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Ruzurgi approved for Lambert-Eaton myasthenic syndrome in patients under age 17
Amifampridine (Ruzurgi) has been approved for the treatment of Lambert-Eaton myasthenic syndrome (LEMS), a rare autoimmune neuromuscular disorder, in patients aged 6 to less than 17 years, according to a statement from the Food and Drug Administration.
The approval is the first for a LEMS treatment specifically for pediatric patients.
“This approval will provide a much-needed treatment option for pediatric patients with LEMS who have significant weakness and fatigue that can often cause great difficulties with daily activities,” Billy Dunn, MD, director of the Division of Neurology Products in the FDA’s Center for Drug Evaluation and Research, said in the statement.
The prevalence of LEMS in pediatric patients is not known, but the overall prevalence of LEMS is estimated to be three per million individuals worldwide, according to the FDA press release.
Use of amifampridine in patients 6 to less than 17 years of age is supported by pharmacokinetic data in adult patients, pharmacokinetic modeling and simulation to identify the dosing regimen in pediatric patients, and safety data from pediatric patients 6 to less than 17 years of age.
A randomized, double-blind, placebo-controlled withdrawal study enrolled 32 adult patients who had taken amifampridine for at least 3 months. The study compared patients continuing on amifampridine with patients switched to placebo. Effectiveness was measured by the degree of change in a test that assessed the time it took the patient to rise from a chair, walk three meters, and return to the chair for three consecutive laps without pause. The patients who continued on amifampridine experienced less impairment compared with those switched to placebo. Effectiveness was also measured with a self-assessment scale for LEMS-related weakness. The scores indicated greater perceived weakening in the patients switched to placebo.
The most common side effects among amifampridine users were paresthesia, abdominal pain, indigestion, dizziness, and nausea. Side effects reported in pediatric patients were similar to those seen in adult patients. Seizures have been observed in patients without a history of seizures. Signs of hypersensitivity reactions include rash, hives, itching, fever, swelling, or trouble breathing.
The FDA granted this application Priority Review and Fast Track designations. Amifampridine also received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases.
The FDA granted the approval of amifampridine (Ruzurgi) to Jacobus Pharmaceutical Company.
Amifampridine (Ruzurgi) has been approved for the treatment of Lambert-Eaton myasthenic syndrome (LEMS), a rare autoimmune neuromuscular disorder, in patients aged 6 to less than 17 years, according to a statement from the Food and Drug Administration.
The approval is the first for a LEMS treatment specifically for pediatric patients.
“This approval will provide a much-needed treatment option for pediatric patients with LEMS who have significant weakness and fatigue that can often cause great difficulties with daily activities,” Billy Dunn, MD, director of the Division of Neurology Products in the FDA’s Center for Drug Evaluation and Research, said in the statement.
The prevalence of LEMS in pediatric patients is not known, but the overall prevalence of LEMS is estimated to be three per million individuals worldwide, according to the FDA press release.
Use of amifampridine in patients 6 to less than 17 years of age is supported by pharmacokinetic data in adult patients, pharmacokinetic modeling and simulation to identify the dosing regimen in pediatric patients, and safety data from pediatric patients 6 to less than 17 years of age.
A randomized, double-blind, placebo-controlled withdrawal study enrolled 32 adult patients who had taken amifampridine for at least 3 months. The study compared patients continuing on amifampridine with patients switched to placebo. Effectiveness was measured by the degree of change in a test that assessed the time it took the patient to rise from a chair, walk three meters, and return to the chair for three consecutive laps without pause. The patients who continued on amifampridine experienced less impairment compared with those switched to placebo. Effectiveness was also measured with a self-assessment scale for LEMS-related weakness. The scores indicated greater perceived weakening in the patients switched to placebo.
The most common side effects among amifampridine users were paresthesia, abdominal pain, indigestion, dizziness, and nausea. Side effects reported in pediatric patients were similar to those seen in adult patients. Seizures have been observed in patients without a history of seizures. Signs of hypersensitivity reactions include rash, hives, itching, fever, swelling, or trouble breathing.
The FDA granted this application Priority Review and Fast Track designations. Amifampridine also received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases.
The FDA granted the approval of amifampridine (Ruzurgi) to Jacobus Pharmaceutical Company.
Amifampridine (Ruzurgi) has been approved for the treatment of Lambert-Eaton myasthenic syndrome (LEMS), a rare autoimmune neuromuscular disorder, in patients aged 6 to less than 17 years, according to a statement from the Food and Drug Administration.
The approval is the first for a LEMS treatment specifically for pediatric patients.
“This approval will provide a much-needed treatment option for pediatric patients with LEMS who have significant weakness and fatigue that can often cause great difficulties with daily activities,” Billy Dunn, MD, director of the Division of Neurology Products in the FDA’s Center for Drug Evaluation and Research, said in the statement.
The prevalence of LEMS in pediatric patients is not known, but the overall prevalence of LEMS is estimated to be three per million individuals worldwide, according to the FDA press release.
Use of amifampridine in patients 6 to less than 17 years of age is supported by pharmacokinetic data in adult patients, pharmacokinetic modeling and simulation to identify the dosing regimen in pediatric patients, and safety data from pediatric patients 6 to less than 17 years of age.
A randomized, double-blind, placebo-controlled withdrawal study enrolled 32 adult patients who had taken amifampridine for at least 3 months. The study compared patients continuing on amifampridine with patients switched to placebo. Effectiveness was measured by the degree of change in a test that assessed the time it took the patient to rise from a chair, walk three meters, and return to the chair for three consecutive laps without pause. The patients who continued on amifampridine experienced less impairment compared with those switched to placebo. Effectiveness was also measured with a self-assessment scale for LEMS-related weakness. The scores indicated greater perceived weakening in the patients switched to placebo.
The most common side effects among amifampridine users were paresthesia, abdominal pain, indigestion, dizziness, and nausea. Side effects reported in pediatric patients were similar to those seen in adult patients. Seizures have been observed in patients without a history of seizures. Signs of hypersensitivity reactions include rash, hives, itching, fever, swelling, or trouble breathing.
The FDA granted this application Priority Review and Fast Track designations. Amifampridine also received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases.
The FDA granted the approval of amifampridine (Ruzurgi) to Jacobus Pharmaceutical Company.
Physical activity slows cognitive decline in patients with Parkinson’s disease
PHILADELPHIA – according to Sneha Mantri, MD, of Duke University in Durham, N.C., and colleagues, who presented the results of their study at the annual meeting of the American Academy of Neurology.
Physical activity is an important component of the management of Parkinson’s disease and is shown to mitigate cognitive decline among patients with moderate disease, said Dr. Mantri and colleagues. “Exercise levels in de novo and early disease may influence risk of future cognitive decline; early disease also presents an opportunity for early intervention and possible disease modification,” Dr. Mantri said.
Physical activity levels in early disease are known to be low, but the effects of activity on cognition are currently unclear. To assess the relationship between physical activity and cognition, Dr. Mantri and colleagues examined patients with Parkinson’s disease who were enrolled in the prospective Parkinson’s Progression Markers Initiative (PPMI) cohort. At annual study visits, participants completed the Physical Activity Scale for the Elderly (PASE), a validated self-reported questionnaire assessing household, leisure, and work activities over the previous 7 days. The researchers used a linear mixed-effects model to compare rates of change in the Montreal Cognitive Assessment (MoCA) according to PASE scores; covariates included age, sex, Unified Parkinson’s Disease Rating Scale (UPDRS) part III score, and baseline MoCA.
A total of 379 patients completed at least one PASE questionnaire over the course of the study. PASE scores in this cohort have been previously described (Mantri S et al. J Park Dis. 2018;8[1]:107-11). Although overall rates of cognitive decline are known to be modest in this early cohort, PASE over time has a significant effect on MoCA during follow-up (P = 0.02) which suggest that higher levels of activity throughout disease are associated with better cognitive performance.
Dr. Mantri had nothing to disclose. Among her coauthors, Dr. Tropea received personal compensation from Genzyme and Medtronics and research support from Sanofi. Dr. Morley had nothing to disclose.
SOURCE: Mantri S et al. AAN 2019, Abstract P2.8-021.
PHILADELPHIA – according to Sneha Mantri, MD, of Duke University in Durham, N.C., and colleagues, who presented the results of their study at the annual meeting of the American Academy of Neurology.
Physical activity is an important component of the management of Parkinson’s disease and is shown to mitigate cognitive decline among patients with moderate disease, said Dr. Mantri and colleagues. “Exercise levels in de novo and early disease may influence risk of future cognitive decline; early disease also presents an opportunity for early intervention and possible disease modification,” Dr. Mantri said.
Physical activity levels in early disease are known to be low, but the effects of activity on cognition are currently unclear. To assess the relationship between physical activity and cognition, Dr. Mantri and colleagues examined patients with Parkinson’s disease who were enrolled in the prospective Parkinson’s Progression Markers Initiative (PPMI) cohort. At annual study visits, participants completed the Physical Activity Scale for the Elderly (PASE), a validated self-reported questionnaire assessing household, leisure, and work activities over the previous 7 days. The researchers used a linear mixed-effects model to compare rates of change in the Montreal Cognitive Assessment (MoCA) according to PASE scores; covariates included age, sex, Unified Parkinson’s Disease Rating Scale (UPDRS) part III score, and baseline MoCA.
A total of 379 patients completed at least one PASE questionnaire over the course of the study. PASE scores in this cohort have been previously described (Mantri S et al. J Park Dis. 2018;8[1]:107-11). Although overall rates of cognitive decline are known to be modest in this early cohort, PASE over time has a significant effect on MoCA during follow-up (P = 0.02) which suggest that higher levels of activity throughout disease are associated with better cognitive performance.
Dr. Mantri had nothing to disclose. Among her coauthors, Dr. Tropea received personal compensation from Genzyme and Medtronics and research support from Sanofi. Dr. Morley had nothing to disclose.
SOURCE: Mantri S et al. AAN 2019, Abstract P2.8-021.
PHILADELPHIA – according to Sneha Mantri, MD, of Duke University in Durham, N.C., and colleagues, who presented the results of their study at the annual meeting of the American Academy of Neurology.
Physical activity is an important component of the management of Parkinson’s disease and is shown to mitigate cognitive decline among patients with moderate disease, said Dr. Mantri and colleagues. “Exercise levels in de novo and early disease may influence risk of future cognitive decline; early disease also presents an opportunity for early intervention and possible disease modification,” Dr. Mantri said.
Physical activity levels in early disease are known to be low, but the effects of activity on cognition are currently unclear. To assess the relationship between physical activity and cognition, Dr. Mantri and colleagues examined patients with Parkinson’s disease who were enrolled in the prospective Parkinson’s Progression Markers Initiative (PPMI) cohort. At annual study visits, participants completed the Physical Activity Scale for the Elderly (PASE), a validated self-reported questionnaire assessing household, leisure, and work activities over the previous 7 days. The researchers used a linear mixed-effects model to compare rates of change in the Montreal Cognitive Assessment (MoCA) according to PASE scores; covariates included age, sex, Unified Parkinson’s Disease Rating Scale (UPDRS) part III score, and baseline MoCA.
A total of 379 patients completed at least one PASE questionnaire over the course of the study. PASE scores in this cohort have been previously described (Mantri S et al. J Park Dis. 2018;8[1]:107-11). Although overall rates of cognitive decline are known to be modest in this early cohort, PASE over time has a significant effect on MoCA during follow-up (P = 0.02) which suggest that higher levels of activity throughout disease are associated with better cognitive performance.
Dr. Mantri had nothing to disclose. Among her coauthors, Dr. Tropea received personal compensation from Genzyme and Medtronics and research support from Sanofi. Dr. Morley had nothing to disclose.
SOURCE: Mantri S et al. AAN 2019, Abstract P2.8-021.
REPORTING FROM AAN 2019
Key clinical point: Physical activity is associated with slower cognitive decline in patients with de novo Parkinson’s disease.
Major finding: Higher scores on the Physical Activity Scale for the Elderly over time had a significant effect on cognitive function.
Study details: A prospective study of 379 patients enrolled in the Parkinson’s Progression Markers Initiative.
Disclosures: Dr. Mantri had no relevant financial disclosures. Among her coauthors, Dr. Tropea received personal compensation from Genzyme and Medtronics and research support from Sanofi. Dr. Morley had nothing to disclose.
Source: Mantri S et al. AAN 2019, Abstract P2.8-021.
Is pro soccer a risk factor for ALS?
according to Italian researchers who reviewed trading cards of about 25,000 male professional soccer players who played in Italy. The researchers then scanned news reports to find which of those players developed the rare neurologic disease. Players who developed ALS were a much younger age at diagnosis when compared with the general population, according to the researchers, who will present their findings at the annual meeting of the American Academy of Neurology.
While the findings might implicate professional-level soccer in the development of ALS, there could be other factors at work, said lead author Ettore Beghi, MD, of the Mario Negri Institute for Pharmacological Research, Milan. “Repeated traumatic events, heavy physical exercise, and substance use could also be factors in the increased ALS risk among soccer players,” Dr. Beghi said in a news release. “In addition, genetics may play a role.”
The ALS-related deaths of several Italian pro soccer players sparked suggestions that the disease and the sport could be somehow linked, according to Dr. Beghi and colleagues. To determine whether professional soccer players are at increased ALS risk, they reviewed the archives of the country’s major soccer card publisher from the years 1959 to 2000, recording the name, date, and place of birth; field position; and team history for the tens of thousands of players they identified.
News reports revealed that 33 players in that cohort developed ALS, compared with 17.6 cases that would be expected based on Italian general population estimates, according to Dr. Beghi and colleagues.
The number of cases per 100,000 person-years was 1.9 for all the soccer players, and 4.7 for those who were younger than 45 years at diagnosis, researchers said. In general, soccer players were younger at diagnosis, with a median age of ALS onset of 43.3 years, versus 62.5 years in the general population, they added.
These findings cannot be applied to those who play soccer below the professional level, since only professional athletes were studied, Dr. Beghi said. Moreover, the results should not be construed to suggest that people avoid playing soccer, he said, adding that the researchers had few specific details on the players’ ALS diagnoses.
Patients with ALS more often report head injuries, compared with the general population, while links between exercise and ALS have been found in some studies, but not others, according to the researchers.
“Clinical and experimental observations suggest an association between ALS and use of nonsteroidal anti-inflammatory agents and dietary supplements, including branched chain amino acids,” researchers added in the abstract for their report.
The study by Dr. Beghi and colleagues was supported by the Mario Negri Institute in Milan.
Source: Beghi E et al. AAN 2019, Abstract S1.001.
according to Italian researchers who reviewed trading cards of about 25,000 male professional soccer players who played in Italy. The researchers then scanned news reports to find which of those players developed the rare neurologic disease. Players who developed ALS were a much younger age at diagnosis when compared with the general population, according to the researchers, who will present their findings at the annual meeting of the American Academy of Neurology.
While the findings might implicate professional-level soccer in the development of ALS, there could be other factors at work, said lead author Ettore Beghi, MD, of the Mario Negri Institute for Pharmacological Research, Milan. “Repeated traumatic events, heavy physical exercise, and substance use could also be factors in the increased ALS risk among soccer players,” Dr. Beghi said in a news release. “In addition, genetics may play a role.”
The ALS-related deaths of several Italian pro soccer players sparked suggestions that the disease and the sport could be somehow linked, according to Dr. Beghi and colleagues. To determine whether professional soccer players are at increased ALS risk, they reviewed the archives of the country’s major soccer card publisher from the years 1959 to 2000, recording the name, date, and place of birth; field position; and team history for the tens of thousands of players they identified.
