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Contributor: Soumya Chatterjee, MD, MS, FRCP
A 68 year old female presents with a several month history of progressive weakness and fatigue. Previously very active, she now notes difficulty arising from a chair or the toilet, lifting cooking pots off the stove and reaching for items above her head. Her husband has to assist her with dressing. She has difficulty swallowing and chokes easily if she is not careful.
On examination, her vital signs are normal. She has to push herself out of the chair using her hands and requires assistance stepping up on the exam table. New erythema over the face, neck, upper chest and upper back is noted. Her cardiac, lung and abdominal exams are normal. Strength in her distal extremities is intact. On proximal muscle testing, while she is able to raise her thigh and arms against gravity, she cannot hold them there against even light resistance. She also has difficulty sitting up from a lying position and has to turn to the side to do so. Reflexes and sensation are intact.
What features of the patient's history and physical examination suggest an inflammatory muscle disease? What work-up would be indicated at this point?
Progressive and painless weakness of proximal muscle groups suggests inflammatory myopathy. The work-up should include the following laboratory tests, which are remarkable for an elevated creatine kinase of 3000 U/L (reference range: 30 – 220 U/L); AST is 180 U/L(reference range: 7 - 40 U/L) and ALT is 150 U/L (reference range: 0 – 45 U/L); Anti-nuclear antibody (ANA) and anti-Jo-1 antibody are negative. There is increased water content in the bilateral thigh muscles as demonstrated in this STIR MRI picture. Electromyogram is consistent with an inflammatory myopathy while nerve conduction velocity testing is normal.
How do you explain the abnormalities above?
In this case elevations in AST and ALT are likely secondary to muscle damage and do not necessarily reflect liver damage. The abnormality of the thigh muscles on MRI suggests muscle edema, as seen in muscle inflammation, but it is non-specific. This finding helps to confirm there is a muscle abnormality, and may distinguish between focal involvement, such as might be seen with injury or strain, versus diffuse involvement such as with a systemic process like myositis. Even in systemic inflammatory muscle disease, there is a variable degree of involvement within muscle groups so that a blind biopsy may yield a falsely normal report; areas of abnormal MRI signal thus help direct the site for biopsy to give the best yield. MRI changes may also serve as a possible imaging modality for following treatment response.
What percent of myositis cases have a negative ANA? What percent are anti-Jo-1 (anti-histidyl tRNA synthetase) positive?
It is generally recognized that approximately 90% of all inflammatory myopathy patients will be positive for either a nuclear or a cytoplasmic antibody. The presence of a positive ANA is therefore much lower once those with cytoplasmic antibodies are excluded. Therefore, greater than 20% of myositis patients have a negative ANA. The rate of positive anti-Jo-1 antibodies is approximately 20% of all those with an inflammatory myopathy.
What other work-up should be pursued at this point?
A 52-year old previously healthy male is admitted to the hospital for a one month history of fever and progressive dyspnea. He has failed two courses of outpatient oral antibiotics for a presumed community-acquired pneumonia. Review of systems is positive for new polyarticular joint pain and muscle aches.
On examination he is febrile to 102º F. He appears ill and uncomfortable. His respiratory rate is 30 and the use of accessory muscles of respiration with speech is noted. Pulse oximetry on room air is 88% and he is placed on supplemental oxygen. On lung exam, fine diffuse bilateral crackles are heard loudest in the bases but extending up to the level of the scapular tip. Cardiac and abdominal examinations are normal.
Bilateral interstitial infiltrates are seen on chest X-ray. CT scan of the chest demonstrates ground glass opacities and diffuse interstitial changes. Laboratory studies are notable for a mild anemia consistent with chronic disease. WBC count is 11,000/cu mm with a normal differential. AST and ALT are elevated at twice the upper limits of normal. CT and ultrasound of the liver are normal. Viral hepatitis and HIV studies are negative. Cultures of blood and sputum are negative, including cultures obtained by bronchoscopy. ANA, rheumatoid factor and anti-CCP antibodies are negative.
