immunotherapy should be considered.
While we highly suspect the liver test elevations are due to myositis itself as the LFTs are improving as the CPK improves, she could also have had DILI-AIH from statins as her LFTs have also improved off statin and on prednisone for myositis. We would recommend continued close monitoring of labs (monthly) and if LFTs go back up as muscle enzymes come down or as pred is tapered then may need to consider a liver biopsy to rule out DILI-AIH.
In regards to steroid sparing agents for her myositis, while I suspect MTX would be safe to use in general because it does not appear she has underlying chronic liver disease, I do think if her LFTs went up while on MTX that might confuse the overall picture. If cellcept is an option would recommend it's use first line for steroid sparing as it generally does not have any risk for DILI.