News reports revealed that 33 players in that cohort developed ALS, compared with 17.6 cases that would be expected based on Italian general population estimates, according to Dr. Beghi and colleagues.
The number of cases per 100,000 person-years was 1.9 for all the soccer players, and 4.7 for those who were younger than 45 years at diagnosis, researchers said. In general, soccer players were younger at diagnosis, with a median age of ALS onset of 43.3 years, versus 62.5 years in the general population, they added.
These findings cannot be applied to those who play soccer below the professional level, since only professional athletes were studied, Dr. Beghi said. Moreover, the results should not be construed to suggest that people avoid playing soccer, he said, adding that the researchers had few specific details on the players’ ALS diagnoses.
Patients with ALS more often report head injuries, compared with the general population, while links between exercise and ALS have been found in some studies, but not others, according to the researchers.
“Clinical and experimental observations suggest an association between ALS and use of nonsteroidal anti-inflammatory agents and dietary supplements, including branched chain amino acids,” researchers added in the abstract for their report.
The study by Dr. Beghi and colleagues was supported by the Mario Negri Institute in Milan.
Source: Beghi E et al. AAN 2019, Abstract S1.001.
according to Italian researchers who reviewed trading cards of about 25,000 male professional soccer players who played in Italy. The researchers then scanned news reports to find which of those players developed the rare neurologic disease. Players who developed ALS were a much younger age at diagnosis when compared with the general population, according to the researchers, who will present their findings at the annual meeting of the American Academy of Neurology.
While the findings might implicate professional-level soccer in the development of ALS, there could be other factors at work, said lead author Ettore Beghi, MD, of the Mario Negri Institute for Pharmacological Research, Milan. “Repeated traumatic events, heavy physical exercise, and substance use could also be factors in the increased ALS risk among soccer players,” Dr. Beghi said in a news release. “In addition, genetics may play a role.”
The ALS-related deaths of several Italian pro soccer players sparked suggestions that the disease and the sport could be somehow linked, according to Dr. Beghi and colleagues. To determine whether professional soccer players are at increased ALS risk, they reviewed the archives of the country’s major soccer card publisher from the years 1959 to 2000, recording the name, date, and place of birth; field position; and team history for the tens of thousands of players they identified.
News reports revealed that 33 players in that cohort developed ALS, compared with 17.6 cases that would be expected based on Italian general population estimates, according to Dr. Beghi and colleagues.
The number of cases per 100,000 person-years was 1.9 for all the soccer players, and 4.7 for those who were younger than 45 years at diagnosis, researchers said. In general, soccer players were younger at diagnosis, with a median age of ALS onset of 43.3 years, versus 62.5 years in the general population, they added.
These findings cannot be applied to those who play soccer below the professional level, since only professional athletes were studied, Dr. Beghi said. Moreover, the results should not be construed to suggest that people avoid playing soccer, he said, adding that the researchers had few specific details on the players’ ALS diagnoses.
Patients with ALS more often report head injuries, compared with the general population, while links between exercise and ALS have been found in some studies, but not others, according to the researchers.
“Clinical and experimental observations suggest an association between ALS and use of nonsteroidal anti-inflammatory agents and dietary supplements, including branched chain amino acids,” researchers added in the abstract for their report.
The study by Dr. Beghi and colleagues was supported by the Mario Negri Institute in Milan.
Source: Beghi E et al. AAN 2019, Abstract S1.001.
FROM AAN 2019
Myositis mimics: Clues for making the right diagnosis
A number of conditions can mimic myositis, but clues that can point to the correct diagnosis are often present in cases involving the mimics, according to Lisa Christopher-Stine, MD.
For example, elevated levels of certain muscle enzymes are an important source of diagnostic information, Dr. Christopher-Stine, director of the Johns Hopkins Myositis Center, Baltimore, said at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.
Isolated elevations in aldolase can be seen in connective tissue–associated interstitial lung disease or in patients with fascial edema, and aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase (LDH), and creatine kinase (CK) levels can also be helpful, she explained.
The latter can also be elevated in the absence of muscle disease, for example, in healthy individuals following exercise. CK peaks at 24 hours after exercise before returning to baseline by 72 hours. In an experimental setting, a threefold increase in CK levels has been seen at 8-24 hours after exercise, Dr. Christopher-Stine said.
“HyperCKemia”
Trauma from causes such as intramuscular injection, electromyography (EMG), major surgery, or biopsy can also lead to increased CK levels. Motor neuron disease can also cause such increases. In one study, 75% of patients with amyotrophic lateral sclerosis had a mean twofold increase in CK levels, she said.
Asymptomatic CK elevations may also represent presymptomatic myopathies, type 1 or 2 macro-CK, manual labor occupations, or they may be idiopathic.
Race can play a role in CK levels as well. Black people tend to have higher CK levels than white people, she said, noting that one study of more than 10,000 adults showed that black race was strongly associated with CK, and that body composition largely explained differences in CK by age, but not by race/ethnicity (Medicine. Aug 2016;95[33]:e4344).
“So elevated CK may not herald any discernible illness,” she said.
Dr. Christopher-Stine described a case involving an otherwise healthy 30-year-old man with a CK level of 695 IU/L that was found incidentally. He had a desk job, no recent travel, and denied weakness, myalgias, joint pain, dysphagia, shortness of breath, and fevers. In this case, the elevated CK was felt to be secondary to his African American race given that other causes were ruled out.
Another case involved a 72-year-old man with left-arm pain. A cardiac event was ruled out, and CK was found to be about 4,500 IU/L. He reported “flare-ups” of diffuse swelling of the hands and feet. X-rays showed concerning signs of erosions. His transaminases and electromyogram were normal; he reported no weakness or myalgia; and an MRI showed no muscle edema. He was diagnosed with macro-CK, which refers to CK with an increased molecular weight. A clue to this diagnosis is a normal liver function test. In some cases, muscle/brain CK levels (CK-MB) are elevated and higher than total CK, she noted.
She presented an algorithm for the diagnostic work-up of patients presenting with elevated CK of unclear significance. Her recommended approach involves repeat CK assessment and a closer look at family history, medication, drug/toxin history, examination for weakness and neurologic abnormalities, and additional lab assessments in those whose levels remain elevated. In those in whom a diagnosis is not identified, the algorithm calls for observation every 3 months – including physical examination and labs – in asymptomatic patients with levels at less than five times the upper limit of normal, and further evaluation, including EMG with nerve-conduction velocity testing, muscle biopsy, and MRI in those with (or who later develop) marked elevation greater than five times the upper limit of normal and/or symptoms.
Patient assessment
The physical examination should involve localization and quantification of weakness, and assessment for fever, rash, atrophy/wasting/scooping of forearms, fasciculations, cranial nerve involvement, Raynaud’s phenomenon, nailfold capillary changes, arthritis, calcinosis, “mechanic’s hands,” signs of other autoimmune diseases, and lung crackles. Initial laboratory testing should include HIV and hepatitis B and C testing; measurement of CK, AST, ALT, aldolase, thyroid-stimulating hormone, and magnesium levels; a comprehensive metabolic panel and complete blood count; and measurement of erythrocyte sedimentation rate and C-reactive protein.
“Weakness may be secondary to a neuropathy, myopathy, or a problem at the neuropathic junction. Many causes of weakness can be readily identified by careful history taking, focused physical examination, and directed laboratory evaluation,” she said.
Features pointing toward a diagnosis of myositis include characteristic rashes, gradual symptom onset, proximal limb and truncal weakness, other connective tissue disease features such as Raynaud’s and arthritis, and the presence of lung disease, including interstitial lung disease or unexplained infiltrates, she said.
Features pointing away from a diagnosis of myositis include a family history of a similar illness, weakness that is associated with eating or fasting, neurologic signs, cranial nerve involvement, fasciculations, severe muscle cramping, early atrophy, and creatine phosphokinase levels that are either less than 2 times or more than 100 times the upper limit of normal.
Among the conditions to consider in the presence of the features that point away from a myositis diagnosis are muscular dystrophies, metabolic myopathies, and toxic (drug-induced) myopathies, to name a few, Dr. Christopher-Stine said.
She described a number of other cases to illustrate the need for – and to help develop – a differential diagnosis in patients presenting with apparent myositis.
Muscular dystrophies
A 38-year-old woman with limited scleroderma and anti-PM/Scl autoantibodies developed proximal weakness over 9 months and was eventually unable to walk up a flight of stairs. She had heliotrope rash and Gottron’s sign, her serum CK was 723 IU/L, and EMG showed an irritable myopathy.
Muscle biopsy showed inflammation, and she was treated with prednisone, but this led to worsening weakness. She complained of prominent fatigue and double vision at the end of the day, and these symptoms did not improve with steroids.
Anti-AChR and anti-MuSK antibodies were negative, but she had a decrement on repetitive nerve stimulation testing.
She was treated with pyridostigmine and experienced near-complete resolution of her proximal weakness and double vision. A chest CT scan showed thymic hyperplasia; thymectomy was recommended.
In another case, a 19-year-old woman who complained of leg pain after exercise was found to have intact strength but asymmetric calf hypertrophy. Her CK level was 5,000 IU/L, and she was referred to rule out acute myositis.
A quadriceps biopsy was performed and showed abnormal dystrophin immunostaining but no inflammation. A molecular genetic analysis showed deletions in Xp21 and she was diagnosed as a manifesting carrier of Duchenne muscular dystrophy. It was recommended that she be evaluated for cardiomyopathy and receive genetic counseling.
A number of other cases presented by Dr. Christopher-Stine highlighted other muscular dystrophies that can mimic myositis, such as:
- Myotonic dystrophies. These are more often type 2 than type 1. Myotonia may be subtle, cataracts are seen early in all patients, and cardiac arrhythmias are common.
- Limb girdle muscular dystrophy type 2 B (dysferlinopathy). In the legs, this often affects the gastrocnemius muscle, and this will be visible on MRI. In the arms, it most often affects the biceps, sparing the deltoids. CKs are typically very high.
- Facioscapulohumeral muscular dystrophy (FSHD). This involves facial weakness, especially obicularis oris, in 95% of cases, as well as scapular weakness and winging, inflammation on muscle biopsy in 75% of cases, and typically is endomysial or perivascular.
Metabolic myopathies
Among metabolic myopathies that can mimic myositis are disorders of carbohydrate metabolism such as McArdle’s disease, 6-phosphofructokinase deficiency, and Pompe’s disease (adult acid maltase deficiency); disorders of lipid metabolism such as carnitine deficiency and carnitine palmitoyltransferase 2 (CPT2) deficiency; and disorders of purine metabolism, such as myoadenylate deaminase deficiency.
A 27-year-old patient who complained of weakness with activity was referred for possible myositis and was found to have a CK of 3,650 IU/L that never normalized. Physical examination showed intact strength and no muscle atrophy or fasciculations, and an enzyme stain for myophosphorylase showed a normal staining pattern and complete absence of the enzyme on quadricep biopsy. A 22-year-old man with similar symptoms plus recent onset of brown/black urine after physical activity had CK of 110,000 IU/L when symptomatic, and also underwent biopsy after being referred for possible myopathy. Both patients were ultimately diagnosed with CPT2 deficiency, which is associated with risk of rhabdomyolysis triggered by prolonged exercise, diets low in carbohydrates and high in fat, or by fasting.
Myalgias are common, and CK levels are normal or only mildly elevated between episodes in CPT2 deficiency, Dr. Christopher-Stine noted.
Toxic myopathies
Drug-induced myopathies are among the most common etiologies of myopathy and can range from mild myalgia to massive rhabdomyolysis. They can cause mild to severe weakness and may be chronic. The mechanism of toxic injury is direct via myotoxins such as ethyl alcohol, glucocorticoids, lipid-lowering drugs, cocaine, antimalarial drugs, antipsychotic drugs, colchicine, and Ipecac syrup.
One case described by Dr. Christopher-Stine involved “statin myopathy.”
A 55-year-old man on atorvastatin complained of myalgias and brown urine, but had no definitive weakness. He had intact strength and diffuse myalgias that weren’t reproducible. His CK was 45,000 IU/L.
Statin myopathy, as seen in this patient, is usually self-limited and is not associated with autoimmunity or with anti-HMGCR autoantibody positivity.
The mechanism is unknown, but statin myopathy has an incidence of 1.2 per 10,000 patient-years. Myalgias, myositis, rhabdomyolysis, and asymptomatic hyperCKemia are commonly seen. This is in contrast to the immune-mediated necrotizing myelitis that can be secondary to statins and is responsive to immunosuppression, she noted.
Other myositis mimics
In addition to these common myositis mimics, certain other neurologic diseases (such as ALS and cervical myelopathy), endocrinopathies (such as hypothyroidism), and infections (like toxoplasmosis) can also be mistaken for myositis, Dr. Christopher-Stine said, noting that cases illustrating these mimics underscore the need for careful consideration of possible alternate diagnoses.
“While most noninflammatory myopathies are self-limited or have no therapies available, knowing the diagnosis can be helpful for genetic counseling of the patient and family, for mitigating risk factors, and for precluding the use of unwarranted immunosuppressive agents,” she said.
Dr. Christopher-Stine reported having intellectual property interest in a novel Inova Diagnostics autoantibody assay detection for anti-HMGCR. She was also the safety officer for the JBT-101 Trial sponsored by Corbus and funded by the National Institutes of Health.
A number of conditions can mimic myositis, but clues that can point to the correct diagnosis are often present in cases involving the mimics, according to Lisa Christopher-Stine, MD.
For example, elevated levels of certain muscle enzymes are an important source of diagnostic information, Dr. Christopher-Stine, director of the Johns Hopkins Myositis Center, Baltimore, said at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.
Isolated elevations in aldolase can be seen in connective tissue–associated interstitial lung disease or in patients with fascial edema, and aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase (LDH), and creatine kinase (CK) levels can also be helpful, she explained.
The latter can also be elevated in the absence of muscle disease, for example, in healthy individuals following exercise. CK peaks at 24 hours after exercise before returning to baseline by 72 hours. In an experimental setting, a threefold increase in CK levels has been seen at 8-24 hours after exercise, Dr. Christopher-Stine said.
“HyperCKemia”
Trauma from causes such as intramuscular injection, electromyography (EMG), major surgery, or biopsy can also lead to increased CK levels. Motor neuron disease can also cause such increases. In one study, 75% of patients with amyotrophic lateral sclerosis had a mean twofold increase in CK levels, she said.
Asymptomatic CK elevations may also represent presymptomatic myopathies, type 1 or 2 macro-CK, manual labor occupations, or they may be idiopathic.
Race can play a role in CK levels as well. Black people tend to have higher CK levels than white people, she said, noting that one study of more than 10,000 adults showed that black race was strongly associated with CK, and that body composition largely explained differences in CK by age, but not by race/ethnicity (Medicine. Aug 2016;95[33]:e4344).
“So elevated CK may not herald any discernible illness,” she said.
Dr. Christopher-Stine described a case involving an otherwise healthy 30-year-old man with a CK level of 695 IU/L that was found incidentally. He had a desk job, no recent travel, and denied weakness, myalgias, joint pain, dysphagia, shortness of breath, and fevers. In this case, the elevated CK was felt to be secondary to his African American race given that other causes were ruled out.