He is initially treated with broad-spectrum IV antibiotics with no improvement. He has continued fever and progressive worsening of his respiratory status. Open-lung biopsy is obtained. Pathology demonstrates non-specific interstitial pneumonitis with no organisms identified.
Because of worsening joint complaints, rheumatology is consulted post-operatively.
His physical examination is notable for mild synovitis in the MCP and wrist joints, and knees. On skin examination he has roughening along the edges of his fingers consistent with mechanic's hands. He denies Raynaud symptoms but dilated capillaries are found on nailfold capillaroscopy. On muscle strength testing there is subtle weakness proximally. He is able to resist against pressure, but only with difficulty and is not able to stand-up from a squatting position. The strength in distal muscle groups and reflexes are intact. CK obtained at that time is elevated at 900 U/L (reference range: 30 – 220 U/L).
What disorder can tie the above findings together?
The constellation of muscle abnormalities (proximal weakness with an elevated CK, AST and ALT), fever, mechanic's hands, inflammatory arthritis, and interstitial lung disease is characteristic of the well-classified anti-synthetase syndrome, a subset of the inflammatory myopathies.
What further work-up is indicated, and which antibody is classically seen?
(Answer questions 1 – 5 on a piece a paper. Find Answer Key at the bottom on the page.)
A 47 year old female patient presented with pain and stiffness in his small hand joints. He had significant morning stiffness. In the next few months, he developed some difficulty swallowing, and progressive difficulty sitting up in bed and getting up from a chair. On examination he had dry cracking skin on the radial margins of his index fingers. His creatine kinase (CK) was 3000 U/L (Normal < 220 U/L).
1) The next best test for this patient is:
A 74 year old male patient was diagnosed with polymyositis. Over the last 7 years, he had progressive dysphagia and slowly progressive muscle weakness affecting his shoulder abductors, glutei, quadriceps, and forearm muscles. He has now become wheelchair bound. Immunosuppressive medications including glucocorticoids, methotrexate, azathioprine, mycophenolate, and intravenous immunoglobulin did not seem to have any significant effect on the course of his muscle disease. On examination he was an emaciated man with significant muscle wasting and proximal muscle weakness. He was unable to make a loop with his thumb and his middle finger. His creatine kinase was 349 U/L (normal < 220 U/L).
The next best test is:
A 53 year old diabetic lady was admitted with severe generalized myalgias and swelling of her upper arms, calf muscles and thighs. She was on metformin, glipizide, simvastatin, and enalapril. A recent bout of sinusitis was treated with a course of clarithromycin. On examination the patient had severe muscle tenderness, especially of the deltoids, quadriceps and calves. Muscle strength was difficult to evaluate because of severe muscle pain with minimal movement. Her CK was 375,000 U/L (normal < 220 U/L). Serum creatinine was 1.2 mg/dL. The patient was admitted for intravenous hydration.
The most appropriate management for this patient is:
A 32 year old female smoker presented with an erythematous scaly rash on her face and knuckles. She had profound proximal myopathy, dysphagia, and orthopnea. There was nailfold erythema and cuticular overgrowth. Her creatine kinase was 10,520 U/L (Normal < 220 U/L). With a working diagnosis of dermatomyositis, she was treated with high dose prednisone and methotrexate. As there was inadequate response in the next 2 months, methotrexate was switched to azathioprine, and eventually monthly intravenous immunoglobulin infusions were added, but her muscle weakness continued to worsen and creatine kinase did not go down.
The best management for this patient is:
A 45 year old female was seen in clinic as she has developed significant muscle aches, cold intolerance, fatigue, constipation, and a 10 lb. unintentional weight gain in the past 6 months. She complained of paresthesias of her thumbs, and index and middle fingers, especially at night. Her CK was 740 U/L (Normal < 220 U/L). On examination, her heart rate was 55/min, and BP was 145/90. She had facial and lower extremity dry skin, coarse facial features, and some painful proximal myopathy.
5) The test which is most likely to give the correct diagnosis is:
This patient has anti-synthetase syndrome. The dry cracking skin on the radial margins of his index fingers is described as 'mechanic's hands', which is a characteristic finding in anti-synthetase syndrome.
