The Role of Nonimmune Factors in IBM
In IBM, the presence of ß-amyloid deposits within vacuolated muscle fibers and abnormal mitochondria with cytochrome oxidase-negative fibers suggest that, in addition to the autoimmune component, there is also a degenerative process. Similar to Alzheimer’s disease, the amyloid deposits in IBM are immunoreactive against amyloid precursor protein (APP), chymotrypsin, apolipoprotein E, and phosphorylated tau, but it is unclear whether these deposits are directly pathogenic or represent secondary phenomena. The same is true for the mitochondrial abnormalities, which may also be secondary to the effects of aging or a bystander effect of upregulated cytokines. Expression of cytokines and upregulation of MHC class I by the muscle fibers may cause an endoplasmic reticulum stress response resulting in intracellular accumulation of misfolded glycoproteins and activation of nuclear factor KB (NFKB),leading to further cytokine activation.
Association with Viral Infections and the Role of Retroviruses
Several viruses, including coxsackieviruses, influenza, paramyxoviruses, mumps, cytomegalovirus, and Epstein-Barr virus, have been indirectly associated with myositis. For the coxsackieviruses, an autoimmune myositis triggered by molecular mimicry has been proposed because of structural homology between histidyl-transfer RNA synthetase, which is the target of the Jo-1 antibody (see above), and genomic RNA of an animal picornavirus, the encephalomyocarditis virus. Sensitive polymerase chain reaction (PCR) studies, however, have repeatedly failed to confirm the presence of such viruses in muscle biopsies.
The best evidence of a viral connection in PM and IBM is with the retroviruses. Some individuals infected with HIV or with human T cell lymphotropic virus I (HTLV-I) develop PM or IBM; a similar disorder has been described in nonhuman primates infected with the simian immunodeficiency virus. The inflammatory myopathy may occur as the initial manifestation of a retroviral infection, or myositis may develop later in the disease course. Retroviral antigens have been detected only in occasional endomysial macrophages and not within the muscle fibers themselves, suggesting that persistent infection and viral replication within the muscle do not occur. Histologic findings are identical to retroviral-negative PM or IBM. The infiltrating T cells in the muscle are clonally driven and a number of them are retroviral specific. This disorder should be distinguished from a toxic myopathy related to long-term therapy with AZT, characterized by fatigue, myalgia, mild muscle weakness, and mild elevation of creatine kinase (CK). AZT-induced myopathy, which generally improves when the drug is discontinued, is a mitochondrial disorder characterized histologically by “ragged-red” fibers. AZT inhibits γ-DNA polymerase, an enzyme found solely in the mitochondrial matrix.
Differential Diagnosis
The clinical picture of the typical skin rash and proximal or diffuse muscle weakness has few causes other than DM. However, proximal muscle weakness without skin involvement can be due to many conditions other than PM or IBM.
Subacute or Chronic Progressive Muscle Weakness
This may be due to denervating conditions such as the spinal muscular atrophies or amyotrophic lateral sclerosis. In addition to the muscle weakness, upper motor neuron signs in the latter and signs of denervation detected by electromyography (EMG) aid in the diagnosis. The muscular dystrophies may be additional considerations; however, these disorders usually develop over years rather than weeks or months and rarely present after the age of 30. It may be difficult, even with a muscle biopsy, to distinguish chronic PM from a rapidly advancing muscular dystrophy. This is particularly true of facioscapulohumeral muscular dystrophy, dysferlin myopathy, and the dystrophinopathies where inflammatory cell infiltration is often found early in the disease. Such doubtful cases should always be given an adequate trial of glucocorticoid therapy and undergo genetic testing to exclude muscular dystrophy. Identification of the MHC/ CD8 lesion by muscle biopsy is helpful to identify cases of PM. Some metabolic myopathies, including glycogen storage disease due to myophosphorylase or acid maltase deficiency, lipid storage myopathies due to carnitine deficiency, and mitochondrial diseases produce weakness that is often associated with other characteristic clinical signs; diagnosis rests upon histochemical and biochemical studies of the muscle biopsy. The endocrine myopathies such as those due to hypercorticosteroidism, hyper- and hypothyroidism, and hyper- and hypoparathyroidism require the appropriate laboratory investigations for diagnosis. Muscle wasting in patients with an underlying neoplasm may be due to disuse, cachexia, or rarely to a paraneoplastic neuromyopathy.