Another case involved a 72-year-old man with left-arm pain. A cardiac event was ruled out, and CK was found to be about 4,500 IU/L. He reported “flare-ups” of diffuse swelling of the hands and feet. X-rays showed concerning signs of erosions. His transaminases and electromyogram were normal; he reported no weakness or myalgia; and an MRI showed no muscle edema. He was diagnosed with macro-CK, which refers to CK with an increased molecular weight. A clue to this diagnosis is a normal liver function test. In some cases, muscle/brain CK levels (CK-MB) are elevated and higher than total CK, she noted.
She presented an algorithm for the diagnostic work-up of patients presenting with elevated CK of unclear significance. Her recommended approach involves repeat CK assessment and a closer look at family history, medication, drug/toxin history, examination for weakness and neurologic abnormalities, and additional lab assessments in those whose levels remain elevated. In those in whom a diagnosis is not identified, the algorithm calls for observation every 3 months – including physical examination and labs – in asymptomatic patients with levels at less than five times the upper limit of normal, and further evaluation, including EMG with nerve-conduction velocity testing, muscle biopsy, and MRI in those with (or who later develop) marked elevation greater than five times the upper limit of normal and/or symptoms.
Patient assessment
The physical examination should involve localization and quantification of weakness, and assessment for fever, rash, atrophy/wasting/scooping of forearms, fasciculations, cranial nerve involvement, Raynaud’s phenomenon, nailfold capillary changes, arthritis, calcinosis, “mechanic’s hands,” signs of other autoimmune diseases, and lung crackles. Initial laboratory testing should include HIV and hepatitis B and C testing; measurement of CK, AST, ALT, aldolase, thyroid-stimulating hormone, and magnesium levels; a comprehensive metabolic panel and complete blood count; and measurement of erythrocyte sedimentation rate and C-reactive protein.
“Weakness may be secondary to a neuropathy, myopathy, or a problem at the neuropathic junction. Many causes of weakness can be readily identified by careful history taking, focused physical examination, and directed laboratory evaluation,” she said.
Features pointing toward a diagnosis of myositis include characteristic rashes, gradual symptom onset, proximal limb and truncal weakness, other connective tissue disease features such as Raynaud’s and arthritis, and the presence of lung disease, including interstitial lung disease or unexplained infiltrates, she said.
Features pointing away from a diagnosis of myositis include a family history of a similar illness, weakness that is associated with eating or fasting, neurologic signs, cranial nerve involvement, fasciculations, severe muscle cramping, early atrophy, and creatine phosphokinase levels that are either less than 2 times or more than 100 times the upper limit of normal.
Among the conditions to consider in the presence of the features that point away from a myositis diagnosis are muscular dystrophies, metabolic myopathies, and toxic (drug-induced) myopathies, to name a few, Dr. Christopher-Stine said.
She described a number of other cases to illustrate the need for – and to help develop – a differential diagnosis in patients presenting with apparent myositis.
Muscular dystrophies
A 38-year-old woman with limited scleroderma and anti-PM/Scl autoantibodies developed proximal weakness over 9 months and was eventually unable to walk up a flight of stairs. She had heliotrope rash and Gottron’s sign, her serum CK was 723 IU/L, and EMG showed an irritable myopathy.
Muscle biopsy showed inflammation, and she was treated with prednisone, but this led to worsening weakness. She complained of prominent fatigue and double vision at the end of the day, and these symptoms did not improve with steroids.
Anti-AChR and anti-MuSK antibodies were negative, but she had a decrement on repetitive nerve stimulation testing.
She was treated with pyridostigmine and experienced near-complete resolution of her proximal weakness and double vision. A chest CT scan showed thymic hyperplasia; thymectomy was recommended.
In another case, a 19-year-old woman who complained of leg pain after exercise was found to have intact strength but asymmetric calf hypertrophy. Her CK level was 5,000 IU/L, and she was referred to rule out acute myositis.
A quadriceps biopsy was performed and showed abnormal dystrophin immunostaining but no inflammation. A molecular genetic analysis showed deletions in Xp21 and she was diagnosed as a manifesting carrier of Duchenne muscular dystrophy. It was recommended that she be evaluated for cardiomyopathy and receive genetic counseling.
A number of other cases presented by Dr. Christopher-Stine highlighted other muscular dystrophies that can mimic myositis, such as:
- Myotonic dystrophies. These are more often type 2 than type 1. Myotonia may be subtle, cataracts are seen early in all patients, and cardiac arrhythmias are common.
- Limb girdle muscular dystrophy type 2 B (dysferlinopathy). In the legs, this often affects the gastrocnemius muscle, and this will be visible on MRI. In the arms, it most often affects the biceps, sparing the deltoids. CKs are typically very high.
- Facioscapulohumeral muscular dystrophy (FSHD). This involves facial weakness, especially obicularis oris, in 95% of cases, as well as scapular weakness and winging, inflammation on muscle biopsy in 75% of cases, and typically is endomysial or perivascular.
Metabolic myopathies
Among metabolic myopathies that can mimic myositis are disorders of carbohydrate metabolism such as McArdle’s disease, 6-phosphofructokinase deficiency, and Pompe’s disease (adult acid maltase deficiency); disorders of lipid metabolism such as carnitine deficiency and carnitine palmitoyltransferase 2 (CPT2) deficiency; and disorders of purine metabolism, such as myoadenylate deaminase deficiency.
A 27-year-old patient who complained of weakness with activity was referred for possible myositis and was found to have a CK of 3,650 IU/L that never normalized. Physical examination showed intact strength and no muscle atrophy or fasciculations, and an enzyme stain for myophosphorylase showed a normal staining pattern and complete absence of the enzyme on quadricep biopsy. A 22-year-old man with similar symptoms plus recent onset of brown/black urine after physical activity had CK of 110,000 IU/L when symptomatic, and also underwent biopsy after being referred for possible myopathy. Both patients were ultimately diagnosed with CPT2 deficiency, which is associated with risk of rhabdomyolysis triggered by prolonged exercise, diets low in carbohydrates and high in fat, or by fasting.
Myalgias are common, and CK levels are normal or only mildly elevated between episodes in CPT2 deficiency, Dr. Christopher-Stine noted.
Toxic myopathies
Drug-induced myopathies are among the most common etiologies of myopathy and can range from mild myalgia to massive rhabdomyolysis. They can cause mild to severe weakness and may be chronic. The mechanism of toxic injury is direct via myotoxins such as ethyl alcohol, glucocorticoids, lipid-lowering drugs, cocaine, antimalarial drugs, antipsychotic drugs, colchicine, and Ipecac syrup.
One case described by Dr. Christopher-Stine involved “statin myopathy.”
A 55-year-old man on atorvastatin complained of myalgias and brown urine, but had no definitive weakness. He had intact strength and diffuse myalgias that weren’t reproducible. His CK was 45,000 IU/L.
Statin myopathy, as seen in this patient, is usually self-limited and is not associated with autoimmunity or with anti-HMGCR autoantibody positivity.
The mechanism is unknown, but statin myopathy has an incidence of 1.2 per 10,000 patient-years. Myalgias, myositis, rhabdomyolysis, and asymptomatic hyperCKemia are commonly seen. This is in contrast to the immune-mediated necrotizing myelitis that can be secondary to statins and is responsive to immunosuppression, she noted.
Other myositis mimics
In addition to these common myositis mimics, certain other neurologic diseases (such as ALS and cervical myelopathy), endocrinopathies (such as hypothyroidism), and infections (like toxoplasmosis) can also be mistaken for myositis, Dr. Christopher-Stine said, noting that cases illustrating these mimics underscore the need for careful consideration of possible alternate diagnoses.
“While most noninflammatory myopathies are self-limited or have no therapies available, knowing the diagnosis can be helpful for genetic counseling of the patient and family, for mitigating risk factors, and for precluding the use of unwarranted immunosuppressive agents,” she said.
Dr. Christopher-Stine reported having intellectual property interest in a novel Inova Diagnostics autoantibody assay detection for anti-HMGCR. She was also the safety officer for the JBT-101 Trial sponsored by Corbus and funded by the National Institutes of Health.
A number of conditions can mimic myositis, but clues that can point to the correct diagnosis are often present in cases involving the mimics, according to Lisa Christopher-Stine, MD.
For example, elevated levels of certain muscle enzymes are an important source of diagnostic information, Dr. Christopher-Stine, director of the Johns Hopkins Myositis Center, Baltimore, said at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.
Isolated elevations in aldolase can be seen in connective tissue–associated interstitial lung disease or in patients with fascial edema, and aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase (LDH), and creatine kinase (CK) levels can also be helpful, she explained.
The latter can also be elevated in the absence of muscle disease, for example, in healthy individuals following exercise. CK peaks at 24 hours after exercise before returning to baseline by 72 hours. In an experimental setting, a threefold increase in CK levels has been seen at 8-24 hours after exercise, Dr. Christopher-Stine said.
“HyperCKemia”
Trauma from causes such as intramuscular injection, electromyography (EMG), major surgery, or biopsy can also lead to increased CK levels. Motor neuron disease can also cause such increases. In one study, 75% of patients with amyotrophic lateral sclerosis had a mean twofold increase in CK levels, she said.
Asymptomatic CK elevations may also represent presymptomatic myopathies, type 1 or 2 macro-CK, manual labor occupations, or they may be idiopathic.
Race can play a role in CK levels as well. Black people tend to have higher CK levels than white people, she said, noting that one study of more than 10,000 adults showed that black race was strongly associated with CK, and that body composition largely explained differences in CK by age, but not by race/ethnicity (Medicine. Aug 2016;95[33]:e4344).
“So elevated CK may not herald any discernible illness,” she said.
Dr. Christopher-Stine described a case involving an otherwise healthy 30-year-old man with a CK level of 695 IU/L that was found incidentally. He had a desk job, no recent travel, and denied weakness, myalgias, joint pain, dysphagia, shortness of breath, and fevers. In this case, the elevated CK was felt to be secondary to his African American race given that other causes were ruled out.
Another case involved a 72-year-old man with left-arm pain. A cardiac event was ruled out, and CK was found to be about 4,500 IU/L. He reported “flare-ups” of diffuse swelling of the hands and feet. X-rays showed concerning signs of erosions. His transaminases and electromyogram were normal; he reported no weakness or myalgia; and an MRI showed no muscle edema. He was diagnosed with macro-CK, which refers to CK with an increased molecular weight. A clue to this diagnosis is a normal liver function test. In some cases, muscle/brain CK levels (CK-MB) are elevated and higher than total CK, she noted.
She presented an algorithm for the diagnostic work-up of patients presenting with elevated CK of unclear significance. Her recommended approach involves repeat CK assessment and a closer look at family history, medication, drug/toxin history, examination for weakness and neurologic abnormalities, and additional lab assessments in those whose levels remain elevated. In those in whom a diagnosis is not identified, the algorithm calls for observation every 3 months – including physical examination and labs – in asymptomatic patients with levels at less than five times the upper limit of normal, and further evaluation, including EMG with nerve-conduction velocity testing, muscle biopsy, and MRI in those with (or who later develop) marked elevation greater than five times the upper limit of normal and/or symptoms.
Patient assessment
The physical examination should involve localization and quantification of weakness, and assessment for fever, rash, atrophy/wasting/scooping of forearms, fasciculations, cranial nerve involvement, Raynaud’s phenomenon, nailfold capillary changes, arthritis, calcinosis, “mechanic’s hands,” signs of other autoimmune diseases, and lung crackles. Initial laboratory testing should include HIV and hepatitis B and C testing; measurement of CK, AST, ALT, aldolase, thyroid-stimulating hormone, and magnesium levels; a comprehensive metabolic panel and complete blood count; and measurement of erythrocyte sedimentation rate and C-reactive protein.
“Weakness may be secondary to a neuropathy, myopathy, or a problem at the neuropathic junction. Many causes of weakness can be readily identified by careful history taking, focused physical examination, and directed laboratory evaluation,” she said.
Features pointing toward a diagnosis of myositis include characteristic rashes, gradual symptom onset, proximal limb and truncal weakness, other connective tissue disease features such as Raynaud’s and arthritis, and the presence of lung disease, including interstitial lung disease or unexplained infiltrates, she said.
Features pointing away from a diagnosis of myositis include a family history of a similar illness, weakness that is associated with eating or fasting, neurologic signs, cranial nerve involvement, fasciculations, severe muscle cramping, early atrophy, and creatine phosphokinase levels that are either less than 2 times or more than 100 times the upper limit of normal.
Among the conditions to consider in the presence of the features that point away from a myositis diagnosis are muscular dystrophies, metabolic myopathies, and toxic (drug-induced) myopathies, to name a few, Dr. Christopher-Stine said.
She described a number of other cases to illustrate the need for – and to help develop – a differential diagnosis in patients presenting with apparent myositis.
Muscular dystrophies
A 38-year-old woman with limited scleroderma and anti-PM/Scl autoantibodies developed proximal weakness over 9 months and was eventually unable to walk up a flight of stairs. She had heliotrope rash and Gottron’s sign, her serum CK was 723 IU/L, and EMG showed an irritable myopathy.
Muscle biopsy showed inflammation, and she was treated with prednisone, but this led to worsening weakness. She complained of prominent fatigue and double vision at the end of the day, and these symptoms did not improve with steroids.
Anti-AChR and anti-MuSK antibodies were negative, but she had a decrement on repetitive nerve stimulation testing.
She was treated with pyridostigmine and experienced near-complete resolution of her proximal weakness and double vision. A chest CT scan showed thymic hyperplasia; thymectomy was recommended.
In another case, a 19-year-old woman who complained of leg pain after exercise was found to have intact strength but asymmetric calf hypertrophy. Her CK level was 5,000 IU/L, and she was referred to rule out acute myositis.
A quadriceps biopsy was performed and showed abnormal dystrophin immunostaining but no inflammation. A molecular genetic analysis showed deletions in Xp21 and she was diagnosed as a manifesting carrier of Duchenne muscular dystrophy. It was recommended that she be evaluated for cardiomyopathy and receive genetic counseling.
A number of other cases presented by Dr. Christopher-Stine highlighted other muscular dystrophies that can mimic myositis, such as:
- Myotonic dystrophies. These are more often type 2 than type 1. Myotonia may be subtle, cataracts are seen early in all patients, and cardiac arrhythmias are common.
- Limb girdle muscular dystrophy type 2 B (dysferlinopathy). In the legs, this often affects the gastrocnemius muscle, and this will be visible on MRI. In the arms, it most often affects the biceps, sparing the deltoids. CKs are typically very high.
- Facioscapulohumeral muscular dystrophy (FSHD). This involves facial weakness, especially obicularis oris, in 95% of cases, as well as scapular weakness and winging, inflammation on muscle biopsy in 75% of cases, and typically is endomysial or perivascular.
Metabolic myopathies
Among metabolic myopathies that can mimic myositis are disorders of carbohydrate metabolism such as McArdle’s disease, 6-phosphofructokinase deficiency, and Pompe’s disease (adult acid maltase deficiency); disorders of lipid metabolism such as carnitine deficiency and carnitine palmitoyltransferase 2 (CPT2) deficiency; and disorders of purine metabolism, such as myoadenylate deaminase deficiency.