Spirometry, transfer factor and high resolution CT scan of lungs will help assess the most serious manifestation of the disease that will dictate treatment plan and prognosis – interstitial lung disease (ILD).
A muscle biopsy will confirm the diagnosis, but the diagnosis is already apparent.
EMG may be abnormal indicating myopathy rather than neuropathy, the patient's history and physical examination findings are already suggestive of an inflammatory myopathy and not a neuropathy. An echocardiogram is not the logical next test as pulmonary hypertension is much less common in anti-synthetase syndrome compared to ILD. A swallow evaluation may be relevant later, and may already confirm what is known and expected in antisynthetase syndrome, but will not help assess the most serious complication of the disease, that will dictate treatment plan and prognosis, ILD.
The presentation is suggestive of inclusion body myositis (IBM), where an underlying malignancy is not more common than that in the background population.a Hence CT scan of chest, abdomen, and pelvis, and colonoscopy are not likely to be helpful. Also, for a patient presenting so late in his life, limb girdle muscular dystrophy is distinctly unlikely. Also, the patient has dysphagia and distal weakness in certain muscle groups, which are features suggestive of IBM. The appropriate test will be a muscle biopsy: light microscopy is expected to show the characteristic rimmed vacuoles, and electron microscopy will show the abnormal filamentous bodies pathognomonic of IBM. A swallow evaluation may be relevant, and may already confirm what is known and expected in IBM. However, it will not help differentiate IBM from poly- or dermatomyositis.
The patient clearly has acute rhabdomyolysis, the likely cause of which is the addition of clarithromycin to simvastatin. Urinalysis may show false positive test for hemoglobin (indicating presence of myoglobin) but no RBCs, but will not help assess the response to hydration, and it not differentiate from other causes of severe CK elevation. Serial CK assessments in the next 7 days will help assess response to hydration, and rapid normalization of CK in the next week or so will help differentiate from inflammatory muscle diseases such as poly- or dermatomyositis, where CK is persistently elevated over weeks to months, especially if immunosuppressive therapy is not initiated. Autoantibody testing will not be relevant, as inflammatory muscle diseases are not suspects here. An EMG will also not be relevant, as it will not help in the diagnosis of rhabdomyolysis. Muscle biopsy, which may show evidence of a necrotizing myopathy, will not be helpful and hence not indicated in rhabdomyolysis. MRI scan of thigh muscles will also not be of any use in a patient with such widespread muscle involvement and such severe creatine kinase elevation, which is seen in rhabdomyolysis as opposed to diabetic myonecrosis or diabetic amyotropy, where the involvement is more focal, usually involving a single muscle group.
When dealing with multi-drug refractory dermatomyositis, an underlying malignancy always needs to be excluded. In a young female ovarian carcinoma is over-represented in patients with dermatomyositis. Also, as she is a smoker, a chest X-ray would be a relevant initial screening test for lung cancer.
ANA testing and myositis specific antibodies will not help further characterize the nature of multi-drug refractory dermatomyositis. EMG will not help further characterize the nature of refractory dermatomyositis. Also, though lying and sitting spirometry may help assess diaphragmatic weakness, it will not help in further evaluating the cause of multi-drug refractory dermatomyositis. Similarly, though a muscle biopsy will help confirm the diagnosis of dermatomyositis, it is not necessary in this patient as the diagnosis of dermatomyositis is not in question.
The description is consistent with a diagnosis of hypothyroidism. Serum aldolase, which is another muscle enzyme, will not help add much to the diagnosis of hypothyroidism. EMG will not add much to the diagnosis either, though it will confirm the diagnosis of carpal tunnel syndrome in this patient with overt hypothyroidism. An elevated TSH will suggest the diagnosis. If TSH is elevated, free T3 and free T4 should also be checked, which together with an elevated TSH, will help confirm the diagnosis of hypothyroidism. A muscle biopsy may show changes consistent with hypothyroid myopathy, but it is not required for the diagnosis. Chest X-ray will not be relevant in the diagnosis of hypothyroidism.
Last updated February 2015.