Treatment of immune-mediated necrotizing myopathy

INTRODUCTION — Immune-mediated necrotizing myopathy (IMNM), also referred to as necrotizing autoimmune myopathy (NAM), is a distinct subgroup of the idiopathic inflammatory myopathies (IIMs). Randomized trials assessing the efficacy and safety of various immunosuppressive regimens for treating IMNM are absent owing to the rarity of the disease. Management is largely based on expert opinion and information from case series that describe symptom improvement and declining creatine kinase (CK) levels with the use of immunosuppressive medications.

The management and prognosis of IMNM will be discussed in this topic. The clinical manifestations and diagnosis of IMNM, as well as other topics related to the idiopathic inflammatory myopathies, are presented separately:

●(See "Clinical manifestations and diagnosis of immune-mediated necrotizing myopathy".)

●(See "Overview of and approach to the idiopathic inflammatory myopathies".)

●(See "Pathogenesis of inflammatory myopathies".)

●(See "Clinical manifestations of dermatomyositis and polymyositis in adults".)

●(See "Diagnosis and differential diagnosis of dermatomyositis and polymyositis in adults".)

●(See "Initial treatment of dermatomyositis and polymyositis in adults".)

●(See "Management of refractory cutaneous dermatomyositis in adults".)

●(See "Clinical manifestations and diagnosis of inclusion body myositis".)

●(See "Management of inclusion body myositis".)

GENERAL PRINCIPLES

●Goals of therapy – The goal of therapy in patients with immune-mediated necrotizing myopathy (IMNM) is to achieve longstanding remission; however, given disease variability, this is often not possible and additional goals include the following:

•Decreasing muscle weakness

•Increasing endurance

•Minimizing atrophy and functional disability that is irreversible

•Addressing quality-of-life measures most meaningful to patient

●Principles of management – The following general principles are important to help guide therapy and achieve treatment goals:

•Initiate prompt, early therapy, which may improve clinical outcomes [1]

•Use an aggressive treatment strategy that often requires combination therapy

•Minimize long-term steroid use

•Titrate therapeutic immunosuppressive/immunomodulatory agents to the lowest possible doses once the disease is stabilized (preferably with full-strength and creatine kinase [CK] normalization)

•Encourage resistance exercises as tolerated as an adjunct to pharmacotherapy

•Evaluate for dysphagia and treat if necessary to avoid aspiration and maximize nutrition

INITIAL MANAGEMENT — There are no widely accepted standard practices, treat-to-target goals, or validated disease-specific patient-reported outcomes for immune-mediated necrotizing myopathy (IMNM). Treatment is largely based on expert opinion, limited observational data from cases of IMNM, and indirect evidence from the treatment of dermatomyositis and other inflammatory myopathies. Our approach is generally consistent with expert consensus-driven treatment guidelines for anti-signal-recognition particle (SRP) IMNM and anti-3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) IMNM that have been proposed [2]. No specific treatment guidelines for seronegative IMNM have been proposed.

Assessment of disease severity — Our approach to initial therapy depends in part upon the disease severity. Specific medication choices are also guided by antibody positivity (ie, anti-HMGCR or anti-SRP antibodies) when known. We define disease severity as follows:

●Severe disease – Patients with severe IMNM include those with severe or rapidly progressive weakness resulting in difficulty walking, dysphagia, respiratory failure, and/or other severe organ damage including rapid progression to muscle atrophy and fatty replacement.

●Non-severe disease – Patients with nonsevere IMNM include those who do not have difficulty walking, dysphagia, or other end-organ damage.

Severe disease — Most patients with severe IMNM will require prompt treatment with immunosuppressive therapy with a combination of glucocorticoids and either intravenous immunoglobulin (IVIG) or rituximab. The approach to immunosuppressive therapy is generally based on whether the patient is anti-SRP-positive or anti-HMGCR-positive. (See 'Anti-SRP-positive' below and 'Anti-HMGCR-positive' below and 'Seronegative or unknown antibody status' below.)

Anti-SRP-positive — For most patients with anti-SRP-positive IMNM, we suggest initial treatment with intravenous glucocorticoids combined with rituximab.

For patients with very severe disease, we suggest adding methotrexate to this regimen. Azathioprine or mycophenolate may be substituted for methotrexate when it is contraindicated or not tolerated. If there is an adequate clinical response within three to six months, then the glucocorticoids are tapered to the lowest possible dose as tolerated.