A 27-year-old patient who complained of weakness with activity was referred for possible myositis and was found to have a CK of 3,650 IU/L that never normalized. Physical examination showed intact strength and no muscle atrophy or fasciculations, and an enzyme stain for myophosphorylase showed a normal staining pattern and complete absence of the enzyme on quadricep biopsy. A 22-year-old man with similar symptoms plus recent onset of brown/black urine after physical activity had CK of 110,000 IU/L when symptomatic, and also underwent biopsy after being referred for possible myopathy. Both patients were ultimately diagnosed with CPT2 deficiency, which is associated with risk of rhabdomyolysis triggered by prolonged exercise, diets low in carbohydrates and high in fat, or by fasting.
Myalgias are common, and CK levels are normal or only mildly elevated between episodes in CPT2 deficiency, Dr. Christopher-Stine noted.
Toxic myopathies
Drug-induced myopathies are among the most common etiologies of myopathy and can range from mild myalgia to massive rhabdomyolysis. They can cause mild to severe weakness and may be chronic. The mechanism of toxic injury is direct via myotoxins such as ethyl alcohol, glucocorticoids, lipid-lowering drugs, cocaine, antimalarial drugs, antipsychotic drugs, colchicine, and Ipecac syrup.
One case described by Dr. Christopher-Stine involved “statin myopathy.”
A 55-year-old man on atorvastatin complained of myalgias and brown urine, but had no definitive weakness. He had intact strength and diffuse myalgias that weren’t reproducible. His CK was 45,000 IU/L.
Statin myopathy, as seen in this patient, is usually self-limited and is not associated with autoimmunity or with anti-HMGCR autoantibody positivity.
The mechanism is unknown, but statin myopathy has an incidence of 1.2 per 10,000 patient-years. Myalgias, myositis, rhabdomyolysis, and asymptomatic hyperCKemia are commonly seen. This is in contrast to the immune-mediated necrotizing myelitis that can be secondary to statins and is responsive to immunosuppression, she noted.
Other myositis mimics
In addition to these common myositis mimics, certain other neurologic diseases (such as ALS and cervical myelopathy), endocrinopathies (such as hypothyroidism), and infections (like toxoplasmosis) can also be mistaken for myositis, Dr. Christopher-Stine said, noting that cases illustrating these mimics underscore the need for careful consideration of possible alternate diagnoses.
“While most noninflammatory myopathies are self-limited or have no therapies available, knowing the diagnosis can be helpful for genetic counseling of the patient and family, for mitigating risk factors, and for precluding the use of unwarranted immunosuppressive agents,” she said.
Dr. Christopher-Stine reported having intellectual property interest in a novel Inova Diagnostics autoantibody assay detection for anti-HMGCR. She was also the safety officer for the JBT-101 Trial sponsored by Corbus and funded by the National Institutes of Health.
EXPERT ANALYSIS FROM THE WINTER RHEUMATOLOGY SYMPOSIUM
Amyloid PET may help facilitate diagnosis of inclusion body myositis
Amyloid PET imaging may help to accurately identify inclusion body myositis and distinguish it from polymyositis, which could potentially avoid misdiagnosis and unnecessary immunosuppressive medication, according to findings from a small prospective cohort study.
The study, which found significantly greater uptake of the imaging agent [18F]florbetapir (Amyvid) in muscle from patients with inclusion body myositis (IBM) than in those with polymyositis (PM), builds on previous research showing that the intramuscular beta-amyloid seen in histopathologic analysis of IBM can help distinguish it from PM, but this approach has a low sensitivity along with high diagnostic specificity. The latest diagnostic criteria for IBM have also shifted away from strict histopathologic analysis toward identifying its characteristic clinical pattern of muscle weakness, first author James B. Lilleker, PhD, of the Centre for Musculoskeletal Research at the University of Manchester (England) and his colleagues wrote in Annals of the Rheumatic Diseases.
“While this has improved sensitivity, clinically detectable weakness implies that significant and irreversible muscle damage has occurred, reducing the likelihood that novel treatments will be effective,” the researchers wrote.
Thomas E. Lloyd II, MD, PhD, codirector of the myositis center at Johns Hopkins University, Baltimore, said in an interview that IBM is difficult to diagnose because of a lack of awareness of the early clinical signs and symptoms of the disease among primary care physicians, neurologists, and rheumatologists.
“Typically, a myositis specialist can make the diagnosis based on a combination of history and exam [slowly progressive weakness affecting distal finger flexors and knee extensors] and muscle biopsy features [endomysial inflammation with rimmed vacuoles and protein aggregates],” said Dr. Lloyd, who was not involved in the current study. “However, early in the course of disease, some patients may be misdiagnosed with polymyositis due to having atypical clinical or pathological features, especially if the muscle biopsy lacks rimmed vacuoles or the patient lacks obvious finger flexor weakness.”
But amyloid PET is promising and needs further analysis comparing it with expert diagnosis, Dr. Lloyd said. “I think this imaging method has greatest potential utility to be helpful diagnostically early in the course of disease, when diagnosis of IBM can be most challenging. This approach may also have potential to identify presymptomatic patients, especially if amyloid imaging becomes used for screening for Alzheimer’s disease in the future.”
Dr. Lilleker and colleagues set out to determine whether amyloid PET with [18F]florbetapir could distinguish between IBM and PM. They identified 10 patients with IBM and 6 patients with PM and scanned each patient from shoulders to ankles with CT and PET, followed by a same-day, whole-body MRI scan. Overall, regions of interest included the left arm, right and left forearms, right and left thighs, and right and left calves. The researchers calculated the [18F]florbetapir standard uptake values (SUVs) for each region of interest while SUV ratios (SUVRs) were calculated using the lumbar fat pad reference region.
The IBM patients (9 men, 1 woman) had a mean age of 68.3 years at the time of the scan and a mean disease duration of 4 years, and they were not currently taking immunosuppressive treatments; however, patients had previously taken prednisolone (3 of 10 patients), azathioprine (1 of 10 patients), and mycophenolate (1 of 10 patients). In the PM group (4 men, 2 women), patients’ mean age was 59.7 years, with a mean disease duration of 1.5 years.
The researchers found significantly increased overall [18F]florbetapir SUVRs among all regions of interest for IBM patients (median total SUVR, 1.45; interquartile range, 1.28-2.05), compared with PM patients (total SUVR, 1.01; IQR, 0.80-1.22; P = .005). In addition, when total [18F]florbetapir SUVR was 1.28 or greater, the diagnostic sensitivity for IBM was 80% and specificity was 100%, with an area under the curve of 0.93. There were also no significant associations between total [18F]florbetapir SUVR and age at the time of the scan, disease duration, or clinical outcome measurements such as manual muscle testing of 26 muscles (MMT26), Health Assessment Questionnaire disability index, and IBM Functional Rating Scale.
Dr. Lilleker and his colleagues noted the small study size as a potential limitation, but said other factors such as age and disease severity, which differed between groups, were unlikely to affect the [18F]florbetapir SUVR.
The rarity of PM may make it difficult to determine amyloid PET imaging’s effectiveness in diagnosing IBM when compared with more traditional methods, Dr. Lloyd noted.
“Whether PET imaging is more sensitive than expert diagnosis using traditional methods [careful physical exam of individual distal interphalangeal finger flexor muscles, MRI imaging of thighs, detailed pathological analysis of muscle biopsy including immunostaining for p62/SQSTM1, detailed serum autoantibody testing, etc.] remains to be determined,” he said.
This study was supported by grants from the National Institute for Health Research Manchester Musculoskeletal Biomedical Research Centre, the Medical Research Council, and an award from the Centre for Imaging Sciences at the University of Manchester. The authors reported no conflicts of interest. Dr. Lloyd reported being a consultant for Acceleron and principal investigator for IBM clinical trials sponsored by Orphazyme and Regeneron.
SOURCE: Lilleker JB et al. Ann Rheum Dis. 2019 Feb 13. doi: 10.1136/annrheumdis-2018-214644.
Amyloid PET imaging may help to accurately identify inclusion body myositis and distinguish it from polymyositis, which could potentially avoid misdiagnosis and unnecessary immunosuppressive medication, according to findings from a small prospective cohort study.
The study, which found significantly greater uptake of the imaging agent [18F]florbetapir (Amyvid) in muscle from patients with inclusion body myositis (IBM) than in those with polymyositis (PM), builds on previous research showing that the intramuscular beta-amyloid seen in histopathologic analysis of IBM can help distinguish it from PM, but this approach has a low sensitivity along with high diagnostic specificity. The latest diagnostic criteria for IBM have also shifted away from strict histopathologic analysis toward identifying its characteristic clinical pattern of muscle weakness, first author James B. Lilleker, PhD, of the Centre for Musculoskeletal Research at the University of Manchester (England) and his colleagues wrote in Annals of the Rheumatic Diseases.
“While this has improved sensitivity, clinically detectable weakness implies that significant and irreversible muscle damage has occurred, reducing the likelihood that novel treatments will be effective,” the researchers wrote.
Thomas E. Lloyd II, MD, PhD, codirector of the myositis center at Johns Hopkins University, Baltimore, said in an interview that IBM is difficult to diagnose because of a lack of awareness of the early clinical signs and symptoms of the disease among primary care physicians, neurologists, and rheumatologists.
“Typically, a myositis specialist can make the diagnosis based on a combination of history and exam [slowly progressive weakness affecting distal finger flexors and knee extensors] and muscle biopsy features [endomysial inflammation with rimmed vacuoles and protein aggregates],” said Dr. Lloyd, who was not involved in the current study. “However, early in the course of disease, some patients may be misdiagnosed with polymyositis due to having atypical clinical or pathological features, especially if the muscle biopsy lacks rimmed vacuoles or the patient lacks obvious finger flexor weakness.”
But amyloid PET is promising and needs further analysis comparing it with expert diagnosis, Dr. Lloyd said. “I think this imaging method has greatest potential utility to be helpful diagnostically early in the course of disease, when diagnosis of IBM can be most challenging. This approach may also have potential to identify presymptomatic patients, especially if amyloid imaging becomes used for screening for Alzheimer’s disease in the future.”
Dr. Lilleker and colleagues set out to determine whether amyloid PET with [18F]florbetapir could distinguish between IBM and PM. They identified 10 patients with IBM and 6 patients with PM and scanned each patient from shoulders to ankles with CT and PET, followed by a same-day, whole-body MRI scan. Overall, regions of interest included the left arm, right and left forearms, right and left thighs, and right and left calves. The researchers calculated the [18F]florbetapir standard uptake values (SUVs) for each region of interest while SUV ratios (SUVRs) were calculated using the lumbar fat pad reference region.
The IBM patients (9 men, 1 woman) had a mean age of 68.3 years at the time of the scan and a mean disease duration of 4 years, and they were not currently taking immunosuppressive treatments; however, patients had previously taken prednisolone (3 of 10 patients), azathioprine (1 of 10 patients), and mycophenolate (1 of 10 patients). In the PM group (4 men, 2 women), patients’ mean age was 59.7 years, with a mean disease duration of 1.5 years.
The researchers found significantly increased overall [18F]florbetapir SUVRs among all regions of interest for IBM patients (median total SUVR, 1.45; interquartile range, 1.28-2.05), compared with PM patients (total SUVR, 1.01; IQR, 0.80-1.22; P = .005). In addition, when total [18F]florbetapir SUVR was 1.28 or greater, the diagnostic sensitivity for IBM was 80% and specificity was 100%, with an area under the curve of 0.93. There were also no significant associations between total [18F]florbetapir SUVR and age at the time of the scan, disease duration, or clinical outcome measurements such as manual muscle testing of 26 muscles (MMT26), Health Assessment Questionnaire disability index, and IBM Functional Rating Scale.
Dr. Lilleker and his colleagues noted the small study size as a potential limitation, but said other factors such as age and disease severity, which differed between groups, were unlikely to affect the [18F]florbetapir SUVR.
The rarity of PM may make it difficult to determine amyloid PET imaging’s effectiveness in diagnosing IBM when compared with more traditional methods, Dr. Lloyd noted.
“Whether PET imaging is more sensitive than expert diagnosis using traditional methods [careful physical exam of individual distal interphalangeal finger flexor muscles, MRI imaging of thighs, detailed pathological analysis of muscle biopsy including immunostaining for p62/SQSTM1, detailed serum autoantibody testing, etc.] remains to be determined,” he said.
This study was supported by grants from the National Institute for Health Research Manchester Musculoskeletal Biomedical Research Centre, the Medical Research Council, and an award from the Centre for Imaging Sciences at the University of Manchester. The authors reported no conflicts of interest. Dr. Lloyd reported being a consultant for Acceleron and principal investigator for IBM clinical trials sponsored by Orphazyme and Regeneron.
SOURCE: Lilleker JB et al. Ann Rheum Dis. 2019 Feb 13. doi: 10.1136/annrheumdis-2018-214644.
Amyloid PET imaging may help to accurately identify inclusion body myositis and distinguish it from polymyositis, which could potentially avoid misdiagnosis and unnecessary immunosuppressive medication, according to findings from a small prospective cohort study.
The study, which found significantly greater uptake of the imaging agent [18F]florbetapir (Amyvid) in muscle from patients with inclusion body myositis (IBM) than in those with polymyositis (PM), builds on previous research showing that the intramuscular beta-amyloid seen in histopathologic analysis of IBM can help distinguish it from PM, but this approach has a low sensitivity along with high diagnostic specificity. The latest diagnostic criteria for IBM have also shifted away from strict histopathologic analysis toward identifying its characteristic clinical pattern of muscle weakness, first author James B. Lilleker, PhD, of the Centre for Musculoskeletal Research at the University of Manchester (England) and his colleagues wrote in Annals of the Rheumatic Diseases.
“While this has improved sensitivity, clinically detectable weakness implies that significant and irreversible muscle damage has occurred, reducing the likelihood that novel treatments will be effective,” the researchers wrote.
Thomas E. Lloyd II, MD, PhD, codirector of the myositis center at Johns Hopkins University, Baltimore, said in an interview that IBM is difficult to diagnose because of a lack of awareness of the early clinical signs and symptoms of the disease among primary care physicians, neurologists, and rheumatologists.
“Typically, a myositis specialist can make the diagnosis based on a combination of history and exam [slowly progressive weakness affecting distal finger flexors and knee extensors] and muscle biopsy features [endomysial inflammation with rimmed vacuoles and protein aggregates],” said Dr. Lloyd, who was not involved in the current study. “However, early in the course of disease, some patients may be misdiagnosed with polymyositis due to having atypical clinical or pathological features, especially if the muscle biopsy lacks rimmed vacuoles or the patient lacks obvious finger flexor weakness.”
But amyloid PET is promising and needs further analysis comparing it with expert diagnosis, Dr. Lloyd said. “I think this imaging method has greatest potential utility to be helpful diagnostically early in the course of disease, when diagnosis of IBM can be most challenging. This approach may also have potential to identify presymptomatic patients, especially if amyloid imaging becomes used for screening for Alzheimer’s disease in the future.”
Dr. Lilleker and colleagues set out to determine whether amyloid PET with [18F]florbetapir could distinguish between IBM and PM. They identified 10 patients with IBM and 6 patients with PM and scanned each patient from shoulders to ankles with CT and PET, followed by a same-day, whole-body MRI scan. Overall, regions of interest included the left arm, right and left forearms, right and left thighs, and right and left calves. The researchers calculated the [18F]florbetapir standard uptake values (SUVs) for each region of interest while SUV ratios (SUVRs) were calculated using the lumbar fat pad reference region.
