Management of inclusion body myositis

INTRODUCTION — Sporadic inclusion body myositis (IBM) is classified along with polymyositis, dermatomyositis, and autoimmune necrotizing myopathy as one of the idiopathic inflammatory myopathies. However, despite some histologic similarities, the clinicopathologic manifestations, treatment, and prognosis of IBM are clearly distinct from the other disorders (table 1). (See "Clinical manifestations of dermatomyositis and polymyositis in adults" and "Initial treatment of dermatomyositis and polymyositis in adults" and "Treatment of recurrent and resistant dermatomyositis and polymyositis in adults".)

The treatment and prognosis of IBM will be reviewed here. The clinical manifestations and diagnosis are presented separately. (See "Clinical manifestations and diagnosis of inclusion body myositis".)

GOALS OF THERAPY — The primary goal of therapy in inclusion body myositis (IBM) is to optimize muscle strength and function. Given the slowly progressive and variable course of the disease, it can be quite challenging to determine if treatment leads to an objective improvement in or stabilization of muscle strength [1]. It is well known that immunosuppressive medications will lower muscle enzyme levels in IBM patients despite continued progression of weakness, and also that creatine kinase (CK) levels decrease with muscle atrophy [2,3]. Therefore, CK levels cannot be used to monitor response to therapy in this disease. Based on the existing data, we only consider a trial of immunosuppressive medications in IBM patients with an atypical presentation or in patients with another autoimmune disease.

OUR APPROACH — Almost all patients with any degree of limitation in activities of daily living will benefit from physical and occupational therapy evaluation. Patients with dysphagia should be evaluated by a speech therapist. Exercise is likely beneficial in all patients. In contrast to other inflammatory myopathies such as dermatomyositis and polymyositis, inclusion body myositis (IBM) is relatively resistant to standard immunomodulatory therapies [4,5]. However, there is limited evidence that some subgroups of patients may benefit from such therapy, in particular those with another systemic autoimmune disease such as Sjögren's disease or systemic lupus erythematosus [6-8]. We typically suggest a trial of immunosuppressive treatment when the diagnosis of IBM is uncertain, or in cases where there appears to be overlap with polymyositis as evidenced by early and prominent proximal weakness (ie, neck flexors, arm abductors, hip flexors). (See 'Immunosuppressive therapy in selected patients' below.)

Nonpharmacologic therapy — The optimal treatment for IBM is not known, and most interventions have demonstrated only limited benefit. Nonpharmacologic interventions such as physical therapy, occupational therapy, and/or speech therapy can be helpful in all patients to achieve the following:

●Provide an exercise program to maintain strength as long as possible

●Address concerns about falling and the use of orthoses and assistive devices such as canes (preferably four-point canes) and walkers

●Address difficulties with the activities of daily living such as finger flexor weakness

●Help learn techniques to minimize the risk of aspiration in patients with dysphagia

●Provide nutritional support or dietary counseling in patients with dysphagia or obesity, respectively

Exercise — All IBM patients should be evaluated by a physical therapist with experience in neuromuscular diseases to develop an individualized exercise program. We favor the combined aerobic and functional muscle strengthening program that is described in a study of IBM patients [9]. Increasing evidence has shown that exercise is beneficial in IBM [9-12]. Since strenuous exercise has long been known to elevate muscle enzyme levels, there has long been a theoretical but unfounded concern that exercise could accelerate muscle damage in myositis. However, data suggest that frequent, low resistance, endurance exercises are not harmful and in fact are likely beneficial. Although strengthening exercises focus on muscles that are minimally to moderately weak, passive range-of-motion exercises for severely weak muscles are also important to prevent joint contractures. Patient education is critical to avoid tendon injuries and to manage delayed-onset muscle soreness and fatigue with exercise. At our center, we have seen improvement in muscle strength in IBM patients with a supervised exercise program, and we recommend reevaluation by a therapist every four months to assess and potentially adjust the exercise regimen. For ambulatory patients who are unwilling or unable to participate in a regimented daily home exercise program, we recommend frequent, low-impact aerobic exercise such as aquatherapy or use of stationary bike.