Diseases of the neuromuscular junction, including myasthenia gravis or the Lambert-Eaton myasthenic syndrome, cause fatiguing weakness that also affects ocular and other cranial muscles. Repetitive nerve stimulation and single-fiber EMG studies aid in diagnosis.
Acute Muscle Weakness
This may be caused by an acute neuropathy such as Guillain-Barré syndrome, transverse myelitis, a neurotoxin, or a neurotropic viral infection such as poliomyelitis or West Nile virus. When acute weakness is associated with painful muscle cramps, rhabdomyolysis, and myoglobinuria, it may be due to a viral infection or a metabolic disorder such as myophosphorylase deficiency or carnitine palmitoyltransferase deficiency. Several animal parasites, including protozoa (toxoplasma, trypanosoma), cestodes (cysticerci), and nematodes (trichinae), may produce a focal or diffuse inflammatory myopathy known as parasitic polymyositis. Staphylococcus aureus, Yersinia, Streptococcus, or anaerobic bacteria may produce a suppurative myositis, known as tropical polymyositis, or pyomyositis. Pyomyositis, previously rare in the West, is now occasionally seen in AIDS patients. Other bacteria, such as Borrelia burgdorferi (Lyme disease) and Legionella pneumophila (Legionnaire’s disease) may infrequently cause myositis.
Patients with periodic paralysis experience recurrent episodes of acute muscle weakness without pain, always beginning in childhood. Chronic alcoholics may develop painful myopathy with myoglobinuria after a bout of heavy drinking. Acute painless muscle weakness with myoglobinuria may occur with prolonged hypokalemia, or hypophosphatemia and hypomagnesemia, usually in chronic alcoholics or in patients on nasogastric suction receiving parenteral hyperalimentation.
Myofasciitis
This distinctive inflammatory disorder affecting muscle and fascia presents as diffuse myalgias, skin induration, fatigue, and mild muscle weakness; mild elevations of serum CK are usually present. The most common form is eosinophilic myofasciitis characterized by peripheral blood eosinophilia and eosinophilic infiltrates in the endomysial tissue. In some patients, the eosinophilic myositis/fasciitis occurs in the context of parasitic infections, vasculitis, mixed connective tissue disease, hypere-osinophilic syndrome, or toxic exposures (e.g., toxic oil syndrome, contaminated L-tryptophan) or with mutations in the calpain gene. A distinct subset of myofasciitis is characterized by pronounced infiltration of the connective tissue around the muscle by sheets of periodic acid-Schiff-positive macrophages and occasional CD8 T cells (macrophagic myofasciitis). Such histologic involvement is focal and limited to sites of previous vaccinations, which may have been administered months or years earlier. This disorder, which to date has not been observed outside of France, has been linked to an aluminum-containing substrate in vaccines. Most patients respond to glucocorticoid therapy, and the overall prognosis seems favorable.
Necrotizing Myositis
This is an increasingly recognized entity that has distinct features, even though it is often labeled as PM. It presents often in the fall or winter as an acute or subacute onset of 2 symmetric muscle weakness; CK is typically extremely high. The weakness can be severe. Coexisting interstitial lung disease and cardiomyopathy may be present. The disorder may develop after a viral infection or in association with cancer. Some patients have antibodies against signal recognition particle (SRP). The muscle biopsy demonstrates necrotic fibers infiltrated by macrophages but only rare, if any, T-cell infiltrates. Muscle MHC-I expression is only slightly and focally upregulated. The capillaries may be swollen with hyalinization, thickening of the capillary wall, and deposition of complement. Some patients respond to immunotherapy, but others are resistant.