The IBM patients (9 men, 1 woman) had a mean age of 68.3 years at the time of the scan and a mean disease duration of 4 years, and they were not currently taking immunosuppressive treatments; however, patients had previously taken prednisolone (3 of 10 patients), azathioprine (1 of 10 patients), and mycophenolate (1 of 10 patients). In the PM group (4 men, 2 women), patients’ mean age was 59.7 years, with a mean disease duration of 1.5 years.
The researchers found significantly increased overall [18F]florbetapir SUVRs among all regions of interest for IBM patients (median total SUVR, 1.45; interquartile range, 1.28-2.05), compared with PM patients (total SUVR, 1.01; IQR, 0.80-1.22; P = .005). In addition, when total [18F]florbetapir SUVR was 1.28 or greater, the diagnostic sensitivity for IBM was 80% and specificity was 100%, with an area under the curve of 0.93. There were also no significant associations between total [18F]florbetapir SUVR and age at the time of the scan, disease duration, or clinical outcome measurements such as manual muscle testing of 26 muscles (MMT26), Health Assessment Questionnaire disability index, and IBM Functional Rating Scale.
Dr. Lilleker and his colleagues noted the small study size as a potential limitation, but said other factors such as age and disease severity, which differed between groups, were unlikely to affect the [18F]florbetapir SUVR.
The rarity of PM may make it difficult to determine amyloid PET imaging’s effectiveness in diagnosing IBM when compared with more traditional methods, Dr. Lloyd noted.
“Whether PET imaging is more sensitive than expert diagnosis using traditional methods [careful physical exam of individual distal interphalangeal finger flexor muscles, MRI imaging of thighs, detailed pathological analysis of muscle biopsy including immunostaining for p62/SQSTM1, detailed serum autoantibody testing, etc.] remains to be determined,” he said.
This study was supported by grants from the National Institute for Health Research Manchester Musculoskeletal Biomedical Research Centre, the Medical Research Council, and an award from the Centre for Imaging Sciences at the University of Manchester. The authors reported no conflicts of interest. Dr. Lloyd reported being a consultant for Acceleron and principal investigator for IBM clinical trials sponsored by Orphazyme and Regeneron.
SOURCE: Lilleker JB et al. Ann Rheum Dis. 2019 Feb 13. doi: 10.1136/annrheumdis-2018-214644.
FROM ANNALS OF THE RHEUMATIC DISEASES
Dr. Lisa Christopher-Stine: Polymyositis? It’s more likely something else
“When someone refers you [a patient with suspected] polymyositis, I want you to do a checklist in your head and say, ‘Have I thought about these five things?’ ” Dr. Christopher-Stine, director of the Johns Hopkins Myositis Center, Baltimore, said at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.
The five most common diagnoses in patients labeled as having polymyositis are immune-mediated necrotizing myopathy (IMNM), overlap with other rheumatologic conditions, antisynthetase syndrome, inclusion body myositis (IBM), and muscular dystrophy, she explained.
“You may say, ‘look, it’s all what you call it,’ but I think we need to be a little bit more careful in what we call it,” she said.
IMNM
Patients with IMNM present with clinical symptoms similar to those seen in polymyositis and dermatomyositis – mainly proximal muscle weakness.
However, there are some important differences, both clinically and histologically, Dr. Christopher-Stine said.
“Look for higher [creatine kinase (CK)] levels,” she said. “In the thousands, usually multiple thousands ... like 5,000, 10,000, 2,000 ... that’s when you’re thinking about a necrotizing phenotype before you even look at the biopsy.”
CK levels will usually be under 30,000 U/L in IMNM, she noted, adding that data increasingly suggest that the extensive muscle necrosis in IMNM explains the elevated CK levels versus those seen in other myopathies.
Myalgias also tend to be more prominent in IMNM than in polymyositis.
“These folks hurt,” she said, noting that IMNM patients tend to have more extensive muscle atrophy and functional disability. “Many will be wheelchair bound within 9 months of diagnosis; it’s not subtle.”
The most important tool for making an IMNM diagnosis is muscle biopsy; look for prominent myocyte necrosis and a relative paucity of lymphocytes, she advised.
Overlap
Sometimes patients with polymyositis also have other rheumatologic conditions that shouldn’t be overlooked, therefore “overlap is its own category,” she said.
“In our experience, the most common overlap is scleroderma,” she noted, adding that the scleroderma is often, but not always, subtle, and that there may be overlapping autoantibodies.
Overt sclerodactyly is rarely seen, although a small amount may be present, but significant Raynaud’s phenomenon is common in these patients, and tiny telangiectasias across the neck are a tell-tale sign.
“Why does that matter? It’s not an esoteric argument; those are the folks that go on to have pulmonary hypertension,” she said. “They can have the same [interstitial lung disease] and all of the other internal scleroderma manifestations.”
Think about overlap and “look close phenotypically and with antibodies,” she advised.
There is also “the typical RA seropositive overlap,” she said, but lupus only rarely overlaps with myositis.
“However, the next diagnosis on the list – antisynthetase syndrome – can be a forme fruste where you first see a seronegative RA-like picture, and it’s important to think about that as well,” she said.
Antisynthetase syndrome
In patients referred for polymyositis, it’s also important to evaluate for antisynthetase syndrome, Dr. Christopher-Stine said.
The arthritis seen in the extramuscular phenotype of the syndrome is rarely deforming, but despite what many physicians were taught, “it absolutely can be erosive,” she said.
In fact, 40% of people with this syndrome present with an isolated forme fruste seronegative rheumatoid arthritis, she said.
Roughening and desquamation of the skin on the radial surface of fingers or palms – a sign known as mechanic’s hands – that doesn’t have another identifiable cause suggests this diagnosis in patients with this type of arthritis, as does interstitial lung disease and Raynaud’s phenomenon.
The Raynaud’s can be “fairly significant in the sense that it is bothersome,” but it usually doesn’t lead to ulceration or digital necrosis.
This is different from what is seen with the scleroderma phenotype, she said, adding that “if you’re starting to see gangrene and digital loss, think of something else.”
IBM
IBM is “probably the No. 1 most-missed diagnosis” among patients referred for what is initially believed to be polymyositis, Dr. Christopher-Stine said.
“I used to think that this was missed at entry, that everybody [with IBM] had all of these criteria and that rheumatologists really didn’t understand this phenotype ... but some people morph into this,” she said, explaining that they often start out looking like they have polymyositis with proximal muscle weakness.
“They may even initially respond to steroids. And then they get this phenotype,” she said.
Older men are more likely to present with the phenotype from the beginning; women, in her experience, tend to present with what appears to be polymyositis, and then develop the phenotype over time, she noted.
An IBM diagnosis requires age over 30 years, but most patients are over 50, she said.
“This is the only one of the myopathies that is preferential to men,” she added, noting that it affects men twice as often as it does women.
The syndrome is characterized by proximal strength loss and muscle atrophy. Also, a finding that a patient’s knee extensors are weaker than their hip flexors is “a fantastic bedside sign” differentiating IBM from polymyositis, she said.
That’s not to say IBM patients don’t have hip flexor weakness, but their knee extensors usually are “considerably weaker by a grade strength or more” versus their hip flexors, she explained.
“It’s a very easy bedside test. In typical other myopathies we have this, but the knee extensors aren’t that weak in general, or they’re not as weak as the hip flexors,” she added.
Another sign is distal strength loss, particularly in the forearm and finger flexors.
“I was taught to have them make a fist; don’t have them make a fist,” she said, explaining that this recruits intrinsic muscles which basically allows cheating that may mask weakness.
Instead, ask them to flex just their distal interphalangeal joints by making a claw and using the fingers to pull against your fingers, she suggested.
Mixed myopathic and neuropathic features on electromyography also indicate IBM, she said.
Muscle biopsy may be helpful, but inclusions are seen in less than one-third of IBM patients.
“At times, we have had to biopsy three times to see them at all, and some people never show them, so you have to rely on your clinical acumen if you don’t see them,” she said.
Also, keep in mind that these patients are often labeled as having treatment-resistant polymyositis.
“Please, when somebody refers to you somebody that’s treatment resistant, that may be the case, but I want you to think maybe they’re treatment resistant because they don’t have that disease.”
Muscular dystrophy
Some cases of myositis mimic certain types of muscular dystrophy, Dr. Christopher-Stine said, providing a checklist of muscular dystrophies that can look “clinically completely indistinguishable from a typical inflammatory myopathy,” and should therefore be considered in these patients.
The checklist includes Duchenne’s manifesting carrier, limb girdle muscular dystrophy type 2b, myotonic dystrophy (usually type 2), and facioscapulohumeral muscular dystrophy.
Dr. Christopher-Stine reported having intellectual property interest in a novel Inova Diagnostics autoantibody assay detection for anti-HMGCR. She was also the safety officer for the JBT-101 Trial sponsored by Corbus and funded by the National Institutes of Health.
“When someone refers you [a patient with suspected] polymyositis, I want you to do a checklist in your head and say, ‘Have I thought about these five things?’ ” Dr. Christopher-Stine, director of the Johns Hopkins Myositis Center, Baltimore, said at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.
The five most common diagnoses in patients labeled as having polymyositis are immune-mediated necrotizing myopathy (IMNM), overlap with other rheumatologic conditions, antisynthetase syndrome, inclusion body myositis (IBM), and muscular dystrophy, she explained.
“You may say, ‘look, it’s all what you call it,’ but I think we need to be a little bit more careful in what we call it,” she said.
IMNM
Patients with IMNM present with clinical symptoms similar to those seen in polymyositis and dermatomyositis – mainly proximal muscle weakness.
However, there are some important differences, both clinically and histologically, Dr. Christopher-Stine said.
“Look for higher [creatine kinase (CK)] levels,” she said. “In the thousands, usually multiple thousands ... like 5,000, 10,000, 2,000 ... that’s when you’re thinking about a necrotizing phenotype before you even look at the biopsy.”
CK levels will usually be under 30,000 U/L in IMNM, she noted, adding that data increasingly suggest that the extensive muscle necrosis in IMNM explains the elevated CK levels versus those seen in other myopathies.
Myalgias also tend to be more prominent in IMNM than in polymyositis.
“These folks hurt,” she said, noting that IMNM patients tend to have more extensive muscle atrophy and functional disability. “Many will be wheelchair bound within 9 months of diagnosis; it’s not subtle.”
The most important tool for making an IMNM diagnosis is muscle biopsy; look for prominent myocyte necrosis and a relative paucity of lymphocytes, she advised.
Overlap
Sometimes patients with polymyositis also have other rheumatologic conditions that shouldn’t be overlooked, therefore “overlap is its own category,” she said.
“In our experience, the most common overlap is scleroderma,” she noted, adding that the scleroderma is often, but not always, subtle, and that there may be overlapping autoantibodies.
Overt sclerodactyly is rarely seen, although a small amount may be present, but significant Raynaud’s phenomenon is common in these patients, and tiny telangiectasias across the neck are a tell-tale sign.
“Why does that matter? It’s not an esoteric argument; those are the folks that go on to have pulmonary hypertension,” she said. “They can have the same [interstitial lung disease] and all of the other internal scleroderma manifestations.”
Think about overlap and “look close phenotypically and with antibodies,” she advised.
There is also “the typical RA seropositive overlap,” she said, but lupus only rarely overlaps with myositis.
“However, the next diagnosis on the list – antisynthetase syndrome – can be a forme fruste where you first see a seronegative RA-like picture, and it’s important to think about that as well,” she said.
Antisynthetase syndrome
In patients referred for polymyositis, it’s also important to evaluate for antisynthetase syndrome, Dr. Christopher-Stine said.
The arthritis seen in the extramuscular phenotype of the syndrome is rarely deforming, but despite what many physicians were taught, “it absolutely can be erosive,” she said.
In fact, 40% of people with this syndrome present with an isolated forme fruste seronegative rheumatoid arthritis, she said.
Roughening and desquamation of the skin on the radial surface of fingers or palms – a sign known as mechanic’s hands – that doesn’t have another identifiable cause suggests this diagnosis in patients with this type of arthritis, as does interstitial lung disease and Raynaud’s phenomenon.
The Raynaud’s can be “fairly significant in the sense that it is bothersome,” but it usually doesn’t lead to ulceration or digital necrosis.
This is different from what is seen with the scleroderma phenotype, she said, adding that “if you’re starting to see gangrene and digital loss, think of something else.”
IBM
IBM is “probably the No. 1 most-missed diagnosis” among patients referred for what is initially believed to be polymyositis, Dr. Christopher-Stine said.
“I used to think that this was missed at entry, that everybody [with IBM] had all of these criteria and that rheumatologists really didn’t understand this phenotype ... but some people morph into this,” she said, explaining that they often start out looking like they have polymyositis with proximal muscle weakness.
“They may even initially respond to steroids. And then they get this phenotype,” she said.
Older men are more likely to present with the phenotype from the beginning; women, in her experience, tend to present with what appears to be polymyositis, and then develop the phenotype over time, she noted.
An IBM diagnosis requires age over 30 years, but most patients are over 50, she said.
“This is the only one of the myopathies that is preferential to men,” she added, noting that it affects men twice as often as it does women.
The syndrome is characterized by proximal strength loss and muscle atrophy. Also, a finding that a patient’s knee extensors are weaker than their hip flexors is “a fantastic bedside sign” differentiating IBM from polymyositis, she said.
That’s not to say IBM patients don’t have hip flexor weakness, but their knee extensors usually are “considerably weaker by a grade strength or more” versus their hip flexors, she explained.
“It’s a very easy bedside test. In typical other myopathies we have this, but the knee extensors aren’t that weak in general, or they’re not as weak as the hip flexors,” she added.
Another sign is distal strength loss, particularly in the forearm and finger flexors.
“I was taught to have them make a fist; don’t have them make a fist,” she said, explaining that this recruits intrinsic muscles which basically allows cheating that may mask weakness.
Instead, ask them to flex just their distal interphalangeal joints by making a claw and using the fingers to pull against your fingers, she suggested.
Mixed myopathic and neuropathic features on electromyography also indicate IBM, she said.
Muscle biopsy may be helpful, but inclusions are seen in less than one-third of IBM patients.
“At times, we have had to biopsy three times to see them at all, and some people never show them, so you have to rely on your clinical acumen if you don’t see them,” she said.
Also, keep in mind that these patients are often labeled as having treatment-resistant polymyositis.
“Please, when somebody refers to you somebody that’s treatment resistant, that may be the case, but I want you to think maybe they’re treatment resistant because they don’t have that disease.”
Muscular dystrophy
Some cases of myositis mimic certain types of muscular dystrophy, Dr. Christopher-Stine said, providing a checklist of muscular dystrophies that can look “clinically completely indistinguishable from a typical inflammatory myopathy,” and should therefore be considered in these patients.
The checklist includes Duchenne’s manifesting carrier, limb girdle muscular dystrophy type 2b, myotonic dystrophy (usually type 2), and facioscapulohumeral muscular dystrophy.
Dr. Christopher-Stine reported having intellectual property interest in a novel Inova Diagnostics autoantibody assay detection for anti-HMGCR. She was also the safety officer for the JBT-101 Trial sponsored by Corbus and funded by the National Institutes of Health.
“When someone refers you [a patient with suspected] polymyositis, I want you to do a checklist in your head and say, ‘Have I thought about these five things?’ ” Dr. Christopher-Stine, director of the Johns Hopkins Myositis Center, Baltimore, said at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.
The five most common diagnoses in patients labeled as having polymyositis are immune-mediated necrotizing myopathy (IMNM), overlap with other rheumatologic conditions, antisynthetase syndrome, inclusion body myositis (IBM), and muscular dystrophy, she explained.
