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Diagnosing patients with sarcoidosis
A 40-year-old women is evaluated for liver abnormalities. She had elevated transaminases and alkaline phosphatase. A liver ultrasound showed multiple lesions. She underwent liver biopsy, which showed granulomas. What test results, if abnormal, would be most suggestive of sarcoidosis?
A. Erythrocyte sedimentation rate
B. C-reactive protein
C. Lymphocyte count
D. Antinuclear antibodies
The correct answer here is lymphocyte count. Sarcoidosis is in just about every differential diagnosis, as it can involve every organ system. I will share with you a few pearls I have learned over 30 years of taking care of patients with sarcoidosis. Lymphocyte counts drop with active sarcoidosis. Sarcoidosis should always be part of the differential when you see lymphopenia. El Jammal et al. studied 90 patients referred for possible granulomatous hepatitis.1 Seventy-three patients had a final diagnosis of granulomatous hepatitis, and 38 of those patients had sarcoidosis. Lymphopenia had a high specificity (85.7%) for the diagnosis of sarcoidosis, with a specificity of 100% in the patients under 50 years old.
Morell and colleagues looked at whether low lymphocyte counts and low lymphocyte percentage were markers of active sarcoidosis.2 Forty patients with biopsy-proven sarcoidosis were prospectively evaluated every 6 months. A low lymphocyte count and a low lymphocyte percentage (< 20%) were detected more frequently in patients with active sarcoidosis than in the patients with asymptomatic sarcoidosis (P < .02 and P < .0001).
Jones et al. looked at lymphopenia as a marker of sarcoidosis in patients presenting with uveitis.3 The study was a retrospective case-control study (112 patients with sarcoidosis-associated uveitis and 398 controls with other forms of uveitis). The mean lymphocyte count for patients with sarcoidosis was 1.43 vs. 2.04 for other causes of uveitis (P ≤ .0001).
Patients with sarcoidosis are at risk of hypercalciuria, hypercalcemia, and kidney stones. These are common in patients with sarcoidosis, with up to 50% of such patients having hypercalciuria. This is because in sarcoidosis patients 25(OH) vitamin D is converted in granulomas by activated macrophages to 1,25(OH)2 vitamin D, which is the active form of vitamin D.
Several studies have looked at the diagnostic utility of 1,25(OH)2 vitamin D levels in patients with suspected sarcoidosis. Rohmer and colleagues looked at whether 1,25(OH)2 vitamin D levels could help with the diagnosis of sarcoidosis as the cause of uveitis.4 They found that the level of 25(OH) vitamin D in sarcoidosis patients with uveitis was lower than in patients with uveitis without sarcoidosis, 34 vs. 43 nmol/mL (P < .02), whereas the 1,25(OH)2 vitamin D level was higher in patients with sarcoidosis than in those with uveitis without sarcoidosis, 132 vs. 108 pmol/L (P = .02). They looked at the 1,25(OH)2D/25(OH)D ratio; a ratio > 3.5 was strongly associated with an abnormal chest CT-scan (OR = 5.7, P = .003) and granulomas on bronchial biopsy (OR = 14.7, P = .007).
Kavathia et al. looked at whether elevated 1,25(OH)2 vitamin D levels predicted chronicity of sarcoidosis.5 A total of 59 sarcoidosis patients were recruited for the study. Higher serum 1,25(OH)2 vitamin D levels were associated with patients requiring repeated systemic immunosuppressive therapy or > 1 year of therapy. Increasing quartiles of serum 1,25(OH)2 vitamin D level were associated with increased odds of patients having chronic sarcoidosis (OR = 1.82; 95% CI, 1.11-2.99, P = .019).
Because of the higher activated vitamin D levels in sarcoidosis patients, they are at risk for problems with vitamin D supplementation. I have seen two patients develop large numbers of kidney stones after receiving high-dose vitamin D. Sodhi and Aldrich reported on a cohort of 196 sarcoidosis patients who had received vitamin D and compared them with 196 control patients with sarcoidosis who were not receiving vitamin D.6 Hypercalcemia was more frequent in the group that received vitamin D (42.3%) than in the group that did not (18.3%, P < .0001). In this study, only a minority (23%) of patients receiving vitamin D had their 1,25(OH)2 vitamin D level checked.
Pearl: Lymphocyte count and 1,25(OH)2 vitamin D levels can be helpful tests in assessing sarcoidosis activity. Patients with sarcoidosis who receive vitamin D should have their 1.25(OH)2 vitamin D levels monitored.
Dr. Paauw is professor of medicine in the division of general internal medicine at the University of Washington, Seattle, and he serves as third-year medical student clerkship director at the University of Washington. Contact Dr. Paauw at [email protected].
References
1. El Jammal et al. Sarcoidosis Vasc Diffuse Lung Dis. 2023 Sep 13;40(3):e2023031.
2. Morell F et al. Chest. 2002 Apr;121(4):1239-44.
3. Jones NP et al. Br J Ophthalmol. 2016 Oct;100(10):1393-6.
4. Rohmer J et al. Ocul Immunol Inflamm. 2020 Apr 2;28(3):341-7.
5. Kavathia D et al. Respir Med. 2010 Apr;104(4):564–70.
6. Sodhi A and Aldrich T. Am J Med Sci. 2016 Sep;352(3):252-7.
A 40-year-old women is evaluated for liver abnormalities. She had elevated transaminases and alkaline phosphatase. A liver ultrasound showed multiple lesions. She underwent liver biopsy, which showed granulomas. What test results, if abnormal, would be most suggestive of sarcoidosis?
A. Erythrocyte sedimentation rate
B. C-reactive protein
C. Lymphocyte count
D. Antinuclear antibodies
The correct answer here is lymphocyte count. Sarcoidosis is in just about every differential diagnosis, as it can involve every organ system. I will share with you a few pearls I have learned over 30 years of taking care of patients with sarcoidosis. Lymphocyte counts drop with active sarcoidosis. Sarcoidosis should always be part of the differential when you see lymphopenia. El Jammal et al. studied 90 patients referred for possible granulomatous hepatitis.1 Seventy-three patients had a final diagnosis of granulomatous hepatitis, and 38 of those patients had sarcoidosis. Lymphopenia had a high specificity (85.7%) for the diagnosis of sarcoidosis, with a specificity of 100% in the patients under 50 years old.
Morell and colleagues looked at whether low lymphocyte counts and low lymphocyte percentage were markers of active sarcoidosis.2 Forty patients with biopsy-proven sarcoidosis were prospectively evaluated every 6 months. A low lymphocyte count and a low lymphocyte percentage (< 20%) were detected more frequently in patients with active sarcoidosis than in the patients with asymptomatic sarcoidosis (P < .02 and P < .0001).
Jones et al. looked at lymphopenia as a marker of sarcoidosis in patients presenting with uveitis.3 The study was a retrospective case-control study (112 patients with sarcoidosis-associated uveitis and 398 controls with other forms of uveitis). The mean lymphocyte count for patients with sarcoidosis was 1.43 vs. 2.04 for other causes of uveitis (P ≤ .0001).
Patients with sarcoidosis are at risk of hypercalciuria, hypercalcemia, and kidney stones. These are common in patients with sarcoidosis, with up to 50% of such patients having hypercalciuria. This is because in sarcoidosis patients 25(OH) vitamin D is converted in granulomas by activated macrophages to 1,25(OH)2 vitamin D, which is the active form of vitamin D.
Several studies have looked at the diagnostic utility of 1,25(OH)2 vitamin D levels in patients with suspected sarcoidosis. Rohmer and colleagues looked at whether 1,25(OH)2 vitamin D levels could help with the diagnosis of sarcoidosis as the cause of uveitis.4 They found that the level of 25(OH) vitamin D in sarcoidosis patients with uveitis was lower than in patients with uveitis without sarcoidosis, 34 vs. 43 nmol/mL (P < .02), whereas the 1,25(OH)2 vitamin D level was higher in patients with sarcoidosis than in those with uveitis without sarcoidosis, 132 vs. 108 pmol/L (P = .02). They looked at the 1,25(OH)2D/25(OH)D ratio; a ratio > 3.5 was strongly associated with an abnormal chest CT-scan (OR = 5.7, P = .003) and granulomas on bronchial biopsy (OR = 14.7, P = .007).
Kavathia et al. looked at whether elevated 1,25(OH)2 vitamin D levels predicted chronicity of sarcoidosis.5 A total of 59 sarcoidosis patients were recruited for the study. Higher serum 1,25(OH)2 vitamin D levels were associated with patients requiring repeated systemic immunosuppressive therapy or > 1 year of therapy. Increasing quartiles of serum 1,25(OH)2 vitamin D level were associated with increased odds of patients having chronic sarcoidosis (OR = 1.82; 95% CI, 1.11-2.99, P = .019).
Because of the higher activated vitamin D levels in sarcoidosis patients, they are at risk for problems with vitamin D supplementation. I have seen two patients develop large numbers of kidney stones after receiving high-dose vitamin D. Sodhi and Aldrich reported on a cohort of 196 sarcoidosis patients who had received vitamin D and compared them with 196 control patients with sarcoidosis who were not receiving vitamin D.6 Hypercalcemia was more frequent in the group that received vitamin D (42.3%) than in the group that did not (18.3%, P < .0001). In this study, only a minority (23%) of patients receiving vitamin D had their 1,25(OH)2 vitamin D level checked.
Pearl: Lymphocyte count and 1,25(OH)2 vitamin D levels can be helpful tests in assessing sarcoidosis activity. Patients with sarcoidosis who receive vitamin D should have their 1.25(OH)2 vitamin D levels monitored.
Dr. Paauw is professor of medicine in the division of general internal medicine at the University of Washington, Seattle, and he serves as third-year medical student clerkship director at the University of Washington. Contact Dr. Paauw at [email protected].
References
1. El Jammal et al. Sarcoidosis Vasc Diffuse Lung Dis. 2023 Sep 13;40(3):e2023031.
2. Morell F et al. Chest. 2002 Apr;121(4):1239-44.
3. Jones NP et al. Br J Ophthalmol. 2016 Oct;100(10):1393-6.
4. Rohmer J et al. Ocul Immunol Inflamm. 2020 Apr 2;28(3):341-7.
5. Kavathia D et al. Respir Med. 2010 Apr;104(4):564–70.
6. Sodhi A and Aldrich T. Am J Med Sci. 2016 Sep;352(3):252-7.
A 40-year-old women is evaluated for liver abnormalities. She had elevated transaminases and alkaline phosphatase. A liver ultrasound showed multiple lesions. She underwent liver biopsy, which showed granulomas. What test results, if abnormal, would be most suggestive of sarcoidosis?
A. Erythrocyte sedimentation rate
B. C-reactive protein
C. Lymphocyte count
D. Antinuclear antibodies
The correct answer here is lymphocyte count. Sarcoidosis is in just about every differential diagnosis, as it can involve every organ system. I will share with you a few pearls I have learned over 30 years of taking care of patients with sarcoidosis. Lymphocyte counts drop with active sarcoidosis. Sarcoidosis should always be part of the differential when you see lymphopenia. El Jammal et al. studied 90 patients referred for possible granulomatous hepatitis.1 Seventy-three patients had a final diagnosis of granulomatous hepatitis, and 38 of those patients had sarcoidosis. Lymphopenia had a high specificity (85.7%) for the diagnosis of sarcoidosis, with a specificity of 100% in the patients under 50 years old.
Morell and colleagues looked at whether low lymphocyte counts and low lymphocyte percentage were markers of active sarcoidosis.2 Forty patients with biopsy-proven sarcoidosis were prospectively evaluated every 6 months. A low lymphocyte count and a low lymphocyte percentage (< 20%) were detected more frequently in patients with active sarcoidosis than in the patients with asymptomatic sarcoidosis (P < .02 and P < .0001).
Jones et al. looked at lymphopenia as a marker of sarcoidosis in patients presenting with uveitis.3 The study was a retrospective case-control study (112 patients with sarcoidosis-associated uveitis and 398 controls with other forms of uveitis). The mean lymphocyte count for patients with sarcoidosis was 1.43 vs. 2.04 for other causes of uveitis (P ≤ .0001).
Patients with sarcoidosis are at risk of hypercalciuria, hypercalcemia, and kidney stones. These are common in patients with sarcoidosis, with up to 50% of such patients having hypercalciuria. This is because in sarcoidosis patients 25(OH) vitamin D is converted in granulomas by activated macrophages to 1,25(OH)2 vitamin D, which is the active form of vitamin D.
Several studies have looked at the diagnostic utility of 1,25(OH)2 vitamin D levels in patients with suspected sarcoidosis. Rohmer and colleagues looked at whether 1,25(OH)2 vitamin D levels could help with the diagnosis of sarcoidosis as the cause of uveitis.4 They found that the level of 25(OH) vitamin D in sarcoidosis patients with uveitis was lower than in patients with uveitis without sarcoidosis, 34 vs. 43 nmol/mL (P < .02), whereas the 1,25(OH)2 vitamin D level was higher in patients with sarcoidosis than in those with uveitis without sarcoidosis, 132 vs. 108 pmol/L (P = .02). They looked at the 1,25(OH)2D/25(OH)D ratio; a ratio > 3.5 was strongly associated with an abnormal chest CT-scan (OR = 5.7, P = .003) and granulomas on bronchial biopsy (OR = 14.7, P = .007).
Kavathia et al. looked at whether elevated 1,25(OH)2 vitamin D levels predicted chronicity of sarcoidosis.5 A total of 59 sarcoidosis patients were recruited for the study. Higher serum 1,25(OH)2 vitamin D levels were associated with patients requiring repeated systemic immunosuppressive therapy or > 1 year of therapy. Increasing quartiles of serum 1,25(OH)2 vitamin D level were associated with increased odds of patients having chronic sarcoidosis (OR = 1.82; 95% CI, 1.11-2.99, P = .019).
Because of the higher activated vitamin D levels in sarcoidosis patients, they are at risk for problems with vitamin D supplementation. I have seen two patients develop large numbers of kidney stones after receiving high-dose vitamin D. Sodhi and Aldrich reported on a cohort of 196 sarcoidosis patients who had received vitamin D and compared them with 196 control patients with sarcoidosis who were not receiving vitamin D.6 Hypercalcemia was more frequent in the group that received vitamin D (42.3%) than in the group that did not (18.3%, P < .0001). In this study, only a minority (23%) of patients receiving vitamin D had their 1,25(OH)2 vitamin D level checked.
Pearl: Lymphocyte count and 1,25(OH)2 vitamin D levels can be helpful tests in assessing sarcoidosis activity. Patients with sarcoidosis who receive vitamin D should have their 1.25(OH)2 vitamin D levels monitored.
Dr. Paauw is professor of medicine in the division of general internal medicine at the University of Washington, Seattle, and he serves as third-year medical student clerkship director at the University of Washington. Contact Dr. Paauw at [email protected].
References
1. El Jammal et al. Sarcoidosis Vasc Diffuse Lung Dis. 2023 Sep 13;40(3):e2023031.
2. Morell F et al. Chest. 2002 Apr;121(4):1239-44.
3. Jones NP et al. Br J Ophthalmol. 2016 Oct;100(10):1393-6.
4. Rohmer J et al. Ocul Immunol Inflamm. 2020 Apr 2;28(3):341-7.
5. Kavathia D et al. Respir Med. 2010 Apr;104(4):564–70.
6. Sodhi A and Aldrich T. Am J Med Sci. 2016 Sep;352(3):252-7.
Unexplained collapse unveils rare blood disorder
This case report was published in the New England Journal of Medicine.
Noting the patient’s confusion and aphasia, emergency medical services were alerted, and she was taken to the emergency department of Massachusetts General Hospital. Initial examination revealed aphasia and coordination difficulties. However, imaging studies, including CT angiography, showed no signs of stroke or other neurological abnormalities.
The patient’s coworkers had observed that she appeared “unwell.” Her medical history included hypertension, which was managed with amlodipine, and there was no known family history of neurologic disorders.
