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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
List of medications linked to drug-induced lupus expands
leaving the overall number now standing at 118.
Among the 118 suspected drugs found in VigiBase, the WHO’s global deduplicated individual case safety reports (ICSR) database, 42 had not been previously reported in association with drug-induced lupus (DIL) and 76 had been previously reported in association with DIL in Medline. DIL was reported as a serious adverse event in 55.4% of cases, according to French researchers led by Laurent Arnaud, MD, PhD, of the department of rheumatology at Hôpitaux Universitaires de Strasbourg and Centre National de Références des Maladies Systémiques Rares, Strasbourg, France.
Dr. Arnaud and his colleagues conducted a case-noncase analysis for each drug associated with DIL in order to compare the proportion of specific adverse drug reactions (ADRs) reported for a single drug with the proportion of the same ADR for all other treatments in VigiBase, which receives reports from more than 130 country members of the WHO Programme for International Drug Monitoring and contains over 16 million deduplicated ICSRs recorded by pharmacovigilance centers since 1967. They searched for cases classified as systemic lupus erythematosus (SLE) and identified 12,166 ICSRs of DIL; from these they found 118 suspected drugs with significant pharmacovigilance signal from 8,163 ICSRs that mostly originated from the Americas (65%) and Europe (23%).
In line with what the study authors expected, the drugs associated with the highest number of DIL cases were the antitumor necrosis factor agents infliximab, adalimumab, and etanercept, and the drugs associated with the highest disproportional reporting of DIL were procainamide and hydralazine.
“This is an important finding because these are the two drugs associated with the highest risk of DIL in the literature, therefore confirming the reliability of our approach using a large pharmacovigilance database,” the researchers wrote in Annals of the Rheumatic Diseases.
Overall, DIL was considered definite for 9 drugs (procainamide, hydralazine, minocycline, quinidine, isoniazid, terbinafine, methyldopa, dihydralazine, and chlorpromazine), probable for 19 drugs, and possible for 45 drugs.
The median age of DIL onset was 49 years, which the authors noted was about 2 decades older than that of spontaneous SLE.
They also observed a marked predominance in females (female to male sex ratio, 4.3), a finding that contrasted with previous studies reporting a female to male sex ratio closer to 1:1.
Dr. Arnaud and his colleagues stated that their finding of a median delay between the reported start of suspected treatment and DIL occurrence of 172 days (interquartile range, 35-610 days) suggested that DIL mostly appears after a few months and usually within the first 2 years of treatment with the suspected drug.
“The analysis of the median reporting years for each suspected drug shows a clear evolution of suspected drugs during the past decades. This further underlines that the constantly changing spectrum of DIL should be monitored continuously, and further validates the interest of our approach using the WHO international pharmacovigilance database, the biggest database of this kind with over 16 million deduplicated ICSRs,” they wrote.
The researchers added that distinguishing DIL from SLE is important because its prognosis is usually good when the drug is withdrawn, but the spectrum of DIL is constantly evolving, with drugs once described as strongly linked to DIL now prescribed less frequently.
“The first case of DIL was reported in 1945 with sulfadiazine, while hydralazine DIL was first reported in 1953. Since then, pharmacopoeia has strongly evolved, and one could hypothesize that so has the spectrum of drugs that can induce DIL,” they wrote.
“The detailed list of suspected drugs may prove useful to physicians when confronted with potential DIL cases. Altogether, these findings may help in improving the identification of this constantly evolving disease,” they concluded.
The current study was limited by the lack of a uniform set of criteria for the diagnosis of DIL and by the level of reported details available in VigiBase.
The authors had no outside funding for the study and reported having no conflicts of interest.
SOURCE: Arnaud L et al. Ann Rheum Dis. 2019 Feb 4. doi: 10.1136/annrheumdis-2018-214598.
This new and updated list of possible lupus-inducing drugs includes a growing range of treatment categories, chemical structures, and pharmacologic actions. Yet it is still unclear what the common denominator is that links them.
Drug-induced lupus (DIL) is a peculiar adverse drug reaction that appears to be unrelated to any known property of the inducing agent, although cytokine modulating biologics are a possible exception. Nevertheless, the in vivo metabolism of dissimilar drugs to products with a common, reactive property may go some way to explaining how compounds with different pharmacologic and chemical structures could induce similar adverse reactions.
The findings by Arnaud et al. need better documentation than just positive pharmacovigilance signals. For example, a drug with a relatively high signal does not necessarily translate to a high propensity for causing lupus-like symptoms. It may be a reflection of high drug usage or an awareness of the report contributors for detecting new-onset systemic lupus erythematosus.
Regardless, this research serves to help and inform the medical community to increase the vigilance of previously unreported DIL and perhaps motivate the publication of novel, convincing case reports.
Robert L. Rubin, PhD, is with the University of New Mexico, Albuquerque. His comments are adapted from an editorial accompanying the report by Arnaud et al. (Ann Rheum Dis. 2019 Feb 13. doi: annrheumdis-2018-214785). He reported having no relevant disclosures.
This new and updated list of possible lupus-inducing drugs includes a growing range of treatment categories, chemical structures, and pharmacologic actions. Yet it is still unclear what the common denominator is that links them.
Drug-induced lupus (DIL) is a peculiar adverse drug reaction that appears to be unrelated to any known property of the inducing agent, although cytokine modulating biologics are a possible exception. Nevertheless, the in vivo metabolism of dissimilar drugs to products with a common, reactive property may go some way to explaining how compounds with different pharmacologic and chemical structures could induce similar adverse reactions.
The findings by Arnaud et al. need better documentation than just positive pharmacovigilance signals. For example, a drug with a relatively high signal does not necessarily translate to a high propensity for causing lupus-like symptoms. It may be a reflection of high drug usage or an awareness of the report contributors for detecting new-onset systemic lupus erythematosus.
Regardless, this research serves to help and inform the medical community to increase the vigilance of previously unreported DIL and perhaps motivate the publication of novel, convincing case reports.
Robert L. Rubin, PhD, is with the University of New Mexico, Albuquerque. His comments are adapted from an editorial accompanying the report by Arnaud et al. (Ann Rheum Dis. 2019 Feb 13. doi: annrheumdis-2018-214785). He reported having no relevant disclosures.
This new and updated list of possible lupus-inducing drugs includes a growing range of treatment categories, chemical structures, and pharmacologic actions. Yet it is still unclear what the common denominator is that links them.
Drug-induced lupus (DIL) is a peculiar adverse drug reaction that appears to be unrelated to any known property of the inducing agent, although cytokine modulating biologics are a possible exception. Nevertheless, the in vivo metabolism of dissimilar drugs to products with a common, reactive property may go some way to explaining how compounds with different pharmacologic and chemical structures could induce similar adverse reactions.
The findings by Arnaud et al. need better documentation than just positive pharmacovigilance signals. For example, a drug with a relatively high signal does not necessarily translate to a high propensity for causing lupus-like symptoms. It may be a reflection of high drug usage or an awareness of the report contributors for detecting new-onset systemic lupus erythematosus.
Regardless, this research serves to help and inform the medical community to increase the vigilance of previously unreported DIL and perhaps motivate the publication of novel, convincing case reports.
Robert L. Rubin, PhD, is with the University of New Mexico, Albuquerque. His comments are adapted from an editorial accompanying the report by Arnaud et al. (Ann Rheum Dis. 2019 Feb 13. doi: annrheumdis-2018-214785). He reported having no relevant disclosures.
leaving the overall number now standing at 118.
Among the 118 suspected drugs found in VigiBase, the WHO’s global deduplicated individual case safety reports (ICSR) database, 42 had not been previously reported in association with drug-induced lupus (DIL) and 76 had been previously reported in association with DIL in Medline. DIL was reported as a serious adverse event in 55.4% of cases, according to French researchers led by Laurent Arnaud, MD, PhD, of the department of rheumatology at Hôpitaux Universitaires de Strasbourg and Centre National de Références des Maladies Systémiques Rares, Strasbourg, France.
Dr. Arnaud and his colleagues conducted a case-noncase analysis for each drug associated with DIL in order to compare the proportion of specific adverse drug reactions (ADRs) reported for a single drug with the proportion of the same ADR for all other treatments in VigiBase, which receives reports from more than 130 country members of the WHO Programme for International Drug Monitoring and contains over 16 million deduplicated ICSRs recorded by pharmacovigilance centers since 1967. They searched for cases classified as systemic lupus erythematosus (SLE) and identified 12,166 ICSRs of DIL; from these they found 118 suspected drugs with significant pharmacovigilance signal from 8,163 ICSRs that mostly originated from the Americas (65%) and Europe (23%).
In line with what the study authors expected, the drugs associated with the highest number of DIL cases were the antitumor necrosis factor agents infliximab, adalimumab, and etanercept, and the drugs associated with the highest disproportional reporting of DIL were procainamide and hydralazine.
“This is an important finding because these are the two drugs associated with the highest risk of DIL in the literature, therefore confirming the reliability of our approach using a large pharmacovigilance database,” the researchers wrote in Annals of the Rheumatic Diseases.
Overall, DIL was considered definite for 9 drugs (procainamide, hydralazine, minocycline, quinidine, isoniazid, terbinafine, methyldopa, dihydralazine, and chlorpromazine), probable for 19 drugs, and possible for 45 drugs.
The median age of DIL onset was 49 years, which the authors noted was about 2 decades older than that of spontaneous SLE.
They also observed a marked predominance in females (female to male sex ratio, 4.3), a finding that contrasted with previous studies reporting a female to male sex ratio closer to 1:1.
Dr. Arnaud and his colleagues stated that their finding of a median delay between the reported start of suspected treatment and DIL occurrence of 172 days (interquartile range, 35-610 days) suggested that DIL mostly appears after a few months and usually within the first 2 years of treatment with the suspected drug.
“The analysis of the median reporting years for each suspected drug shows a clear evolution of suspected drugs during the past decades. This further underlines that the constantly changing spectrum of DIL should be monitored continuously, and further validates the interest of our approach using the WHO international pharmacovigilance database, the biggest database of this kind with over 16 million deduplicated ICSRs,” they wrote.
The researchers added that distinguishing DIL from SLE is important because its prognosis is usually good when the drug is withdrawn, but the spectrum of DIL is constantly evolving, with drugs once described as strongly linked to DIL now prescribed less frequently.
“The first case of DIL was reported in 1945 with sulfadiazine, while hydralazine DIL was first reported in 1953. Since then, pharmacopoeia has strongly evolved, and one could hypothesize that so has the spectrum of drugs that can induce DIL,” they wrote.
“The detailed list of suspected drugs may prove useful to physicians when confronted with potential DIL cases. Altogether, these findings may help in improving the identification of this constantly evolving disease,” they concluded.
The current study was limited by the lack of a uniform set of criteria for the diagnosis of DIL and by the level of reported details available in VigiBase.
The authors had no outside funding for the study and reported having no conflicts of interest.
SOURCE: Arnaud L et al. Ann Rheum Dis. 2019 Feb 4. doi: 10.1136/annrheumdis-2018-214598.
leaving the overall number now standing at 118.
Among the 118 suspected drugs found in VigiBase, the WHO’s global deduplicated individual case safety reports (ICSR) database, 42 had not been previously reported in association with drug-induced lupus (DIL) and 76 had been previously reported in association with DIL in Medline. DIL was reported as a serious adverse event in 55.4% of cases, according to French researchers led by Laurent Arnaud, MD, PhD, of the department of rheumatology at Hôpitaux Universitaires de Strasbourg and Centre National de Références des Maladies Systémiques Rares, Strasbourg, France.
Dr. Arnaud and his colleagues conducted a case-noncase analysis for each drug associated with DIL in order to compare the proportion of specific adverse drug reactions (ADRs) reported for a single drug with the proportion of the same ADR for all other treatments in VigiBase, which receives reports from more than 130 country members of the WHO Programme for International Drug Monitoring and contains over 16 million deduplicated ICSRs recorded by pharmacovigilance centers since 1967. They searched for cases classified as systemic lupus erythematosus (SLE) and identified 12,166 ICSRs of DIL; from these they found 118 suspected drugs with significant pharmacovigilance signal from 8,163 ICSRs that mostly originated from the Americas (65%) and Europe (23%).
In line with what the study authors expected, the drugs associated with the highest number of DIL cases were the antitumor necrosis factor agents infliximab, adalimumab, and etanercept, and the drugs associated with the highest disproportional reporting of DIL were procainamide and hydralazine.
“This is an important finding because these are the two drugs associated with the highest risk of DIL in the literature, therefore confirming the reliability of our approach using a large pharmacovigilance database,” the researchers wrote in Annals of the Rheumatic Diseases.
Overall, DIL was considered definite for 9 drugs (procainamide, hydralazine, minocycline, quinidine, isoniazid, terbinafine, methyldopa, dihydralazine, and chlorpromazine), probable for 19 drugs, and possible for 45 drugs.
The median age of DIL onset was 49 years, which the authors noted was about 2 decades older than that of spontaneous SLE.
They also observed a marked predominance in females (female to male sex ratio, 4.3), a finding that contrasted with previous studies reporting a female to male sex ratio closer to 1:1.
Dr. Arnaud and his colleagues stated that their finding of a median delay between the reported start of suspected treatment and DIL occurrence of 172 days (interquartile range, 35-610 days) suggested that DIL mostly appears after a few months and usually within the first 2 years of treatment with the suspected drug.
“The analysis of the median reporting years for each suspected drug shows a clear evolution of suspected drugs during the past decades. This further underlines that the constantly changing spectrum of DIL should be monitored continuously, and further validates the interest of our approach using the WHO international pharmacovigilance database, the biggest database of this kind with over 16 million deduplicated ICSRs,” they wrote.
