Rare Diseases

The U.S. Food and Drug Administration has approved a new enzyme replacement therapy, avalglucosidase alfa (Nexviazyme, Genzyme), for patients aged 1 year and older with late-onset Pompe disease.

Pompe disease is a rare genetic disease that occurs in an estimated 1 in 40,000 births. It is caused by a genetic deficiency or dysfunction of the lysosomal enzyme acid alpha-glucosidase (GAA), which leads to a buildup of glycogen in skeletal and cardiac muscle cells, causing muscle weakness and premature death from respiratory failure or heart failure.

Nexviazyme, administered by intravenous infusion every 2 weeks, supplements GAA and helps reduce glycogen accumulation.

The approval of this product “brings patients with Pompe disease another enzyme replacement therapy option for this rare disease,” said Janet Maynard, MD, deputy director, Office of Rare Diseases, Pediatrics, Urologic and Reproductive Medicine, in the FDA’s Center for Drug Evaluation and Research, in a news release.

In 2010, the FDA approved alglucosidase alfa (Lumizyme) for the treatment of late-onset Pompe disease.

“The FDA will continue to work with stakeholders to advance the development of additional new, effective, and safe therapies for rare diseases, including Pompe disease,” said Dr. Maynard.

The approval is based on positive phase 3 data that demonstrated improvements in key disease burden measures, including respiratory function and walking disease, and that established the drug’s safety profile, Genzyme said in a news release.

The most common side effects were headache, fatigue, diarrhea, nausea, joint pain, dizziness, myalgia, pruritus, vomiting, dyspnea, erythema, paresthesia, and urticaria.

Serious reactions included hypersensitivity reactions, such as anaphylaxis, and infusion-associated reactions, including respiratory distress, chills, and pyrexia.

Patients susceptible to fluid volume overload or those with compromised cardiac or respiratory function may be at risk for serious acute cardiorespiratory failure.

The FDA granted Nexviazyme orphan drug designation, priority review, and breakthrough status.

Genzyme expects the new therapy to be available in the United States in the coming weeks and said it will be priced on par with Lumizyme.

A version of this article first appeared on Medscape.com.

The U.S. Food and Drug Administration has approved a new enzyme replacement therapy, avalglucosidase alfa (Nexviazyme, Genzyme), for patients aged 1 year and older with late-onset Pompe disease.

Pompe disease is a rare genetic disease that occurs in an estimated 1 in 40,000 births. It is caused by a genetic deficiency or dysfunction of the lysosomal enzyme acid alpha-glucosidase (GAA), which leads to a buildup of glycogen in skeletal and cardiac muscle cells, causing muscle weakness and premature death from respiratory failure or heart failure.

Nexviazyme, administered by intravenous infusion every 2 weeks, supplements GAA and helps reduce glycogen accumulation.

The approval of this product “brings patients with Pompe disease another enzyme replacement therapy option for this rare disease,” said Janet Maynard, MD, deputy director, Office of Rare Diseases, Pediatrics, Urologic and Reproductive Medicine, in the FDA’s Center for Drug Evaluation and Research, in a news release.

In 2010, the FDA approved alglucosidase alfa (Lumizyme) for the treatment of late-onset Pompe disease.

“The FDA will continue to work with stakeholders to advance the development of additional new, effective, and safe therapies for rare diseases, including Pompe disease,” said Dr. Maynard.

The approval is based on positive phase 3 data that demonstrated improvements in key disease burden measures, including respiratory function and walking disease, and that established the drug’s safety profile, Genzyme said in a news release.

The most common side effects were headache, fatigue, diarrhea, nausea, joint pain, dizziness, myalgia, pruritus, vomiting, dyspnea, erythema, paresthesia, and urticaria.

Serious reactions included hypersensitivity reactions, such as anaphylaxis, and infusion-associated reactions, including respiratory distress, chills, and pyrexia.

Patients susceptible to fluid volume overload or those with compromised cardiac or respiratory function may be at risk for serious acute cardiorespiratory failure.

The FDA granted Nexviazyme orphan drug designation, priority review, and breakthrough status.

Genzyme expects the new therapy to be available in the United States in the coming weeks and said it will be priced on par with Lumizyme.

A version of this article first appeared on Medscape.com.

The U.S. Food and Drug Administration has approved a new enzyme replacement therapy, avalglucosidase alfa (Nexviazyme, Genzyme), for patients aged 1 year and older with late-onset Pompe disease.

Pompe disease is a rare genetic disease that occurs in an estimated 1 in 40,000 births. It is caused by a genetic deficiency or dysfunction of the lysosomal enzyme acid alpha-glucosidase (GAA), which leads to a buildup of glycogen in skeletal and cardiac muscle cells, causing muscle weakness and premature death from respiratory failure or heart failure.

Nexviazyme, administered by intravenous infusion every 2 weeks, supplements GAA and helps reduce glycogen accumulation.

The approval of this product “brings patients with Pompe disease another enzyme replacement therapy option for this rare disease,” said Janet Maynard, MD, deputy director, Office of Rare Diseases, Pediatrics, Urologic and Reproductive Medicine, in the FDA’s Center for Drug Evaluation and Research, in a news release.

In 2010, the FDA approved alglucosidase alfa (Lumizyme) for the treatment of late-onset Pompe disease.

“The FDA will continue to work with stakeholders to advance the development of additional new, effective, and safe therapies for rare diseases, including Pompe disease,” said Dr. Maynard.

The approval is based on positive phase 3 data that demonstrated improvements in key disease burden measures, including respiratory function and walking disease, and that established the drug’s safety profile, Genzyme said in a news release.

The most common side effects were headache, fatigue, diarrhea, nausea, joint pain, dizziness, myalgia, pruritus, vomiting, dyspnea, erythema, paresthesia, and urticaria.

Serious reactions included hypersensitivity reactions, such as anaphylaxis, and infusion-associated reactions, including respiratory distress, chills, and pyrexia.

Patients susceptible to fluid volume overload or those with compromised cardiac or respiratory function may be at risk for serious acute cardiorespiratory failure.

The FDA granted Nexviazyme orphan drug designation, priority review, and breakthrough status.

Genzyme expects the new therapy to be available in the United States in the coming weeks and said it will be priced on par with Lumizyme.

A version of this article first appeared on Medscape.com.

To the Editor:

A 62-year-old woman with a history of dermatomyositis (DM) presented to dermatology clinic for evaluation of multiple subcutaneous nodules. Two years prior to the current presentation, the patient was diagnosed by her primary care physician with DM based on clinical presentation. She initially developed body aches, muscle pain, and weakness of the upper extremities, specifically around the shoulders, and later the lower extremities, specifically around the thighs. The initial physical examination revealed pain with movement, tenderness to palpation, and proximal extremity weakness. The patient also noted a 50-lb weight loss. Over the next year, she noted dysphagia and developed multiple subcutaneous nodules on the right arm, chest, and left axilla. Subsequently, she developed a violaceous, hyperpigmented, periorbital rash and erythema of the anterior chest. She did not experience hair loss, oral ulcers, photosensitivity, or joint pain.

Laboratory testing in the months following the initial presentation revealed a creatine phosphokinase level of 436 U/L (reference range, 20–200 U/L), an erythrocyte sedimentation rate of 60 mm/h (reference range, <31 mm/h), and an aldolase level of 10.4 U/L (reference range, 1.0–8.0 U/L). Lactate dehydrogenase and thyroid function tests were within normal limits. Antinuclear antibodies, anti–double-stranded DNA, anti-Smith antibodies, anti-ribonucleoprotein, anti–Jo-1 antibodies, and anti–smooth muscle antibodies all were negative. Total blood complement levels were elevated, but complement C3 and C4 were within normal limits. Imaging demonstrated normal chest radiographs, and a modified barium swallow confirmed swallowing dysfunction. A right quadricep muscle biopsy confirmed the diagnosis of DM. A malignancy work-up including mammography, colonoscopy, and computed tomography of the chest, abdomen, and pelvis was negative aside from nodular opacities in the chest. She was treated with prednisone (60 mg, 0.9 mg/kg) daily and methotrexate (15–20 mg) weekly for several months. While the treatment attenuated the rash and improved weakness, the nodules persisted, prompting a referral to dermatology.

Physical examination at the dermatology clinic demonstrated the persistent subcutaneous nodules were indurated and bilaterally located on the arms, axillae, chest, abdomen, buttocks, and thighs with no pain or erythema (Figure). Laboratory tests demonstrated a normal creatine phosphokinase level, elevated erythrocyte sedimentation rate (70 mm/h), and elevated aldolase level (9.3 U/L). Complement levels were elevated, though complement C3 and C4 remained within normal limits. Histopathology of nodules from the medial right upper arm and left thigh showed lobular panniculitis with fat necrosis, calcification, and interface changes. The patient was treated for several months with daily mycophenolate mofetil (1 g increased to 3 g) and daily hydroxychloroquine (200 mg) without any effect on the nodules.

A majority of the reported panniculitis cases in DM have responded to treatment with prednisone; however, treatment with prednisone has been more recalcitrant in other cases. Reports of successful additional therapies include methotrexate, cyclosporine, azathioprine, hydroxychloroquine, intravenous immunoglobulin, mepacrine, or a combination of these entities.^19,22 In most cases, improvement of the panniculitis and other DM symptoms occurred simultaneously.²⁵ It is noteworthy that the muscular symptoms often resolved more rapidly than cutaneous manifestations.³³ Few reported cases (6 including the current case) found a persistent panniculitis despite improvement and remission of the myositis.^3,5,10,11,30

Our patient was treated with both prednisone and methotrexate for several months, leading to remission of muscular symptoms (along with return to baseline of creatine phosphokinase), yet the panniculitis did not improve. The subcutaneous nodules also did not respond to treatment with mycophenolate mofetil and hydroxychloroquine.

Recent immunohistochemical studies have suggested that panniculitic lesions show better outcomes with immunosuppressive therapy when compared with other DM-related skin lesions.⁴⁰ However, this was not the case for our patient, who after months of immunosuppressive therapy showed complete resolution of the periorbital and chest rashes with persistence of multiple indurated subcutaneous nodules.

Our case adds to a number of reports of DM presenting with panniculitis. Our patient fit the classic demographic of previously reported cases, as she was an adult woman without evidence of underlying malignancy; however, our case remains an example of the therapeutic challenge that exists when encountering a persistent, treatment-resistant panniculitis despite resolution of all other features of DM.

TABLE IS AVAILABLE IN THE PDF OF THIS ARTICLE

To the Editor:

A 62-year-old woman with a history of dermatomyositis (DM) presented to dermatology clinic for evaluation of multiple subcutaneous nodules. Two years prior to the current presentation, the patient was diagnosed by her primary care physician with DM based on clinical presentation. She initially developed body aches, muscle pain, and weakness of the upper extremities, specifically around the shoulders, and later the lower extremities, specifically around the thighs. The initial physical examination revealed pain with movement, tenderness to palpation, and proximal extremity weakness. The patient also noted a 50-lb weight loss. Over the next year, she noted dysphagia and developed multiple subcutaneous nodules on the right arm, chest, and left axilla. Subsequently, she developed a violaceous, hyperpigmented, periorbital rash and erythema of the anterior chest. She did not experience hair loss, oral ulcers, photosensitivity, or joint pain.

Laboratory testing in the months following the initial presentation revealed a creatine phosphokinase level of 436 U/L (reference range, 20–200 U/L), an erythrocyte sedimentation rate of 60 mm/h (reference range, <31 mm/h), and an aldolase level of 10.4 U/L (reference range, 1.0–8.0 U/L). Lactate dehydrogenase and thyroid function tests were within normal limits. Antinuclear antibodies, anti–double-stranded DNA, anti-Smith antibodies, anti-ribonucleoprotein, anti–Jo-1 antibodies, and anti–smooth muscle antibodies all were negative. Total blood complement levels were elevated, but complement C3 and C4 were within normal limits. Imaging demonstrated normal chest radiographs, and a modified barium swallow confirmed swallowing dysfunction. A right quadricep muscle biopsy confirmed the diagnosis of DM. A malignancy work-up including mammography, colonoscopy, and computed tomography of the chest, abdomen, and pelvis was negative aside from nodular opacities in the chest. She was treated with prednisone (60 mg, 0.9 mg/kg) daily and methotrexate (15–20 mg) weekly for several months. While the treatment attenuated the rash and improved weakness, the nodules persisted, prompting a referral to dermatology.

Physical examination at the dermatology clinic demonstrated the persistent subcutaneous nodules were indurated and bilaterally located on the arms, axillae, chest, abdomen, buttocks, and thighs with no pain or erythema (Figure). Laboratory tests demonstrated a normal creatine phosphokinase level, elevated erythrocyte sedimentation rate (70 mm/h), and elevated aldolase level (9.3 U/L). Complement levels were elevated, though complement C3 and C4 remained within normal limits. Histopathology of nodules from the medial right upper arm and left thigh showed lobular panniculitis with fat necrosis, calcification, and interface changes. The patient was treated for several months with daily mycophenolate mofetil (1 g increased to 3 g) and daily hydroxychloroquine (200 mg) without any effect on the nodules.

A majority of the reported panniculitis cases in DM have responded to treatment with prednisone; however, treatment with prednisone has been more recalcitrant in other cases. Reports of successful additional therapies include methotrexate, cyclosporine, azathioprine, hydroxychloroquine, intravenous immunoglobulin, mepacrine, or a combination of these entities.^19,22 In most cases, improvement of the panniculitis and other DM symptoms occurred simultaneously.²⁵ It is noteworthy that the muscular symptoms often resolved more rapidly than cutaneous manifestations.³³ Few reported cases (6 including the current case) found a persistent panniculitis despite improvement and remission of the myositis.^3,5,10,11,30

Our patient was treated with both prednisone and methotrexate for several months, leading to remission of muscular symptoms (along with return to baseline of creatine phosphokinase), yet the panniculitis did not improve. The subcutaneous nodules also did not respond to treatment with mycophenolate mofetil and hydroxychloroquine.

Recent immunohistochemical studies have suggested that panniculitic lesions show better outcomes with immunosuppressive therapy when compared with other DM-related skin lesions.⁴⁰ However, this was not the case for our patient, who after months of immunosuppressive therapy showed complete resolution of the periorbital and chest rashes with persistence of multiple indurated subcutaneous nodules.

Our case adds to a number of reports of DM presenting with panniculitis. Our patient fit the classic demographic of previously reported cases, as she was an adult woman without evidence of underlying malignancy; however, our case remains an example of the therapeutic challenge that exists when encountering a persistent, treatment-resistant panniculitis despite resolution of all other features of DM.

TABLE IS AVAILABLE IN THE PDF OF THIS ARTICLE

To the Editor:

A 62-year-old woman with a history of dermatomyositis (DM) presented to dermatology clinic for evaluation of multiple subcutaneous nodules. Two years prior to the current presentation, the patient was diagnosed by her primary care physician with DM based on clinical presentation. She initially developed body aches, muscle pain, and weakness of the upper extremities, specifically around the shoulders, and later the lower extremities, specifically around the thighs. The initial physical examination revealed pain with movement, tenderness to palpation, and proximal extremity weakness. The patient also noted a 50-lb weight loss. Over the next year, she noted dysphagia and developed multiple subcutaneous nodules on the right arm, chest, and left axilla. Subsequently, she developed a violaceous, hyperpigmented, periorbital rash and erythema of the anterior chest. She did not experience hair loss, oral ulcers, photosensitivity, or joint pain.

Laboratory testing in the months following the initial presentation revealed a creatine phosphokinase level of 436 U/L (reference range, 20–200 U/L), an erythrocyte sedimentation rate of 60 mm/h (reference range, <31 mm/h), and an aldolase level of 10.4 U/L (reference range, 1.0–8.0 U/L). Lactate dehydrogenase and thyroid function tests were within normal limits. Antinuclear antibodies, anti–double-stranded DNA, anti-Smith antibodies, anti-ribonucleoprotein, anti–Jo-1 antibodies, and anti–smooth muscle antibodies all were negative. Total blood complement levels were elevated, but complement C3 and C4 were within normal limits. Imaging demonstrated normal chest radiographs, and a modified barium swallow confirmed swallowing dysfunction. A right quadricep muscle biopsy confirmed the diagnosis of DM. A malignancy work-up including mammography, colonoscopy, and computed tomography of the chest, abdomen, and pelvis was negative aside from nodular opacities in the chest. She was treated with prednisone (60 mg, 0.9 mg/kg) daily and methotrexate (15–20 mg) weekly for several months. While the treatment attenuated the rash and improved weakness, the nodules persisted, prompting a referral to dermatology.

Physical examination at the dermatology clinic demonstrated the persistent subcutaneous nodules were indurated and bilaterally located on the arms, axillae, chest, abdomen, buttocks, and thighs with no pain or erythema (Figure). Laboratory tests demonstrated a normal creatine phosphokinase level, elevated erythrocyte sedimentation rate (70 mm/h), and elevated aldolase level (9.3 U/L). Complement levels were elevated, though complement C3 and C4 remained within normal limits. Histopathology of nodules from the medial right upper arm and left thigh showed lobular panniculitis with fat necrosis, calcification, and interface changes. The patient was treated for several months with daily mycophenolate mofetil (1 g increased to 3 g) and daily hydroxychloroquine (200 mg) without any effect on the nodules.

