Kaposi sarcoma is an AIDS-defining illness associated with human herpes virus-8 (HHV-8) co-infection. It was described in 1872 by the Hungarian dermatologist Mortiz Kaposi, and was an isolated and sporadic occurrence before the emergence of HIV infection and AIDS.¹ It was first affiliated as an AIDS-associated neoplasm in 1981.¹ Kaposi sarcoma is a systemic disease that can present with cutaneous lesions with or without internal involvement. There are four subtypes: Classic, African endemic, AIDS-related (CD4 count, <200), and Kaposi sarcoma in iatrogenically immunosuppressed patients. The disease has the propensity to manifest in the skin and gastro-intestinal and respiratory tracts, and osseous involvement is rarely encountered. We present here the case of an AIDS-positive man with generalized bone pain as a result of metastasis from Kaposi sarcoma. Our discussion includes the epidemiological, clinical, pathological, and radiological facets of AIDS-related Kaposi sarcoma, and the anomaly of osseous involvement.

Case presentation and summary

A 26-year-old African American man with a history of AIDS (CD4 count, 13 cells/mm³ [normal, 500-1,600 cells/mm³]) who was noncompliant with HAART (highly active antiretroviral therapy), presented to the emergency department in January 2016 with chest, abdominal, and back pain. His HAART regimen included darunavir 8 mL oral suspension daily, emtricitabine 4 mL oral suspension daily, and ritonavir 100 mg tab daily. A computed-tomography (CT) scan of the man’s abdomen revealed axillary, mediastinal, and abdominal lymphadenopathy, with splenomegaly and innumerable osseous lucent spinal lesions. A left axillary lymph node biopsy was positive for Kaposi sarcoma; pathology showed fascicles of spindle, oval- to round-shaped atypical cells positive for HHV-8 (granular nuclear staining), CD31, and CD34 (partial; Figure 1). Serum and urine protein electrophoresis showed no paraproteins.

He restarted his previous HAART regimen in March 2016, and was subsequently started on chemotherapy with liposomal doxorubicin (50 mg [20 mg/m²] in 250 ml D5W IV every 2 weeks) because of his extensive disease.² He completed 6 cycles by June 2016. However, he returned in July 2016 with worsening back pain. A repeat CT scan revealed significant improvement in the disseminated lymphadenopathy, but worsening osseous metastatic disease was seen in the lumbar, thoracic, and pelvic regions. A pelvic lytic lesion biopsy revealed Kaposi sarcoma; pathology showed spindle cells positive for CD34, CD31, and HHV-8 (Figure 2). The patient received palliative radiation to the spine, aiding in pain management and ambulatory dysfunction. He continued with his noncompliance with all medications and outpatient follow-ups, and succumbed to his disease burden.

Discussion

Kaposi sarcoma is a low-grade mesenchymal tumor that involves the blood and lymphatic vessels.³ Its association with AIDS was revealed in the early 1980s at the start of the HIV epidemic in the United States. In 1994, Chang and colleagues discovered the association between Karposi sarcoma and HHV-8 by isolating DNA fragments of HHV in Kaposi sarcoma tumors from AIDS patients.⁴ The mode of transmission of HHV-8 has not been fully decoded. It has been presumed that adult homosexual contact continues to be an important route of transmission, inferring a common route of infection. In 1990, the overall risk of developing Kaposi sarcoma in AIDS patients was 20,000 times greater than it was in the general population, and 300 times greater than in other immunosuppressed patients.⁵ This suggests an increase in incidence, in direct relation, with a decrease in the CD4 count.

Kaposi sarcoma can present with a range of clinical features, from negligible cutaneous lesions to a hastily progressing neoplasm. Involvement in the musculoskeletal system is infrequent, but encountered increasingly in the AIDS-related subtype. Moreover, it is recurrently observed in the African population.⁶ In one of the largest reviews to date exploring Kaposi sarcoma involving the musculoskeletal system, Caponetti and colleagues observed the greatest osseous involvement distinctly in patients with CD4 and T-cell counts below 100 cells/mm³.⁶

Kaposi sarcoma musculoskeletal involvement, specifically bone, is atypical. If it does occur, it usually manifests as a result of contiguous invasion from an adjacent nonosseous lesion. Caponetti and colleagues that isolated osseous Kaposi sarcoma lesions (with no overlying skin lesion) were found to be more likely to be associated with AIDS in the review by Caponetti and colleagues.⁶ As in our patient, it is also typically a manifestation of more widely disseminated disease.⁷

Most of the osseous lytic lesions in AIDS patients are located in the axial skeleton. Radiological features of musculoskeletal Kaposi sarcoma are variable. As observed by Caponetti and colleagues, Kaposi sarcoma lesions can appear as a periosteal reaction, cortical erosions, osteolysis, or osseous destruction, with irregular-shaped cortical erosions being most typical.⁶ Despite their osteolytic features, Kaposi sarcoma lesions are often not visualized by conventional radiography.⁶ The preferred imaging for identification of lytic bone changes is CT (Figure 3). Magnetic resonance imaging can also help distinguish marrow abnormalities as well as adjacent soft tissues masses. Radiologically, Kaposi sarcoma osseous lesions have parallel features to bacillary angiomatosis, tuberculosis, or lymphoma.⁸ Therefore, biopsy of the lesion is essential in establishing the diagnosis of Kaposi sarcoma.

Kaposi sarcoma is an AIDS-defining illness associated with human herpes virus-8 (HHV-8) co-infection. It was described in 1872 by the Hungarian dermatologist Mortiz Kaposi, and was an isolated and sporadic occurrence before the emergence of HIV infection and AIDS.¹ It was first affiliated as an AIDS-associated neoplasm in 1981.¹ Kaposi sarcoma is a systemic disease that can present with cutaneous lesions with or without internal involvement. There are four subtypes: Classic, African endemic, AIDS-related (CD4 count, <200), and Kaposi sarcoma in iatrogenically immunosuppressed patients. The disease has the propensity to manifest in the skin and gastro-intestinal and respiratory tracts, and osseous involvement is rarely encountered. We present here the case of an AIDS-positive man with generalized bone pain as a result of metastasis from Kaposi sarcoma. Our discussion includes the epidemiological, clinical, pathological, and radiological facets of AIDS-related Kaposi sarcoma, and the anomaly of osseous involvement.

Case presentation and summary

A 26-year-old African American man with a history of AIDS (CD4 count, 13 cells/mm³ [normal, 500-1,600 cells/mm³]) who was noncompliant with HAART (highly active antiretroviral therapy), presented to the emergency department in January 2016 with chest, abdominal, and back pain. His HAART regimen included darunavir 8 mL oral suspension daily, emtricitabine 4 mL oral suspension daily, and ritonavir 100 mg tab daily. A computed-tomography (CT) scan of the man’s abdomen revealed axillary, mediastinal, and abdominal lymphadenopathy, with splenomegaly and innumerable osseous lucent spinal lesions. A left axillary lymph node biopsy was positive for Kaposi sarcoma; pathology showed fascicles of spindle, oval- to round-shaped atypical cells positive for HHV-8 (granular nuclear staining), CD31, and CD34 (partial; Figure 1). Serum and urine protein electrophoresis showed no paraproteins.

He restarted his previous HAART regimen in March 2016, and was subsequently started on chemotherapy with liposomal doxorubicin (50 mg [20 mg/m²] in 250 ml D5W IV every 2 weeks) because of his extensive disease.² He completed 6 cycles by June 2016. However, he returned in July 2016 with worsening back pain. A repeat CT scan revealed significant improvement in the disseminated lymphadenopathy, but worsening osseous metastatic disease was seen in the lumbar, thoracic, and pelvic regions. A pelvic lytic lesion biopsy revealed Kaposi sarcoma; pathology showed spindle cells positive for CD34, CD31, and HHV-8 (Figure 2). The patient received palliative radiation to the spine, aiding in pain management and ambulatory dysfunction. He continued with his noncompliance with all medications and outpatient follow-ups, and succumbed to his disease burden.