The researchers added that distinguishing DIL from SLE is important because its prognosis is usually good when the drug is withdrawn, but the spectrum of DIL is constantly evolving, with drugs once described as strongly linked to DIL now prescribed less frequently.
“The first case of DIL was reported in 1945 with sulfadiazine, while hydralazine DIL was first reported in 1953. Since then, pharmacopoeia has strongly evolved, and one could hypothesize that so has the spectrum of drugs that can induce DIL,” they wrote.
“The detailed list of suspected drugs may prove useful to physicians when confronted with potential DIL cases. Altogether, these findings may help in improving the identification of this constantly evolving disease,” they concluded.
The current study was limited by the lack of a uniform set of criteria for the diagnosis of DIL and by the level of reported details available in VigiBase.
The authors had no outside funding for the study and reported having no conflicts of interest.
SOURCE: Arnaud L et al. Ann Rheum Dis. 2019 Feb 4. doi: 10.1136/annrheumdis-2018-214598.
FROM ANNALS OF THE RHEUMATIC DISEASES
Ehlers-Danlos syndrome: Increased IUGR risk reported
LAS VEGAS – Women with Ehlers-Danlos syndrome who became pregnant were more likely to experience antepartum hemorrhage, placenta previa, cervical incompetence, and preterm birth, according to a retrospective cohort study of national birth data. Long hospital stays also were more likely among these women.
Infants born to women with Ehlers-Danlos syndrome (EDS) were significantly more likely to have intrauterine growth retardation (IUGR) as well, an unexpected and as-yet unexplained finding, said the study’s first author, Laura Nicholls-Dempsey, MD, speaking at a poster session at the meeting sponsored by the Society for Maternal-Fetal Medicine.
Complications were infrequent overall, with a very low rate of intrauterine demise and no maternal mortality seen in the 910 women with EDS who were studied, said Dr. Nicholls-Dempsey, an ob.gyn. resident at McGill University, Montreal.
In counseling women with EDS, Dr. Nicholls-Dempsey said that she would advise them that “these are the types of things we’re going to watch out for, and we’ll see how the pregnancy goes. But we have to be careful about these: preterm birth, antepartum bleeding, placenta previa. We’ll watch the growth of the baby; we just have to be more careful about these specific things.”
Compared with women without EDS, those with the inherited connective tissue disorder had adjusted odds ratios (AORs) of 3.2 for cervical incompetence (95% confidence interval, 2.0-5.1) and 2.2 for placenta previa (95% CI, 1.3-3.9; P less than .01 for both). Absolute rates for these complications were 0.8% and 0.7% for women without EDS and 2.1% and 1.4% for women with EDS, respectively.
Women with EDS also had AORs of 1.8 for antepartum hemorrhage (2.8% versus 1.6%; 95% CI, 1.2-2.7; P less than .01). Cesarean delivery was more likely in women with EDS, with an AOR of 1.6 (37.4% versus 26.9%; 95% CI, 2.0-5.1); conversely, instrumental vaginal delivery was less likely in women with EDS (AOR = 0.5; 95% CI, 0.4-0.7; P less than .01 for both), meaning that spontaneous vaginal delivery was less likely in the EDS cohort.
The higher frequency of Cesarean deliveries may be attributable to anticipatory management by physicians seeking to avoid such complications as antepartum hemorrhage, as well as to the increased rate of placenta previa seen among the EDS cohort, Dr. Nicholls-Dempsey said.
After statistical adjustment, women in the EDS cohort were more than three times as likely to have hospital stays of both more than 7 days and 14 days (5.7% versus 2.1%, AOR = 3.1 for 7 days; 2.3% versus 0.7%, AOR = 3.8 for 14 days; P less than .01 for both).
Rates of some other maternal complications, such as pre-eclampsia, eclampsia, and gestational hypertension, were not elevated in the EDS cohort. Rates of premature rupture of membranes, chorioamnionitis, uterine rupture, postpartum hemorrhage, perineal laceration, and venous thromboembolism were also similar between groups.
However, not only was the AOR for preterm birth 1.5 for infants of women with EDS, but IUGR was more common in these neonates as well (AOR = 1.7, P less than .01 for both). The latter finding was unexpected, and Dr. Nicholls-Dempsey and her colleagues currently don’t have a mechanistic explanation for the higher IUGR rate.
Dr. Nicholls-Dempsey explained that she and her colleagues used data from the United States’ Health Care Cost and Utilization Project’s Nationwide Inpatient Sample (HCUP-NIS) to compare outcomes of women with EDS with the national sample as a whole.
Between 1999 and 2013, 13,881,592 births occurred in the HCUP-NIS cohort, with 910 deliveries to women who had EDS. These women were identified by ICD-9 codes, she said.
Comparing women with EDS to the non-EDS cohort, women with EDS were more likely to be Caucasian, have a higher income, and to be smokers; the cohorts were otherwise similar.
Ehlers-Danlos syndrome is a heterogeneous disorder involving abnormalities of collagen synthesis, with 13 known subtypes not captured in the HCUP-NIS data, Dr. Nicholls-Dempsey acknowledged. She characterized this as both a limitation but also a potential strength of the study.
“I really like this study because ... we know there’s 13 types of EDS that are genetically different ... They have their overlapping symptoms, but each one is different,” she said. “In an ideal world, we would have each subtype, and we would run this type of analysis on each subtype, to really be able to say to a patient, ‘You have this mutation, and this complication is going to be a big problem for you.’” The numbers of each subtype are so small that this is infeasible, she noted.
Still, the national sample acquired over many years offers real-world outcomes that clinicians can use in shared decision-making with EDS patients who are contemplating pregnancy or are already pregnant. Also, knowing which complications are more likely in patients with EDS can help plan optimal management of labor and delivery, Dr. Nicholls-Dempsey said.
Over the study’s 14-year span, the overall arc of EDS pregnancy outcomes is well captured regardless of mutation type. “It’s very applicable to the general population” of individuals with EDS, she noted. “Because it’s not type-specific, it’s really a good overview of what you can expect in EDS patients, regardless of the type.”
Dr. Nicholls-Dempsey reported no conflicts of interest and no outside sources of funding.
SOURCE: Nicholls-Dempsey L et al. Am J Obstet Gynecol. 2019 Jan;220(1):S381-382. Abstract 574
LAS VEGAS – Women with Ehlers-Danlos syndrome who became pregnant were more likely to experience antepartum hemorrhage, placenta previa, cervical incompetence, and preterm birth, according to a retrospective cohort study of national birth data. Long hospital stays also were more likely among these women.
Infants born to women with Ehlers-Danlos syndrome (EDS) were significantly more likely to have intrauterine growth retardation (IUGR) as well, an unexpected and as-yet unexplained finding, said the study’s first author, Laura Nicholls-Dempsey, MD, speaking at a poster session at the meeting sponsored by the Society for Maternal-Fetal Medicine.
Complications were infrequent overall, with a very low rate of intrauterine demise and no maternal mortality seen in the 910 women with EDS who were studied, said Dr. Nicholls-Dempsey, an ob.gyn. resident at McGill University, Montreal.
In counseling women with EDS, Dr. Nicholls-Dempsey said that she would advise them that “these are the types of things we’re going to watch out for, and we’ll see how the pregnancy goes. But we have to be careful about these: preterm birth, antepartum bleeding, placenta previa. We’ll watch the growth of the baby; we just have to be more careful about these specific things.”
Compared with women without EDS, those with the inherited connective tissue disorder had adjusted odds ratios (AORs) of 3.2 for cervical incompetence (95% confidence interval, 2.0-5.1) and 2.2 for placenta previa (95% CI, 1.3-3.9; P less than .01 for both). Absolute rates for these complications were 0.8% and 0.7% for women without EDS and 2.1% and 1.4% for women with EDS, respectively.
Women with EDS also had AORs of 1.8 for antepartum hemorrhage (2.8% versus 1.6%; 95% CI, 1.2-2.7; P less than .01). Cesarean delivery was more likely in women with EDS, with an AOR of 1.6 (37.4% versus 26.9%; 95% CI, 2.0-5.1); conversely, instrumental vaginal delivery was less likely in women with EDS (AOR = 0.5; 95% CI, 0.4-0.7; P less than .01 for both), meaning that spontaneous vaginal delivery was less likely in the EDS cohort.
The higher frequency of Cesarean deliveries may be attributable to anticipatory management by physicians seeking to avoid such complications as antepartum hemorrhage, as well as to the increased rate of placenta previa seen among the EDS cohort, Dr. Nicholls-Dempsey said.
After statistical adjustment, women in the EDS cohort were more than three times as likely to have hospital stays of both more than 7 days and 14 days (5.7% versus 2.1%, AOR = 3.1 for 7 days; 2.3% versus 0.7%, AOR = 3.8 for 14 days; P less than .01 for both).
Rates of some other maternal complications, such as pre-eclampsia, eclampsia, and gestational hypertension, were not elevated in the EDS cohort. Rates of premature rupture of membranes, chorioamnionitis, uterine rupture, postpartum hemorrhage, perineal laceration, and venous thromboembolism were also similar between groups.
However, not only was the AOR for preterm birth 1.5 for infants of women with EDS, but IUGR was more common in these neonates as well (AOR = 1.7, P less than .01 for both). The latter finding was unexpected, and Dr. Nicholls-Dempsey and her colleagues currently don’t have a mechanistic explanation for the higher IUGR rate.
Dr. Nicholls-Dempsey explained that she and her colleagues used data from the United States’ Health Care Cost and Utilization Project’s Nationwide Inpatient Sample (HCUP-NIS) to compare outcomes of women with EDS with the national sample as a whole.
Between 1999 and 2013, 13,881,592 births occurred in the HCUP-NIS cohort, with 910 deliveries to women who had EDS. These women were identified by ICD-9 codes, she said.
Comparing women with EDS to the non-EDS cohort, women with EDS were more likely to be Caucasian, have a higher income, and to be smokers; the cohorts were otherwise similar.
Ehlers-Danlos syndrome is a heterogeneous disorder involving abnormalities of collagen synthesis, with 13 known subtypes not captured in the HCUP-NIS data, Dr. Nicholls-Dempsey acknowledged. She characterized this as both a limitation but also a potential strength of the study.
“I really like this study because ... we know there’s 13 types of EDS that are genetically different ... They have their overlapping symptoms, but each one is different,” she said. “In an ideal world, we would have each subtype, and we would run this type of analysis on each subtype, to really be able to say to a patient, ‘You have this mutation, and this complication is going to be a big problem for you.’” The numbers of each subtype are so small that this is infeasible, she noted.
Still, the national sample acquired over many years offers real-world outcomes that clinicians can use in shared decision-making with EDS patients who are contemplating pregnancy or are already pregnant. Also, knowing which complications are more likely in patients with EDS can help plan optimal management of labor and delivery, Dr. Nicholls-Dempsey said.
Over the study’s 14-year span, the overall arc of EDS pregnancy outcomes is well captured regardless of mutation type. “It’s very applicable to the general population” of individuals with EDS, she noted. “Because it’s not type-specific, it’s really a good overview of what you can expect in EDS patients, regardless of the type.”
Dr. Nicholls-Dempsey reported no conflicts of interest and no outside sources of funding.
SOURCE: Nicholls-Dempsey L et al. Am J Obstet Gynecol. 2019 Jan;220(1):S381-382. Abstract 574
LAS VEGAS – Women with Ehlers-Danlos syndrome who became pregnant were more likely to experience antepartum hemorrhage, placenta previa, cervical incompetence, and preterm birth, according to a retrospective cohort study of national birth data. Long hospital stays also were more likely among these women.
Infants born to women with Ehlers-Danlos syndrome (EDS) were significantly more likely to have intrauterine growth retardation (IUGR) as well, an unexpected and as-yet unexplained finding, said the study’s first author, Laura Nicholls-Dempsey, MD, speaking at a poster session at the meeting sponsored by the Society for Maternal-Fetal Medicine.
Complications were infrequent overall, with a very low rate of intrauterine demise and no maternal mortality seen in the 910 women with EDS who were studied, said Dr. Nicholls-Dempsey, an ob.gyn. resident at McGill University, Montreal.
In counseling women with EDS, Dr. Nicholls-Dempsey said that she would advise them that “these are the types of things we’re going to watch out for, and we’ll see how the pregnancy goes. But we have to be careful about these: preterm birth, antepartum bleeding, placenta previa. We’ll watch the growth of the baby; we just have to be more careful about these specific things.”
Compared with women without EDS, those with the inherited connective tissue disorder had adjusted odds ratios (AORs) of 3.2 for cervical incompetence (95% confidence interval, 2.0-5.1) and 2.2 for placenta previa (95% CI, 1.3-3.9; P less than .01 for both). Absolute rates for these complications were 0.8% and 0.7% for women without EDS and 2.1% and 1.4% for women with EDS, respectively.
Women with EDS also had AORs of 1.8 for antepartum hemorrhage (2.8% versus 1.6%; 95% CI, 1.2-2.7; P less than .01). Cesarean delivery was more likely in women with EDS, with an AOR of 1.6 (37.4% versus 26.9%; 95% CI, 2.0-5.1); conversely, instrumental vaginal delivery was less likely in women with EDS (AOR = 0.5; 95% CI, 0.4-0.7; P less than .01 for both), meaning that spontaneous vaginal delivery was less likely in the EDS cohort.