A majority of the reported panniculitis cases in DM have responded to treatment with prednisone; however, treatment with prednisone has been more recalcitrant in other cases. Reports of successful additional therapies include methotrexate, cyclosporine, azathioprine, hydroxychloroquine, intravenous immunoglobulin, mepacrine, or a combination of these entities.^19,22 In most cases, improvement of the panniculitis and other DM symptoms occurred simultaneously.²⁵ It is noteworthy that the muscular symptoms often resolved more rapidly than cutaneous manifestations.³³ Few reported cases (6 including the current case) found a persistent panniculitis despite improvement and remission of the myositis.^3,5,10,11,30

Our patient was treated with both prednisone and methotrexate for several months, leading to remission of muscular symptoms (along with return to baseline of creatine phosphokinase), yet the panniculitis did not improve. The subcutaneous nodules also did not respond to treatment with mycophenolate mofetil and hydroxychloroquine.

Recent immunohistochemical studies have suggested that panniculitic lesions show better outcomes with immunosuppressive therapy when compared with other DM-related skin lesions.⁴⁰ However, this was not the case for our patient, who after months of immunosuppressive therapy showed complete resolution of the periorbital and chest rashes with persistence of multiple indurated subcutaneous nodules.

Our case adds to a number of reports of DM presenting with panniculitis. Our patient fit the classic demographic of previously reported cases, as she was an adult woman without evidence of underlying malignancy; however, our case remains an example of the therapeutic challenge that exists when encountering a persistent, treatment-resistant panniculitis despite resolution of all other features of DM.

TABLE IS AVAILABLE IN THE PDF OF THIS ARTICLE

Study Overview

Objective. To evaluate the efficacy and safety of the combination of nivolumab plus cabozantinib as compared with sunitinib monotherapy in the treatment of previously untreated advanced renal cell carcinoma (RCC).

Design. Multicenter, international, open-label, randomized, phase 3 trial.

Intervention. Patients were randomized in a 1:1 fashion to 1 of 2 treatment arms:

• Arm A: Nivolumab intravenously 240 mg every 2 weeks plus cabozantinib orally 40 mg once daily.
• Arm B: Sunitinib orally 50 mg daily for 4 weeks, followed by 2 weeks off therapy (6-week cycle).

Randomization was stratified by the International Metastatic RCC Database Consortium prognostic risk score (low-, intermediate-, and high-risk). Treatment was continued until disease progression or development of unacceptable toxic side effects with a maximum of 2-year duration of Nivolumab therapy.

Settings and participants. Adults with previously untreated advanced RCC with a clear cell component were eligible for enrollment. Subjects were excluded if they had active central nervous system metastases or active autoimmune disease.

Main outcome measures. The primary outcome of this study was progression-free survival (PFS) as assessed by an independent review committee. Secondary endpoints included overall survival, objective response rate, safety, and PFS as assessed by investigators. All subgroup analyses were prespecified. Efficacy was assessed in the intention-to-treat population, including all patients who underwent randomization.

Main results. A total of 651 patients underwent randomization: 323 to the nivolumab plus cabozantinib group, and 328 to the sunitinib group. Baseline demographics were balanced. The median follow-up period for overall survival (OS) was 18.1 months. The primary reason for treatment discontinuation in any group was disease progression. PFS as indicated by an independent review committee was significantly longer in the nivolumab plus cabozantinib group compared to the sunitinib group (median 16.6 months vs 8.2 months; hazard ratio [HR] 0.51, P < .001). The median OS was not reached for any group. Overall survival was longer in the nivolumab plus cabozantinib group compared to the sunitinib group (HR 0.60, 95% CI: 0.40-0.89; P = .001). The objective response rate was 55.7% with the nivolumab plus cabozantinib group versus 27.1% with sunitinib (P < .001). The complete response rate was 8% in the nivolumab plus cabozantinib group compared to 4.6% in the sunitinib group. The median time to response was 2.8 months with nivolumab plus cabozantinib and 4.2 months in the sunitinib group, while the median duration of response was 20.2 months and 11.5 months, respectively.

Nearly all patients (about 99% in each group) had an adverse event (AE). Hypertension was the most common side effect, with grade 3 or higher seen in 12.5% in the nivolumab plus cabzantinib group and 13.1% in the sunitinib group. Other grade 3 or higher side effects occurring in at least 10% of patients in any group were hyponatremia, diarrhea, palmar-plantar erythrodysesthesia, hypothyroidism, and fatigue. AEs of any cause leading to discontinuation of the therapy occurred in 19.7% in the nivolumab plus cabzantinib group vs 16.9% of the sunitinib group. One death was considered to be treatment-related (small intestinal perforation) in the nivolumab plus cabozantinib group vs 2 treatment-related deaths with sunitinib (pneumonia and respiratory distress). In the nivolumab plus cabozantinib group, 57% of the patients had a dose reduction of cabozantinib and 52% had a reduction in sunitinib dosage.

Using the Functional Assessment of Cancer Therapy-Kidney Symptoms Index, patients in the nivolumab plus cabozantinib group reported better health-related quality of life and less disease-related symptoms compared to the sunitinib group.

Commentary

The treatment landscape for frontline therapy for patients with advanced RCC has rapidly expanded over the last several years and has revolutionized cancer care. Ushered in by the results from the CheckMate 214 study highlighting the efficacy of dual checkpoint inhibition with nivolumab and ipilimumab in intermediate and poor risk patients, several subsequent trials have demonstrated improved outcomes with combination therapy with immune checkpoint inhibitors and tyrosine-kinase inhibitors (TKI). To date, data from Keynote-426 (pembrolizumab plus axitinib vs sunitinib), Javelin Renal 101 (avelumab plus axitinib vs sunitinib) and the CLEAR trial (lenvatinib plus pembrolizumab vs levatinib plus everolimus vs sunitinib) have demonstrated superiority of immune checkpoint inhibitor/TKI combinations over sunitinb in the first-line setting.^1-5

The current phase 3, CheckMate 9ER trial adds yet another dynamic option for patients with advanced clear cell RCC. While cross-trial comparisons are fraught with important caveats, the median PFS of almost 16.6 months and complete response rate of 8% the nivolumab plus cabozantinib group compares favorably with other combinations. Data from the CLEAR study with the combination of lenvatinib and pembrolizumab showed a complete response rate approaching 16%. Importantly, the current study highlights improved quality of life with the combination of cabozantinib and nivolumab compared to sunitinib alone adding to the efficacy and benefits of this combination treatment.

The selection of first line therapy for patients with advanced RCC should be always guided by individual patient characteristics, and any single immune checkpoint inhibitor/TKI combination is not “superior” to any other. Perhaps more importantly is developing an understanding of the overlapping toxicity profiles of checkpoint inhibitors and TKIs. Again, this trial results are consistent with prior studies in terms of the adverse event profile which were not trivial, and almost all patients (99%) experienced AEs. It is important for oncologists to understand the management of the toxicities with these combinations and dose reductions as appropriate. It is worth noting that 19% of patients with nivolumab plus cabozantinib received glucocorticoids for management of immune-related AEs.

While long-term follow-up data will be needed to further understand the durability of response to this combination, nivolumab-cabozantinib represents an exciting new option for patients with advanced clear cell RCC. As we continue to see improvement in outcomes in clear cell histology, further work must focus on optimization of therapy in non-clear cell RCC as this is a population that is not represented in these data sets. Furthermore, future efforts should begin to explore triplet combinations and biomarker driven patient selection for upfront therapy in ordercontinue to improve outcomes in patients with advanced RCC.

Applications for Clinical Practice

The combination of nivolumab plus cabozantinib adds to the growing list of highly active checkpoint inhibitor/TKI combinations for first-line treatment of advanced RCC. With significant higher response rates, improved outcomes, and improvement in the quality of life, this combination will add another standard treatment option for patients with previously untreated advanced RCC.

Study Overview

Objective. To evaluate the efficacy and safety of the combination of nivolumab plus cabozantinib as compared with sunitinib monotherapy in the treatment of previously untreated advanced renal cell carcinoma (RCC).

Design. Multicenter, international, open-label, randomized, phase 3 trial.

Intervention. Patients were randomized in a 1:1 fashion to 1 of 2 treatment arms:

• Arm A: Nivolumab intravenously 240 mg every 2 weeks plus cabozantinib orally 40 mg once daily.
• Arm B: Sunitinib orally 50 mg daily for 4 weeks, followed by 2 weeks off therapy (6-week cycle).

Randomization was stratified by the International Metastatic RCC Database Consortium prognostic risk score (low-, intermediate-, and high-risk). Treatment was continued until disease progression or development of unacceptable toxic side effects with a maximum of 2-year duration of Nivolumab therapy.

Settings and participants. Adults with previously untreated advanced RCC with a clear cell component were eligible for enrollment. Subjects were excluded if they had active central nervous system metastases or active autoimmune disease.

Main outcome measures. The primary outcome of this study was progression-free survival (PFS) as assessed by an independent review committee. Secondary endpoints included overall survival, objective response rate, safety, and PFS as assessed by investigators. All subgroup analyses were prespecified. Efficacy was assessed in the intention-to-treat population, including all patients who underwent randomization.

Main results. A total of 651 patients underwent randomization: 323 to the nivolumab plus cabozantinib group, and 328 to the sunitinib group. Baseline demographics were balanced. The median follow-up period for overall survival (OS) was 18.1 months. The primary reason for treatment discontinuation in any group was disease progression. PFS as indicated by an independent review committee was significantly longer in the nivolumab plus cabozantinib group compared to the sunitinib group (median 16.6 months vs 8.2 months; hazard ratio [HR] 0.51, P < .001). The median OS was not reached for any group. Overall survival was longer in the nivolumab plus cabozantinib group compared to the sunitinib group (HR 0.60, 95% CI: 0.40-0.89; P = .001). The objective response rate was 55.7% with the nivolumab plus cabozantinib group versus 27.1% with sunitinib (P < .001). The complete response rate was 8% in the nivolumab plus cabozantinib group compared to 4.6% in the sunitinib group. The median time to response was 2.8 months with nivolumab plus cabozantinib and 4.2 months in the sunitinib group, while the median duration of response was 20.2 months and 11.5 months, respectively.

Nearly all patients (about 99% in each group) had an adverse event (AE). Hypertension was the most common side effect, with grade 3 or higher seen in 12.5% in the nivolumab plus cabzantinib group and 13.1% in the sunitinib group. Other grade 3 or higher side effects occurring in at least 10% of patients in any group were hyponatremia, diarrhea, palmar-plantar erythrodysesthesia, hypothyroidism, and fatigue. AEs of any cause leading to discontinuation of the therapy occurred in 19.7% in the nivolumab plus cabzantinib group vs 16.9% of the sunitinib group. One death was considered to be treatment-related (small intestinal perforation) in the nivolumab plus cabozantinib group vs 2 treatment-related deaths with sunitinib (pneumonia and respiratory distress). In the nivolumab plus cabozantinib group, 57% of the patients had a dose reduction of cabozantinib and 52% had a reduction in sunitinib dosage.

Using the Functional Assessment of Cancer Therapy-Kidney Symptoms Index, patients in the nivolumab plus cabozantinib group reported better health-related quality of life and less disease-related symptoms compared to the sunitinib group.

Commentary

The treatment landscape for frontline therapy for patients with advanced RCC has rapidly expanded over the last several years and has revolutionized cancer care. Ushered in by the results from the CheckMate 214 study highlighting the efficacy of dual checkpoint inhibition with nivolumab and ipilimumab in intermediate and poor risk patients, several subsequent trials have demonstrated improved outcomes with combination therapy with immune checkpoint inhibitors and tyrosine-kinase inhibitors (TKI). To date, data from Keynote-426 (pembrolizumab plus axitinib vs sunitinib), Javelin Renal 101 (avelumab plus axitinib vs sunitinib) and the CLEAR trial (lenvatinib plus pembrolizumab vs levatinib plus everolimus vs sunitinib) have demonstrated superiority of immune checkpoint inhibitor/TKI combinations over sunitinb in the first-line setting.^1-5

The current phase 3, CheckMate 9ER trial adds yet another dynamic option for patients with advanced clear cell RCC. While cross-trial comparisons are fraught with important caveats, the median PFS of almost 16.6 months and complete response rate of 8% the nivolumab plus cabozantinib group compares favorably with other combinations. Data from the CLEAR study with the combination of lenvatinib and pembrolizumab showed a complete response rate approaching 16%. Importantly, the current study highlights improved quality of life with the combination of cabozantinib and nivolumab compared to sunitinib alone adding to the efficacy and benefits of this combination treatment.

The selection of first line therapy for patients with advanced RCC should be always guided by individual patient characteristics, and any single immune checkpoint inhibitor/TKI combination is not “superior” to any other. Perhaps more importantly is developing an understanding of the overlapping toxicity profiles of checkpoint inhibitors and TKIs. Again, this trial results are consistent with prior studies in terms of the adverse event profile which were not trivial, and almost all patients (99%) experienced AEs. It is important for oncologists to understand the management of the toxicities with these combinations and dose reductions as appropriate. It is worth noting that 19% of patients with nivolumab plus cabozantinib received glucocorticoids for management of immune-related AEs.

While long-term follow-up data will be needed to further understand the durability of response to this combination, nivolumab-cabozantinib represents an exciting new option for patients with advanced clear cell RCC. As we continue to see improvement in outcomes in clear cell histology, further work must focus on optimization of therapy in non-clear cell RCC as this is a population that is not represented in these data sets. Furthermore, future efforts should begin to explore triplet combinations and biomarker driven patient selection for upfront therapy in ordercontinue to improve outcomes in patients with advanced RCC.

Applications for Clinical Practice

The combination of nivolumab plus cabozantinib adds to the growing list of highly active checkpoint inhibitor/TKI combinations for first-line treatment of advanced RCC. With significant higher response rates, improved outcomes, and improvement in the quality of life, this combination will add another standard treatment option for patients with previously untreated advanced RCC.

Study Overview

Objective. To evaluate the efficacy and safety of the combination of nivolumab plus cabozantinib as compared with sunitinib monotherapy in the treatment of previously untreated advanced renal cell carcinoma (RCC).

Design. Multicenter, international, open-label, randomized, phase 3 trial.

Intervention. Patients were randomized in a 1:1 fashion to 1 of 2 treatment arms:

• Arm A: Nivolumab intravenously 240 mg every 2 weeks plus cabozantinib orally 40 mg once daily.
• Arm B: Sunitinib orally 50 mg daily for 4 weeks, followed by 2 weeks off therapy (6-week cycle).

Randomization was stratified by the International Metastatic RCC Database Consortium prognostic risk score (low-, intermediate-, and high-risk). Treatment was continued until disease progression or development of unacceptable toxic side effects with a maximum of 2-year duration of Nivolumab therapy.

Settings and participants. Adults with previously untreated advanced RCC with a clear cell component were eligible for enrollment. Subjects were excluded if they had active central nervous system metastases or active autoimmune disease.

Main outcome measures. The primary outcome of this study was progression-free survival (PFS) as assessed by an independent review committee. Secondary endpoints included overall survival, objective response rate, safety, and PFS as assessed by investigators. All subgroup analyses were prespecified. Efficacy was assessed in the intention-to-treat population, including all patients who underwent randomization.

Main results. A total of 651 patients underwent randomization: 323 to the nivolumab plus cabozantinib group, and 328 to the sunitinib group. Baseline demographics were balanced. The median follow-up period for overall survival (OS) was 18.1 months. The primary reason for treatment discontinuation in any group was disease progression. PFS as indicated by an independent review committee was significantly longer in the nivolumab plus cabozantinib group compared to the sunitinib group (median 16.6 months vs 8.2 months; hazard ratio [HR] 0.51, P < .001). The median OS was not reached for any group. Overall survival was longer in the nivolumab plus cabozantinib group compared to the sunitinib group (HR 0.60, 95% CI: 0.40-0.89; P = .001). The objective response rate was 55.7% with the nivolumab plus cabozantinib group versus 27.1% with sunitinib (P < .001). The complete response rate was 8% in the nivolumab plus cabozantinib group compared to 4.6% in the sunitinib group. The median time to response was 2.8 months with nivolumab plus cabozantinib and 4.2 months in the sunitinib group, while the median duration of response was 20.2 months and 11.5 months, respectively.

Nearly all patients (about 99% in each group) had an adverse event (AE). Hypertension was the most common side effect, with grade 3 or higher seen in 12.5% in the nivolumab plus cabzantinib group and 13.1% in the sunitinib group. Other grade 3 or higher side effects occurring in at least 10% of patients in any group were hyponatremia, diarrhea, palmar-plantar erythrodysesthesia, hypothyroidism, and fatigue. AEs of any cause leading to discontinuation of the therapy occurred in 19.7% in the nivolumab plus cabzantinib group vs 16.9% of the sunitinib group. One death was considered to be treatment-related (small intestinal perforation) in the nivolumab plus cabozantinib group vs 2 treatment-related deaths with sunitinib (pneumonia and respiratory distress). In the nivolumab plus cabozantinib group, 57% of the patients had a dose reduction of cabozantinib and 52% had a reduction in sunitinib dosage.

Using the Functional Assessment of Cancer Therapy-Kidney Symptoms Index, patients in the nivolumab plus cabozantinib group reported better health-related quality of life and less disease-related symptoms compared to the sunitinib group.

Commentary

The treatment landscape for frontline therapy for patients with advanced RCC has rapidly expanded over the last several years and has revolutionized cancer care. Ushered in by the results from the CheckMate 214 study highlighting the efficacy of dual checkpoint inhibition with nivolumab and ipilimumab in intermediate and poor risk patients, several subsequent trials have demonstrated improved outcomes with combination therapy with immune checkpoint inhibitors and tyrosine-kinase inhibitors (TKI). To date, data from Keynote-426 (pembrolizumab plus axitinib vs sunitinib), Javelin Renal 101 (avelumab plus axitinib vs sunitinib) and the CLEAR trial (lenvatinib plus pembrolizumab vs levatinib plus everolimus vs sunitinib) have demonstrated superiority of immune checkpoint inhibitor/TKI combinations over sunitinb in the first-line setting.^1-5

The current phase 3, CheckMate 9ER trial adds yet another dynamic option for patients with advanced clear cell RCC. While cross-trial comparisons are fraught with important caveats, the median PFS of almost 16.6 months and complete response rate of 8% the nivolumab plus cabozantinib group compares favorably with other combinations. Data from the CLEAR study with the combination of lenvatinib and pembrolizumab showed a complete response rate approaching 16%. Importantly, the current study highlights improved quality of life with the combination of cabozantinib and nivolumab compared to sunitinib alone adding to the efficacy and benefits of this combination treatment.