During the examination, her vital signs were within normal ranges.
The patient’s potassium level of 2.5 mmol/L was noteworthy, indicating hypokalemia. Additionally, the patient presented with anemia and thrombocytopenia. Additional laboratory results unveiled thrombotic thrombocytopenic purpura (TTP), a rare blood disorder characterized by microangiopathic hemolytic anemia. The microscopic examination of a peripheral blood smear confirmed the extent of thrombocytopenia and was particularly notable for the increased number of schistocytes. The patient’s peripheral blood smear revealed five or six schistocytes per high-power field, constituting approximately 5% of the red cells. This significant number of schistocytes aligned with the severity of anemia and thrombocytopenia, confirming the diagnosis of microangiopathic hemolytic anemia.
Acquired TTP is an autoimmune condition driven by antibody-mediated clearance of the plasma enzyme ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin motif 13). Confirmatory laboratory testing for ADAMTS13 takes 1-3 days; therefore, therapeutic plasma exchange with glucocorticoid therapy and rituximab was initiated, which promptly improved her condition.
In this patient, the ADAMTS13 activity level was severely reduced (< 5%; reference value > 67%), and the inhibitor was present (1.4 inhibitor units; reference value ≤ 0.4).
Rectal cancer was diagnosed in this patient 2 months after the diagnosis of acquired TTP.
After undergoing four weekly infusions of rituximab and a 2-month tapering course of glucocorticoids, the patient experienced a relapse, approximately 6 months following the acquired TTP diagnosis. In response, therapeutic plasma exchange and glucocorticoid therapy were administered. There is a possibility that the underlying cancer played a role in the relapse. To minimize the risk for recurrence, the patient also received a second round of rituximab.
While establishing a clear cause is difficult, acquired TTP often appears to arise in connection with either an immune trigger, such as a viral infection, or immune dysregulation associated with another autoimmune disease or ongoing cancer. In this case, 4 weeks before the acquired TTP diagnosis, the patient had experienced COVID-19, which was likely to be the most probable trigger. However, rectal cancer was also identified in the patient, and whether these conditions are directly linked remains unclear.
A version of this article first appeared on Medscape.com.
This case report was published in the New England Journal of Medicine.
Noting the patient’s confusion and aphasia, emergency medical services were alerted, and she was taken to the emergency department of Massachusetts General Hospital. Initial examination revealed aphasia and coordination difficulties. However, imaging studies, including CT angiography, showed no signs of stroke or other neurological abnormalities.
The patient’s coworkers had observed that she appeared “unwell.” Her medical history included hypertension, which was managed with amlodipine, and there was no known family history of neurologic disorders.
During the examination, her vital signs were within normal ranges.
The patient’s potassium level of 2.5 mmol/L was noteworthy, indicating hypokalemia. Additionally, the patient presented with anemia and thrombocytopenia. Additional laboratory results unveiled thrombotic thrombocytopenic purpura (TTP), a rare blood disorder characterized by microangiopathic hemolytic anemia. The microscopic examination of a peripheral blood smear confirmed the extent of thrombocytopenia and was particularly notable for the increased number of schistocytes. The patient’s peripheral blood smear revealed five or six schistocytes per high-power field, constituting approximately 5% of the red cells. This significant number of schistocytes aligned with the severity of anemia and thrombocytopenia, confirming the diagnosis of microangiopathic hemolytic anemia.
Acquired TTP is an autoimmune condition driven by antibody-mediated clearance of the plasma enzyme ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin motif 13). Confirmatory laboratory testing for ADAMTS13 takes 1-3 days; therefore, therapeutic plasma exchange with glucocorticoid therapy and rituximab was initiated, which promptly improved her condition.
In this patient, the ADAMTS13 activity level was severely reduced (< 5%; reference value > 67%), and the inhibitor was present (1.4 inhibitor units; reference value ≤ 0.4).
Rectal cancer was diagnosed in this patient 2 months after the diagnosis of acquired TTP.
After undergoing four weekly infusions of rituximab and a 2-month tapering course of glucocorticoids, the patient experienced a relapse, approximately 6 months following the acquired TTP diagnosis. In response, therapeutic plasma exchange and glucocorticoid therapy were administered. There is a possibility that the underlying cancer played a role in the relapse. To minimize the risk for recurrence, the patient also received a second round of rituximab.
While establishing a clear cause is difficult, acquired TTP often appears to arise in connection with either an immune trigger, such as a viral infection, or immune dysregulation associated with another autoimmune disease or ongoing cancer. In this case, 4 weeks before the acquired TTP diagnosis, the patient had experienced COVID-19, which was likely to be the most probable trigger. However, rectal cancer was also identified in the patient, and whether these conditions are directly linked remains unclear.
A version of this article first appeared on Medscape.com.
This case report was published in the New England Journal of Medicine.
Noting the patient’s confusion and aphasia, emergency medical services were alerted, and she was taken to the emergency department of Massachusetts General Hospital. Initial examination revealed aphasia and coordination difficulties. However, imaging studies, including CT angiography, showed no signs of stroke or other neurological abnormalities.
The patient’s coworkers had observed that she appeared “unwell.” Her medical history included hypertension, which was managed with amlodipine, and there was no known family history of neurologic disorders.
During the examination, her vital signs were within normal ranges.
The patient’s potassium level of 2.5 mmol/L was noteworthy, indicating hypokalemia. Additionally, the patient presented with anemia and thrombocytopenia. Additional laboratory results unveiled thrombotic thrombocytopenic purpura (TTP), a rare blood disorder characterized by microangiopathic hemolytic anemia. The microscopic examination of a peripheral blood smear confirmed the extent of thrombocytopenia and was particularly notable for the increased number of schistocytes. The patient’s peripheral blood smear revealed five or six schistocytes per high-power field, constituting approximately 5% of the red cells. This significant number of schistocytes aligned with the severity of anemia and thrombocytopenia, confirming the diagnosis of microangiopathic hemolytic anemia.
Acquired TTP is an autoimmune condition driven by antibody-mediated clearance of the plasma enzyme ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin motif 13). Confirmatory laboratory testing for ADAMTS13 takes 1-3 days; therefore, therapeutic plasma exchange with glucocorticoid therapy and rituximab was initiated, which promptly improved her condition.
In this patient, the ADAMTS13 activity level was severely reduced (< 5%; reference value > 67%), and the inhibitor was present (1.4 inhibitor units; reference value ≤ 0.4).
Rectal cancer was diagnosed in this patient 2 months after the diagnosis of acquired TTP.
After undergoing four weekly infusions of rituximab and a 2-month tapering course of glucocorticoids, the patient experienced a relapse, approximately 6 months following the acquired TTP diagnosis. In response, therapeutic plasma exchange and glucocorticoid therapy were administered. There is a possibility that the underlying cancer played a role in the relapse. To minimize the risk for recurrence, the patient also received a second round of rituximab.
While establishing a clear cause is difficult, acquired TTP often appears to arise in connection with either an immune trigger, such as a viral infection, or immune dysregulation associated with another autoimmune disease or ongoing cancer. In this case, 4 weeks before the acquired TTP diagnosis, the patient had experienced COVID-19, which was likely to be the most probable trigger. However, rectal cancer was also identified in the patient, and whether these conditions are directly linked remains unclear.
A version of this article first appeared on Medscape.com.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
Newly approved myasthenia gravis drug shows sustained benefits in early responders
PHOENIX – , a new analyses show.
“The information [in the studies] is valuable in making clinical decisions in managing myasthenia gravis, which is a chronic autoimmune condition that requires long-term use of immunosuppressives,” said Xinli Du, MD, PhD, an assistant professor in the department of neurology at Virginia Commonwealth University in Richmond, who was not involved in the research.
“Compared with conventional immunosuppressants, which take 3-9 months to know if the patient will respond, this is definitely a game-changer,” she said.
The research was presented at the 2023 annual meeting of the American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM).
FDA approval
Approved by the U.S. Food and Drug Administration in October, the targeted peptide inhibitor of complement component 5 represents the only once-daily self-administered subcutaneous injection for adult patients with acetylcholine receptor autoantibody–positive (AChR+) generalized myasthenia gravis.
The multicenter, phase 3, placebo-controlled RAISE trial demonstrated that zilucoplan was associated with significant improvement in myasthenia gravis–specific outcomes in adult patients with mild to severe AChR+ generalized myasthenia gravis.
Of note, approximately 40% of patients in the zilucoplan phase 2 and 3 clinical trials have a significant response as early as the first week of treatment. For the current post hoc analysis, first author Miriam Freimer, MD, and colleagues took a closer look at the longer-term outcomes in these patients in the ongoing RAISE-XT open-label extension study.
In these two double-blind studies, patients were randomly assigned to receive either daily subcutaneous injections of 0.3 mg/kg zilucoplan or placebo.
Among 93 patients receiving zilucoplan in the two studies, 40 (43%) were identified as early responders based on having at least a 3-point reduction from baseline on the Myasthenia Gravis Activities of Daily Living scale (MG-ADL) within 1 week of treatment, and 31 (33%) qualified based on having at least 5-point reductions in Quantitative Myasthenia Gravis (QMG), at week 1.
Of these early responders, more than 80% meeting the MG-ADL and 85% meeting QMG criteria continued to show a treatment response at each assessment through week 60 in the open-label RAISE-XT trial.
Furthermore, week 1 responders maintained their response for 88.1% of their total treatment time in the MG-ADL group and 88.8% of their total treatment time on treatment in the QMG group, representing a median zilucoplan treatment duration of 450 days.
Of note, the week 1 early responders had no significant differences, compared with the study’s overall population. Participants had a mean age of 49.6 years versus 52.9 years in the overall population. Approximately 40% of patients in both studies were men, and 60%-64% were disease class III as assessed by the Myasthenia Gravis Foundation of America criteria.
“It is very exciting to see such a high response of rapid responders. This means that some patients may be able to avoid steroids or be able to taper them faster than with other accepted treatments for myasthenia gravis,” said Dr. Freimer, director of the division of neuromuscular disorders and the codirector of the Myasthenia Gravis Clinic at the Ohio State University in Columbus.
Impact on fatigue
In a separate post hoc analysis of patients who entered RAISE-XT, the researchers evaluated long-term effects of zilucoplan on fatigue.
Improvements in fatigue were already apparent at the end of the RAISE trial, with the least squares mean (LSM) change from baseline in fatigue assessed after 12 weeks with the Neuro-QOL T-score being –6.26 for zilucoplan (n = 86) compared with an increase of 2.65 for placebo (n = 88; LSM difference, –3.61; nominal P = .0060).
Patients who received placebo in the RAISE trial were able to switch to zilucoplan in the RAISE-XT open-label trail, and among those who did, fatigue, as measured in the T-scores, improved significantly within 1 week of switching.
Fatigue further improved out to week 16 in terms of T-scores for the placebo-switch as well as zilucoplan groups, and the improvements in the scores were sustained through week 60 (mean change from RAISE baseline, –10.71 [n = 42] and –9.15 [n = 42], respectively).
“Fatigue is a challenge for patients with [generalized myasthenia gravis]. Zilucoplan significantly and clinically meaningfully improved myasthenic fatigue versus placebo during RAISE,” the investigators report.
“Further improvements were observed during RAISE-XT and were sustained up to 60 weeks of treatment,” they added.
Favorable safety profile
Zilucoplan continued to show a favorable safety profile in the RAISE-XT trial and was well tolerated in the long term.
The most common adverse reactions (10% or more) in patients with generalized myasthenia gravis were injection-site reactions, upper respiratory tract infection, and diarrhea.
Though additional therapies have also recently entered the market for generalized myasthenia gravis, they are either intravenous or subcutaneous infusions requiring a health care professional to administer them.
“This self-administered medication allows patients to be more independent and can even travel since it is not dependent on an infusion center,” Dr. Freimer noted.
However, similar to the other complement inhibitors, zilucoplan carries a risk for infection, particularly meningitis, Dr. Du noted. “Complement meningitis vaccination protocol and close monitoring for signs of infection are required,” she said.
However, she added, “the rapid action benefits shown as early as week 1 are impressive, and potentially open the door to use as adjunctive therapy in myasthenia gravis crisis.”
“I think zilucoplan definitely adds more excitement to the already active field of myasthenia gravis management,” she said.
The study was funded by UCB Pharma. Dr. Freimer has reports she has served as a paid consultant for argenx, UCB Pharma, and Alexion Pharmaceuticals and reports research support from the National Institutes of Health, UCB Pharma, Jansen Pharmaceuticals, Alnylam, Avidity, and Fulcrum. Dr. Du reports no disclosures.
A version of this article appeared on Medscape.com.
PHOENIX – , a new analyses show.
“The information [in the studies] is valuable in making clinical decisions in managing myasthenia gravis, which is a chronic autoimmune condition that requires long-term use of immunosuppressives,” said Xinli Du, MD, PhD, an assistant professor in the department of neurology at Virginia Commonwealth University in Richmond, who was not involved in the research.
“Compared with conventional immunosuppressants, which take 3-9 months to know if the patient will respond, this is definitely a game-changer,” she said.
The research was presented at the 2023 annual meeting of the American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM).
FDA approval
Approved by the U.S. Food and Drug Administration in October, the targeted peptide inhibitor of complement component 5 represents the only once-daily self-administered subcutaneous injection for adult patients with acetylcholine receptor autoantibody–positive (AChR+) generalized myasthenia gravis.
The multicenter, phase 3, placebo-controlled RAISE trial demonstrated that zilucoplan was associated with significant improvement in myasthenia gravis–specific outcomes in adult patients with mild to severe AChR+ generalized myasthenia gravis.
Of note, approximately 40% of patients in the zilucoplan phase 2 and 3 clinical trials have a significant response as early as the first week of treatment. For the current post hoc analysis, first author Miriam Freimer, MD, and colleagues took a closer look at the longer-term outcomes in these patients in the ongoing RAISE-XT open-label extension study.
In these two double-blind studies, patients were randomly assigned to receive either daily subcutaneous injections of 0.3 mg/kg zilucoplan or placebo.
Among 93 patients receiving zilucoplan in the two studies, 40 (43%) were identified as early responders based on having at least a 3-point reduction from baseline on the Myasthenia Gravis Activities of Daily Living scale (MG-ADL) within 1 week of treatment, and 31 (33%) qualified based on having at least 5-point reductions in Quantitative Myasthenia Gravis (QMG), at week 1.
Of these early responders, more than 80% meeting the MG-ADL and 85% meeting QMG criteria continued to show a treatment response at each assessment through week 60 in the open-label RAISE-XT trial.
Furthermore, week 1 responders maintained their response for 88.1% of their total treatment time in the MG-ADL group and 88.8% of their total treatment time on treatment in the QMG group, representing a median zilucoplan treatment duration of 450 days.
Of note, the week 1 early responders had no significant differences, compared with the study’s overall population. Participants had a mean age of 49.6 years versus 52.9 years in the overall population. Approximately 40% of patients in both studies were men, and 60%-64% were disease class III as assessed by the Myasthenia Gravis Foundation of America criteria.
“It is very exciting to see such a high response of rapid responders. This means that some patients may be able to avoid steroids or be able to taper them faster than with other accepted treatments for myasthenia gravis,” said Dr. Freimer, director of the division of neuromuscular disorders and the codirector of the Myasthenia Gravis Clinic at the Ohio State University in Columbus.
Impact on fatigue
In a separate post hoc analysis of patients who entered RAISE-XT, the researchers evaluated long-term effects of zilucoplan on fatigue.
Improvements in fatigue were already apparent at the end of the RAISE trial, with the least squares mean (LSM) change from baseline in fatigue assessed after 12 weeks with the Neuro-QOL T-score being –6.26 for zilucoplan (n = 86) compared with an increase of 2.65 for placebo (n = 88; LSM difference, –3.61; nominal P = .0060).
Patients who received placebo in the RAISE trial were able to switch to zilucoplan in the RAISE-XT open-label trail, and among those who did, fatigue, as measured in the T-scores, improved significantly within 1 week of switching.