The higher frequency of Cesarean deliveries may be attributable to anticipatory management by physicians seeking to avoid such complications as antepartum hemorrhage, as well as to the increased rate of placenta previa seen among the EDS cohort, Dr. Nicholls-Dempsey said.
After statistical adjustment, women in the EDS cohort were more than three times as likely to have hospital stays of both more than 7 days and 14 days (5.7% versus 2.1%, AOR = 3.1 for 7 days; 2.3% versus 0.7%, AOR = 3.8 for 14 days; P less than .01 for both).
Rates of some other maternal complications, such as pre-eclampsia, eclampsia, and gestational hypertension, were not elevated in the EDS cohort. Rates of premature rupture of membranes, chorioamnionitis, uterine rupture, postpartum hemorrhage, perineal laceration, and venous thromboembolism were also similar between groups.
However, not only was the AOR for preterm birth 1.5 for infants of women with EDS, but IUGR was more common in these neonates as well (AOR = 1.7, P less than .01 for both). The latter finding was unexpected, and Dr. Nicholls-Dempsey and her colleagues currently don’t have a mechanistic explanation for the higher IUGR rate.
Dr. Nicholls-Dempsey explained that she and her colleagues used data from the United States’ Health Care Cost and Utilization Project’s Nationwide Inpatient Sample (HCUP-NIS) to compare outcomes of women with EDS with the national sample as a whole.
Between 1999 and 2013, 13,881,592 births occurred in the HCUP-NIS cohort, with 910 deliveries to women who had EDS. These women were identified by ICD-9 codes, she said.
Comparing women with EDS to the non-EDS cohort, women with EDS were more likely to be Caucasian, have a higher income, and to be smokers; the cohorts were otherwise similar.
Ehlers-Danlos syndrome is a heterogeneous disorder involving abnormalities of collagen synthesis, with 13 known subtypes not captured in the HCUP-NIS data, Dr. Nicholls-Dempsey acknowledged. She characterized this as both a limitation but also a potential strength of the study.
“I really like this study because ... we know there’s 13 types of EDS that are genetically different ... They have their overlapping symptoms, but each one is different,” she said. “In an ideal world, we would have each subtype, and we would run this type of analysis on each subtype, to really be able to say to a patient, ‘You have this mutation, and this complication is going to be a big problem for you.’” The numbers of each subtype are so small that this is infeasible, she noted.
Still, the national sample acquired over many years offers real-world outcomes that clinicians can use in shared decision-making with EDS patients who are contemplating pregnancy or are already pregnant. Also, knowing which complications are more likely in patients with EDS can help plan optimal management of labor and delivery, Dr. Nicholls-Dempsey said.
Over the study’s 14-year span, the overall arc of EDS pregnancy outcomes is well captured regardless of mutation type. “It’s very applicable to the general population” of individuals with EDS, she noted. “Because it’s not type-specific, it’s really a good overview of what you can expect in EDS patients, regardless of the type.”
Dr. Nicholls-Dempsey reported no conflicts of interest and no outside sources of funding.
SOURCE: Nicholls-Dempsey L et al. Am J Obstet Gynecol. 2019 Jan;220(1):S381-382. Abstract 574
REPORTING FROM THE PREGNANCY MEETING
New findings raise questions about the role of ANAs in SLE
Antinuclear antibodies (ANAs) have long been considered an important marker in rheumatologic conditions, particularly for the diagnosis and classification of patients with systemic lupus erythematosus, but recent findings are raising new questions about their role.
“We’ve measured ANAs for a long time – it’s a very important test in rheumatology,” David S. Pisetsky, MD, PhD, explained in an interview.
However, even though this test has been around for decades, “some interesting things have developed around it that have made a lot of people, including me, take a second look,” said Dr. Pisetsky, professor of medicine and immunology at Duke University, Durham, N.C.
He elaborated on those recent findings, which relate to the findings of ANA negativity in patients with an established diagnosis of systemic lupus erythematosus (SLE) and to variability among ANA test kit findings, during a presentation at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.
“Screening of patients during clinical trials for new treatments of SLE suggest that a significant number of people with lupus – 20%-30%, in fact – are ANA negative despite disease activity at the time the test is done,” he said.
For example, unpublished (but recently submitted) data from a phase 2 trial looking at the efficacy and safety of an interleukin-6 monoclonal antibody for the treatment of SLE showed that 23.8% of baseline samples from 183 SLE patients with positive historical ANA and clinically active lupus prior to randomization were ANA negative.
A particular concern with respect to such findings is that ANA positivity is typically a criterion for entry into clinical trials of therapies for lupus and prescription of medications approved for active lupus, Dr. Pisetsky said.
“On the other hand, about 20% of otherwise healthy people – especially women – can be ANA positive, so it’s always been problematic as a screening test due to these false positives, but these new findings suggest that in lupus a real concern is false negatives,” he said. “It’s quite a surprise.”
The findings raise questions about whether ANA negativity in SLE reflects the natural history of the disease, an effect of treatments, or a problem with the assays.
It appears an important problem relates to test kit variability, he said.
“There are lots of different ANA test kits. Their performance characteristics are very different. The performance of ANA tests is much more variable than people realize,” he said, citing data from an analysis that he and his colleagues conducted using 103 samples from a cohort of patients with established SLE.
In that 2017 study, an ANA enzyme-linked immunosorbent assay showed an ANA-negativity rate of 11.7% with zero indeterminate tests, whereas three different test kits showed ANA-negativity rates of 22.3% (with 8.7% of samples reported as indeterminate), 9.7% (with another 9.7% indeterminate), and 4.9% (with another 1.9% indeterminate), respectively. Multiplex testing showed a 13.6% ANA-negativity rate and an indeterminate rate of 7.8% (Ann Rheum Dis. 2018;77:911-3).
Only one sample tested negative for ANA on all three test kits, and disagreement about ANA negativity occurred in one-third of the samples, he said.
Anti–double-stranded DNA assays
Recent findings also raise questions about the use of assays that specifically assess for anti–double-stranded DNA (anti-dsDNA) antibodies, which are highly associated with SLE and have been used as a biomarker for the disease, Dr. Pisetsky said.
For example, a comparison of two anti-dsDNA assays showed discordant results with respect to negativity for anti-dsDNA antibodies in 64 of 181 samples from SLE patients. One assay showed a 70.7% rate of anti-dsDNA negativity and the other showed a 37.6% rate.
The concern regarding test variability relates to the issue of ANA positivity and eligibility for study enrollment and certain treatments; test variability can affect the diagnosis of patients with SLE because ANA positivity is an important finding in routine clinical care, and for anti-dsDNA, test variability can affect assessment of disease activity, he explained.
Tests may differ in a number of ways, such as in their specificity, sensitivity, avidity, and range of epitopes detected. Unfortunately, not enough is known at this point to make specific recommendations regarding best test kits, and while there are alternative technologies that could be useful for ANA testing, none has been validated for particular use in the assessment of trial eligibility, Dr. Pisetsky said.
Nonetheless, awareness of the test variability is important, especially when it comes to assessing patients for trial eligibility and prescribing medications, he added. “For practical, real-world utilization, people need to know about this.”
Dr. Pisetsky reported receiving ANA-related research support from Pfizer, conducting collaborative research with Bio-Rad and EuroImmun, and serving as an adviser to ImmunArray.
Antinuclear antibodies (ANAs) have long been considered an important marker in rheumatologic conditions, particularly for the diagnosis and classification of patients with systemic lupus erythematosus, but recent findings are raising new questions about their role.
“We’ve measured ANAs for a long time – it’s a very important test in rheumatology,” David S. Pisetsky, MD, PhD, explained in an interview.
However, even though this test has been around for decades, “some interesting things have developed around it that have made a lot of people, including me, take a second look,” said Dr. Pisetsky, professor of medicine and immunology at Duke University, Durham, N.C.
He elaborated on those recent findings, which relate to the findings of ANA negativity in patients with an established diagnosis of systemic lupus erythematosus (SLE) and to variability among ANA test kit findings, during a presentation at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.
“Screening of patients during clinical trials for new treatments of SLE suggest that a significant number of people with lupus – 20%-30%, in fact – are ANA negative despite disease activity at the time the test is done,” he said.
For example, unpublished (but recently submitted) data from a phase 2 trial looking at the efficacy and safety of an interleukin-6 monoclonal antibody for the treatment of SLE showed that 23.8% of baseline samples from 183 SLE patients with positive historical ANA and clinically active lupus prior to randomization were ANA negative.
A particular concern with respect to such findings is that ANA positivity is typically a criterion for entry into clinical trials of therapies for lupus and prescription of medications approved for active lupus, Dr. Pisetsky said.
“On the other hand, about 20% of otherwise healthy people – especially women – can be ANA positive, so it’s always been problematic as a screening test due to these false positives, but these new findings suggest that in lupus a real concern is false negatives,” he said. “It’s quite a surprise.”
The findings raise questions about whether ANA negativity in SLE reflects the natural history of the disease, an effect of treatments, or a problem with the assays.
It appears an important problem relates to test kit variability, he said.
“There are lots of different ANA test kits. Their performance characteristics are very different. The performance of ANA tests is much more variable than people realize,” he said, citing data from an analysis that he and his colleagues conducted using 103 samples from a cohort of patients with established SLE.
In that 2017 study, an ANA enzyme-linked immunosorbent assay showed an ANA-negativity rate of 11.7% with zero indeterminate tests, whereas three different test kits showed ANA-negativity rates of 22.3% (with 8.7% of samples reported as indeterminate), 9.7% (with another 9.7% indeterminate), and 4.9% (with another 1.9% indeterminate), respectively. Multiplex testing showed a 13.6% ANA-negativity rate and an indeterminate rate of 7.8% (Ann Rheum Dis. 2018;77:911-3).
Only one sample tested negative for ANA on all three test kits, and disagreement about ANA negativity occurred in one-third of the samples, he said.
Anti–double-stranded DNA assays
Recent findings also raise questions about the use of assays that specifically assess for anti–double-stranded DNA (anti-dsDNA) antibodies, which are highly associated with SLE and have been used as a biomarker for the disease, Dr. Pisetsky said.
For example, a comparison of two anti-dsDNA assays showed discordant results with respect to negativity for anti-dsDNA antibodies in 64 of 181 samples from SLE patients. One assay showed a 70.7% rate of anti-dsDNA negativity and the other showed a 37.6% rate.
The concern regarding test variability relates to the issue of ANA positivity and eligibility for study enrollment and certain treatments; test variability can affect the diagnosis of patients with SLE because ANA positivity is an important finding in routine clinical care, and for anti-dsDNA, test variability can affect assessment of disease activity, he explained.
Tests may differ in a number of ways, such as in their specificity, sensitivity, avidity, and range of epitopes detected. Unfortunately, not enough is known at this point to make specific recommendations regarding best test kits, and while there are alternative technologies that could be useful for ANA testing, none has been validated for particular use in the assessment of trial eligibility, Dr. Pisetsky said.
Nonetheless, awareness of the test variability is important, especially when it comes to assessing patients for trial eligibility and prescribing medications, he added. “For practical, real-world utilization, people need to know about this.”
Dr. Pisetsky reported receiving ANA-related research support from Pfizer, conducting collaborative research with Bio-Rad and EuroImmun, and serving as an adviser to ImmunArray.
Antinuclear antibodies (ANAs) have long been considered an important marker in rheumatologic conditions, particularly for the diagnosis and classification of patients with systemic lupus erythematosus, but recent findings are raising new questions about their role.
“We’ve measured ANAs for a long time – it’s a very important test in rheumatology,” David S. Pisetsky, MD, PhD, explained in an interview.
However, even though this test has been around for decades, “some interesting things have developed around it that have made a lot of people, including me, take a second look,” said Dr. Pisetsky, professor of medicine and immunology at Duke University, Durham, N.C.
He elaborated on those recent findings, which relate to the findings of ANA negativity in patients with an established diagnosis of systemic lupus erythematosus (SLE) and to variability among ANA test kit findings, during a presentation at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.
“Screening of patients during clinical trials for new treatments of SLE suggest that a significant number of people with lupus – 20%-30%, in fact – are ANA negative despite disease activity at the time the test is done,” he said.
For example, unpublished (but recently submitted) data from a phase 2 trial looking at the efficacy and safety of an interleukin-6 monoclonal antibody for the treatment of SLE showed that 23.8% of baseline samples from 183 SLE patients with positive historical ANA and clinically active lupus prior to randomization were ANA negative.
A particular concern with respect to such findings is that ANA positivity is typically a criterion for entry into clinical trials of therapies for lupus and prescription of medications approved for active lupus, Dr. Pisetsky said.
“On the other hand, about 20% of otherwise healthy people – especially women – can be ANA positive, so it’s always been problematic as a screening test due to these false positives, but these new findings suggest that in lupus a real concern is false negatives,” he said. “It’s quite a surprise.”
The findings raise questions about whether ANA negativity in SLE reflects the natural history of the disease, an effect of treatments, or a problem with the assays.
It appears an important problem relates to test kit variability, he said.
“There are lots of different ANA test kits. Their performance characteristics are very different. The performance of ANA tests is much more variable than people realize,” he said, citing data from an analysis that he and his colleagues conducted using 103 samples from a cohort of patients with established SLE.
In that 2017 study, an ANA enzyme-linked immunosorbent assay showed an ANA-negativity rate of 11.7% with zero indeterminate tests, whereas three different test kits showed ANA-negativity rates of 22.3% (with 8.7% of samples reported as indeterminate), 9.7% (with another 9.7% indeterminate), and 4.9% (with another 1.9% indeterminate), respectively. Multiplex testing showed a 13.6% ANA-negativity rate and an indeterminate rate of 7.8% (Ann Rheum Dis. 2018;77:911-3).