Drug-Induced Myopathies
D-Penicillamine and procainamide may produce a true myositis resembling PM, and a DM-like illness had been associated with the contaminated preparations of L-tryptophan. As noted above, AZT causes a mitochondrial myopathy. Other drugs may elicit a toxic noninflammatory myopathy that is histologically different from DM, PM, or IBM. These include cholesterol-lowering agents such as clofibrate, lovastatin, simvastatin, or pravastatin, especially when combined with cyclosporine or gemfibrozil. Rhabdomyolysis and myoglobinuria have been rarely associated with amphotericin B, ε-aminocaproic acid, fenfluramine, heroin, and phencyclidine. The use of amiodarone, chloroquine, colchicine, carbimazole, emetine, etretinate, ipecac syrup, chronic laxative or licorice use resulting in hypokalemia, and glucocorticoids or growth hormone administration have also been associated with myopathic muscle weakness. Some neuromuscular blocking agents such as pancuronium, in combination with glucocorticoids, may cause an acute critical illness myopathy. A careful drug history is essential for diagnosis of these drug-induced myopathies, which do not require immunosuppressive therapy.
“Weakness” Due to Muscle Pain and Muscle Tenderness
A number of conditions including polymyalgia rheumatica and arthritic disorders of adjacent joints may enter into the differential diagnosis of inflammatory myopathy, even though they do not cause myositis. The muscle biopsy is either normal or discloses type II muscle fiber atrophy. Patients with fibromyalgia (Chap. 21) complain of focal or diffuse muscle tenderness, fatigue, and aching, which is sometimes poorly differentiated from joint pain. Some patients, however, have muscle tenderness, painful muscles on movement, and signs suggestive of a collagen vascular disorder, such as an increased erythrocyte sedimentation rate, C-reactive protein, antinuclear antibody, or rheumatoid factor, along with modest elevation of the serum CK and aldolase. They demonstrate a “give-way” pattern of weakness with difficulty sustaining effort but not true muscle weakness. The muscle biopsy is usually normal or nonspecific. Many such patients show some response to nonsteroidal anti-inflammatory agents or glucocorticoids, though most continue to have indolent complaints. An indolent fasciitis in the setting of an ill-defined connective tissue disorder may be present, and these patients should not be labeled as having a psychosomatic disorder. Chronic fatigue syndrome, which may follow a viral infection, can present with debilitating fatigue, fever, sore throat, painful lymphadenopathy, myalgia, arthralgia, sleep disorder, and headache. These patients do not have muscle weakness, and the muscle biopsy is normal.
Diagnosis
The clinically suspected diagnosis of PM, DM, or IBM is confirmed by examining the serum muscle enzymes, EMG findings, and muscle biopsy (Table 16-2).
The most sensitive enzyme is CK, which in active disease can be elevated as much as 50-fold.Although the CK level usually parallels disease activity, it can be normal in some patients with active IBM or DM, especially when associated with a connective tissue disease. The CK is always elevated in patients with active PM. Along with the CK, the serum glutamic-oxaloacetic and glutamate pyruvate transaminases, lactate dehydrogenase, and aldolase may be elevated.
Needle EMG shows myopathic potentials characterized by short-duration, low-amplitude polyphasic units on voluntary activation and increased spontaneous activity with fibrillations, complex repetitive discharges, and positive sharp waves. Mixed potentials (polyphasic units of short and long duration) indicating a chronic process and muscle fiber regeneration are often present in IBM. These EMG findings are not diagnostic of an inflammatory myopathy but are useful to identify the presence of active or chronic myopathy and to exclude neurogenic disorders.
MRI is not routinely used for the diagnosis of PM, DM, or IBM. However, it may guide the location of the muscle biopsy in certain clinical settings.
Muscle biopsy is the definitive test for establishing the diagnosis of inflammatory myopathy and for excluding other neuromuscular diseases. Inflammation is the histologic hallmark for these diseases; however, additional features are characteristic of each subtype (Figs. 16-3,16-4, and 16-5).