Discussion

Kaposi sarcoma is a low-grade mesenchymal tumor that involves the blood and lymphatic vessels.³ Its association with AIDS was revealed in the early 1980s at the start of the HIV epidemic in the United States. In 1994, Chang and colleagues discovered the association between Karposi sarcoma and HHV-8 by isolating DNA fragments of HHV in Kaposi sarcoma tumors from AIDS patients.⁴ The mode of transmission of HHV-8 has not been fully decoded. It has been presumed that adult homosexual contact continues to be an important route of transmission, inferring a common route of infection. In 1990, the overall risk of developing Kaposi sarcoma in AIDS patients was 20,000 times greater than it was in the general population, and 300 times greater than in other immunosuppressed patients.⁵ This suggests an increase in incidence, in direct relation, with a decrease in the CD4 count.

Kaposi sarcoma can present with a range of clinical features, from negligible cutaneous lesions to a hastily progressing neoplasm. Involvement in the musculoskeletal system is infrequent, but encountered increasingly in the AIDS-related subtype. Moreover, it is recurrently observed in the African population.⁶ In one of the largest reviews to date exploring Kaposi sarcoma involving the musculoskeletal system, Caponetti and colleagues observed the greatest osseous involvement distinctly in patients with CD4 and T-cell counts below 100 cells/mm³.⁶

Kaposi sarcoma musculoskeletal involvement, specifically bone, is atypical. If it does occur, it usually manifests as a result of contiguous invasion from an adjacent nonosseous lesion. Caponetti and colleagues that isolated osseous Kaposi sarcoma lesions (with no overlying skin lesion) were found to be more likely to be associated with AIDS in the review by Caponetti and colleagues.⁶ As in our patient, it is also typically a manifestation of more widely disseminated disease.⁷

Most of the osseous lytic lesions in AIDS patients are located in the axial skeleton. Radiological features of musculoskeletal Kaposi sarcoma are variable. As observed by Caponetti and colleagues, Kaposi sarcoma lesions can appear as a periosteal reaction, cortical erosions, osteolysis, or osseous destruction, with irregular-shaped cortical erosions being most typical.⁶ Despite their osteolytic features, Kaposi sarcoma lesions are often not visualized by conventional radiography.⁶ The preferred imaging for identification of lytic bone changes is CT (Figure 3). Magnetic resonance imaging can also help distinguish marrow abnormalities as well as adjacent soft tissues masses. Radiologically, Kaposi sarcoma osseous lesions have parallel features to bacillary angiomatosis, tuberculosis, or lymphoma.⁸ Therefore, biopsy of the lesion is essential in establishing the diagnosis of Kaposi sarcoma.

Kaposi sarcoma is an AIDS-defining illness associated with human herpes virus-8 (HHV-8) co-infection. It was described in 1872 by the Hungarian dermatologist Mortiz Kaposi, and was an isolated and sporadic occurrence before the emergence of HIV infection and AIDS.¹ It was first affiliated as an AIDS-associated neoplasm in 1981.¹ Kaposi sarcoma is a systemic disease that can present with cutaneous lesions with or without internal involvement. There are four subtypes: Classic, African endemic, AIDS-related (CD4 count, <200), and Kaposi sarcoma in iatrogenically immunosuppressed patients. The disease has the propensity to manifest in the skin and gastro-intestinal and respiratory tracts, and osseous involvement is rarely encountered. We present here the case of an AIDS-positive man with generalized bone pain as a result of metastasis from Kaposi sarcoma. Our discussion includes the epidemiological, clinical, pathological, and radiological facets of AIDS-related Kaposi sarcoma, and the anomaly of osseous involvement.

Case presentation and summary

A 26-year-old African American man with a history of AIDS (CD4 count, 13 cells/mm³ [normal, 500-1,600 cells/mm³]) who was noncompliant with HAART (highly active antiretroviral therapy), presented to the emergency department in January 2016 with chest, abdominal, and back pain. His HAART regimen included darunavir 8 mL oral suspension daily, emtricitabine 4 mL oral suspension daily, and ritonavir 100 mg tab daily. A computed-tomography (CT) scan of the man’s abdomen revealed axillary, mediastinal, and abdominal lymphadenopathy, with splenomegaly and innumerable osseous lucent spinal lesions. A left axillary lymph node biopsy was positive for Kaposi sarcoma; pathology showed fascicles of spindle, oval- to round-shaped atypical cells positive for HHV-8 (granular nuclear staining), CD31, and CD34 (partial; Figure 1). Serum and urine protein electrophoresis showed no paraproteins.

He restarted his previous HAART regimen in March 2016, and was subsequently started on chemotherapy with liposomal doxorubicin (50 mg [20 mg/m²] in 250 ml D5W IV every 2 weeks) because of his extensive disease.² He completed 6 cycles by June 2016. However, he returned in July 2016 with worsening back pain. A repeat CT scan revealed significant improvement in the disseminated lymphadenopathy, but worsening osseous metastatic disease was seen in the lumbar, thoracic, and pelvic regions. A pelvic lytic lesion biopsy revealed Kaposi sarcoma; pathology showed spindle cells positive for CD34, CD31, and HHV-8 (Figure 2). The patient received palliative radiation to the spine, aiding in pain management and ambulatory dysfunction. He continued with his noncompliance with all medications and outpatient follow-ups, and succumbed to his disease burden.

Discussion

Kaposi sarcoma is a low-grade mesenchymal tumor that involves the blood and lymphatic vessels.³ Its association with AIDS was revealed in the early 1980s at the start of the HIV epidemic in the United States. In 1994, Chang and colleagues discovered the association between Karposi sarcoma and HHV-8 by isolating DNA fragments of HHV in Kaposi sarcoma tumors from AIDS patients.⁴ The mode of transmission of HHV-8 has not been fully decoded. It has been presumed that adult homosexual contact continues to be an important route of transmission, inferring a common route of infection. In 1990, the overall risk of developing Kaposi sarcoma in AIDS patients was 20,000 times greater than it was in the general population, and 300 times greater than in other immunosuppressed patients.⁵ This suggests an increase in incidence, in direct relation, with a decrease in the CD4 count.

Kaposi sarcoma can present with a range of clinical features, from negligible cutaneous lesions to a hastily progressing neoplasm. Involvement in the musculoskeletal system is infrequent, but encountered increasingly in the AIDS-related subtype. Moreover, it is recurrently observed in the African population.⁶ In one of the largest reviews to date exploring Kaposi sarcoma involving the musculoskeletal system, Caponetti and colleagues observed the greatest osseous involvement distinctly in patients with CD4 and T-cell counts below 100 cells/mm³.⁶

Kaposi sarcoma musculoskeletal involvement, specifically bone, is atypical. If it does occur, it usually manifests as a result of contiguous invasion from an adjacent nonosseous lesion. Caponetti and colleagues that isolated osseous Kaposi sarcoma lesions (with no overlying skin lesion) were found to be more likely to be associated with AIDS in the review by Caponetti and colleagues.⁶ As in our patient, it is also typically a manifestation of more widely disseminated disease.⁷

Most of the osseous lytic lesions in AIDS patients are located in the axial skeleton. Radiological features of musculoskeletal Kaposi sarcoma are variable. As observed by Caponetti and colleagues, Kaposi sarcoma lesions can appear as a periosteal reaction, cortical erosions, osteolysis, or osseous destruction, with irregular-shaped cortical erosions being most typical.⁶ Despite their osteolytic features, Kaposi sarcoma lesions are often not visualized by conventional radiography.⁶ The preferred imaging for identification of lytic bone changes is CT (Figure 3). Magnetic resonance imaging can also help distinguish marrow abnormalities as well as adjacent soft tissues masses. Radiologically, Kaposi sarcoma osseous lesions have parallel features to bacillary angiomatosis, tuberculosis, or lymphoma.⁸ Therefore, biopsy of the lesion is essential in establishing the diagnosis of Kaposi sarcoma.

