Background

Merkel cell carcinoma (MCC) is a rare, aggressive cutaneous malignancy.¹ Immunosuppression, advanced age, and UV light exposure of fair skin are major risk factors; additionally, polyomavirus infection is detected in as many as 80% of cases.^2-5 Merkel cells are slow-responding mechanoreceptors located within the basal layer of the epidermis.⁶ Approximately half of patients present with localized disease, in which surgical resection with or without adjuvant radiotherapy is usually indicated. However, overall prognosis is poor with MCC due to high recurrence rates.³ 

This neuroendocrine carcinoma has remarkable metastatic potential (34%–75%) and can invade regional lymph nodes; distant metastasis also can occur, most commonly to the liver, lungs, bones, and brain.^7,8 Approximately 25% of patients present with palpable lymphadenopathy and 5% with distant metastasis at the time of diagnosis. The frequency of metastasis at diagnosis as well as high recurrence rates after treatment contribute to the overall poor prognosis of MCC. Local recurrence rates have been reported at 25%, with lymph node involvement in 52% and metastasis in 34% of cases; most recurrences occur within 2 years of diagnosis.⁸ The aggressiveness of the tumor determines patient mortality; in cases without lymph node involvement, the 5-year survival rate is 83.3%. However, the 5-year survival rate drops to 58.3% with lymph node involvement; in patients with metastatic disease, it is just 31.3%.^8,9 Although MCC is a chemosensitive disease, durable responses are rarely seen in the advanced setting.³ Most patients with metastatic disease have a median progression-free survival of only 3 months.¹ 

Presentation and Diagnosis

An MCC tumor classically presents as a red to violaceous, painless nodule with a smooth shiny surface, most often on the sun-exposed head and neck region.^3,9-11 Approximately 50% of MCC cases present in the head and neck region, 32% to 38% present on the extremities, and 12% to 14% on the trunk.⁶ Unfortunately, this nonspecific presentation may lead to diagnostic uncertainty and a consequent delay in treatment. Definitive diagnosis of MCC can only be achieved with a skin biopsy, which allows for distinction from other clinically similar-appearing neoplasms. 

Specific guidelines for an MCC diagnostic evaluation have been proposed by the National Comprehensive Cancer Network (NCCN) based on a framework of clinical presentation, preliminary workup, diagnosis, and additional workup.¹² The simplified algorithm for evaluation includes the following^12,13: 

1. Examine skin and lymph nodes
2. Obtain a biopsy specimen stained with hematoxylin and eosin (including Breslow thickness and evidence of lymphovascular invasion) and immunostaining (including but not limited to cytokeratin (CK) 20 and thyroid transcription factor 1)
3. Obtain a sentinel lymph node biopsy specimen from patients with negative clinical nodes, prior to excision when possible
4. Perform fine-needle aspiration or core biopsy first for patients with positive clinical nodes; if negative, consider open biopsy, but if positive, proceed to next step
5. Perform imaging as clinically indicated with magnetic resonance imaging, computed tomography, or positron emission tomography–computed tomography
6. Consider consultation with a multidisciplinary tumor board

Histologic Features of MCC 

Merkel cell carcinoma presents histologically as small round basophilic cells penetrating through the dermis in 3 histologic patterns: the trabecular, intermediate (80% of cases), and small cell type.^8,10 Immunohistochemical features include CK20 positivity (showing paranuclear dotlike depositions in the cytoplasm or cell membrane) and CK7 negativity, which allows it to be differentiated from other neoplasms. Chromogranin and synaptophysin positivity provide further histologic confirmation. The absence of peripheral palisading, retraction artifact, and a fibromyxoid stroma allow for distinction from cutaneous basal cell carcinoma, which may display these features histologically. Other immunohistochemical markers that may be of value include thyroid transcription factor 1, which is typically positive in cutaneous metastasis of neuroendocrine carcinoma of the lung; S-100 and human melanoma black 45, which are positive in melanoma; and leukocyte common antigen (CD45), which can be positive in lymphoma. These stains are classically negative in MCC.^4,8 

Merkel Cell Polyomavirus and Other Risk Factors

Merkel cell carcinoma is frequently associated with the presence of Merkel cell polyomavirus (MCPyV) in tumor specimens, with a prevalence of 70% to 80% in all cases.⁸ Merkel cell polyomavirus is a class 2A carcinogen (ie, a probable carcinogen to humans) and is classified among a group of viruses that encode T antigens (ie, an antigen coded by a viral genome associated with transformation of infected cells by tumor viruses), which can lead to initiation of tumorigenesis through interference with cellular tumor suppressing proteins such as p53.¹⁰ 

Immunosuppression and UV-exposed fair skin also are considered major risk factors, which may be explained by the increase in MCPyV small T-antigen transcripts induced by UV irradiation.¹⁰ Moreover, as is seen in other cancers induced by viruses, host immunity can hinder tumor progression and development. Therefore, impairment of normal immune function likely creates a higher risk for MCC development as well as the potential for a worse prognosis.^4,8 The precise incidence of MCC in immunosuppressed patients appears unclear; it is possible that chronic immunosuppressive therapy may play a notable role in the pathogenesis of the tumor.^4,8 

Impact of Comorbidities on MCC

These risk factors were all observed in the case patient. However, it also is possible that his associated comorbidities also had an impact on the presentation of his disease.⁸ For example, patients with rheumatoid arthritis have been shown to have an elevated risk for the development of MCC.¹⁴ Moreover, inflammatory monocytes infected with MCPyV, as would be expected in a patient with a history of chronic psoriasis prior to diagnosis of MCC, also may contribute to the pathogenesis of MCC by migrating to inflammatory skin lesions, such as those seen in psoriasis, releasing MCPyV locally and infecting Merkel cells.^8,15 Testing for MCPyV was never performed in the case patient; however, it certainly would be prudent to do so in such a presentation. Additionally, further studies to determine the correlation of MCC to these disease processes are warranted.⁸ 

Given that MCC tends to affect an older population in which other notable comorbidities are not uncommon, the cost, side effects, and convenience for patients of any treatment plan are important considerations.⁸ In the case study, a combined regimen of carboplatin and VP-16 (etoposide) was utilized. This regimen was well tolerated by the patient and successful in achieving complete radiologic and clinical remission of his metastatic disease. This combination has been shown to prolong survival in patients with distant metastasis compared to those patients not receiving chemotherapy.⁶ In all high-risk patients, close clinical monitoring is essential to help optimize outcomes.

Bottom Line

Merkel cell carcinoma is a rare but aggressive cutaneous neoplasm that most frequently affects elderly patients, immunosuppressed patients, and individuals with chronic UV sun damage. An association between the oncogenesis of MCC and infection with MCPyV has been documented, but other underlying diseases such as psoriasis and rheumatoid arthritis also may play a role. In this case, the patient’s history of chronic immunosuppressive therapy for treatment of psoriasis and inflammatory joint disease likely played a role in the pathogenesis of the tumor. This potential risk should be an important point of discussion with any patient requiring this type of long-term management for disease control. This unique clinical case highlights a patient with substantial comorbidities who developed metastatic MCC and achieved complete clinical and radiologic remission following treatment with surgery and chemotherapy.

Background

Merkel cell carcinoma (MCC) is a rare, aggressive cutaneous malignancy.¹ Immunosuppression, advanced age, and UV light exposure of fair skin are major risk factors; additionally, polyomavirus infection is detected in as many as 80% of cases.^2-5 Merkel cells are slow-responding mechanoreceptors located within the basal layer of the epidermis.⁶ Approximately half of patients present with localized disease, in which surgical resection with or without adjuvant radiotherapy is usually indicated. However, overall prognosis is poor with MCC due to high recurrence rates.³ 

This neuroendocrine carcinoma has remarkable metastatic potential (34%–75%) and can invade regional lymph nodes; distant metastasis also can occur, most commonly to the liver, lungs, bones, and brain.^7,8 Approximately 25% of patients present with palpable lymphadenopathy and 5% with distant metastasis at the time of diagnosis. The frequency of metastasis at diagnosis as well as high recurrence rates after treatment contribute to the overall poor prognosis of MCC. Local recurrence rates have been reported at 25%, with lymph node involvement in 52% and metastasis in 34% of cases; most recurrences occur within 2 years of diagnosis.⁸ The aggressiveness of the tumor determines patient mortality; in cases without lymph node involvement, the 5-year survival rate is 83.3%. However, the 5-year survival rate drops to 58.3% with lymph node involvement; in patients with metastatic disease, it is just 31.3%.^8,9 Although MCC is a chemosensitive disease, durable responses are rarely seen in the advanced setting.³ Most patients with metastatic disease have a median progression-free survival of only 3 months.¹ 

Presentation and Diagnosis

An MCC tumor classically presents as a red to violaceous, painless nodule with a smooth shiny surface, most often on the sun-exposed head and neck region.^3,9-11 Approximately 50% of MCC cases present in the head and neck region, 32% to 38% present on the extremities, and 12% to 14% on the trunk.⁶ Unfortunately, this nonspecific presentation may lead to diagnostic uncertainty and a consequent delay in treatment. Definitive diagnosis of MCC can only be achieved with a skin biopsy, which allows for distinction from other clinically similar-appearing neoplasms. 