Fatigue further improved out to week 16 in terms of T-scores for the placebo-switch as well as zilucoplan groups, and the improvements in the scores were sustained through week 60 (mean change from RAISE baseline, –10.71 [n = 42] and –9.15 [n = 42], respectively).
“Fatigue is a challenge for patients with [generalized myasthenia gravis]. Zilucoplan significantly and clinically meaningfully improved myasthenic fatigue versus placebo during RAISE,” the investigators report.
“Further improvements were observed during RAISE-XT and were sustained up to 60 weeks of treatment,” they added.
Favorable safety profile
Zilucoplan continued to show a favorable safety profile in the RAISE-XT trial and was well tolerated in the long term.
The most common adverse reactions (10% or more) in patients with generalized myasthenia gravis were injection-site reactions, upper respiratory tract infection, and diarrhea.
Though additional therapies have also recently entered the market for generalized myasthenia gravis, they are either intravenous or subcutaneous infusions requiring a health care professional to administer them.
“This self-administered medication allows patients to be more independent and can even travel since it is not dependent on an infusion center,” Dr. Freimer noted.
However, similar to the other complement inhibitors, zilucoplan carries a risk for infection, particularly meningitis, Dr. Du noted. “Complement meningitis vaccination protocol and close monitoring for signs of infection are required,” she said.
However, she added, “the rapid action benefits shown as early as week 1 are impressive, and potentially open the door to use as adjunctive therapy in myasthenia gravis crisis.”
“I think zilucoplan definitely adds more excitement to the already active field of myasthenia gravis management,” she said.
The study was funded by UCB Pharma. Dr. Freimer has reports she has served as a paid consultant for argenx, UCB Pharma, and Alexion Pharmaceuticals and reports research support from the National Institutes of Health, UCB Pharma, Jansen Pharmaceuticals, Alnylam, Avidity, and Fulcrum. Dr. Du reports no disclosures.
A version of this article appeared on Medscape.com.
PHOENIX – , a new analyses show.
“The information [in the studies] is valuable in making clinical decisions in managing myasthenia gravis, which is a chronic autoimmune condition that requires long-term use of immunosuppressives,” said Xinli Du, MD, PhD, an assistant professor in the department of neurology at Virginia Commonwealth University in Richmond, who was not involved in the research.
“Compared with conventional immunosuppressants, which take 3-9 months to know if the patient will respond, this is definitely a game-changer,” she said.
The research was presented at the 2023 annual meeting of the American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM).
FDA approval
Approved by the U.S. Food and Drug Administration in October, the targeted peptide inhibitor of complement component 5 represents the only once-daily self-administered subcutaneous injection for adult patients with acetylcholine receptor autoantibody–positive (AChR+) generalized myasthenia gravis.
The multicenter, phase 3, placebo-controlled RAISE trial demonstrated that zilucoplan was associated with significant improvement in myasthenia gravis–specific outcomes in adult patients with mild to severe AChR+ generalized myasthenia gravis.
Of note, approximately 40% of patients in the zilucoplan phase 2 and 3 clinical trials have a significant response as early as the first week of treatment. For the current post hoc analysis, first author Miriam Freimer, MD, and colleagues took a closer look at the longer-term outcomes in these patients in the ongoing RAISE-XT open-label extension study.
In these two double-blind studies, patients were randomly assigned to receive either daily subcutaneous injections of 0.3 mg/kg zilucoplan or placebo.
Among 93 patients receiving zilucoplan in the two studies, 40 (43%) were identified as early responders based on having at least a 3-point reduction from baseline on the Myasthenia Gravis Activities of Daily Living scale (MG-ADL) within 1 week of treatment, and 31 (33%) qualified based on having at least 5-point reductions in Quantitative Myasthenia Gravis (QMG), at week 1.
Of these early responders, more than 80% meeting the MG-ADL and 85% meeting QMG criteria continued to show a treatment response at each assessment through week 60 in the open-label RAISE-XT trial.
Furthermore, week 1 responders maintained their response for 88.1% of their total treatment time in the MG-ADL group and 88.8% of their total treatment time on treatment in the QMG group, representing a median zilucoplan treatment duration of 450 days.
Of note, the week 1 early responders had no significant differences, compared with the study’s overall population. Participants had a mean age of 49.6 years versus 52.9 years in the overall population. Approximately 40% of patients in both studies were men, and 60%-64% were disease class III as assessed by the Myasthenia Gravis Foundation of America criteria.
“It is very exciting to see such a high response of rapid responders. This means that some patients may be able to avoid steroids or be able to taper them faster than with other accepted treatments for myasthenia gravis,” said Dr. Freimer, director of the division of neuromuscular disorders and the codirector of the Myasthenia Gravis Clinic at the Ohio State University in Columbus.
Impact on fatigue
In a separate post hoc analysis of patients who entered RAISE-XT, the researchers evaluated long-term effects of zilucoplan on fatigue.
Improvements in fatigue were already apparent at the end of the RAISE trial, with the least squares mean (LSM) change from baseline in fatigue assessed after 12 weeks with the Neuro-QOL T-score being –6.26 for zilucoplan (n = 86) compared with an increase of 2.65 for placebo (n = 88; LSM difference, –3.61; nominal P = .0060).
Patients who received placebo in the RAISE trial were able to switch to zilucoplan in the RAISE-XT open-label trail, and among those who did, fatigue, as measured in the T-scores, improved significantly within 1 week of switching.
Fatigue further improved out to week 16 in terms of T-scores for the placebo-switch as well as zilucoplan groups, and the improvements in the scores were sustained through week 60 (mean change from RAISE baseline, –10.71 [n = 42] and –9.15 [n = 42], respectively).
“Fatigue is a challenge for patients with [generalized myasthenia gravis]. Zilucoplan significantly and clinically meaningfully improved myasthenic fatigue versus placebo during RAISE,” the investigators report.
“Further improvements were observed during RAISE-XT and were sustained up to 60 weeks of treatment,” they added.
Favorable safety profile
Zilucoplan continued to show a favorable safety profile in the RAISE-XT trial and was well tolerated in the long term.
The most common adverse reactions (10% or more) in patients with generalized myasthenia gravis were injection-site reactions, upper respiratory tract infection, and diarrhea.
Though additional therapies have also recently entered the market for generalized myasthenia gravis, they are either intravenous or subcutaneous infusions requiring a health care professional to administer them.
“This self-administered medication allows patients to be more independent and can even travel since it is not dependent on an infusion center,” Dr. Freimer noted.
However, similar to the other complement inhibitors, zilucoplan carries a risk for infection, particularly meningitis, Dr. Du noted. “Complement meningitis vaccination protocol and close monitoring for signs of infection are required,” she said.
However, she added, “the rapid action benefits shown as early as week 1 are impressive, and potentially open the door to use as adjunctive therapy in myasthenia gravis crisis.”
“I think zilucoplan definitely adds more excitement to the already active field of myasthenia gravis management,” she said.
The study was funded by UCB Pharma. Dr. Freimer has reports she has served as a paid consultant for argenx, UCB Pharma, and Alexion Pharmaceuticals and reports research support from the National Institutes of Health, UCB Pharma, Jansen Pharmaceuticals, Alnylam, Avidity, and Fulcrum. Dr. Du reports no disclosures.
A version of this article appeared on Medscape.com.
At AANEM 2023
AI tool perfect in study of inflammatory diseases
Artificial intelligence can distinguish overlapping inflammatory conditions with total accuracy, according to a new study presented at the annual meeting of the American College of Rheumatology.
Texas pediatricians faced a conundrum during the pandemic. Endemic typhus, a flea-borne tropical infection common to the region, is nearly indistinguishable from multisystem inflammatory syndrome in children (MIS-C), a rare condition set in motion by SARS-CoV-2 infection. Children with either ailment had seemingly identical symptoms: fever, rash, gastrointestinal issues, and in need of swift treatment. A diagnosis of endemic typhus can take 4-6 days to confirm.
Tiphanie Vogel, MD, PhD, a pediatric rheumatologist at Texas Children’s Hospital, Houston, and colleagues sought to create a tool to hasten diagnosis and, ideally, treatment. To do so, they incorporated machine learning and clinical factors available within the first 6 hours of the onset of symptoms.
The team analyzed 49 demographic, clinical, and laboratory measures from the medical records of 133 children with MIS-C and 87 with endemic typhus. Using deep learning, they narrowed the model to 30 essential features that became the backbone of AI-MET, a two-phase clinical-decision support system.
Phase 1 uses 17 clinical factors and can be performed on paper. If a patient’s score in phase 1 is not determinative, clinicians proceed to phase 2, which uses an additional 13 weighted factors and machine learning.
In testing, the two-part tool classified each of the 220 test patients perfectly. And it diagnosed a second group of 111 patients with MIS-C with 99% (110/111) accuracy.
Of note, “that first step classifies [a patient] correctly half of the time,” Dr. Vogel said, so the second, AI phase of the tool was necessary for only half of cases. Dr. Vogel said that’s a good sign; it means that the tool is useful in settings where AI may not always be feasible, like in a busy ED.
Melissa Mizesko, MD, a pediatric rheumatologist at Driscoll Children’s Hospital in Corpus Christi, Tex., said that the new tool could help clinicians streamline care. When cases of MIS-C peaked in Texas, clinicians often would start sick children on doxycycline and treat for MIS-C at the same time, then wait to see whether the antibiotic brought the fever down.
“This [new tool] is helpful if you live in a part of the country that has typhus,” said Jane Burns, MD, director of the Kawasaki Disease Research Center at the University of California, San Diego, who helped develop a similar AI-based tool to distinguish MIS-C from Kawasaki disease. But she encouraged the researchers to expand their testing to include other conditions. Although the AI model Dr. Vogel’s group developed can pinpoint MIS-C or endemic typhus, what if a child has neither condition? “It’s not often you’re dealing with a diagnosis between just two specific diseases,” Dr. Burns said.
Dr. Vogel is also interested in making AI-MET more efficient. “This go-round we prioritized perfect accuracy,” she said. But 30 clinical factors, with 17 of them recorded and calculated by hand, is a lot. “Could we still get this to be very accurate, maybe not perfect, with less inputs?”
In addition to refining AI-MET, which Texas Children’s eventually hopes to make available to other institutions, Dr. Vogel and associates are also considering other use cases for AI. Lupus is one option. “Maybe with machine learning we could identify clues at diagnosis that would help recommend targeted treatment,” she said
Dr. Vogel disclosed potential conflicts of interest with Moderna, Novartis, Pfizer, and SOBI. Dr. Burns and Dr. Mizesko disclosed no relevant conflicts of interest.
A version of this article appeared on Medscape.com.
Artificial intelligence can distinguish overlapping inflammatory conditions with total accuracy, according to a new study presented at the annual meeting of the American College of Rheumatology.
Texas pediatricians faced a conundrum during the pandemic. Endemic typhus, a flea-borne tropical infection common to the region, is nearly indistinguishable from multisystem inflammatory syndrome in children (MIS-C), a rare condition set in motion by SARS-CoV-2 infection. Children with either ailment had seemingly identical symptoms: fever, rash, gastrointestinal issues, and in need of swift treatment. A diagnosis of endemic typhus can take 4-6 days to confirm.
Tiphanie Vogel, MD, PhD, a pediatric rheumatologist at Texas Children’s Hospital, Houston, and colleagues sought to create a tool to hasten diagnosis and, ideally, treatment. To do so, they incorporated machine learning and clinical factors available within the first 6 hours of the onset of symptoms.
The team analyzed 49 demographic, clinical, and laboratory measures from the medical records of 133 children with MIS-C and 87 with endemic typhus. Using deep learning, they narrowed the model to 30 essential features that became the backbone of AI-MET, a two-phase clinical-decision support system.
Phase 1 uses 17 clinical factors and can be performed on paper. If a patient’s score in phase 1 is not determinative, clinicians proceed to phase 2, which uses an additional 13 weighted factors and machine learning.
In testing, the two-part tool classified each of the 220 test patients perfectly. And it diagnosed a second group of 111 patients with MIS-C with 99% (110/111) accuracy.
Of note, “that first step classifies [a patient] correctly half of the time,” Dr. Vogel said, so the second, AI phase of the tool was necessary for only half of cases. Dr. Vogel said that’s a good sign; it means that the tool is useful in settings where AI may not always be feasible, like in a busy ED.
Melissa Mizesko, MD, a pediatric rheumatologist at Driscoll Children’s Hospital in Corpus Christi, Tex., said that the new tool could help clinicians streamline care. When cases of MIS-C peaked in Texas, clinicians often would start sick children on doxycycline and treat for MIS-C at the same time, then wait to see whether the antibiotic brought the fever down.
“This [new tool] is helpful if you live in a part of the country that has typhus,” said Jane Burns, MD, director of the Kawasaki Disease Research Center at the University of California, San Diego, who helped develop a similar AI-based tool to distinguish MIS-C from Kawasaki disease. But she encouraged the researchers to expand their testing to include other conditions. Although the AI model Dr. Vogel’s group developed can pinpoint MIS-C or endemic typhus, what if a child has neither condition? “It’s not often you’re dealing with a diagnosis between just two specific diseases,” Dr. Burns said.
Dr. Vogel is also interested in making AI-MET more efficient. “This go-round we prioritized perfect accuracy,” she said. But 30 clinical factors, with 17 of them recorded and calculated by hand, is a lot. “Could we still get this to be very accurate, maybe not perfect, with less inputs?”
In addition to refining AI-MET, which Texas Children’s eventually hopes to make available to other institutions, Dr. Vogel and associates are also considering other use cases for AI. Lupus is one option. “Maybe with machine learning we could identify clues at diagnosis that would help recommend targeted treatment,” she said
Dr. Vogel disclosed potential conflicts of interest with Moderna, Novartis, Pfizer, and SOBI. Dr. Burns and Dr. Mizesko disclosed no relevant conflicts of interest.
A version of this article appeared on Medscape.com.
Artificial intelligence can distinguish overlapping inflammatory conditions with total accuracy, according to a new study presented at the annual meeting of the American College of Rheumatology.
Texas pediatricians faced a conundrum during the pandemic. Endemic typhus, a flea-borne tropical infection common to the region, is nearly indistinguishable from multisystem inflammatory syndrome in children (MIS-C), a rare condition set in motion by SARS-CoV-2 infection. Children with either ailment had seemingly identical symptoms: fever, rash, gastrointestinal issues, and in need of swift treatment. A diagnosis of endemic typhus can take 4-6 days to confirm.
Tiphanie Vogel, MD, PhD, a pediatric rheumatologist at Texas Children’s Hospital, Houston, and colleagues sought to create a tool to hasten diagnosis and, ideally, treatment. To do so, they incorporated machine learning and clinical factors available within the first 6 hours of the onset of symptoms.
The team analyzed 49 demographic, clinical, and laboratory measures from the medical records of 133 children with MIS-C and 87 with endemic typhus. Using deep learning, they narrowed the model to 30 essential features that became the backbone of AI-MET, a two-phase clinical-decision support system.
Phase 1 uses 17 clinical factors and can be performed on paper. If a patient’s score in phase 1 is not determinative, clinicians proceed to phase 2, which uses an additional 13 weighted factors and machine learning.
In testing, the two-part tool classified each of the 220 test patients perfectly. And it diagnosed a second group of 111 patients with MIS-C with 99% (110/111) accuracy.
Of note, “that first step classifies [a patient] correctly half of the time,” Dr. Vogel said, so the second, AI phase of the tool was necessary for only half of cases. Dr. Vogel said that’s a good sign; it means that the tool is useful in settings where AI may not always be feasible, like in a busy ED.
Melissa Mizesko, MD, a pediatric rheumatologist at Driscoll Children’s Hospital in Corpus Christi, Tex., said that the new tool could help clinicians streamline care. When cases of MIS-C peaked in Texas, clinicians often would start sick children on doxycycline and treat for MIS-C at the same time, then wait to see whether the antibiotic brought the fever down.