“You may say, ‘look, it’s all what you call it,’ but I think we need to be a little bit more careful in what we call it,” she said.
IMNM
Patients with IMNM present with clinical symptoms similar to those seen in polymyositis and dermatomyositis – mainly proximal muscle weakness.
However, there are some important differences, both clinically and histologically, Dr. Christopher-Stine said.
“Look for higher [creatine kinase (CK)] levels,” she said. “In the thousands, usually multiple thousands ... like 5,000, 10,000, 2,000 ... that’s when you’re thinking about a necrotizing phenotype before you even look at the biopsy.”
CK levels will usually be under 30,000 U/L in IMNM, she noted, adding that data increasingly suggest that the extensive muscle necrosis in IMNM explains the elevated CK levels versus those seen in other myopathies.
Myalgias also tend to be more prominent in IMNM than in polymyositis.
“These folks hurt,” she said, noting that IMNM patients tend to have more extensive muscle atrophy and functional disability. “Many will be wheelchair bound within 9 months of diagnosis; it’s not subtle.”
The most important tool for making an IMNM diagnosis is muscle biopsy; look for prominent myocyte necrosis and a relative paucity of lymphocytes, she advised.
Overlap
Sometimes patients with polymyositis also have other rheumatologic conditions that shouldn’t be overlooked, therefore “overlap is its own category,” she said.
“In our experience, the most common overlap is scleroderma,” she noted, adding that the scleroderma is often, but not always, subtle, and that there may be overlapping autoantibodies.
Overt sclerodactyly is rarely seen, although a small amount may be present, but significant Raynaud’s phenomenon is common in these patients, and tiny telangiectasias across the neck are a tell-tale sign.
“Why does that matter? It’s not an esoteric argument; those are the folks that go on to have pulmonary hypertension,” she said. “They can have the same [interstitial lung disease] and all of the other internal scleroderma manifestations.”
Think about overlap and “look close phenotypically and with antibodies,” she advised.
There is also “the typical RA seropositive overlap,” she said, but lupus only rarely overlaps with myositis.
“However, the next diagnosis on the list – antisynthetase syndrome – can be a forme fruste where you first see a seronegative RA-like picture, and it’s important to think about that as well,” she said.
Antisynthetase syndrome
In patients referred for polymyositis, it’s also important to evaluate for antisynthetase syndrome, Dr. Christopher-Stine said.
The arthritis seen in the extramuscular phenotype of the syndrome is rarely deforming, but despite what many physicians were taught, “it absolutely can be erosive,” she said.
In fact, 40% of people with this syndrome present with an isolated forme fruste seronegative rheumatoid arthritis, she said.
Roughening and desquamation of the skin on the radial surface of fingers or palms – a sign known as mechanic’s hands – that doesn’t have another identifiable cause suggests this diagnosis in patients with this type of arthritis, as does interstitial lung disease and Raynaud’s phenomenon.
The Raynaud’s can be “fairly significant in the sense that it is bothersome,” but it usually doesn’t lead to ulceration or digital necrosis.
This is different from what is seen with the scleroderma phenotype, she said, adding that “if you’re starting to see gangrene and digital loss, think of something else.”
IBM
IBM is “probably the No. 1 most-missed diagnosis” among patients referred for what is initially believed to be polymyositis, Dr. Christopher-Stine said.
“I used to think that this was missed at entry, that everybody [with IBM] had all of these criteria and that rheumatologists really didn’t understand this phenotype ... but some people morph into this,” she said, explaining that they often start out looking like they have polymyositis with proximal muscle weakness.
“They may even initially respond to steroids. And then they get this phenotype,” she said.
Older men are more likely to present with the phenotype from the beginning; women, in her experience, tend to present with what appears to be polymyositis, and then develop the phenotype over time, she noted.
An IBM diagnosis requires age over 30 years, but most patients are over 50, she said.
“This is the only one of the myopathies that is preferential to men,” she added, noting that it affects men twice as often as it does women.
The syndrome is characterized by proximal strength loss and muscle atrophy. Also, a finding that a patient’s knee extensors are weaker than their hip flexors is “a fantastic bedside sign” differentiating IBM from polymyositis, she said.
That’s not to say IBM patients don’t have hip flexor weakness, but their knee extensors usually are “considerably weaker by a grade strength or more” versus their hip flexors, she explained.
“It’s a very easy bedside test. In typical other myopathies we have this, but the knee extensors aren’t that weak in general, or they’re not as weak as the hip flexors,” she added.
Another sign is distal strength loss, particularly in the forearm and finger flexors.
“I was taught to have them make a fist; don’t have them make a fist,” she said, explaining that this recruits intrinsic muscles which basically allows cheating that may mask weakness.
Instead, ask them to flex just their distal interphalangeal joints by making a claw and using the fingers to pull against your fingers, she suggested.
Mixed myopathic and neuropathic features on electromyography also indicate IBM, she said.
Muscle biopsy may be helpful, but inclusions are seen in less than one-third of IBM patients.
“At times, we have had to biopsy three times to see them at all, and some people never show them, so you have to rely on your clinical acumen if you don’t see them,” she said.
Also, keep in mind that these patients are often labeled as having treatment-resistant polymyositis.
“Please, when somebody refers to you somebody that’s treatment resistant, that may be the case, but I want you to think maybe they’re treatment resistant because they don’t have that disease.”
Muscular dystrophy
Some cases of myositis mimic certain types of muscular dystrophy, Dr. Christopher-Stine said, providing a checklist of muscular dystrophies that can look “clinically completely indistinguishable from a typical inflammatory myopathy,” and should therefore be considered in these patients.
The checklist includes Duchenne’s manifesting carrier, limb girdle muscular dystrophy type 2b, myotonic dystrophy (usually type 2), and facioscapulohumeral muscular dystrophy.
Dr. Christopher-Stine reported having intellectual property interest in a novel Inova Diagnostics autoantibody assay detection for anti-HMGCR. She was also the safety officer for the JBT-101 Trial sponsored by Corbus and funded by the National Institutes of Health.
EXPERT ANALYSIS FROM THE WINTER RHEUMATOLOGY SYMPOSIUM
Clinical benefits persist 5 years after thymectomy for myasthenia gravis
Thymectomy may continue to benefit patients with myasthenia gravis 5 years after the procedure, according to an extension study published in Lancet Neurology.
The study evaluated the clinical status, medication requirements, and adverse events of patients with myasthenia gravis who completed a randomized controlled trial of thymectomy plus prednisone versus prednisone alone and agreed to participate in a rater-blinded 2-year extension.
“Thymectomy within the first few years of the disease course in addition to prednisone therapy confers benefits that persist for 5 years ... in patients with generalized nonthymomatous myasthenia gravis,” said lead study author Gil I. Wolfe, MD, chair of the department of neurology at the University at Buffalo in New York, and his research colleagues. “Results from the extension study provide further support for the use of thymectomy in management of myasthenia gravis and should encourage serious consideration of this treatment option in discussions between clinicians and their patients,” they wrote. “Our results should lead to revision of clinical guidelines in favor of thymectomy and could potentially reverse downward trends in the use of thymectomy in overall management of myasthenia gravis.”
The main 3-year results of the Thymectomy Trial in Nonthymomatous Myasthenia Gravis Patients Receiving Prednisone (MGTX) were reported in 2016; the international trial found that thymectomy plus prednisone was superior to prednisone alone at 3 years (N Engl J Med. 2016 Aug 11;375[6]:511-22). The extension study aimed to assess the durability of the treatment response.
MGTX enrolled patients aged 18-65 years who had generalized nonthymomatous myasthenia gravis of less than 5 years’ duration and Myasthenia Gravis Foundation of America Clinical Classification Class II-IV disease. Of 111 patients who completed MGTX, 68 entered the extension study, and 50 completed the 60-month assessment (24 patients in the prednisone alone group and 26 patients in the prednisone plus thymectomy group).
At 5 years, patients in the thymectomy plus prednisone group had significantly lower time-weighted average Quantitative Myasthenia Gravis (QMG) scores (5.47 vs. 9.34) and mean alternate-day prednisone doses (24 mg vs. 48 mg), compared with patients who received prednisone alone. Twelve of 35 patients in the thymectomy group and 14 of 33 patients in the prednisone group had at least one adverse event by month 60. No treatment-related deaths occurred in the extension phase.
At 5 years, significantly more patients who underwent thymectomy had minimal manifestation status (i.e., no functional limitations from the disease other than some muscle weakness) – 88% versus 58%. The corresponding figures at 3 years were 67% and 47%.
In addition, 3-year and 5-year data indicate that the need for hospitalization is reduced after surgery, compared with medical therapy alone, Dr. Wolfe said.
Two patients in each treatment arm had an increase of 2 points or more in the QMG score, indicating clinical worsening.
“Our current findings reinforce the benefit of thymectomy seen in [MGTX], dispelling doubts about the procedure’s benefits and how long those benefits last,” said Dr. Wolfe. “We do hope that the new findings help reverse the apparent reluctance to do thymectomy and that the proportion of patients with myasthenia gravis who undergo thymectomy will increase.”
The authors noted that the small sample size of the extension study may limit its generalizability.
The study received funding from the National Institutes of Health. Dr. Wolfe reported grants from the NIH, the Muscular Dystrophy Association, the Myasthenia Gravis Foundation of America, CSL-Behring, and ArgenX, as well as personal fees from Grifols, Shire, and Alexion Pharmaceuticals. Coauthors reported working with and receiving funds from agencies, foundations, and pharmaceutical companies.
SOURCE: Wolfe GI et al. Lancet Neurol. 2019 Jan 25. doi: 10.1016/S1474-4422(18)30392-2.
Thymectomy may continue to benefit patients with myasthenia gravis 5 years after the procedure, according to an extension study published in Lancet Neurology.
The study evaluated the clinical status, medication requirements, and adverse events of patients with myasthenia gravis who completed a randomized controlled trial of thymectomy plus prednisone versus prednisone alone and agreed to participate in a rater-blinded 2-year extension.
“Thymectomy within the first few years of the disease course in addition to prednisone therapy confers benefits that persist for 5 years ... in patients with generalized nonthymomatous myasthenia gravis,” said lead study author Gil I. Wolfe, MD, chair of the department of neurology at the University at Buffalo in New York, and his research colleagues. “Results from the extension study provide further support for the use of thymectomy in management of myasthenia gravis and should encourage serious consideration of this treatment option in discussions between clinicians and their patients,” they wrote. “Our results should lead to revision of clinical guidelines in favor of thymectomy and could potentially reverse downward trends in the use of thymectomy in overall management of myasthenia gravis.”
The main 3-year results of the Thymectomy Trial in Nonthymomatous Myasthenia Gravis Patients Receiving Prednisone (MGTX) were reported in 2016; the international trial found that thymectomy plus prednisone was superior to prednisone alone at 3 years (N Engl J Med. 2016 Aug 11;375[6]:511-22). The extension study aimed to assess the durability of the treatment response.
MGTX enrolled patients aged 18-65 years who had generalized nonthymomatous myasthenia gravis of less than 5 years’ duration and Myasthenia Gravis Foundation of America Clinical Classification Class II-IV disease. Of 111 patients who completed MGTX, 68 entered the extension study, and 50 completed the 60-month assessment (24 patients in the prednisone alone group and 26 patients in the prednisone plus thymectomy group).
At 5 years, patients in the thymectomy plus prednisone group had significantly lower time-weighted average Quantitative Myasthenia Gravis (QMG) scores (5.47 vs. 9.34) and mean alternate-day prednisone doses (24 mg vs. 48 mg), compared with patients who received prednisone alone. Twelve of 35 patients in the thymectomy group and 14 of 33 patients in the prednisone group had at least one adverse event by month 60. No treatment-related deaths occurred in the extension phase.
At 5 years, significantly more patients who underwent thymectomy had minimal manifestation status (i.e., no functional limitations from the disease other than some muscle weakness) – 88% versus 58%. The corresponding figures at 3 years were 67% and 47%.
In addition, 3-year and 5-year data indicate that the need for hospitalization is reduced after surgery, compared with medical therapy alone, Dr. Wolfe said.
Two patients in each treatment arm had an increase of 2 points or more in the QMG score, indicating clinical worsening.
“Our current findings reinforce the benefit of thymectomy seen in [MGTX], dispelling doubts about the procedure’s benefits and how long those benefits last,” said Dr. Wolfe. “We do hope that the new findings help reverse the apparent reluctance to do thymectomy and that the proportion of patients with myasthenia gravis who undergo thymectomy will increase.”
The authors noted that the small sample size of the extension study may limit its generalizability.
The study received funding from the National Institutes of Health. Dr. Wolfe reported grants from the NIH, the Muscular Dystrophy Association, the Myasthenia Gravis Foundation of America, CSL-Behring, and ArgenX, as well as personal fees from Grifols, Shire, and Alexion Pharmaceuticals. Coauthors reported working with and receiving funds from agencies, foundations, and pharmaceutical companies.
SOURCE: Wolfe GI et al. Lancet Neurol. 2019 Jan 25. doi: 10.1016/S1474-4422(18)30392-2.
Thymectomy may continue to benefit patients with myasthenia gravis 5 years after the procedure, according to an extension study published in Lancet Neurology.
The study evaluated the clinical status, medication requirements, and adverse events of patients with myasthenia gravis who completed a randomized controlled trial of thymectomy plus prednisone versus prednisone alone and agreed to participate in a rater-blinded 2-year extension.
“Thymectomy within the first few years of the disease course in addition to prednisone therapy confers benefits that persist for 5 years ... in patients with generalized nonthymomatous myasthenia gravis,” said lead study author Gil I. Wolfe, MD, chair of the department of neurology at the University at Buffalo in New York, and his research colleagues. “Results from the extension study provide further support for the use of thymectomy in management of myasthenia gravis and should encourage serious consideration of this treatment option in discussions between clinicians and their patients,” they wrote. “Our results should lead to revision of clinical guidelines in favor of thymectomy and could potentially reverse downward trends in the use of thymectomy in overall management of myasthenia gravis.”
The main 3-year results of the Thymectomy Trial in Nonthymomatous Myasthenia Gravis Patients Receiving Prednisone (MGTX) were reported in 2016; the international trial found that thymectomy plus prednisone was superior to prednisone alone at 3 years (N Engl J Med. 2016 Aug 11;375[6]:511-22). The extension study aimed to assess the durability of the treatment response.
MGTX enrolled patients aged 18-65 years who had generalized nonthymomatous myasthenia gravis of less than 5 years’ duration and Myasthenia Gravis Foundation of America Clinical Classification Class II-IV disease. Of 111 patients who completed MGTX, 68 entered the extension study, and 50 completed the 60-month assessment (24 patients in the prednisone alone group and 26 patients in the prednisone plus thymectomy group).
At 5 years, patients in the thymectomy plus prednisone group had significantly lower time-weighted average Quantitative Myasthenia Gravis (QMG) scores (5.47 vs. 9.34) and mean alternate-day prednisone doses (24 mg vs. 48 mg), compared with patients who received prednisone alone. Twelve of 35 patients in the thymectomy group and 14 of 33 patients in the prednisone group had at least one adverse event by month 60. No treatment-related deaths occurred in the extension phase.
At 5 years, significantly more patients who underwent thymectomy had minimal manifestation status (i.e., no functional limitations from the disease other than some muscle weakness) – 88% versus 58%. The corresponding figures at 3 years were 67% and 47%.