●Dosing and administration – We administer IV pulse methylprednisolone 500 to 1000 mg daily for three days prior to the initiation of oral glucocorticoids. Oral glucocorticoid therapy is then started at 0.5 to 1 mg/kg daily of prednisone (or its equivalent) and tapered gradually according to patient response to additional therapy with a glucocorticoid-sparing agent. Similar to other idiopathic inflammatory myopathies, prednisone is typically decreased by 20 to 25 percent of the existing dose monthly, with the goal of achieving a low daily dose (eg, prednisone 5 mg daily) or discontinuation by four to six months [3]. There are no standard glucocorticoid tapering regimens, but a reasonable approach is one that we use for dermatomyositis, which is described separately. (See "Initial treatment of dermatomyositis and polymyositis in adults", section on 'Glucocorticoid tapering'.)

Rituximab is typically administered as a dose of 1000 mg, given twice, two weeks apart, by IV infusion. However, some studies have suggested that a lower dose, either 500 mg given twice two weeks apart or 1000 mg given once, may be adequate. This approach is generally consistent with the dosing used for rheumatoid arthritis, which is discussed separately (see "Rituximab: Principles of use and adverse effects in rheumatoid arthritis", section on 'Initial dose'). Additional information regarding pretreatment testing, immunizations and response to vaccines, and adverse effects is presented separately. (See "Rituximab: Principles of use and adverse effects in rheumatoid arthritis", section on 'Immunizations and baseline studies' and "Rituximab: Principles of use and adverse effects in rheumatoid arthritis", section on 'Adverse effects'.)

Methotrexate is typically initiated at a dose of 10 to 15 mg/week, with increases in dose every two to eight weeks of 5 mg/week up to 25 mg/week. We use the same regimen and approach to titration as that used in rheumatoid arthritis. Additional information regarding dosing, pretreatment precautions, and adverse effects is presented separately. (See "Use of methotrexate in the treatment of rheumatoid arthritis", section on 'Dosing and administration' and "Major side effects of low-dose methotrexate".)

●Efficacy – The use of rituximab for patients with anti-SRP-positive disease is supported by observational data from case series, along with expert experience [4,5]. In a case series including eight patients with refractory anti-SRP-positive IMNM, six patients demonstrated a decrease in creatine kinase (CK) levels and improved strength with rituximab [5]. The patients included in the study had an inadequate response to various other therapies that included methotrexate, IVIG, mycophenolate and cyclophosphamide. In another larger case series in which treatments were individualized, 13 of 17 patients with anti-SRP-positive IMNM responded well to rituximab [4]. Some patients required retreatment after one year, and others recovered strength more than two years after the first dose.

The efficacy of methotrexate for IMNM is based on expert opinion, our clinical experience, case series, and its use in treating other inflammatory myopathies [6]. (See "Initial treatment of dermatomyositis and polymyositis in adults", section on 'Methotrexate'.)

Anti-HMGCR-positive — For most patients with anti-HMGCR-positive IMNM, we suggest treatment with intravenous glucocorticoids combined with IVIG. However, monotherapy with IVIG is a reasonable alternative and may be preferred in patients who are at increased risk of developing glucocorticoid-related side effects (eg, patients with diabetes). Methotrexate may also be added to this regimen.

●Dosing and administration – The dosing of glucocorticoids and methotrexate is described above. (See 'Anti-SRP-positive' above.)

We typically give a total of 2 g/kg of IVIG per month, often administered as 1g/kg divided over two consecutive days or as 0.4 g/kg divided over five consecutive days. IVIG is usually administered for at least five months and often must be continued for years. Serious adverse effects associated with IVIG include anaphylaxis, thromboembolic events, transfusion-associated lung injury, and others and are discussed separately. (See "Overview of intravenous immune globulin (IVIG) therapy", section on 'Adverse effects'.)

●Efficacy – The use of IVIG has been associated with partial and complete remissions in cases of anti-HMGCR-positive patients [1,6,7]. Monotherapy with IVIG in the absence of glucocorticoids has also been shown to be effective in some patients, especially those with a contraindication to steroid use, and can reduce complications in patients with comorbidities such as diabetes mellitus DM [8,9]. In the author’s experience, IVIG monotherapy has been effective in many cases.

●Use of statins – Reintroduction or initiation of statins should be avoided in patients with anti-HMGCR-positive IMNM given the potential risk of disease flare [10-12].

Seronegative or unknown antibody status — Patients with severe disease who are seronegative or have an unknown antibody status may be treated just as those with either anti-SRP-positive or anti-HMGCR-positive myopathy. The decision to treat with specific therapies (ie, rituximab or IVIG) depends on several factors including considerations regarding comorbidities, patient preferences, and availability of specific agents. As an example, IVIG should be avoided in patients with congestive heart failure or previous unprovoked deep venous thrombosis.

Nonsevere disease

●Initial therapy – For most patients with nonsevere IMNM, we suggest initial treatment with oral glucocorticoids in combination with methotrexate. Azathioprine or mycophenolate may be substituted for methotrexate if it is contraindicated or not tolerated. (See "Initial treatment of dermatomyositis and polymyositis in adults", section on 'Azathioprine' and "Treatment of recurrent and resistant dermatomyositis and polymyositis in adults", section on 'Mycophenolate mofetil'.)