Ambulation and fall prevention — Gait difficulties and falls are a major source of morbidity in IBM, and older adult patients with gait instability or a history of falls are at high risk for significant falls and fractures. Falls usually occur due to quadriceps weakness causing knees to buckle while standing, turning, or stepping. We refer all patients with prior falls to physical therapy for education regarding interventions to minimize risk of falls. (See "Falls in older persons: Risk factors and patient evaluation" and "Falls: Prevention in community-dwelling older persons".)

Many patients will benefit from assistive devices such as a cane or walker. Patients with foot drop should be evaluated for ankle foot orthoses (AFOs) that can improve gait dynamics and knee stability. We favor anterior, carbon fiber ground (floor) reaction AFOs that help keep the knee locked during extension. Stance control orthoses (SCOs) stabilize the knee during extension but release to allow flexion during the swing phase of gait and thereby prevent falls due to knee buckling. In a study of nine subjects with IBM, while most patients who used an SCO felt that it improved stability and prevented falls, most patients complained about the size and weight of the device, as well as difficulty putting it on and taking it off due to finger weakness [13]. While there are many different orthotic devices available, our experience is that most patients with foot drop have reduced frequency of falls with AFOs, whereas the difficulty using SCOs limits their utility. (See "Geriatric rehabilitation interventions", section on 'Orthoses'.)

Hand strengthening — The vast majority of IBM patients have significant finger flexor weakness at diagnosis [14,15]. Occupational therapists, especially certified hand therapists, have expertise in improving hand function with splints, adaptive equipment, and exercises. Many types of grip-strengthening devices exist that may help maintain finger flexor function. A single case of a patient having a tendon transfer surgery to improve grip strength in IBM has been reported [16]. At our center, we have seen several patients benefit from this procedure in which an extensor tendon is transferred to a flexor tendon in the forearm (typically extensor carpi radialis brevis tendon to index finger flexor digitorum profundus tendon), enabling wrist extension to power distal finger flexion. This procedure is often done along with a distal interphalangeal fusion to help improve prehension of the index finger. This procedure can be considered in patients with limitation in activities of daily living due to pincher weakness (such as using utensils, buttoning, or writing) who do not have significant wrist extension weakness. A relative contraindication is an inability to stand without use of the limb undergoing the procedure, since the operated arm cannot be used for about six weeks after surgery.

Speech therapy — Approximately half of patients develop swallowing difficulty during the course of disease, usually due to a combination of oropharyngeal weakness and upper esophageal sphincter (UES) dysfunction [17]. Although there is insufficient evidence to support interventions for dysphagia caused by any chronic, progressive muscle disease [18], we typically refer all patients with any swallowing difficulties to speech therapy for evaluation, and most patients will undergo a video fluoroscopic swallow study with speech therapist guidance. Oropharyngeal weakness may be compensated for by head positioning maneuvers and changes in diet consistency. For UES constriction (typically evidenced by a "cricopharyngeal bar" on swallow study), we recommend balloon dilation by a gastroenterologist [19]. For severe or refractory UES constriction, a cricopharyngeal myotomy can be performed by an experienced otolaryngologist [20,21]. A percutaneous endoscopic gastrostomy (PEG) tube may be required to maintain caloric intake in refractory patients. (See "Oropharyngeal dysphagia: Clinical features, diagnosis, and management", section on 'Neuromuscular disorders'.)

Nutritional support — In patients with significant dysphagia or in overweight patients, we frequently refer to a nutritionist since malnutrition can exacerbate muscle atrophy and central obesity can contribute to gait imbalance and falls. (See "Nutrition support in intubated critically ill adult patients: Initial evaluation and prescription" and "Obesity in adults: Overview of management".)

Creatine — A placebo-controlled trial has not been performed in IBM, but, given negligible side effects and evidence for improved muscle strength in muscular dystrophy [22], we suggest supplementation with 3 g of creatine monohydrate per day. Some IBM patients find that creatine monohydrate supplementation improves muscle fatigue. (See "Muscle enzymes in the evaluation of neuromuscular diseases", section on 'Creatine kinase'.)

IMMUNOSUPPRESSIVE THERAPY IN SELECTED PATIENTS — Most experts do not recommend immunosuppressive therapy for inclusion body myositis (IBM) [23,24]. However, in some patients with another systemic autoimmune disease (eg, Sjögren's disease) or an atypical presentation, such as rapidly progressive proximal limb weakness, markedly elevated creatine kinase (CK; >15x normal), and/or evidence for severe inflammation out of proportion to fibrosis on muscle biopsy and/or magnetic resonance imaging (MRI), we may initiate a trial of immunosuppressive medication.