Only one sample tested negative for ANA on all three test kits, and disagreement about ANA negativity occurred in one-third of the samples, he said.
Anti–double-stranded DNA assays
Recent findings also raise questions about the use of assays that specifically assess for anti–double-stranded DNA (anti-dsDNA) antibodies, which are highly associated with SLE and have been used as a biomarker for the disease, Dr. Pisetsky said.
For example, a comparison of two anti-dsDNA assays showed discordant results with respect to negativity for anti-dsDNA antibodies in 64 of 181 samples from SLE patients. One assay showed a 70.7% rate of anti-dsDNA negativity and the other showed a 37.6% rate.
The concern regarding test variability relates to the issue of ANA positivity and eligibility for study enrollment and certain treatments; test variability can affect the diagnosis of patients with SLE because ANA positivity is an important finding in routine clinical care, and for anti-dsDNA, test variability can affect assessment of disease activity, he explained.
Tests may differ in a number of ways, such as in their specificity, sensitivity, avidity, and range of epitopes detected. Unfortunately, not enough is known at this point to make specific recommendations regarding best test kits, and while there are alternative technologies that could be useful for ANA testing, none has been validated for particular use in the assessment of trial eligibility, Dr. Pisetsky said.
Nonetheless, awareness of the test variability is important, especially when it comes to assessing patients for trial eligibility and prescribing medications, he added. “For practical, real-world utilization, people need to know about this.”
Dr. Pisetsky reported receiving ANA-related research support from Pfizer, conducting collaborative research with Bio-Rad and EuroImmun, and serving as an adviser to ImmunArray.
EXPERT ANALYSIS FROM THE WINTER RHEUMATOLOGY SYMPOSIUM
New SLE disease activity measure beats SLEDAI-2K
In terms of identifying clinically significant changes, the Systemic Lupus Erythematosus Disease Activity Score (SLE-DAS) was superior to the SLE Disease Activity Index 2000 (SLEDAI-2K), said the authors of a longitudinal cohort study comparing the two instruments.
The SLE-DAS maintained high specificity compared with the SLEDAI-2K and had a similar clinical workup time requirement, according to Diogo Jesus, MD, of the rheumatology department at Centro Hospitalar e Universitário de Coimbra, Portugal, and his colleagues.
“Such a performance can have major implications in the interpretation of clinical trials applying the disease activity as the primary endpoint, and in daily clinical practice, where SLE-DAS could provide robust guidance for treatment in the individual patient,” Dr. Jesus and his coauthors wrote in Annals of the Rheumatic Diseases.
The longitudinal cohort study by Dr. Jesus and his colleagues included 520 patients with SLE from tertiary care centers in Coimbra, Portugal, and Padova, Italy. These included a derivation cohort of 324 patients and an external validation cohort of 196 patients (the Padova Lupus Cohort).
A cutoff value of 1.72 for change in the 17-item SLE-DAS had significantly higher sensitivities to detect a clinical meaningful improvement in both the derivation (82.1%) and external validation (89.5%) cohorts, compared with a cutoff value of 4 or higher in the SLEDAI-2K at 44.8% and 47.4%, respectively, the investigators reported. Likewise, ability to detect clinically meaningful worsening was significantly higher with SLE-DAS, with sensitivities of 93.1% in the derivation cohort and 95.5% in the external validation group versus a respective 46.6% and 59.1% for SLEDAI-2K. Both clinical improvement and worsening were defined by a change in the Physician Global Assessment score of 0.3 or more.
Specificity was high for both instruments, with values around 98%-99% in both cohorts for clinically meaningful worsening and about 97%-100% for clinically meaningful improvement, the report shows.
Further analyses showed that disease activity tracked over time with SLE-DAS had a higher predictive value for damage accrual versus the SLEDAI-2K, according to the investigators.
The SLE-DAS formula, published in the journal by Dr. Jesus and his colleagues, includes a total of 17 weighted and mostly binary variables: presence or absence of alopecia, arthritis, cardiac/pulmonary involvement, generalized cutaneous rash, hemolytic anemia, hypocomplementemia, increased anti-dsDNA levels, leukopenia, localized cutaneous rash, mucocutaneous vasculitis, mucosal ulcers, myositis, neuropsychiatric involvement, proteinuria, serositis, systemic vasculitis, and thrombocytopenia.
Next, the researchers plan to define SLE-DAS cutoff values for remission, low disease activity, and moderate or high disease activity. An online calculator is also in the works, they said.
Dr. Jesus and his coauthors did not report any outside funding for the study and said they had no competing interests related to their research.
SOURCE: Jesus D et al. Ann Rheum Dis. 2019 Jan 9. doi: 10.1136/annrheumdis-2018-214502.
In terms of identifying clinically significant changes, the Systemic Lupus Erythematosus Disease Activity Score (SLE-DAS) was superior to the SLE Disease Activity Index 2000 (SLEDAI-2K), said the authors of a longitudinal cohort study comparing the two instruments.
The SLE-DAS maintained high specificity compared with the SLEDAI-2K and had a similar clinical workup time requirement, according to Diogo Jesus, MD, of the rheumatology department at Centro Hospitalar e Universitário de Coimbra, Portugal, and his colleagues.
“Such a performance can have major implications in the interpretation of clinical trials applying the disease activity as the primary endpoint, and in daily clinical practice, where SLE-DAS could provide robust guidance for treatment in the individual patient,” Dr. Jesus and his coauthors wrote in Annals of the Rheumatic Diseases.
The longitudinal cohort study by Dr. Jesus and his colleagues included 520 patients with SLE from tertiary care centers in Coimbra, Portugal, and Padova, Italy. These included a derivation cohort of 324 patients and an external validation cohort of 196 patients (the Padova Lupus Cohort).
A cutoff value of 1.72 for change in the 17-item SLE-DAS had significantly higher sensitivities to detect a clinical meaningful improvement in both the derivation (82.1%) and external validation (89.5%) cohorts, compared with a cutoff value of 4 or higher in the SLEDAI-2K at 44.8% and 47.4%, respectively, the investigators reported. Likewise, ability to detect clinically meaningful worsening was significantly higher with SLE-DAS, with sensitivities of 93.1% in the derivation cohort and 95.5% in the external validation group versus a respective 46.6% and 59.1% for SLEDAI-2K. Both clinical improvement and worsening were defined by a change in the Physician Global Assessment score of 0.3 or more.
Specificity was high for both instruments, with values around 98%-99% in both cohorts for clinically meaningful worsening and about 97%-100% for clinically meaningful improvement, the report shows.
Further analyses showed that disease activity tracked over time with SLE-DAS had a higher predictive value for damage accrual versus the SLEDAI-2K, according to the investigators.
The SLE-DAS formula, published in the journal by Dr. Jesus and his colleagues, includes a total of 17 weighted and mostly binary variables: presence or absence of alopecia, arthritis, cardiac/pulmonary involvement, generalized cutaneous rash, hemolytic anemia, hypocomplementemia, increased anti-dsDNA levels, leukopenia, localized cutaneous rash, mucocutaneous vasculitis, mucosal ulcers, myositis, neuropsychiatric involvement, proteinuria, serositis, systemic vasculitis, and thrombocytopenia.
Next, the researchers plan to define SLE-DAS cutoff values for remission, low disease activity, and moderate or high disease activity. An online calculator is also in the works, they said.
Dr. Jesus and his coauthors did not report any outside funding for the study and said they had no competing interests related to their research.
SOURCE: Jesus D et al. Ann Rheum Dis. 2019 Jan 9. doi: 10.1136/annrheumdis-2018-214502.
In terms of identifying clinically significant changes, the Systemic Lupus Erythematosus Disease Activity Score (SLE-DAS) was superior to the SLE Disease Activity Index 2000 (SLEDAI-2K), said the authors of a longitudinal cohort study comparing the two instruments.
The SLE-DAS maintained high specificity compared with the SLEDAI-2K and had a similar clinical workup time requirement, according to Diogo Jesus, MD, of the rheumatology department at Centro Hospitalar e Universitário de Coimbra, Portugal, and his colleagues.
“Such a performance can have major implications in the interpretation of clinical trials applying the disease activity as the primary endpoint, and in daily clinical practice, where SLE-DAS could provide robust guidance for treatment in the individual patient,” Dr. Jesus and his coauthors wrote in Annals of the Rheumatic Diseases.
The longitudinal cohort study by Dr. Jesus and his colleagues included 520 patients with SLE from tertiary care centers in Coimbra, Portugal, and Padova, Italy. These included a derivation cohort of 324 patients and an external validation cohort of 196 patients (the Padova Lupus Cohort).
A cutoff value of 1.72 for change in the 17-item SLE-DAS had significantly higher sensitivities to detect a clinical meaningful improvement in both the derivation (82.1%) and external validation (89.5%) cohorts, compared with a cutoff value of 4 or higher in the SLEDAI-2K at 44.8% and 47.4%, respectively, the investigators reported. Likewise, ability to detect clinically meaningful worsening was significantly higher with SLE-DAS, with sensitivities of 93.1% in the derivation cohort and 95.5% in the external validation group versus a respective 46.6% and 59.1% for SLEDAI-2K. Both clinical improvement and worsening were defined by a change in the Physician Global Assessment score of 0.3 or more.
Specificity was high for both instruments, with values around 98%-99% in both cohorts for clinically meaningful worsening and about 97%-100% for clinically meaningful improvement, the report shows.
Further analyses showed that disease activity tracked over time with SLE-DAS had a higher predictive value for damage accrual versus the SLEDAI-2K, according to the investigators.
The SLE-DAS formula, published in the journal by Dr. Jesus and his colleagues, includes a total of 17 weighted and mostly binary variables: presence or absence of alopecia, arthritis, cardiac/pulmonary involvement, generalized cutaneous rash, hemolytic anemia, hypocomplementemia, increased anti-dsDNA levels, leukopenia, localized cutaneous rash, mucocutaneous vasculitis, mucosal ulcers, myositis, neuropsychiatric involvement, proteinuria, serositis, systemic vasculitis, and thrombocytopenia.
Next, the researchers plan to define SLE-DAS cutoff values for remission, low disease activity, and moderate or high disease activity. An online calculator is also in the works, they said.
Dr. Jesus and his coauthors did not report any outside funding for the study and said they had no competing interests related to their research.
SOURCE: Jesus D et al. Ann Rheum Dis. 2019 Jan 9. doi: 10.1136/annrheumdis-2018-214502.
FROM ANNALS OF THE RHEUMATIC DISEASES
Key clinical point: The Systemic Lupus Erythematosus Disease Activity Score (SLE-DAS) had better performance in detecting clinically significant changes, compared with the commonly used SLE Disease Activity Index 2000 (SLEDAI-2K).
Major finding: In a validation cohort, the SLE-DAS (vs. SLEDAI-2K) had a significantly higher sensitivity to detect a clinical meaningful improvement (89.5% vs. 47.4%) and clinically meaningful worsening (95.5% vs. 59.1%), with comparably high specificity for both tools.
Study details: Longitudinal cohort study including 520 patients with SLE from two tertiary care centers.
Disclosures: The study authors did not report any outside funding for the study and said they had no competing interests related to the research.
Source: Jesus D et al. Ann Rheum Dis. 2019 Jan 9. doi: 10.1136/annrheumdis-2018-214502.
Primary Sjögren’s syndrome: New research and new resources improve outlook
Recent findings, new classification criteria and treatment guidelines, and concerted efforts by various organizations to provide educational resources are among a number of factors improving the outlook for patients with primary Sjögren’s syndrome, according to Judith James, MD, PhD.
Additionally, the number of studies of primary Sjögren’s syndrome (pSS) is increasing, albeit slowly, and ongoing studies of biologics are showing promise, Dr. James said during a clinical update at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.
Classification criteria
The ACR in conjunction with the European League Against Rheumatism (EULAR) published new criteria for pSS classification in 2016 based on the available evidence and expert consensus. Inclusion criteria include daily, persistent, troublesome dry eyes for more than 3 months, recurrent sensation of sand or gravel in the eyes, use of tear substitutes more than three times each day, frequent drinking of liquids to aid in swallowing dry food, or at least one EULAR Sjögren’s syndrome disease activity index (ESSDAI) domain with a positive item. Exclusion criteria include prior head and neck radiation treatment, polymerase chain reaction–confirmed active hepatitis C infection, AIDS, sarcoidosis, amyloidosis, graft-versus-host disease, or IgG4-related disease, said Dr. James, professor and chair of the arthritis and clinical immunology research program at the University of Oklahoma, Oklahoma City (Arthritis Rheumatol. Jan 2017;69[1]:35-45).
- A score of 4 or higher in patients who meet the inclusion criteria and do not have any of the exclusion criteria leads to classification with pSS, based on the following findings:
- Labial salivary gland with focal lymphocytic sialadenitis and focus score of at least 1 foci/4 mm2 (weight/score = 3).
- Anti-SSA/Ro-positivity (weight/score = 3).
- Ocular Staining Score of at least 5, or van Bijsterveld score of at least 4, in at least one eye (weight/score = 1).
- Schirmer’s test of no more than 5 mm/5 min in at least one eye (weight/score = 1).
- Unstimulated whole saliva flow rate of no more than 0.1 mL/min (weight/score = 1).
Clinical pearls for detection and management
In Dr. James’ experience, the three symptoms (taken together) with the highest predictive value for diagnosing pSS are dry mouth, sore mouth/tongue, and dry eyes. About 25% of Sjögren’s patients may have no detectable salivary flow, she said.
