Statins and myositis: the role of anti-HMGCR antibodies

Abstract

Muscle toxicity is a recognized adverse effect of statin use. Recently, a new myositis syndrome was described in association with antibodies directed against the pharmacologic target of statins, anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase (anti-HMGCR antibody). The patient’s genetic background, characteristic histologic patterns (immune-mediated necrotizing myopathy), and presence of anti-HMGCR antibodies define the syndrome. In most patients, statin discontinuation is insufficient to reverse the myositis symptoms, and immunosuppressive therapy is needed. The mechanisms by which these antibodies may lead to disease are not fully elucidated. Several important questions remain unsolved and warrant further research.

KEYWORDS:

• anti-HMGCR
• immune mediated necrotizing myopathy
• myalgia
• myositis
• statins

Statins are extensively prescribed lipid-lowering drugs that have contributed to increase survival rates in patients with cardiovascular disease.[1] A major drawback of these useful drugs is muscle toxicity, which affects a considerable number of patients and results in treatment discontinuation in 5–20%.[2] Myalgia, mild serum CK elevation and rhabdomyolysis are well-recognized musculoskeletal manifestations related to administration of these drugs.

Recently, Mammen et al. [3] described a new autoantibody directed against the pharmacologic target of statins, 3-hydroxy-3-methylglutaryl-coenzyme A reductase, known as anti-HMGCR antibody, whose detection enabled identification of a new type of statin-associated myopathy. This condition is characterized by a specific genetic background, recognized as HLA-DRB1*11:01,[4] and a characteristic pathology pattern of scattered muscle necrosis and regeneration, with few endomysial inflammatory infiltrates of CD4+ and CD8+ T cells and plasmacytoid dendritic cells. In addition to these distinctive features, sarcolemmal complement deposition on the surface of non-necrotic muscle fibers, and discrete macrophage infiltrates with MHC-I expression in necrotic and non-necrotic muscle fibers have been observed in these patients. This aggregation of features is described as a statin-associated immune-mediated necrotizing myopathy (IMNM) with anti-HMGCR antibodies.[5] Interestingly, the manifestations of the anti-HMGCR clinical syndrome mainly affect the skeletal muscle; the cutaneous or pulmonary involvement of other major types of inflammatory myopathies is lacking.

Several laboratory techniques have been developed to detect anti-HMCGR antibody, with ELISA, addressable laser bead immunoassay and in-house developed or commercial immunoblotting being the most easily accessible.[6,7] Laboratory technicians should be aware that when anti-HMCGR is determined by ELISA, the test may yield false-positive results in patients with anti-cortactin antibody, another recently described myositis-associated antibody.[8] Therefore, confirmation of positive ELISA results by immunoblotting is mandatory. Immunoprecipitation, the first technique used to detect anti-HMCGR, may have a role for confirmatory purposes, despite its complexity. Indirect immunofluorescence studies seem to show a characteristic pattern and could be used as a general screening method in clinical practice.[6]

Anti-HMGCR antibodies enable identification of another type of myopathy that may require immunosuppressive therapy to improve the typical symptoms of severe proximal muscle weakness. Terminating statin administration is usually inadequate, as the muscle damage initiated in the presence of statins may be sustained even after the statin is discontinued, through persistently increased HMGCR expression associated with muscle repair.[3] The seemingly odd persistence of symptoms even after drug removal is not unique to statin-associated IMNM with anti-HMGCR antibodies. In clinical practice, noninflammatory statin myalgia and/or mildly elevated creatine kinase (CK) can also last for a lengthy period after statin discontinuation. This puzzling delay warrants further research into the intrinsic mechanisms of statin-induced muscle toxicity, muscle biology and the pathogenesis of inflammatory muscle disease.

Large epidemiologic studies have demonstrated that neither statin-associated myalgia nor moderately high CK levels (less than fivefold the normal value) without muscle weakness are associated with anti-HMGCR antibodies.[9] Therefore, as occurs with other myositis-specific autoantibodies (e.g., anti-TIF1γ in patients with cancer-associated myositis or anti-MDA5 in clinically amyopathic dermatomyositis with rapidly progressive interstitial lung disease [10]), anti-HMGCR determination delineates a subgroup of patients in which both statin withdrawal and immunosuppressive therapy may be needed to achieve a favorable clinical response.