“This [new tool] is helpful if you live in a part of the country that has typhus,” said Jane Burns, MD, director of the Kawasaki Disease Research Center at the University of California, San Diego, who helped develop a similar AI-based tool to distinguish MIS-C from Kawasaki disease. But she encouraged the researchers to expand their testing to include other conditions. Although the AI model Dr. Vogel’s group developed can pinpoint MIS-C or endemic typhus, what if a child has neither condition? “It’s not often you’re dealing with a diagnosis between just two specific diseases,” Dr. Burns said.
Dr. Vogel is also interested in making AI-MET more efficient. “This go-round we prioritized perfect accuracy,” she said. But 30 clinical factors, with 17 of them recorded and calculated by hand, is a lot. “Could we still get this to be very accurate, maybe not perfect, with less inputs?”
In addition to refining AI-MET, which Texas Children’s eventually hopes to make available to other institutions, Dr. Vogel and associates are also considering other use cases for AI. Lupus is one option. “Maybe with machine learning we could identify clues at diagnosis that would help recommend targeted treatment,” she said
Dr. Vogel disclosed potential conflicts of interest with Moderna, Novartis, Pfizer, and SOBI. Dr. Burns and Dr. Mizesko disclosed no relevant conflicts of interest.
A version of this article appeared on Medscape.com.
FROM ACR 2023
FDA approves first tx for rare, deadly clotting disorder
Congenital TTP affects fewer than 1,000 people in the United States and is caused by a mutation in the ADAMTS13 gene, which makes an enzyme that regulates blood clotting. Patients with the congenital TTP typically receive prophylactic plasma-based therapy to replenish the ADAMTS13 enzyme and reduce the risk for clotting and bleeding. The condition, however, can be fatal if left untreated.
The new agent is a purified recombinant form of the ADAMTS13 enzyme that works by replacing low levels of the deficient enzyme in patients with congenital TTP. Adzynma is given prophylactically to reduce the risk for disease symptoms and on demand when a patient is experiencing an acute event, according to the FDA approval announcement.
The approval was based on a global randomized phase 3 study comparing the product with plasma-based therapies in 46 patients with congenital TTP. Patients in the trial were randomized to receive 6 months of treatment with either intravenous Adzynma — given once every other week as prophylactic enzyme replacement therapy or once daily as on-demand enzyme replacement therapy — or plasma-based therapies. The patients then crossed over to the other treatment for 6 months.
Interim findings from the study showed that Adzynma reduced the incidence of thrombocytopenia — the most common symptom of congenital TTP — by 60% compared with plasma-based therapy (rate ratio, 0.40). No patients experienced an acute TTP event during Adzynma prophylaxis, Takeda said.
Significantly more patients receiving plasma-based therapies experienced treatment-emergent adverse events compared with those receiving the biologic.
The most common side effects associated with the biologic were headache (31.3%), diarrhea (16.7%), migraine (14.6%), abdominal pain (12.5%), nausea (12.5%), upper respiratory tract infection (12.5%), dizziness (10.4%), and vomiting (10.4%). No treatment-related adverse events, including allergic reactions, were observed during administration.
“The FDA remains deeply committed in our efforts to help facilitate the development and approval of safe and effective therapies for patients with rare diseases,” Peter Marks, MD, PhD, director of the FDA’s Center for Biologics Evaluation and Research, stated. The “approval reflects important progress in the development of much-needed treatment options for patients affected by this life-threatening disorder.”
A version of this article first appeared on Medscape.com.
Congenital TTP affects fewer than 1,000 people in the United States and is caused by a mutation in the ADAMTS13 gene, which makes an enzyme that regulates blood clotting. Patients with the congenital TTP typically receive prophylactic plasma-based therapy to replenish the ADAMTS13 enzyme and reduce the risk for clotting and bleeding. The condition, however, can be fatal if left untreated.
The new agent is a purified recombinant form of the ADAMTS13 enzyme that works by replacing low levels of the deficient enzyme in patients with congenital TTP. Adzynma is given prophylactically to reduce the risk for disease symptoms and on demand when a patient is experiencing an acute event, according to the FDA approval announcement.
The approval was based on a global randomized phase 3 study comparing the product with plasma-based therapies in 46 patients with congenital TTP. Patients in the trial were randomized to receive 6 months of treatment with either intravenous Adzynma — given once every other week as prophylactic enzyme replacement therapy or once daily as on-demand enzyme replacement therapy — or plasma-based therapies. The patients then crossed over to the other treatment for 6 months.
Interim findings from the study showed that Adzynma reduced the incidence of thrombocytopenia — the most common symptom of congenital TTP — by 60% compared with plasma-based therapy (rate ratio, 0.40). No patients experienced an acute TTP event during Adzynma prophylaxis, Takeda said.
Significantly more patients receiving plasma-based therapies experienced treatment-emergent adverse events compared with those receiving the biologic.
The most common side effects associated with the biologic were headache (31.3%), diarrhea (16.7%), migraine (14.6%), abdominal pain (12.5%), nausea (12.5%), upper respiratory tract infection (12.5%), dizziness (10.4%), and vomiting (10.4%). No treatment-related adverse events, including allergic reactions, were observed during administration.
“The FDA remains deeply committed in our efforts to help facilitate the development and approval of safe and effective therapies for patients with rare diseases,” Peter Marks, MD, PhD, director of the FDA’s Center for Biologics Evaluation and Research, stated. The “approval reflects important progress in the development of much-needed treatment options for patients affected by this life-threatening disorder.”
A version of this article first appeared on Medscape.com.
Congenital TTP affects fewer than 1,000 people in the United States and is caused by a mutation in the ADAMTS13 gene, which makes an enzyme that regulates blood clotting. Patients with the congenital TTP typically receive prophylactic plasma-based therapy to replenish the ADAMTS13 enzyme and reduce the risk for clotting and bleeding. The condition, however, can be fatal if left untreated.
The new agent is a purified recombinant form of the ADAMTS13 enzyme that works by replacing low levels of the deficient enzyme in patients with congenital TTP. Adzynma is given prophylactically to reduce the risk for disease symptoms and on demand when a patient is experiencing an acute event, according to the FDA approval announcement.
The approval was based on a global randomized phase 3 study comparing the product with plasma-based therapies in 46 patients with congenital TTP. Patients in the trial were randomized to receive 6 months of treatment with either intravenous Adzynma — given once every other week as prophylactic enzyme replacement therapy or once daily as on-demand enzyme replacement therapy — or plasma-based therapies. The patients then crossed over to the other treatment for 6 months.
Interim findings from the study showed that Adzynma reduced the incidence of thrombocytopenia — the most common symptom of congenital TTP — by 60% compared with plasma-based therapy (rate ratio, 0.40). No patients experienced an acute TTP event during Adzynma prophylaxis, Takeda said.
Significantly more patients receiving plasma-based therapies experienced treatment-emergent adverse events compared with those receiving the biologic.
The most common side effects associated with the biologic were headache (31.3%), diarrhea (16.7%), migraine (14.6%), abdominal pain (12.5%), nausea (12.5%), upper respiratory tract infection (12.5%), dizziness (10.4%), and vomiting (10.4%). No treatment-related adverse events, including allergic reactions, were observed during administration.
“The FDA remains deeply committed in our efforts to help facilitate the development and approval of safe and effective therapies for patients with rare diseases,” Peter Marks, MD, PhD, director of the FDA’s Center for Biologics Evaluation and Research, stated. The “approval reflects important progress in the development of much-needed treatment options for patients affected by this life-threatening disorder.”
A version of this article first appeared on Medscape.com.
Pregnancies with low anti-SSA/Ro autoantibody levels: Forgo fetal heart rhythm monitoring?
SAN DIEGO – Pregnant women with anti-SSA/Ro autoantibodies at titer levels of less than 1,000 ELISA units per mL are at minimal to no risk for fetal atrioventricular (AV) block and may be able to forgo traditional echocardiographic heart rhythm monitoring, results from an ongoing, prospective, multicenter trial demonstrated.
However, pregnant patients with higher titer antibodies seem to be at greatest risk for fetal AV block and may benefit from ambulatory fetal heart rhythm monitoring (FHRM), which can detect emergent AV block, according to the study findings. The findings were published online in Arthritis & Rheumatology and will be presented Nov. 13 at the American College of Rheumatology (ACR) 2023 Annual Meeting by Jill P. Buyon, MD, a rheumatologist who directs the division of rheumatology and the Lupus Center at NYU Langone Health in New York.
“While anti-Ro antibodies have been known to be associated with AV block for decades, it has become increasingly clear that antibody titers matter,” Dr. Buyon said in an interview.
For the investigation, which is the largest of its kind, researchers at 22 sites drew from the large multiracial national study of pregnant women, Surveillance To Prevent AV Block Likely to Occur Quickly (STOP BLOQ), to address the impact of anti-Ro titers and use of frequent ambulatory FHRM on outcomes in women with no previously affected children and those at risk for recurrence. Monitoring occurred during the second trimester of pregnancy (from 17 weeks through 26 weeks) and consisted of daily fetal home testing by mothers using handheld, commercially available Doppler devices.
These were followed up by weekly or biweekly echocardiograms, and ultrasound tests to evaluate fetal heart rhythm and function, as well as to show any structural problems. Three times per day, the pregnant women texted the Doppler sound recordings in real time to a pediatric cardiologist, who immediately ordered an additional echocardiogram in cases of irregular or slowing fetal heart rates. If second-degree heart block was detected, drug therapy was initiated.
No AV block seen with low anti-Ro titers
Dr. Buyon, who led the study with Bettina Cuneo, MD, clinical scholar and professor of surgery and pediatrics at the University of Arizona in Tucson, presented findings from 413 pregnant subjects with a mean age of 33 years who finished monitoring surveillance: 152 women had low titers of both anti-Ro60 and –Ro52 (defined as < 1,000 ELISA units per mL), and 261 women with titers above the threshold for either antibody (defined as ≥ 1,000 ELISA units per mL). Of the 152 women with low titers of both anti-Ro60 and –Ro52, none of the pregnancies past 26 weeks resulted in AV block. Of the 261 women with titers above the threshold for either antibody, 10 of the pregnancies resulted in AV block (3.8%). The incidence of AV block increased with higher antibody titer levels, reaching 7.7% for those in the top quartile for anti–60-kD SSA/Ro; this increased to 27.3% in study participants with a previous child who had AV block, although numbers in this category were small.
Analysis of cumulative FHRM recordings between surveillance echocardiograms revealed that no case of second-degree or third-degree AV block was missed. In addition, 70% of AV blocks detected by FHRM were second-degree and all occurred less than 12 hours from normal FHRM and within another 45 minutes to 4.5 hours to echocardiogram. The one case of second/third-degree and two cases of third-degree AV block were diagnosed by urgent echocardiogram more than 17 to 72 hours from a previously normal FHRM episode.
Other factors besides high anti-Ro titer likely play a role
“STOP BLOQ nicely demonstrates that low titer is associated with a very low risk AV block, and intense monitoring may not be needed,” Dr. Buyon told this news organization. “However, high titer is not the whole answer since even women with the very highest titers can have healthy babies. This report also shows that titers stay constant through pregnancies in the same mother, whether there is the complication of AV block or not. This suggests other factors contribute to AV block.”
She added that FHRM can be easily performed by the mother, but at this time is still best interpreted by a cardiologist. “FHRM detected all cases of AV block, which can happen in hours,” she said. “FHRM should decrease the need for frequent echocardiograms. Some mothers do have more difficulty in deciding whether the baby’s heart is beating irregularly. We need [to improve our teaching] and for how best to have a cardiologist or trained listener interpret. FHRM can be done by the mother but needs interpretation by a cardiologist until we develop a device which can identify abnormalities.”
She acknowledged certain limitations of the study, including the fact that a commercial test for anti-SSA/Ro antibody levels is not available to all clinicians. “Try to find a lab that measures high titer anti-Ro antibodies, but if not, then use one of the common commercial tests such as the BioPlex 2000 autoimmune panels and consider decreased surveillance if titer is < 8,” Dr. Buyon advised.
Vaneet K. Sandhu, MD, a rheumatologist with Loma Linda (Calif.) Medical Center, who was asked to comment on the work, said that the study not only justifies the limited use of FHRM in those with high titer antibodies (followed by urgent fetal echocardiography where indicated), but also risk stratification for fetal AV block.
“For years, we have recommended frequent fetal echocardiography testing in pregnant women with positive anti-SSA/Ro,” Dr. Sandhu said. “This study tells us we need to look deeper. On one hand, recognizing that low titer anti-Ro antibodies do not confer a risk of AV block is cost effective. On the other hand, while the titer of the antibody appears to contribute to fetal AV block, we need to delve deeper into additional factors contributing to fetal AV block risk in order to better navigate our surveillance methods.”
The study was supported by NIH grants from the National Institute of Child Health and Human Development and the National Institute of Arthritis and Musculoskeletal and Skin Diseases. Dr. Sandhu has disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
SAN DIEGO – Pregnant women with anti-SSA/Ro autoantibodies at titer levels of less than 1,000 ELISA units per mL are at minimal to no risk for fetal atrioventricular (AV) block and may be able to forgo traditional echocardiographic heart rhythm monitoring, results from an ongoing, prospective, multicenter trial demonstrated.
However, pregnant patients with higher titer antibodies seem to be at greatest risk for fetal AV block and may benefit from ambulatory fetal heart rhythm monitoring (FHRM), which can detect emergent AV block, according to the study findings. The findings were published online in Arthritis & Rheumatology and will be presented Nov. 13 at the American College of Rheumatology (ACR) 2023 Annual Meeting by Jill P. Buyon, MD, a rheumatologist who directs the division of rheumatology and the Lupus Center at NYU Langone Health in New York.
“While anti-Ro antibodies have been known to be associated with AV block for decades, it has become increasingly clear that antibody titers matter,” Dr. Buyon said in an interview.
For the investigation, which is the largest of its kind, researchers at 22 sites drew from the large multiracial national study of pregnant women, Surveillance To Prevent AV Block Likely to Occur Quickly (STOP BLOQ), to address the impact of anti-Ro titers and use of frequent ambulatory FHRM on outcomes in women with no previously affected children and those at risk for recurrence. Monitoring occurred during the second trimester of pregnancy (from 17 weeks through 26 weeks) and consisted of daily fetal home testing by mothers using handheld, commercially available Doppler devices.
These were followed up by weekly or biweekly echocardiograms, and ultrasound tests to evaluate fetal heart rhythm and function, as well as to show any structural problems. Three times per day, the pregnant women texted the Doppler sound recordings in real time to a pediatric cardiologist, who immediately ordered an additional echocardiogram in cases of irregular or slowing fetal heart rates. If second-degree heart block was detected, drug therapy was initiated.
No AV block seen with low anti-Ro titers
Dr. Buyon, who led the study with Bettina Cuneo, MD, clinical scholar and professor of surgery and pediatrics at the University of Arizona in Tucson, presented findings from 413 pregnant subjects with a mean age of 33 years who finished monitoring surveillance: 152 women had low titers of both anti-Ro60 and –Ro52 (defined as < 1,000 ELISA units per mL), and 261 women with titers above the threshold for either antibody (defined as ≥ 1,000 ELISA units per mL). Of the 152 women with low titers of both anti-Ro60 and –Ro52, none of the pregnancies past 26 weeks resulted in AV block. Of the 261 women with titers above the threshold for either antibody, 10 of the pregnancies resulted in AV block (3.8%). The incidence of AV block increased with higher antibody titer levels, reaching 7.7% for those in the top quartile for anti–60-kD SSA/Ro; this increased to 27.3% in study participants with a previous child who had AV block, although numbers in this category were small.
Analysis of cumulative FHRM recordings between surveillance echocardiograms revealed that no case of second-degree or third-degree AV block was missed. In addition, 70% of AV blocks detected by FHRM were second-degree and all occurred less than 12 hours from normal FHRM and within another 45 minutes to 4.5 hours to echocardiogram. The one case of second/third-degree and two cases of third-degree AV block were diagnosed by urgent echocardiogram more than 17 to 72 hours from a previously normal FHRM episode.