Photo by Chad McNeeley

MADRID—Updated results of a phase 1/2 study suggest the T-cell product BPX-501 lowers the risks associated with haploidentical hematopoietic stem cell transplant (haplo-HSCT).

In this ongoing study, researchers are testing BPX-501 in pediatric patients undergoing haplo-HSCT to treat a range of hematologic disorders.

Patients treated thus far have experienced rapid engraftment and early hospital discharge, a low rate of acute graft-versus-host disease (GHVD), no extensive chronic GVHD, and a low rate of transplant-related mortality at 180 days.

“The combination of haploidentical transplantation and BPX-501 infusion is an effective strategy for children in need of an allograft lacking a compatible donor,” said study investigator Mattia Algeri, MD, of Ospedale Pediatrico Bambino Gesù in Rome, Italy.

Dr Algeri presented these results during the Presidential Symposium at the 22nd Congress of the European Hematology Association (EHA) as abstract S146.

The research was sponsored by Bellicum Pharmaceuticals, Inc., the company developing BPX-501.

About BPX-501

BPX-501 consists of genetically modified donor T cells incorporating the CaspaCIDe safety switch, which is designed to eliminate the T cells in the event of toxicity.

Rimiducid is used to activate the CaspaCIDe safety switch, which consists of the CID-binding domain coupled to the signaling domain of caspase-9, an enzyme that is part of the apoptotic pathway.

The goal of this therapy is to allow physicians to more safely perform haplo-HSCTs.

Patients

Dr Algeri and his colleagues have tested BPX-501 in 98 pediatric patients treated at centers in Europe and the US.

Fifty-nine patients had non-malignant conditions, including primary immune deficiency (n=26), thalassemia major (n=8), sickle cell disease (n=5), Diamond-Blackfan anemia (n=2), Swachman-Diamond syndrome (n=1), Fanconi anemia (n=9), hemophagocytic lymphohistiocytosis (n=6), aplastic anemia (n=1), and osteoporosis (n=1).

Thirty-nine patients had malignant conditions, including acute lymphoblastic leukemia (ALL, n=21), acute myeloid leukemia (AML, n=14), myelodysplastic syndromes (MDS, n=3), and non-Hodgkin lymphoma (NHL, n=1).

The patients received BPX-501 after an alpha/beta T-cell-depleted haplo-HSCT. All patients had at least 6 months of follow-up.

Overall results

Ninety-five percent of the patients engrafted (93/98), and the researchers said they observed rapid recovery of T cells, B cells, and immunoglobulins.

At 180 days, the incidence of transplant-related mortality was 5%, and there were no cases of post-transplant lymphoproliferative disorder.

The cumulative incidence of grade 2-4 acute GVHD was 14%. For patients with at least 1 year of follow-up, the cumulative incidence of chronic GVHD at 1 year was 3%.

Eleven patients received rimiducid—10 who had uncontrollable acute GVHD and 1 who developed late acute GVHD. In all of these patients, GVHD resolved and has not recurred.

There were no adverse events associated with BPX-501 or rimiducid.

European cohort

Dr Algeri presented more detailed data on the 61 patients treated at centers in Europe.

Fifteen of these patients had ALL, 10 had AML, 16 had primary immune deficiency, 7 had thalassemia major, 1 had sickle cell disease, 2 had Diamond-Blackfan anemia, 5 had Fanconi anemia, 4 had hemophagocytic lymphohistiocytosis, and 1 had osteoporosis.

Their median age was 4.8 (range, 0.25-17), and 56% were male. The patients received busulfan-based conditioning (41%), total body irradiation (36%), treosulfan-based conditioning (18%), and other conditioning (5%).

Ninety-five percent of the patients had a parent donor, and the other 5% had a sibling donor. The median donor age was 36 (range, 19-50).

The patients’ median time to neutrophil recovery was 15 days (range, 9-75), and their median time to platelet recovery was 10 days (range, 4-64). Their median time to discharge was 25 days (range, 14-122).

The cumulative incidence of acute grade 2-4 GVHD was 9.9%, and the cumulative incidence of acute grade 3-4 GVHD was 3.3%.

There were no cases of transplant-related mortality at 180 days and no cases of extensive chronic GVHD.

“These preliminary data compare favorably to previously published data on matched, unrelated donor transplantation,” Dr Algeri said. “And for this reason, an observational matched, unrelated donor study is being initiated to enable comparison of the safety and efficacy of haploidentical transplantation and BPX-501 infusion to the standard of care for patients without a matched sibling donor.”

Photo by Chad McNeeley

MADRID—Updated results of a phase 1/2 study suggest the T-cell product BPX-501 lowers the risks associated with haploidentical hematopoietic stem cell transplant (haplo-HSCT).

In this ongoing study, researchers are testing BPX-501 in pediatric patients undergoing haplo-HSCT to treat a range of hematologic disorders.

Patients treated thus far have experienced rapid engraftment and early hospital discharge, a low rate of acute graft-versus-host disease (GHVD), no extensive chronic GVHD, and a low rate of transplant-related mortality at 180 days.

“The combination of haploidentical transplantation and BPX-501 infusion is an effective strategy for children in need of an allograft lacking a compatible donor,” said study investigator Mattia Algeri, MD, of Ospedale Pediatrico Bambino Gesù in Rome, Italy.

Dr Algeri presented these results during the Presidential Symposium at the 22nd Congress of the European Hematology Association (EHA) as abstract S146.

The research was sponsored by Bellicum Pharmaceuticals, Inc., the company developing BPX-501.

About BPX-501

BPX-501 consists of genetically modified donor T cells incorporating the CaspaCIDe safety switch, which is designed to eliminate the T cells in the event of toxicity.

Rimiducid is used to activate the CaspaCIDe safety switch, which consists of the CID-binding domain coupled to the signaling domain of caspase-9, an enzyme that is part of the apoptotic pathway.

The goal of this therapy is to allow physicians to more safely perform haplo-HSCTs.

Patients

Dr Algeri and his colleagues have tested BPX-501 in 98 pediatric patients treated at centers in Europe and the US.

Fifty-nine patients had non-malignant conditions, including primary immune deficiency (n=26), thalassemia major (n=8), sickle cell disease (n=5), Diamond-Blackfan anemia (n=2), Swachman-Diamond syndrome (n=1), Fanconi anemia (n=9), hemophagocytic lymphohistiocytosis (n=6), aplastic anemia (n=1), and osteoporosis (n=1).

Thirty-nine patients had malignant conditions, including acute lymphoblastic leukemia (ALL, n=21), acute myeloid leukemia (AML, n=14), myelodysplastic syndromes (MDS, n=3), and non-Hodgkin lymphoma (NHL, n=1).

The patients received BPX-501 after an alpha/beta T-cell-depleted haplo-HSCT. All patients had at least 6 months of follow-up.

Overall results

Ninety-five percent of the patients engrafted (93/98), and the researchers said they observed rapid recovery of T cells, B cells, and immunoglobulins.

At 180 days, the incidence of transplant-related mortality was 5%, and there were no cases of post-transplant lymphoproliferative disorder.

The cumulative incidence of grade 2-4 acute GVHD was 14%. For patients with at least 1 year of follow-up, the cumulative incidence of chronic GVHD at 1 year was 3%.

Eleven patients received rimiducid—10 who had uncontrollable acute GVHD and 1 who developed late acute GVHD. In all of these patients, GVHD resolved and has not recurred.

There were no adverse events associated with BPX-501 or rimiducid.

European cohort

Dr Algeri presented more detailed data on the 61 patients treated at centers in Europe.