The selection of first line therapy for patients with advanced RCC should be always guided by individual patient characteristics, and any single immune checkpoint inhibitor/TKI combination is not “superior” to any other. Perhaps more importantly is developing an understanding of the overlapping toxicity profiles of checkpoint inhibitors and TKIs. Again, this trial results are consistent with prior studies in terms of the adverse event profile which were not trivial, and almost all patients (99%) experienced AEs. It is important for oncologists to understand the management of the toxicities with these combinations and dose reductions as appropriate. It is worth noting that 19% of patients with nivolumab plus cabozantinib received glucocorticoids for management of immune-related AEs.

While long-term follow-up data will be needed to further understand the durability of response to this combination, nivolumab-cabozantinib represents an exciting new option for patients with advanced clear cell RCC. As we continue to see improvement in outcomes in clear cell histology, further work must focus on optimization of therapy in non-clear cell RCC as this is a population that is not represented in these data sets. Furthermore, future efforts should begin to explore triplet combinations and biomarker driven patient selection for upfront therapy in ordercontinue to improve outcomes in patients with advanced RCC.

Applications for Clinical Practice

The combination of nivolumab plus cabozantinib adds to the growing list of highly active checkpoint inhibitor/TKI combinations for first-line treatment of advanced RCC. With significant higher response rates, improved outcomes, and improvement in the quality of life, this combination will add another standard treatment option for patients with previously untreated advanced RCC.

When a child presents with café au lait macules, when is genetic testing for neurofibromatosis type 1 (NF1) advised?

According to Peter Kannu, MB, ChB, DCH, PhD, a definitive diagnosis of NF1 can be made in most children using National Institutes of Health criteria published in 1988, which include the presence of two of the following:

• Six or more café au lait macules over 5 mm in diameter in prepubertal individuals and over 15 mm in greatest diameter in postpubertal individuals
• Two or more neurofibromas of any type or one plexiform neurofibroma
• Freckling in the axillary or inguinal regions
• Two or more Lisch nodules
• Optic glioma
• A distinctive osseous lesion such as sphenoid dysplasia or thinning of long bone cortex, with or without pseudarthrosis
• Having a first-degree relative with NF1

For example, in the case of an 8-year-old child who presents with multiple café au lait macules, axillary and inguinal freckling, Lisch nodules, and an optic glioma, “the diagnosis is secure and genetic testing is not going to change clinical management or surveillance,” Dr. Kannu, a clinical geneticist at the University of Alberta, Edmonton, said during the annual meeting of the Society for Pediatric Dermatology. “The only reason for genetic testing in this situation is so that we know the mutation in order to inform reproductive risk counseling in the future.”

However, while a diagnosis of NF1 may be suspected in a 6- to 12-month-old presenting with only café au lait macules, “the diagnosis is not secure because the clinical criteria cannot be met. In this situation, a genetic test can speed up the diagnosis,” he added. “Or, if the test is negative, it can decrease your suspicion for NF1 and you wouldn’t refer the child on to an NF1 screening clinic for intensive surveillance.”

Dr. Kannu based his remarks largely on his 5 years working at the multidisciplinary Genodermatoses Clinic at the Hospital for Sick Children, Toronto. Founded in 2015, the clinic is a “one-stop shop” designed to reduce the wait time for diagnosis and management and the number of hospital visits. The team – composed of a dermatologist, medical geneticist, genetic counselor, residents, and fellows – meets to review the charts of each patient before the appointment, and decides on a preliminary management plan. All children are then seen by one of the trainees in the clinic who devises a differential diagnosis that is presented to staff physicians, at which point genetic testing is decided on. A genetics counselor handles follow-up for those who do have genetic testing.

In 2018, Dr. Kannu and colleagues conducted an informal review of 300 patients who had been seen in the clinic. The mean age at referral was about 6 years, 51% were female, and the top three referral sources were pediatricians (51%), dermatologists (18%), and family physicians (18%). Of the 300 children, 84 (28%) were confirmed to have a diagnosis of NF1. Two patients were diagnosed with NF2 and 5% of the total cohort was diagnosed with mosaic NF1 (MNF1), “which is higher than what you would expect based on the incidence of MNF1 in the literature,” he said.

He separates genetic tests for NF1 into one of two categories: Conventional testing, which is offered by most labs in North America; and comprehensive testing, which is offered by the medical genomics lab at the University of Alabama at Birmingham. Conventional testing focuses on the exons, “the protein coding regions of the gene where most of the mutations lie,” he said. “The test also sequences about 20 base pairs or so of the intron exon boundary and may pick up some intronic mutations. But this test will not detect anything that’s hidden deep in the intronic region.”

Comprehensive testing, meanwhile, checks for mutations in both introns and exons.

Dr. Kannu and colleagues published a case of a paraspinal ganglioneuroma in the proband of a large family with mild cutaneous manifestations of NF1, carrying a deep NF1 intronic mutation. “The clinicians were suspicious that this was NF1, rightly so. The diagnosis was only confirmed after we sent samples to the University of Alabama lab where the deep intronic mutation was found,” he said.

The other situation where conventional genetic testing may be negative is in the case of MNF1, where there “are mutations in some cells but not all cells,” Dr. Kannu explained. “It may only be present in the melanocytes of the skin but not present in the lymphocytes in the blood. Mosaicism is characterized by the regional distribution of pigmentary or other NF1 associated findings. Mosaicism may be detected in the blood if it’s more than 20%. Anything less than that is not detected with conventional genetic testing using DNA from blood and requires extracting DNA from a punch biopsy sample of a café au lait macule.”

The differential diagnosis of café au lait macules includes several conditions associated mutations in the RAS pathway. “Neurofibromin is a key signal of molecules which regulates the activation of RAS,” Dr. Kannu said. “A close binding partner of NF1 is SPRED 1. We know that mutations in this gene cause Legius syndrome, a condition which presents with multiple café au lait macules.”

Two key receptors in the RAS pathway include EGFR and KITL, he continued. Mutations in the EGFR receptor cause a rare condition known as neonatal skin and bowel disease, while mutations in the KITL receptor cause familial progressive hyperpigmentation with or without hypopigmentation. “Looking into the pathway and focusing downstream of RAS, we have genes such as RAF and CBL, which are mutated in Noonan syndrome,” he said. “Further along in the pathway you have mutations in PTEN, which cause Cowden syndrome, and mutations in TSC1 and TSC2, which cause tuberous sclerosis. Mutations in any of these genes can also present with café au lait macules.”

During a question-and-answer session Dr. Kannu was asked to comment about revised diagnostic criteria for NF1 based on an international consensus recommendation, such as changes in the eye that require a formal opthalmologic examination, which were recently published.

“We are understanding more about the phenotype,” he said. “If you fulfill diagnostic criteria for NF1, the main reasons for doing genetic testing are, one, if the family wants to know that information, and two, it informs our reproductive risk counseling. Genotype-phenotype correlations do exist in NF1 but they’re not very robust, so that information is not clinically useful.”

Dr. Kannu disclosed that he has been an advisory board member for Ipsen, Novartis, and Alexion. He has also been a primary investigator for QED and Clementia.

[email protected]

When a child presents with café au lait macules, when is genetic testing for neurofibromatosis type 1 (NF1) advised?

According to Peter Kannu, MB, ChB, DCH, PhD, a definitive diagnosis of NF1 can be made in most children using National Institutes of Health criteria published in 1988, which include the presence of two of the following:

• Six or more café au lait macules over 5 mm in diameter in prepubertal individuals and over 15 mm in greatest diameter in postpubertal individuals
• Two or more neurofibromas of any type or one plexiform neurofibroma
• Freckling in the axillary or inguinal regions
• Two or more Lisch nodules
• Optic glioma
• A distinctive osseous lesion such as sphenoid dysplasia or thinning of long bone cortex, with or without pseudarthrosis
• Having a first-degree relative with NF1

For example, in the case of an 8-year-old child who presents with multiple café au lait macules, axillary and inguinal freckling, Lisch nodules, and an optic glioma, “the diagnosis is secure and genetic testing is not going to change clinical management or surveillance,” Dr. Kannu, a clinical geneticist at the University of Alberta, Edmonton, said during the annual meeting of the Society for Pediatric Dermatology. “The only reason for genetic testing in this situation is so that we know the mutation in order to inform reproductive risk counseling in the future.”

However, while a diagnosis of NF1 may be suspected in a 6- to 12-month-old presenting with only café au lait macules, “the diagnosis is not secure because the clinical criteria cannot be met. In this situation, a genetic test can speed up the diagnosis,” he added. “Or, if the test is negative, it can decrease your suspicion for NF1 and you wouldn’t refer the child on to an NF1 screening clinic for intensive surveillance.”

Dr. Kannu based his remarks largely on his 5 years working at the multidisciplinary Genodermatoses Clinic at the Hospital for Sick Children, Toronto. Founded in 2015, the clinic is a “one-stop shop” designed to reduce the wait time for diagnosis and management and the number of hospital visits. The team – composed of a dermatologist, medical geneticist, genetic counselor, residents, and fellows – meets to review the charts of each patient before the appointment, and decides on a preliminary management plan. All children are then seen by one of the trainees in the clinic who devises a differential diagnosis that is presented to staff physicians, at which point genetic testing is decided on. A genetics counselor handles follow-up for those who do have genetic testing.

In 2018, Dr. Kannu and colleagues conducted an informal review of 300 patients who had been seen in the clinic. The mean age at referral was about 6 years, 51% were female, and the top three referral sources were pediatricians (51%), dermatologists (18%), and family physicians (18%). Of the 300 children, 84 (28%) were confirmed to have a diagnosis of NF1. Two patients were diagnosed with NF2 and 5% of the total cohort was diagnosed with mosaic NF1 (MNF1), “which is higher than what you would expect based on the incidence of MNF1 in the literature,” he said.

He separates genetic tests for NF1 into one of two categories: Conventional testing, which is offered by most labs in North America; and comprehensive testing, which is offered by the medical genomics lab at the University of Alabama at Birmingham. Conventional testing focuses on the exons, “the protein coding regions of the gene where most of the mutations lie,” he said. “The test also sequences about 20 base pairs or so of the intron exon boundary and may pick up some intronic mutations. But this test will not detect anything that’s hidden deep in the intronic region.”

Comprehensive testing, meanwhile, checks for mutations in both introns and exons.

Dr. Kannu and colleagues published a case of a paraspinal ganglioneuroma in the proband of a large family with mild cutaneous manifestations of NF1, carrying a deep NF1 intronic mutation. “The clinicians were suspicious that this was NF1, rightly so. The diagnosis was only confirmed after we sent samples to the University of Alabama lab where the deep intronic mutation was found,” he said.

The other situation where conventional genetic testing may be negative is in the case of MNF1, where there “are mutations in some cells but not all cells,” Dr. Kannu explained. “It may only be present in the melanocytes of the skin but not present in the lymphocytes in the blood. Mosaicism is characterized by the regional distribution of pigmentary or other NF1 associated findings. Mosaicism may be detected in the blood if it’s more than 20%. Anything less than that is not detected with conventional genetic testing using DNA from blood and requires extracting DNA from a punch biopsy sample of a café au lait macule.”

The differential diagnosis of café au lait macules includes several conditions associated mutations in the RAS pathway. “Neurofibromin is a key signal of molecules which regulates the activation of RAS,” Dr. Kannu said. “A close binding partner of NF1 is SPRED 1. We know that mutations in this gene cause Legius syndrome, a condition which presents with multiple café au lait macules.”

Two key receptors in the RAS pathway include EGFR and KITL, he continued. Mutations in the EGFR receptor cause a rare condition known as neonatal skin and bowel disease, while mutations in the KITL receptor cause familial progressive hyperpigmentation with or without hypopigmentation. “Looking into the pathway and focusing downstream of RAS, we have genes such as RAF and CBL, which are mutated in Noonan syndrome,” he said. “Further along in the pathway you have mutations in PTEN, which cause Cowden syndrome, and mutations in TSC1 and TSC2, which cause tuberous sclerosis. Mutations in any of these genes can also present with café au lait macules.”

During a question-and-answer session Dr. Kannu was asked to comment about revised diagnostic criteria for NF1 based on an international consensus recommendation, such as changes in the eye that require a formal opthalmologic examination, which were recently published.

“We are understanding more about the phenotype,” he said. “If you fulfill diagnostic criteria for NF1, the main reasons for doing genetic testing are, one, if the family wants to know that information, and two, it informs our reproductive risk counseling. Genotype-phenotype correlations do exist in NF1 but they’re not very robust, so that information is not clinically useful.”

Dr. Kannu disclosed that he has been an advisory board member for Ipsen, Novartis, and Alexion. He has also been a primary investigator for QED and Clementia.

[email protected]

When a child presents with café au lait macules, when is genetic testing for neurofibromatosis type 1 (NF1) advised?

According to Peter Kannu, MB, ChB, DCH, PhD, a definitive diagnosis of NF1 can be made in most children using National Institutes of Health criteria published in 1988, which include the presence of two of the following:

• Six or more café au lait macules over 5 mm in diameter in prepubertal individuals and over 15 mm in greatest diameter in postpubertal individuals
• Two or more neurofibromas of any type or one plexiform neurofibroma
• Freckling in the axillary or inguinal regions
• Two or more Lisch nodules
• Optic glioma
• A distinctive osseous lesion such as sphenoid dysplasia or thinning of long bone cortex, with or without pseudarthrosis
• Having a first-degree relative with NF1

For example, in the case of an 8-year-old child who presents with multiple café au lait macules, axillary and inguinal freckling, Lisch nodules, and an optic glioma, “the diagnosis is secure and genetic testing is not going to change clinical management or surveillance,” Dr. Kannu, a clinical geneticist at the University of Alberta, Edmonton, said during the annual meeting of the Society for Pediatric Dermatology. “The only reason for genetic testing in this situation is so that we know the mutation in order to inform reproductive risk counseling in the future.”

However, while a diagnosis of NF1 may be suspected in a 6- to 12-month-old presenting with only café au lait macules, “the diagnosis is not secure because the clinical criteria cannot be met. In this situation, a genetic test can speed up the diagnosis,” he added. “Or, if the test is negative, it can decrease your suspicion for NF1 and you wouldn’t refer the child on to an NF1 screening clinic for intensive surveillance.”

Dr. Kannu based his remarks largely on his 5 years working at the multidisciplinary Genodermatoses Clinic at the Hospital for Sick Children, Toronto. Founded in 2015, the clinic is a “one-stop shop” designed to reduce the wait time for diagnosis and management and the number of hospital visits. The team – composed of a dermatologist, medical geneticist, genetic counselor, residents, and fellows – meets to review the charts of each patient before the appointment, and decides on a preliminary management plan. All children are then seen by one of the trainees in the clinic who devises a differential diagnosis that is presented to staff physicians, at which point genetic testing is decided on. A genetics counselor handles follow-up for those who do have genetic testing.

In 2018, Dr. Kannu and colleagues conducted an informal review of 300 patients who had been seen in the clinic. The mean age at referral was about 6 years, 51% were female, and the top three referral sources were pediatricians (51%), dermatologists (18%), and family physicians (18%). Of the 300 children, 84 (28%) were confirmed to have a diagnosis of NF1. Two patients were diagnosed with NF2 and 5% of the total cohort was diagnosed with mosaic NF1 (MNF1), “which is higher than what you would expect based on the incidence of MNF1 in the literature,” he said.

He separates genetic tests for NF1 into one of two categories: Conventional testing, which is offered by most labs in North America; and comprehensive testing, which is offered by the medical genomics lab at the University of Alabama at Birmingham. Conventional testing focuses on the exons, “the protein coding regions of the gene where most of the mutations lie,” he said. “The test also sequences about 20 base pairs or so of the intron exon boundary and may pick up some intronic mutations. But this test will not detect anything that’s hidden deep in the intronic region.”

Comprehensive testing, meanwhile, checks for mutations in both introns and exons.

Dr. Kannu and colleagues published a case of a paraspinal ganglioneuroma in the proband of a large family with mild cutaneous manifestations of NF1, carrying a deep NF1 intronic mutation. “The clinicians were suspicious that this was NF1, rightly so. The diagnosis was only confirmed after we sent samples to the University of Alabama lab where the deep intronic mutation was found,” he said.

The other situation where conventional genetic testing may be negative is in the case of MNF1, where there “are mutations in some cells but not all cells,” Dr. Kannu explained. “It may only be present in the melanocytes of the skin but not present in the lymphocytes in the blood. Mosaicism is characterized by the regional distribution of pigmentary or other NF1 associated findings. Mosaicism may be detected in the blood if it’s more than 20%. Anything less than that is not detected with conventional genetic testing using DNA from blood and requires extracting DNA from a punch biopsy sample of a café au lait macule.”

The differential diagnosis of café au lait macules includes several conditions associated mutations in the RAS pathway. “Neurofibromin is a key signal of molecules which regulates the activation of RAS,” Dr. Kannu said. “A close binding partner of NF1 is SPRED 1. We know that mutations in this gene cause Legius syndrome, a condition which presents with multiple café au lait macules.”