TABLE 16-2
CRITERIA FOR DIAGNOSIS OF INFLAMMA
|
CRITERIA FOR DIAGNOSIS OF INFLAMMA |
TORY MYOPATHIES |
|
|
|
|
|
POLYMYOSITIS |
|
|
|
|
CRITERION |
DEFINITE |
PROBABLE |
DERMATOMYOSITIS |
INCLUSION BODY MYOSITIS |
|
Myopathic muscle weaknessa |
Yes |
Yes |
Yesb |
Yes; slow onset, early involvement of distal muscles, frequent falls |
|
Electromyographic findings |
Myopathic |
Myopathic |
Myopathic |
Myopathic with mixed potentials |
|
Muscle enzymes |
Elevated (up to 50-fold) |
Elevated (up to 50-fold) |
Elevated (up to 50-fold) or normal |
Elevated (up to 10-fold) or normal |
|
Muscle biopsy findingsc |
“Primary” inflammation with the CD8/MHC-I complex and no vacuoles |
Ubiquitous MCH-I expression but minimal inflammation and no vacuolesd |
Perifascicular, perimysial, or perivascular infiltrates, perifascicular atrophy |
Primary inflammation with CD8/MHC-I complex; vacuolated fibers with ß-amyloid deposits; cytochrome oxygenase-negative fibers; signs of chronic myopathye |
|
Rash or calcinosis |
Absent |
Absent |
Presentf |
Absent |
aMyopathic muscle weakness, affecting proximal muscles more than distal ones and sparing eye and facial muscles, is characterized by a subacute onset (weeks to months) and rapid progression in patients who have no family history of neuromuscular disease, no endocrinopathy, no exposure to myotoxic drugs or toxins, and no biochemical muscle disease (excluded on the basis of muscle-biopsy findings).
bIn some cases with the typical rash, the muscle strength is seemingly normal (dermatomyositis sine myositis); these patients often have newonset of easy fatigue and reduced endurance. Careful muscle testing may reveal mild muscle weakness.
cSee text for details.
dAn adequate trial of prednisone or other immunosuppressive drugs is warranted in probable cases. If, in retrospect, the disease is unresponsive to therapy, another muscle biopsy should be considered to exclude other diseases or possible evolution in inclusion body myositis.
eIf the muscle biopsy does not contain vacuolated fibers but shows chronic myopathy with hypertrophic fibers, primary inflammation with the CD8/MHC-I complex and cytochrome oxygenase-negative fibers, the diagnosis is probable inclusion body myositis.
fIf rash is absent but muscle biopsy findings are characteristic of dermatomyositis, the diagnosis is probable DM.
FIGURE 16-3
Cross section of a muscle biopsy from a patient with polymyositis demonstrates scattered inflammatory foci with lymphocytes invading or surrounding muscle fibers. Note lack of chronic myopathic features (increased connective tissue, atrophic or hypertrophic fibers) as seen in inclusion body myositis.
In PM the inflammation is primary, a term used to indicate that T-cell infiltrates, located primarily within the muscle fascicles (endomysially), surround individual, healthy muscle fibers and result in phagocytosis and necrosis (Fig. 16-3). The MHC-I molecule is ubiquitously expressed on the sarcolemma, even in fibers not invaded by CD8+ cells.The CD8/MHC-I lesion is now fundamental for confirming or establishing the diagnosis and to exclude disorders with secondary, nonspecific, inflammation. When the disease is chronic, connective tissue is increased and may react positively with alkaline phosphatase.
FIGURE 16-4
Cross section of a muscle biopsy from a patient with dermatomyositis demonstrates atrophy of the fibers at the periphery of the fascicle (perifascicular atrophy).
In DM the endomysial inflammation is predominantly perivascular or in the interfascicular septae and around, rather than within, the muscle fascicles (Fig. 16-4).The intramuscular blood vessels show endothelial hyperplasia with tubuloreticular profiles, fibrin thrombi, and obliteration of capillaries. The muscle fibers undergo necrosis, degeneration, and phagocytosis, often in groups involving a portion of a muscle fasciculus in a wedgelike shape or at the periphery of the fascicle, due to microinfarcts within the muscle. This results in perifascicular atrophy, characterized by 2-10 layers of atrophic fibers at the periphery of the fascicles. The presence of perifascicular atrophy is diagnostic of DM, even in the absence of inflammation.