Fifteen of these patients had ALL, 10 had AML, 16 had primary immune deficiency, 7 had thalassemia major, 1 had sickle cell disease, 2 had Diamond-Blackfan anemia, 5 had Fanconi anemia, 4 had hemophagocytic lymphohistiocytosis, and 1 had osteoporosis.

Their median age was 4.8 (range, 0.25-17), and 56% were male. The patients received busulfan-based conditioning (41%), total body irradiation (36%), treosulfan-based conditioning (18%), and other conditioning (5%).

Ninety-five percent of the patients had a parent donor, and the other 5% had a sibling donor. The median donor age was 36 (range, 19-50).

The patients’ median time to neutrophil recovery was 15 days (range, 9-75), and their median time to platelet recovery was 10 days (range, 4-64). Their median time to discharge was 25 days (range, 14-122).

The cumulative incidence of acute grade 2-4 GVHD was 9.9%, and the cumulative incidence of acute grade 3-4 GVHD was 3.3%.

There were no cases of transplant-related mortality at 180 days and no cases of extensive chronic GVHD.

“These preliminary data compare favorably to previously published data on matched, unrelated donor transplantation,” Dr Algeri said. “And for this reason, an observational matched, unrelated donor study is being initiated to enable comparison of the safety and efficacy of haploidentical transplantation and BPX-501 infusion to the standard of care for patients without a matched sibling donor.”

Photo by Chad McNeeley

MADRID—Updated results of a phase 1/2 study suggest the T-cell product BPX-501 lowers the risks associated with haploidentical hematopoietic stem cell transplant (haplo-HSCT).

In this ongoing study, researchers are testing BPX-501 in pediatric patients undergoing haplo-HSCT to treat a range of hematologic disorders.

Patients treated thus far have experienced rapid engraftment and early hospital discharge, a low rate of acute graft-versus-host disease (GHVD), no extensive chronic GVHD, and a low rate of transplant-related mortality at 180 days.

“The combination of haploidentical transplantation and BPX-501 infusion is an effective strategy for children in need of an allograft lacking a compatible donor,” said study investigator Mattia Algeri, MD, of Ospedale Pediatrico Bambino Gesù in Rome, Italy.

Dr Algeri presented these results during the Presidential Symposium at the 22nd Congress of the European Hematology Association (EHA) as abstract S146.

The research was sponsored by Bellicum Pharmaceuticals, Inc., the company developing BPX-501.

About BPX-501

BPX-501 consists of genetically modified donor T cells incorporating the CaspaCIDe safety switch, which is designed to eliminate the T cells in the event of toxicity.

Rimiducid is used to activate the CaspaCIDe safety switch, which consists of the CID-binding domain coupled to the signaling domain of caspase-9, an enzyme that is part of the apoptotic pathway.

The goal of this therapy is to allow physicians to more safely perform haplo-HSCTs.

Patients

Dr Algeri and his colleagues have tested BPX-501 in 98 pediatric patients treated at centers in Europe and the US.

Fifty-nine patients had non-malignant conditions, including primary immune deficiency (n=26), thalassemia major (n=8), sickle cell disease (n=5), Diamond-Blackfan anemia (n=2), Swachman-Diamond syndrome (n=1), Fanconi anemia (n=9), hemophagocytic lymphohistiocytosis (n=6), aplastic anemia (n=1), and osteoporosis (n=1).

Thirty-nine patients had malignant conditions, including acute lymphoblastic leukemia (ALL, n=21), acute myeloid leukemia (AML, n=14), myelodysplastic syndromes (MDS, n=3), and non-Hodgkin lymphoma (NHL, n=1).

The patients received BPX-501 after an alpha/beta T-cell-depleted haplo-HSCT. All patients had at least 6 months of follow-up.

Overall results

Ninety-five percent of the patients engrafted (93/98), and the researchers said they observed rapid recovery of T cells, B cells, and immunoglobulins.

At 180 days, the incidence of transplant-related mortality was 5%, and there were no cases of post-transplant lymphoproliferative disorder.

The cumulative incidence of grade 2-4 acute GVHD was 14%. For patients with at least 1 year of follow-up, the cumulative incidence of chronic GVHD at 1 year was 3%.

Eleven patients received rimiducid—10 who had uncontrollable acute GVHD and 1 who developed late acute GVHD. In all of these patients, GVHD resolved and has not recurred.

There were no adverse events associated with BPX-501 or rimiducid.

European cohort

Dr Algeri presented more detailed data on the 61 patients treated at centers in Europe.

Fifteen of these patients had ALL, 10 had AML, 16 had primary immune deficiency, 7 had thalassemia major, 1 had sickle cell disease, 2 had Diamond-Blackfan anemia, 5 had Fanconi anemia, 4 had hemophagocytic lymphohistiocytosis, and 1 had osteoporosis.

Their median age was 4.8 (range, 0.25-17), and 56% were male. The patients received busulfan-based conditioning (41%), total body irradiation (36%), treosulfan-based conditioning (18%), and other conditioning (5%).

Ninety-five percent of the patients had a parent donor, and the other 5% had a sibling donor. The median donor age was 36 (range, 19-50).

The patients’ median time to neutrophil recovery was 15 days (range, 9-75), and their median time to platelet recovery was 10 days (range, 4-64). Their median time to discharge was 25 days (range, 14-122).

The cumulative incidence of acute grade 2-4 GVHD was 9.9%, and the cumulative incidence of acute grade 3-4 GVHD was 3.3%.

There were no cases of transplant-related mortality at 180 days and no cases of extensive chronic GVHD.

“These preliminary data compare favorably to previously published data on matched, unrelated donor transplantation,” Dr Algeri said. “And for this reason, an observational matched, unrelated donor study is being initiated to enable comparison of the safety and efficacy of haploidentical transplantation and BPX-501 infusion to the standard of care for patients without a matched sibling donor.”

Photo by Bill Branson

WASHINGTON, DC—In a head-to-head study comparing a single-dose oral antiemetic to a 3-day oral regimen, the single dose has shown itself to be non-inferior to the multi-day regimen in preventing chemotherapy-induced nausea and vomiting (CINV).

The investigators evaluated netupitant/palonosetron (NEPA) against aprepitant/granisetron (APR/GRAN) in patients on highly emetogenic chemotherapy.

They found the data suggest “that NEPA, in a single dose, had equivalent efficacy to a 3-day oral aprepitant/granisetron regimen,” according to the lead investigator and abstract presenter.

Li Zhang, MD, of Sun Yat-sen University Cancer Center in Guangzhou, China, presented the data at the Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology (MASCC/ISOO) Congress (abstract PS049, pp S55 – S56).

NEPA is a combination of the selective NK₁RA netupitant (300 mg) and the clinically and pharmacologically active 5-HT₃RA, palonosetron (0.5 mg) for the prevention of CINV.

Oral palonosetron prevents nausea and vomiting during the acute phase of treatment.

Netupitant prevents nausea and vomiting during both the acute and delayed phase after cancer chemotherapy.

It is formulated into a single oral capsule.

Study design

The study was a phase 3 randomized, double-blind, double-dummy study conducted in 828 chemotherapy-naïve Asian patients receiving cisplatin-based highly emetogenic chemotherapy (HEC) agents.

Patients received a single oral dose of NEPA on day 1 or a 3-day oral APR/GRAN regimen (days 1-3).

All patients received oral dexamethasone on days 1-4.

The primary efficacy endpoint was complete response (CR), defined as no emesis or rescue medication needed during the overall (0-120 hour) phase.

The investigators defined non-inferiority to be the lower limit of the two-sided 95% confidence interval greater than the non-inferiority margin set at  ̶ 10%.

Secondary endpoints included no emesis, no rescue medication, and no significant nausea (NSN), defined as <25 mm on 100 mm visual analog scale (VAS).