Two key receptors in the RAS pathway include EGFR and KITL, he continued. Mutations in the EGFR receptor cause a rare condition known as neonatal skin and bowel disease, while mutations in the KITL receptor cause familial progressive hyperpigmentation with or without hypopigmentation. “Looking into the pathway and focusing downstream of RAS, we have genes such as RAF and CBL, which are mutated in Noonan syndrome,” he said. “Further along in the pathway you have mutations in PTEN, which cause Cowden syndrome, and mutations in TSC1 and TSC2, which cause tuberous sclerosis. Mutations in any of these genes can also present with café au lait macules.”

During a question-and-answer session Dr. Kannu was asked to comment about revised diagnostic criteria for NF1 based on an international consensus recommendation, such as changes in the eye that require a formal opthalmologic examination, which were recently published.

“We are understanding more about the phenotype,” he said. “If you fulfill diagnostic criteria for NF1, the main reasons for doing genetic testing are, one, if the family wants to know that information, and two, it informs our reproductive risk counseling. Genotype-phenotype correlations do exist in NF1 but they’re not very robust, so that information is not clinically useful.”

Dr. Kannu disclosed that he has been an advisory board member for Ipsen, Novartis, and Alexion. He has also been a primary investigator for QED and Clementia.

[email protected]

Not long ago, physicians considered autoinflammatory diseases in pediatric patients as rare, one-in-a-million types of diagnoses, but with the rapid expansion of genetic testing, pediatric rheumatologists like Dilan Dissanayake, MD, PhD, are finding that these diseases aren’t so rare after all.

“Patients with autoinflammatory diseases are all around us, but many go several years without a diagnosis,” Dr. Dissanayake, a rheumatologist at the Autoinflammatory Disease Clinic at the Hospital for Sick Children, Toronto, said during the annual meeting of the Society for Pediatric Dermatology. “The median time to diagnosis has been estimated to be between 2.5 and 5 years. You can imagine that this type of delay can lead to significant issues, not only with quality of life but also morbidity due to unchecked inflammation that can cause organ damage, and in the most severe cases, can result in an early death.”

Effective treatment options such as biologic medications, however, can prevent these negative sequelae if the disease is recognized early. “Dermatologists are in a unique position because they will often be the first specialist to see these patients and therefore make the diagnosis early on and really alter the lives of these patients,” he said.

While it’s common to classify autoinflammatory diseases by presenting features, such as age of onset, associated symptoms, family history/ethnicity, and triggers/alleviating factors for episodes, Dr. Dissanayake prefers to classify them into one of three groups based on pathophysiology, the first being inflammasomopathies. “When activated, an inflammasome is responsible for processing cytokines from the [interleukin]-1 family from the pro form to the active form,” he explained. As a result, if there is dysregulation and overactivity of the inflammasome, there is excessive production of cytokines like IL-1 beta and IL-18 driving the disease.

Clinical characteristics include fevers and organ involvement, notably abdominal pain, nonvasculitic rashes, uveitis, arthritis, elevated white blood cell count/neutrophils, and highly elevated inflammatory markers. Potential treatments include IL-1 blockers.

The second category of autoinflammatory diseases are the interferonopathies, which are caused by overactivity of the antiviral side of the innate immune system. “For example, if you have overactivity of a sensor for a nucleic acid in your cytosol, the cell misinterprets this as a viral infection and will turn on type 1 interferon production,” said Dr. Dissanayake, who is also an assistant professor of pediatrics at the University of Toronto. “As a result, if you have dysregulation of these pathways, you will get excessive type 1 interferon that contributes to your disease manifestations.” Clinical characteristics include fevers and organ involvement, notably vasculitic rashes, interstitial lung disease, and intracranial calcifications. Inflammatory markers may not be as elevated, and autoantibodies may be present. Janus kinase inhibitors are a potential treatment, he said.

The third category of autoinflammatory diseases are the NF-kappaBopathies, which are caused by overactivity of the NF-kappaB signaling pathway. Clinical characteristics can include fevers with organ involvement that can be highly variable but may include mucocutaneous lesions or granulomatous disease as potential clues. Treatment options depend on the pathway that is involved but tumor necrosis factor blockers often play a role because of the importance of NF-KB in this signaling pathway.

From a skin perspective, most of the rashes Dr. Dissanayake and colleagues see in the rheumatology clinic consist of nonspecific dermohypodermatitis: macules, papules, patches, or plaques. The most common monogenic autoinflammatory disease is Familial Mediterranean Fever syndrome, which “commonly presents as an erysipelas-like rash of the lower extremities, typically below the knee, often over the malleolus,” he said.

Other monogenic autoinflammatory diseases with similar rashes include TNF receptor–associated periodic syndrome, Hyper-IgD syndrome, and systemic juvenile idiopathic arthritis.

Other patients present with urticarial rashes, most commonly cryopyrin-associated periodic syndrome (CAPS). “This is a neutrophilic urticaria, so it tends not to be pruritic and can actually sometimes be tender,” he said. “It also tends not to be as transient as your typical urticaria.” Urticarial rashes can also appear with NLRP12-associated autoinflammatory syndrome (familial cold autoinflammatory syndrome–2), PLCgamma2-associated antibody deficiency and immune dysregulation, and Schnitzler syndrome (monoclonal IgM gammopathy).

Patients can also present with pyogenic or pustular lesions, which can appear with pyoderma gangrenosum–related diseases, such as pyogenic arthritis, pyoderma gangrenosum, arthritis (PAPA) syndrome; pyrin-associated inflammation with neutrophilic dermatosis; deficiency of the IL-1 receptor antagonist; deficiency of IL-36 receptor antagonist; and Majeed syndrome, a mutation in the LPIN2 gene.

The mucocutaneous system can also be affected in autoinflammatory diseases, often presenting with symptoms such as periodic fever, aphthous stomatitis, and pharyngitis. Cervical adenitis syndrome is the most common autoinflammatory disease in childhood and can present with aphthous stomatitis, he said, while Behcet’s disease typically presents with oral and genital ulcers. “More recently, monogenic forms of Behcet’s disease have been described, with haploinsufficiency of A20 and RelA, which are both part of the NF-KB pathway,” he said.

Finally, the presence of vasculitic lesions often suggest interferonopathies such as STING-associated vasculopathy in infancy, proteasome-associated autoinflammatory syndrome and deficiency of adenosine deaminase 2.

Dr. Dissanayake noted that dermatologists should suspect an autoimmune disease if a patient has recurrent fevers, evidence of systemic inflammation on blood work, and if multiple organ systems are involved, especially the lungs, gut, joints, CNS system, and eyes. “Many of these patients have episodic and stereotypical attacks,” he said.

“One of the tools we use in the autoinflammatory clinic is to have patients and families keep a symptom diary where they track the dates of the various symptoms. We can review this during their appointment and try to come up with a diagnosis based on the pattern,” he said.

Since many of these diseases are due to a single gene defect, if there’s any evidence to suggest a monogenic cause, consider an autoinflammatory disease, he added. “If there’s a family history, if there’s consanguinity, or if there’s early age of onset – these may all lead you to think about monogenic autoinflammatory disease.”

During a question-and-answer session, a meeting attendee asked what type of workup he recommends when an autoinflammatory syndrome is suspected. “It partially depends on what organ systems you suspect to be involved,” Dr. Dissanayake said. “As a routine baseline, typically what we would check is CBC and differential, [erythrocyte sedimentation rate] and [C-reactive protein], and we screen for liver transaminases and creatinine to check for liver and kidney issues. A serum albumin will also tell you if the patient is hypoalbuminemic, that there’s been some chronic inflammation and they’re starting to leak the protein out. It’s good to check blood work during the flare and off the flare, to get a sense of the persistence of that inflammation.”

Dr. Dissanayake disclosed that he has received research finding from Gilead Sciences and speaker fees from Novartis.

[email protected]

*This story was updated on 9/20/2021.

Not long ago, physicians considered autoinflammatory diseases in pediatric patients as rare, one-in-a-million types of diagnoses, but with the rapid expansion of genetic testing, pediatric rheumatologists like Dilan Dissanayake, MD, PhD, are finding that these diseases aren’t so rare after all.

“Patients with autoinflammatory diseases are all around us, but many go several years without a diagnosis,” Dr. Dissanayake, a rheumatologist at the Autoinflammatory Disease Clinic at the Hospital for Sick Children, Toronto, said during the annual meeting of the Society for Pediatric Dermatology. “The median time to diagnosis has been estimated to be between 2.5 and 5 years. You can imagine that this type of delay can lead to significant issues, not only with quality of life but also morbidity due to unchecked inflammation that can cause organ damage, and in the most severe cases, can result in an early death.”

Effective treatment options such as biologic medications, however, can prevent these negative sequelae if the disease is recognized early. “Dermatologists are in a unique position because they will often be the first specialist to see these patients and therefore make the diagnosis early on and really alter the lives of these patients,” he said.

While it’s common to classify autoinflammatory diseases by presenting features, such as age of onset, associated symptoms, family history/ethnicity, and triggers/alleviating factors for episodes, Dr. Dissanayake prefers to classify them into one of three groups based on pathophysiology, the first being inflammasomopathies. “When activated, an inflammasome is responsible for processing cytokines from the [interleukin]-1 family from the pro form to the active form,” he explained. As a result, if there is dysregulation and overactivity of the inflammasome, there is excessive production of cytokines like IL-1 beta and IL-18 driving the disease.

Clinical characteristics include fevers and organ involvement, notably abdominal pain, nonvasculitic rashes, uveitis, arthritis, elevated white blood cell count/neutrophils, and highly elevated inflammatory markers. Potential treatments include IL-1 blockers.

The second category of autoinflammatory diseases are the interferonopathies, which are caused by overactivity of the antiviral side of the innate immune system. “For example, if you have overactivity of a sensor for a nucleic acid in your cytosol, the cell misinterprets this as a viral infection and will turn on type 1 interferon production,” said Dr. Dissanayake, who is also an assistant professor of pediatrics at the University of Toronto. “As a result, if you have dysregulation of these pathways, you will get excessive type 1 interferon that contributes to your disease manifestations.” Clinical characteristics include fevers and organ involvement, notably vasculitic rashes, interstitial lung disease, and intracranial calcifications. Inflammatory markers may not be as elevated, and autoantibodies may be present. Janus kinase inhibitors are a potential treatment, he said.

The third category of autoinflammatory diseases are the NF-kappaBopathies, which are caused by overactivity of the NF-kappaB signaling pathway. Clinical characteristics can include fevers with organ involvement that can be highly variable but may include mucocutaneous lesions or granulomatous disease as potential clues. Treatment options depend on the pathway that is involved but tumor necrosis factor blockers often play a role because of the importance of NF-KB in this signaling pathway.

From a skin perspective, most of the rashes Dr. Dissanayake and colleagues see in the rheumatology clinic consist of nonspecific dermohypodermatitis: macules, papules, patches, or plaques. The most common monogenic autoinflammatory disease is Familial Mediterranean Fever syndrome, which “commonly presents as an erysipelas-like rash of the lower extremities, typically below the knee, often over the malleolus,” he said.

Other monogenic autoinflammatory diseases with similar rashes include TNF receptor–associated periodic syndrome, Hyper-IgD syndrome, and systemic juvenile idiopathic arthritis.

Other patients present with urticarial rashes, most commonly cryopyrin-associated periodic syndrome (CAPS). “This is a neutrophilic urticaria, so it tends not to be pruritic and can actually sometimes be tender,” he said. “It also tends not to be as transient as your typical urticaria.” Urticarial rashes can also appear with NLRP12-associated autoinflammatory syndrome (familial cold autoinflammatory syndrome–2), PLCgamma2-associated antibody deficiency and immune dysregulation, and Schnitzler syndrome (monoclonal IgM gammopathy).

Patients can also present with pyogenic or pustular lesions, which can appear with pyoderma gangrenosum–related diseases, such as pyogenic arthritis, pyoderma gangrenosum, arthritis (PAPA) syndrome; pyrin-associated inflammation with neutrophilic dermatosis; deficiency of the IL-1 receptor antagonist; deficiency of IL-36 receptor antagonist; and Majeed syndrome, a mutation in the LPIN2 gene.

The mucocutaneous system can also be affected in autoinflammatory diseases, often presenting with symptoms such as periodic fever, aphthous stomatitis, and pharyngitis. Cervical adenitis syndrome is the most common autoinflammatory disease in childhood and can present with aphthous stomatitis, he said, while Behcet’s disease typically presents with oral and genital ulcers. “More recently, monogenic forms of Behcet’s disease have been described, with haploinsufficiency of A20 and RelA, which are both part of the NF-KB pathway,” he said.

Finally, the presence of vasculitic lesions often suggest interferonopathies such as STING-associated vasculopathy in infancy, proteasome-associated autoinflammatory syndrome and deficiency of adenosine deaminase 2.

Dr. Dissanayake noted that dermatologists should suspect an autoimmune disease if a patient has recurrent fevers, evidence of systemic inflammation on blood work, and if multiple organ systems are involved, especially the lungs, gut, joints, CNS system, and eyes. “Many of these patients have episodic and stereotypical attacks,” he said.

“One of the tools we use in the autoinflammatory clinic is to have patients and families keep a symptom diary where they track the dates of the various symptoms. We can review this during their appointment and try to come up with a diagnosis based on the pattern,” he said.

Since many of these diseases are due to a single gene defect, if there’s any evidence to suggest a monogenic cause, consider an autoinflammatory disease, he added. “If there’s a family history, if there’s consanguinity, or if there’s early age of onset – these may all lead you to think about monogenic autoinflammatory disease.”

During a question-and-answer session, a meeting attendee asked what type of workup he recommends when an autoinflammatory syndrome is suspected. “It partially depends on what organ systems you suspect to be involved,” Dr. Dissanayake said. “As a routine baseline, typically what we would check is CBC and differential, [erythrocyte sedimentation rate] and [C-reactive protein], and we screen for liver transaminases and creatinine to check for liver and kidney issues. A serum albumin will also tell you if the patient is hypoalbuminemic, that there’s been some chronic inflammation and they’re starting to leak the protein out. It’s good to check blood work during the flare and off the flare, to get a sense of the persistence of that inflammation.”

Dr. Dissanayake disclosed that he has received research finding from Gilead Sciences and speaker fees from Novartis.

[email protected]

*This story was updated on 9/20/2021.

Not long ago, physicians considered autoinflammatory diseases in pediatric patients as rare, one-in-a-million types of diagnoses, but with the rapid expansion of genetic testing, pediatric rheumatologists like Dilan Dissanayake, MD, PhD, are finding that these diseases aren’t so rare after all.

“Patients with autoinflammatory diseases are all around us, but many go several years without a diagnosis,” Dr. Dissanayake, a rheumatologist at the Autoinflammatory Disease Clinic at the Hospital for Sick Children, Toronto, said during the annual meeting of the Society for Pediatric Dermatology. “The median time to diagnosis has been estimated to be between 2.5 and 5 years. You can imagine that this type of delay can lead to significant issues, not only with quality of life but also morbidity due to unchecked inflammation that can cause organ damage, and in the most severe cases, can result in an early death.”

Effective treatment options such as biologic medications, however, can prevent these negative sequelae if the disease is recognized early. “Dermatologists are in a unique position because they will often be the first specialist to see these patients and therefore make the diagnosis early on and really alter the lives of these patients,” he said.

While it’s common to classify autoinflammatory diseases by presenting features, such as age of onset, associated symptoms, family history/ethnicity, and triggers/alleviating factors for episodes, Dr. Dissanayake prefers to classify them into one of three groups based on pathophysiology, the first being inflammasomopathies. “When activated, an inflammasome is responsible for processing cytokines from the [interleukin]-1 family from the pro form to the active form,” he explained. As a result, if there is dysregulation and overactivity of the inflammasome, there is excessive production of cytokines like IL-1 beta and IL-18 driving the disease.

Clinical characteristics include fevers and organ involvement, notably abdominal pain, nonvasculitic rashes, uveitis, arthritis, elevated white blood cell count/neutrophils, and highly elevated inflammatory markers. Potential treatments include IL-1 blockers.

The second category of autoinflammatory diseases are the interferonopathies, which are caused by overactivity of the antiviral side of the innate immune system. “For example, if you have overactivity of a sensor for a nucleic acid in your cytosol, the cell misinterprets this as a viral infection and will turn on type 1 interferon production,” said Dr. Dissanayake, who is also an assistant professor of pediatrics at the University of Toronto. “As a result, if you have dysregulation of these pathways, you will get excessive type 1 interferon that contributes to your disease manifestations.” Clinical characteristics include fevers and organ involvement, notably vasculitic rashes, interstitial lung disease, and intracranial calcifications. Inflammatory markers may not be as elevated, and autoantibodies may be present. Janus kinase inhibitors are a potential treatment, he said.

The third category of autoinflammatory diseases are the NF-kappaBopathies, which are caused by overactivity of the NF-kappaB signaling pathway. Clinical characteristics can include fevers with organ involvement that can be highly variable but may include mucocutaneous lesions or granulomatous disease as potential clues. Treatment options depend on the pathway that is involved but tumor necrosis factor blockers often play a role because of the importance of NF-KB in this signaling pathway.

From a skin perspective, most of the rashes Dr. Dissanayake and colleagues see in the rheumatology clinic consist of nonspecific dermohypodermatitis: macules, papules, patches, or plaques. The most common monogenic autoinflammatory disease is Familial Mediterranean Fever syndrome, which “commonly presents as an erysipelas-like rash of the lower extremities, typically below the knee, often over the malleolus,” he said.

Other monogenic autoinflammatory diseases with similar rashes include TNF receptor–associated periodic syndrome, Hyper-IgD syndrome, and systemic juvenile idiopathic arthritis.