Interestingly, several other groups around the world, from Europe to Australia, have made similar discoveries related to anti-HMGCR antibodies, although the findings differ due to differences in the study designs and methods used.[11–15] Evidence has emerged of a pathogenic role for anti-HMGCR antibodies, as high levels of these antibodies positively correlate with serum CK value and the severity of muscle weakness.[16] Nevertheless, the mechanism that links autoimmunity to statins has not been entirely clarified by the current hypothesis that statin exposure increases HMGCR expression and may be accompanied by aberrant proteolysis of this molecule. This theory suggests that the protein peptides released as a consequence would be displayed by antigen-presenting cells via HLA class II molecules, thereby promoting an immune response in the context of continuous statin exposure. Immune-mediated muscle necrosis derived from this process could enhance the growth of regenerative muscle fibers, which would consequently express HMGCR in excess; the activity of anti-HMGCR antibodies against this antigen would thus close the vicious circle of injury and autoimmunity.[5]

Most patients with statin-associated IMNM require several lines of immunosuppressive therapy, and often immunosuppression must be maintained over a prolonged period to avoid relapses. It may be possible to wean patients from immunosuppressive therapy after they show an improvement for 6 months to 1 year with treatment. In mild cases, patients occasionally improve spontaneously after statin removal, making administration of immunosuppressive agents unnecessary. Choosing the best therapy or combination of therapies at the right time is a complicated task in this group of patients, and large prospective studies defining the efficacy of available treatments are lacking.

Unexpectedly, 30–50% of patients with anti-HMGCR antibodies and IMNM have never received statins,[3,11] and these patients are reported to be more refractory to immunosuppressive treatment than statin-exposed anti-HMGCR patients. Alimentary sources of statins such as red yeast rice or oyster mushrooms may be the hidden trigger in this subset of patients, but further research is needed to fully understand the specific phenotype of this subgroup. In addition, one recent report has shown that patients with other inflammatory myopathies, such as polymyositis or dermatomyositis (exposed or not to statins), may also develop anti-HMGCR, a finding that also requires further research.[13] It may be that statins act as trigger for autoimmunity that is expressed as IMNM, polymyositis or dermatomyositis, in all cases with positive testing to anti-HMGCR antibodies. The presence of microvascular deposition of membrane–attack complex in some patients further argues for this possibility.[15]

Nevertheless, the major contribution of anti-HMGCR antibody from the clinician’s viewpoint is that it enables identification of a group of patients who may benefit from immunosuppressive therapy in the appropriate clinical scenario (high pretest probability). This scenario would include subacute proximal muscle weakness in a patient treated with statins and having the typical genetic background (HLA-DRB1*11:01), with muscle biopsy showing muscle fiber necrosis, minimal inflammation and MHC-I expression in necrotic and non-necrotic fibers (features of IMNM).

Several questions remain to be solved. What triggers IMNM in anti-HMGCR-positive patients who have not been exposed to statins? Why are these patients refractory to treatment? What is the best treatment or combination of treatments for these patients? And, in patients at high cardiovascular risk (e.g., recent myocardial infarction), is it feasible to administer statins again? What would be the benefit–risk ratio?

These and other questions that will undoubtedly arise over time can only be answered through large prospective patient series from different centers and countries. Therefore, physicians devoted to the study of these fascinating rare diseases should seize the opportunity to join in an effort that will lead to a better understanding of these conditions. The time is right, so let’s do it!

Financial & competing interests disclosure

This study was funded in part by a grant from the Spanish Ministry of Health and Consumer Affairs (PI15-02100). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Acknowledgments

The authors would like to thank Cassie Parks for her critical reading and suggestions.

Additional information

Notes on contributors

Albert Selva-O’Callaghan

Marcelo Alvarado-Cardenas

Ana Marin

Iago Pinal-Fernandez