Results

The baseline demographics were comparable between the NEPA (n=413) and APR/GRAN (n=416) arms: 71% of the patients were male, a mean age of 55 years, and a little more than half were ECOG performance status 1.

The most common cancer types were lung and head and neck cancer.

Patients had received a median cisplatin dose of 73 and 72 mg/m² in the NEPA and APR/GRAN arms, respectively.

Within the first 24 hours (acute phase), NEPA was non-inferior to APR/GRAN. NEPA had a CR rate of 84.5% and APR/GRAN had a CR rate of 87.0%. The risk difference between the 2 agents was -2.5% (range, -7.2%, 2.3%).

In the delayed phase (25-120 hours), NEPA had a CR rate of 77.9% and APR/GRAN, 74.3%. The risk difference was 3.7% (range, -2.1%, 9.5%).

Overall, for both phases, the CR rate was 73.8% for NEPA and 72.4% for APR/GRAN. The risk difference was 1.5% (range, -4.5%, 7.5%).

Dr Zhang pointed out that although the overall CR rates were similar, the daily rates of patients experiencing CINV remained in the range of 13% - 15% for patients in the APR/GRAN arm.

However, daily rates of CINV for patients receiving NEPA declined from 16% to 8% over the 5 days. The investigators believe this suggests a benefit for delayed CINV.

Regarding secondary endpoints, significantly more patients receiving NEPA did not require rescue medication in the delayed phase and overall than patients in the APR/GRAN arm.

Treatment-emergent adverse events (TEAEs) were comparable between the arms—58.1% in the NEPA arm and 57.5% in the APR/GRAN arm, as were serious TEAS, at 4.5% and 4.6% for NEPA and APR/GRAN, respectively. And the no emesis and no significant nausea rates favored NEPA.

The most common treatment-emergent adverse events occurring in 2% or more of the patients in both arms were constipation and hiccups.

Two serious treatment-related adverse events occurred in each arm, 1 leading to discontinuation in the NEPA arm.

The investigators concluded that NEPA, as a convenient capsule administered once per cycle, is at least as effective as the 3-day regimen of APR/GRAN in patients receiving HEC.

NEPA (Akynzeo®) is approved by the US Food and Drug Administration and marketed globally by Helsinn, Lugano, Switzerland, the sponsor of the trial.

For the full US prescribing information, see the package insert.

Photo by Bill Branson

WASHINGTON, DC—In a head-to-head study comparing a single-dose oral antiemetic to a 3-day oral regimen, the single dose has shown itself to be non-inferior to the multi-day regimen in preventing chemotherapy-induced nausea and vomiting (CINV).

The investigators evaluated netupitant/palonosetron (NEPA) against aprepitant/granisetron (APR/GRAN) in patients on highly emetogenic chemotherapy.

They found the data suggest “that NEPA, in a single dose, had equivalent efficacy to a 3-day oral aprepitant/granisetron regimen,” according to the lead investigator and abstract presenter.

Li Zhang, MD, of Sun Yat-sen University Cancer Center in Guangzhou, China, presented the data at the Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology (MASCC/ISOO) Congress (abstract PS049, pp S55 – S56).

NEPA is a combination of the selective NK₁RA netupitant (300 mg) and the clinically and pharmacologically active 5-HT₃RA, palonosetron (0.5 mg) for the prevention of CINV.

Oral palonosetron prevents nausea and vomiting during the acute phase of treatment.

Netupitant prevents nausea and vomiting during both the acute and delayed phase after cancer chemotherapy.

It is formulated into a single oral capsule.

Study design

The study was a phase 3 randomized, double-blind, double-dummy study conducted in 828 chemotherapy-naïve Asian patients receiving cisplatin-based highly emetogenic chemotherapy (HEC) agents.

Patients received a single oral dose of NEPA on day 1 or a 3-day oral APR/GRAN regimen (days 1-3).

All patients received oral dexamethasone on days 1-4.

The primary efficacy endpoint was complete response (CR), defined as no emesis or rescue medication needed during the overall (0-120 hour) phase.

The investigators defined non-inferiority to be the lower limit of the two-sided 95% confidence interval greater than the non-inferiority margin set at  ̶ 10%.

Secondary endpoints included no emesis, no rescue medication, and no significant nausea (NSN), defined as <25 mm on 100 mm visual analog scale (VAS).

Results

The baseline demographics were comparable between the NEPA (n=413) and APR/GRAN (n=416) arms: 71% of the patients were male, a mean age of 55 years, and a little more than half were ECOG performance status 1.

The most common cancer types were lung and head and neck cancer.

Patients had received a median cisplatin dose of 73 and 72 mg/m² in the NEPA and APR/GRAN arms, respectively.

Within the first 24 hours (acute phase), NEPA was non-inferior to APR/GRAN. NEPA had a CR rate of 84.5% and APR/GRAN had a CR rate of 87.0%. The risk difference between the 2 agents was -2.5% (range, -7.2%, 2.3%).

In the delayed phase (25-120 hours), NEPA had a CR rate of 77.9% and APR/GRAN, 74.3%. The risk difference was 3.7% (range, -2.1%, 9.5%).

Overall, for both phases, the CR rate was 73.8% for NEPA and 72.4% for APR/GRAN. The risk difference was 1.5% (range, -4.5%, 7.5%).

Dr Zhang pointed out that although the overall CR rates were similar, the daily rates of patients experiencing CINV remained in the range of 13% - 15% for patients in the APR/GRAN arm.

However, daily rates of CINV for patients receiving NEPA declined from 16% to 8% over the 5 days. The investigators believe this suggests a benefit for delayed CINV.

Regarding secondary endpoints, significantly more patients receiving NEPA did not require rescue medication in the delayed phase and overall than patients in the APR/GRAN arm.

Treatment-emergent adverse events (TEAEs) were comparable between the arms—58.1% in the NEPA arm and 57.5% in the APR/GRAN arm, as were serious TEAS, at 4.5% and 4.6% for NEPA and APR/GRAN, respectively. And the no emesis and no significant nausea rates favored NEPA.

The most common treatment-emergent adverse events occurring in 2% or more of the patients in both arms were constipation and hiccups.

Two serious treatment-related adverse events occurred in each arm, 1 leading to discontinuation in the NEPA arm.

The investigators concluded that NEPA, as a convenient capsule administered once per cycle, is at least as effective as the 3-day regimen of APR/GRAN in patients receiving HEC.

NEPA (Akynzeo®) is approved by the US Food and Drug Administration and marketed globally by Helsinn, Lugano, Switzerland, the sponsor of the trial.

For the full US prescribing information, see the package insert.

Photo by Bill Branson

WASHINGTON, DC—In a head-to-head study comparing a single-dose oral antiemetic to a 3-day oral regimen, the single dose has shown itself to be non-inferior to the multi-day regimen in preventing chemotherapy-induced nausea and vomiting (CINV).

The investigators evaluated netupitant/palonosetron (NEPA) against aprepitant/granisetron (APR/GRAN) in patients on highly emetogenic chemotherapy.

They found the data suggest “that NEPA, in a single dose, had equivalent efficacy to a 3-day oral aprepitant/granisetron regimen,” according to the lead investigator and abstract presenter.

Li Zhang, MD, of Sun Yat-sen University Cancer Center in Guangzhou, China, presented the data at the Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology (MASCC/ISOO) Congress (abstract PS049, pp S55 – S56).

NEPA is a combination of the selective NK₁RA netupitant (300 mg) and the clinically and pharmacologically active 5-HT₃RA, palonosetron (0.5 mg) for the prevention of CINV.

Oral palonosetron prevents nausea and vomiting during the acute phase of treatment.

Netupitant prevents nausea and vomiting during both the acute and delayed phase after cancer chemotherapy.

It is formulated into a single oral capsule.

Study design

The study was a phase 3 randomized, double-blind, double-dummy study conducted in 828 chemotherapy-naïve Asian patients receiving cisplatin-based highly emetogenic chemotherapy (HEC) agents.