Dry, cracked skin that can lead to secondary infections is another common issue affecting about 55% of patients.
“So we always have to talk to our Sjögren’s patients about skin,” she said. “We also have recurrent sinusitis, chronic cough, dyspepsia, constipation, and other symptoms.”
Concurrent autoimmune diseases are another concern in Sjögren’s patients, she said. One to particularly keep in mind, in addition to lupus and rheumatoid arthritis, is autoimmune thyroid disease.
Data suggest that up to 45% of Sjögren’s patients have thyroid dysfunction, and if you look at just those with autoimmune thyroiditis, their risk of Sjögren’s is increased 10-fold vs. those without autoimmune thyroiditis, she said.
Other conditions to keep in mind when it comes to diagnosing and managing patients, as has been shown in numerous studies over the years, include Raynaud’s phenomenon, which affects at least 13% of patients, and subclinical muscle inflammation, which affects more than 50% of patients, Dr. James said.
“Depression ... as well as anxiety, is quite common in Sjögren’s patients, and fatigue is profound,” she added, noting that fatigue is “the No. 1 issue” for many patients.
Another area of particular concern in Sjögren’s is the increased risk of lymphoma, she said.
Studies show varying rates of lymphoma in Sjögren’s, with one suggesting a 44-fold increased risk, but this is likely only among those at very high risk. Other studies suggest the increase is risk overall is in the range of 4- to 10-fold, she said.
Mortality in Sjögren’s patients
A 2015 study by Soledad Retamozo et al. showed that the presence of cryoglobulinemic vasculitis (CV) at diagnosis is associated with increased mortality risk.
Of 515 consecutive pSS patients with a mean follow-up of 110 months, 65 (12%) had cryoglobulins detected, and 21 of those (32%) fulfilled CV criteria. The patients with cryoglobulins had higher cumulative mean disease activity, 45 (9%) developed B-cell lymphoma, and 33 (6%) died (Arthritis Rheumatol. 2015;67[suppl 10]. Abstract 628).
Additionally, both CV-positive and CV-negative patients had higher risk of B-cell lymphoma, but the risk was greatest in the CV-positive group (hazard ratios, 7.47 and 2.56, respectively), and the CV-positive patients had a higher risk of death (HR, 11.68).
“This actually has changed practice in our Sjögren’s clinic because we didn’t used to do cryos on everybody unless they had leukocytoclastic vasculitis, because they also have a higher risk of death,” Dr. James said.
Systemic activity also predicts pSS mortality, according to findings published in 2016 by Pilar Brito-Zerón et al. Of 1,045 patients who were part of the Spanish Group of Autoimmune Disease-SS Study Group and who were followed for a mean of 117 months, mortality was 11%. Survival was 96% at 5 years, 90% at 10 years, 81% at 20 years, and 60% at 30 years (Ann Rheum Dis. 2016;75:348-55).
Baseline factors associated with increased mortality on multivariate analysis included male gender, cryoglobulins, and low complement levels; the strongest model for death included high activity in at least one ESSDAI domain, baseline ESSDAI of at least 14, more than one laboratory predictive marker such as lymphopenia, anti-La, monoclonal gammopathy, low C3, low C4, and/or cryoglobulins.
Predicting progression to pSS
Progress has also been made with respect to predicting progression to pSS among patients who present with some related symptoms but don’t meet Sjögren’s criteria, Dr. James noted.
A 2017 study by Caroline Shiboski et al. looked at 771 patients from the Sjögren’s International Collaborative Clinical Alliance (SICCA) registry who had previously had objective measures of salivary hypofunction, dry eyes, focal lymphocytic sialadenitis or anti-Ro/anti-La. When these patients were recalled 2-3 years after their baseline evaluation, 28 (9%) of 308 patients who did not meet pSS criteria at baseline had then progressed to pSS (Arthritis Care Res. 2017;70[2]:284-94).
Those with baseline hypergammaglobulinemia were four times more likely to progress, and those with baseline low complement levels were six times more likely to progress.
Many patients will present with symptoms, but won’t ever develop Sjögren’s, but the subset of patients with these baseline characteristics may be at greater risk, she said.
Autoantibodies and pathogenesis
Up to 90% of pSS patients will have one or more of anti-Ro, anti-La, or rheumatoid factor, and many will have a positive antinuclear antibody (ANA) level of at least 1:320, Dr. James said, adding that anti-Ro and anti-La are linked with earlier disease onset, increased disease severity, longer disease duration, and extraglandular involvement.
Ro52, a target of Sjögren’s autoantibodies, may also confer more severe disease, and autoantibodies to muscarinic acetylcholine receptors appear to contribute to pathogenesis in Sjögren’s patients “above and beyond what we see with lymphocytic infiltrates and other things that are happening in the salivary gland,” she said.
Other exciting progress with respect to disease pathogenesis includes an increased focus on genetics and genetic predisposition beyond human leukocyte antigen associations.
Mutations in genes that overlap with Sjögren’s and lupus or Sjögren’s and RA, such as IRF5, Blk, and STAT4 appear to contribute to Sjögren’s syndrome development.
“And then there’s also some new genetics looking at Sjögren’s-specific genes, and these may help us as we think about new targetable pathways in this disorder,” she said.
Genomics and gene-environment interactions, such as interactions with viral infections or “other things that lead to molecular mimicry that get the disease process started,” are also getting increased attention; gene-expression profiling has shown overlap between Sjögren’s and lupus (shared genetics, autoantibodies, and similarly strong interferon signatures, for example), which isn’t surprising.
“But we’re also seeing NF-kB [NF-kappa B] activation, antigen presentation, and migration pathways that are being found in Sjögren’s that aren’t necessarily the ones that we see in lupus,” she added.
Clinical practice guidelines
A number of practice guidelines addressing various symptoms and issues associated with pSS have been released in the last few years, including several from EULAR, the United States, Brazil, and the United Kingdom, are summarized and reviewed in a recent paper by Vasco Romão et al. (RMD Open. 2018;4:e000789. doi: 10.1136/rmdopen-2018-000789).
The British Society of Rheumatology guideline, which came out about a year ago, has particularly practical guidance on the management of dryness and systemic disease, she said (Rheumatology. 2017;56[10]:1643-7).
The increasing focus on pSS research has important implications both for trial design and patient care, especially in light of the new classification criteria, practice guidelines, and educational resources provided by organizations such as the Sjögren’s Syndrome Foundation (including videos, health care provider information, and downloadable brochures and resource sheets) and the European Research Network’s ReCONNET Disease Info Toolbox for Sjögren’s, Dr. James concluded.
Dr. James reported having no disclosures.
Recent findings, new classification criteria and treatment guidelines, and concerted efforts by various organizations to provide educational resources are among a number of factors improving the outlook for patients with primary Sjögren’s syndrome, according to Judith James, MD, PhD.
Additionally, the number of studies of primary Sjögren’s syndrome (pSS) is increasing, albeit slowly, and ongoing studies of biologics are showing promise, Dr. James said during a clinical update at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.
Classification criteria
The ACR in conjunction with the European League Against Rheumatism (EULAR) published new criteria for pSS classification in 2016 based on the available evidence and expert consensus. Inclusion criteria include daily, persistent, troublesome dry eyes for more than 3 months, recurrent sensation of sand or gravel in the eyes, use of tear substitutes more than three times each day, frequent drinking of liquids to aid in swallowing dry food, or at least one EULAR Sjögren’s syndrome disease activity index (ESSDAI) domain with a positive item. Exclusion criteria include prior head and neck radiation treatment, polymerase chain reaction–confirmed active hepatitis C infection, AIDS, sarcoidosis, amyloidosis, graft-versus-host disease, or IgG4-related disease, said Dr. James, professor and chair of the arthritis and clinical immunology research program at the University of Oklahoma, Oklahoma City (Arthritis Rheumatol. Jan 2017;69[1]:35-45).
- A score of 4 or higher in patients who meet the inclusion criteria and do not have any of the exclusion criteria leads to classification with pSS, based on the following findings:
- Labial salivary gland with focal lymphocytic sialadenitis and focus score of at least 1 foci/4 mm2 (weight/score = 3).
- Anti-SSA/Ro-positivity (weight/score = 3).
- Ocular Staining Score of at least 5, or van Bijsterveld score of at least 4, in at least one eye (weight/score = 1).
- Schirmer’s test of no more than 5 mm/5 min in at least one eye (weight/score = 1).
- Unstimulated whole saliva flow rate of no more than 0.1 mL/min (weight/score = 1).
Clinical pearls for detection and management
In Dr. James’ experience, the three symptoms (taken together) with the highest predictive value for diagnosing pSS are dry mouth, sore mouth/tongue, and dry eyes. About 25% of Sjögren’s patients may have no detectable salivary flow, she said.
Dry, cracked skin that can lead to secondary infections is another common issue affecting about 55% of patients.
“So we always have to talk to our Sjögren’s patients about skin,” she said. “We also have recurrent sinusitis, chronic cough, dyspepsia, constipation, and other symptoms.”
Concurrent autoimmune diseases are another concern in Sjögren’s patients, she said. One to particularly keep in mind, in addition to lupus and rheumatoid arthritis, is autoimmune thyroid disease.
Data suggest that up to 45% of Sjögren’s patients have thyroid dysfunction, and if you look at just those with autoimmune thyroiditis, their risk of Sjögren’s is increased 10-fold vs. those without autoimmune thyroiditis, she said.
Other conditions to keep in mind when it comes to diagnosing and managing patients, as has been shown in numerous studies over the years, include Raynaud’s phenomenon, which affects at least 13% of patients, and subclinical muscle inflammation, which affects more than 50% of patients, Dr. James said.
“Depression ... as well as anxiety, is quite common in Sjögren’s patients, and fatigue is profound,” she added, noting that fatigue is “the No. 1 issue” for many patients.
Another area of particular concern in Sjögren’s is the increased risk of lymphoma, she said.
Studies show varying rates of lymphoma in Sjögren’s, with one suggesting a 44-fold increased risk, but this is likely only among those at very high risk. Other studies suggest the increase is risk overall is in the range of 4- to 10-fold, she said.
Mortality in Sjögren’s patients
A 2015 study by Soledad Retamozo et al. showed that the presence of cryoglobulinemic vasculitis (CV) at diagnosis is associated with increased mortality risk.
Of 515 consecutive pSS patients with a mean follow-up of 110 months, 65 (12%) had cryoglobulins detected, and 21 of those (32%) fulfilled CV criteria. The patients with cryoglobulins had higher cumulative mean disease activity, 45 (9%) developed B-cell lymphoma, and 33 (6%) died (Arthritis Rheumatol. 2015;67[suppl 10]. Abstract 628).
Additionally, both CV-positive and CV-negative patients had higher risk of B-cell lymphoma, but the risk was greatest in the CV-positive group (hazard ratios, 7.47 and 2.56, respectively), and the CV-positive patients had a higher risk of death (HR, 11.68).
“This actually has changed practice in our Sjögren’s clinic because we didn’t used to do cryos on everybody unless they had leukocytoclastic vasculitis, because they also have a higher risk of death,” Dr. James said.
Systemic activity also predicts pSS mortality, according to findings published in 2016 by Pilar Brito-Zerón et al. Of 1,045 patients who were part of the Spanish Group of Autoimmune Disease-SS Study Group and who were followed for a mean of 117 months, mortality was 11%. Survival was 96% at 5 years, 90% at 10 years, 81% at 20 years, and 60% at 30 years (Ann Rheum Dis. 2016;75:348-55).
Baseline factors associated with increased mortality on multivariate analysis included male gender, cryoglobulins, and low complement levels; the strongest model for death included high activity in at least one ESSDAI domain, baseline ESSDAI of at least 14, more than one laboratory predictive marker such as lymphopenia, anti-La, monoclonal gammopathy, low C3, low C4, and/or cryoglobulins.
Predicting progression to pSS
Progress has also been made with respect to predicting progression to pSS among patients who present with some related symptoms but don’t meet Sjögren’s criteria, Dr. James noted.
A 2017 study by Caroline Shiboski et al. looked at 771 patients from the Sjögren’s International Collaborative Clinical Alliance (SICCA) registry who had previously had objective measures of salivary hypofunction, dry eyes, focal lymphocytic sialadenitis or anti-Ro/anti-La. When these patients were recalled 2-3 years after their baseline evaluation, 28 (9%) of 308 patients who did not meet pSS criteria at baseline had then progressed to pSS (Arthritis Care Res. 2017;70[2]:284-94).
Those with baseline hypergammaglobulinemia were four times more likely to progress, and those with baseline low complement levels were six times more likely to progress.
Many patients will present with symptoms, but won’t ever develop Sjögren’s, but the subset of patients with these baseline characteristics may be at greater risk, she said.
Autoantibodies and pathogenesis
Up to 90% of pSS patients will have one or more of anti-Ro, anti-La, or rheumatoid factor, and many will have a positive antinuclear antibody (ANA) level of at least 1:320, Dr. James said, adding that anti-Ro and anti-La are linked with earlier disease onset, increased disease severity, longer disease duration, and extraglandular involvement.
Ro52, a target of Sjögren’s autoantibodies, may also confer more severe disease, and autoantibodies to muscarinic acetylcholine receptors appear to contribute to pathogenesis in Sjögren’s patients “above and beyond what we see with lymphocytic infiltrates and other things that are happening in the salivary gland,” she said.
Other exciting progress with respect to disease pathogenesis includes an increased focus on genetics and genetic predisposition beyond human leukocyte antigen associations.