Specific guidelines for an MCC diagnostic evaluation have been proposed by the National Comprehensive Cancer Network (NCCN) based on a framework of clinical presentation, preliminary workup, diagnosis, and additional workup.¹² The simplified algorithm for evaluation includes the following^12,13: 

1. Examine skin and lymph nodes
2. Obtain a biopsy specimen stained with hematoxylin and eosin (including Breslow thickness and evidence of lymphovascular invasion) and immunostaining (including but not limited to cytokeratin (CK) 20 and thyroid transcription factor 1)
3. Obtain a sentinel lymph node biopsy specimen from patients with negative clinical nodes, prior to excision when possible
4. Perform fine-needle aspiration or core biopsy first for patients with positive clinical nodes; if negative, consider open biopsy, but if positive, proceed to next step
5. Perform imaging as clinically indicated with magnetic resonance imaging, computed tomography, or positron emission tomography–computed tomography
6. Consider consultation with a multidisciplinary tumor board

Histologic Features of MCC 

Merkel cell carcinoma presents histologically as small round basophilic cells penetrating through the dermis in 3 histologic patterns: the trabecular, intermediate (80% of cases), and small cell type.^8,10 Immunohistochemical features include CK20 positivity (showing paranuclear dotlike depositions in the cytoplasm or cell membrane) and CK7 negativity, which allows it to be differentiated from other neoplasms. Chromogranin and synaptophysin positivity provide further histologic confirmation. The absence of peripheral palisading, retraction artifact, and a fibromyxoid stroma allow for distinction from cutaneous basal cell carcinoma, which may display these features histologically. Other immunohistochemical markers that may be of value include thyroid transcription factor 1, which is typically positive in cutaneous metastasis of neuroendocrine carcinoma of the lung; S-100 and human melanoma black 45, which are positive in melanoma; and leukocyte common antigen (CD45), which can be positive in lymphoma. These stains are classically negative in MCC.^4,8 

Merkel Cell Polyomavirus and Other Risk Factors

Merkel cell carcinoma is frequently associated with the presence of Merkel cell polyomavirus (MCPyV) in tumor specimens, with a prevalence of 70% to 80% in all cases.⁸ Merkel cell polyomavirus is a class 2A carcinogen (ie, a probable carcinogen to humans) and is classified among a group of viruses that encode T antigens (ie, an antigen coded by a viral genome associated with transformation of infected cells by tumor viruses), which can lead to initiation of tumorigenesis through interference with cellular tumor suppressing proteins such as p53.¹⁰ 

Immunosuppression and UV-exposed fair skin also are considered major risk factors, which may be explained by the increase in MCPyV small T-antigen transcripts induced by UV irradiation.¹⁰ Moreover, as is seen in other cancers induced by viruses, host immunity can hinder tumor progression and development. Therefore, impairment of normal immune function likely creates a higher risk for MCC development as well as the potential for a worse prognosis.^4,8 The precise incidence of MCC in immunosuppressed patients appears unclear; it is possible that chronic immunosuppressive therapy may play a notable role in the pathogenesis of the tumor.^4,8 

Impact of Comorbidities on MCC

These risk factors were all observed in the case patient. However, it also is possible that his associated comorbidities also had an impact on the presentation of his disease.⁸ For example, patients with rheumatoid arthritis have been shown to have an elevated risk for the development of MCC.¹⁴ Moreover, inflammatory monocytes infected with MCPyV, as would be expected in a patient with a history of chronic psoriasis prior to diagnosis of MCC, also may contribute to the pathogenesis of MCC by migrating to inflammatory skin lesions, such as those seen in psoriasis, releasing MCPyV locally and infecting Merkel cells.^8,15 Testing for MCPyV was never performed in the case patient; however, it certainly would be prudent to do so in such a presentation. Additionally, further studies to determine the correlation of MCC to these disease processes are warranted.⁸ 

Given that MCC tends to affect an older population in which other notable comorbidities are not uncommon, the cost, side effects, and convenience for patients of any treatment plan are important considerations.⁸ In the case study, a combined regimen of carboplatin and VP-16 (etoposide) was utilized. This regimen was well tolerated by the patient and successful in achieving complete radiologic and clinical remission of his metastatic disease. This combination has been shown to prolong survival in patients with distant metastasis compared to those patients not receiving chemotherapy.⁶ In all high-risk patients, close clinical monitoring is essential to help optimize outcomes.

Bottom Line

Merkel cell carcinoma is a rare but aggressive cutaneous neoplasm that most frequently affects elderly patients, immunosuppressed patients, and individuals with chronic UV sun damage. An association between the oncogenesis of MCC and infection with MCPyV has been documented, but other underlying diseases such as psoriasis and rheumatoid arthritis also may play a role. In this case, the patient’s history of chronic immunosuppressive therapy for treatment of psoriasis and inflammatory joint disease likely played a role in the pathogenesis of the tumor. This potential risk should be an important point of discussion with any patient requiring this type of long-term management for disease control. This unique clinical case highlights a patient with substantial comorbidities who developed metastatic MCC and achieved complete clinical and radiologic remission following treatment with surgery and chemotherapy.

Background

Merkel cell carcinoma (MCC) is a rare, aggressive cutaneous malignancy.¹ Immunosuppression, advanced age, and UV light exposure of fair skin are major risk factors; additionally, polyomavirus infection is detected in as many as 80% of cases.^2-5 Merkel cells are slow-responding mechanoreceptors located within the basal layer of the epidermis.⁶ Approximately half of patients present with localized disease, in which surgical resection with or without adjuvant radiotherapy is usually indicated. However, overall prognosis is poor with MCC due to high recurrence rates.³ 

This neuroendocrine carcinoma has remarkable metastatic potential (34%–75%) and can invade regional lymph nodes; distant metastasis also can occur, most commonly to the liver, lungs, bones, and brain.^7,8 Approximately 25% of patients present with palpable lymphadenopathy and 5% with distant metastasis at the time of diagnosis. The frequency of metastasis at diagnosis as well as high recurrence rates after treatment contribute to the overall poor prognosis of MCC. Local recurrence rates have been reported at 25%, with lymph node involvement in 52% and metastasis in 34% of cases; most recurrences occur within 2 years of diagnosis.⁸ The aggressiveness of the tumor determines patient mortality; in cases without lymph node involvement, the 5-year survival rate is 83.3%. However, the 5-year survival rate drops to 58.3% with lymph node involvement; in patients with metastatic disease, it is just 31.3%.^8,9 Although MCC is a chemosensitive disease, durable responses are rarely seen in the advanced setting.³ Most patients with metastatic disease have a median progression-free survival of only 3 months.¹ 

Presentation and Diagnosis

An MCC tumor classically presents as a red to violaceous, painless nodule with a smooth shiny surface, most often on the sun-exposed head and neck region.^3,9-11 Approximately 50% of MCC cases present in the head and neck region, 32% to 38% present on the extremities, and 12% to 14% on the trunk.⁶ Unfortunately, this nonspecific presentation may lead to diagnostic uncertainty and a consequent delay in treatment. Definitive diagnosis of MCC can only be achieved with a skin biopsy, which allows for distinction from other clinically similar-appearing neoplasms. 

Specific guidelines for an MCC diagnostic evaluation have been proposed by the National Comprehensive Cancer Network (NCCN) based on a framework of clinical presentation, preliminary workup, diagnosis, and additional workup.¹² The simplified algorithm for evaluation includes the following^12,13: 

1. Examine skin and lymph nodes
2. Obtain a biopsy specimen stained with hematoxylin and eosin (including Breslow thickness and evidence of lymphovascular invasion) and immunostaining (including but not limited to cytokeratin (CK) 20 and thyroid transcription factor 1)
3. Obtain a sentinel lymph node biopsy specimen from patients with negative clinical nodes, prior to excision when possible
4. Perform fine-needle aspiration or core biopsy first for patients with positive clinical nodes; if negative, consider open biopsy, but if positive, proceed to next step
5. Perform imaging as clinically indicated with magnetic resonance imaging, computed tomography, or positron emission tomography–computed tomography
6. Consider consultation with a multidisciplinary tumor board

Histologic Features of MCC 

Merkel cell carcinoma presents histologically as small round basophilic cells penetrating through the dermis in 3 histologic patterns: the trabecular, intermediate (80% of cases), and small cell type.^8,10 Immunohistochemical features include CK20 positivity (showing paranuclear dotlike depositions in the cytoplasm or cell membrane) and CK7 negativity, which allows it to be differentiated from other neoplasms. Chromogranin and synaptophysin positivity provide further histologic confirmation. The absence of peripheral palisading, retraction artifact, and a fibromyxoid stroma allow for distinction from cutaneous basal cell carcinoma, which may display these features histologically. Other immunohistochemical markers that may be of value include thyroid transcription factor 1, which is typically positive in cutaneous metastasis of neuroendocrine carcinoma of the lung; S-100 and human melanoma black 45, which are positive in melanoma; and leukocyte common antigen (CD45), which can be positive in lymphoma. These stains are classically negative in MCC.^4,8 

Merkel Cell Polyomavirus and Other Risk Factors

Merkel cell carcinoma is frequently associated with the presence of Merkel cell polyomavirus (MCPyV) in tumor specimens, with a prevalence of 70% to 80% in all cases.⁸ Merkel cell polyomavirus is a class 2A carcinogen (ie, a probable carcinogen to humans) and is classified among a group of viruses that encode T antigens (ie, an antigen coded by a viral genome associated with transformation of infected cells by tumor viruses), which can lead to initiation of tumorigenesis through interference with cellular tumor suppressing proteins such as p53.¹⁰ 

Immunosuppression and UV-exposed fair skin also are considered major risk factors, which may be explained by the increase in MCPyV small T-antigen transcripts induced by UV irradiation.¹⁰ Moreover, as is seen in other cancers induced by viruses, host immunity can hinder tumor progression and development. Therefore, impairment of normal immune function likely creates a higher risk for MCC development as well as the potential for a worse prognosis.^4,8 The precise incidence of MCC in immunosuppressed patients appears unclear; it is possible that chronic immunosuppressive therapy may play a notable role in the pathogenesis of the tumor.^4,8 

Impact of Comorbidities on MCC

These risk factors were all observed in the case patient. However, it also is possible that his associated comorbidities also had an impact on the presentation of his disease.⁸ For example, patients with rheumatoid arthritis have been shown to have an elevated risk for the development of MCC.¹⁴ Moreover, inflammatory monocytes infected with MCPyV, as would be expected in a patient with a history of chronic psoriasis prior to diagnosis of MCC, also may contribute to the pathogenesis of MCC by migrating to inflammatory skin lesions, such as those seen in psoriasis, releasing MCPyV locally and infecting Merkel cells.^8,15 Testing for MCPyV was never performed in the case patient; however, it certainly would be prudent to do so in such a presentation. Additionally, further studies to determine the correlation of MCC to these disease processes are warranted.⁸ 

Given that MCC tends to affect an older population in which other notable comorbidities are not uncommon, the cost, side effects, and convenience for patients of any treatment plan are important considerations.⁸ In the case study, a combined regimen of carboplatin and VP-16 (etoposide) was utilized. This regimen was well tolerated by the patient and successful in achieving complete radiologic and clinical remission of his metastatic disease. This combination has been shown to prolong survival in patients with distant metastasis compared to those patients not receiving chemotherapy.⁶ In all high-risk patients, close clinical monitoring is essential to help optimize outcomes.

Bottom Line

Merkel cell carcinoma is a rare but aggressive cutaneous neoplasm that most frequently affects elderly patients, immunosuppressed patients, and individuals with chronic UV sun damage. An association between the oncogenesis of MCC and infection with MCPyV has been documented, but other underlying diseases such as psoriasis and rheumatoid arthritis also may play a role. In this case, the patient’s history of chronic immunosuppressive therapy for treatment of psoriasis and inflammatory joint disease likely played a role in the pathogenesis of the tumor. This potential risk should be an important point of discussion with any patient requiring this type of long-term management for disease control. This unique clinical case highlights a patient with substantial comorbidities who developed metastatic MCC and achieved complete clinical and radiologic remission following treatment with surgery and chemotherapy.