Patients received a single oral dose of NEPA on day 1 or a 3-day oral APR/GRAN regimen (days 1-3).

All patients received oral dexamethasone on days 1-4.

The primary efficacy endpoint was complete response (CR), defined as no emesis or rescue medication needed during the overall (0-120 hour) phase.

The investigators defined non-inferiority to be the lower limit of the two-sided 95% confidence interval greater than the non-inferiority margin set at  ̶ 10%.

Secondary endpoints included no emesis, no rescue medication, and no significant nausea (NSN), defined as <25 mm on 100 mm visual analog scale (VAS).

Results

The baseline demographics were comparable between the NEPA (n=413) and APR/GRAN (n=416) arms: 71% of the patients were male, a mean age of 55 years, and a little more than half were ECOG performance status 1.

The most common cancer types were lung and head and neck cancer.

Patients had received a median cisplatin dose of 73 and 72 mg/m² in the NEPA and APR/GRAN arms, respectively.

Within the first 24 hours (acute phase), NEPA was non-inferior to APR/GRAN. NEPA had a CR rate of 84.5% and APR/GRAN had a CR rate of 87.0%. The risk difference between the 2 agents was -2.5% (range, -7.2%, 2.3%).

In the delayed phase (25-120 hours), NEPA had a CR rate of 77.9% and APR/GRAN, 74.3%. The risk difference was 3.7% (range, -2.1%, 9.5%).

Overall, for both phases, the CR rate was 73.8% for NEPA and 72.4% for APR/GRAN. The risk difference was 1.5% (range, -4.5%, 7.5%).

Dr Zhang pointed out that although the overall CR rates were similar, the daily rates of patients experiencing CINV remained in the range of 13% - 15% for patients in the APR/GRAN arm.

However, daily rates of CINV for patients receiving NEPA declined from 16% to 8% over the 5 days. The investigators believe this suggests a benefit for delayed CINV.

Regarding secondary endpoints, significantly more patients receiving NEPA did not require rescue medication in the delayed phase and overall than patients in the APR/GRAN arm.

Treatment-emergent adverse events (TEAEs) were comparable between the arms—58.1% in the NEPA arm and 57.5% in the APR/GRAN arm, as were serious TEAS, at 4.5% and 4.6% for NEPA and APR/GRAN, respectively. And the no emesis and no significant nausea rates favored NEPA.

The most common treatment-emergent adverse events occurring in 2% or more of the patients in both arms were constipation and hiccups.

Two serious treatment-related adverse events occurred in each arm, 1 leading to discontinuation in the NEPA arm.

The investigators concluded that NEPA, as a convenient capsule administered once per cycle, is at least as effective as the 3-day regimen of APR/GRAN in patients receiving HEC.

NEPA (Akynzeo®) is approved by the US Food and Drug Administration and marketed globally by Helsinn, Lugano, Switzerland, the sponsor of the trial.

For the full US prescribing information, see the package insert.

Image by Andre E.X. Brown

The US Food and Drug Administration (FDA) has accepted for priority review a supplemental new drug application (sNDA) for rivaroxaban (XARELTO®).

The sNDA is for a 10 mg once-daily dose of rivaroxaban to reduce the risk of venous thromboembolism (VTE) in patients who have received at least 6 months of standard anticoagulant therapy.

The FDA grants priority review to applications for products that may provide significant improvements in the treatment, diagnosis, or prevention of serious conditions.

The agency’s goal is to take action on a priority review application within 6 months of receiving it, rather than the standard 10 months.

The FDA plans to make a decision on the rivaroxaban sNDA by October 28, 2017.

The sNDA is supported by data from the EINSTEIN CHOICE study. Patients enrolled in this study had confirmed VTE and were treated initially with standard anticoagulant therapy for 6 to 12 months.

During EINSTEIN CHOICE, 3365 patients received rivaroxaban at 10 mg, rivaroxaban at 20 mg, or aspirin at 100 mg once daily for up to 12 months of extended treatment.

Both rivaroxaban doses were superior to aspirin in preventing fatal or non-fatal recurrent VTE, the study’s primary efficacy endpoint.

The rate of recurrent VTE was 1.2% in the 10 mg rivaroxaban arm (hazard ratio [HR]=0.26; 95% CI, 0.14 to 0.47; P<0.001), 1.5% in the 20 mg rivaroxaban arm (HR=0.34; 95% CI, 0.20 to 0.59; P<0.001), and 4.4% in the aspirin arm. Fatal VTE occurred in 0%, 0.2%, and 0.2% of patients, respectively.

The primary safety endpoint was major bleeding as defined by the International Society on Thrombosis and Haemostasis.

The rate of major bleeding was 0.4% for the 10 mg rivaroxaban group (HR=1.64; 95% CI, 0.39 to 6.84; P=0.50), 0.5% for the 20 mg rivaroxaban group (HR=2.01; 95% CI, 0.50 to 8.04; P=0.32), and 0.3% for the aspirin group.

Image by Andre E.X. Brown

The US Food and Drug Administration (FDA) has accepted for priority review a supplemental new drug application (sNDA) for rivaroxaban (XARELTO®).

The sNDA is for a 10 mg once-daily dose of rivaroxaban to reduce the risk of venous thromboembolism (VTE) in patients who have received at least 6 months of standard anticoagulant therapy.

The FDA grants priority review to applications for products that may provide significant improvements in the treatment, diagnosis, or prevention of serious conditions.

The agency’s goal is to take action on a priority review application within 6 months of receiving it, rather than the standard 10 months.

The FDA plans to make a decision on the rivaroxaban sNDA by October 28, 2017.

The sNDA is supported by data from the EINSTEIN CHOICE study. Patients enrolled in this study had confirmed VTE and were treated initially with standard anticoagulant therapy for 6 to 12 months.

During EINSTEIN CHOICE, 3365 patients received rivaroxaban at 10 mg, rivaroxaban at 20 mg, or aspirin at 100 mg once daily for up to 12 months of extended treatment.

Both rivaroxaban doses were superior to aspirin in preventing fatal or non-fatal recurrent VTE, the study’s primary efficacy endpoint.

The rate of recurrent VTE was 1.2% in the 10 mg rivaroxaban arm (hazard ratio [HR]=0.26; 95% CI, 0.14 to 0.47; P<0.001), 1.5% in the 20 mg rivaroxaban arm (HR=0.34; 95% CI, 0.20 to 0.59; P<0.001), and 4.4% in the aspirin arm. Fatal VTE occurred in 0%, 0.2%, and 0.2% of patients, respectively.

The primary safety endpoint was major bleeding as defined by the International Society on Thrombosis and Haemostasis.

The rate of major bleeding was 0.4% for the 10 mg rivaroxaban group (HR=1.64; 95% CI, 0.39 to 6.84; P=0.50), 0.5% for the 20 mg rivaroxaban group (HR=2.01; 95% CI, 0.50 to 8.04; P=0.32), and 0.3% for the aspirin group.

Image by Andre E.X. Brown

The US Food and Drug Administration (FDA) has accepted for priority review a supplemental new drug application (sNDA) for rivaroxaban (XARELTO®).

The sNDA is for a 10 mg once-daily dose of rivaroxaban to reduce the risk of venous thromboembolism (VTE) in patients who have received at least 6 months of standard anticoagulant therapy.

The FDA grants priority review to applications for products that may provide significant improvements in the treatment, diagnosis, or prevention of serious conditions.

The agency’s goal is to take action on a priority review application within 6 months of receiving it, rather than the standard 10 months.

The FDA plans to make a decision on the rivaroxaban sNDA by October 28, 2017.

The sNDA is supported by data from the EINSTEIN CHOICE study. Patients enrolled in this study had confirmed VTE and were treated initially with standard anticoagulant therapy for 6 to 12 months.