In IBM (Fig. 16-5), there is endomysial inflammation with T cells invading MHC-I-expressing nonvacuolated muscle fibers; basophilic granular deposits distributed around the edge of slitlike vacuoles (rimmed vacuoles); loss of fibers, replaced by fat and connective tissue, hypertrophic fibers, and angulated or round fibers; eosinophilic cytoplasmic inclusions; abnormal mitochondria characterized by the presence of ragged-red fibers or cytochrome oxidase-negative fibers; amyloid deposits within or next to the vacuoles; and filamentous inclusions seen by electron microscopy in the vicinity of the rimmed vacuoles.
Treatment:
INFLAMMATORY MYOPATHIES
The goal of therapy is to improve muscle strength, thereby improving function in activities of daily living, and ameliorate the extramuscular manifestations (rash, dysphagia,dyspnea,fever).When strength improves,the serum CK falls concurrently; however, the reverse is not always true. Unfortunately, there is a common tendency to "chase" or treat the CK level instead of the muscle weakness, a practice that has led to prolonged and unnecessary use of immunosuppressive drugs and erroneous assessment of their efficacy. It is prudent to discontinue these drugs if, after an adequate trial, there is no objective improvement in muscle strength whether or not CK levels are reduced. Agents used in the treatment of PM and DM include:
1. Glucocorticoids. Oral prednisone is the initial treatment of choice; the effectiveness and side effects of this therapy determine the future need for stronger immunosuppressive drugs. High-dose prednisone, at least 1 mg/kg per d, is initiated as early in the disease as possible. After 3-4 weeks, prednisone is tapered slowly over a period of 10 weeks to 1 mg/kg every other day.
FIGURE 16-5
Cross sections of a muscle biopsy from a patient with inclusion body myositis demonstrate the typical features of vacuoles with lymphocytic infiltrates surrounding nonvacuolated or necrotic fibers (A), tiny endomysial deposits of amyloid visualized with crystal violet (B), cytochrome oxidase-negative fibers, indicative of mitochondrial dysfunction (C), and ubiquitous MHC-I expression at the periphery of all fibers (D).
If there is evidence of efficacy and no serious side effects, the dosage is then further reduced by 5 or 10 mg every 3-4 weeks until the lowest possible dose that controls the disease is reached.The efficacy of prednisone is determined by an objective increase in muscle strength and activities of daily living, which almost always occurs by the third month of therapy. A feeling of increased energy or a reduction of the CK level without a concomitant increase in muscle strength is not a reliable sign of improvement. If prednisone provides no objective benefit after ~3 months of high-dose therapy, the disease is probably unresponsive to the drug and tapering should be accelerated while the next-in-line immunosuppressive drug is started.Although controlled trials have not been performed, almost all patients with true PM or DM respond to glucocorticoids to some degree and for some period of time; in general, DM responds better than PM.
The long-term use of prednisone may cause increased weakness associated with a normal or unchanged CK level; this effect is referred to as steroid myopathy. In a patient who previously responded to high doses of prednisone, the development of new weakness may be related to steroid myopathy or to disease activity that either will respond to a higher dose of glucocorticoids or has become glucocorticoid resistant. In uncertain cases, the prednisone dosage can be steadily increased or decreased as desired:the cause of the weakness is usually evident in 2-8 weeks.
2. Other immunosuppressive drugs. Approximately 75% of patients ultimately require additional treatment. This occurs when a patient fails to respond adequately to glucocorticoids after a 3-month trial, the patient becomes glucocorticoid resistant, glucocorticoid-related side effects appear, attempts to lower the prednisone dose repeatedly result in a new relapse, or rapidly progressive disease with evolving severe weakness and respiratory failure develops.