SEATTLE – Treatment of psoriasis has been profoundly impacted by the advent of biologic therapies, but “topical therapy is not dead,” Linda Stein Gold, MD, said at the annual Coastal Dermatology Symposium.

Jim Kling/MDedge News

“We have to remember when we think back to our practice, how many topical prescriptions do we write, compared to preventive prescriptions? Probably most are topical,” said Dr. Stein Gold, director of dermatology clinical research at the Henry Ford Hospital Center, Detroit.

Topical agents have a place when a patient is doing well on treatment with a biologic but is not responding completely, she noted. One open-label, single-arm study looked at adjunctive calcipotriene 0.005%/betamethasone dipropionate 0.064% (Enstilar) foam, applied once daily for 4 week, then twice a week on consecutive days for 12 weeks in 25 patients with psoriasis who had a mean body surface area (BSA) of less than 5% but significant remaining disease despite treatment with biologics.

At week 4, 76% achieved a BSA of 1% or less and Physician’s Global Assessment score of 1 or less at week 4, as did 68% at week 16. This was compared with 12% and 4%, respectively (J Drugs Dermatol. 2018 Aug 1;17[8]:845-50). “They found that a good potent topical on top of a biologic does really well. That can really kick up the last part of the efficacy to get the patients almost to clear,” she observed.

At the meeting, jointly presented by the University of Louisville and Global Academy for Medical Education, Dr. Stein Gold also discussed tazarotene, a topical retinoid approved by the Food and Drug Administration for treating psoriasis and is available as a 0.1% and 0.05% cream and gel. About 10%-30% of patients experience side effects with tazarotene, such as pruritus, stinging, and burning. Topical corticosteroids can help, which prompted development of a combined product, she noted.

She referred to a phase 2 study of patients with moderate to severe plaque psoriasis, which compared the fixed combination lotion formulation of tazarotene plus halobetasol propionate to the two components alone. The investigators found almost a 9% rate of treatment success with tazarotene alone, versus about 23% with halobetasol propionate alone and about 43% with the combined product. The combined individual effect of the two drugs was about 32%, so the 43% efficacy of the combined product had an absolute synergistic effect of about 11%, Dr. Stein Gold pointed out.

Two phase 3 trials of adults with moderate to severe psoriasis supported the phase 2 results of the combined lotion formulation (halobetasol 0.01% with tazarotene 0.045%), said Dr. Stein Gold, the first author (J Am Acad Dermatol. 2018 Aug;79[2]:287-93). Treatment success was defined as at least a 2-grade Investigator’s Global Assessment score and improvement from baseline and a score of “clear” or “almost clear.” In one of the studies, 36% of those on the combination versus 7% of those on the vehicle met this endpoint at week 8, as did 45% versus 13%, respectively, in the second study (P less than .001 for both studies).

Patients also had less itching, drying, and stinging than typically seen with tazarotene alone, Dr. Stein Gold said. In the studies, contact dermatitis was the most common side effect associated with treatment, reported in 6.3%

Dr. Stein Gold has received research support from Galderma, Leo, Novan, Valeant, Dermira, Novartis, Celgene, Allergan, and Foamix. She has been a consultant for Sol-gel, Galderma, Leo, Novan, Valeant, Dermira, Novartis, Celgene, Allergan, Foamix, Promis, Anacor, and Medimetriks. She has been on the speakers bureau of Galderma, Leo, Valeant, Novartis, Celgene, and Allergan. She has been a member of scientific advisory boards for Galderma, Leo, Novan, Valeant, Dermira, Novartis, Celgene, Allergan, Foamix, and Promius.

This publication and Global Academy for Medical Education are owned by the same parent company.

SEATTLE – Treatment of psoriasis has been profoundly impacted by the advent of biologic therapies, but “topical therapy is not dead,” Linda Stein Gold, MD, said at the annual Coastal Dermatology Symposium.

Jim Kling/MDedge News

“We have to remember when we think back to our practice, how many topical prescriptions do we write, compared to preventive prescriptions? Probably most are topical,” said Dr. Stein Gold, director of dermatology clinical research at the Henry Ford Hospital Center, Detroit.

Topical agents have a place when a patient is doing well on treatment with a biologic but is not responding completely, she noted. One open-label, single-arm study looked at adjunctive calcipotriene 0.005%/betamethasone dipropionate 0.064% (Enstilar) foam, applied once daily for 4 week, then twice a week on consecutive days for 12 weeks in 25 patients with psoriasis who had a mean body surface area (BSA) of less than 5% but significant remaining disease despite treatment with biologics.

At week 4, 76% achieved a BSA of 1% or less and Physician’s Global Assessment score of 1 or less at week 4, as did 68% at week 16. This was compared with 12% and 4%, respectively (J Drugs Dermatol. 2018 Aug 1;17[8]:845-50). “They found that a good potent topical on top of a biologic does really well. That can really kick up the last part of the efficacy to get the patients almost to clear,” she observed.

At the meeting, jointly presented by the University of Louisville and Global Academy for Medical Education, Dr. Stein Gold also discussed tazarotene, a topical retinoid approved by the Food and Drug Administration for treating psoriasis and is available as a 0.1% and 0.05% cream and gel. About 10%-30% of patients experience side effects with tazarotene, such as pruritus, stinging, and burning. Topical corticosteroids can help, which prompted development of a combined product, she noted.

She referred to a phase 2 study of patients with moderate to severe plaque psoriasis, which compared the fixed combination lotion formulation of tazarotene plus halobetasol propionate to the two components alone. The investigators found almost a 9% rate of treatment success with tazarotene alone, versus about 23% with halobetasol propionate alone and about 43% with the combined product. The combined individual effect of the two drugs was about 32%, so the 43% efficacy of the combined product had an absolute synergistic effect of about 11%, Dr. Stein Gold pointed out.

Two phase 3 trials of adults with moderate to severe psoriasis supported the phase 2 results of the combined lotion formulation (halobetasol 0.01% with tazarotene 0.045%), said Dr. Stein Gold, the first author (J Am Acad Dermatol. 2018 Aug;79[2]:287-93). Treatment success was defined as at least a 2-grade Investigator’s Global Assessment score and improvement from baseline and a score of “clear” or “almost clear.” In one of the studies, 36% of those on the combination versus 7% of those on the vehicle met this endpoint at week 8, as did 45% versus 13%, respectively, in the second study (P less than .001 for both studies).

Patients also had less itching, drying, and stinging than typically seen with tazarotene alone, Dr. Stein Gold said. In the studies, contact dermatitis was the most common side effect associated with treatment, reported in 6.3%

Dr. Stein Gold has received research support from Galderma, Leo, Novan, Valeant, Dermira, Novartis, Celgene, Allergan, and Foamix. She has been a consultant for Sol-gel, Galderma, Leo, Novan, Valeant, Dermira, Novartis, Celgene, Allergan, Foamix, Promis, Anacor, and Medimetriks. She has been on the speakers bureau of Galderma, Leo, Valeant, Novartis, Celgene, and Allergan. She has been a member of scientific advisory boards for Galderma, Leo, Novan, Valeant, Dermira, Novartis, Celgene, Allergan, Foamix, and Promius.

This publication and Global Academy for Medical Education are owned by the same parent company.

SEATTLE – Treatment of psoriasis has been profoundly impacted by the advent of biologic therapies, but “topical therapy is not dead,” Linda Stein Gold, MD, said at the annual Coastal Dermatology Symposium.

Jim Kling/MDedge News

“We have to remember when we think back to our practice, how many topical prescriptions do we write, compared to preventive prescriptions? Probably most are topical,” said Dr. Stein Gold, director of dermatology clinical research at the Henry Ford Hospital Center, Detroit.

Topical agents have a place when a patient is doing well on treatment with a biologic but is not responding completely, she noted. One open-label, single-arm study looked at adjunctive calcipotriene 0.005%/betamethasone dipropionate 0.064% (Enstilar) foam, applied once daily for 4 week, then twice a week on consecutive days for 12 weeks in 25 patients with psoriasis who had a mean body surface area (BSA) of less than 5% but significant remaining disease despite treatment with biologics.

At week 4, 76% achieved a BSA of 1% or less and Physician’s Global Assessment score of 1 or less at week 4, as did 68% at week 16. This was compared with 12% and 4%, respectively (J Drugs Dermatol. 2018 Aug 1;17[8]:845-50). “They found that a good potent topical on top of a biologic does really well. That can really kick up the last part of the efficacy to get the patients almost to clear,” she observed.

At the meeting, jointly presented by the University of Louisville and Global Academy for Medical Education, Dr. Stein Gold also discussed tazarotene, a topical retinoid approved by the Food and Drug Administration for treating psoriasis and is available as a 0.1% and 0.05% cream and gel. About 10%-30% of patients experience side effects with tazarotene, such as pruritus, stinging, and burning. Topical corticosteroids can help, which prompted development of a combined product, she noted.

She referred to a phase 2 study of patients with moderate to severe plaque psoriasis, which compared the fixed combination lotion formulation of tazarotene plus halobetasol propionate to the two components alone. The investigators found almost a 9% rate of treatment success with tazarotene alone, versus about 23% with halobetasol propionate alone and about 43% with the combined product. The combined individual effect of the two drugs was about 32%, so the 43% efficacy of the combined product had an absolute synergistic effect of about 11%, Dr. Stein Gold pointed out.

Two phase 3 trials of adults with moderate to severe psoriasis supported the phase 2 results of the combined lotion formulation (halobetasol 0.01% with tazarotene 0.045%), said Dr. Stein Gold, the first author (J Am Acad Dermatol. 2018 Aug;79[2]:287-93). Treatment success was defined as at least a 2-grade Investigator’s Global Assessment score and improvement from baseline and a score of “clear” or “almost clear.” In one of the studies, 36% of those on the combination versus 7% of those on the vehicle met this endpoint at week 8, as did 45% versus 13%, respectively, in the second study (P less than .001 for both studies).