Other patients present with urticarial rashes, most commonly cryopyrin-associated periodic syndrome (CAPS). “This is a neutrophilic urticaria, so it tends not to be pruritic and can actually sometimes be tender,” he said. “It also tends not to be as transient as your typical urticaria.” Urticarial rashes can also appear with NLRP12-associated autoinflammatory syndrome (familial cold autoinflammatory syndrome–2), PLCgamma2-associated antibody deficiency and immune dysregulation, and Schnitzler syndrome (monoclonal IgM gammopathy).

Patients can also present with pyogenic or pustular lesions, which can appear with pyoderma gangrenosum–related diseases, such as pyogenic arthritis, pyoderma gangrenosum, arthritis (PAPA) syndrome; pyrin-associated inflammation with neutrophilic dermatosis; deficiency of the IL-1 receptor antagonist; deficiency of IL-36 receptor antagonist; and Majeed syndrome, a mutation in the LPIN2 gene.

The mucocutaneous system can also be affected in autoinflammatory diseases, often presenting with symptoms such as periodic fever, aphthous stomatitis, and pharyngitis. Cervical adenitis syndrome is the most common autoinflammatory disease in childhood and can present with aphthous stomatitis, he said, while Behcet’s disease typically presents with oral and genital ulcers. “More recently, monogenic forms of Behcet’s disease have been described, with haploinsufficiency of A20 and RelA, which are both part of the NF-KB pathway,” he said.

Finally, the presence of vasculitic lesions often suggest interferonopathies such as STING-associated vasculopathy in infancy, proteasome-associated autoinflammatory syndrome and deficiency of adenosine deaminase 2.

Dr. Dissanayake noted that dermatologists should suspect an autoimmune disease if a patient has recurrent fevers, evidence of systemic inflammation on blood work, and if multiple organ systems are involved, especially the lungs, gut, joints, CNS system, and eyes. “Many of these patients have episodic and stereotypical attacks,” he said.

“One of the tools we use in the autoinflammatory clinic is to have patients and families keep a symptom diary where they track the dates of the various symptoms. We can review this during their appointment and try to come up with a diagnosis based on the pattern,” he said.

Since many of these diseases are due to a single gene defect, if there’s any evidence to suggest a monogenic cause, consider an autoinflammatory disease, he added. “If there’s a family history, if there’s consanguinity, or if there’s early age of onset – these may all lead you to think about monogenic autoinflammatory disease.”

During a question-and-answer session, a meeting attendee asked what type of workup he recommends when an autoinflammatory syndrome is suspected. “It partially depends on what organ systems you suspect to be involved,” Dr. Dissanayake said. “As a routine baseline, typically what we would check is CBC and differential, [erythrocyte sedimentation rate] and [C-reactive protein], and we screen for liver transaminases and creatinine to check for liver and kidney issues. A serum albumin will also tell you if the patient is hypoalbuminemic, that there’s been some chronic inflammation and they’re starting to leak the protein out. It’s good to check blood work during the flare and off the flare, to get a sense of the persistence of that inflammation.”

Dr. Dissanayake disclosed that he has received research finding from Gilead Sciences and speaker fees from Novartis.

[email protected]

*This story was updated on 9/20/2021.

Five of the more uncommon dermatologic disorders – sarcoidosis, Rosai-Dorfman disease, Erdheim-Chester disease, eosinophilic fasciitis, and cutaneous Crohn disease – are linked to internal diseases and may spawn misdiagnoses, a dermatologist told colleagues.

“Proper diagnosis can lead to an effective management in our patients,” said Jeffrey Callen, MD, professor of medicine and chief of dermatology at the University of Louisville (Ky.), who spoke at the Inaugural Symposium for Inflammatory Skin Disease.
 

Sarcoidosis

The cause of sarcoidosis, an inflammatory disease that tends to affect the lungs, “is unknown, but it’s probably an immunologic disorder,” Dr. Callen said, “and there probably is a genetic predisposition.” About 20%-25% of patients with sarcoidosis have skin lesions that are either “specific” (a biopsy that reveals a noncaseating – “naked” – granuloma) or “nonspecific” (most commonly, erythema nodosum, or EN).

The specific lesions in sarcoidosis may occur in parts of the body, such as the knees, which were injured earlier in life and may have taken in foreign bodies, Dr. Callen said. As for nonspecific lesions, about 20% of patients with EN have an acute, self-limiting form of sarcoidosis. “These patients will have bilateral hilar lymphadenopathy, anterior uveitis, and polyarthritis. It’s generally treated symptomatically because it goes away on its own.”

He cautioned colleagues to beware of indurated, infiltrative facial lesions known as lupus pernio that are commonly found on the nose. They’re more prevalent in Black patients and possibly women, who are at higher risk of manifestations outside the skin, he said. “If you have it along the nasal rim, you should look into the upper respiratory tract for involvement.”

Dr. Callen recommends an extensive workup in patients with suspected sarcoidosis, including biopsy (with the exception of EN lesions), cultures and special stains, and screening when appropriate, for disease in organs such as the eyes, lungs, heart, and kidneys.

As for treatment, “the disease is in the dermis, and some topical therapies are not highly effective,” he said. There are injections that can be given, including corticosteroids, and there are a variety of oral treatments that are all off label.” These include corticosteroids, antimalarials, allopurinol, and tetracyclines, among several others. Subcutaneous and intravenous treatments are also options, along with surgery and laser therapy to treat specific lesions.

Rosai-Dorfman disease

This rare disorder is caused by overproduction of certain white blood cells in the lymph nodes, which can cause nodular lesions. The disease most often appears in children and young adults, often Black individuals and males. It is fatal in as many as 11% of patients, justifying aggressive treatment in patients with aggressive disease, Dr. Callen said. When it’s limited to the skin, however, “nothing may need to be done.”

Dr. Callen highlighted consensus recommendations about diagnosis and treatment of Rosai-Dorfman disease published in 2018.

He also noted the existence of cutaneous Rosai-Dorfman disease, a “solitary process” that appears more commonly in females, and in people of Asian heritage, compared with White individuals. It is characterized by single, clustered or widespread lesions: They can be xanthomatous, erythematous, or red-brown papules, nodules, and plaques. They’re acneiform, pustular, giant granuloma annulare–like, subcutaneous, and vasculitis-like, he said.

While Rosai-Dorfman disease can be linked to lymphoma, hypothyroidism, and lupus erythematosus, “nothing necessarily needs to be done when it’s skin-limited since it can be self-resolving,” he noted. Other treatments include radiotherapy, cryotherapy, excision, topical and oral corticosteroids, thalidomide, and methotrexate.

The disease can be serious, and is fatal in 5% of cases. When a vital organ is threatened, Dr. Callen suggested surgery, chemotherapy, or radiation.
 

Erdheim-Chester disease

This disease – which is extremely rare, with just 500 cases noted before 2014 – occurs when the body overproduces macrophages. It’s most common in middle-aged people and in men, who make up 75% of cases. About a quarter of patients develop skin lesions: Red-brown to yellow nodules and xanthelasma-like indurated plaques on the eyelids, scalp, neck, trunk, and axillae, and “other cutaneous manifestations have been reported in patients,” Dr. Callen said.

The disease also frequently affects the bones, large vessels, heart, lungs, and central nervous system. Interferon-alpha is the first-line treatment, and there are several other alternative therapies, although 5-year survival (68%) is poor, and it is especially likely to be fatal in those with central nervous system involvement.
 

Eosinophilic fasciitis

Eosinophilic fasciitis (EF) “is a disorder of unknown etiology that causes sclerosis of the skin” without Raynaud’s phenomenon, Dr. Callen said. Look for erythema, swelling, and induration of the extremities that is accompanied by peripheral eosinophilia, and if necessary, confirm the diagnosis with full skin-to-muscle biopsy or MRI.

There are many possible triggers, including strenuous exercise, initiation with hemodialysis, radiation therapy and burns, and graft-versus-host disease. Other potential causes include exposure to medications such as statins, phenytoin, ramipril, subcutaneous heparin, and immune checkpoint inhibitor therapy. The disorder is also linked to autoimmune and hematologic disorders.

Dr. Callen, who highlighted EF guidelines published in 2018, said treatments include physical therapy, prednisone, methotrexate, mycophenolate, and hydroxychloroquine.
 

Metastatic Crohn’s disease

This is a rare granulomatous inflammation of skin that often affects the genitals, especially in children. It is noncontiguous with the GI tract, and severity of skin involvement does not always parallel the severity of the disease in the GI tract, Dr. Callen said. However, the condition can occur before or simultaneously with the development of GI disease, or after GI surgery.

He highlighted a review of metastatic Crohn’s disease, published in 2014, and noted that there are multiple treatments, including systemic corticosteroids, tumor necrosis factor–alpha inhibitors, and topical therapies.

Dr. Callen reported no relevant disclosures.

Five of the more uncommon dermatologic disorders – sarcoidosis, Rosai-Dorfman disease, Erdheim-Chester disease, eosinophilic fasciitis, and cutaneous Crohn disease – are linked to internal diseases and may spawn misdiagnoses, a dermatologist told colleagues.

“Proper diagnosis can lead to an effective management in our patients,” said Jeffrey Callen, MD, professor of medicine and chief of dermatology at the University of Louisville (Ky.), who spoke at the Inaugural Symposium for Inflammatory Skin Disease.
 

Sarcoidosis

The cause of sarcoidosis, an inflammatory disease that tends to affect the lungs, “is unknown, but it’s probably an immunologic disorder,” Dr. Callen said, “and there probably is a genetic predisposition.” About 20%-25% of patients with sarcoidosis have skin lesions that are either “specific” (a biopsy that reveals a noncaseating – “naked” – granuloma) or “nonspecific” (most commonly, erythema nodosum, or EN).

The specific lesions in sarcoidosis may occur in parts of the body, such as the knees, which were injured earlier in life and may have taken in foreign bodies, Dr. Callen said. As for nonspecific lesions, about 20% of patients with EN have an acute, self-limiting form of sarcoidosis. “These patients will have bilateral hilar lymphadenopathy, anterior uveitis, and polyarthritis. It’s generally treated symptomatically because it goes away on its own.”

He cautioned colleagues to beware of indurated, infiltrative facial lesions known as lupus pernio that are commonly found on the nose. They’re more prevalent in Black patients and possibly women, who are at higher risk of manifestations outside the skin, he said. “If you have it along the nasal rim, you should look into the upper respiratory tract for involvement.”

Dr. Callen recommends an extensive workup in patients with suspected sarcoidosis, including biopsy (with the exception of EN lesions), cultures and special stains, and screening when appropriate, for disease in organs such as the eyes, lungs, heart, and kidneys.

As for treatment, “the disease is in the dermis, and some topical therapies are not highly effective,” he said. There are injections that can be given, including corticosteroids, and there are a variety of oral treatments that are all off label.” These include corticosteroids, antimalarials, allopurinol, and tetracyclines, among several others. Subcutaneous and intravenous treatments are also options, along with surgery and laser therapy to treat specific lesions.

Rosai-Dorfman disease

This rare disorder is caused by overproduction of certain white blood cells in the lymph nodes, which can cause nodular lesions. The disease most often appears in children and young adults, often Black individuals and males. It is fatal in as many as 11% of patients, justifying aggressive treatment in patients with aggressive disease, Dr. Callen said. When it’s limited to the skin, however, “nothing may need to be done.”

Dr. Callen highlighted consensus recommendations about diagnosis and treatment of Rosai-Dorfman disease published in 2018.

He also noted the existence of cutaneous Rosai-Dorfman disease, a “solitary process” that appears more commonly in females, and in people of Asian heritage, compared with White individuals. It is characterized by single, clustered or widespread lesions: They can be xanthomatous, erythematous, or red-brown papules, nodules, and plaques. They’re acneiform, pustular, giant granuloma annulare–like, subcutaneous, and vasculitis-like, he said.

While Rosai-Dorfman disease can be linked to lymphoma, hypothyroidism, and lupus erythematosus, “nothing necessarily needs to be done when it’s skin-limited since it can be self-resolving,” he noted. Other treatments include radiotherapy, cryotherapy, excision, topical and oral corticosteroids, thalidomide, and methotrexate.

The disease can be serious, and is fatal in 5% of cases. When a vital organ is threatened, Dr. Callen suggested surgery, chemotherapy, or radiation.
 

Erdheim-Chester disease

This disease – which is extremely rare, with just 500 cases noted before 2014 – occurs when the body overproduces macrophages. It’s most common in middle-aged people and in men, who make up 75% of cases. About a quarter of patients develop skin lesions: Red-brown to yellow nodules and xanthelasma-like indurated plaques on the eyelids, scalp, neck, trunk, and axillae, and “other cutaneous manifestations have been reported in patients,” Dr. Callen said.

The disease also frequently affects the bones, large vessels, heart, lungs, and central nervous system. Interferon-alpha is the first-line treatment, and there are several other alternative therapies, although 5-year survival (68%) is poor, and it is especially likely to be fatal in those with central nervous system involvement.
 

Eosinophilic fasciitis

Eosinophilic fasciitis (EF) “is a disorder of unknown etiology that causes sclerosis of the skin” without Raynaud’s phenomenon, Dr. Callen said. Look for erythema, swelling, and induration of the extremities that is accompanied by peripheral eosinophilia, and if necessary, confirm the diagnosis with full skin-to-muscle biopsy or MRI.

There are many possible triggers, including strenuous exercise, initiation with hemodialysis, radiation therapy and burns, and graft-versus-host disease. Other potential causes include exposure to medications such as statins, phenytoin, ramipril, subcutaneous heparin, and immune checkpoint inhibitor therapy. The disorder is also linked to autoimmune and hematologic disorders.

Dr. Callen, who highlighted EF guidelines published in 2018, said treatments include physical therapy, prednisone, methotrexate, mycophenolate, and hydroxychloroquine.
 

Metastatic Crohn’s disease

This is a rare granulomatous inflammation of skin that often affects the genitals, especially in children. It is noncontiguous with the GI tract, and severity of skin involvement does not always parallel the severity of the disease in the GI tract, Dr. Callen said. However, the condition can occur before or simultaneously with the development of GI disease, or after GI surgery.

He highlighted a review of metastatic Crohn’s disease, published in 2014, and noted that there are multiple treatments, including systemic corticosteroids, tumor necrosis factor–alpha inhibitors, and topical therapies.

Dr. Callen reported no relevant disclosures.

Five of the more uncommon dermatologic disorders – sarcoidosis, Rosai-Dorfman disease, Erdheim-Chester disease, eosinophilic fasciitis, and cutaneous Crohn disease – are linked to internal diseases and may spawn misdiagnoses, a dermatologist told colleagues.

“Proper diagnosis can lead to an effective management in our patients,” said Jeffrey Callen, MD, professor of medicine and chief of dermatology at the University of Louisville (Ky.), who spoke at the Inaugural Symposium for Inflammatory Skin Disease.
 

Sarcoidosis

The cause of sarcoidosis, an inflammatory disease that tends to affect the lungs, “is unknown, but it’s probably an immunologic disorder,” Dr. Callen said, “and there probably is a genetic predisposition.” About 20%-25% of patients with sarcoidosis have skin lesions that are either “specific” (a biopsy that reveals a noncaseating – “naked” – granuloma) or “nonspecific” (most commonly, erythema nodosum, or EN).

The specific lesions in sarcoidosis may occur in parts of the body, such as the knees, which were injured earlier in life and may have taken in foreign bodies, Dr. Callen said. As for nonspecific lesions, about 20% of patients with EN have an acute, self-limiting form of sarcoidosis. “These patients will have bilateral hilar lymphadenopathy, anterior uveitis, and polyarthritis. It’s generally treated symptomatically because it goes away on its own.”

He cautioned colleagues to beware of indurated, infiltrative facial lesions known as lupus pernio that are commonly found on the nose. They’re more prevalent in Black patients and possibly women, who are at higher risk of manifestations outside the skin, he said. “If you have it along the nasal rim, you should look into the upper respiratory tract for involvement.”

Dr. Callen recommends an extensive workup in patients with suspected sarcoidosis, including biopsy (with the exception of EN lesions), cultures and special stains, and screening when appropriate, for disease in organs such as the eyes, lungs, heart, and kidneys.

As for treatment, “the disease is in the dermis, and some topical therapies are not highly effective,” he said. There are injections that can be given, including corticosteroids, and there are a variety of oral treatments that are all off label.” These include corticosteroids, antimalarials, allopurinol, and tetracyclines, among several others. Subcutaneous and intravenous treatments are also options, along with surgery and laser therapy to treat specific lesions.

Rosai-Dorfman disease

This rare disorder is caused by overproduction of certain white blood cells in the lymph nodes, which can cause nodular lesions. The disease most often appears in children and young adults, often Black individuals and males. It is fatal in as many as 11% of patients, justifying aggressive treatment in patients with aggressive disease, Dr. Callen said. When it’s limited to the skin, however, “nothing may need to be done.”

Dr. Callen highlighted consensus recommendations about diagnosis and treatment of Rosai-Dorfman disease published in 2018.

He also noted the existence of cutaneous Rosai-Dorfman disease, a “solitary process” that appears more commonly in females, and in people of Asian heritage, compared with White individuals. It is characterized by single, clustered or widespread lesions: They can be xanthomatous, erythematous, or red-brown papules, nodules, and plaques. They’re acneiform, pustular, giant granuloma annulare–like, subcutaneous, and vasculitis-like, he said.

While Rosai-Dorfman disease can be linked to lymphoma, hypothyroidism, and lupus erythematosus, “nothing necessarily needs to be done when it’s skin-limited since it can be self-resolving,” he noted. Other treatments include radiotherapy, cryotherapy, excision, topical and oral corticosteroids, thalidomide, and methotrexate.