During EINSTEIN CHOICE, 3365 patients received rivaroxaban at 10 mg, rivaroxaban at 20 mg, or aspirin at 100 mg once daily for up to 12 months of extended treatment.

Both rivaroxaban doses were superior to aspirin in preventing fatal or non-fatal recurrent VTE, the study’s primary efficacy endpoint.

The rate of recurrent VTE was 1.2% in the 10 mg rivaroxaban arm (hazard ratio [HR]=0.26; 95% CI, 0.14 to 0.47; P<0.001), 1.5% in the 20 mg rivaroxaban arm (HR=0.34; 95% CI, 0.20 to 0.59; P<0.001), and 4.4% in the aspirin arm. Fatal VTE occurred in 0%, 0.2%, and 0.2% of patients, respectively.

The primary safety endpoint was major bleeding as defined by the International Society on Thrombosis and Haemostasis.

The rate of major bleeding was 0.4% for the 10 mg rivaroxaban group (HR=1.64; 95% CI, 0.39 to 6.84; P=0.50), 0.5% for the 20 mg rivaroxaban group (HR=2.01; 95% CI, 0.50 to 8.04; P=0.32), and 0.3% for the aspirin group.

Given the history that the rash persisted for longer than 3 months, the FP made the diagnosis of chronic urticaria. The cause of chronic urticaria (>6 weeks duration) is determined in less than 20% of cases. Because no cause was found in this case, the patient’s urticaria was determined to be chronic idiopathic urticaria.

Chronic urticaria is twice as common in women than in men. Urticaria is a dynamic process in which new wheals evolve as old ones resolve. The wheals result from localized capillary vasodilation, followed by transudation of protein-rich fluid into the surrounding skin. The wheals resolve when the fluid is slowly reabsorbed. Patients may benefit from avoiding potential urticarial precipitants such as aspirin, nonsteroidal anti-inflammatory drugs, opiates, and alcohol.

Second-generation H1 antihistamines, such as cetirizine, should be prescribed as first-line treatment for chronic urticaria. Increasing the dose of cetirizine from 10 mg/d to 20 mg/d produces a significant improvement in the severity of wheals and itching in urticaria refractory to the standard doses of antihistamines. The National Institute for Health and Care Excellence (NICE) notes in its 2014 evidence summary that international guidelines suggest that non-sedating antihistamines may be used at up to quadruple the manufacturers’ recommended dosages before changing to an alternative therapy. NICE recommends waiting up to 4 weeks to allow full effectiveness of the antihistamines before considering referral to a specialist.

The patient in this case was started on cetirizine 10 mg twice daily with written instructions to gradually increase up to 20 mg twice daily if the lower doses were not working. With cetirizine 20 mg twice daily, the chronic urticaria subsided and the patient was satisfied with the results.

Photos and text for Photo Rounds Friday courtesy of Richard P. Usatine, MD. This case was adapted from: Usatine R. Urticaria and angioedema. In: Usatine R, Smith M, Mayeaux EJ, et al, eds. Color Atlas of Family Medicine. 2nd ed. New York, NY: McGraw-Hill; 2013: 863-870.

To learn more about the Color Atlas of Family Medicine, see: www.amazon.com/Color-Family-Medicine-Richard-Usatine/dp/0071769641/

You can now get the second edition of the Color Atlas of Family Medicine as an app by clicking on this link: usatinemedia.com

Given the history that the rash persisted for longer than 3 months, the FP made the diagnosis of chronic urticaria. The cause of chronic urticaria (>6 weeks duration) is determined in less than 20% of cases. Because no cause was found in this case, the patient’s urticaria was determined to be chronic idiopathic urticaria.

Chronic urticaria is twice as common in women than in men. Urticaria is a dynamic process in which new wheals evolve as old ones resolve. The wheals result from localized capillary vasodilation, followed by transudation of protein-rich fluid into the surrounding skin. The wheals resolve when the fluid is slowly reabsorbed. Patients may benefit from avoiding potential urticarial precipitants such as aspirin, nonsteroidal anti-inflammatory drugs, opiates, and alcohol.

Second-generation H1 antihistamines, such as cetirizine, should be prescribed as first-line treatment for chronic urticaria. Increasing the dose of cetirizine from 10 mg/d to 20 mg/d produces a significant improvement in the severity of wheals and itching in urticaria refractory to the standard doses of antihistamines. The National Institute for Health and Care Excellence (NICE) notes in its 2014 evidence summary that international guidelines suggest that non-sedating antihistamines may be used at up to quadruple the manufacturers’ recommended dosages before changing to an alternative therapy. NICE recommends waiting up to 4 weeks to allow full effectiveness of the antihistamines before considering referral to a specialist.

The patient in this case was started on cetirizine 10 mg twice daily with written instructions to gradually increase up to 20 mg twice daily if the lower doses were not working. With cetirizine 20 mg twice daily, the chronic urticaria subsided and the patient was satisfied with the results.

Photos and text for Photo Rounds Friday courtesy of Richard P. Usatine, MD. This case was adapted from: Usatine R. Urticaria and angioedema. In: Usatine R, Smith M, Mayeaux EJ, et al, eds. Color Atlas of Family Medicine. 2nd ed. New York, NY: McGraw-Hill; 2013: 863-870.

To learn more about the Color Atlas of Family Medicine, see: www.amazon.com/Color-Family-Medicine-Richard-Usatine/dp/0071769641/

You can now get the second edition of the Color Atlas of Family Medicine as an app by clicking on this link: usatinemedia.com

Given the history that the rash persisted for longer than 3 months, the FP made the diagnosis of chronic urticaria. The cause of chronic urticaria (>6 weeks duration) is determined in less than 20% of cases. Because no cause was found in this case, the patient’s urticaria was determined to be chronic idiopathic urticaria.

Chronic urticaria is twice as common in women than in men. Urticaria is a dynamic process in which new wheals evolve as old ones resolve. The wheals result from localized capillary vasodilation, followed by transudation of protein-rich fluid into the surrounding skin. The wheals resolve when the fluid is slowly reabsorbed. Patients may benefit from avoiding potential urticarial precipitants such as aspirin, nonsteroidal anti-inflammatory drugs, opiates, and alcohol.

Second-generation H1 antihistamines, such as cetirizine, should be prescribed as first-line treatment for chronic urticaria. Increasing the dose of cetirizine from 10 mg/d to 20 mg/d produces a significant improvement in the severity of wheals and itching in urticaria refractory to the standard doses of antihistamines. The National Institute for Health and Care Excellence (NICE) notes in its 2014 evidence summary that international guidelines suggest that non-sedating antihistamines may be used at up to quadruple the manufacturers’ recommended dosages before changing to an alternative therapy. NICE recommends waiting up to 4 weeks to allow full effectiveness of the antihistamines before considering referral to a specialist.

The patient in this case was started on cetirizine 10 mg twice daily with written instructions to gradually increase up to 20 mg twice daily if the lower doses were not working. With cetirizine 20 mg twice daily, the chronic urticaria subsided and the patient was satisfied with the results.

Photos and text for Photo Rounds Friday courtesy of Richard P. Usatine, MD. This case was adapted from: Usatine R. Urticaria and angioedema. In: Usatine R, Smith M, Mayeaux EJ, et al, eds. Color Atlas of Family Medicine. 2nd ed. New York, NY: McGraw-Hill; 2013: 863-870.

To learn more about the Color Atlas of Family Medicine, see: www.amazon.com/Color-Family-Medicine-Richard-Usatine/dp/0071769641/

You can now get the second edition of the Color Atlas of Family Medicine as an app by clicking on this link: usatinemedia.com

Hypoglycemia, a frequently encountered medical emergency, is usually seen in patients with diabetes, most commonly as a result of iatrogenesis. However, it can also be encountered in nondiabetic patients. Various causes, such as pancreatic islet cell tumors producing insulin, primary or secondary adrenal insufficiency, advanced liver disease, pheochromocytoma and hypothyroidism, have been found to contribute to the condition in the nondiabetic population.¹ In rare cases, an excessive production of insulin-like growth factor (IGF-2) – a condition known as nonislet cell tumor-induced hypoglycemia (NICTH) – has also been found to cause hypoglycemia. Hypoinsulinemic hypoglycemia, with low IGF-1 levels and an IGF-2-IgF1 ratio of greater than 10, is found to be suggestive of NICTH.