Patients also had less itching, drying, and stinging than typically seen with tazarotene alone, Dr. Stein Gold said. In the studies, contact dermatitis was the most common side effect associated with treatment, reported in 6.3%

Dr. Stein Gold has received research support from Galderma, Leo, Novan, Valeant, Dermira, Novartis, Celgene, Allergan, and Foamix. She has been a consultant for Sol-gel, Galderma, Leo, Novan, Valeant, Dermira, Novartis, Celgene, Allergan, Foamix, Promis, Anacor, and Medimetriks. She has been on the speakers bureau of Galderma, Leo, Valeant, Novartis, Celgene, and Allergan. She has been a member of scientific advisory boards for Galderma, Leo, Novan, Valeant, Dermira, Novartis, Celgene, Allergan, Foamix, and Promius.

This publication and Global Academy for Medical Education are owned by the same parent company.

An update to the 2007 guidelines on the treatment of community-acquired pneumonia (CAP) was published by two medical societies, based upon the work of a multidisciplinary panel that “conducted pragmatic systematic reviews of the relevant research and applied Grading of Recommendations, Assessment, Development, and Evaluation methodology for clinical recommendations.”

copyright stockdevil/Thinkstock

The panel addressed 16 questions in the areas including diagnostic testing, determination of site of care, selection of initial empiric antibiotic therapy, and subsequent management decisions. Some of their recommendations remained unchanged from the 2007 guideline, but others were updated based upon more-recent clinical trials and epidemiological studies, according to Joshua P. Metlay, MD, of Massachusetts General Hospital, Boston, and colleagues on behalf of the Infectious Diseases Society of America and the American Thoracic Society.

Among the key recommendations differing from the previous guidelines, the 2019 guidelines include the following:

• Sputum and blood culture samples are recommended in patients with severe disease, as well as in all inpatients empirically treated for methicillin-resistant Staphylococcus aureus (MRSA) or Pseudomonas aeruginosa.
• Macrolide monotherapy is only conditionally recommended for outpatients based on resistance levels.
• Procalcitonin assessment, not covered in the 2007 guidelines, is not recommended in order to determine initial antibiotic therapy.
• Corticosteroid use, not covered in the 2007 guidelines, is not recommended, though it may be considered in patients with refractory septic shock.
• The use of health care–associated pneumonia (HCAP) as a category should be dropped, with a switch to an emphasis on local epidemiology and validated risk factors to determine the need for MRSA or P. aeruginosa treatment.
• Standard empiric therapy for severe CAP should be beta-lactam/macrolide and beta-lactam/fluoroquinolone combinations, but with stronger evidence in favor of the beta-lactam/macrolide combination.

The updated guidelines also include a number of other recommendations, such as those dealing with the management of patients with comorbidities, and were published in the American Journal of Respiratory and Critical Care Medicine.

“A difference between this guideline and previous ones is that we have significantly increased the proportion of patients in whom we recommend routinely obtaining respiratory tract samples for microbiologic studies. This decision is largely based on a desire to correct the overuse of anti-MRSA and antipseudomonal therapy that has occurred since the introduction of the HCAP classification (which we recommend abandoning) rather than high-quality evidence,” the authors stated in their conclusions. They added that they “expect our move against endorsing monotherapy with macrolides, which is based on population resistance data rather than high-quality clinical studies, will generate future outcomes studies comparing different treatment strategies.”

Many of the authors reported relationships with a variety of pharmaceutical companies; full disclosures are detailed at the end of the guideline publication.

[email protected]

SOURCE: Metlay JP et al. Am J Respir Crit Med. 2019;200(7):e45-67.

An update to the 2007 guidelines on the treatment of community-acquired pneumonia (CAP) was published by two medical societies, based upon the work of a multidisciplinary panel that “conducted pragmatic systematic reviews of the relevant research and applied Grading of Recommendations, Assessment, Development, and Evaluation methodology for clinical recommendations.”

copyright stockdevil/Thinkstock

The panel addressed 16 questions in the areas including diagnostic testing, determination of site of care, selection of initial empiric antibiotic therapy, and subsequent management decisions. Some of their recommendations remained unchanged from the 2007 guideline, but others were updated based upon more-recent clinical trials and epidemiological studies, according to Joshua P. Metlay, MD, of Massachusetts General Hospital, Boston, and colleagues on behalf of the Infectious Diseases Society of America and the American Thoracic Society.

Among the key recommendations differing from the previous guidelines, the 2019 guidelines include the following:

• Sputum and blood culture samples are recommended in patients with severe disease, as well as in all inpatients empirically treated for methicillin-resistant Staphylococcus aureus (MRSA) or Pseudomonas aeruginosa.
• Macrolide monotherapy is only conditionally recommended for outpatients based on resistance levels.
• Procalcitonin assessment, not covered in the 2007 guidelines, is not recommended in order to determine initial antibiotic therapy.
• Corticosteroid use, not covered in the 2007 guidelines, is not recommended, though it may be considered in patients with refractory septic shock.
• The use of health care–associated pneumonia (HCAP) as a category should be dropped, with a switch to an emphasis on local epidemiology and validated risk factors to determine the need for MRSA or P. aeruginosa treatment.
• Standard empiric therapy for severe CAP should be beta-lactam/macrolide and beta-lactam/fluoroquinolone combinations, but with stronger evidence in favor of the beta-lactam/macrolide combination.

The updated guidelines also include a number of other recommendations, such as those dealing with the management of patients with comorbidities, and were published in the American Journal of Respiratory and Critical Care Medicine.

“A difference between this guideline and previous ones is that we have significantly increased the proportion of patients in whom we recommend routinely obtaining respiratory tract samples for microbiologic studies. This decision is largely based on a desire to correct the overuse of anti-MRSA and antipseudomonal therapy that has occurred since the introduction of the HCAP classification (which we recommend abandoning) rather than high-quality evidence,” the authors stated in their conclusions. They added that they “expect our move against endorsing monotherapy with macrolides, which is based on population resistance data rather than high-quality clinical studies, will generate future outcomes studies comparing different treatment strategies.”

Many of the authors reported relationships with a variety of pharmaceutical companies; full disclosures are detailed at the end of the guideline publication.

[email protected]

SOURCE: Metlay JP et al. Am J Respir Crit Med. 2019;200(7):e45-67.

An update to the 2007 guidelines on the treatment of community-acquired pneumonia (CAP) was published by two medical societies, based upon the work of a multidisciplinary panel that “conducted pragmatic systematic reviews of the relevant research and applied Grading of Recommendations, Assessment, Development, and Evaluation methodology for clinical recommendations.”

copyright stockdevil/Thinkstock

The panel addressed 16 questions in the areas including diagnostic testing, determination of site of care, selection of initial empiric antibiotic therapy, and subsequent management decisions. Some of their recommendations remained unchanged from the 2007 guideline, but others were updated based upon more-recent clinical trials and epidemiological studies, according to Joshua P. Metlay, MD, of Massachusetts General Hospital, Boston, and colleagues on behalf of the Infectious Diseases Society of America and the American Thoracic Society.

Among the key recommendations differing from the previous guidelines, the 2019 guidelines include the following:

• Sputum and blood culture samples are recommended in patients with severe disease, as well as in all inpatients empirically treated for methicillin-resistant Staphylococcus aureus (MRSA) or Pseudomonas aeruginosa.
• Macrolide monotherapy is only conditionally recommended for outpatients based on resistance levels.
• Procalcitonin assessment, not covered in the 2007 guidelines, is not recommended in order to determine initial antibiotic therapy.
• Corticosteroid use, not covered in the 2007 guidelines, is not recommended, though it may be considered in patients with refractory septic shock.
• The use of health care–associated pneumonia (HCAP) as a category should be dropped, with a switch to an emphasis on local epidemiology and validated risk factors to determine the need for MRSA or P. aeruginosa treatment.
• Standard empiric therapy for severe CAP should be beta-lactam/macrolide and beta-lactam/fluoroquinolone combinations, but with stronger evidence in favor of the beta-lactam/macrolide combination.

The updated guidelines also include a number of other recommendations, such as those dealing with the management of patients with comorbidities, and were published in the American Journal of Respiratory and Critical Care Medicine.

“A difference between this guideline and previous ones is that we have significantly increased the proportion of patients in whom we recommend routinely obtaining respiratory tract samples for microbiologic studies. This decision is largely based on a desire to correct the overuse of anti-MRSA and antipseudomonal therapy that has occurred since the introduction of the HCAP classification (which we recommend abandoning) rather than high-quality evidence,” the authors stated in their conclusions. They added that they “expect our move against endorsing monotherapy with macrolides, which is based on population resistance data rather than high-quality clinical studies, will generate future outcomes studies comparing different treatment strategies.”

Many of the authors reported relationships with a variety of pharmaceutical companies; full disclosures are detailed at the end of the guideline publication.

[email protected]

SOURCE: Metlay JP et al. Am J Respir Crit Med. 2019;200(7):e45-67.

MADRID – Abrocitinib took a giant step closer to becoming the first once-daily oral Janus kinase 1 (JAK1) inhibitor to be approved for treatment of atopic dermatitis (AD) on the strength of its knockout performance in the pivotal phase 3 JADE MONO-1 trial, presented at the annual congress of the European Academy of Dermatology and Venereology.

Bruce Jancin/MDedge News

“The IGA [Investigator Global Assessment] and EASI [Eczema Area and Severity Index]-75 responses for both doses of abrocitinib were significantly greater than placebo as early as week 2 and continued to increase until week 12 with no plateau. This study stopped at week 12. I would have liked to see what happened at 16 weeks or further. I don’t know where this is going to end up maxing out,” commented principal investigator Eric Simpson, MD, professor of dermatology at Oregon Health & Science University, Portland.

JADE MONO-1 (JAK1 Atopic Dermatitis Efficacy and Safety Monotherapy–1) was a 12-week, double-blind, multicenter study which included 387 adolescents and adults with moderate or severe AD randomized 2:2:1 to abrocitinib at 200 mg or 100 mg once daily, or to placebo. Overall, this was a fairly severely affected population, with a mean baseline EASI (Eczema Area and Severity Index) score of about 30, a peak pruritus numeric rating scale score of 7 out of 10, and a mean Dermatology Quality Life Index score greater than 14. Nonetheless, this was a rigorous abrocitinib monotherapy trial, as participants were not allowed to take even a single dose of topical corticosteroids.

The coprimary endpoints in JADE MONO-1 were achievement of an IGA score of 0 or 1 – that is, clear or almost clear – at week 12 plus at least a 2-point improvement, compared with baseline on the 0-4 scale, and an EASI-75 response as defined by a 75% or greater improvement from baseline.