The disease can be serious, and is fatal in 5% of cases. When a vital organ is threatened, Dr. Callen suggested surgery, chemotherapy, or radiation.
 

Erdheim-Chester disease

This disease – which is extremely rare, with just 500 cases noted before 2014 – occurs when the body overproduces macrophages. It’s most common in middle-aged people and in men, who make up 75% of cases. About a quarter of patients develop skin lesions: Red-brown to yellow nodules and xanthelasma-like indurated plaques on the eyelids, scalp, neck, trunk, and axillae, and “other cutaneous manifestations have been reported in patients,” Dr. Callen said.

The disease also frequently affects the bones, large vessels, heart, lungs, and central nervous system. Interferon-alpha is the first-line treatment, and there are several other alternative therapies, although 5-year survival (68%) is poor, and it is especially likely to be fatal in those with central nervous system involvement.
 

Eosinophilic fasciitis

Eosinophilic fasciitis (EF) “is a disorder of unknown etiology that causes sclerosis of the skin” without Raynaud’s phenomenon, Dr. Callen said. Look for erythema, swelling, and induration of the extremities that is accompanied by peripheral eosinophilia, and if necessary, confirm the diagnosis with full skin-to-muscle biopsy or MRI.

There are many possible triggers, including strenuous exercise, initiation with hemodialysis, radiation therapy and burns, and graft-versus-host disease. Other potential causes include exposure to medications such as statins, phenytoin, ramipril, subcutaneous heparin, and immune checkpoint inhibitor therapy. The disorder is also linked to autoimmune and hematologic disorders.

Dr. Callen, who highlighted EF guidelines published in 2018, said treatments include physical therapy, prednisone, methotrexate, mycophenolate, and hydroxychloroquine.
 

Metastatic Crohn’s disease

This is a rare granulomatous inflammation of skin that often affects the genitals, especially in children. It is noncontiguous with the GI tract, and severity of skin involvement does not always parallel the severity of the disease in the GI tract, Dr. Callen said. However, the condition can occur before or simultaneously with the development of GI disease, or after GI surgery.

He highlighted a review of metastatic Crohn’s disease, published in 2014, and noted that there are multiple treatments, including systemic corticosteroids, tumor necrosis factor–alpha inhibitors, and topical therapies.

Dr. Callen reported no relevant disclosures.

An experimental gene therapy produced marked clinical improvement in children with aromatic L-amino acid decarboxylase (AADC) deficiency, a rare genetic disorder that affects the synthesis of key neurotransmitters to cause severe developmental and motor disability.

In an article published July 12, 2021, in Nature Communications, a group of researchers based at the University of California, San Francisco, and Ohio State University, Columbus, described results from seven children ages 4-9 with AADC deficiency who underwent a novel form of surgery to deliver a viral vector expressing the human AADC gene to the midbrain.

Previous trials of this gene therapy in children with AADC deficiency targeted a different region of the brain, the putamen, with only slight clinical improvement. Here, investigators chose two midbrain regions – the substantia nigra pars compacta and the ventral tegmental area – in the hope of restoring healthy AADC enzyme activity in those neurons.

The study’s corresponding author, Krystof Bankiewicz, MD, PhD, professor and vice chair of research at Ohio State University, director of the Brain Health and Performance Center at Ohio State University, and professor emeritus and vice chair for research at UCSF, said in an interview that the brain regions chosen for this trial resulted from years of efforts to identify an ideal target in this disease.

“This particular vector undergoes axonal transport,” he said. “If you inject it into specific regions of the brain it will be transported into the terminals [of the nerve fibers]. And by looking at the imaging of these patients, we found that they still have the wiring in the brain that’s so critical. So we decided to aim at a much more difficult target, going directly to the source of the problem, which is the substantia nigra and the ventral tegmental area. This targets two critical pathways in the brain: one that drives motor responses and another that controls emotions.”
 

‘Surprising’ improvement seen

The children in the study – four girls and three boys – underwent surgery from 2016 to the end of 2018, and were divided into two dose cohorts, with one receiving three times the amount of vector as the other. Both groups, however, saw similar levels of improvement.

All but one child saw complete resolution of a hallmark symptom of the disease – oculogyric crises, or prolonged spasms of muscles controlling eye movement – within 3 months of surgery. Of the children followed at least 18 months, six attained head control within a year, two became able to eat and drink by mouth, and four gained the ability to sit up unaided in that time. At 18 months one child had learned to speak 50 words using an augmentative communication device.

One child died unexpectedly 7 months after the procedure, Dr. Bankiewicz said in an interview. This death appeared to be caused by cardiac complications of his disease, Dr. Bankiewicz said, which are common in AADC deficiency.

While the investigators are now looking at delivering the AADC gene therapy in younger children – who were excluded from this trial because of safety concerns surrounding the complex procedure – investigators were surprised by the level of improvement seen in older children.

“We initially didn’t believe – at least not all of us – that we could actually make an impact in the older patients, and that is not the case,” said Dr. Bankiewicz, who has since used the same gene therapy on a compassionate-use basis in Europe and seen durable clinical improvement in patients as old as 26. “The fact that we saw a response in that patient tells us something about how incredibly plastic the brain is.”

While the new study does not detail improvements in the children’s social and emotional well-being, Dr. Bankiewicz said these, too, were pronounced. “Kids fall into oculogyric crises in stress-inducing situation. They might be in a stroller being taken for a walk, and something in the environment would stress them. Sometimes they had to be kept in a dark room isolated from stress.” Following the gene therapy, “they’re laughing, they’re social, they can interact with their environment. It’s really touching to see them able to develop a bond now with their caregivers.”
 

Implication for other disorders

Dr. Bankiewicz and colleagues have previously used the same gene to boost AADC activity in patients with Parkinson’s disease. The group is also in trials to deliver a neuroprotective gene to the brains of people with early-stage Alzheimer’s disease, and a gene-silencing therapy in patients with Huntington’s disease. They will also continue recruiting pediatric patients for trials of the AADC gene therapy.

“We have been developing a method for safely treating younger children, so now we will go to 3 years old and maybe even below,” Dr. Bankiewicz said. “Earlier is probably better, but for technical and safety considerations we needed to be conservative first. It is hugely stressful to go into very sick patients with that type of therapy in that part of the brain. We had to get it right the first time, and it looks like we did.”

The study was funded by the National Institutes of Health, the AADC Research Trust, the Pediatric Neurotransmitter Disease Association, and Ohio State University, with materials and technical support donated by ClearPoint Neuro. Several coauthors disclosed financial relationships with producers of diagnostic tests or biotechnology firms. Dr. Bankiewicz is a founder and shareholder of Brain Neurotherapy Bio, a company that develops gene therapies for Parkinson’s and other diseases.


 

An experimental gene therapy produced marked clinical improvement in children with aromatic L-amino acid decarboxylase (AADC) deficiency, a rare genetic disorder that affects the synthesis of key neurotransmitters to cause severe developmental and motor disability.

In an article published July 12, 2021, in Nature Communications, a group of researchers based at the University of California, San Francisco, and Ohio State University, Columbus, described results from seven children ages 4-9 with AADC deficiency who underwent a novel form of surgery to deliver a viral vector expressing the human AADC gene to the midbrain.

Previous trials of this gene therapy in children with AADC deficiency targeted a different region of the brain, the putamen, with only slight clinical improvement. Here, investigators chose two midbrain regions – the substantia nigra pars compacta and the ventral tegmental area – in the hope of restoring healthy AADC enzyme activity in those neurons.

The study’s corresponding author, Krystof Bankiewicz, MD, PhD, professor and vice chair of research at Ohio State University, director of the Brain Health and Performance Center at Ohio State University, and professor emeritus and vice chair for research at UCSF, said in an interview that the brain regions chosen for this trial resulted from years of efforts to identify an ideal target in this disease.

“This particular vector undergoes axonal transport,” he said. “If you inject it into specific regions of the brain it will be transported into the terminals [of the nerve fibers]. And by looking at the imaging of these patients, we found that they still have the wiring in the brain that’s so critical. So we decided to aim at a much more difficult target, going directly to the source of the problem, which is the substantia nigra and the ventral tegmental area. This targets two critical pathways in the brain: one that drives motor responses and another that controls emotions.”
 

‘Surprising’ improvement seen

The children in the study – four girls and three boys – underwent surgery from 2016 to the end of 2018, and were divided into two dose cohorts, with one receiving three times the amount of vector as the other. Both groups, however, saw similar levels of improvement.

All but one child saw complete resolution of a hallmark symptom of the disease – oculogyric crises, or prolonged spasms of muscles controlling eye movement – within 3 months of surgery. Of the children followed at least 18 months, six attained head control within a year, two became able to eat and drink by mouth, and four gained the ability to sit up unaided in that time. At 18 months one child had learned to speak 50 words using an augmentative communication device.

One child died unexpectedly 7 months after the procedure, Dr. Bankiewicz said in an interview. This death appeared to be caused by cardiac complications of his disease, Dr. Bankiewicz said, which are common in AADC deficiency.

While the investigators are now looking at delivering the AADC gene therapy in younger children – who were excluded from this trial because of safety concerns surrounding the complex procedure – investigators were surprised by the level of improvement seen in older children.

“We initially didn’t believe – at least not all of us – that we could actually make an impact in the older patients, and that is not the case,” said Dr. Bankiewicz, who has since used the same gene therapy on a compassionate-use basis in Europe and seen durable clinical improvement in patients as old as 26. “The fact that we saw a response in that patient tells us something about how incredibly plastic the brain is.”

While the new study does not detail improvements in the children’s social and emotional well-being, Dr. Bankiewicz said these, too, were pronounced. “Kids fall into oculogyric crises in stress-inducing situation. They might be in a stroller being taken for a walk, and something in the environment would stress them. Sometimes they had to be kept in a dark room isolated from stress.” Following the gene therapy, “they’re laughing, they’re social, they can interact with their environment. It’s really touching to see them able to develop a bond now with their caregivers.”
 

Implication for other disorders

Dr. Bankiewicz and colleagues have previously used the same gene to boost AADC activity in patients with Parkinson’s disease. The group is also in trials to deliver a neuroprotective gene to the brains of people with early-stage Alzheimer’s disease, and a gene-silencing therapy in patients with Huntington’s disease. They will also continue recruiting pediatric patients for trials of the AADC gene therapy.

“We have been developing a method for safely treating younger children, so now we will go to 3 years old and maybe even below,” Dr. Bankiewicz said. “Earlier is probably better, but for technical and safety considerations we needed to be conservative first. It is hugely stressful to go into very sick patients with that type of therapy in that part of the brain. We had to get it right the first time, and it looks like we did.”

The study was funded by the National Institutes of Health, the AADC Research Trust, the Pediatric Neurotransmitter Disease Association, and Ohio State University, with materials and technical support donated by ClearPoint Neuro. Several coauthors disclosed financial relationships with producers of diagnostic tests or biotechnology firms. Dr. Bankiewicz is a founder and shareholder of Brain Neurotherapy Bio, a company that develops gene therapies for Parkinson’s and other diseases.


 

An experimental gene therapy produced marked clinical improvement in children with aromatic L-amino acid decarboxylase (AADC) deficiency, a rare genetic disorder that affects the synthesis of key neurotransmitters to cause severe developmental and motor disability.

In an article published July 12, 2021, in Nature Communications, a group of researchers based at the University of California, San Francisco, and Ohio State University, Columbus, described results from seven children ages 4-9 with AADC deficiency who underwent a novel form of surgery to deliver a viral vector expressing the human AADC gene to the midbrain.

Previous trials of this gene therapy in children with AADC deficiency targeted a different region of the brain, the putamen, with only slight clinical improvement. Here, investigators chose two midbrain regions – the substantia nigra pars compacta and the ventral tegmental area – in the hope of restoring healthy AADC enzyme activity in those neurons.

The study’s corresponding author, Krystof Bankiewicz, MD, PhD, professor and vice chair of research at Ohio State University, director of the Brain Health and Performance Center at Ohio State University, and professor emeritus and vice chair for research at UCSF, said in an interview that the brain regions chosen for this trial resulted from years of efforts to identify an ideal target in this disease.

“This particular vector undergoes axonal transport,” he said. “If you inject it into specific regions of the brain it will be transported into the terminals [of the nerve fibers]. And by looking at the imaging of these patients, we found that they still have the wiring in the brain that’s so critical. So we decided to aim at a much more difficult target, going directly to the source of the problem, which is the substantia nigra and the ventral tegmental area. This targets two critical pathways in the brain: one that drives motor responses and another that controls emotions.”
 

‘Surprising’ improvement seen

The children in the study – four girls and three boys – underwent surgery from 2016 to the end of 2018, and were divided into two dose cohorts, with one receiving three times the amount of vector as the other. Both groups, however, saw similar levels of improvement.

All but one child saw complete resolution of a hallmark symptom of the disease – oculogyric crises, or prolonged spasms of muscles controlling eye movement – within 3 months of surgery. Of the children followed at least 18 months, six attained head control within a year, two became able to eat and drink by mouth, and four gained the ability to sit up unaided in that time. At 18 months one child had learned to speak 50 words using an augmentative communication device.

One child died unexpectedly 7 months after the procedure, Dr. Bankiewicz said in an interview. This death appeared to be caused by cardiac complications of his disease, Dr. Bankiewicz said, which are common in AADC deficiency.

While the investigators are now looking at delivering the AADC gene therapy in younger children – who were excluded from this trial because of safety concerns surrounding the complex procedure – investigators were surprised by the level of improvement seen in older children.

“We initially didn’t believe – at least not all of us – that we could actually make an impact in the older patients, and that is not the case,” said Dr. Bankiewicz, who has since used the same gene therapy on a compassionate-use basis in Europe and seen durable clinical improvement in patients as old as 26. “The fact that we saw a response in that patient tells us something about how incredibly plastic the brain is.”

While the new study does not detail improvements in the children’s social and emotional well-being, Dr. Bankiewicz said these, too, were pronounced. “Kids fall into oculogyric crises in stress-inducing situation. They might be in a stroller being taken for a walk, and something in the environment would stress them. Sometimes they had to be kept in a dark room isolated from stress.” Following the gene therapy, “they’re laughing, they’re social, they can interact with their environment. It’s really touching to see them able to develop a bond now with their caregivers.”
 

Implication for other disorders

Dr. Bankiewicz and colleagues have previously used the same gene to boost AADC activity in patients with Parkinson’s disease. The group is also in trials to deliver a neuroprotective gene to the brains of people with early-stage Alzheimer’s disease, and a gene-silencing therapy in patients with Huntington’s disease. They will also continue recruiting pediatric patients for trials of the AADC gene therapy.

“We have been developing a method for safely treating younger children, so now we will go to 3 years old and maybe even below,” Dr. Bankiewicz said. “Earlier is probably better, but for technical and safety considerations we needed to be conservative first. It is hugely stressful to go into very sick patients with that type of therapy in that part of the brain. We had to get it right the first time, and it looks like we did.”

The study was funded by the National Institutes of Health, the AADC Research Trust, the Pediatric Neurotransmitter Disease Association, and Ohio State University, with materials and technical support donated by ClearPoint Neuro. Several coauthors disclosed financial relationships with producers of diagnostic tests or biotechnology firms. Dr. Bankiewicz is a founder and shareholder of Brain Neurotherapy Bio, a company that develops gene therapies for Parkinson’s and other diseases.


 

The Food and Drug Administration has approved Octagam 10% as the first intravenous immunoglobulin with an indication specifically for adult dermatomyositis, according to a statement from manufacturer Octapharma USA.

Dermatomyositis is a rare, idiopathic autoimmune disorder that affects approximately 10 out of every million people in the United States, mainly adults in their late 40s to early 60s, according to the company, but children aged 5-15 years can be affected. The disease is characterized by skin rashes, chronic muscle inflammation, progressive muscle weakness, and risk for mortality that is three times higher than for the general population.

There are no previously approved treatments for dermatomyositis prior to Octagam 10%, which also is indicated for chronic immune thrombocytopenic purpura in adults.

The approval for dermatomyositis was based on the results of a phase 3 randomized, double-blind, placebo-controlled clinical trial (the ProDERM trial) that included 95 adult patients at 36 sites worldwide, with 17 sites in the United States. In the trial, 78.7% of patients with dermatomyositis who were randomized to receive 2 g/kg of Octagam 10% every 4 weeks showed response at 16 weeks, compared with 43.8% of patients who received placebo. Response was based on the 2016 American College of Rheumatology/European Alliance of Associations for Rheumatology myositis response criteria. Placebo patients who switched to intravenous immunoglobulin (IVIG) during a trial extension had response rates at week 40 similar to the original patients at week 16.

“The study gives clinicians much more confidence in the efficacy and safety of intravenous immunoglobulin and provides valuable information about what type of patient is best suited for the treatment,” Rohit Aggarwal, MD, medical director of the Arthritis and Autoimmunity Center at the University of Pittsburgh and a member of the ProDERM study Steering Committee, said in the Octapharma statement.

Safety and tolerability were similar to profiles seen with other IVIG medications, according to the statement. The medication does carry a boxed warning from its chronic ITP approval, cautioning about the potential for thrombosis, renal dysfunction, and acute renal failure.

The most common adverse reactions reported by dermatomyositis patients in the ProDERM trial were headache, fever, nausea, vomiting, increased blood pressure, chills, musculoskeletal pain, increased heart rate, dyspnea, and reactions at the infusion sites.

Read the full prescribing information here.

The Food and Drug Administration has approved Octagam 10% as the first intravenous immunoglobulin with an indication specifically for adult dermatomyositis, according to a statement from manufacturer Octapharma USA.