In addition, 3-year and 5-year data indicate that the need for hospitalization is reduced after surgery, compared with medical therapy alone, Dr. Wolfe said.
Two patients in each treatment arm had an increase of 2 points or more in the QMG score, indicating clinical worsening.
“Our current findings reinforce the benefit of thymectomy seen in [MGTX], dispelling doubts about the procedure’s benefits and how long those benefits last,” said Dr. Wolfe. “We do hope that the new findings help reverse the apparent reluctance to do thymectomy and that the proportion of patients with myasthenia gravis who undergo thymectomy will increase.”
The authors noted that the small sample size of the extension study may limit its generalizability.
The study received funding from the National Institutes of Health. Dr. Wolfe reported grants from the NIH, the Muscular Dystrophy Association, the Myasthenia Gravis Foundation of America, CSL-Behring, and ArgenX, as well as personal fees from Grifols, Shire, and Alexion Pharmaceuticals. Coauthors reported working with and receiving funds from agencies, foundations, and pharmaceutical companies.
SOURCE: Wolfe GI et al. Lancet Neurol. 2019 Jan 25. doi: 10.1016/S1474-4422(18)30392-2.
FROM LANCET NEUROLOGY
Key clinical point: The benefits of thymectomy for myasthenia gravis persist 5 years after the procedure.
Major finding: Patients who undergo thymectomy and receive prednisone have lower time-weighted average Quantitative Myasthenia Gravis scores (5.47 vs. 9.34) and mean alternate-day prednisone doses (24 mg vs. 48 mg), compared with patients who receive prednisone alone.
Study details: A rater-blinded 2-year extension study that enrolled 68 patients who had completed a 3-year randomized controlled trial.
Disclosures: The study received funding from the National Institutes of Health. Dr. Wolfe reported grants from the NIH, the Muscular Dystrophy Association, the Myasthenia Gravis Foundation of America, CSL-Behring, and ArgenX, as well as personal fees from Grifols, Shire, and Alexion Pharmaceuticals. Other authors reported working with and receiving funds from various agencies, foundations, and pharmaceutical companies.
Source: Wolfe GI et al. Lancet Neurol. 2019 Jan 25. doi: 10.1016/S1474-4422(18)30392-2.
Nuedexta mainly prescribed for dementia, Parkinson’s
Only 15% of patients prescribed dextromethorphan hydrobromide plus quinidine sulfate had pseudobulbar affect due to multiple sclerosis or amyotrophic lateral sclerosis, the condition for which this drug is labeled, according to an analysis of two national commercial insurance claims databases published online Jan. 7 in JAMA Internal Medicine.
Conversely, 57% of patients prescribed dextromethorphan-quinidine (Nuedexta) had a diagnosis of Parkinson’s disease or dementia. Furthermore, according to Medicare Part D data, prescriptions for dextromethorphan-quinidine rose 15-fold during a recent 6-year period, with a concurrent 50-fold rise in reimbursement. “In response to findings such as ours, further attention should be paid to educating prescribers about the actual benefits and risks of this costly drug combination,” Michael Fralick, MD, and his associates at Brigham and Women’s Hospital and Harvard Medical School, Boston, wrote in their paper.
The Food and Drug Administration approved Nuedexta in 2010 for the treatment of pseudobulbar affect after it produced modest improvements in laughing or crying episodes in a 12-week, placebo-controlled trial of patients with multiple sclerosis (MS) or amyotrophic lateral sclerosis (ALS). The initial FDA label noted: “Nuedexta has not been shown to be safe or effective in other types of emotional lability that can commonly occur, for example, in Alzheimer’s disease and other dementias.” Then, in 2015, patients with Alzheimer’s disease showed modest improvements in agitation scores when they received dextromethorphan-quinidine in a 10-week, placebo-controlled, industry-designed and sponsored trial. Although the dextromethorphan-quinidine arm also had higher rates of falls, urinary tract infections, and serious adverse events, the prescribing information was updated in 2015 to remove the statement about patients with dementia.
To assess real-world prescribing patterns for dextromethorphan-quinidine, Dr. Fralick and his associates analyzed data from 12,858 patients who filled a prescription for this medication between 2010 and 2017 and were recorded in the Optum Clinformatics Data Mart or Truven Health MarketScan databases. Only 8.4% of patients had a diagnosis of MS and only 6.8% had ALS, while 57% had dementia and/or Parkinson’s disease and 28% had an unknown diagnosis. The number of patients prescribed dextromethorphan-quinidine rose from nearly 3,300 in 2011 to more than 50,000 in 2016, while spending on this medication by the Centers for Medicare & Medicaid Services increased from $3.9 million to $200.4 million during the same time period.
Current treatments for behavioral symptoms of dementia “are largely ineffective, and thus clinicians may want to prescribe dextromethorphan-quinidine to see if it helps their patients,” the researchers wrote. “Yet the absence of data showing efficacy, coupled with the demonstrated risks of falls and possible cardiac effects, calls this strategy into question.
“Further studies should be required to evaluate the safety and effectiveness of this medication as it is currently being used,” the authors suggested.
Study funders included the Laura and John Arnold Foundation, the Harvard Program in Therapeutic Science, the Engelberg Foundation, and the University of Toronto Clinician Scientist Training Program. One author disclosed grants from the Food and Drug Administration Office of Generic Drugs and Division of Health Communication unrelated to the study topic.
SOURCE: Fralick M et al. JAMA Inter Med. 2019 Jan 7. doi: 10.1001/jamainternmed.2018.6112
Only 15% of patients prescribed dextromethorphan hydrobromide plus quinidine sulfate had pseudobulbar affect due to multiple sclerosis or amyotrophic lateral sclerosis, the condition for which this drug is labeled, according to an analysis of two national commercial insurance claims databases published online Jan. 7 in JAMA Internal Medicine.
Conversely, 57% of patients prescribed dextromethorphan-quinidine (Nuedexta) had a diagnosis of Parkinson’s disease or dementia. Furthermore, according to Medicare Part D data, prescriptions for dextromethorphan-quinidine rose 15-fold during a recent 6-year period, with a concurrent 50-fold rise in reimbursement. “In response to findings such as ours, further attention should be paid to educating prescribers about the actual benefits and risks of this costly drug combination,” Michael Fralick, MD, and his associates at Brigham and Women’s Hospital and Harvard Medical School, Boston, wrote in their paper.
The Food and Drug Administration approved Nuedexta in 2010 for the treatment of pseudobulbar affect after it produced modest improvements in laughing or crying episodes in a 12-week, placebo-controlled trial of patients with multiple sclerosis (MS) or amyotrophic lateral sclerosis (ALS). The initial FDA label noted: “Nuedexta has not been shown to be safe or effective in other types of emotional lability that can commonly occur, for example, in Alzheimer’s disease and other dementias.” Then, in 2015, patients with Alzheimer’s disease showed modest improvements in agitation scores when they received dextromethorphan-quinidine in a 10-week, placebo-controlled, industry-designed and sponsored trial. Although the dextromethorphan-quinidine arm also had higher rates of falls, urinary tract infections, and serious adverse events, the prescribing information was updated in 2015 to remove the statement about patients with dementia.
To assess real-world prescribing patterns for dextromethorphan-quinidine, Dr. Fralick and his associates analyzed data from 12,858 patients who filled a prescription for this medication between 2010 and 2017 and were recorded in the Optum Clinformatics Data Mart or Truven Health MarketScan databases. Only 8.4% of patients had a diagnosis of MS and only 6.8% had ALS, while 57% had dementia and/or Parkinson’s disease and 28% had an unknown diagnosis. The number of patients prescribed dextromethorphan-quinidine rose from nearly 3,300 in 2011 to more than 50,000 in 2016, while spending on this medication by the Centers for Medicare & Medicaid Services increased from $3.9 million to $200.4 million during the same time period.
Current treatments for behavioral symptoms of dementia “are largely ineffective, and thus clinicians may want to prescribe dextromethorphan-quinidine to see if it helps their patients,” the researchers wrote. “Yet the absence of data showing efficacy, coupled with the demonstrated risks of falls and possible cardiac effects, calls this strategy into question.
“Further studies should be required to evaluate the safety and effectiveness of this medication as it is currently being used,” the authors suggested.
Study funders included the Laura and John Arnold Foundation, the Harvard Program in Therapeutic Science, the Engelberg Foundation, and the University of Toronto Clinician Scientist Training Program. One author disclosed grants from the Food and Drug Administration Office of Generic Drugs and Division of Health Communication unrelated to the study topic.
SOURCE: Fralick M et al. JAMA Inter Med. 2019 Jan 7. doi: 10.1001/jamainternmed.2018.6112
Only 15% of patients prescribed dextromethorphan hydrobromide plus quinidine sulfate had pseudobulbar affect due to multiple sclerosis or amyotrophic lateral sclerosis, the condition for which this drug is labeled, according to an analysis of two national commercial insurance claims databases published online Jan. 7 in JAMA Internal Medicine.
Conversely, 57% of patients prescribed dextromethorphan-quinidine (Nuedexta) had a diagnosis of Parkinson’s disease or dementia. Furthermore, according to Medicare Part D data, prescriptions for dextromethorphan-quinidine rose 15-fold during a recent 6-year period, with a concurrent 50-fold rise in reimbursement. “In response to findings such as ours, further attention should be paid to educating prescribers about the actual benefits and risks of this costly drug combination,” Michael Fralick, MD, and his associates at Brigham and Women’s Hospital and Harvard Medical School, Boston, wrote in their paper.
The Food and Drug Administration approved Nuedexta in 2010 for the treatment of pseudobulbar affect after it produced modest improvements in laughing or crying episodes in a 12-week, placebo-controlled trial of patients with multiple sclerosis (MS) or amyotrophic lateral sclerosis (ALS). The initial FDA label noted: “Nuedexta has not been shown to be safe or effective in other types of emotional lability that can commonly occur, for example, in Alzheimer’s disease and other dementias.” Then, in 2015, patients with Alzheimer’s disease showed modest improvements in agitation scores when they received dextromethorphan-quinidine in a 10-week, placebo-controlled, industry-designed and sponsored trial. Although the dextromethorphan-quinidine arm also had higher rates of falls, urinary tract infections, and serious adverse events, the prescribing information was updated in 2015 to remove the statement about patients with dementia.
To assess real-world prescribing patterns for dextromethorphan-quinidine, Dr. Fralick and his associates analyzed data from 12,858 patients who filled a prescription for this medication between 2010 and 2017 and were recorded in the Optum Clinformatics Data Mart or Truven Health MarketScan databases. Only 8.4% of patients had a diagnosis of MS and only 6.8% had ALS, while 57% had dementia and/or Parkinson’s disease and 28% had an unknown diagnosis. The number of patients prescribed dextromethorphan-quinidine rose from nearly 3,300 in 2011 to more than 50,000 in 2016, while spending on this medication by the Centers for Medicare & Medicaid Services increased from $3.9 million to $200.4 million during the same time period.
Current treatments for behavioral symptoms of dementia “are largely ineffective, and thus clinicians may want to prescribe dextromethorphan-quinidine to see if it helps their patients,” the researchers wrote. “Yet the absence of data showing efficacy, coupled with the demonstrated risks of falls and possible cardiac effects, calls this strategy into question.
“Further studies should be required to evaluate the safety and effectiveness of this medication as it is currently being used,” the authors suggested.
Study funders included the Laura and John Arnold Foundation, the Harvard Program in Therapeutic Science, the Engelberg Foundation, and the University of Toronto Clinician Scientist Training Program. One author disclosed grants from the Food and Drug Administration Office of Generic Drugs and Division of Health Communication unrelated to the study topic.
SOURCE: Fralick M et al. JAMA Inter Med. 2019 Jan 7. doi: 10.1001/jamainternmed.2018.6112
FROM JAMA INTERNAL MEDICINE
Key clinical point:
Major finding: Only 8.4% of patients had a diagnosis of multiple sclerosis and only 6.8% had amyotrophic lateral sclerosis, while 57% had dementia and/or Parkinson’s disease and 28% had an unknown diagnosis.
Study details: Population-based cohort study of 12,858 patients prescribed dextromethorphan-quinidine between 2010 and 2017.
Disclosures: Study funders included the Laura and John Arnold Foundation, the Harvard Program in Therapeutic Science, the Engelberg Foundation, and the University of Toronto Clinician Scientist Training Program. One author disclosed grants from the Food and Drug Administration Office of Generic Drugs and Division of Health Communication unrelated to the study topic.
Source: Fralick M et al. JAMA Intern Med. 2019 Jan 7. doi: 10.1001/jamainternmed.2018.6112.
Motor neuron disease spasticity improved with cannabis-based oral spray, antispasticity drugs
Nabiximols, a cannabis-based oral spray containing delta-9 tetrahydrocannabinol and cannabidiol, significantly improved spasticity symptoms in combination with antispasticity drugs in patients with motor neuron disease in a randomized, double-blind, placebo-controlled, parallel-group, phase 2 clinical trial.
Nabiximols proved superior to a placebo spray when both were given to patients with either amyotrophic lateral sclerosis or primary lateral sclerosis as part of an antispasticity regimen in the 6-week, CANALS (Cannabis Sativa Extract in Amyotrophic Lateral Sclerosis and other Motor Neuron Disease) study at four Italian centers, Nilo Riva, MD, PhD, of the San Raffaele Scientific Institute in Milan and his colleagues reported in The Lancet Neurology. Nabiximols is approved for the treatment of spasticity due to multiple sclerosis in multiple countries, but not in the United States.
“There is no cure for motor neuron disease, so improved symptom control and quality of life are important for patients,” Dr. Riva stated in a press release. “Our proof-of-concept trial showed a beneficial effect of THC-CBD [delta-9 tetrahydrocannabinol and cannabidiol] spray in people on treatment-resistant spasticity and pain.
“Despite these encouraging findings, we must first confirm that THC-CBD spray is effective and safe in larger, longer-term phase 3 trials,” Dr. Riva added.
The patients enrolled in the phase 2 trial between January 2013 and December 2014 and were between 18 and 80 years old with a probable diagnosis of amyotrophic lateral sclerosis or primary lateral sclerosis, were on an antispasticity regimen for at least 30 days, and had a spasticity score of at least 1 in two muscle groups on the 5-point Modified Ashworth Scale. Participants titrated for the first 2 weeks before maintaining their treatment for 4 weeks.
Of 59 participants at final follow-up, Modified Ashworth Scale scores improved in the nabiximols group (29 participants) by a mean of –0.11 points, compared with worsening by a mean of 0.16 points in the placebo group (30 participants). The researchers noted that there were no participants who withdrew from the study, nabiximols was well-tolerated, and there were no serious adverse events in the nabiximols group; however, there were 22 participants in the nabiximols group and 8 participants in the placebo group who experienced an adverse event from any cause.
“This study is, to our knowledge, the first randomized controlled trial of safety and efficacy of a pharmacological treatment for spasticity and the first trial of nabiximols in motor neuron disease,” Dr. Riva and his colleagues wrote. “Our results suggest that the study drug is well tolerated and provides first evidence of efficacy in terms of controlling spasticity in patients with motor neuron disease.”
The study was funded by the Italian Research Foundation for Amyotrophic Lateral Sclerosis. GW Pharma, which developed nabiximols, provided the study drug and placebo. Many of the authors reported financial disclosures with pharmaceutical companies.
SOURCE: Riva N et al. Lancet Neurol. 2018 Dec 13. doi: 10.1016/S1474-4422(18)30406-X.