A clear-cut dose response was evident: the IGA response rate was 43.8% in the group on abrocitinib at 200 mg/day, 23.7% with 100 mg, and 7.9% with placebo. The EASI-75 response rates were 62.7%, 39.7%, and 11.8%, respectively, with a statistically significant separation from placebo by week 2.

Key secondary endpoints included the rigorous EASI-90 response rate: 38.6% with the higher dose of abrocitinib, 18.6% at 100 mg per day, and 5.3% with placebo. And again, that’s without resort to topical steroids, Dr. Simpson noted.

Another important secondary endpoint was the proportion of patients who achieved at least a 4-point improvement in itch on the pruritus self-rating scale by week 12: 57.2%, 37.7%, and 15.3%. The rapidity of the improvement was notable: By week 2, this endpoint was achieved in 45.6% of patients on abrocitinib on the 200-mg dose, 20.4% on the 100-mg dose, and 2.7% of placebo-treated controls.

“By day 2, 1 day after taking the first pill, you can see really nice reductions in itch at both doses, compared with placebo,” the dermatologist said.

Study dropout rates were low despite the inability to utilize topical steroids: 11% in the higher-dose abrocitinib group and 13.5% with abrocitinib at 100 mg/day, both of which were lower than in controls.

Turning to safety results, Dr. Simpson noted that the 9.1% rate of discontinuations because of adverse events in the placebo group was significantly higher than the 5.8% rates in each of the active treatment arms. The serious adverse event rate was 3.2% in each of the abrocitinib groups and 1.9% with placebo. Among the serious adverse events in abrocitinib-treated patients Dr. Simpson considered worthy of special mention were a single case of inflammatory bowel disease, which resolved after halting treatment; one case of peritonsillitis; and a case of pancreatitis in an alcoholic patient. No deaths, major adverse cardiovascular events, or malignancies occurred in this brief 12-week trial. Nor were there any cases of deep vein thrombosis or pulmonary embolism, which has been an issue with some other JAK inhibitors.

“We need long-term safety data, of course,” he said.

Laboratory findings were generally unremarkable, with no clinically significant changes. Platelet counts dropped to a nadir at about 4 weeks while staying within normal range, then came back up. Mean LDL cholesterol levels rose by about 10%, an unwelcome event that was counterbalanced by a favorable 20% rise in HDL cholesterol.

Asked about the efficacy rates in the 20%-plus adolescent study participants, compared with the adults, Dr. Simpson replied that a detailed analysis is planned, adding: “I can say that things are looking pretty similar.”

Abrocitinib is selective for inhibition of JAK1, with resultant modulation of interleukins-4, -13, and -31, as well as interferon-gamma, all of which are cytokines involved in the pathophysiology of AD.

Of note, Pfizer, the drug’s developer, has announced positive results from the sister pivotal phase 3 trial, JADE MONO-2, with full details forthcoming in early 2020. Results of a phase 2b study of abrocitinib were also recently published (JAMA Dermatol. 2019 Oct 2. doi: 10.1001/jamadermatol.2019.2855).

Dr. Simpson reported receiving research grants from and serving as a consultant to Pfizer, the study sponsor. He has similar financial relationships with close to a dozen other pharmaceutical companies.

[email protected]

MADRID – Abrocitinib took a giant step closer to becoming the first once-daily oral Janus kinase 1 (JAK1) inhibitor to be approved for treatment of atopic dermatitis (AD) on the strength of its knockout performance in the pivotal phase 3 JADE MONO-1 trial, presented at the annual congress of the European Academy of Dermatology and Venereology.

Bruce Jancin/MDedge News

“The IGA [Investigator Global Assessment] and EASI [Eczema Area and Severity Index]-75 responses for both doses of abrocitinib were significantly greater than placebo as early as week 2 and continued to increase until week 12 with no plateau. This study stopped at week 12. I would have liked to see what happened at 16 weeks or further. I don’t know where this is going to end up maxing out,” commented principal investigator Eric Simpson, MD, professor of dermatology at Oregon Health & Science University, Portland.

JADE MONO-1 (JAK1 Atopic Dermatitis Efficacy and Safety Monotherapy–1) was a 12-week, double-blind, multicenter study which included 387 adolescents and adults with moderate or severe AD randomized 2:2:1 to abrocitinib at 200 mg or 100 mg once daily, or to placebo. Overall, this was a fairly severely affected population, with a mean baseline EASI (Eczema Area and Severity Index) score of about 30, a peak pruritus numeric rating scale score of 7 out of 10, and a mean Dermatology Quality Life Index score greater than 14. Nonetheless, this was a rigorous abrocitinib monotherapy trial, as participants were not allowed to take even a single dose of topical corticosteroids.

The coprimary endpoints in JADE MONO-1 were achievement of an IGA score of 0 or 1 – that is, clear or almost clear – at week 12 plus at least a 2-point improvement, compared with baseline on the 0-4 scale, and an EASI-75 response as defined by a 75% or greater improvement from baseline.

A clear-cut dose response was evident: the IGA response rate was 43.8% in the group on abrocitinib at 200 mg/day, 23.7% with 100 mg, and 7.9% with placebo. The EASI-75 response rates were 62.7%, 39.7%, and 11.8%, respectively, with a statistically significant separation from placebo by week 2.

Key secondary endpoints included the rigorous EASI-90 response rate: 38.6% with the higher dose of abrocitinib, 18.6% at 100 mg per day, and 5.3% with placebo. And again, that’s without resort to topical steroids, Dr. Simpson noted.

Another important secondary endpoint was the proportion of patients who achieved at least a 4-point improvement in itch on the pruritus self-rating scale by week 12: 57.2%, 37.7%, and 15.3%. The rapidity of the improvement was notable: By week 2, this endpoint was achieved in 45.6% of patients on abrocitinib on the 200-mg dose, 20.4% on the 100-mg dose, and 2.7% of placebo-treated controls.

“By day 2, 1 day after taking the first pill, you can see really nice reductions in itch at both doses, compared with placebo,” the dermatologist said.

Study dropout rates were low despite the inability to utilize topical steroids: 11% in the higher-dose abrocitinib group and 13.5% with abrocitinib at 100 mg/day, both of which were lower than in controls.

Turning to safety results, Dr. Simpson noted that the 9.1% rate of discontinuations because of adverse events in the placebo group was significantly higher than the 5.8% rates in each of the active treatment arms. The serious adverse event rate was 3.2% in each of the abrocitinib groups and 1.9% with placebo. Among the serious adverse events in abrocitinib-treated patients Dr. Simpson considered worthy of special mention were a single case of inflammatory bowel disease, which resolved after halting treatment; one case of peritonsillitis; and a case of pancreatitis in an alcoholic patient. No deaths, major adverse cardiovascular events, or malignancies occurred in this brief 12-week trial. Nor were there any cases of deep vein thrombosis or pulmonary embolism, which has been an issue with some other JAK inhibitors.

“We need long-term safety data, of course,” he said.

Laboratory findings were generally unremarkable, with no clinically significant changes. Platelet counts dropped to a nadir at about 4 weeks while staying within normal range, then came back up. Mean LDL cholesterol levels rose by about 10%, an unwelcome event that was counterbalanced by a favorable 20% rise in HDL cholesterol.

Asked about the efficacy rates in the 20%-plus adolescent study participants, compared with the adults, Dr. Simpson replied that a detailed analysis is planned, adding: “I can say that things are looking pretty similar.”

Abrocitinib is selective for inhibition of JAK1, with resultant modulation of interleukins-4, -13, and -31, as well as interferon-gamma, all of which are cytokines involved in the pathophysiology of AD.

Of note, Pfizer, the drug’s developer, has announced positive results from the sister pivotal phase 3 trial, JADE MONO-2, with full details forthcoming in early 2020. Results of a phase 2b study of abrocitinib were also recently published (JAMA Dermatol. 2019 Oct 2. doi: 10.1001/jamadermatol.2019.2855).

Dr. Simpson reported receiving research grants from and serving as a consultant to Pfizer, the study sponsor. He has similar financial relationships with close to a dozen other pharmaceutical companies.

[email protected]

MADRID – Abrocitinib took a giant step closer to becoming the first once-daily oral Janus kinase 1 (JAK1) inhibitor to be approved for treatment of atopic dermatitis (AD) on the strength of its knockout performance in the pivotal phase 3 JADE MONO-1 trial, presented at the annual congress of the European Academy of Dermatology and Venereology.

Bruce Jancin/MDedge News

“The IGA [Investigator Global Assessment] and EASI [Eczema Area and Severity Index]-75 responses for both doses of abrocitinib were significantly greater than placebo as early as week 2 and continued to increase until week 12 with no plateau. This study stopped at week 12. I would have liked to see what happened at 16 weeks or further. I don’t know where this is going to end up maxing out,” commented principal investigator Eric Simpson, MD, professor of dermatology at Oregon Health & Science University, Portland.

JADE MONO-1 (JAK1 Atopic Dermatitis Efficacy and Safety Monotherapy–1) was a 12-week, double-blind, multicenter study which included 387 adolescents and adults with moderate or severe AD randomized 2:2:1 to abrocitinib at 200 mg or 100 mg once daily, or to placebo. Overall, this was a fairly severely affected population, with a mean baseline EASI (Eczema Area and Severity Index) score of about 30, a peak pruritus numeric rating scale score of 7 out of 10, and a mean Dermatology Quality Life Index score greater than 14. Nonetheless, this was a rigorous abrocitinib monotherapy trial, as participants were not allowed to take even a single dose of topical corticosteroids.

The coprimary endpoints in JADE MONO-1 were achievement of an IGA score of 0 or 1 – that is, clear or almost clear – at week 12 plus at least a 2-point improvement, compared with baseline on the 0-4 scale, and an EASI-75 response as defined by a 75% or greater improvement from baseline.

A clear-cut dose response was evident: the IGA response rate was 43.8% in the group on abrocitinib at 200 mg/day, 23.7% with 100 mg, and 7.9% with placebo. The EASI-75 response rates were 62.7%, 39.7%, and 11.8%, respectively, with a statistically significant separation from placebo by week 2.

Key secondary endpoints included the rigorous EASI-90 response rate: 38.6% with the higher dose of abrocitinib, 18.6% at 100 mg per day, and 5.3% with placebo. And again, that’s without resort to topical steroids, Dr. Simpson noted.

Another important secondary endpoint was the proportion of patients who achieved at least a 4-point improvement in itch on the pruritus self-rating scale by week 12: 57.2%, 37.7%, and 15.3%. The rapidity of the improvement was notable: By week 2, this endpoint was achieved in 45.6% of patients on abrocitinib on the 200-mg dose, 20.4% on the 100-mg dose, and 2.7% of placebo-treated controls.