We discuss potential side effects of glucocorticoid therapy with patients and involve patients in the decision as to whether the small chance of benefit would potentially outweigh the risks. We typically try prednisone at a dose of 1 mg/kg per day for about two to three months. In our experience, some patients will show transient but definite improvement in proximal limb weakness or dysphagia despite continued progression of distal weakness.

If there is continued decline in strength and function after approximately two to three months of treatment with glucocorticoids, we recommend discontinuation. If there is stabilization or improvement of proximal limb strength, we add methotrexate (starting at 10 mg/week) or azathioprine (1.5 to 2.5 mg/kg per day) for a trial period of three to six months and slowly taper the prednisone dose. There are no data to support the use of one of these agents rather than the other. The choice may be determined, in part, by other factors such as concern about hepatotoxicity with methotrexate in a patient with underlying liver disease. (See "Use of methotrexate in the treatment of rheumatoid arthritis" and "Pharmacology and side effects of azathioprine when used in rheumatic diseases".)

All medications should be slowly weaned if there is a continued decline in strength to avoid exposing patients who are non-responders to the toxicity of long-term glucocorticoid and immunosuppressive therapy.

Glucocorticoids — Glucocorticoids have not shown efficacy in most studies of IBM patients [2,25-28]. In the largest observational study of 136 IBM patients, 71 patients received immunosuppressants, with prednisone being the most frequently prescribed drug in over 90 percent [28]. There were no differences in grip strength, CK levels, or deaths between untreated and treated patients, but patients who had been treated were more severely affected on disability scales. In another study of 40 patients with IBM, muscle strength continued to deteriorate in all 25 prednisone-treated patients who were followed for at least two years [25]. Some other reports have noted a partial response to glucocorticoids with either mild improvement in or stabilization of muscle strength [2,26]. Serum CK levels often fall and may even normalize with glucocorticoid therapy; however, this biochemical response does not predict clinical benefit [2]. A 12-year observational study showed that patients treated with steroids long-term had a faster rate of progression to disability than untreated patients, possibly due to steroid-induced myopathy [28].

Methotrexate or azathioprine — Methotrexate and azathioprine, alone or in combination, have similarly shown, at best, minor benefit with no complete responses or major improvement [2,8,26,29]. As with glucocorticoids, plasma CK levels often fall and may even normalize with immunosuppressive treatment; however, this biochemical response does not predict clinical benefit [2,29]. This observation was confirmed in a randomized study of 44 patients who received either weekly methotrexate or placebo for 48 weeks [29]. Although the plasma CK decreased significantly in the methotrexate group, there was no significant difference in muscle strength between the two groups (decrease of 0.2 and 3.4 percent for methotrexate and placebo, respectively; 95% CI for the difference in strength between groups -2.5 to +9.1).

AGENTS WITHOUT CLEAR BENEFIT — Many drugs that have an immunomodulatory effect have been studied in inclusion body myositis (IBM). Based on limited data, other agents without clear benefit that we typically do not recommend include oxandrolone [30], intravenous immune globulin (IVIG) [31-36], anti-T-lymphocyte globulin [37], inhibitors of tumor necrosis factor (TNF) alpha (such as etanercept) [38], alemtuzumab [39], interferon beta [40,41], or interleukin 1 (IL-1) blockade with anakinra [42]. Also, as described above, in most patients there is no clear benefit associated with glucocorticoids [2,3,25-28], methotrexate [29], azathioprine [2]. (See 'Glucocorticoids' above and 'Methotrexate or azathioprine' above.)

●Intravenous immune globulin – Though some studies have suggested a modest improvement in dysphagia with IVIG, given lack of objective evidence for efficacy, expense, and potential for harm, most experts do not recommend IVIG [43]. In one report, four patients with severe dysphagia due to upper esophageal dysfunction recovered swallowing function after treatment with six to eight monthly infusions of IVIG [44]. In another study of 16 patients treated with a mean of 10 IVIG infusions, IVIG appeared to improve swallowing function in three patients, but the effect was not sustained over the mean follow-up period of 23 months [31].