Other factors besides high anti-Ro titer likely play a role
“STOP BLOQ nicely demonstrates that low titer is associated with a very low risk AV block, and intense monitoring may not be needed,” Dr. Buyon told this news organization. “However, high titer is not the whole answer since even women with the very highest titers can have healthy babies. This report also shows that titers stay constant through pregnancies in the same mother, whether there is the complication of AV block or not. This suggests other factors contribute to AV block.”
She added that FHRM can be easily performed by the mother, but at this time is still best interpreted by a cardiologist. “FHRM detected all cases of AV block, which can happen in hours,” she said. “FHRM should decrease the need for frequent echocardiograms. Some mothers do have more difficulty in deciding whether the baby’s heart is beating irregularly. We need [to improve our teaching] and for how best to have a cardiologist or trained listener interpret. FHRM can be done by the mother but needs interpretation by a cardiologist until we develop a device which can identify abnormalities.”
She acknowledged certain limitations of the study, including the fact that a commercial test for anti-SSA/Ro antibody levels is not available to all clinicians. “Try to find a lab that measures high titer anti-Ro antibodies, but if not, then use one of the common commercial tests such as the BioPlex 2000 autoimmune panels and consider decreased surveillance if titer is < 8,” Dr. Buyon advised.
Vaneet K. Sandhu, MD, a rheumatologist with Loma Linda (Calif.) Medical Center, who was asked to comment on the work, said that the study not only justifies the limited use of FHRM in those with high titer antibodies (followed by urgent fetal echocardiography where indicated), but also risk stratification for fetal AV block.
“For years, we have recommended frequent fetal echocardiography testing in pregnant women with positive anti-SSA/Ro,” Dr. Sandhu said. “This study tells us we need to look deeper. On one hand, recognizing that low titer anti-Ro antibodies do not confer a risk of AV block is cost effective. On the other hand, while the titer of the antibody appears to contribute to fetal AV block, we need to delve deeper into additional factors contributing to fetal AV block risk in order to better navigate our surveillance methods.”
The study was supported by NIH grants from the National Institute of Child Health and Human Development and the National Institute of Arthritis and Musculoskeletal and Skin Diseases. Dr. Sandhu has disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
SAN DIEGO – Pregnant women with anti-SSA/Ro autoantibodies at titer levels of less than 1,000 ELISA units per mL are at minimal to no risk for fetal atrioventricular (AV) block and may be able to forgo traditional echocardiographic heart rhythm monitoring, results from an ongoing, prospective, multicenter trial demonstrated.
However, pregnant patients with higher titer antibodies seem to be at greatest risk for fetal AV block and may benefit from ambulatory fetal heart rhythm monitoring (FHRM), which can detect emergent AV block, according to the study findings. The findings were published online in Arthritis & Rheumatology and will be presented Nov. 13 at the American College of Rheumatology (ACR) 2023 Annual Meeting by Jill P. Buyon, MD, a rheumatologist who directs the division of rheumatology and the Lupus Center at NYU Langone Health in New York.
“While anti-Ro antibodies have been known to be associated with AV block for decades, it has become increasingly clear that antibody titers matter,” Dr. Buyon said in an interview.
For the investigation, which is the largest of its kind, researchers at 22 sites drew from the large multiracial national study of pregnant women, Surveillance To Prevent AV Block Likely to Occur Quickly (STOP BLOQ), to address the impact of anti-Ro titers and use of frequent ambulatory FHRM on outcomes in women with no previously affected children and those at risk for recurrence. Monitoring occurred during the second trimester of pregnancy (from 17 weeks through 26 weeks) and consisted of daily fetal home testing by mothers using handheld, commercially available Doppler devices.
These were followed up by weekly or biweekly echocardiograms, and ultrasound tests to evaluate fetal heart rhythm and function, as well as to show any structural problems. Three times per day, the pregnant women texted the Doppler sound recordings in real time to a pediatric cardiologist, who immediately ordered an additional echocardiogram in cases of irregular or slowing fetal heart rates. If second-degree heart block was detected, drug therapy was initiated.
No AV block seen with low anti-Ro titers
Dr. Buyon, who led the study with Bettina Cuneo, MD, clinical scholar and professor of surgery and pediatrics at the University of Arizona in Tucson, presented findings from 413 pregnant subjects with a mean age of 33 years who finished monitoring surveillance: 152 women had low titers of both anti-Ro60 and –Ro52 (defined as < 1,000 ELISA units per mL), and 261 women with titers above the threshold for either antibody (defined as ≥ 1,000 ELISA units per mL). Of the 152 women with low titers of both anti-Ro60 and –Ro52, none of the pregnancies past 26 weeks resulted in AV block. Of the 261 women with titers above the threshold for either antibody, 10 of the pregnancies resulted in AV block (3.8%). The incidence of AV block increased with higher antibody titer levels, reaching 7.7% for those in the top quartile for anti–60-kD SSA/Ro; this increased to 27.3% in study participants with a previous child who had AV block, although numbers in this category were small.
Analysis of cumulative FHRM recordings between surveillance echocardiograms revealed that no case of second-degree or third-degree AV block was missed. In addition, 70% of AV blocks detected by FHRM were second-degree and all occurred less than 12 hours from normal FHRM and within another 45 minutes to 4.5 hours to echocardiogram. The one case of second/third-degree and two cases of third-degree AV block were diagnosed by urgent echocardiogram more than 17 to 72 hours from a previously normal FHRM episode.
Other factors besides high anti-Ro titer likely play a role
“STOP BLOQ nicely demonstrates that low titer is associated with a very low risk AV block, and intense monitoring may not be needed,” Dr. Buyon told this news organization. “However, high titer is not the whole answer since even women with the very highest titers can have healthy babies. This report also shows that titers stay constant through pregnancies in the same mother, whether there is the complication of AV block or not. This suggests other factors contribute to AV block.”
She added that FHRM can be easily performed by the mother, but at this time is still best interpreted by a cardiologist. “FHRM detected all cases of AV block, which can happen in hours,” she said. “FHRM should decrease the need for frequent echocardiograms. Some mothers do have more difficulty in deciding whether the baby’s heart is beating irregularly. We need [to improve our teaching] and for how best to have a cardiologist or trained listener interpret. FHRM can be done by the mother but needs interpretation by a cardiologist until we develop a device which can identify abnormalities.”
She acknowledged certain limitations of the study, including the fact that a commercial test for anti-SSA/Ro antibody levels is not available to all clinicians. “Try to find a lab that measures high titer anti-Ro antibodies, but if not, then use one of the common commercial tests such as the BioPlex 2000 autoimmune panels and consider decreased surveillance if titer is < 8,” Dr. Buyon advised.
Vaneet K. Sandhu, MD, a rheumatologist with Loma Linda (Calif.) Medical Center, who was asked to comment on the work, said that the study not only justifies the limited use of FHRM in those with high titer antibodies (followed by urgent fetal echocardiography where indicated), but also risk stratification for fetal AV block.
“For years, we have recommended frequent fetal echocardiography testing in pregnant women with positive anti-SSA/Ro,” Dr. Sandhu said. “This study tells us we need to look deeper. On one hand, recognizing that low titer anti-Ro antibodies do not confer a risk of AV block is cost effective. On the other hand, while the titer of the antibody appears to contribute to fetal AV block, we need to delve deeper into additional factors contributing to fetal AV block risk in order to better navigate our surveillance methods.”
The study was supported by NIH grants from the National Institute of Child Health and Human Development and the National Institute of Arthritis and Musculoskeletal and Skin Diseases. Dr. Sandhu has disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
AT ACR 2023
Short steroid taper tested with tocilizumab for giant cell arteritis
TOPLINE:
A combination of tocilizumab (Actemra) and 8 weeks of tapering prednisone was effective for inducing and maintaining disease remission in adults with giant cell arteritis (GCA).
METHODOLOGY:
- In a single-center, single-arm, open-label pilot study, 30 adults (mean age, 73.7 years) with GCA received 162 mg of tocilizumab as a subcutaneous injection once a week for 52 weeks, plus prednisone starting between 20 mg and 60 mg with a prespecified 8-week taper off the glucocorticoid.
- Patients had to be at least 50 years of age and could have either new-onset (diagnosis within 6 weeks of baseline) or relapsing disease (diagnosis > 6 weeks from baseline).
- The primary endpoint was sustained, prednisone-free remission at 52 weeks, defined by an erythrocyte sedimentation rate of less than 40 mm/h, C-reactive protein level less than 10 mg/L, and adherence to the prednisone taper; secondary endpoints included the proportions of patients in remission and relapse, cumulative prednisone dose, and glucocorticoid toxicity.
TAKEAWAY:
- At 52 weeks, 23 patients (77%) met the criteria for sustained remission after weaning off prednisone within 8 weeks of starting tocilizumab; 7 relapsed after a mean of 15.8 weeks.
- Of the patients who relapsed, six underwent a second prednisone taper for 8 weeks with a mean initial daily dose of 32.1 mg, four regained and maintained remission, and two experienced a second relapse and withdrew from the study.
- The mean cumulative prednisone dose at week 52 was 1,051.5 mg for responders and 1,673.1 mg for nonresponders.
- All 30 patients had at least one adverse event; four patients had a serious adverse event likely related to tocilizumab, prednisone, or both.
IN PRACTICE:
Studies such as this “are highly valuable as proof of concept, but of course cannot be definitive guides to treatment decisions without a comparator group,” according to authors of an editorial accompanying the study.
SOURCE:
The study, by Sebastian Unizony, MD, Harvard Medical School, Boston, and colleagues, was published in The Lancet Rheumatology .
LIMITATIONS:
The small size and open-label design with no control group were limiting factors; more research is needed to confirm the findings before this treatment strategy can be recommended for clinical practice.
DISCLOSURES:
The study was funded by Genentech. Two authors reported financial relationships with pharmaceutical companies outside of this report.
A version of this article first appeared on Medscape.com.
TOPLINE:
A combination of tocilizumab (Actemra) and 8 weeks of tapering prednisone was effective for inducing and maintaining disease remission in adults with giant cell arteritis (GCA).
METHODOLOGY:
- In a single-center, single-arm, open-label pilot study, 30 adults (mean age, 73.7 years) with GCA received 162 mg of tocilizumab as a subcutaneous injection once a week for 52 weeks, plus prednisone starting between 20 mg and 60 mg with a prespecified 8-week taper off the glucocorticoid.
- Patients had to be at least 50 years of age and could have either new-onset (diagnosis within 6 weeks of baseline) or relapsing disease (diagnosis > 6 weeks from baseline).
- The primary endpoint was sustained, prednisone-free remission at 52 weeks, defined by an erythrocyte sedimentation rate of less than 40 mm/h, C-reactive protein level less than 10 mg/L, and adherence to the prednisone taper; secondary endpoints included the proportions of patients in remission and relapse, cumulative prednisone dose, and glucocorticoid toxicity.
TAKEAWAY:
- At 52 weeks, 23 patients (77%) met the criteria for sustained remission after weaning off prednisone within 8 weeks of starting tocilizumab; 7 relapsed after a mean of 15.8 weeks.
- Of the patients who relapsed, six underwent a second prednisone taper for 8 weeks with a mean initial daily dose of 32.1 mg, four regained and maintained remission, and two experienced a second relapse and withdrew from the study.
- The mean cumulative prednisone dose at week 52 was 1,051.5 mg for responders and 1,673.1 mg for nonresponders.
- All 30 patients had at least one adverse event; four patients had a serious adverse event likely related to tocilizumab, prednisone, or both.
IN PRACTICE:
Studies such as this “are highly valuable as proof of concept, but of course cannot be definitive guides to treatment decisions without a comparator group,” according to authors of an editorial accompanying the study.
SOURCE:
The study, by Sebastian Unizony, MD, Harvard Medical School, Boston, and colleagues, was published in The Lancet Rheumatology .
LIMITATIONS:
The small size and open-label design with no control group were limiting factors; more research is needed to confirm the findings before this treatment strategy can be recommended for clinical practice.
DISCLOSURES:
The study was funded by Genentech. Two authors reported financial relationships with pharmaceutical companies outside of this report.
A version of this article first appeared on Medscape.com.
TOPLINE:
A combination of tocilizumab (Actemra) and 8 weeks of tapering prednisone was effective for inducing and maintaining disease remission in adults with giant cell arteritis (GCA).
METHODOLOGY:
- In a single-center, single-arm, open-label pilot study, 30 adults (mean age, 73.7 years) with GCA received 162 mg of tocilizumab as a subcutaneous injection once a week for 52 weeks, plus prednisone starting between 20 mg and 60 mg with a prespecified 8-week taper off the glucocorticoid.
- Patients had to be at least 50 years of age and could have either new-onset (diagnosis within 6 weeks of baseline) or relapsing disease (diagnosis > 6 weeks from baseline).
- The primary endpoint was sustained, prednisone-free remission at 52 weeks, defined by an erythrocyte sedimentation rate of less than 40 mm/h, C-reactive protein level less than 10 mg/L, and adherence to the prednisone taper; secondary endpoints included the proportions of patients in remission and relapse, cumulative prednisone dose, and glucocorticoid toxicity.
TAKEAWAY:
- At 52 weeks, 23 patients (77%) met the criteria for sustained remission after weaning off prednisone within 8 weeks of starting tocilizumab; 7 relapsed after a mean of 15.8 weeks.
- Of the patients who relapsed, six underwent a second prednisone taper for 8 weeks with a mean initial daily dose of 32.1 mg, four regained and maintained remission, and two experienced a second relapse and withdrew from the study.
- The mean cumulative prednisone dose at week 52 was 1,051.5 mg for responders and 1,673.1 mg for nonresponders.
- All 30 patients had at least one adverse event; four patients had a serious adverse event likely related to tocilizumab, prednisone, or both.
IN PRACTICE:
Studies such as this “are highly valuable as proof of concept, but of course cannot be definitive guides to treatment decisions without a comparator group,” according to authors of an editorial accompanying the study.
SOURCE:
The study, by Sebastian Unizony, MD, Harvard Medical School, Boston, and colleagues, was published in The Lancet Rheumatology .
LIMITATIONS:
The small size and open-label design with no control group were limiting factors; more research is needed to confirm the findings before this treatment strategy can be recommended for clinical practice.
DISCLOSURES:
The study was funded by Genentech. Two authors reported financial relationships with pharmaceutical companies outside of this report.
A version of this article first appeared on Medscape.com.
The challenges of palmoplantar pustulosis and other acral psoriatic disease
WASHINGTON – The approval last year of the interleukin (IL)-36 receptor antagonist spesolimab for treating generalized pustular psoriasis flares brightened the treatment landscape for this rare condition, and a recently published phase 2 study suggests a potential role of spesolimab for flare prevention. , according to speakers at the annual research symposium of the National Psoriasis Foundation.
“The IL-36 receptor antagonists don’t seem to be quite the answer for [palmoplantar pustulosis] that they are for generalized pustular psoriasis [GPP],” Megan H. Noe, MD, MPH, assistant professor of dermatology at Harvard Medical School and a dermatologist at Brigham and Women’s Hospital, Boston, said at the meeting.
Psoriasis affecting the hands and feet – both pustular and nonpustular – has a higher impact on quality of life and higher functional disability than does non-acral psoriasis, is less responsive to treatment, and has a “very confusing nomenclature” that complicates research and thus management, said Jason Ezra Hawkes, MD, a dermatologist in Rocklin, Calif., and former faculty member of several departments of dermatology. Both he and Dr. Noe spoke during a tough-to-treat session at the NPF meeting.
IL-17 and IL-23 blockade, as well as tumor necrosis factor (TNF) inhibition, are effective overall for palmoplantar psoriasis (nonpustular), but in general, responses are lower than for plaque psoriasis. Apremilast (Otezla), a phosphodiesterase-4 inhibitor, has some efficacy for pustular variants, but for hyperkeratotic variants it “does not perform as well as more selective inhibition of IL-17 and IL-23 blockade,” he said.