“By day 2, 1 day after taking the first pill, you can see really nice reductions in itch at both doses, compared with placebo,” the dermatologist said.

Study dropout rates were low despite the inability to utilize topical steroids: 11% in the higher-dose abrocitinib group and 13.5% with abrocitinib at 100 mg/day, both of which were lower than in controls.

Turning to safety results, Dr. Simpson noted that the 9.1% rate of discontinuations because of adverse events in the placebo group was significantly higher than the 5.8% rates in each of the active treatment arms. The serious adverse event rate was 3.2% in each of the abrocitinib groups and 1.9% with placebo. Among the serious adverse events in abrocitinib-treated patients Dr. Simpson considered worthy of special mention were a single case of inflammatory bowel disease, which resolved after halting treatment; one case of peritonsillitis; and a case of pancreatitis in an alcoholic patient. No deaths, major adverse cardiovascular events, or malignancies occurred in this brief 12-week trial. Nor were there any cases of deep vein thrombosis or pulmonary embolism, which has been an issue with some other JAK inhibitors.

“We need long-term safety data, of course,” he said.

Laboratory findings were generally unremarkable, with no clinically significant changes. Platelet counts dropped to a nadir at about 4 weeks while staying within normal range, then came back up. Mean LDL cholesterol levels rose by about 10%, an unwelcome event that was counterbalanced by a favorable 20% rise in HDL cholesterol.

Asked about the efficacy rates in the 20%-plus adolescent study participants, compared with the adults, Dr. Simpson replied that a detailed analysis is planned, adding: “I can say that things are looking pretty similar.”

Abrocitinib is selective for inhibition of JAK1, with resultant modulation of interleukins-4, -13, and -31, as well as interferon-gamma, all of which are cytokines involved in the pathophysiology of AD.

Of note, Pfizer, the drug’s developer, has announced positive results from the sister pivotal phase 3 trial, JADE MONO-2, with full details forthcoming in early 2020. Results of a phase 2b study of abrocitinib were also recently published (JAMA Dermatol. 2019 Oct 2. doi: 10.1001/jamadermatol.2019.2855).

Dr. Simpson reported receiving research grants from and serving as a consultant to Pfizer, the study sponsor. He has similar financial relationships with close to a dozen other pharmaceutical companies.

[email protected]

"The Child Neurology Society Annual Meeting is the meeting of choice for child neurologists and professionals in other fields of study related to neurologic and neurodevelopmental disorders in children and adolescents,” according to the society. Check back later this month for top news from the 48th conference in Charlotte, NC.

"The Child Neurology Society Annual Meeting is the meeting of choice for child neurologists and professionals in other fields of study related to neurologic and neurodevelopmental disorders in children and adolescents,” according to the society. Check back later this month for top news from the 48th conference in Charlotte, NC.

"The Child Neurology Society Annual Meeting is the meeting of choice for child neurologists and professionals in other fields of study related to neurologic and neurodevelopmental disorders in children and adolescents,” according to the society. Check back later this month for top news from the 48th conference in Charlotte, NC.

BARCELONA – The androgen receptor inhibitor apalutamide was associated with a 45% improvement in time to second progression in patients with nonmetastatic, castration-resistant prostate cancer as well as an overall survival edge, although the latter fell just short of statistical significance in an interim analysis of results from the SPARTAN trial.

Among 1,207 men with nonmetastatic castration-resistant prostate cancer (CRPC), those randomly assigned to apalutamide had significantly longer second progression-free survival (PFS2), an exploratory endpoint defined as the time of study entry to progression on subsequent treatment.

In all, 69% of patients on placebo and 40% of those on apalutamide went on to another life-prolonging therapy, usually abiraterone acetate (Zytiga) plus prednisone. The respective median PFS2s were 43.8 and 55.6 months, translating into a hazard ratio for second progression in the apalutamide group of 0.55 (P less than .0001).

Overall survival (OS) also trended toward a benefit for apalutamide, but the difference did not reach the prespecified boundary for significance in this planned interim analysis, reported Matthew R. Smith, MD, PhD, from the Massachusetts General Hospital Cancer Center in Boston.

Among men randomly assigned in the phase 3 trial to receive apalutamide (Erleada), the 4-year OS rate was 72.1%, compared with 64.7% for patients assigned to placebo.

“This OS benefit for apalutamide was observed despite crossover of placebo patients to apalutamide, and higher rates of subsequent life-prolonging therapy in the placebo group,” he said at the European Society for Medical Oncology Congress.

Apalutamide was approved by the Food and Drug Administration in 2018 for treatment of patients with nonmetastatic CRPC who were on androgen deprivation therapy with a rapidly rising prostate-specific antigen level and no detectable distant metastases on conventional imaging.

That approval was based on the primary results from SPARTAN, which showed a median metastasis-free survival for patients taking apalutamide of 40.5 months, compared with 16.2 months for patients taking placebo.

The drug also recently received FDA approval for treatment of men with metastatic CRPC, based on results of the TITAN trial.

Overall survival

At the time of the primary analysis of SPARTAN for metastasis-free survival, the OS data were immature, with only 104 of 427 events required for the prespecified analysis.

At ESMO 2019, Dr. Smith presented results of the second interim survival analysis looking at the effects of apalutamide on OS, as well as time to chemotherapy, PFS2, and safety.

In the trial, men with nonmetastatic CRPC were randomized on a 2:1 basis to receive either apalutamide 240 mg daily (806 patients) or placebo (401) plus androgen deprivation therapy, either with gonadotropin-releasing hormone analogue therapy or with surgical castration.

At a median follow-up of 41 months, median OS was not reached in either arm. As noted before, the 4-year OS rate was higher in the apalutamide group, translating into a HR for death of 0.75. However, the P value of .0197 was higher than the prespecified O’Brien-Fleming boundary of 0.0121, which means that the study follow-up will continue per protocol, with the final analysis for overall survival planned after 427 deaths have occurred, Dr. Smith said.

The survival benefit with apalutamide either trended toward significance across all subgroups, with notable benefits in patients aged younger than 65 years, those with good performance status, prostate-specific antigen doubling time longer than 6 months, and those with locoregional disease status of N1 versus N0.

The secondary endpoint of time to chemotherapy initiation was not formally tested because OS did not reach statistical significance, but proportionally fewer patients on apalutamide had started cytotoxic chemotherapy at the time of the interim analysis (14% vs. 20% of patients on placebo). The median time to initiation of chemotherapy has not been reached in either trial arm, however.

The safety profile of the androgen receptor inhibitor was consistent with that seen in the primary PFS analysis, with any adverse event seen in 97.3% of patients versus 93.7% of patients on placebo, grade 3-4 adverse events in 53.1% versus 36.7%, any serious adverse event in 33.5% versus 24.9%, events leading to treatment discontinuation in 13.8% versus 7.3%, and fatal adverse events in 2.1 versus .5%.

“Of some note, discontinuation due to disease progression was 34% in the apalutamide group, compared to 74% in the placebo group,” Dr. Smith said.

“These results further support apalutamide as a standard-of-care option for men with high-risk, nonmetastatic CRPC,” he concluded.

PFS2 data ‘important’

Invited discussant Karim Fizazi, MD, PhD, from the Institut Gustave Roussy in Villejuif, France, acknowledged it’s too early to draw conclusions about OS, but added that the PFS2 data are important.

Neil Osterweil/MDedge News

The 45% reduction in risk of progression “is particularly important in this trial because abiraterone was provided as a potential salvage treatment in both arms. So in other words, in that trial they were almost truly comparing early AR [androgen receptor] targeting versus deferred AR targeting, at least in some patients, and it seems that [apalutamide] is making a difference in terms of second progression,” he said.

An unanswered question about the trial, however, is how active abiraterone was post apalutamide in the experimental, because there are data suggesting minimal efficacy in sequential therapy of AR-targeted agents, he added.

The SPARTAN trial was funded by Janssen. Dr. Smith disclosed an advisory role, research funding, and travel reimbursement for Janssen and others. Dr. Fizazi disclosed consulting for Janssen and others.

SOURCE: Smith MR et al. ESMO 2019, Abstract 843O

BARCELONA – The androgen receptor inhibitor apalutamide was associated with a 45% improvement in time to second progression in patients with nonmetastatic, castration-resistant prostate cancer as well as an overall survival edge, although the latter fell just short of statistical significance in an interim analysis of results from the SPARTAN trial.

Among 1,207 men with nonmetastatic castration-resistant prostate cancer (CRPC), those randomly assigned to apalutamide had significantly longer second progression-free survival (PFS2), an exploratory endpoint defined as the time of study entry to progression on subsequent treatment.

In all, 69% of patients on placebo and 40% of those on apalutamide went on to another life-prolonging therapy, usually abiraterone acetate (Zytiga) plus prednisone. The respective median PFS2s were 43.8 and 55.6 months, translating into a hazard ratio for second progression in the apalutamide group of 0.55 (P less than .0001).

Overall survival (OS) also trended toward a benefit for apalutamide, but the difference did not reach the prespecified boundary for significance in this planned interim analysis, reported Matthew R. Smith, MD, PhD, from the Massachusetts General Hospital Cancer Center in Boston.

Among men randomly assigned in the phase 3 trial to receive apalutamide (Erleada), the 4-year OS rate was 72.1%, compared with 64.7% for patients assigned to placebo.

“This OS benefit for apalutamide was observed despite crossover of placebo patients to apalutamide, and higher rates of subsequent life-prolonging therapy in the placebo group,” he said at the European Society for Medical Oncology Congress.

Apalutamide was approved by the Food and Drug Administration in 2018 for treatment of patients with nonmetastatic CRPC who were on androgen deprivation therapy with a rapidly rising prostate-specific antigen level and no detectable distant metastases on conventional imaging.

That approval was based on the primary results from SPARTAN, which showed a median metastasis-free survival for patients taking apalutamide of 40.5 months, compared with 16.2 months for patients taking placebo.

The drug also recently received FDA approval for treatment of men with metastatic CRPC, based on results of the TITAN trial.

Overall survival

At the time of the primary analysis of SPARTAN for metastasis-free survival, the OS data were immature, with only 104 of 427 events required for the prespecified analysis.

At ESMO 2019, Dr. Smith presented results of the second interim survival analysis looking at the effects of apalutamide on OS, as well as time to chemotherapy, PFS2, and safety.