Most studies on the efficacy of IVIG in the treatment of IBM do not show evidence for long-term benefit [31-36]. The following studies are illustrative:

•A double-blind study randomly assigned 36 patients to either IVIG (monthly infusions for three months) or placebo infusions; all patients also received high-dose glucocorticoids [32]. When compared with baseline, there were no significant differences in muscle strength during four months of observation. Follow-up biopsies revealed a greater reduction in the number of necrotic muscle fibers in those who received IVIG than in the placebo group, but this appeared to be of no clinical significance. The authors concluded that the combination of prednisone and IVIG was ineffective in treating IBM.

•A double-blind, placebo-controlled crossover study involved 19 patients; no statistically significant improvement in overall muscle strength due to IVIG was observed. However, there was a trend toward improvement during IVIG treatment, and nine of the patients continued IVIG therapy independently after the study was concluded because of a sense of improved quality of life [33].

•A double-blind, placebo-controlled crossover study of 11 patients did not suggest any benefit from IVIG in muscle strength, symptoms, or myographic test results [34].

●Statins – Because of potential antiinflammatory effects of statins, one small pilot study of 10 patients evaluated the safety and efficacy of simvastatin 40 mg in treatment of IBM [45]. Though no significant benefit was seen, simvastatin appeared to be safe and well tolerated in this small study. In our experience, statins are generally safe in IBM, though given their potential myotoxicity, we recommend minimizing the statin dose and using medications with the lowest potential of myotoxicity such as pravastatin and rosuvastatin.

●Bimagrumab – Bimagrumab is a monoclonal antibody that inhibits the myostatin pathway by binding and inhibiting activin type II receptors (ActRII), which mediate the differentiation and growth of skeletal muscle. By blocking myostatin signaling, bimagrumab can induce muscle hypertrophy [46,47]. Although initial studies with bimagrumab were promising, this benefit was not observed in subsequent long-term studies. A proof-of-concept trial including 14 patients with IBM found that bimagrumab-treated patients had increased muscle mass on magnetic resonance imaging (MRI) at eight weeks when compared with patients who received placebo [46]. No serious adverse events were reported in this small study, and the most common side effects were mild acne and transient, involuntary muscle contractions. A randomized, placebo-controlled phase II trial of 251 patients with IBM found that while bimagrumab failed to meet the primary endpoint of improvement in the 6-minute walk test (6MWT) at 12 months, there was a statistically significant improvement in lean body mass and self-reported physical function [48]. In an extension of the aforementioned study, continued treatment with bimagrumab was well-tolerated but did not appear to provide a clinical meaningful functional benefit compared with placebo, and the study was terminated early [49]. In another small study that followed 10 patients with IBM who continued bimagrumab for up to 2 years, an increase in muscle mass was also detected, but there was no evidence of clinical improvement [50].

●AAV1 follistatin – Follistatin is a natural hormone that antagonizes the myostatin signaling pathway by binding ActRII and inhibiting its activation [51]. Gene therapy using adeno-associated virus (AAV) is a promising therapeutic strategy for muscle disease, and AAV1-Follistatin can be delivered to muscles via intramuscular (IM) injection, thereby minimizing systemic side effects. IM injection of AAV1-Follistatin led to significant muscle hypertrophy in mice and non-human primates [52]. A small study of AAV1-Follistatin injected into bilateral quadriceps muscles of six IBM patients reported an improvement in six-minute walk time [53], though this interpretation has been questioned based on trial design and post-hoc analysis [54].

●Arimoclomol – Arimoclomol is an orally bioavailable small molecule chaperone inducer that inhibits protein aggregation in stressed cells. Arimoclomol has been shown to be effective in animal models of IBM and amyotrophic lateral sclerosis (ALS), and it is both safe and well tolerated in ALS and IBM patients in phase I studies [55,56]. A randomized phase II/III trial of 150 patients failed to meet its primary and secondary endpoints at 20 months, and the open-label extension study was terminated early [57].

●Oxandrolone – Oxandrolone is no longer available in most parts of the world. Additionally, because of the uncertain benefit and concerns for adverse effects, we do not typically recommend its use. A randomized, double-blind, placebo-controlled 12-week crossover study of oxandrolone (10 mg twice a day) in 13 patients showed a small but significant improvement in upper extremity strength and borderline improvement in whole body strength [30]. In this study, the drug was well tolerated; however, there was a significant increase in low-density lipoprotein (LDL), a decrease in high-density lipoprotein (HDL), and an increase in transaminases in most patients. Furthermore, anabolic steroids increase the risk of breast and prostate cancer, and they may have virilizing side effects in females (eg, temporal balding or facial hair). Treated patients should have monitoring of transaminases, cholesterol, and prostate-specific antigen (PSA; in males).