In general, ”what’s happening in the acral sites is different from an immune perspective than what’s happening in the non-acral sites,” and more research utilizing a clearer, descriptive nomenclature is needed to tease out differing immunophenotypes, explained Dr. Hawkes, who has led multiple clinical trials of treatments for psoriasis and other inflammatory skin conditions.
Palmoplantar pustulosis, and a word on generalized disease
Dermatologists are using a variety of treatments for palmoplantar pustulosis, with no clear first-line choices, Dr. Noe said. In a case series of almost 200 patients with palmoplantar pustulosis across 20 dermatology practices, published in JAMA Dermatology, 35% of patients received a systemic therapy prescription at their initial encounter – most commonly acitretin, followed by methotrexate and phototherapy. “Biologics were used, but use was varied and not as often as with oral agents,” said Dr. Noe, a coauthor of the study.
TNF blockers led to improvements ranging from 57% to 84%, depending on the agent, in a 2020 retrospective study of patients with palmoplantar pustulosis or acrodermatitis continua of Hallopeau, Dr. Noe noted. However, rates of complete clearance were only 20%-29%.
Apremilast showed modest efficacy after 5 months of treatment, with 62% of patients achieving at least a 50% improvement in the Palmoplantar Pustulosis Psoriasis Area and Severity Index (PPPASI) in a 2021 open-label, phase 2 study involving 21 patients. “This may represent a potential treatment option,” Dr. Noe said. “It’s something, but not what we’re used to seeing in our plaque psoriasis patients.”
A 2021 phase 2a, double-blind, randomized, placebo-controlled study of spesolimab in patients with palmoplantar pustulosis, meanwhile, failed to meet its primary endpoint, with only 32% of patients achieving a 50% improvement at 16 weeks, compared with 24% of patients in the placebo arm. And a recently published network meta-analysis found that none of the five drugs studied in seven randomized controlled trials – biologic or oral – was more effective than placebo for clearance or improvement of palmoplantar pustulosis.
The spesolimab (Spevigo) results have been disappointing considering the biologic’s newfound efficacy and role as the first Food and Drug Administration–approved therapy for generalized pustular disease, according to Dr. Noe. The ability of a single 900-mg intravenous dose of the IL-36 receptor antagonist to completely clear pustules at 1 week in 54% of patients with generalized disease, compared with 6% of the placebo group, was “groundbreaking,” she said, referring to results of the pivotal trial published in the New England Journal of Medicine.
And given that “preventing GPP flares is ultimately what we want,” she said, more good news was reported this year in The Lancet: The finding from an international, randomized, placebo-controlled study that high-dose subcutaneous spesolimab significantly reduced the risk of a flare over 48 weeks. “There are lots of ongoing studies right now to understand the best way to dose spesolimab,” she said.
Moreover, another IL-36 receptor antagonist, imsidolimab, is being investigated in a phase 3 trial for generalized pustular disease, she noted. A phase 2, open-label study of patients with GPP found that “more than half of patients were very much improved at 4 weeks, and some patients started showing improvement at day 3,” Dr. Noe said.
An area of research she is interested in is the potential for Janus kinase (JAK) inhibitors as a treatment for palmoplantar pustulosis. For pustulosis on the hands and feet, recent case reports describing the efficacy of JAK inhibitors have caught her eye. “Right now, all we have is this case report data, mostly with tofacitinib, but I think it’s exciting,” she said, noting a recently published report in the British Journal of Dermatology.
Palmoplantar psoriasis
Pustular psoriatic disease can be localized to the hand and/or feet only, or can co-occur with generalized pustular disease, just as palmoplantar psoriasis can be localized to the hands and/or feet or, more commonly, can co-occur with widespread plaque psoriasis. Research has shown, Dr. Hawkes said, that with both types of acral disease, many patients have or have had plaque psoriasis outside of acral sites.
The nomenclature and acronyms for palmoplantar psoriatic disease have complicated patient education, communication, and research, Dr. Hawkes said. Does PPP refer to palmoplantar psoriasis, or palmoplantar pustulosis, for instance? What is the difference between palmoplantar pustulosis (coined PPP) and palmoplantar pustular psoriasis (referred to as PPPP)?
What if disease is only on the hands, only on the feet, or only on the backs of the hands? And at what point is disease not classified as palmoplantar psoriasis, but plaque psoriasis with involvement of the hands and feet? Inconsistencies and lack of clarification lead to “confusing” literature, he said.
Heterogeneity in populations across trials resulting from “inconsistent categorization and phenotype inclusion” may partly account for the recalcitrance to treatment reported in the literature, he said. Misdiagnosis as psoriasis in cases of localized disease (confusion with eczema, for instance), and the fact that hands and feet are subject to increased trauma and injury, compared with non-acral sites, are also at play.
Trials may also allow insufficient time for improvement, compared with non-acral sites. “What we’ve learned about the hands and feet is that it takes a much longer time for disease to improve,” Dr. Hawkes said, so primary endpoints must take this into account.
There is unique immunologic signaling in palmoplantar disease that differs from the predominant signaling in traditional plaque psoriasis, he emphasized, and “mixed immunophenotypes” that need to be unraveled.
Dr. Hawkes disclosed ties with AbbVie, Arcutis, Bristol-Myers Squibb, Boehringer Ingelheim, Janssen, LEO, Lilly, Novartis, Pfizer, Regeneron, Sanofi, Sun Pharma, and UCB. Dr. Noe disclosed ties to Bristol-Myers Squibb and Boehringer Ingelheim.
WASHINGTON – The approval last year of the interleukin (IL)-36 receptor antagonist spesolimab for treating generalized pustular psoriasis flares brightened the treatment landscape for this rare condition, and a recently published phase 2 study suggests a potential role of spesolimab for flare prevention. , according to speakers at the annual research symposium of the National Psoriasis Foundation.
“The IL-36 receptor antagonists don’t seem to be quite the answer for [palmoplantar pustulosis] that they are for generalized pustular psoriasis [GPP],” Megan H. Noe, MD, MPH, assistant professor of dermatology at Harvard Medical School and a dermatologist at Brigham and Women’s Hospital, Boston, said at the meeting.
Psoriasis affecting the hands and feet – both pustular and nonpustular – has a higher impact on quality of life and higher functional disability than does non-acral psoriasis, is less responsive to treatment, and has a “very confusing nomenclature” that complicates research and thus management, said Jason Ezra Hawkes, MD, a dermatologist in Rocklin, Calif., and former faculty member of several departments of dermatology. Both he and Dr. Noe spoke during a tough-to-treat session at the NPF meeting.
IL-17 and IL-23 blockade, as well as tumor necrosis factor (TNF) inhibition, are effective overall for palmoplantar psoriasis (nonpustular), but in general, responses are lower than for plaque psoriasis. Apremilast (Otezla), a phosphodiesterase-4 inhibitor, has some efficacy for pustular variants, but for hyperkeratotic variants it “does not perform as well as more selective inhibition of IL-17 and IL-23 blockade,” he said.
In general, ”what’s happening in the acral sites is different from an immune perspective than what’s happening in the non-acral sites,” and more research utilizing a clearer, descriptive nomenclature is needed to tease out differing immunophenotypes, explained Dr. Hawkes, who has led multiple clinical trials of treatments for psoriasis and other inflammatory skin conditions.
Palmoplantar pustulosis, and a word on generalized disease
Dermatologists are using a variety of treatments for palmoplantar pustulosis, with no clear first-line choices, Dr. Noe said. In a case series of almost 200 patients with palmoplantar pustulosis across 20 dermatology practices, published in JAMA Dermatology, 35% of patients received a systemic therapy prescription at their initial encounter – most commonly acitretin, followed by methotrexate and phototherapy. “Biologics were used, but use was varied and not as often as with oral agents,” said Dr. Noe, a coauthor of the study.
TNF blockers led to improvements ranging from 57% to 84%, depending on the agent, in a 2020 retrospective study of patients with palmoplantar pustulosis or acrodermatitis continua of Hallopeau, Dr. Noe noted. However, rates of complete clearance were only 20%-29%.
Apremilast showed modest efficacy after 5 months of treatment, with 62% of patients achieving at least a 50% improvement in the Palmoplantar Pustulosis Psoriasis Area and Severity Index (PPPASI) in a 2021 open-label, phase 2 study involving 21 patients. “This may represent a potential treatment option,” Dr. Noe said. “It’s something, but not what we’re used to seeing in our plaque psoriasis patients.”
A 2021 phase 2a, double-blind, randomized, placebo-controlled study of spesolimab in patients with palmoplantar pustulosis, meanwhile, failed to meet its primary endpoint, with only 32% of patients achieving a 50% improvement at 16 weeks, compared with 24% of patients in the placebo arm. And a recently published network meta-analysis found that none of the five drugs studied in seven randomized controlled trials – biologic or oral – was more effective than placebo for clearance or improvement of palmoplantar pustulosis.
The spesolimab (Spevigo) results have been disappointing considering the biologic’s newfound efficacy and role as the first Food and Drug Administration–approved therapy for generalized pustular disease, according to Dr. Noe. The ability of a single 900-mg intravenous dose of the IL-36 receptor antagonist to completely clear pustules at 1 week in 54% of patients with generalized disease, compared with 6% of the placebo group, was “groundbreaking,” she said, referring to results of the pivotal trial published in the New England Journal of Medicine.
And given that “preventing GPP flares is ultimately what we want,” she said, more good news was reported this year in The Lancet: The finding from an international, randomized, placebo-controlled study that high-dose subcutaneous spesolimab significantly reduced the risk of a flare over 48 weeks. “There are lots of ongoing studies right now to understand the best way to dose spesolimab,” she said.
Moreover, another IL-36 receptor antagonist, imsidolimab, is being investigated in a phase 3 trial for generalized pustular disease, she noted. A phase 2, open-label study of patients with GPP found that “more than half of patients were very much improved at 4 weeks, and some patients started showing improvement at day 3,” Dr. Noe said.
An area of research she is interested in is the potential for Janus kinase (JAK) inhibitors as a treatment for palmoplantar pustulosis. For pustulosis on the hands and feet, recent case reports describing the efficacy of JAK inhibitors have caught her eye. “Right now, all we have is this case report data, mostly with tofacitinib, but I think it’s exciting,” she said, noting a recently published report in the British Journal of Dermatology.
Palmoplantar psoriasis
Pustular psoriatic disease can be localized to the hand and/or feet only, or can co-occur with generalized pustular disease, just as palmoplantar psoriasis can be localized to the hands and/or feet or, more commonly, can co-occur with widespread plaque psoriasis. Research has shown, Dr. Hawkes said, that with both types of acral disease, many patients have or have had plaque psoriasis outside of acral sites.
The nomenclature and acronyms for palmoplantar psoriatic disease have complicated patient education, communication, and research, Dr. Hawkes said. Does PPP refer to palmoplantar psoriasis, or palmoplantar pustulosis, for instance? What is the difference between palmoplantar pustulosis (coined PPP) and palmoplantar pustular psoriasis (referred to as PPPP)?
What if disease is only on the hands, only on the feet, or only on the backs of the hands? And at what point is disease not classified as palmoplantar psoriasis, but plaque psoriasis with involvement of the hands and feet? Inconsistencies and lack of clarification lead to “confusing” literature, he said.
Heterogeneity in populations across trials resulting from “inconsistent categorization and phenotype inclusion” may partly account for the recalcitrance to treatment reported in the literature, he said. Misdiagnosis as psoriasis in cases of localized disease (confusion with eczema, for instance), and the fact that hands and feet are subject to increased trauma and injury, compared with non-acral sites, are also at play.
Trials may also allow insufficient time for improvement, compared with non-acral sites. “What we’ve learned about the hands and feet is that it takes a much longer time for disease to improve,” Dr. Hawkes said, so primary endpoints must take this into account.
There is unique immunologic signaling in palmoplantar disease that differs from the predominant signaling in traditional plaque psoriasis, he emphasized, and “mixed immunophenotypes” that need to be unraveled.
Dr. Hawkes disclosed ties with AbbVie, Arcutis, Bristol-Myers Squibb, Boehringer Ingelheim, Janssen, LEO, Lilly, Novartis, Pfizer, Regeneron, Sanofi, Sun Pharma, and UCB. Dr. Noe disclosed ties to Bristol-Myers Squibb and Boehringer Ingelheim.
WASHINGTON – The approval last year of the interleukin (IL)-36 receptor antagonist spesolimab for treating generalized pustular psoriasis flares brightened the treatment landscape for this rare condition, and a recently published phase 2 study suggests a potential role of spesolimab for flare prevention. , according to speakers at the annual research symposium of the National Psoriasis Foundation.
“The IL-36 receptor antagonists don’t seem to be quite the answer for [palmoplantar pustulosis] that they are for generalized pustular psoriasis [GPP],” Megan H. Noe, MD, MPH, assistant professor of dermatology at Harvard Medical School and a dermatologist at Brigham and Women’s Hospital, Boston, said at the meeting.
Psoriasis affecting the hands and feet – both pustular and nonpustular – has a higher impact on quality of life and higher functional disability than does non-acral psoriasis, is less responsive to treatment, and has a “very confusing nomenclature” that complicates research and thus management, said Jason Ezra Hawkes, MD, a dermatologist in Rocklin, Calif., and former faculty member of several departments of dermatology. Both he and Dr. Noe spoke during a tough-to-treat session at the NPF meeting.
IL-17 and IL-23 blockade, as well as tumor necrosis factor (TNF) inhibition, are effective overall for palmoplantar psoriasis (nonpustular), but in general, responses are lower than for plaque psoriasis. Apremilast (Otezla), a phosphodiesterase-4 inhibitor, has some efficacy for pustular variants, but for hyperkeratotic variants it “does not perform as well as more selective inhibition of IL-17 and IL-23 blockade,” he said.
In general, ”what’s happening in the acral sites is different from an immune perspective than what’s happening in the non-acral sites,” and more research utilizing a clearer, descriptive nomenclature is needed to tease out differing immunophenotypes, explained Dr. Hawkes, who has led multiple clinical trials of treatments for psoriasis and other inflammatory skin conditions.
Palmoplantar pustulosis, and a word on generalized disease
Dermatologists are using a variety of treatments for palmoplantar pustulosis, with no clear first-line choices, Dr. Noe said. In a case series of almost 200 patients with palmoplantar pustulosis across 20 dermatology practices, published in JAMA Dermatology, 35% of patients received a systemic therapy prescription at their initial encounter – most commonly acitretin, followed by methotrexate and phototherapy. “Biologics were used, but use was varied and not as often as with oral agents,” said Dr. Noe, a coauthor of the study.
TNF blockers led to improvements ranging from 57% to 84%, depending on the agent, in a 2020 retrospective study of patients with palmoplantar pustulosis or acrodermatitis continua of Hallopeau, Dr. Noe noted. However, rates of complete clearance were only 20%-29%.
Apremilast showed modest efficacy after 5 months of treatment, with 62% of patients achieving at least a 50% improvement in the Palmoplantar Pustulosis Psoriasis Area and Severity Index (PPPASI) in a 2021 open-label, phase 2 study involving 21 patients. “This may represent a potential treatment option,” Dr. Noe said. “It’s something, but not what we’re used to seeing in our plaque psoriasis patients.”
A 2021 phase 2a, double-blind, randomized, placebo-controlled study of spesolimab in patients with palmoplantar pustulosis, meanwhile, failed to meet its primary endpoint, with only 32% of patients achieving a 50% improvement at 16 weeks, compared with 24% of patients in the placebo arm. And a recently published network meta-analysis found that none of the five drugs studied in seven randomized controlled trials – biologic or oral – was more effective than placebo for clearance or improvement of palmoplantar pustulosis.