Dermatomyositis is a rare, idiopathic autoimmune disorder that affects approximately 10 out of every million people in the United States, mainly adults in their late 40s to early 60s, according to the company, but children aged 5-15 years can be affected. The disease is characterized by skin rashes, chronic muscle inflammation, progressive muscle weakness, and risk for mortality that is three times higher than for the general population.

There are no previously approved treatments for dermatomyositis prior to Octagam 10%, which also is indicated for chronic immune thrombocytopenic purpura in adults.

The approval for dermatomyositis was based on the results of a phase 3 randomized, double-blind, placebo-controlled clinical trial (the ProDERM trial) that included 95 adult patients at 36 sites worldwide, with 17 sites in the United States. In the trial, 78.7% of patients with dermatomyositis who were randomized to receive 2 g/kg of Octagam 10% every 4 weeks showed response at 16 weeks, compared with 43.8% of patients who received placebo. Response was based on the 2016 American College of Rheumatology/European Alliance of Associations for Rheumatology myositis response criteria. Placebo patients who switched to intravenous immunoglobulin (IVIG) during a trial extension had response rates at week 40 similar to the original patients at week 16.

“The study gives clinicians much more confidence in the efficacy and safety of intravenous immunoglobulin and provides valuable information about what type of patient is best suited for the treatment,” Rohit Aggarwal, MD, medical director of the Arthritis and Autoimmunity Center at the University of Pittsburgh and a member of the ProDERM study Steering Committee, said in the Octapharma statement.

Safety and tolerability were similar to profiles seen with other IVIG medications, according to the statement. The medication does carry a boxed warning from its chronic ITP approval, cautioning about the potential for thrombosis, renal dysfunction, and acute renal failure.

The most common adverse reactions reported by dermatomyositis patients in the ProDERM trial were headache, fever, nausea, vomiting, increased blood pressure, chills, musculoskeletal pain, increased heart rate, dyspnea, and reactions at the infusion sites.

Read the full prescribing information here.

The Food and Drug Administration has approved Octagam 10% as the first intravenous immunoglobulin with an indication specifically for adult dermatomyositis, according to a statement from manufacturer Octapharma USA.

Dermatomyositis is a rare, idiopathic autoimmune disorder that affects approximately 10 out of every million people in the United States, mainly adults in their late 40s to early 60s, according to the company, but children aged 5-15 years can be affected. The disease is characterized by skin rashes, chronic muscle inflammation, progressive muscle weakness, and risk for mortality that is three times higher than for the general population.

There are no previously approved treatments for dermatomyositis prior to Octagam 10%, which also is indicated for chronic immune thrombocytopenic purpura in adults.

The approval for dermatomyositis was based on the results of a phase 3 randomized, double-blind, placebo-controlled clinical trial (the ProDERM trial) that included 95 adult patients at 36 sites worldwide, with 17 sites in the United States. In the trial, 78.7% of patients with dermatomyositis who were randomized to receive 2 g/kg of Octagam 10% every 4 weeks showed response at 16 weeks, compared with 43.8% of patients who received placebo. Response was based on the 2016 American College of Rheumatology/European Alliance of Associations for Rheumatology myositis response criteria. Placebo patients who switched to intravenous immunoglobulin (IVIG) during a trial extension had response rates at week 40 similar to the original patients at week 16.

“The study gives clinicians much more confidence in the efficacy and safety of intravenous immunoglobulin and provides valuable information about what type of patient is best suited for the treatment,” Rohit Aggarwal, MD, medical director of the Arthritis and Autoimmunity Center at the University of Pittsburgh and a member of the ProDERM study Steering Committee, said in the Octapharma statement.

Safety and tolerability were similar to profiles seen with other IVIG medications, according to the statement. The medication does carry a boxed warning from its chronic ITP approval, cautioning about the potential for thrombosis, renal dysfunction, and acute renal failure.

The most common adverse reactions reported by dermatomyositis patients in the ProDERM trial were headache, fever, nausea, vomiting, increased blood pressure, chills, musculoskeletal pain, increased heart rate, dyspnea, and reactions at the infusion sites.

Read the full prescribing information here.

THE CASE

A 27-year-old woman presented to the family medicine clinic to establish care for a recent onset of seizures, for which she had previously been admitted, 4 months after delivering her first child. Her pregnancy was complicated by type 1 diabetes and poor glycemic control. Labor was induced at 37 weeks; however, vaginal delivery was impeded by arrest of dilation. An emergency cesarean section was performed under general anesthesia, resulting in a healthy newborn male.

Six weeks after giving birth, the patient was started on sertraline 50 mg/d for postpartum depression. Her history was significant for depression 8 years prior that was controlled with psychotherapy, and treated prior to coming to our clinic. She had not experienced any depressive symptoms during pregnancy.

Three months postpartum, she was hospitalized for recurrent syncopal episodes. They lasted about 2 minutes, with prodromal generalized weakness followed by loss of consciousness. There was no post-event confusion, tongue-biting, or incontinence. Physical exam, electroencephalogram (EEG), echocardiogram, and magnetic resonance imaging of the head and neck demonstrated no acute findings.

These episodes escalated in frequency weeks after they began, involving as many as 40 daily attacks, some of which lasted up to 45 minutes. During these events, the patient was nonresponsive but reported reliving the delivery of her child. Upon initial consultation with Neurology, no cause was found, and she was advised to wear a helmet, stop driving, and refrain from carrying her son. No antiepileptic medications were initiated because there were no EEG findings that supported seizure, and her mood had not improved, despite an increase in sertraline dosage, a switch to citalopram, and the addition of bupropion. She described anxiety, nightmares, and intrusive thoughts during psychotherapy sessions. Her psychiatrist gave her an additional diagnosis of posttraumatic stress disorder (PTSD) secondary to her delivery. The family medicine clinic assisted the patient and her family throughout her care by functioning as a home base for her.

Eight months following initial symptoms, repeat evaluation with a video-EEG revealed no evidence of EEG changes during seizure-like activity.

THE DIAGNOSIS

The patient was given a diagnosis of psychogenic nonepileptic seizure (PNES) by a neurologist experienced in diagnosing both epilepsy and PNES. The physician made the diagnosis after noting that the seizures on video had no corresponding epileptiform activity on EEG. This represents a “documented” diagnosis, the highest level of confidence possible in diagnosing PNES, as reported by the International League Against Epilepsy Nonepileptic Seizures Task Force.¹

DISCUSSION

With a prevalence of 5% to 10% and 20% to 40% in outpatient and inpatient epilepsy clinics respectively, PNES events have become of increasing interest to physicians.² There are few cases of PNES in women during pregnancy reported in the literature.^3,4 This is the first case report of PNES with postpartum onset.

Continue to: Epilepsy vs psychogenic nonepileptic seizures

PNES episodes appear similar to epileptic seizures, but without a definitive neurobiologic source.^2,3 However, recent literature suggests the root cause may be found in abnormalities in neurologic networks, such as dysfunction of frontal and parietal lobe connectivity and increased communication from emotional centers of the brain.^2,5 There are no typical pathognomonic symptoms of PNES, leading to diagnostic difficulty.² A definitive diagnosis may be made when a patient experiences seizures without EEG abnormalities.² Further diagnostic brain imaging is unnecessary.

Trauma may be the underlying cause

A predominance of PNES in both women and young adults, with no definitive associated factors, has been reported in the literature.² Studies suggest childhood sexual abuse, physical abuse, traumatic brain injury, and health-related trauma, such as distressing medical experiences and surgeries, may be risk factors, while depression, misdiagnosis, and mistreatment can heighten seizure activity.^2,3

Treatment requires a multidisciplinary team

Effective management of PNES requires collaboration between the primary care physician, neurologist, psychiatrist, and psychotherapist, with an emphasis on evaluation and control of the underlying trigger(s).³ Randomized controlled trials have demonstrated the efficacy of cognitive behavioral therapy (CBT), supportive care, and patient education in reducing seizure frequency at the 6-month follow-up.^3,6 Additional studies have reported the best prognostic factor in PNES management is patient employment of an internal locus of control—the patient’s belief that they control life events.^7,8 Case series suggest electroconvulsive therapy (ECT) is an effective alternative mood stabilization and seizure reduction therapy when tolerated.⁹

Our patient tried several combinations of treatment to manage PNES and comorbid psychiatric conditions, including CBT, antidepressants, and anxiolytics. After about 5 treatment failures, she pursued ECT for treatment-resistant depression and PNES frequency reduction but failed to tolerate therapy. Currently, her PNES has been reduced to 1 to 2 weekly episodes with a 200 mg/d dose of lamotrigine as a mood stabilizer combined with CBT.

THE TAKEAWAY

Providers should investigate a patient’s history and psychologic disposition when the patient presents with seizure-like behavior without a neurobiologic source or with a negative video-EEG study. A history of depression, traumatic experience, PTSD, or other psychosocial triggers must be noted early to prevent a delay in treatment when PNES is part of the differential. Due to a delayed diagnosis of PNES in our patient, she went without full treatment for almost 12 months and experienced worsening episodes. The primary care physician plays an integral role in early identification and intervention through anticipatory guidance, initial work-up, and support for patients with suspected PNES (TABLE).

CORRESPONDENCE
Karim Hanna, MD, 13330 USF Laurel Drive, Tampa, FL; [email protected]

THE CASE

A 27-year-old woman presented to the family medicine clinic to establish care for a recent onset of seizures, for which she had previously been admitted, 4 months after delivering her first child. Her pregnancy was complicated by type 1 diabetes and poor glycemic control. Labor was induced at 37 weeks; however, vaginal delivery was impeded by arrest of dilation. An emergency cesarean section was performed under general anesthesia, resulting in a healthy newborn male.

Six weeks after giving birth, the patient was started on sertraline 50 mg/d for postpartum depression. Her history was significant for depression 8 years prior that was controlled with psychotherapy, and treated prior to coming to our clinic. She had not experienced any depressive symptoms during pregnancy.

Three months postpartum, she was hospitalized for recurrent syncopal episodes. They lasted about 2 minutes, with prodromal generalized weakness followed by loss of consciousness. There was no post-event confusion, tongue-biting, or incontinence. Physical exam, electroencephalogram (EEG), echocardiogram, and magnetic resonance imaging of the head and neck demonstrated no acute findings.

These episodes escalated in frequency weeks after they began, involving as many as 40 daily attacks, some of which lasted up to 45 minutes. During these events, the patient was nonresponsive but reported reliving the delivery of her child. Upon initial consultation with Neurology, no cause was found, and she was advised to wear a helmet, stop driving, and refrain from carrying her son. No antiepileptic medications were initiated because there were no EEG findings that supported seizure, and her mood had not improved, despite an increase in sertraline dosage, a switch to citalopram, and the addition of bupropion. She described anxiety, nightmares, and intrusive thoughts during psychotherapy sessions. Her psychiatrist gave her an additional diagnosis of posttraumatic stress disorder (PTSD) secondary to her delivery. The family medicine clinic assisted the patient and her family throughout her care by functioning as a home base for her.

Eight months following initial symptoms, repeat evaluation with a video-EEG revealed no evidence of EEG changes during seizure-like activity.

THE DIAGNOSIS

The patient was given a diagnosis of psychogenic nonepileptic seizure (PNES) by a neurologist experienced in diagnosing both epilepsy and PNES. The physician made the diagnosis after noting that the seizures on video had no corresponding epileptiform activity on EEG. This represents a “documented” diagnosis, the highest level of confidence possible in diagnosing PNES, as reported by the International League Against Epilepsy Nonepileptic Seizures Task Force.¹

DISCUSSION

With a prevalence of 5% to 10% and 20% to 40% in outpatient and inpatient epilepsy clinics respectively, PNES events have become of increasing interest to physicians.² There are few cases of PNES in women during pregnancy reported in the literature.^3,4 This is the first case report of PNES with postpartum onset.

Continue to: Epilepsy vs psychogenic nonepileptic seizures

PNES episodes appear similar to epileptic seizures, but without a definitive neurobiologic source.^2,3 However, recent literature suggests the root cause may be found in abnormalities in neurologic networks, such as dysfunction of frontal and parietal lobe connectivity and increased communication from emotional centers of the brain.^2,5 There are no typical pathognomonic symptoms of PNES, leading to diagnostic difficulty.² A definitive diagnosis may be made when a patient experiences seizures without EEG abnormalities.² Further diagnostic brain imaging is unnecessary.

Trauma may be the underlying cause

A predominance of PNES in both women and young adults, with no definitive associated factors, has been reported in the literature.² Studies suggest childhood sexual abuse, physical abuse, traumatic brain injury, and health-related trauma, such as distressing medical experiences and surgeries, may be risk factors, while depression, misdiagnosis, and mistreatment can heighten seizure activity.^2,3

Treatment requires a multidisciplinary team

Effective management of PNES requires collaboration between the primary care physician, neurologist, psychiatrist, and psychotherapist, with an emphasis on evaluation and control of the underlying trigger(s).³ Randomized controlled trials have demonstrated the efficacy of cognitive behavioral therapy (CBT), supportive care, and patient education in reducing seizure frequency at the 6-month follow-up.^3,6 Additional studies have reported the best prognostic factor in PNES management is patient employment of an internal locus of control—the patient’s belief that they control life events.^7,8 Case series suggest electroconvulsive therapy (ECT) is an effective alternative mood stabilization and seizure reduction therapy when tolerated.⁹

Our patient tried several combinations of treatment to manage PNES and comorbid psychiatric conditions, including CBT, antidepressants, and anxiolytics. After about 5 treatment failures, she pursued ECT for treatment-resistant depression and PNES frequency reduction but failed to tolerate therapy. Currently, her PNES has been reduced to 1 to 2 weekly episodes with a 200 mg/d dose of lamotrigine as a mood stabilizer combined with CBT.

THE TAKEAWAY

Providers should investigate a patient’s history and psychologic disposition when the patient presents with seizure-like behavior without a neurobiologic source or with a negative video-EEG study. A history of depression, traumatic experience, PTSD, or other psychosocial triggers must be noted early to prevent a delay in treatment when PNES is part of the differential. Due to a delayed diagnosis of PNES in our patient, she went without full treatment for almost 12 months and experienced worsening episodes. The primary care physician plays an integral role in early identification and intervention through anticipatory guidance, initial work-up, and support for patients with suspected PNES (TABLE).

CORRESPONDENCE
Karim Hanna, MD, 13330 USF Laurel Drive, Tampa, FL; [email protected]

THE CASE

A 27-year-old woman presented to the family medicine clinic to establish care for a recent onset of seizures, for which she had previously been admitted, 4 months after delivering her first child. Her pregnancy was complicated by type 1 diabetes and poor glycemic control. Labor was induced at 37 weeks; however, vaginal delivery was impeded by arrest of dilation. An emergency cesarean section was performed under general anesthesia, resulting in a healthy newborn male.

Six weeks after giving birth, the patient was started on sertraline 50 mg/d for postpartum depression. Her history was significant for depression 8 years prior that was controlled with psychotherapy, and treated prior to coming to our clinic. She had not experienced any depressive symptoms during pregnancy.

Three months postpartum, she was hospitalized for recurrent syncopal episodes. They lasted about 2 minutes, with prodromal generalized weakness followed by loss of consciousness. There was no post-event confusion, tongue-biting, or incontinence. Physical exam, electroencephalogram (EEG), echocardiogram, and magnetic resonance imaging of the head and neck demonstrated no acute findings.

These episodes escalated in frequency weeks after they began, involving as many as 40 daily attacks, some of which lasted up to 45 minutes. During these events, the patient was nonresponsive but reported reliving the delivery of her child. Upon initial consultation with Neurology, no cause was found, and she was advised to wear a helmet, stop driving, and refrain from carrying her son. No antiepileptic medications were initiated because there were no EEG findings that supported seizure, and her mood had not improved, despite an increase in sertraline dosage, a switch to citalopram, and the addition of bupropion. She described anxiety, nightmares, and intrusive thoughts during psychotherapy sessions. Her psychiatrist gave her an additional diagnosis of posttraumatic stress disorder (PTSD) secondary to her delivery. The family medicine clinic assisted the patient and her family throughout her care by functioning as a home base for her.

Eight months following initial symptoms, repeat evaluation with a video-EEG revealed no evidence of EEG changes during seizure-like activity.

THE DIAGNOSIS

The patient was given a diagnosis of psychogenic nonepileptic seizure (PNES) by a neurologist experienced in diagnosing both epilepsy and PNES. The physician made the diagnosis after noting that the seizures on video had no corresponding epileptiform activity on EEG. This represents a “documented” diagnosis, the highest level of confidence possible in diagnosing PNES, as reported by the International League Against Epilepsy Nonepileptic Seizures Task Force.¹

DISCUSSION

With a prevalence of 5% to 10% and 20% to 40% in outpatient and inpatient epilepsy clinics respectively, PNES events have become of increasing interest to physicians.² There are few cases of PNES in women during pregnancy reported in the literature.^3,4 This is the first case report of PNES with postpartum onset.

Continue to: Epilepsy vs psychogenic nonepileptic seizures

PNES episodes appear similar to epileptic seizures, but without a definitive neurobiologic source.^2,3 However, recent literature suggests the root cause may be found in abnormalities in neurologic networks, such as dysfunction of frontal and parietal lobe connectivity and increased communication from emotional centers of the brain.^2,5 There are no typical pathognomonic symptoms of PNES, leading to diagnostic difficulty.² A definitive diagnosis may be made when a patient experiences seizures without EEG abnormalities.² Further diagnostic brain imaging is unnecessary.