Oral glucocorticoid therapy is typically started at 0.5 to 1 mg/kg/day of prednisone (or equivalent). Glucocorticoids are then gradually tapered to the lowest dose as tolerated in the same manner as described above for severe disease. (See 'Anti-SRP-positive' above.)

The dosing and rationale for using methotrexate is the same as that for severe disease. (See 'Anti-SRP-positive' above.)

●Subsequent treatment – For patients who do not adequately respond to initial therapy with glucocorticoids and methotrexate after three to six months, the subsequent choice of glucocorticoid-sparing agent depends upon whether the patient is anti-SRP-positive or anti-HMGCR-positive and generally follows the same approach as severe disease:

•For patients with IMNM who are anti-SRP-positive, we add rituximab to the initial treatment regimen and reassess the response after another three to six months. Rituximab is typically continued every six months for at least two years of well-controlled disease. (See 'Anti-SRP-positive' above.)

•For patients with IMNM who are anti-HMGCR-positive, we add IVIG to the initial treatment regimen. IVIG is typically dosed at 2 g/kg/month for at least five months and often must be continued for years. IVIG monotherapy in the absence of glucocorticoids may be effective in some patients. (See 'Anti-HMGCR-positive' above.)

Monitoring treatment response — The majority of patients with IMNM require long-term immunosuppressive therapy. When therapy is tapered off, the disease often flares. Most therapies are continued for at least one to two years. The goal is to use the lowest number of therapeutic agents needed to maintain remission.

All patients receiving immunosuppressive therapy for IMNM should be closely monitored. Monitoring response to therapy is mostly clinical and includes serial assessments of muscle strength and endurance. Clinicians should be aware that fatigability, decreased endurance, and sometimes pain can linger despite normal strength [13]. Many experts agree that improvement to a stable muscle strength that may not approximate baseline strength is still an indication of clinical response to therapy.

Patients should also be assessed for toxicity to the medication regimen (eg, adverse effects, infections due to immunosuppression).

We generally include the following labs during follow-up visits:

●CK

●Complete blood count

●Complete metabolic panel

CK levels often do not normalize, but we try to achieve a level below 1000 international units/L. While we aim for full remission of symptoms, it is possible that atrophy and fatty replacement of the muscles will persist from disease damage. Thus, there may be residual muscle weakness that is not amenable to further immunosuppressive therapy. Magnetic resonance imaging (MRI) can be instructive in such a situation as it can help distinguish fatty replacement within the muscles from persistent muscular edema. The presence of fatty replacement in the absence of edema would generally not mandate further aggressive treatment; however, because whole-body MRI is not routinely performed, it is conceivable that there could be residual inflammation elsewhere such as the upper extremities, Thus, if upper-extremity weakness and elevated CK persist, there may indeed be residual disease activity.

Rehabilitation — For all patients with IMNM, we suggest physical therapy. Exercise appears to be beneficial across all idiopathic inflammatory myopathy (IIM) subclasses [14,15]. Resistance exercises with light weights and increased repetitions are associated with a decreased immune response, increased aerobic metabolism, and decreased muscular atrophy [16]. Exercise induces microRNAs that target transcripts and proteins important for muscle and immune response.

In addition, referral to a speech therapist for diagnosis and management of dysphagia when present is imperative to maximize nutritional intake and to help prevent aspiration pneumonia.

RELAPSING OR REFRACTORY DISEASE — A clinical relapse is defined by a recurrence of signs or symptoms of active disease including weakness and elevated creatine kinases (CKs). In most cases of relapse, we typically restart an induction therapy that includes either rituximab or intravenous immunoglobulin (IVIG).

Patients with refractory disease are those who continue to have persistent weakness and/or elevated CKs despite optimal immunosuppressive therapy for an adequate period (usually up to six months). In such patients, it may be necessary to try alternative medications. Other medications that have been used include azathioprine, mycophenolate, and tacrolimus, although the evidence to guide choosing any specific agent is limited [2]. Plasmapheresis has been used in patients with refractory disease, but there are few published reports [17-19].

PROGNOSIS — The prognosis is variable among immune-mediated necrotizing myopathy (IMNM) patients; however, younger seropositive patients appear to fare worse clinically than older patients [4]. This is particularly notable in anti-signal-recognition particle (SRP) patients; younger patients are weaker at the first clinic visit and they remain weaker than older patients subsequently, even after accounting for confounders [4,20]. Disease severity appears to be increased in anti-SRP-positive myopathy and statin-naïve, younger, anti-3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR)-positive myopathy, and it is more destructive in females and African American patients [4,21].