Mutations in genes that overlap with Sjögren’s and lupus or Sjögren’s and RA, such as IRF5, Blk, and STAT4 appear to contribute to Sjögren’s syndrome development.
“And then there’s also some new genetics looking at Sjögren’s-specific genes, and these may help us as we think about new targetable pathways in this disorder,” she said.
Genomics and gene-environment interactions, such as interactions with viral infections or “other things that lead to molecular mimicry that get the disease process started,” are also getting increased attention; gene-expression profiling has shown overlap between Sjögren’s and lupus (shared genetics, autoantibodies, and similarly strong interferon signatures, for example), which isn’t surprising.
“But we’re also seeing NF-kB [NF-kappa B] activation, antigen presentation, and migration pathways that are being found in Sjögren’s that aren’t necessarily the ones that we see in lupus,” she added.
Clinical practice guidelines
A number of practice guidelines addressing various symptoms and issues associated with pSS have been released in the last few years, including several from EULAR, the United States, Brazil, and the United Kingdom, are summarized and reviewed in a recent paper by Vasco Romão et al. (RMD Open. 2018;4:e000789. doi: 10.1136/rmdopen-2018-000789).
The British Society of Rheumatology guideline, which came out about a year ago, has particularly practical guidance on the management of dryness and systemic disease, she said (Rheumatology. 2017;56[10]:1643-7).
The increasing focus on pSS research has important implications both for trial design and patient care, especially in light of the new classification criteria, practice guidelines, and educational resources provided by organizations such as the Sjögren’s Syndrome Foundation (including videos, health care provider information, and downloadable brochures and resource sheets) and the European Research Network’s ReCONNET Disease Info Toolbox for Sjögren’s, Dr. James concluded.
Dr. James reported having no disclosures.
Recent findings, new classification criteria and treatment guidelines, and concerted efforts by various organizations to provide educational resources are among a number of factors improving the outlook for patients with primary Sjögren’s syndrome, according to Judith James, MD, PhD.
Additionally, the number of studies of primary Sjögren’s syndrome (pSS) is increasing, albeit slowly, and ongoing studies of biologics are showing promise, Dr. James said during a clinical update at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.
Classification criteria
The ACR in conjunction with the European League Against Rheumatism (EULAR) published new criteria for pSS classification in 2016 based on the available evidence and expert consensus. Inclusion criteria include daily, persistent, troublesome dry eyes for more than 3 months, recurrent sensation of sand or gravel in the eyes, use of tear substitutes more than three times each day, frequent drinking of liquids to aid in swallowing dry food, or at least one EULAR Sjögren’s syndrome disease activity index (ESSDAI) domain with a positive item. Exclusion criteria include prior head and neck radiation treatment, polymerase chain reaction–confirmed active hepatitis C infection, AIDS, sarcoidosis, amyloidosis, graft-versus-host disease, or IgG4-related disease, said Dr. James, professor and chair of the arthritis and clinical immunology research program at the University of Oklahoma, Oklahoma City (Arthritis Rheumatol. Jan 2017;69[1]:35-45).
- A score of 4 or higher in patients who meet the inclusion criteria and do not have any of the exclusion criteria leads to classification with pSS, based on the following findings:
- Labial salivary gland with focal lymphocytic sialadenitis and focus score of at least 1 foci/4 mm2 (weight/score = 3).
- Anti-SSA/Ro-positivity (weight/score = 3).
- Ocular Staining Score of at least 5, or van Bijsterveld score of at least 4, in at least one eye (weight/score = 1).
- Schirmer’s test of no more than 5 mm/5 min in at least one eye (weight/score = 1).
- Unstimulated whole saliva flow rate of no more than 0.1 mL/min (weight/score = 1).
Clinical pearls for detection and management
In Dr. James’ experience, the three symptoms (taken together) with the highest predictive value for diagnosing pSS are dry mouth, sore mouth/tongue, and dry eyes. About 25% of Sjögren’s patients may have no detectable salivary flow, she said.
Dry, cracked skin that can lead to secondary infections is another common issue affecting about 55% of patients.
“So we always have to talk to our Sjögren’s patients about skin,” she said. “We also have recurrent sinusitis, chronic cough, dyspepsia, constipation, and other symptoms.”
Concurrent autoimmune diseases are another concern in Sjögren’s patients, she said. One to particularly keep in mind, in addition to lupus and rheumatoid arthritis, is autoimmune thyroid disease.
Data suggest that up to 45% of Sjögren’s patients have thyroid dysfunction, and if you look at just those with autoimmune thyroiditis, their risk of Sjögren’s is increased 10-fold vs. those without autoimmune thyroiditis, she said.
Other conditions to keep in mind when it comes to diagnosing and managing patients, as has been shown in numerous studies over the years, include Raynaud’s phenomenon, which affects at least 13% of patients, and subclinical muscle inflammation, which affects more than 50% of patients, Dr. James said.
“Depression ... as well as anxiety, is quite common in Sjögren’s patients, and fatigue is profound,” she added, noting that fatigue is “the No. 1 issue” for many patients.
Another area of particular concern in Sjögren’s is the increased risk of lymphoma, she said.
Studies show varying rates of lymphoma in Sjögren’s, with one suggesting a 44-fold increased risk, but this is likely only among those at very high risk. Other studies suggest the increase is risk overall is in the range of 4- to 10-fold, she said.
Mortality in Sjögren’s patients
A 2015 study by Soledad Retamozo et al. showed that the presence of cryoglobulinemic vasculitis (CV) at diagnosis is associated with increased mortality risk.
Of 515 consecutive pSS patients with a mean follow-up of 110 months, 65 (12%) had cryoglobulins detected, and 21 of those (32%) fulfilled CV criteria. The patients with cryoglobulins had higher cumulative mean disease activity, 45 (9%) developed B-cell lymphoma, and 33 (6%) died (Arthritis Rheumatol. 2015;67[suppl 10]. Abstract 628).
Additionally, both CV-positive and CV-negative patients had higher risk of B-cell lymphoma, but the risk was greatest in the CV-positive group (hazard ratios, 7.47 and 2.56, respectively), and the CV-positive patients had a higher risk of death (HR, 11.68).
“This actually has changed practice in our Sjögren’s clinic because we didn’t used to do cryos on everybody unless they had leukocytoclastic vasculitis, because they also have a higher risk of death,” Dr. James said.
Systemic activity also predicts pSS mortality, according to findings published in 2016 by Pilar Brito-Zerón et al. Of 1,045 patients who were part of the Spanish Group of Autoimmune Disease-SS Study Group and who were followed for a mean of 117 months, mortality was 11%. Survival was 96% at 5 years, 90% at 10 years, 81% at 20 years, and 60% at 30 years (Ann Rheum Dis. 2016;75:348-55).
Baseline factors associated with increased mortality on multivariate analysis included male gender, cryoglobulins, and low complement levels; the strongest model for death included high activity in at least one ESSDAI domain, baseline ESSDAI of at least 14, more than one laboratory predictive marker such as lymphopenia, anti-La, monoclonal gammopathy, low C3, low C4, and/or cryoglobulins.
Predicting progression to pSS
Progress has also been made with respect to predicting progression to pSS among patients who present with some related symptoms but don’t meet Sjögren’s criteria, Dr. James noted.
A 2017 study by Caroline Shiboski et al. looked at 771 patients from the Sjögren’s International Collaborative Clinical Alliance (SICCA) registry who had previously had objective measures of salivary hypofunction, dry eyes, focal lymphocytic sialadenitis or anti-Ro/anti-La. When these patients were recalled 2-3 years after their baseline evaluation, 28 (9%) of 308 patients who did not meet pSS criteria at baseline had then progressed to pSS (Arthritis Care Res. 2017;70[2]:284-94).
Those with baseline hypergammaglobulinemia were four times more likely to progress, and those with baseline low complement levels were six times more likely to progress.
Many patients will present with symptoms, but won’t ever develop Sjögren’s, but the subset of patients with these baseline characteristics may be at greater risk, she said.
Autoantibodies and pathogenesis
Up to 90% of pSS patients will have one or more of anti-Ro, anti-La, or rheumatoid factor, and many will have a positive antinuclear antibody (ANA) level of at least 1:320, Dr. James said, adding that anti-Ro and anti-La are linked with earlier disease onset, increased disease severity, longer disease duration, and extraglandular involvement.
Ro52, a target of Sjögren’s autoantibodies, may also confer more severe disease, and autoantibodies to muscarinic acetylcholine receptors appear to contribute to pathogenesis in Sjögren’s patients “above and beyond what we see with lymphocytic infiltrates and other things that are happening in the salivary gland,” she said.
Other exciting progress with respect to disease pathogenesis includes an increased focus on genetics and genetic predisposition beyond human leukocyte antigen associations.
Mutations in genes that overlap with Sjögren’s and lupus or Sjögren’s and RA, such as IRF5, Blk, and STAT4 appear to contribute to Sjögren’s syndrome development.
“And then there’s also some new genetics looking at Sjögren’s-specific genes, and these may help us as we think about new targetable pathways in this disorder,” she said.
Genomics and gene-environment interactions, such as interactions with viral infections or “other things that lead to molecular mimicry that get the disease process started,” are also getting increased attention; gene-expression profiling has shown overlap between Sjögren’s and lupus (shared genetics, autoantibodies, and similarly strong interferon signatures, for example), which isn’t surprising.
“But we’re also seeing NF-kB [NF-kappa B] activation, antigen presentation, and migration pathways that are being found in Sjögren’s that aren’t necessarily the ones that we see in lupus,” she added.
Clinical practice guidelines
A number of practice guidelines addressing various symptoms and issues associated with pSS have been released in the last few years, including several from EULAR, the United States, Brazil, and the United Kingdom, are summarized and reviewed in a recent paper by Vasco Romão et al. (RMD Open. 2018;4:e000789. doi: 10.1136/rmdopen-2018-000789).
The British Society of Rheumatology guideline, which came out about a year ago, has particularly practical guidance on the management of dryness and systemic disease, she said (Rheumatology. 2017;56[10]:1643-7).
The increasing focus on pSS research has important implications both for trial design and patient care, especially in light of the new classification criteria, practice guidelines, and educational resources provided by organizations such as the Sjögren’s Syndrome Foundation (including videos, health care provider information, and downloadable brochures and resource sheets) and the European Research Network’s ReCONNET Disease Info Toolbox for Sjögren’s, Dr. James concluded.
Dr. James reported having no disclosures.
EXPERT ANALYSIS FROM THE WINTER RHEUMATOLOGY SYMPOSIUM
Precision medicine in rheumatology: Enormous opportunity exists
Advances in precision medicine present enormous opportunity for rheumatology, but optimizing its benefits requires more input from the specialty and a sharper focus on related training for rheumatologists, according to Judith A. James, MD, PhD.
Precision medicine is getting a great deal of attention and is an exciting area, but it is already widely used in the field; think treat-to-target in rheumatoid arthritis, autoantibody testing for patient stratification across various conditions, and individual monitoring and dose escalation to achieve optimal uric acid levels in gout patients, Dr. James, professor of medicine and associate vice provost of clinical and translational science at the University of Oklahoma, Oklahoma City, said at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.
“We have historically ... actually had the highest number of FDA approved biomarker tests in rheumatology compared to all other specialties until this last couple of years where we’re starting to see this explosion of genetic testing in oncology – and we’ve been doing genetic testing,” she said.
However, there is a great deal more work to be done.
“We still have a long way to go to go to get the right drug at the right dose at the right time in the right patient in order to optimize outcomes in all of these diseases that we are responsible for as rheumatologists,” she said.
The fields of oncology and hematology have been intensely focused on precision medicine – the development of unique therapies based on specific genetic abnormalities in an individual’s tumor – and this focus is apparent in practice patterns: A recent survey of 132 medical oncologists and hematologists/oncologists showed that nearly 90% had ordered DNA sequencing, about 65% do so monthly, and 25% do so weekly.
“Those numbers are just going to continue to climb, and I think will see this in other disciplines as well,” she said.
The possibilities for improved outcomes in rheumatologic conditions using tailored treatments based on individual characteristics are practically limitless, she said, noting the heterogeneity of many rheumatologic conditions.
This is particularly true for systemic lupus erythematosus (SLE) patients, she said.
Identifying patient subsets based on organ involvement, demographics, and biomarkers, for example, could lead to personalized treatments with different doses, routes of administration, and concurrent medications, she explained.
Genetics in SLE
Dr. James highlighted the role of genetics and the value of precision medicine in the SLE setting in a large transancestral association study published in 2017. The investigators analyzed Immunochip genotype data from 27,574 SLE cases and controls and identified 58 distinct non–human leukocyte antigen (HLA) regions in Americans with European ancestry, 9 in those with African ancestry, and 16 in those with Hispanic ancestry. The investigators found that these non-HLA regions included 24 novel to SLE, and in their analysis the researchers were able to refine association signals in previously established regions, extend associations to additional ancestries, and reveal a complex multigenic effect just outside of the HLA region (Nature Commun. 2017;8:16021).
The findings led to a “cumulative hit hypothesis” for autoimmune disease, and help to clarify genetic architecture and ethnic disparities in SLE, they concluded.
“So we now have over a hundred genetic regions that have been associated with lupus, compared to healthy controls,” Dr. James said.
A frustration with genetic data such as these, however, is the challenge of “getting it into the clinic,” she noted.
“I think that looking at individual [single nuclear polymorphisms] is probably not what we’re going to be doing, but we’re seeing a lot of interest in the idea of genetic load,” she said, explaining that it may soon be possible to use genetic load information to evaluate patient risk.