Trauma may be the underlying cause

A predominance of PNES in both women and young adults, with no definitive associated factors, has been reported in the literature.² Studies suggest childhood sexual abuse, physical abuse, traumatic brain injury, and health-related trauma, such as distressing medical experiences and surgeries, may be risk factors, while depression, misdiagnosis, and mistreatment can heighten seizure activity.^2,3

Treatment requires a multidisciplinary team

Effective management of PNES requires collaboration between the primary care physician, neurologist, psychiatrist, and psychotherapist, with an emphasis on evaluation and control of the underlying trigger(s).³ Randomized controlled trials have demonstrated the efficacy of cognitive behavioral therapy (CBT), supportive care, and patient education in reducing seizure frequency at the 6-month follow-up.^3,6 Additional studies have reported the best prognostic factor in PNES management is patient employment of an internal locus of control—the patient’s belief that they control life events.^7,8 Case series suggest electroconvulsive therapy (ECT) is an effective alternative mood stabilization and seizure reduction therapy when tolerated.⁹

Our patient tried several combinations of treatment to manage PNES and comorbid psychiatric conditions, including CBT, antidepressants, and anxiolytics. After about 5 treatment failures, she pursued ECT for treatment-resistant depression and PNES frequency reduction but failed to tolerate therapy. Currently, her PNES has been reduced to 1 to 2 weekly episodes with a 200 mg/d dose of lamotrigine as a mood stabilizer combined with CBT.

THE TAKEAWAY

Providers should investigate a patient’s history and psychologic disposition when the patient presents with seizure-like behavior without a neurobiologic source or with a negative video-EEG study. A history of depression, traumatic experience, PTSD, or other psychosocial triggers must be noted early to prevent a delay in treatment when PNES is part of the differential. Due to a delayed diagnosis of PNES in our patient, she went without full treatment for almost 12 months and experienced worsening episodes. The primary care physician plays an integral role in early identification and intervention through anticipatory guidance, initial work-up, and support for patients with suspected PNES (TABLE).

CORRESPONDENCE
Karim Hanna, MD, 13330 USF Laurel Drive, Tampa, FL; [email protected]

Guillain-Barré syndrome, a rare peripheral nerve disorder that can occur after certain types of viral and bacterial infections, has not to date been definitively linked to infection by SARS-CoV-2 or with vaccination against the virus, despite surveillance searching for such associations.

Spikes in Guillain-Barré syndrome incidence have previously, but rarely, been associated with outbreaks of other viral diseases, including Zika, but not with vaccination, except for a 1976-1977 swine influenza vaccine campaign in the United States that was seen associated with a slight elevation in risk, and was halted when that risk became known. Since then, all sorts of vaccines in the European Union and United States have come with warnings about Guillain-Barré syndrome in their package inserts – a fact that some Guillain-Barré syndrome experts lament as perpetuating the notion that vaccines cause Guillain-Barré syndrome.

Epidemiologic studies in the United Kingdom and Singapore did not detect increases in Guillain-Barré syndrome incidence during the COVID-19 pandemic. And as mass vaccination against COVID-19 got underway early this year, experts cautioned against the temptation to attribute incident Guillain-Barré syndrome cases following vaccination to SARS-CoV-2 without careful statistical and epidemiological analysis. Until now reports of Guillain-Barré syndrome have been scant: clinical trials of a viral vector vaccine developed by Johnson & Johnson saw one in the placebo arm and another in the intervention arm, while another case was reported following administration of a Pfizer mRNA SARS-Cov-2 vaccine.
 

Recent case reports

Two reports published this month in the Annals of Neurology – one from India and one from the United Kingdom – describe multiple cases of Guillain-Barré syndrome following a first dose of the ChAdOx1-S/nCoV-19, (Covishield, AstraZeneca) vector vaccine. None of the patients had evidence of current SARS-CoV-2 infection.

From India, Boby V. Maramattom, MD, of Aster Medcity in Kochi, India, and colleagues reported on seven severe cases of Guillain-Barré syndrome occurring between 10 and 14 days after a first dose of the AstraZeneca vaccine. All but one of the patients were women, all had bilateral facial paresis, all progressed to areflexic quadriplegia, and six required respiratory support. Patients’ ages ranged from 43 to 70. Four developed other cranial neuropathies, including abducens palsy and trigeminal sensory nerve involvement, which are rare in reports of Guillain-Barré syndrome from India, Dr. Maramattom and colleagues noted.

The authors argued that their findings “should prompt all physicians to be vigilant in recognizing Guillain-Barré syndrome in patients who have received the AstraZeneca vaccine. While the risk per patient (5.8 per million) may be relatively low, our observations suggest that this clinically distinct [Guillain-Barré syndrome] variant is more severe than usual and may require mechanical ventilation.”

The U.K. cases, reported by Christopher Martin Allen, MD, and colleagues at Nottingham (England) University Hospitals NHS Trust, describe bifacial weakness and normal facial sensation in four men between 11 and 22 days after their first doses of the Astra-Zeneca vaccine. This type of facial palsy, the authors wrote, was unusual Guillain-Barré syndrome variant that one rapid review found in 3 of 42 European patients diagnosed with Guillain-Barré syndrome following SARS-CoV-2 infection.

Dr. Allen and colleagues acknowledged that causality could not be assumed from the temporal relationship of immunization to onset of bifacial weakness in their report, but argued that their findings argued for “robust postvaccination surveillance” and that “the report of a similar syndrome in the setting of SARS-CoV-2 infection suggests an immunologic response to the spike protein.” If the link is casual, they wrote, “it could be due to a cross-reactive immune response to the SARS-CoV-2 spike protein and components of the peripheral immune system.”
 

‘The jury is still out’

Asked for comment, neurologist Anthony Amato, MD, of Brigham and Women’s Hospital, Boston, said that he did not see what the two new studies add to what is already known. “Guillain-Barré syndrome has already been reported temporally following COVID-19 along with accompanying editorials that such temporal occurrences do not imply causation and there is a need for surveillance and epidemiological studies.”

Robert Lisak, MD, of Wayne State University, Detroit, and a longtime adviser to the GBS-CIDP Foundation International, commented that “the relationship between vaccines and association with Guillain-Barré syndrome continues to be controversial in part because Guillain-Barré syndrome, a rare disorder, has many reported associated illnesses including infections. Many vaccines have been implicated but with the probable exception of the ‘swine flu’ vaccine in the 1970s, most have not stood up to scrutiny.”

With SARS-Cov-2 infection and vaccines, “the jury is still out,” Dr. Lisak said. “The report from the U.K. is intriguing since they report several cases of an uncommon variant, but the cases from India seem to be more of the usual forms of Guillain-Barré syndrome.”

Dr. Lisak noted that, even if an association turns out to be valid, “we are talking about a very low incidence of Guillain-Barré syndrome associated with COVID-19 vaccines,” one that would not justify avoiding them because of a possible association with Guillain-Barré syndrome.

The GBS-CIDP Foundation, which supports research into Guillain-Barré syndrome and related diseases, has likewise stressed the low risk presented by SARS-CoV-2 vaccines, noting on its website that “the risk of death or long-term complications from COVID in adults still far exceeds the risk of any possible risk of Guillain-Barré syndrome by several orders of magnitude.”

None of the study authors reported financial conflicts of interest related to their research. Dr. Amato is an adviser to the pharmaceutical firms Alexion and Argenx, while Dr. Lisak has received research support or honoraria from Alexion, Novartis, Hoffmann–La Roche, and others.

Guillain-Barré syndrome, a rare peripheral nerve disorder that can occur after certain types of viral and bacterial infections, has not to date been definitively linked to infection by SARS-CoV-2 or with vaccination against the virus, despite surveillance searching for such associations.

Spikes in Guillain-Barré syndrome incidence have previously, but rarely, been associated with outbreaks of other viral diseases, including Zika, but not with vaccination, except for a 1976-1977 swine influenza vaccine campaign in the United States that was seen associated with a slight elevation in risk, and was halted when that risk became known. Since then, all sorts of vaccines in the European Union and United States have come with warnings about Guillain-Barré syndrome in their package inserts – a fact that some Guillain-Barré syndrome experts lament as perpetuating the notion that vaccines cause Guillain-Barré syndrome.

Epidemiologic studies in the United Kingdom and Singapore did not detect increases in Guillain-Barré syndrome incidence during the COVID-19 pandemic. And as mass vaccination against COVID-19 got underway early this year, experts cautioned against the temptation to attribute incident Guillain-Barré syndrome cases following vaccination to SARS-CoV-2 without careful statistical and epidemiological analysis. Until now reports of Guillain-Barré syndrome have been scant: clinical trials of a viral vector vaccine developed by Johnson & Johnson saw one in the placebo arm and another in the intervention arm, while another case was reported following administration of a Pfizer mRNA SARS-Cov-2 vaccine.
 

Recent case reports

Two reports published this month in the Annals of Neurology – one from India and one from the United Kingdom – describe multiple cases of Guillain-Barré syndrome following a first dose of the ChAdOx1-S/nCoV-19, (Covishield, AstraZeneca) vector vaccine. None of the patients had evidence of current SARS-CoV-2 infection.

From India, Boby V. Maramattom, MD, of Aster Medcity in Kochi, India, and colleagues reported on seven severe cases of Guillain-Barré syndrome occurring between 10 and 14 days after a first dose of the AstraZeneca vaccine. All but one of the patients were women, all had bilateral facial paresis, all progressed to areflexic quadriplegia, and six required respiratory support. Patients’ ages ranged from 43 to 70. Four developed other cranial neuropathies, including abducens palsy and trigeminal sensory nerve involvement, which are rare in reports of Guillain-Barré syndrome from India, Dr. Maramattom and colleagues noted.

The authors argued that their findings “should prompt all physicians to be vigilant in recognizing Guillain-Barré syndrome in patients who have received the AstraZeneca vaccine. While the risk per patient (5.8 per million) may be relatively low, our observations suggest that this clinically distinct [Guillain-Barré syndrome] variant is more severe than usual and may require mechanical ventilation.”

The U.K. cases, reported by Christopher Martin Allen, MD, and colleagues at Nottingham (England) University Hospitals NHS Trust, describe bifacial weakness and normal facial sensation in four men between 11 and 22 days after their first doses of the Astra-Zeneca vaccine. This type of facial palsy, the authors wrote, was unusual Guillain-Barré syndrome variant that one rapid review found in 3 of 42 European patients diagnosed with Guillain-Barré syndrome following SARS-CoV-2 infection.

Dr. Allen and colleagues acknowledged that causality could not be assumed from the temporal relationship of immunization to onset of bifacial weakness in their report, but argued that their findings argued for “robust postvaccination surveillance” and that “the report of a similar syndrome in the setting of SARS-CoV-2 infection suggests an immunologic response to the spike protein.” If the link is casual, they wrote, “it could be due to a cross-reactive immune response to the SARS-CoV-2 spike protein and components of the peripheral immune system.”
 

‘The jury is still out’

Asked for comment, neurologist Anthony Amato, MD, of Brigham and Women’s Hospital, Boston, said that he did not see what the two new studies add to what is already known. “Guillain-Barré syndrome has already been reported temporally following COVID-19 along with accompanying editorials that such temporal occurrences do not imply causation and there is a need for surveillance and epidemiological studies.”

Robert Lisak, MD, of Wayne State University, Detroit, and a longtime adviser to the GBS-CIDP Foundation International, commented that “the relationship between vaccines and association with Guillain-Barré syndrome continues to be controversial in part because Guillain-Barré syndrome, a rare disorder, has many reported associated illnesses including infections. Many vaccines have been implicated but with the probable exception of the ‘swine flu’ vaccine in the 1970s, most have not stood up to scrutiny.”

With SARS-Cov-2 infection and vaccines, “the jury is still out,” Dr. Lisak said. “The report from the U.K. is intriguing since they report several cases of an uncommon variant, but the cases from India seem to be more of the usual forms of Guillain-Barré syndrome.”

Dr. Lisak noted that, even if an association turns out to be valid, “we are talking about a very low incidence of Guillain-Barré syndrome associated with COVID-19 vaccines,” one that would not justify avoiding them because of a possible association with Guillain-Barré syndrome.

The GBS-CIDP Foundation, which supports research into Guillain-Barré syndrome and related diseases, has likewise stressed the low risk presented by SARS-CoV-2 vaccines, noting on its website that “the risk of death or long-term complications from COVID in adults still far exceeds the risk of any possible risk of Guillain-Barré syndrome by several orders of magnitude.”

None of the study authors reported financial conflicts of interest related to their research. Dr. Amato is an adviser to the pharmaceutical firms Alexion and Argenx, while Dr. Lisak has received research support or honoraria from Alexion, Novartis, Hoffmann–La Roche, and others.

Guillain-Barré syndrome, a rare peripheral nerve disorder that can occur after certain types of viral and bacterial infections, has not to date been definitively linked to infection by SARS-CoV-2 or with vaccination against the virus, despite surveillance searching for such associations.

Spikes in Guillain-Barré syndrome incidence have previously, but rarely, been associated with outbreaks of other viral diseases, including Zika, but not with vaccination, except for a 1976-1977 swine influenza vaccine campaign in the United States that was seen associated with a slight elevation in risk, and was halted when that risk became known. Since then, all sorts of vaccines in the European Union and United States have come with warnings about Guillain-Barré syndrome in their package inserts – a fact that some Guillain-Barré syndrome experts lament as perpetuating the notion that vaccines cause Guillain-Barré syndrome.

Epidemiologic studies in the United Kingdom and Singapore did not detect increases in Guillain-Barré syndrome incidence during the COVID-19 pandemic. And as mass vaccination against COVID-19 got underway early this year, experts cautioned against the temptation to attribute incident Guillain-Barré syndrome cases following vaccination to SARS-CoV-2 without careful statistical and epidemiological analysis. Until now reports of Guillain-Barré syndrome have been scant: clinical trials of a viral vector vaccine developed by Johnson & Johnson saw one in the placebo arm and another in the intervention arm, while another case was reported following administration of a Pfizer mRNA SARS-Cov-2 vaccine.
 

Recent case reports

Two reports published this month in the Annals of Neurology – one from India and one from the United Kingdom – describe multiple cases of Guillain-Barré syndrome following a first dose of the ChAdOx1-S/nCoV-19, (Covishield, AstraZeneca) vector vaccine. None of the patients had evidence of current SARS-CoV-2 infection.

From India, Boby V. Maramattom, MD, of Aster Medcity in Kochi, India, and colleagues reported on seven severe cases of Guillain-Barré syndrome occurring between 10 and 14 days after a first dose of the AstraZeneca vaccine. All but one of the patients were women, all had bilateral facial paresis, all progressed to areflexic quadriplegia, and six required respiratory support. Patients’ ages ranged from 43 to 70. Four developed other cranial neuropathies, including abducens palsy and trigeminal sensory nerve involvement, which are rare in reports of Guillain-Barré syndrome from India, Dr. Maramattom and colleagues noted.

The authors argued that their findings “should prompt all physicians to be vigilant in recognizing Guillain-Barré syndrome in patients who have received the AstraZeneca vaccine. While the risk per patient (5.8 per million) may be relatively low, our observations suggest that this clinically distinct [Guillain-Barré syndrome] variant is more severe than usual and may require mechanical ventilation.”

The U.K. cases, reported by Christopher Martin Allen, MD, and colleagues at Nottingham (England) University Hospitals NHS Trust, describe bifacial weakness and normal facial sensation in four men between 11 and 22 days after their first doses of the Astra-Zeneca vaccine. This type of facial palsy, the authors wrote, was unusual Guillain-Barré syndrome variant that one rapid review found in 3 of 42 European patients diagnosed with Guillain-Barré syndrome following SARS-CoV-2 infection.

Dr. Allen and colleagues acknowledged that causality could not be assumed from the temporal relationship of immunization to onset of bifacial weakness in their report, but argued that their findings argued for “robust postvaccination surveillance” and that “the report of a similar syndrome in the setting of SARS-CoV-2 infection suggests an immunologic response to the spike protein.” If the link is casual, they wrote, “it could be due to a cross-reactive immune response to the SARS-CoV-2 spike protein and components of the peripheral immune system.”
 

‘The jury is still out’

Asked for comment, neurologist Anthony Amato, MD, of Brigham and Women’s Hospital, Boston, said that he did not see what the two new studies add to what is already known. “Guillain-Barré syndrome has already been reported temporally following COVID-19 along with accompanying editorials that such temporal occurrences do not imply causation and there is a need for surveillance and epidemiological studies.”

Robert Lisak, MD, of Wayne State University, Detroit, and a longtime adviser to the GBS-CIDP Foundation International, commented that “the relationship between vaccines and association with Guillain-Barré syndrome continues to be controversial in part because Guillain-Barré syndrome, a rare disorder, has many reported associated illnesses including infections. Many vaccines have been implicated but with the probable exception of the ‘swine flu’ vaccine in the 1970s, most have not stood up to scrutiny.”

With SARS-Cov-2 infection and vaccines, “the jury is still out,” Dr. Lisak said. “The report from the U.K. is intriguing since they report several cases of an uncommon variant, but the cases from India seem to be more of the usual forms of Guillain-Barré syndrome.”

Dr. Lisak noted that, even if an association turns out to be valid, “we are talking about a very low incidence of Guillain-Barré syndrome associated with COVID-19 vaccines,” one that would not justify avoiding them because of a possible association with Guillain-Barré syndrome.

The GBS-CIDP Foundation, which supports research into Guillain-Barré syndrome and related diseases, has likewise stressed the low risk presented by SARS-CoV-2 vaccines, noting on its website that “the risk of death or long-term complications from COVID in adults still far exceeds the risk of any possible risk of Guillain-Barré syndrome by several orders of magnitude.”

None of the study authors reported financial conflicts of interest related to their research. Dr. Amato is an adviser to the pharmaceutical firms Alexion and Argenx, while Dr. Lisak has received research support or honoraria from Alexion, Novartis, Hoffmann–La Roche, and others.