However, with regard to anti-HMGCR-positive myopathy, younger patients are more often statin naïve; thus, it is unclear if the statin-naïve state or the younger age is the risk factor for worse prognosis. For example, one study noted that compared with statin-associated anti-HMGCR-positive IMNM, statin-naïve anti-HMGCR-positive IMNM patients more frequently required third-line therapy (50 versus 9 percent) and had a poor to fatal outcome (50 versus 0 percent) [22].

With regard to anti-SRP-positive myopathy, observational data have shown that the clinical risk factors for refractory patients include male sex (odds ratio [OR] 19.57), severe muscle weakness (OR 7.51), and concurrent interstitial lung disease (OR 39.7) [23]. On imaging, the rate of fatty infiltration of thigh muscles over three months was also predictive of refractory disease.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Dermatomyositis and polymyositis".)

SUMMARY AND RECOMMENDATIONS

●Goals of therapy – The goal of therapy is to achieve longstanding remission. However, this is not always achieved. Other treatment goals include (see 'General principles' above):

•Decreasing muscle weakness

•Increasing endurance

•Minimizing functional disability

•Improving quality of life

●Management – Most patients with immune-mediated necrotizing myopathy (IMNM) require long-term immunosuppressive therapy. When therapy is tapered off, the disease often flares. The goal is to use the lowest number of therapeutic agents needed to maintaining remission. Most therapies are continued for at least one to two years.

Treatment recommendations are based on expert opinion, limited observational data, and indirect evidence from the treatment of dermatomyositis and other inflammatory myopathies. (See 'Initial management' above.)

●Factors that guide initial therapy – Our approach to initial therapy depends upon the disease severity (see 'Assessment of disease severity' above):

•Severe disease – Patients with severe IMNM include those with severe or rapidly progressive weakness resulting in difficulty walking, dysphagia, respiratory failure, and/or other severe organ damage.

•Nonsevere disease – Patients with nonsevere IMNM include those who do not have difficulty walking or dysphagia.

Specific medication choices are also guided by antibody positivity (ie, anti-3-hydroxy-3-methylglutaryl coenzyme A reductase [HMGCR] or anti-signal-recognition particle [SRP] antibodies) when known.

●Treatment of severe disease – The approach to immunosuppressive therapy for patients with severe disease is generally guided by the patient’s autoantibody status.

•Anti-SRP-positive – For most patients with anti-SRP-positive IMNM, we suggest treatment with intravenous (IV) glucocorticoids combined with rituximab (Grade 2C). Methotrexate may be added to this regimen for patients with more severe disease.

If there is an adequate clinical response within three to six months, then the glucocorticoids are tapered to the lowest possible dose as tolerated. (See 'Anti-SRP-positive' above.)

•Anti-HMGCR-positive – For most patients with anti-HMGCR-positive IMNM, we suggest treatment with IV glucocorticoids combined with IVIG (Grade 2C). Methotrexate may be added to this regimen.

Glucocorticoids are tapered according to clinical response. (See 'Anti-HMGCR-positive' above.)

•Seronegative or unknown antibody status – Patients with severe disease who are seronegative or have an unknown antibody status are treated as those with either anti-SRP-positive or anti-HMGCR-positive myopathy. The decision to treat with specific therapies (ie, rituximab or intravenous immunoglobulin [IVIG]) depends on several factors including considerations regarding comorbidities, patient preferences, and availability of specific agents. (See 'Seronegative or unknown antibody status' above.)

●Treatment of nonsevere disease – For most patients with nonsevere IMNM, we suggest initial treatment with oral glucocorticoids in combination with methotrexate (Grade 2C). Azathioprine or mycophenolate may be substituted for methotrexate if it is contraindicated or not tolerated.

For patients who do not adequately respond to initial therapy with glucocorticoids and methotrexate after three to six months, the subsequent choice of glucocorticoid-agent depends upon whether the patient is anti-SRP-positive or anti-HMGCR-positive and generally follows the same approach as for severe disease. (See 'Nonsevere disease' above.)

•Other treatment considerations – Exercise appears to be beneficial; we refer all patients to physical therapy. In addition, referral to a speech therapist for diagnosis and management of dysphagia is imperative to maximize nutritional intake and to help prevent aspiration pneumonia. (See 'Rehabilitation' above.)

●Monitoring response to therapy – Monitoring response to therapy includes serial assessments of muscle strength and endurance. (See 'Monitoring treatment response' above.)

●Relapsing or refractory disease – In most cases of relapse, we typically restart an induction therapy that includes either rituximab or IVIG. (See 'Relapsing or refractory disease' above.)

●Prognosis – The prognosis is variable. Younger seropositive patients appear to fare worse clinically than older patients. (See 'Prognosis' above.)