●Alternative agents – Since there are no specific medical treatments to offer, patients frequently inquire about diet, dietary supplements, growth factors, acupuncture, massage, hyperbaric oxygen, electrical stimulation, stem cell injections, and other therapies that have not been studied in IBM. While some of these treatments may have theoretical benefit and minimal risk (eg, antioxidants such as coenzyme Q10), many of these nonconventional treatments are quite expensive and lack evidence for safety or efficacy.

PROGNOSIS — Patients with inclusion body myositis (IBM) usually progress to disability over a period of years. The older the age at onset of the disease, the more rapid the loss of strength and function [58,59]. As an example, an observational study including 78 patients with biopsy-proven IBM found that patients presenting before age 60 progress to the use of a walker after an average of 10.2 years, and those presenting after age 60 require a walker after only 5.7 years of disease [58].

By 15 years, most patients require assistance with basic daily activities, and some will become dependent on a wheelchair or will be confined to bed [28,60]. Natural history studies have not shown reduced lifespan in IBM [60], though most experts agree that IBM can be an indirect cause of death, especially due to aspiration pneumonia in patients with dysphagia [60,61]. Clinically significant diaphragmatic weakness is uncommon, though rare cases of respiratory failure due to respiratory muscle weakness have been described [62]. (See "Clinical manifestations and diagnosis of inclusion body myositis", section on 'Clinical manifestations'.)

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: Inclusion body myositis".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Beyond the Basics topics (see "Patient education: Polymyositis, dermatomyositis, and other forms of idiopathic inflammatory myopathy (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Goals of therapy – The primary goal of therapy in inclusion body myositis (IBM) is to optimize muscle strength and function. Given the slowly progressive and variable course of the disease, it can be quite challenging to determine if treatment leads to an objective improvement in or stabilization of muscle strength. (See 'Goals of therapy' above.)

●Nonpharmacologic therapy – The optimal treatment for IBM is not known, and most interventions have demonstrated only limited benefit. Nonpharmacologic interventions such as physical therapy, occupational therapy, and/or speech therapy can be helpful in all patients to achieve the following (see 'Nonpharmacologic therapy' above):

•Provide an exercise program to maintain strength as long as possible

•Address concerns about falling and the use of orthoses and assistive devices such as canes and walkers

•Address difficulties with the activities of daily living such as finger flexor weakness

•Help learn techniques to minimize the risk of aspiration in patients with dysphagia

•Provide nutritional support or dietary counseling in patients with dysphagia or obesity, respectively

●Creatinine supplementation – Given negligible side effects and evidence for improved muscle strength in muscular dystrophy [22], we suggest supplementation with 3 g of creatine monohydrate per day (Grade 2C). Some IBM patients find that creatine monohydrate supplementation improves muscle fatigue. It is also reasonable not to give creatine monohydrate supplementation. (See 'Creatine' above.)

●Limited role for immunosuppression – In contrast to other inflammatory myopathies such as dermatomyositis and polymyositis, IBM is relatively resistant to standard immunomodulatory therapies. We only consider a trial of immunosuppressive medications in IBM patients with an atypical presentation or in patients with another systemic autoimmune disease (such as Sjögren's disease). (See 'Immunosuppressive therapy in selected patients' above.)

Many drugs that have an immunomodulatory effect have been studied in IBM. Based on limited data, agents without clear benefit that we typically do not recommend include oxandrolone, prednisone, methotrexate, azathioprine, intravenous immune globulin (IVIG), anti-T-lymphocyte globulin, inhibitors of tumor necrosis factor (TNF) alpha (such as etanercept), alemtuzumab, interferon beta, or interleukin 1 (IL-1) blockade. (See 'Agents without clear benefit' above.)

●Prognosis – Patients with IBM usually progress to disability over a period of years. The older the age at onset of the disease, the more rapid the loss of strength and function. By 15 years, most patients require assistance with basic daily activities, and some will need to use a wheelchair or need to stay in bed. (See 'Prognosis' above.)