Although the results of Riva et al. are encouraging, the study had several major limitations and future research in the form of larger, multicenter, randomized controlled trials is needed, Marianne de Visser, MD, PhD, wrote in a related editorial.
Dr. de Visser noted a bias in the study as it randomized 16 patients with predominantly upper motor neuron involvement to the nabiximols group. The treatment could potentially have benefited those patients, for whom spasticity is the prevailing symptom, more than the 13 patients randomized to the nabiximols group who had classic amyotrophic lateral sclerosis involving both upper and lower neurons. In addition, Riva et al. did not differentiate between patients with upper and lower limb spasticity or patients with bulbar spasticity and those without, she said.
The use of the Modified Ashworth Scale was also a potential issue, because while it has been used in previous studies examining antispastic treatment efficacy, “it lacked sensitivity in studies of the efficacy of cannabinoids in patients with multiple sclerosis–related spasticity, and new spasticity numeric rating or visual analogue scales are being adopted,” Dr. de Visser wrote.
The number of adverse effects in the treatment group could have also unblinded researchers, which may have affected the significant findings, she said.
“Before asking for approval of cannabinoids for symptomatic treatment of spasticity in patients with amyotrophic lateral sclerosis, further studies are needed to establish the frequency of spasticity in the various presentations of motor neuron disease, and also whether reductions in spasticity improve quality of life,” Dr. de Visser said in a press release. “Natural history studies including all subtypes of motor neuron disease and better outcome measures aimed at assessment of spasticity are required. Dr. Riva and colleagues’ data are encouraging, and larger multicenter, randomized controlled trials should be done to identify which subgroups of patients derive clinically significant benefits from nabiximols.”
Marianne de Visser, MD, PhD, is with the department of neurology at Amsterdam University Medical Center. She reported no relevant conflicts of interest. Her remarks are taken from an editorial accompanying the study by Dr. Riva and associates (Lancet Neurol. 2018 Dec 13. doi: 10.1016/S1474-4422[18]30493-9 ).
Although the results of Riva et al. are encouraging, the study had several major limitations and future research in the form of larger, multicenter, randomized controlled trials is needed, Marianne de Visser, MD, PhD, wrote in a related editorial.
Dr. de Visser noted a bias in the study as it randomized 16 patients with predominantly upper motor neuron involvement to the nabiximols group. The treatment could potentially have benefited those patients, for whom spasticity is the prevailing symptom, more than the 13 patients randomized to the nabiximols group who had classic amyotrophic lateral sclerosis involving both upper and lower neurons. In addition, Riva et al. did not differentiate between patients with upper and lower limb spasticity or patients with bulbar spasticity and those without, she said.
The use of the Modified Ashworth Scale was also a potential issue, because while it has been used in previous studies examining antispastic treatment efficacy, “it lacked sensitivity in studies of the efficacy of cannabinoids in patients with multiple sclerosis–related spasticity, and new spasticity numeric rating or visual analogue scales are being adopted,” Dr. de Visser wrote.
The number of adverse effects in the treatment group could have also unblinded researchers, which may have affected the significant findings, she said.
“Before asking for approval of cannabinoids for symptomatic treatment of spasticity in patients with amyotrophic lateral sclerosis, further studies are needed to establish the frequency of spasticity in the various presentations of motor neuron disease, and also whether reductions in spasticity improve quality of life,” Dr. de Visser said in a press release. “Natural history studies including all subtypes of motor neuron disease and better outcome measures aimed at assessment of spasticity are required. Dr. Riva and colleagues’ data are encouraging, and larger multicenter, randomized controlled trials should be done to identify which subgroups of patients derive clinically significant benefits from nabiximols.”
Marianne de Visser, MD, PhD, is with the department of neurology at Amsterdam University Medical Center. She reported no relevant conflicts of interest. Her remarks are taken from an editorial accompanying the study by Dr. Riva and associates (Lancet Neurol. 2018 Dec 13. doi: 10.1016/S1474-4422[18]30493-9 ).
Although the results of Riva et al. are encouraging, the study had several major limitations and future research in the form of larger, multicenter, randomized controlled trials is needed, Marianne de Visser, MD, PhD, wrote in a related editorial.
Dr. de Visser noted a bias in the study as it randomized 16 patients with predominantly upper motor neuron involvement to the nabiximols group. The treatment could potentially have benefited those patients, for whom spasticity is the prevailing symptom, more than the 13 patients randomized to the nabiximols group who had classic amyotrophic lateral sclerosis involving both upper and lower neurons. In addition, Riva et al. did not differentiate between patients with upper and lower limb spasticity or patients with bulbar spasticity and those without, she said.
The use of the Modified Ashworth Scale was also a potential issue, because while it has been used in previous studies examining antispastic treatment efficacy, “it lacked sensitivity in studies of the efficacy of cannabinoids in patients with multiple sclerosis–related spasticity, and new spasticity numeric rating or visual analogue scales are being adopted,” Dr. de Visser wrote.
The number of adverse effects in the treatment group could have also unblinded researchers, which may have affected the significant findings, she said.
“Before asking for approval of cannabinoids for symptomatic treatment of spasticity in patients with amyotrophic lateral sclerosis, further studies are needed to establish the frequency of spasticity in the various presentations of motor neuron disease, and also whether reductions in spasticity improve quality of life,” Dr. de Visser said in a press release. “Natural history studies including all subtypes of motor neuron disease and better outcome measures aimed at assessment of spasticity are required. Dr. Riva and colleagues’ data are encouraging, and larger multicenter, randomized controlled trials should be done to identify which subgroups of patients derive clinically significant benefits from nabiximols.”
Marianne de Visser, MD, PhD, is with the department of neurology at Amsterdam University Medical Center. She reported no relevant conflicts of interest. Her remarks are taken from an editorial accompanying the study by Dr. Riva and associates (Lancet Neurol. 2018 Dec 13. doi: 10.1016/S1474-4422[18]30493-9 ).
Nabiximols, a cannabis-based oral spray containing delta-9 tetrahydrocannabinol and cannabidiol, significantly improved spasticity symptoms in combination with antispasticity drugs in patients with motor neuron disease in a randomized, double-blind, placebo-controlled, parallel-group, phase 2 clinical trial.
Nabiximols proved superior to a placebo spray when both were given to patients with either amyotrophic lateral sclerosis or primary lateral sclerosis as part of an antispasticity regimen in the 6-week, CANALS (Cannabis Sativa Extract in Amyotrophic Lateral Sclerosis and other Motor Neuron Disease) study at four Italian centers, Nilo Riva, MD, PhD, of the San Raffaele Scientific Institute in Milan and his colleagues reported in The Lancet Neurology. Nabiximols is approved for the treatment of spasticity due to multiple sclerosis in multiple countries, but not in the United States.
“There is no cure for motor neuron disease, so improved symptom control and quality of life are important for patients,” Dr. Riva stated in a press release. “Our proof-of-concept trial showed a beneficial effect of THC-CBD [delta-9 tetrahydrocannabinol and cannabidiol] spray in people on treatment-resistant spasticity and pain.
“Despite these encouraging findings, we must first confirm that THC-CBD spray is effective and safe in larger, longer-term phase 3 trials,” Dr. Riva added.
The patients enrolled in the phase 2 trial between January 2013 and December 2014 and were between 18 and 80 years old with a probable diagnosis of amyotrophic lateral sclerosis or primary lateral sclerosis, were on an antispasticity regimen for at least 30 days, and had a spasticity score of at least 1 in two muscle groups on the 5-point Modified Ashworth Scale. Participants titrated for the first 2 weeks before maintaining their treatment for 4 weeks.
Of 59 participants at final follow-up, Modified Ashworth Scale scores improved in the nabiximols group (29 participants) by a mean of –0.11 points, compared with worsening by a mean of 0.16 points in the placebo group (30 participants). The researchers noted that there were no participants who withdrew from the study, nabiximols was well-tolerated, and there were no serious adverse events in the nabiximols group; however, there were 22 participants in the nabiximols group and 8 participants in the placebo group who experienced an adverse event from any cause.
“This study is, to our knowledge, the first randomized controlled trial of safety and efficacy of a pharmacological treatment for spasticity and the first trial of nabiximols in motor neuron disease,” Dr. Riva and his colleagues wrote. “Our results suggest that the study drug is well tolerated and provides first evidence of efficacy in terms of controlling spasticity in patients with motor neuron disease.”
The study was funded by the Italian Research Foundation for Amyotrophic Lateral Sclerosis. GW Pharma, which developed nabiximols, provided the study drug and placebo. Many of the authors reported financial disclosures with pharmaceutical companies.
SOURCE: Riva N et al. Lancet Neurol. 2018 Dec 13. doi: 10.1016/S1474-4422(18)30406-X.
Nabiximols, a cannabis-based oral spray containing delta-9 tetrahydrocannabinol and cannabidiol, significantly improved spasticity symptoms in combination with antispasticity drugs in patients with motor neuron disease in a randomized, double-blind, placebo-controlled, parallel-group, phase 2 clinical trial.
Nabiximols proved superior to a placebo spray when both were given to patients with either amyotrophic lateral sclerosis or primary lateral sclerosis as part of an antispasticity regimen in the 6-week, CANALS (Cannabis Sativa Extract in Amyotrophic Lateral Sclerosis and other Motor Neuron Disease) study at four Italian centers, Nilo Riva, MD, PhD, of the San Raffaele Scientific Institute in Milan and his colleagues reported in The Lancet Neurology. Nabiximols is approved for the treatment of spasticity due to multiple sclerosis in multiple countries, but not in the United States.
“There is no cure for motor neuron disease, so improved symptom control and quality of life are important for patients,” Dr. Riva stated in a press release. “Our proof-of-concept trial showed a beneficial effect of THC-CBD [delta-9 tetrahydrocannabinol and cannabidiol] spray in people on treatment-resistant spasticity and pain.
“Despite these encouraging findings, we must first confirm that THC-CBD spray is effective and safe in larger, longer-term phase 3 trials,” Dr. Riva added.
The patients enrolled in the phase 2 trial between January 2013 and December 2014 and were between 18 and 80 years old with a probable diagnosis of amyotrophic lateral sclerosis or primary lateral sclerosis, were on an antispasticity regimen for at least 30 days, and had a spasticity score of at least 1 in two muscle groups on the 5-point Modified Ashworth Scale. Participants titrated for the first 2 weeks before maintaining their treatment for 4 weeks.
Of 59 participants at final follow-up, Modified Ashworth Scale scores improved in the nabiximols group (29 participants) by a mean of –0.11 points, compared with worsening by a mean of 0.16 points in the placebo group (30 participants). The researchers noted that there were no participants who withdrew from the study, nabiximols was well-tolerated, and there were no serious adverse events in the nabiximols group; however, there were 22 participants in the nabiximols group and 8 participants in the placebo group who experienced an adverse event from any cause.
“This study is, to our knowledge, the first randomized controlled trial of safety and efficacy of a pharmacological treatment for spasticity and the first trial of nabiximols in motor neuron disease,” Dr. Riva and his colleagues wrote. “Our results suggest that the study drug is well tolerated and provides first evidence of efficacy in terms of controlling spasticity in patients with motor neuron disease.”
The study was funded by the Italian Research Foundation for Amyotrophic Lateral Sclerosis. GW Pharma, which developed nabiximols, provided the study drug and placebo. Many of the authors reported financial disclosures with pharmaceutical companies.
SOURCE: Riva N et al. Lancet Neurol. 2018 Dec 13. doi: 10.1016/S1474-4422(18)30406-X.
FROM THE LANCET NEUROLOGY
Key clinical point:
Major finding: In the nabiximols group, Modified Ashworth Scale scores improved by mean of –0.11 points, compared with worsening by a mean of 0.16 points in the placebo group.
Study details: A multicenter, double-blinded, randomized, placebo-controlled, phase 2 trial of 59 participants with spasticity symptoms from motor neuron disease from four tertiary motor neuron centers in Italy.
Disclosures: The study was funded by the Italian Research Foundation for Amyotrophic Lateral Sclerosis. GW Pharma, which developed nabiximols, provided the study drug and placebo. Many of the authors reported financial disclosures with pharmaceutical companies.
Source: Riva N et al. Lancet Neurol. 2018 Dec 13. doi: 10.1016/S1474-4422(18)30406-X
CDC: Acute flaccid myelitis on the decline for 2018
, according to the Centers for Disease Control and Prevention.
Through Nov. 30, 134 cases of AFM in 33 states have been confirmed out of the 299 reported to the CDC. That represents “an increase of 18 confirmed cases from the previous week, but most of the latest confirmed AFM cases occurred in September and October,” the CDC reported Dec. 3.
There has been a pattern of increased AFM cases every other year for the previous 4 years: 120 cases in 2014, 22 cases in 2015, 149 cases in 2016, and 33 cases in 2017. “Most cases are reported between August and October, and a marked reduction in cases is seen in November. That pattern appears to be repeating in 2018 because states have reported fewer [persons under investigation] over the past couple of weeks. CDC expects this decline to continue,” the statement said.
The 16 confirmed cases in Texas are the most for any state this year, followed by Colorado with 15; Ohio with 10; and Illinois, New Jersey, and Washington with 9 each. California and Florida have not had any confirmed cases as of Nov. 30. Since 2014, over 90% of all confirmed AFM cases have occurred in children, the CDC noted.
More information on AFM is available at a CDC website for health care professionals.
, according to the Centers for Disease Control and Prevention.
Through Nov. 30, 134 cases of AFM in 33 states have been confirmed out of the 299 reported to the CDC. That represents “an increase of 18 confirmed cases from the previous week, but most of the latest confirmed AFM cases occurred in September and October,” the CDC reported Dec. 3.
There has been a pattern of increased AFM cases every other year for the previous 4 years: 120 cases in 2014, 22 cases in 2015, 149 cases in 2016, and 33 cases in 2017. “Most cases are reported between August and October, and a marked reduction in cases is seen in November. That pattern appears to be repeating in 2018 because states have reported fewer [persons under investigation] over the past couple of weeks. CDC expects this decline to continue,” the statement said.
The 16 confirmed cases in Texas are the most for any state this year, followed by Colorado with 15; Ohio with 10; and Illinois, New Jersey, and Washington with 9 each. California and Florida have not had any confirmed cases as of Nov. 30. Since 2014, over 90% of all confirmed AFM cases have occurred in children, the CDC noted.
More information on AFM is available at a CDC website for health care professionals.
, according to the Centers for Disease Control and Prevention.
Through Nov. 30, 134 cases of AFM in 33 states have been confirmed out of the 299 reported to the CDC. That represents “an increase of 18 confirmed cases from the previous week, but most of the latest confirmed AFM cases occurred in September and October,” the CDC reported Dec. 3.
There has been a pattern of increased AFM cases every other year for the previous 4 years: 120 cases in 2014, 22 cases in 2015, 149 cases in 2016, and 33 cases in 2017. “Most cases are reported between August and October, and a marked reduction in cases is seen in November. That pattern appears to be repeating in 2018 because states have reported fewer [persons under investigation] over the past couple of weeks. CDC expects this decline to continue,” the statement said.
The 16 confirmed cases in Texas are the most for any state this year, followed by Colorado with 15; Ohio with 10; and Illinois, New Jersey, and Washington with 9 each. California and Florida have not had any confirmed cases as of Nov. 30. Since 2014, over 90% of all confirmed AFM cases have occurred in children, the CDC noted.
More information on AFM is available at a CDC website for health care professionals.