The spesolimab (Spevigo) results have been disappointing considering the biologic’s newfound efficacy and role as the first Food and Drug Administration–approved therapy for generalized pustular disease, according to Dr. Noe. The ability of a single 900-mg intravenous dose of the IL-36 receptor antagonist to completely clear pustules at 1 week in 54% of patients with generalized disease, compared with 6% of the placebo group, was “groundbreaking,” she said, referring to results of the pivotal trial published in the New England Journal of Medicine.
And given that “preventing GPP flares is ultimately what we want,” she said, more good news was reported this year in The Lancet: The finding from an international, randomized, placebo-controlled study that high-dose subcutaneous spesolimab significantly reduced the risk of a flare over 48 weeks. “There are lots of ongoing studies right now to understand the best way to dose spesolimab,” she said.
Moreover, another IL-36 receptor antagonist, imsidolimab, is being investigated in a phase 3 trial for generalized pustular disease, she noted. A phase 2, open-label study of patients with GPP found that “more than half of patients were very much improved at 4 weeks, and some patients started showing improvement at day 3,” Dr. Noe said.
An area of research she is interested in is the potential for Janus kinase (JAK) inhibitors as a treatment for palmoplantar pustulosis. For pustulosis on the hands and feet, recent case reports describing the efficacy of JAK inhibitors have caught her eye. “Right now, all we have is this case report data, mostly with tofacitinib, but I think it’s exciting,” she said, noting a recently published report in the British Journal of Dermatology.
Palmoplantar psoriasis
Pustular psoriatic disease can be localized to the hand and/or feet only, or can co-occur with generalized pustular disease, just as palmoplantar psoriasis can be localized to the hands and/or feet or, more commonly, can co-occur with widespread plaque psoriasis. Research has shown, Dr. Hawkes said, that with both types of acral disease, many patients have or have had plaque psoriasis outside of acral sites.
The nomenclature and acronyms for palmoplantar psoriatic disease have complicated patient education, communication, and research, Dr. Hawkes said. Does PPP refer to palmoplantar psoriasis, or palmoplantar pustulosis, for instance? What is the difference between palmoplantar pustulosis (coined PPP) and palmoplantar pustular psoriasis (referred to as PPPP)?
What if disease is only on the hands, only on the feet, or only on the backs of the hands? And at what point is disease not classified as palmoplantar psoriasis, but plaque psoriasis with involvement of the hands and feet? Inconsistencies and lack of clarification lead to “confusing” literature, he said.
Heterogeneity in populations across trials resulting from “inconsistent categorization and phenotype inclusion” may partly account for the recalcitrance to treatment reported in the literature, he said. Misdiagnosis as psoriasis in cases of localized disease (confusion with eczema, for instance), and the fact that hands and feet are subject to increased trauma and injury, compared with non-acral sites, are also at play.
Trials may also allow insufficient time for improvement, compared with non-acral sites. “What we’ve learned about the hands and feet is that it takes a much longer time for disease to improve,” Dr. Hawkes said, so primary endpoints must take this into account.
There is unique immunologic signaling in palmoplantar disease that differs from the predominant signaling in traditional plaque psoriasis, he emphasized, and “mixed immunophenotypes” that need to be unraveled.
Dr. Hawkes disclosed ties with AbbVie, Arcutis, Bristol-Myers Squibb, Boehringer Ingelheim, Janssen, LEO, Lilly, Novartis, Pfizer, Regeneron, Sanofi, Sun Pharma, and UCB. Dr. Noe disclosed ties to Bristol-Myers Squibb and Boehringer Ingelheim.
AT THE NPF RESEARCH SYMPOSIUM 2023
U.S. study finds unexpectedly high prevalence of myasthenia gravis
PHOENIX – The prevalence is higher than what has been seen in other studies, which could represent a true difference in prevalence, or reflect limitations of the database.
Worldwide estimates suggest that myasthenia gravis affects 700,000 people globally, with incidence rates ranging between 6.3 and 29 per 1,000,000 person-years in Europe and a prevalence between 111.7 and 361 per 1,000,000. Data from Australia, Taiwan, and South Korea also show evidence of increased prevalence in recent years.
However, there is little data about the prevalence of myasthenia gravis in the United States, or about differences between racial groups, according to Bhaskar Roy, MBBS, who presented the study at the 2023 annual meeting of the American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM). He noted that most studies are outdated, and the most recent study focused on ocular myasthenia gravis.
True incidence or artifact?
The finding is surprising and may be an artifact of the immature nature of the All of Us database, according to Srikanth Muppidi, MD, who asked about the limitation during the Q&A session following the talk. “The incidence of 0.13 is definitely higher than what we would think would be the true incidence of myasthenia gravis from [clinical experience]. It’s possible that our understanding of true incidence is wrong and this is the actual incidence. What I would like them to do, and I think they’re trying to do, is to look at this finding [and compare it with] other more mature databases and other regional databases. One of the current challenges of All of Us is that our patients are basically being recruited from some parts of the country, and the middle of the country has hardly any presence in the database, so it becomes really challenging to understand it,” Dr. Muppidi said in an interview.
However, Dr. Muppidi, who is a clinical professor of neurology at Stanford (Calif.) Medicine, noted that the All of Us database is still growing. When it has recruited more patients with a diverse population, “it [will be a] valuable source for rare diseases to try to understand true incidence of those diseases,” he said.
Understanding the true prevalence
Dr. Roy recognized the geographic limitations of the database. “Some states, particularly Massachusetts, New York, and California, had a lot of patients in the database, where there were no patients from many states,” said Dr. Roy, associate professor of neurology at Yale University, New Haven, Conn.
He said that the group is working with other databases, including UK Biobank. “The goal is to incorporate all of these databases together [to determine the true incidence],” said Dr. Roy.
It’s critical to understand the true prevalence of myasthenia gravis since new therapies are in development and coming to market. “I worry that myasthenia gravis might be considered less common than it truly is, and that will limit growth of the field if the feeling is that there are not that many [myasthenia gravis patients] in the country,” said Dr. Muppidi.
The study included data from 369,297 adult patients, using Systematized Nomenclature of Medicine (SNOMED) and International Classification of Diseases (ICD) codes to identify patients with myasthenia gravis. There were 479 cases of myasthenia gravis, for a prevalence of 0.13 (95% confidence interval [CI], 0.12-0.14). Of myasthenia gravis patients, 65% were female and the mean age was 64 years. The prevalence of myasthenia gravis in White individuals was 0.16 (95% CI, 0.15-0.18), of which 63% were female, and the mean age was 66 years. The prevalence among Black individuals was 0.078 (95% CI, 0.060-0.10), with 77% of the population female and a mean age of 58 years. The prevalence in Hispanics was 0.091 (95% CI, 0.070-0.12), with 80% female and a mean age of 58 years. Among Asians, the prevalence was 0.056 (95% CI, 0.025-0.12) and 57% were female, with a mean age of 58 years.
The researchers also looked at the EXPLORE-MG database drawn from Yale (n = 3,269,000), which showed a much lower overall myasthenia gravis prevalence of 0.019 (95% CI, 0.017-0.020), a female proportion of 46.8%, and a mean age of 56.6 years. Notably, EXPLORE-MG had a lower proportion of women and a younger population than All of Us.
The researchers compared data from All of Us with other databases for other conditions. The prevalence of ALS was the same as in other conditions, while diabetic neuropathy was significantly lower (2.7 versus 28.5-50 among diabetic patients) and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) was higher (0.084 versus 0.028).
Dr. Muppidi has been on advisory boards for Alexion, Argenx, UBC, and Immunovant. Dr. Roy has consulted for Alexion, Takeda Pharmaceuticals, and Argenx and owns stock in Cabaletta Bio. He has received research support from Takeda, Abcuro, and Argenx.
PHOENIX – The prevalence is higher than what has been seen in other studies, which could represent a true difference in prevalence, or reflect limitations of the database.
Worldwide estimates suggest that myasthenia gravis affects 700,000 people globally, with incidence rates ranging between 6.3 and 29 per 1,000,000 person-years in Europe and a prevalence between 111.7 and 361 per 1,000,000. Data from Australia, Taiwan, and South Korea also show evidence of increased prevalence in recent years.
However, there is little data about the prevalence of myasthenia gravis in the United States, or about differences between racial groups, according to Bhaskar Roy, MBBS, who presented the study at the 2023 annual meeting of the American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM). He noted that most studies are outdated, and the most recent study focused on ocular myasthenia gravis.
True incidence or artifact?
The finding is surprising and may be an artifact of the immature nature of the All of Us database, according to Srikanth Muppidi, MD, who asked about the limitation during the Q&A session following the talk. “The incidence of 0.13 is definitely higher than what we would think would be the true incidence of myasthenia gravis from [clinical experience]. It’s possible that our understanding of true incidence is wrong and this is the actual incidence. What I would like them to do, and I think they’re trying to do, is to look at this finding [and compare it with] other more mature databases and other regional databases. One of the current challenges of All of Us is that our patients are basically being recruited from some parts of the country, and the middle of the country has hardly any presence in the database, so it becomes really challenging to understand it,” Dr. Muppidi said in an interview.
However, Dr. Muppidi, who is a clinical professor of neurology at Stanford (Calif.) Medicine, noted that the All of Us database is still growing. When it has recruited more patients with a diverse population, “it [will be a] valuable source for rare diseases to try to understand true incidence of those diseases,” he said.
Understanding the true prevalence
Dr. Roy recognized the geographic limitations of the database. “Some states, particularly Massachusetts, New York, and California, had a lot of patients in the database, where there were no patients from many states,” said Dr. Roy, associate professor of neurology at Yale University, New Haven, Conn.
He said that the group is working with other databases, including UK Biobank. “The goal is to incorporate all of these databases together [to determine the true incidence],” said Dr. Roy.
It’s critical to understand the true prevalence of myasthenia gravis since new therapies are in development and coming to market. “I worry that myasthenia gravis might be considered less common than it truly is, and that will limit growth of the field if the feeling is that there are not that many [myasthenia gravis patients] in the country,” said Dr. Muppidi.
The study included data from 369,297 adult patients, using Systematized Nomenclature of Medicine (SNOMED) and International Classification of Diseases (ICD) codes to identify patients with myasthenia gravis. There were 479 cases of myasthenia gravis, for a prevalence of 0.13 (95% confidence interval [CI], 0.12-0.14). Of myasthenia gravis patients, 65% were female and the mean age was 64 years. The prevalence of myasthenia gravis in White individuals was 0.16 (95% CI, 0.15-0.18), of which 63% were female, and the mean age was 66 years. The prevalence among Black individuals was 0.078 (95% CI, 0.060-0.10), with 77% of the population female and a mean age of 58 years. The prevalence in Hispanics was 0.091 (95% CI, 0.070-0.12), with 80% female and a mean age of 58 years. Among Asians, the prevalence was 0.056 (95% CI, 0.025-0.12) and 57% were female, with a mean age of 58 years.
The researchers also looked at the EXPLORE-MG database drawn from Yale (n = 3,269,000), which showed a much lower overall myasthenia gravis prevalence of 0.019 (95% CI, 0.017-0.020), a female proportion of 46.8%, and a mean age of 56.6 years. Notably, EXPLORE-MG had a lower proportion of women and a younger population than All of Us.
The researchers compared data from All of Us with other databases for other conditions. The prevalence of ALS was the same as in other conditions, while diabetic neuropathy was significantly lower (2.7 versus 28.5-50 among diabetic patients) and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) was higher (0.084 versus 0.028).
Dr. Muppidi has been on advisory boards for Alexion, Argenx, UBC, and Immunovant. Dr. Roy has consulted for Alexion, Takeda Pharmaceuticals, and Argenx and owns stock in Cabaletta Bio. He has received research support from Takeda, Abcuro, and Argenx.
PHOENIX – The prevalence is higher than what has been seen in other studies, which could represent a true difference in prevalence, or reflect limitations of the database.
Worldwide estimates suggest that myasthenia gravis affects 700,000 people globally, with incidence rates ranging between 6.3 and 29 per 1,000,000 person-years in Europe and a prevalence between 111.7 and 361 per 1,000,000. Data from Australia, Taiwan, and South Korea also show evidence of increased prevalence in recent years.
However, there is little data about the prevalence of myasthenia gravis in the United States, or about differences between racial groups, according to Bhaskar Roy, MBBS, who presented the study at the 2023 annual meeting of the American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM). He noted that most studies are outdated, and the most recent study focused on ocular myasthenia gravis.
True incidence or artifact?
The finding is surprising and may be an artifact of the immature nature of the All of Us database, according to Srikanth Muppidi, MD, who asked about the limitation during the Q&A session following the talk. “The incidence of 0.13 is definitely higher than what we would think would be the true incidence of myasthenia gravis from [clinical experience]. It’s possible that our understanding of true incidence is wrong and this is the actual incidence. What I would like them to do, and I think they’re trying to do, is to look at this finding [and compare it with] other more mature databases and other regional databases. One of the current challenges of All of Us is that our patients are basically being recruited from some parts of the country, and the middle of the country has hardly any presence in the database, so it becomes really challenging to understand it,” Dr. Muppidi said in an interview.
However, Dr. Muppidi, who is a clinical professor of neurology at Stanford (Calif.) Medicine, noted that the All of Us database is still growing. When it has recruited more patients with a diverse population, “it [will be a] valuable source for rare diseases to try to understand true incidence of those diseases,” he said.
Understanding the true prevalence
Dr. Roy recognized the geographic limitations of the database. “Some states, particularly Massachusetts, New York, and California, had a lot of patients in the database, where there were no patients from many states,” said Dr. Roy, associate professor of neurology at Yale University, New Haven, Conn.
He said that the group is working with other databases, including UK Biobank. “The goal is to incorporate all of these databases together [to determine the true incidence],” said Dr. Roy.
It’s critical to understand the true prevalence of myasthenia gravis since new therapies are in development and coming to market. “I worry that myasthenia gravis might be considered less common than it truly is, and that will limit growth of the field if the feeling is that there are not that many [myasthenia gravis patients] in the country,” said Dr. Muppidi.
The study included data from 369,297 adult patients, using Systematized Nomenclature of Medicine (SNOMED) and International Classification of Diseases (ICD) codes to identify patients with myasthenia gravis. There were 479 cases of myasthenia gravis, for a prevalence of 0.13 (95% confidence interval [CI], 0.12-0.14). Of myasthenia gravis patients, 65% were female and the mean age was 64 years. The prevalence of myasthenia gravis in White individuals was 0.16 (95% CI, 0.15-0.18), of which 63% were female, and the mean age was 66 years. The prevalence among Black individuals was 0.078 (95% CI, 0.060-0.10), with 77% of the population female and a mean age of 58 years. The prevalence in Hispanics was 0.091 (95% CI, 0.070-0.12), with 80% female and a mean age of 58 years. Among Asians, the prevalence was 0.056 (95% CI, 0.025-0.12) and 57% were female, with a mean age of 58 years.
The researchers also looked at the EXPLORE-MG database drawn from Yale (n = 3,269,000), which showed a much lower overall myasthenia gravis prevalence of 0.019 (95% CI, 0.017-0.020), a female proportion of 46.8%, and a mean age of 56.6 years. Notably, EXPLORE-MG had a lower proportion of women and a younger population than All of Us.
The researchers compared data from All of Us with other databases for other conditions. The prevalence of ALS was the same as in other conditions, while diabetic neuropathy was significantly lower (2.7 versus 28.5-50 among diabetic patients) and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) was higher (0.084 versus 0.028).
Dr. Muppidi has been on advisory boards for Alexion, Argenx, UBC, and Immunovant. Dr. Roy has consulted for Alexion, Takeda Pharmaceuticals, and Argenx and owns stock in Cabaletta Bio. He has received research support from Takeda, Abcuro, and Argenx.
AT AANEM 2023
RNA therapeutics will ‘change everything’ in epilepsy
Epilepsy affects over 50 million people worldwide, making it one of the most common neurologic disorders. Though current antiseizure medications can control seizures in two-thirds of patients, drug-resistant epilepsy remains a major challenge for the remaining one-third, as does the lack of disease-modifying therapies.