A recent study at her institution looked at lupus risk from another angle: She and her colleagues recontacted family members from Oklahoma Lupus Genetics studies to look more closely at which blood relatives of SLE patients transitioned to SLE, and what factors were associated with that transition when compared with relatives who remained unaffected (Arthritis Rheumatol. 2017;69[3]:630-42).
Among the findings was a higher risk of transitioning among family members with both a positive antinuclear antibody test and a baseline Connective Tissue Disease Screening Questionnaire score indicative of connective tissue disease.
“We also found, of course, biomarkers, or blood markers, that helped us identify the individuals who were at the highest risk of transitioning, so we think a blood test might really be helpful,” she said.
That study also suggested that there may be ways to intervene in SLE patients’ relatives at increased risk for also developing lupus. For example, those who transitioned had increased levels of soluble tumor necrosis factor receptors and the interferon-driven chemokine MCP-3; a prevention trial is now underway, she noted.
Beyond genetics
Genetics are just one piece of the precision medicine puzzle, and other areas of investigation that may help to divide patients into subgroups for more precise treatment include genomics, soluble mediators, and immunophenotyping, Dr. James said.
“It may be that we need different pieces of all of these things to help guide our treatment in lupus patients,” she said.
Longitudinal clinical and blood transcriptional profiling of patients in the Dallas Pediatric SLE cohort, for example, identified a molecular classification system for SLE patients. The analysis of 972 samples from 158 SLE patients and 48 healthy controls, which were collected for up to 4 years, showed that an interferon response signature was present in 784 of the samples.
The investigators found that a plasmablast signature, which is found more in African-American patients than in other populations, best correlates with disease activity and that a neutrophil-related signature is associated with progression to active lupus nephritis (Cell. 2016;165[3]:551-65).
“This is something that will potentially be helpful [in the clinic], and we need to test this in the adult population,” Dr. James said.
The investigators also were able to stratify patients, based on individual immunoprofiling, into seven major groups based on molecular correlates. They concluded that such stratification could help improve the outcomes of clinical trials in SLE.
In another study, researchers looked at longitudinal gene expression in SLE patients by stratifying each of two independent sets of patients (a pediatric cohort and an adult cohort) into three clinically differentiated disease clusters defined by mechanisms of disease progression (Arthritis Rheumatol. Dec 2018;70[12]:2025-35).
The clusters included one showing a correlation between the percentage of neutrophils and disease activity progression, one showing a correlation between the percentage of lymphocytes and disease activity progression, and a third for which the percentage of neutrophils correlated to a lesser degree with disease activity but was functionally more heterogeneous. Patients in the two neutrophil‐driven clusters had an increased risk of developing proliferative nephritis.
The results have implications for treatment, trial design, and understanding of disease etiology, the investigators concluded.
“This may help us in the future as we think about which medicine to start patients on, and which medicines to start patients on first,” Dr. James said.
It is clear that precision medicine will play an increasingly important role in rheumatology, Dr. James said, when considering the context of other findings in recent years, such as those from studies looking at soluble mediators of inflammation associated with disease flare, as well as those that involved extensive immunophenotyping and showed widely divergent transcriptional patterns based on ancestral backgrounds. Other research, such as the BOLD (Biomarkers of Lupus Disease) study, looked at various mechanisms of disease flare.
Numerous types of personalized therapies are being considered in rheumatology, ranging from expanded regulatory T cells to chimeric antigen receptor T cell therapy to risk profiling for disease prevention, just to name a few. Going forward it will be important to perform more systems biology analyses to assemble precision medicine–related data that can inform clinical diagnosis, prognosis, and therapy selection and optimization, she said.
The future of personalized therapies in rheumatology will require more input from rheumatologists on large-scale precision medicine projects such as the National Institutes of Health’s All of Us Research Project and the Million Veteran Program, as well as other similar programs of major health systems, she noted, adding that different types of training and interaction with molecular pathologists, genetic counselors, health coaches, and other key players also are needed.
Dr. James reported having no relevant disclosures.
Advances in precision medicine present enormous opportunity for rheumatology, but optimizing its benefits requires more input from the specialty and a sharper focus on related training for rheumatologists, according to Judith A. James, MD, PhD.
Precision medicine is getting a great deal of attention and is an exciting area, but it is already widely used in the field; think treat-to-target in rheumatoid arthritis, autoantibody testing for patient stratification across various conditions, and individual monitoring and dose escalation to achieve optimal uric acid levels in gout patients, Dr. James, professor of medicine and associate vice provost of clinical and translational science at the University of Oklahoma, Oklahoma City, said at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.
“We have historically ... actually had the highest number of FDA approved biomarker tests in rheumatology compared to all other specialties until this last couple of years where we’re starting to see this explosion of genetic testing in oncology – and we’ve been doing genetic testing,” she said.
However, there is a great deal more work to be done.
“We still have a long way to go to go to get the right drug at the right dose at the right time in the right patient in order to optimize outcomes in all of these diseases that we are responsible for as rheumatologists,” she said.
The fields of oncology and hematology have been intensely focused on precision medicine – the development of unique therapies based on specific genetic abnormalities in an individual’s tumor – and this focus is apparent in practice patterns: A recent survey of 132 medical oncologists and hematologists/oncologists showed that nearly 90% had ordered DNA sequencing, about 65% do so monthly, and 25% do so weekly.
“Those numbers are just going to continue to climb, and I think will see this in other disciplines as well,” she said.
The possibilities for improved outcomes in rheumatologic conditions using tailored treatments based on individual characteristics are practically limitless, she said, noting the heterogeneity of many rheumatologic conditions.
This is particularly true for systemic lupus erythematosus (SLE) patients, she said.
Identifying patient subsets based on organ involvement, demographics, and biomarkers, for example, could lead to personalized treatments with different doses, routes of administration, and concurrent medications, she explained.
Genetics in SLE
Dr. James highlighted the role of genetics and the value of precision medicine in the SLE setting in a large transancestral association study published in 2017. The investigators analyzed Immunochip genotype data from 27,574 SLE cases and controls and identified 58 distinct non–human leukocyte antigen (HLA) regions in Americans with European ancestry, 9 in those with African ancestry, and 16 in those with Hispanic ancestry. The investigators found that these non-HLA regions included 24 novel to SLE, and in their analysis the researchers were able to refine association signals in previously established regions, extend associations to additional ancestries, and reveal a complex multigenic effect just outside of the HLA region (Nature Commun. 2017;8:16021).
The findings led to a “cumulative hit hypothesis” for autoimmune disease, and help to clarify genetic architecture and ethnic disparities in SLE, they concluded.
“So we now have over a hundred genetic regions that have been associated with lupus, compared to healthy controls,” Dr. James said.
A frustration with genetic data such as these, however, is the challenge of “getting it into the clinic,” she noted.
“I think that looking at individual [single nuclear polymorphisms] is probably not what we’re going to be doing, but we’re seeing a lot of interest in the idea of genetic load,” she said, explaining that it may soon be possible to use genetic load information to evaluate patient risk.
A recent study at her institution looked at lupus risk from another angle: She and her colleagues recontacted family members from Oklahoma Lupus Genetics studies to look more closely at which blood relatives of SLE patients transitioned to SLE, and what factors were associated with that transition when compared with relatives who remained unaffected (Arthritis Rheumatol. 2017;69[3]:630-42).
Among the findings was a higher risk of transitioning among family members with both a positive antinuclear antibody test and a baseline Connective Tissue Disease Screening Questionnaire score indicative of connective tissue disease.
“We also found, of course, biomarkers, or blood markers, that helped us identify the individuals who were at the highest risk of transitioning, so we think a blood test might really be helpful,” she said.
That study also suggested that there may be ways to intervene in SLE patients’ relatives at increased risk for also developing lupus. For example, those who transitioned had increased levels of soluble tumor necrosis factor receptors and the interferon-driven chemokine MCP-3; a prevention trial is now underway, she noted.
Beyond genetics
Genetics are just one piece of the precision medicine puzzle, and other areas of investigation that may help to divide patients into subgroups for more precise treatment include genomics, soluble mediators, and immunophenotyping, Dr. James said.
“It may be that we need different pieces of all of these things to help guide our treatment in lupus patients,” she said.
Longitudinal clinical and blood transcriptional profiling of patients in the Dallas Pediatric SLE cohort, for example, identified a molecular classification system for SLE patients. The analysis of 972 samples from 158 SLE patients and 48 healthy controls, which were collected for up to 4 years, showed that an interferon response signature was present in 784 of the samples.
The investigators found that a plasmablast signature, which is found more in African-American patients than in other populations, best correlates with disease activity and that a neutrophil-related signature is associated with progression to active lupus nephritis (Cell. 2016;165[3]:551-65).
“This is something that will potentially be helpful [in the clinic], and we need to test this in the adult population,” Dr. James said.
The investigators also were able to stratify patients, based on individual immunoprofiling, into seven major groups based on molecular correlates. They concluded that such stratification could help improve the outcomes of clinical trials in SLE.
In another study, researchers looked at longitudinal gene expression in SLE patients by stratifying each of two independent sets of patients (a pediatric cohort and an adult cohort) into three clinically differentiated disease clusters defined by mechanisms of disease progression (Arthritis Rheumatol. Dec 2018;70[12]:2025-35).
The clusters included one showing a correlation between the percentage of neutrophils and disease activity progression, one showing a correlation between the percentage of lymphocytes and disease activity progression, and a third for which the percentage of neutrophils correlated to a lesser degree with disease activity but was functionally more heterogeneous. Patients in the two neutrophil‐driven clusters had an increased risk of developing proliferative nephritis.
The results have implications for treatment, trial design, and understanding of disease etiology, the investigators concluded.
“This may help us in the future as we think about which medicine to start patients on, and which medicines to start patients on first,” Dr. James said.
It is clear that precision medicine will play an increasingly important role in rheumatology, Dr. James said, when considering the context of other findings in recent years, such as those from studies looking at soluble mediators of inflammation associated with disease flare, as well as those that involved extensive immunophenotyping and showed widely divergent transcriptional patterns based on ancestral backgrounds. Other research, such as the BOLD (Biomarkers of Lupus Disease) study, looked at various mechanisms of disease flare.
Numerous types of personalized therapies are being considered in rheumatology, ranging from expanded regulatory T cells to chimeric antigen receptor T cell therapy to risk profiling for disease prevention, just to name a few. Going forward it will be important to perform more systems biology analyses to assemble precision medicine–related data that can inform clinical diagnosis, prognosis, and therapy selection and optimization, she said.
The future of personalized therapies in rheumatology will require more input from rheumatologists on large-scale precision medicine projects such as the National Institutes of Health’s All of Us Research Project and the Million Veteran Program, as well as other similar programs of major health systems, she noted, adding that different types of training and interaction with molecular pathologists, genetic counselors, health coaches, and other key players also are needed.
Dr. James reported having no relevant disclosures.
Advances in precision medicine present enormous opportunity for rheumatology, but optimizing its benefits requires more input from the specialty and a sharper focus on related training for rheumatologists, according to Judith A. James, MD, PhD.
Precision medicine is getting a great deal of attention and is an exciting area, but it is already widely used in the field; think treat-to-target in rheumatoid arthritis, autoantibody testing for patient stratification across various conditions, and individual monitoring and dose escalation to achieve optimal uric acid levels in gout patients, Dr. James, professor of medicine and associate vice provost of clinical and translational science at the University of Oklahoma, Oklahoma City, said at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.
“We have historically ... actually had the highest number of FDA approved biomarker tests in rheumatology compared to all other specialties until this last couple of years where we’re starting to see this explosion of genetic testing in oncology – and we’ve been doing genetic testing,” she said.
However, there is a great deal more work to be done.
“We still have a long way to go to go to get the right drug at the right dose at the right time in the right patient in order to optimize outcomes in all of these diseases that we are responsible for as rheumatologists,” she said.
The fields of oncology and hematology have been intensely focused on precision medicine – the development of unique therapies based on specific genetic abnormalities in an individual’s tumor – and this focus is apparent in practice patterns: A recent survey of 132 medical oncologists and hematologists/oncologists showed that nearly 90% had ordered DNA sequencing, about 65% do so monthly, and 25% do so weekly.
“Those numbers are just going to continue to climb, and I think will see this in other disciplines as well,” she said.
The possibilities for improved outcomes in rheumatologic conditions using tailored treatments based on individual characteristics are practically limitless, she said, noting the heterogeneity of many rheumatologic conditions.
This is particularly true for systemic lupus erythematosus (SLE) patients, she said.
Identifying patient subsets based on organ involvement, demographics, and biomarkers, for example, could lead to personalized treatments with different doses, routes of administration, and concurrent medications, she explained.
Genetics in SLE
Dr. James highlighted the role of genetics and the value of precision medicine in the SLE setting in a large transancestral association study published in 2017. The investigators analyzed Immunochip genotype data from 27,574 SLE cases and controls and identified 58 distinct non–human leukocyte antigen (HLA) regions in Americans with European ancestry, 9 in those with African ancestry, and 16 in those with Hispanic ancestry. The investigators found that these non-HLA regions included 24 novel to SLE, and in their analysis the researchers were able to refine association signals in previously established regions, extend associations to additional ancestries, and reveal a complex multigenic effect just outside of the HLA region (Nature Commun. 2017;8:16021).
The findings led to a “cumulative hit hypothesis” for autoimmune disease, and help to clarify genetic architecture and ethnic disparities in SLE, they concluded.
“So we now have over a hundred genetic regions that have been associated with lupus, compared to healthy controls,” Dr. James said.
A frustration with genetic data such as these, however, is the challenge of “getting it into the clinic,” she noted.