The following drugs are commonly used but have never been tested in controlled studies: (1) Azathioprine is well tolerated, has few side effects, and appears to be as effective for long-term therapy as other drugs. The dose is up to 3 mg/kg daily. (2) Methotrexate has a faster onset of action than azathioprine. It is given orally starting at 7.5 mg weekly for the first 3 weeks (2.5 mg every 12 h for 3 doses),with gradual dose escalation by 2.5 mg per week to a total of 25 mg weekly. A rare side effect is methotrexate pneumonitis, which can be difficult to distinguish from the interstitial lung disease of the primary myopathy associated with Jo-1 antibodies (described above). (3) Mycophenolate mofetil also has a faster onset of action than azathioprine. At doses up to 2.5 mg/d, it is well tolerated and appears promising for long-term use. (4) Monoclonal anti-CD20 (rituximab) has been shown in a small uncontrolled series to benefit patients with DM. (5) Cyclosporine has inconsistent and mild benefit. (6) Cyclophosphamide (0.5-1 g IV monthly for 6 months) has limited success and significant toxicity. (7) Tacrolimus (formerly known as Fk506) has been effective in some difficult cases of PM.
3. Immunomodulation. In a controlled trial of patients with refractory DM, intravenous immunoglobulin (IVIg) improved not only strength and rash but also the underlying immunopathology. The benefit is often short-lived (<8 weeks); repeated infusions every 6-8 weeks are generally required to maintain improvement. A dose of 2 g/kg divided over 2-5 days per course is recommended. Uncontrolled observations suggest that IVIg may also be beneficial for patients with PM. Neither plasmapheresis nor leuka-pheresis appears to be effective in PM and DM.
The following sequential empirical approach to the treatment of PM and DM is suggested:Step 7:high-dose prednisone; Step 2: azathioprine, mycophenolate, or methotrexate for steroid-sparing effect; Step 3: IVIg; Step 4: a trial, with guarded optimism, of one of the following agents, chosen according to the patient’s age, degree of disability, tolerance, experience with the drug, and general health: rituximab, cyclosporine, cyclophosphamide, or tacrolimus. Patients with interstitial lung disease may benefit from aggressive treatment with cyclophosphamide or tacrolimus.
A patient with presumed PM who has not responded to any form of immunotherapy most likely has IBM or another disease, usually a metabolic myopathy, a muscular dystrophy, a drug-induced myopathy, or an endocrinopathy. In these cases, a repeat muscle biopsy and a renewed search for another cause of the myopathy is indicated.
Calcinosis, a manifestation of DM, is difficult to treat; however, new calcium deposits may be prevented if the primary disease responds to the available therapies. Bisphosphonates, aluminum hydroxide, probenecid, colchicine, low doses of warfarin, calcium blockers, and surgical excision have all been tried without success.
IBM is generally resistant to immunosuppressive therapies. Prednisone together with azathioprine or methotrexate is often tried for a few months in newly diagnosed patients, although results are generally disappointing. Because occasional patients may feel subjectively weaker after these drugs are discontinued, some clinicians prefer to maintain some patients on low-dose, every-other-day prednisone or weekly methotrexate in an effort to slow disease progression,even though there is no objective evidence or controlled study to support this practice. In two controlled studies of IVIg in IBM, minimal benefit in up to 30% of patients was found; the strength gains, however, were not of sufficient magnitude to justify its routine use. Another trial of IVIg combined with prednisone was ineffective. Nonetheless, many experts believe that a 2- to 3-month trial with IVIg may be reasonable for selected patients with IBM who experience rapid progression of muscle weakness or choking episodes due to worsening dysphagia.
Prognosis
The 5-year survival rate for treated patients with PM and DM is ~95% and the 10-year survival is 84%; death is usually due to pulmonary, cardiac, or other systemic complications. Patients severely affected at presentation or treated after long delays, those with severe dysphagia or respiratory difficulties, older patients, and those with associated cancer have a worse prognosis. DM responds more favorably to therapy than PM and thus has a better prognosis. Most patients improve with therapy, and many make a full functional recovery, which is often sustained with maintenance therapy. Up to 30% may be left with some residual muscle weakness. Relapses may occur at any time.
IBM has the least favorable prognosis of the inflammatory myopathies. Most patients will require the use of an assistive device such as a cane, walker, or wheelchair within 5-10 years of onset. In general, the older the age of onset in IBM, the more rapidly progressive is the course.