But RNA-based therapeutics offer new hope, and experts predict they could fill these gaps and revolutionize epilepsy treatment.
“Current medicines for epilepsy are barely scraping the surface of what could be targeted. RNA therapeutics is going to change everything. It opens up entirely new targets – virtually anything in our genome becomes ‘druggable,’ ” said David Henshall, PhD, Royal College of Surgeons Ireland, Dublin.
Edward Kaye, MD, a pediatric neurologist and CEO of Stoke Therapeutics, agrees. “RNA therapeutics open up possibilities that could not have been imagined when I started my career,” he said in an interview.
Dr. Kaye said.
Thank COVID?
Henrik Klitgaard, PhD, and Sakari Kauppinen, PhD, scientific co-founders of NEUmiRNA Therapeutics, noted that the success of messenger RNA (mRNA) vaccines to counter the COVID-19 pandemic has fueled interest in exploring the potential of RNA-based therapies as a new modality in epilepsy with improved therapeutic properties.
Dr. Klitgaard and Dr. Kauppinen recently co-authored a “critical review” on RNA therapies for epilepsy published online in Epilepsia.
Unlike current antiseizure medications, which only target ion channels and receptors, RNA therapeutics can directly intervene at the genetic level.
RNA drugs can be targeted toward noncoding RNAs, such as microRNAs, or toward mRNA. Targeting noncoding RNAs shows promise in sporadic, nongenetic epilepsies, and targeting of mRNAs shows promise in childhood monogenic epilepsies.
Preclinical studies have highlighted the potential of RNA therapies for treatment of epilepsy.
“At NEUmiRNA Therapeutics, we have successfully designed potent and selective RNA drugs for a novel disease target that enable unprecedented elimination of the drug resistance and chronic epilepsy in a preclinical model mimicking temporal lobe epilepsy,” said Dr. Klitgaard.
“Interestingly,” he said, “these experiments also showed a disappearance of symptoms for epilepsy that outlasted drug exposure, suggesting significant disease-modifying properties with a curative potential for epilepsy.”
Hope for Dravet syndrome
Currently, there is significant interest in development of antisense oligonucleotides (ASOs), particularly for Dravet syndrome, a rare genetic epileptic encephalopathy that begins in infancy and gives rise to seizures that don’t respond well to seizure medications.
Stoke Therapeutics is developing antisense therapies aimed at correcting mutations in sodium channel genes, which cause up to 80% of cases of Dravet syndrome.
The company recently reported positive safety and efficacy data from patients treated with STK-001, a proprietary ASO, in the two ongoing phase 1/2a studies (MONARCH and ADMIRAL) and the SWALLOWTAIL open-label extension study.
“These new data suggest clinical benefit for patients 2-18 years of age treated with multiple doses of STK-001. The observed reductions in convulsive seizure frequency as well as substantial improvements in cognition and behavior support the potential for disease modification in a highly refractory patient population,” the company said in a news release.
Dr. Kaye noted that the company anticipates reporting additional data in the first quarter of 2024 and expects to provide an update on phase 3 planning in the first half of 2024.
“Twenty-five years ago, when I was caring for patients in my clinic, half of epilepsy was considered idiopathic because we didn’t know the cause,” Dr. Kaye commented.
“Since then, thanks to an understanding of the genetics and more widely available access to genetic testing, we can determine the root cause of most of them. Today, I believe we are on the verge of a fundamental shift in how we approach the treatment of Dravet syndrome and, hopefully, other genetic epilepsies,” said Dr. Kaye.
“We are now finally getting to the point that we not only know the causes, but we are in a position to develop medicines that target those causes. We have seen this happen in other diseases like cystic fibrosis, and the time has come for genetic epilepsies,” he added.
A promising future
Dr. Henshall said that the ability to target the cause rather than just the symptoms of epilepsy “offers the promise of disease-modifying and potentially curative medicines in the future.”
And what’s exciting is that the time frame of developing RNA medicines may be “radically” different than it is for traditional small-drug development, he noted.
Take, for example, a case reported recently in the New England Journal of Medicine.
Researchers identified a novel mutation in a child with neuronal ceroid lipofuscinosis 7 (a form of Batten’s disease), a rare and fatal neurodegenerative disease. Identification of the mutation was followed by the development and use (within 1 year) of a tailored RNA drug to treat the patient.
One downside perhaps is that current RNA drugs for epilepsy are delivered intrathecally, which is different from oral administration of small-molecule drugs.
However, Dr. Kauppinen from NEUmiRNA Therapeutics noted that “advances in intrathecal delivery technologies [and] the frequent use of this route of administration in other diseases and IT administration only being required two to three times per year will certainly facilitate use of RNA medicines.”
“This will also eliminate the issue of drug adherence by ensuring full patient compliance to treatment,” Dr. Kauppinen said.
The review article on RNA therapies in epilepsy had no commercial funding. Dr. Henshall holds a patent and has filed intellectual property related to microRNA targeting therapies for epilepsy and has received funding for microRNA research from NEUmiRNA Therapeutics. Dr. Klitgaard and Dr. Kauppinen are cofounders of NEUmiRNA Therapeutics. Dr. Kaye is CEO of Stoke Therapeutics.
A version of this article first appeared on Medscape.com.
Epilepsy affects over 50 million people worldwide, making it one of the most common neurologic disorders. Though current antiseizure medications can control seizures in two-thirds of patients, drug-resistant epilepsy remains a major challenge for the remaining one-third, as does the lack of disease-modifying therapies.
But RNA-based therapeutics offer new hope, and experts predict they could fill these gaps and revolutionize epilepsy treatment.
“Current medicines for epilepsy are barely scraping the surface of what could be targeted. RNA therapeutics is going to change everything. It opens up entirely new targets – virtually anything in our genome becomes ‘druggable,’ ” said David Henshall, PhD, Royal College of Surgeons Ireland, Dublin.
Edward Kaye, MD, a pediatric neurologist and CEO of Stoke Therapeutics, agrees. “RNA therapeutics open up possibilities that could not have been imagined when I started my career,” he said in an interview.
Dr. Kaye said.
Thank COVID?
Henrik Klitgaard, PhD, and Sakari Kauppinen, PhD, scientific co-founders of NEUmiRNA Therapeutics, noted that the success of messenger RNA (mRNA) vaccines to counter the COVID-19 pandemic has fueled interest in exploring the potential of RNA-based therapies as a new modality in epilepsy with improved therapeutic properties.
Dr. Klitgaard and Dr. Kauppinen recently co-authored a “critical review” on RNA therapies for epilepsy published online in Epilepsia.
Unlike current antiseizure medications, which only target ion channels and receptors, RNA therapeutics can directly intervene at the genetic level.
RNA drugs can be targeted toward noncoding RNAs, such as microRNAs, or toward mRNA. Targeting noncoding RNAs shows promise in sporadic, nongenetic epilepsies, and targeting of mRNAs shows promise in childhood monogenic epilepsies.
Preclinical studies have highlighted the potential of RNA therapies for treatment of epilepsy.
“At NEUmiRNA Therapeutics, we have successfully designed potent and selective RNA drugs for a novel disease target that enable unprecedented elimination of the drug resistance and chronic epilepsy in a preclinical model mimicking temporal lobe epilepsy,” said Dr. Klitgaard.
“Interestingly,” he said, “these experiments also showed a disappearance of symptoms for epilepsy that outlasted drug exposure, suggesting significant disease-modifying properties with a curative potential for epilepsy.”
Hope for Dravet syndrome
Currently, there is significant interest in development of antisense oligonucleotides (ASOs), particularly for Dravet syndrome, a rare genetic epileptic encephalopathy that begins in infancy and gives rise to seizures that don’t respond well to seizure medications.
Stoke Therapeutics is developing antisense therapies aimed at correcting mutations in sodium channel genes, which cause up to 80% of cases of Dravet syndrome.
The company recently reported positive safety and efficacy data from patients treated with STK-001, a proprietary ASO, in the two ongoing phase 1/2a studies (MONARCH and ADMIRAL) and the SWALLOWTAIL open-label extension study.
“These new data suggest clinical benefit for patients 2-18 years of age treated with multiple doses of STK-001. The observed reductions in convulsive seizure frequency as well as substantial improvements in cognition and behavior support the potential for disease modification in a highly refractory patient population,” the company said in a news release.
Dr. Kaye noted that the company anticipates reporting additional data in the first quarter of 2024 and expects to provide an update on phase 3 planning in the first half of 2024.
“Twenty-five years ago, when I was caring for patients in my clinic, half of epilepsy was considered idiopathic because we didn’t know the cause,” Dr. Kaye commented.
“Since then, thanks to an understanding of the genetics and more widely available access to genetic testing, we can determine the root cause of most of them. Today, I believe we are on the verge of a fundamental shift in how we approach the treatment of Dravet syndrome and, hopefully, other genetic epilepsies,” said Dr. Kaye.
“We are now finally getting to the point that we not only know the causes, but we are in a position to develop medicines that target those causes. We have seen this happen in other diseases like cystic fibrosis, and the time has come for genetic epilepsies,” he added.
A promising future
Dr. Henshall said that the ability to target the cause rather than just the symptoms of epilepsy “offers the promise of disease-modifying and potentially curative medicines in the future.”
And what’s exciting is that the time frame of developing RNA medicines may be “radically” different than it is for traditional small-drug development, he noted.
Take, for example, a case reported recently in the New England Journal of Medicine.
Researchers identified a novel mutation in a child with neuronal ceroid lipofuscinosis 7 (a form of Batten’s disease), a rare and fatal neurodegenerative disease. Identification of the mutation was followed by the development and use (within 1 year) of a tailored RNA drug to treat the patient.
One downside perhaps is that current RNA drugs for epilepsy are delivered intrathecally, which is different from oral administration of small-molecule drugs.
However, Dr. Kauppinen from NEUmiRNA Therapeutics noted that “advances in intrathecal delivery technologies [and] the frequent use of this route of administration in other diseases and IT administration only being required two to three times per year will certainly facilitate use of RNA medicines.”
“This will also eliminate the issue of drug adherence by ensuring full patient compliance to treatment,” Dr. Kauppinen said.
The review article on RNA therapies in epilepsy had no commercial funding. Dr. Henshall holds a patent and has filed intellectual property related to microRNA targeting therapies for epilepsy and has received funding for microRNA research from NEUmiRNA Therapeutics. Dr. Klitgaard and Dr. Kauppinen are cofounders of NEUmiRNA Therapeutics. Dr. Kaye is CEO of Stoke Therapeutics.
A version of this article first appeared on Medscape.com.
Epilepsy affects over 50 million people worldwide, making it one of the most common neurologic disorders. Though current antiseizure medications can control seizures in two-thirds of patients, drug-resistant epilepsy remains a major challenge for the remaining one-third, as does the lack of disease-modifying therapies.
But RNA-based therapeutics offer new hope, and experts predict they could fill these gaps and revolutionize epilepsy treatment.
“Current medicines for epilepsy are barely scraping the surface of what could be targeted. RNA therapeutics is going to change everything. It opens up entirely new targets – virtually anything in our genome becomes ‘druggable,’ ” said David Henshall, PhD, Royal College of Surgeons Ireland, Dublin.
Edward Kaye, MD, a pediatric neurologist and CEO of Stoke Therapeutics, agrees. “RNA therapeutics open up possibilities that could not have been imagined when I started my career,” he said in an interview.
Dr. Kaye said.
Thank COVID?
Henrik Klitgaard, PhD, and Sakari Kauppinen, PhD, scientific co-founders of NEUmiRNA Therapeutics, noted that the success of messenger RNA (mRNA) vaccines to counter the COVID-19 pandemic has fueled interest in exploring the potential of RNA-based therapies as a new modality in epilepsy with improved therapeutic properties.
Dr. Klitgaard and Dr. Kauppinen recently co-authored a “critical review” on RNA therapies for epilepsy published online in Epilepsia.
Unlike current antiseizure medications, which only target ion channels and receptors, RNA therapeutics can directly intervene at the genetic level.
RNA drugs can be targeted toward noncoding RNAs, such as microRNAs, or toward mRNA. Targeting noncoding RNAs shows promise in sporadic, nongenetic epilepsies, and targeting of mRNAs shows promise in childhood monogenic epilepsies.
Preclinical studies have highlighted the potential of RNA therapies for treatment of epilepsy.
“At NEUmiRNA Therapeutics, we have successfully designed potent and selective RNA drugs for a novel disease target that enable unprecedented elimination of the drug resistance and chronic epilepsy in a preclinical model mimicking temporal lobe epilepsy,” said Dr. Klitgaard.
“Interestingly,” he said, “these experiments also showed a disappearance of symptoms for epilepsy that outlasted drug exposure, suggesting significant disease-modifying properties with a curative potential for epilepsy.”
Hope for Dravet syndrome
Currently, there is significant interest in development of antisense oligonucleotides (ASOs), particularly for Dravet syndrome, a rare genetic epileptic encephalopathy that begins in infancy and gives rise to seizures that don’t respond well to seizure medications.
Stoke Therapeutics is developing antisense therapies aimed at correcting mutations in sodium channel genes, which cause up to 80% of cases of Dravet syndrome.
The company recently reported positive safety and efficacy data from patients treated with STK-001, a proprietary ASO, in the two ongoing phase 1/2a studies (MONARCH and ADMIRAL) and the SWALLOWTAIL open-label extension study.
“These new data suggest clinical benefit for patients 2-18 years of age treated with multiple doses of STK-001. The observed reductions in convulsive seizure frequency as well as substantial improvements in cognition and behavior support the potential for disease modification in a highly refractory patient population,” the company said in a news release.
Dr. Kaye noted that the company anticipates reporting additional data in the first quarter of 2024 and expects to provide an update on phase 3 planning in the first half of 2024.
“Twenty-five years ago, when I was caring for patients in my clinic, half of epilepsy was considered idiopathic because we didn’t know the cause,” Dr. Kaye commented.
“Since then, thanks to an understanding of the genetics and more widely available access to genetic testing, we can determine the root cause of most of them. Today, I believe we are on the verge of a fundamental shift in how we approach the treatment of Dravet syndrome and, hopefully, other genetic epilepsies,” said Dr. Kaye.
“We are now finally getting to the point that we not only know the causes, but we are in a position to develop medicines that target those causes. We have seen this happen in other diseases like cystic fibrosis, and the time has come for genetic epilepsies,” he added.
A promising future
Dr. Henshall said that the ability to target the cause rather than just the symptoms of epilepsy “offers the promise of disease-modifying and potentially curative medicines in the future.”
And what’s exciting is that the time frame of developing RNA medicines may be “radically” different than it is for traditional small-drug development, he noted.
Take, for example, a case reported recently in the New England Journal of Medicine.
Researchers identified a novel mutation in a child with neuronal ceroid lipofuscinosis 7 (a form of Batten’s disease), a rare and fatal neurodegenerative disease. Identification of the mutation was followed by the development and use (within 1 year) of a tailored RNA drug to treat the patient.
One downside perhaps is that current RNA drugs for epilepsy are delivered intrathecally, which is different from oral administration of small-molecule drugs.
However, Dr. Kauppinen from NEUmiRNA Therapeutics noted that “advances in intrathecal delivery technologies [and] the frequent use of this route of administration in other diseases and IT administration only being required two to three times per year will certainly facilitate use of RNA medicines.”
“This will also eliminate the issue of drug adherence by ensuring full patient compliance to treatment,” Dr. Kauppinen said.
The review article on RNA therapies in epilepsy had no commercial funding. Dr. Henshall holds a patent and has filed intellectual property related to microRNA targeting therapies for epilepsy and has received funding for microRNA research from NEUmiRNA Therapeutics. Dr. Klitgaard and Dr. Kauppinen are cofounders of NEUmiRNA Therapeutics. Dr. Kaye is CEO of Stoke Therapeutics.
A version of this article first appeared on Medscape.com.