In the trial, men with nonmetastatic CRPC were randomized on a 2:1 basis to receive either apalutamide 240 mg daily (806 patients) or placebo (401) plus androgen deprivation therapy, either with gonadotropin-releasing hormone analogue therapy or with surgical castration.

At a median follow-up of 41 months, median OS was not reached in either arm. As noted before, the 4-year OS rate was higher in the apalutamide group, translating into a HR for death of 0.75. However, the P value of .0197 was higher than the prespecified O’Brien-Fleming boundary of 0.0121, which means that the study follow-up will continue per protocol, with the final analysis for overall survival planned after 427 deaths have occurred, Dr. Smith said.

The survival benefit with apalutamide either trended toward significance across all subgroups, with notable benefits in patients aged younger than 65 years, those with good performance status, prostate-specific antigen doubling time longer than 6 months, and those with locoregional disease status of N1 versus N0.

The secondary endpoint of time to chemotherapy initiation was not formally tested because OS did not reach statistical significance, but proportionally fewer patients on apalutamide had started cytotoxic chemotherapy at the time of the interim analysis (14% vs. 20% of patients on placebo). The median time to initiation of chemotherapy has not been reached in either trial arm, however.

The safety profile of the androgen receptor inhibitor was consistent with that seen in the primary PFS analysis, with any adverse event seen in 97.3% of patients versus 93.7% of patients on placebo, grade 3-4 adverse events in 53.1% versus 36.7%, any serious adverse event in 33.5% versus 24.9%, events leading to treatment discontinuation in 13.8% versus 7.3%, and fatal adverse events in 2.1 versus .5%.

“Of some note, discontinuation due to disease progression was 34% in the apalutamide group, compared to 74% in the placebo group,” Dr. Smith said.

“These results further support apalutamide as a standard-of-care option for men with high-risk, nonmetastatic CRPC,” he concluded.

PFS2 data ‘important’

Invited discussant Karim Fizazi, MD, PhD, from the Institut Gustave Roussy in Villejuif, France, acknowledged it’s too early to draw conclusions about OS, but added that the PFS2 data are important.

Neil Osterweil/MDedge News

The 45% reduction in risk of progression “is particularly important in this trial because abiraterone was provided as a potential salvage treatment in both arms. So in other words, in that trial they were almost truly comparing early AR [androgen receptor] targeting versus deferred AR targeting, at least in some patients, and it seems that [apalutamide] is making a difference in terms of second progression,” he said.

An unanswered question about the trial, however, is how active abiraterone was post apalutamide in the experimental, because there are data suggesting minimal efficacy in sequential therapy of AR-targeted agents, he added.

The SPARTAN trial was funded by Janssen. Dr. Smith disclosed an advisory role, research funding, and travel reimbursement for Janssen and others. Dr. Fizazi disclosed consulting for Janssen and others.

SOURCE: Smith MR et al. ESMO 2019, Abstract 843O

BARCELONA – The androgen receptor inhibitor apalutamide was associated with a 45% improvement in time to second progression in patients with nonmetastatic, castration-resistant prostate cancer as well as an overall survival edge, although the latter fell just short of statistical significance in an interim analysis of results from the SPARTAN trial.

Among 1,207 men with nonmetastatic castration-resistant prostate cancer (CRPC), those randomly assigned to apalutamide had significantly longer second progression-free survival (PFS2), an exploratory endpoint defined as the time of study entry to progression on subsequent treatment.

In all, 69% of patients on placebo and 40% of those on apalutamide went on to another life-prolonging therapy, usually abiraterone acetate (Zytiga) plus prednisone. The respective median PFS2s were 43.8 and 55.6 months, translating into a hazard ratio for second progression in the apalutamide group of 0.55 (P less than .0001).

Overall survival (OS) also trended toward a benefit for apalutamide, but the difference did not reach the prespecified boundary for significance in this planned interim analysis, reported Matthew R. Smith, MD, PhD, from the Massachusetts General Hospital Cancer Center in Boston.

Among men randomly assigned in the phase 3 trial to receive apalutamide (Erleada), the 4-year OS rate was 72.1%, compared with 64.7% for patients assigned to placebo.

“This OS benefit for apalutamide was observed despite crossover of placebo patients to apalutamide, and higher rates of subsequent life-prolonging therapy in the placebo group,” he said at the European Society for Medical Oncology Congress.

Apalutamide was approved by the Food and Drug Administration in 2018 for treatment of patients with nonmetastatic CRPC who were on androgen deprivation therapy with a rapidly rising prostate-specific antigen level and no detectable distant metastases on conventional imaging.

That approval was based on the primary results from SPARTAN, which showed a median metastasis-free survival for patients taking apalutamide of 40.5 months, compared with 16.2 months for patients taking placebo.

The drug also recently received FDA approval for treatment of men with metastatic CRPC, based on results of the TITAN trial.

Overall survival

At the time of the primary analysis of SPARTAN for metastasis-free survival, the OS data were immature, with only 104 of 427 events required for the prespecified analysis.

At ESMO 2019, Dr. Smith presented results of the second interim survival analysis looking at the effects of apalutamide on OS, as well as time to chemotherapy, PFS2, and safety.

In the trial, men with nonmetastatic CRPC were randomized on a 2:1 basis to receive either apalutamide 240 mg daily (806 patients) or placebo (401) plus androgen deprivation therapy, either with gonadotropin-releasing hormone analogue therapy or with surgical castration.

At a median follow-up of 41 months, median OS was not reached in either arm. As noted before, the 4-year OS rate was higher in the apalutamide group, translating into a HR for death of 0.75. However, the P value of .0197 was higher than the prespecified O’Brien-Fleming boundary of 0.0121, which means that the study follow-up will continue per protocol, with the final analysis for overall survival planned after 427 deaths have occurred, Dr. Smith said.

The survival benefit with apalutamide either trended toward significance across all subgroups, with notable benefits in patients aged younger than 65 years, those with good performance status, prostate-specific antigen doubling time longer than 6 months, and those with locoregional disease status of N1 versus N0.

The secondary endpoint of time to chemotherapy initiation was not formally tested because OS did not reach statistical significance, but proportionally fewer patients on apalutamide had started cytotoxic chemotherapy at the time of the interim analysis (14% vs. 20% of patients on placebo). The median time to initiation of chemotherapy has not been reached in either trial arm, however.

The safety profile of the androgen receptor inhibitor was consistent with that seen in the primary PFS analysis, with any adverse event seen in 97.3% of patients versus 93.7% of patients on placebo, grade 3-4 adverse events in 53.1% versus 36.7%, any serious adverse event in 33.5% versus 24.9%, events leading to treatment discontinuation in 13.8% versus 7.3%, and fatal adverse events in 2.1 versus .5%.

“Of some note, discontinuation due to disease progression was 34% in the apalutamide group, compared to 74% in the placebo group,” Dr. Smith said.

“These results further support apalutamide as a standard-of-care option for men with high-risk, nonmetastatic CRPC,” he concluded.

PFS2 data ‘important’

Invited discussant Karim Fizazi, MD, PhD, from the Institut Gustave Roussy in Villejuif, France, acknowledged it’s too early to draw conclusions about OS, but added that the PFS2 data are important.

Neil Osterweil/MDedge News

The 45% reduction in risk of progression “is particularly important in this trial because abiraterone was provided as a potential salvage treatment in both arms. So in other words, in that trial they were almost truly comparing early AR [androgen receptor] targeting versus deferred AR targeting, at least in some patients, and it seems that [apalutamide] is making a difference in terms of second progression,” he said.

An unanswered question about the trial, however, is how active abiraterone was post apalutamide in the experimental, because there are data suggesting minimal efficacy in sequential therapy of AR-targeted agents, he added.

The SPARTAN trial was funded by Janssen. Dr. Smith disclosed an advisory role, research funding, and travel reimbursement for Janssen and others. Dr. Fizazi disclosed consulting for Janssen and others.

SOURCE: Smith MR et al. ESMO 2019, Abstract 843O

Romiplostim (Nplate) earned a new indication from the Food and Drug Administration, allowing for earlier usage in adult patients with immune thrombocytopenia (ITP) who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy.

Olivier Le Moal/Getty Images

The new indication is for newly diagnosed and persistent adult patients.

Romiplostim is already approved for the treatment of pediatric patients aged 1 year and older who have had ITP for at least 6 months and had an insufficient response to other treatments, as well as for adults patients with chronic ITP who had insufficient response to other therapies.

The latest approval is based on positive results from a single-arm, phase 2 trial in adults with ITP who had an insufficient response to first-line treatment. The study met its primary endpoint – platelet response (50 x 10⁹/L or greater). The median number of months with platelet response was 11 months during a 12-month treatment period. The median time to first platelet response was just over 2 weeks.

Adverse events of at least 5% incidence in patients taking romiplostim with an ITP duration up to 12 months included bronchitis, sinusitis, vomiting, arthralgia, myalgia, headache, dizziness, diarrhea, upper respiratory tract infection, cough, nausea, and oropharyngeal pain. There was a 2% incidence of thrombocytosis among adults with an ITP duration up to 12 months.

[email protected]

Romiplostim (Nplate) earned a new indication from the Food and Drug Administration, allowing for earlier usage in adult patients with immune thrombocytopenia (ITP) who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy.

Olivier Le Moal/Getty Images

The new indication is for newly diagnosed and persistent adult patients.

Romiplostim is already approved for the treatment of pediatric patients aged 1 year and older who have had ITP for at least 6 months and had an insufficient response to other treatments, as well as for adults patients with chronic ITP who had insufficient response to other therapies.

The latest approval is based on positive results from a single-arm, phase 2 trial in adults with ITP who had an insufficient response to first-line treatment. The study met its primary endpoint – platelet response (50 x 10⁹/L or greater). The median number of months with platelet response was 11 months during a 12-month treatment period. The median time to first platelet response was just over 2 weeks.

Adverse events of at least 5% incidence in patients taking romiplostim with an ITP duration up to 12 months included bronchitis, sinusitis, vomiting, arthralgia, myalgia, headache, dizziness, diarrhea, upper respiratory tract infection, cough, nausea, and oropharyngeal pain. There was a 2% incidence of thrombocytosis among adults with an ITP duration up to 12 months.

[email protected]

Romiplostim (Nplate) earned a new indication from the Food and Drug Administration, allowing for earlier usage in adult patients with immune thrombocytopenia (ITP) who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy.

Olivier Le Moal/Getty Images

The new indication is for newly diagnosed and persistent adult patients.