“I think that looking at individual [single nuclear polymorphisms] is probably not what we’re going to be doing, but we’re seeing a lot of interest in the idea of genetic load,” she said, explaining that it may soon be possible to use genetic load information to evaluate patient risk.
A recent study at her institution looked at lupus risk from another angle: She and her colleagues recontacted family members from Oklahoma Lupus Genetics studies to look more closely at which blood relatives of SLE patients transitioned to SLE, and what factors were associated with that transition when compared with relatives who remained unaffected (Arthritis Rheumatol. 2017;69[3]:630-42).
Among the findings was a higher risk of transitioning among family members with both a positive antinuclear antibody test and a baseline Connective Tissue Disease Screening Questionnaire score indicative of connective tissue disease.
“We also found, of course, biomarkers, or blood markers, that helped us identify the individuals who were at the highest risk of transitioning, so we think a blood test might really be helpful,” she said.
That study also suggested that there may be ways to intervene in SLE patients’ relatives at increased risk for also developing lupus. For example, those who transitioned had increased levels of soluble tumor necrosis factor receptors and the interferon-driven chemokine MCP-3; a prevention trial is now underway, she noted.
Beyond genetics
Genetics are just one piece of the precision medicine puzzle, and other areas of investigation that may help to divide patients into subgroups for more precise treatment include genomics, soluble mediators, and immunophenotyping, Dr. James said.
“It may be that we need different pieces of all of these things to help guide our treatment in lupus patients,” she said.
Longitudinal clinical and blood transcriptional profiling of patients in the Dallas Pediatric SLE cohort, for example, identified a molecular classification system for SLE patients. The analysis of 972 samples from 158 SLE patients and 48 healthy controls, which were collected for up to 4 years, showed that an interferon response signature was present in 784 of the samples.
The investigators found that a plasmablast signature, which is found more in African-American patients than in other populations, best correlates with disease activity and that a neutrophil-related signature is associated with progression to active lupus nephritis (Cell. 2016;165[3]:551-65).
“This is something that will potentially be helpful [in the clinic], and we need to test this in the adult population,” Dr. James said.
The investigators also were able to stratify patients, based on individual immunoprofiling, into seven major groups based on molecular correlates. They concluded that such stratification could help improve the outcomes of clinical trials in SLE.
In another study, researchers looked at longitudinal gene expression in SLE patients by stratifying each of two independent sets of patients (a pediatric cohort and an adult cohort) into three clinically differentiated disease clusters defined by mechanisms of disease progression (Arthritis Rheumatol. Dec 2018;70[12]:2025-35).
The clusters included one showing a correlation between the percentage of neutrophils and disease activity progression, one showing a correlation between the percentage of lymphocytes and disease activity progression, and a third for which the percentage of neutrophils correlated to a lesser degree with disease activity but was functionally more heterogeneous. Patients in the two neutrophil‐driven clusters had an increased risk of developing proliferative nephritis.
The results have implications for treatment, trial design, and understanding of disease etiology, the investigators concluded.
“This may help us in the future as we think about which medicine to start patients on, and which medicines to start patients on first,” Dr. James said.
It is clear that precision medicine will play an increasingly important role in rheumatology, Dr. James said, when considering the context of other findings in recent years, such as those from studies looking at soluble mediators of inflammation associated with disease flare, as well as those that involved extensive immunophenotyping and showed widely divergent transcriptional patterns based on ancestral backgrounds. Other research, such as the BOLD (Biomarkers of Lupus Disease) study, looked at various mechanisms of disease flare.
Numerous types of personalized therapies are being considered in rheumatology, ranging from expanded regulatory T cells to chimeric antigen receptor T cell therapy to risk profiling for disease prevention, just to name a few. Going forward it will be important to perform more systems biology analyses to assemble precision medicine–related data that can inform clinical diagnosis, prognosis, and therapy selection and optimization, she said.
The future of personalized therapies in rheumatology will require more input from rheumatologists on large-scale precision medicine projects such as the National Institutes of Health’s All of Us Research Project and the Million Veteran Program, as well as other similar programs of major health systems, she noted, adding that different types of training and interaction with molecular pathologists, genetic counselors, health coaches, and other key players also are needed.
Dr. James reported having no relevant disclosures.
EXPERT ANALYSIS FROM THE WINTER RHEUMATOLOGY SYMPOSIUM
Four distinct IgG4-related disease groups described in study
IgG4-related disease can be grouped into four distinct clusters based on the distribution of organs involved, according to researchers who analyzed a large, multicenter cohort of patients with this heterogeneous, autoimmune-mediated condition.
The four groups also varied by age, race, sex, time to diagnosis, and concentration of serum IgG4, according to the investigators, led by Zachary S. Wallace, MD, of the division of rheumatology, allergy, and immunology at Massachusetts General Hospital and Harvard Medical School, both in Boston.
“These phenotypes may be used by clinicians to improve recognition of IgG4-related disease,” Dr. Wallace and his coauthors wrote in a report on the study that appears in the Annals of the Rheumatic Diseases.
First described in a Japanese population, IgG4-related disease has been subsequently seen in all racial and ethnic groups, according to the researchers. It is associated with organ failure and can affect nearly any organ or anatomic site, most notably the lungs, kidneys, lymph nodes, salivary glands, pancreatobiliary structures, and retroperitoneum.
In the present study, Dr. Wallace and his coinvestigators used a novel cluster analysis method, called latent class analysis, to categorize 765 cases of IgG4-related disease submitted by 52 investigators from 17 countries. The investigators included 493 of those cases in a primary study population, and the remaining 272 in a smaller cohort used to replicate the results.
In the larger, primary study cohort, about 65% of cases were male, 58% were non-Asian and 40% were white, and the mean age at diagnosis was 59.5 years. The replication cohort had similar characteristics, according to the investigators.
The clustering analysis revealed four distinct subgroups, characterized by pancreato-hepatobiliary, accounting for 31% of cases; retroperitoneal fibrosis and/or aortitis in 24%; disease generally limited to head and neck structures in 24%, and head and neck disease consistent with Mikulicz syndrome plus systemic involvement in 22%.
The highest IgG4 concentrations were seen in the group of patients with Mikulicz syndrome and systemic involvement, according to Dr. Wallace and his coauthors. The serum concentration was 1,170 mg/dL in that group, compared with 445 mg/dL in the group of patients with head and neck-limited disease, 316 mg/dL in the pancreato-hepatobiliary group, and just 178 mg/dL in the retroperitoneal fibrosis/aorta group.
Female and Asian patients were overrepresented in the group characterized by head and neck involvement, investigators also found. Moreover, that group had a significantly lower mean age at diagnosis than did the other groups.
Those variations suggested differences in genetic or environmental risk factors between clusters, according to the investigators.
“Given the similar distribution of subspecialists among investigators in this study practicing in Asian and non-Asian countries, the observed differences are unlikely to be the result of detection or selection biases,” they said in their report.
The findings of this study help to inform subsequent investigations intended to evaluate those factors in more detail, they said.
Dr. Wallace and his coauthors reported no conflicts of interest related to their work, which was previously presented at the American College of Rheumatology annual meeting.
SOURCE: Wallace ZS et al. Ann Rheum Dis. 2019 Jan 5. doi: 10.1136/annrheumdis-2018-214603
IgG4-related disease can be grouped into four distinct clusters based on the distribution of organs involved, according to researchers who analyzed a large, multicenter cohort of patients with this heterogeneous, autoimmune-mediated condition.
The four groups also varied by age, race, sex, time to diagnosis, and concentration of serum IgG4, according to the investigators, led by Zachary S. Wallace, MD, of the division of rheumatology, allergy, and immunology at Massachusetts General Hospital and Harvard Medical School, both in Boston.
“These phenotypes may be used by clinicians to improve recognition of IgG4-related disease,” Dr. Wallace and his coauthors wrote in a report on the study that appears in the Annals of the Rheumatic Diseases.
First described in a Japanese population, IgG4-related disease has been subsequently seen in all racial and ethnic groups, according to the researchers. It is associated with organ failure and can affect nearly any organ or anatomic site, most notably the lungs, kidneys, lymph nodes, salivary glands, pancreatobiliary structures, and retroperitoneum.
In the present study, Dr. Wallace and his coinvestigators used a novel cluster analysis method, called latent class analysis, to categorize 765 cases of IgG4-related disease submitted by 52 investigators from 17 countries. The investigators included 493 of those cases in a primary study population, and the remaining 272 in a smaller cohort used to replicate the results.
In the larger, primary study cohort, about 65% of cases were male, 58% were non-Asian and 40% were white, and the mean age at diagnosis was 59.5 years. The replication cohort had similar characteristics, according to the investigators.
The clustering analysis revealed four distinct subgroups, characterized by pancreato-hepatobiliary, accounting for 31% of cases; retroperitoneal fibrosis and/or aortitis in 24%; disease generally limited to head and neck structures in 24%, and head and neck disease consistent with Mikulicz syndrome plus systemic involvement in 22%.
The highest IgG4 concentrations were seen in the group of patients with Mikulicz syndrome and systemic involvement, according to Dr. Wallace and his coauthors. The serum concentration was 1,170 mg/dL in that group, compared with 445 mg/dL in the group of patients with head and neck-limited disease, 316 mg/dL in the pancreato-hepatobiliary group, and just 178 mg/dL in the retroperitoneal fibrosis/aorta group.
Female and Asian patients were overrepresented in the group characterized by head and neck involvement, investigators also found. Moreover, that group had a significantly lower mean age at diagnosis than did the other groups.
Those variations suggested differences in genetic or environmental risk factors between clusters, according to the investigators.
“Given the similar distribution of subspecialists among investigators in this study practicing in Asian and non-Asian countries, the observed differences are unlikely to be the result of detection or selection biases,” they said in their report.
The findings of this study help to inform subsequent investigations intended to evaluate those factors in more detail, they said.
Dr. Wallace and his coauthors reported no conflicts of interest related to their work, which was previously presented at the American College of Rheumatology annual meeting.
SOURCE: Wallace ZS et al. Ann Rheum Dis. 2019 Jan 5. doi: 10.1136/annrheumdis-2018-214603
IgG4-related disease can be grouped into four distinct clusters based on the distribution of organs involved, according to researchers who analyzed a large, multicenter cohort of patients with this heterogeneous, autoimmune-mediated condition.
The four groups also varied by age, race, sex, time to diagnosis, and concentration of serum IgG4, according to the investigators, led by Zachary S. Wallace, MD, of the division of rheumatology, allergy, and immunology at Massachusetts General Hospital and Harvard Medical School, both in Boston.
“These phenotypes may be used by clinicians to improve recognition of IgG4-related disease,” Dr. Wallace and his coauthors wrote in a report on the study that appears in the Annals of the Rheumatic Diseases.
First described in a Japanese population, IgG4-related disease has been subsequently seen in all racial and ethnic groups, according to the researchers. It is associated with organ failure and can affect nearly any organ or anatomic site, most notably the lungs, kidneys, lymph nodes, salivary glands, pancreatobiliary structures, and retroperitoneum.
In the present study, Dr. Wallace and his coinvestigators used a novel cluster analysis method, called latent class analysis, to categorize 765 cases of IgG4-related disease submitted by 52 investigators from 17 countries. The investigators included 493 of those cases in a primary study population, and the remaining 272 in a smaller cohort used to replicate the results.
In the larger, primary study cohort, about 65% of cases were male, 58% were non-Asian and 40% were white, and the mean age at diagnosis was 59.5 years. The replication cohort had similar characteristics, according to the investigators.
The clustering analysis revealed four distinct subgroups, characterized by pancreato-hepatobiliary, accounting for 31% of cases; retroperitoneal fibrosis and/or aortitis in 24%; disease generally limited to head and neck structures in 24%, and head and neck disease consistent with Mikulicz syndrome plus systemic involvement in 22%.
The highest IgG4 concentrations were seen in the group of patients with Mikulicz syndrome and systemic involvement, according to Dr. Wallace and his coauthors. The serum concentration was 1,170 mg/dL in that group, compared with 445 mg/dL in the group of patients with head and neck-limited disease, 316 mg/dL in the pancreato-hepatobiliary group, and just 178 mg/dL in the retroperitoneal fibrosis/aorta group.
Female and Asian patients were overrepresented in the group characterized by head and neck involvement, investigators also found. Moreover, that group had a significantly lower mean age at diagnosis than did the other groups.
Those variations suggested differences in genetic or environmental risk factors between clusters, according to the investigators.
“Given the similar distribution of subspecialists among investigators in this study practicing in Asian and non-Asian countries, the observed differences are unlikely to be the result of detection or selection biases,” they said in their report.
The findings of this study help to inform subsequent investigations intended to evaluate those factors in more detail, they said.
Dr. Wallace and his coauthors reported no conflicts of interest related to their work, which was previously presented at the American College of Rheumatology annual meeting.
SOURCE: Wallace ZS et al. Ann Rheum Dis. 2019 Jan 5. doi: 10.1136/annrheumdis-2018-214603
FROM ANNALS OF THE RHEUMATIC DISEASES
Key clinical point:
Major finding: The highest IgG4 concentrations (1,170 mg/dL) were seen in a group of patients with Mikulicz syndrome and systemic involvement. Females and Asian patients were overrepresented in a group characterized by head and neck involvement.
Study details: Two cross-sectional studies including a total of 765 cases of IgG4-related disease submitted by 52 investigators in 17 countries.
Disclosures: Authors reported no conflicts of interest.
Source: Wallace ZS et al. Ann Rheum Dis. 2019 Jan 5. doi: 10.1136/annrheumdis-2018-214603.