Romiplostim is already approved for the treatment of pediatric patients aged 1 year and older who have had ITP for at least 6 months and had an insufficient response to other treatments, as well as for adults patients with chronic ITP who had insufficient response to other therapies.

The latest approval is based on positive results from a single-arm, phase 2 trial in adults with ITP who had an insufficient response to first-line treatment. The study met its primary endpoint – platelet response (50 x 10⁹/L or greater). The median number of months with platelet response was 11 months during a 12-month treatment period. The median time to first platelet response was just over 2 weeks.

Adverse events of at least 5% incidence in patients taking romiplostim with an ITP duration up to 12 months included bronchitis, sinusitis, vomiting, arthralgia, myalgia, headache, dizziness, diarrhea, upper respiratory tract infection, cough, nausea, and oropharyngeal pain. There was a 2% incidence of thrombocytosis among adults with an ITP duration up to 12 months.

[email protected]

MADRID – For the treatment of chronic thromboembolic pulmonary hypertension (CTEPH), balloon pulmonary angioplasty (BPA) is more effective than riociguat for reducing pulmonary vascular resistance (PVR) and improving functional class, according to a multicenter trial presented at the annual congress of the European Respiratory Congress.

Both therapies are widely used in the treatment of CTEPH, but this is the first controlled trial in which they were directly compared, according to Xavier Jaïs, MD, of the Pulmonology Service, Kremlin-Bicêtre Hospital, University of Paris-Sud.

In this randomized trial, called RACE, newly diagnosed and previously untreated patients with nonoperable CTEPH were enrolled. The key eligibility criteria included PVR greater than 320 dynes/sec per cm^–5 and a pulmonary capillary wedge pressure of 15 mm Hg or less.

The patients were randomized to BPA or riociguat and followed for 26 weeks. The primary endpoint was relative change in PVR from baseline. The 6-minute walk distance, change in functional class, time to clinical worsening and safety were among secondary endpoints.

As calculated by geometric mean from baseline, PVR was reduced by nearly 60% in the BPA group and by 32% in the riociguat group, providing a 40% (P less than .0001) relative advantage of BPA.

Although there was a small relative advantage in the 6-minute walk distance for the BPA group at the end of the study, it did not reach statistical significant. However, 88% of those randomized to BPA versus 49% of those treated with riociguat (P less than .0001) improved by at least one WHO class by the end of the study.

Clinical worsening events over the course of the trial were uncommon. All three of these events occurred in the riociguat group, but the difference was not significant.

The end-of-study reduction in brain natriuretic peptide, which was another secondary endpoint, was 67% greater in the BPA group (P less than .0001).

There was a safety cost for the greater efficacy of BPA. This included a higher proportion of patients in the BPA group with at least one serious adverse event (50% vs. 26%) and at least one serious treatment-related adverse event (14% vs. 9%). No patient in either arm discontinued therapy because of treatment-related adverse events, and there were no deaths over the course of the study in either arm.

The study has included a 6-month extension to allow patients symptomatic on their originally assigned therapy to switch to the opposite treatment. Results of the extension are not yet available, but Dr. Jaïs said that these data might provide insight about which therapy to start first.

“It was very important to do this trial,” according to the ERS-invited discussant, Martin Kolb, MD, of the Firestone Institute of Respiratory Health, McMaster University, Hamilton, Ont. The most recent World Symposium on Pulmonary Hypertension identified BPA and medical therapy as reasonable choices in inoperable CTEPH, but Dr. Kolb said there has been an unmet need for comparative data.

“This was a very strong study that demonstrated a powerful impact for both interventions on pulmonary vascular resistance,” Dr. Kolb said, adding that, although BPA proved to be more effective, clinicians consider the greater risk of adverse events. He believes further work needs to be done in identifying the best candidates for each and to explore hybrid approaches.

“What do you think about doing these sequentially so that you lower the pressure first with medical therapy and then go in with the balloon?” Dr. Kolb asked Dr. Jaïs during a discussion that followed presentation of the RACE results.

Dr. Jaïs conceded this point, noting that the treatments have different targets and might be complementary.

“We plan to do a study like this in the future,” Dr. Jaïs said.

Dr. Jaïs reported no potential conflicts of interest.

MADRID – For the treatment of chronic thromboembolic pulmonary hypertension (CTEPH), balloon pulmonary angioplasty (BPA) is more effective than riociguat for reducing pulmonary vascular resistance (PVR) and improving functional class, according to a multicenter trial presented at the annual congress of the European Respiratory Congress.

Both therapies are widely used in the treatment of CTEPH, but this is the first controlled trial in which they were directly compared, according to Xavier Jaïs, MD, of the Pulmonology Service, Kremlin-Bicêtre Hospital, University of Paris-Sud.

In this randomized trial, called RACE, newly diagnosed and previously untreated patients with nonoperable CTEPH were enrolled. The key eligibility criteria included PVR greater than 320 dynes/sec per cm^–5 and a pulmonary capillary wedge pressure of 15 mm Hg or less.

The patients were randomized to BPA or riociguat and followed for 26 weeks. The primary endpoint was relative change in PVR from baseline. The 6-minute walk distance, change in functional class, time to clinical worsening and safety were among secondary endpoints.

As calculated by geometric mean from baseline, PVR was reduced by nearly 60% in the BPA group and by 32% in the riociguat group, providing a 40% (P less than .0001) relative advantage of BPA.

Although there was a small relative advantage in the 6-minute walk distance for the BPA group at the end of the study, it did not reach statistical significant. However, 88% of those randomized to BPA versus 49% of those treated with riociguat (P less than .0001) improved by at least one WHO class by the end of the study.

Clinical worsening events over the course of the trial were uncommon. All three of these events occurred in the riociguat group, but the difference was not significant.

The end-of-study reduction in brain natriuretic peptide, which was another secondary endpoint, was 67% greater in the BPA group (P less than .0001).

There was a safety cost for the greater efficacy of BPA. This included a higher proportion of patients in the BPA group with at least one serious adverse event (50% vs. 26%) and at least one serious treatment-related adverse event (14% vs. 9%). No patient in either arm discontinued therapy because of treatment-related adverse events, and there were no deaths over the course of the study in either arm.

The study has included a 6-month extension to allow patients symptomatic on their originally assigned therapy to switch to the opposite treatment. Results of the extension are not yet available, but Dr. Jaïs said that these data might provide insight about which therapy to start first.

“It was very important to do this trial,” according to the ERS-invited discussant, Martin Kolb, MD, of the Firestone Institute of Respiratory Health, McMaster University, Hamilton, Ont. The most recent World Symposium on Pulmonary Hypertension identified BPA and medical therapy as reasonable choices in inoperable CTEPH, but Dr. Kolb said there has been an unmet need for comparative data.

“This was a very strong study that demonstrated a powerful impact for both interventions on pulmonary vascular resistance,” Dr. Kolb said, adding that, although BPA proved to be more effective, clinicians consider the greater risk of adverse events. He believes further work needs to be done in identifying the best candidates for each and to explore hybrid approaches.

“What do you think about doing these sequentially so that you lower the pressure first with medical therapy and then go in with the balloon?” Dr. Kolb asked Dr. Jaïs during a discussion that followed presentation of the RACE results.

Dr. Jaïs conceded this point, noting that the treatments have different targets and might be complementary.

“We plan to do a study like this in the future,” Dr. Jaïs said.

Dr. Jaïs reported no potential conflicts of interest.

MADRID – For the treatment of chronic thromboembolic pulmonary hypertension (CTEPH), balloon pulmonary angioplasty (BPA) is more effective than riociguat for reducing pulmonary vascular resistance (PVR) and improving functional class, according to a multicenter trial presented at the annual congress of the European Respiratory Congress.

Both therapies are widely used in the treatment of CTEPH, but this is the first controlled trial in which they were directly compared, according to Xavier Jaïs, MD, of the Pulmonology Service, Kremlin-Bicêtre Hospital, University of Paris-Sud.

In this randomized trial, called RACE, newly diagnosed and previously untreated patients with nonoperable CTEPH were enrolled. The key eligibility criteria included PVR greater than 320 dynes/sec per cm^–5 and a pulmonary capillary wedge pressure of 15 mm Hg or less.

The patients were randomized to BPA or riociguat and followed for 26 weeks. The primary endpoint was relative change in PVR from baseline. The 6-minute walk distance, change in functional class, time to clinical worsening and safety were among secondary endpoints.

As calculated by geometric mean from baseline, PVR was reduced by nearly 60% in the BPA group and by 32% in the riociguat group, providing a 40% (P less than .0001) relative advantage of BPA.

Although there was a small relative advantage in the 6-minute walk distance for the BPA group at the end of the study, it did not reach statistical significant. However, 88% of those randomized to BPA versus 49% of those treated with riociguat (P less than .0001) improved by at least one WHO class by the end of the study.

Clinical worsening events over the course of the trial were uncommon. All three of these events occurred in the riociguat group, but the difference was not significant.

The end-of-study reduction in brain natriuretic peptide, which was another secondary endpoint, was 67% greater in the BPA group (P less than .0001).

There was a safety cost for the greater efficacy of BPA. This included a higher proportion of patients in the BPA group with at least one serious adverse event (50% vs. 26%) and at least one serious treatment-related adverse event (14% vs. 9%). No patient in either arm discontinued therapy because of treatment-related adverse events, and there were no deaths over the course of the study in either arm.

The study has included a 6-month extension to allow patients symptomatic on their originally assigned therapy to switch to the opposite treatment. Results of the extension are not yet available, but Dr. Jaïs said that these data might provide insight about which therapy to start first.

“It was very important to do this trial,” according to the ERS-invited discussant, Martin Kolb, MD, of the Firestone Institute of Respiratory Health, McMaster University, Hamilton, Ont. The most recent World Symposium on Pulmonary Hypertension identified BPA and medical therapy as reasonable choices in inoperable CTEPH, but Dr. Kolb said there has been an unmet need for comparative data.

“This was a very strong study that demonstrated a powerful impact for both interventions on pulmonary vascular resistance,” Dr. Kolb said, adding that, although BPA proved to be more effective, clinicians consider the greater risk of adverse events. He believes further work needs to be done in identifying the best candidates for each and to explore hybrid approaches.

“What do you think about doing these sequentially so that you lower the pressure first with medical therapy and then go in with the balloon?” Dr. Kolb asked Dr. Jaïs during a discussion that followed presentation of the RACE results.

Dr. Jaïs conceded this point, noting that the treatments have different targets and might be complementary.

“We plan to do a study like this in the future,” Dr. Jaïs said.

Dr. Jaïs reported no potential conflicts of interest.