Case presentation and summary

An 81-year-old man with a history of diabetes mellitus, systolic heart failure, chronic kidney disease, and metastatic classical gastrointestinal spindle cell sarcoma presented to the emergency department with an acute change in mental status resulting from a new onset hypoglycemia. He was admitted, and during his hospital stay, he experienced severe hypoglycemic episodes with symptomatic presentations of diaphoresis on multiple occasions. A detailed history revealed that for diabetes, the patient had been on insulin for the first 12 years after his diagnosis, after which he was switched to metformin 500 mg twice daily for about 2 years, and as a satisfactory glycemic control was attained, eventually metformin had also been stopped 3 years prior to the current presentation.

The patient’s past medical records were obtained from the hospital at which he had been diagnosed gastrointestinal spindle cell sarcoma. Patient had not received treatment for the cancer as the disease was too widespread to be treated. The gastrointestinal spindle cell sarcoma, which had initially been surgically resected 7 years before the current presentation, had a recurrence 3 years later with abdominal and pulmonary metastasis, but no liver metastasis. No further intervention was carried out because the widely metastasized disease would not have benefited from any more surgical intervention and chemotherapy was not initiated because of the patient’s comorbid illnesses.

A blood sample drawn from the patient at the time of one hypoglycemic event, revealed low serum insulin <0.1 U/ml (normal, 2-19.6 U/ml); low C-peptide level, 0.59 ng/ml (0.8-3.85 ng/ml); low IGF-1, 16 ng/ml (5-4 ng/ml); and IGF-3, 0.9 ng/ml (2.2-4.5 ng/ml). IGF-2 levels were found to be markedly elevated at 945 ng/ml (47-350 ng/ml). The calculated IGF-2-IGF-1 ratio was 59.06 (normal, <10), suggesting NICTH as the etiology for the patient’s hypoglycemia.

The hypoglycemic episodes were initially treated with a continuous dextrose infusion followed by diazoxide treatment. However, diazoxide did not prevent his hypoglycemic episodes, so dexamethasone was considered as an alternative for his condition. The dexamethasone treatment resulted in the normalization of the patient’s serum glucose levels and resolution of his symptoms. The patient was discharged in a satisfactory state few days later and followed up thereafter. No recurrence of hypoglycemic episodes was found, and he was continued on dexamethasone therapy.

Discussion

Hypoglycemia due to NICTH is rare, with a prevalence of four times less than that of insulinoma.³ In most cases, NICTH occurs in patients with solid tumors of mesenchymal and epithelial origins such as hepatocellular carcinoma, gastric carcinoma or mesothelioma.⁴ In NICTH, the serum levels of insulin, C-peptide, and IGF-1 are usually decreased or undetectable. However, the circulating levels of total IGF2 may be increased, decreased, or normal. Concurrent normal to high morning cortisol and normal response to cosyntropin stimulation can rule out adrenal insufficiency and suggest NICTH. An IGF-2: IGF-1 ratio of >10 is considered to be clinically significant and highly suggestive of NICTH.⁵ Hypoglycemia in NICTH can be managed by administration of oral glucose, intravenous dextrose or glucagon. In some cases, diazoxide, a potent inhibitor of insulin secretion, has been found to be useful.⁶ Diazoxide directly inhibits the release of insulin through stimulation of adrenergic receptors and also has an extra pancreatic hyperglycemic effect, probably by inhibiting cyclic adenosine monophosphate phosphodiesterase, resulting in higher plasma levels of cyclic AMP and enhanced glycogenolysis.

Glucocorticoid therapy has been shown to suppress IGF-2 in a dose dependent manner and also by increasing gluconeogenesis.⁷ Surgical resection of the tumor whenever possible is the treatment of choice followed by radiotherapy and chemotherapy for inoperable disease and if successful, usually results in resolution of hypoglycemia. Imatinib, is the chemotherapeutic drug of choice for metastatic GIST, but many case reports have suggested worsening of hypoglycemia in advanced GIST with the use of the drug.⁸ The patient described in our report was not on any chemotherapy, hence hypoglycemia could not be attributed to it. On the basis of findings among 24 patients with GIST, Rikhof and colleagues have recommended monitoring plasma levels of pro-IGF-IIE to identify patients at high risk for developing hypoglycemia, especially those with progressive disease.⁹ Furthermore, over expression of IGF-2 as a predictor of potential relapse may be an area for potential research and further study.¹⁰

Hypoglycemia, a frequently encountered medical emergency, is usually seen in patients with diabetes, most commonly as a result of iatrogenesis. However, it can also be encountered in nondiabetic patients. Various causes, such as pancreatic islet cell tumors producing insulin, primary or secondary adrenal insufficiency, advanced liver disease, pheochromocytoma and hypothyroidism, have been found to contribute to the condition in the nondiabetic population.¹ In rare cases, an excessive production of insulin-like growth factor (IGF-2) – a condition known as nonislet cell tumor-induced hypoglycemia (NICTH) – has also been found to cause hypoglycemia. Hypoinsulinemic hypoglycemia, with low IGF-1 levels and an IGF-2-IgF1 ratio of greater than 10, is found to be suggestive of NICTH.

Case presentation and summary

An 81-year-old man with a history of diabetes mellitus, systolic heart failure, chronic kidney disease, and metastatic classical gastrointestinal spindle cell sarcoma presented to the emergency department with an acute change in mental status resulting from a new onset hypoglycemia. He was admitted, and during his hospital stay, he experienced severe hypoglycemic episodes with symptomatic presentations of diaphoresis on multiple occasions. A detailed history revealed that for diabetes, the patient had been on insulin for the first 12 years after his diagnosis, after which he was switched to metformin 500 mg twice daily for about 2 years, and as a satisfactory glycemic control was attained, eventually metformin had also been stopped 3 years prior to the current presentation.

The patient’s past medical records were obtained from the hospital at which he had been diagnosed gastrointestinal spindle cell sarcoma. Patient had not received treatment for the cancer as the disease was too widespread to be treated. The gastrointestinal spindle cell sarcoma, which had initially been surgically resected 7 years before the current presentation, had a recurrence 3 years later with abdominal and pulmonary metastasis, but no liver metastasis. No further intervention was carried out because the widely metastasized disease would not have benefited from any more surgical intervention and chemotherapy was not initiated because of the patient’s comorbid illnesses.

A blood sample drawn from the patient at the time of one hypoglycemic event, revealed low serum insulin <0.1 U/ml (normal, 2-19.6 U/ml); low C-peptide level, 0.59 ng/ml (0.8-3.85 ng/ml); low IGF-1, 16 ng/ml (5-4 ng/ml); and IGF-3, 0.9 ng/ml (2.2-4.5 ng/ml). IGF-2 levels were found to be markedly elevated at 945 ng/ml (47-350 ng/ml). The calculated IGF-2-IGF-1 ratio was 59.06 (normal, <10), suggesting NICTH as the etiology for the patient’s hypoglycemia.

The hypoglycemic episodes were initially treated with a continuous dextrose infusion followed by diazoxide treatment. However, diazoxide did not prevent his hypoglycemic episodes, so dexamethasone was considered as an alternative for his condition. The dexamethasone treatment resulted in the normalization of the patient’s serum glucose levels and resolution of his symptoms. The patient was discharged in a satisfactory state few days later and followed up thereafter. No recurrence of hypoglycemic episodes was found, and he was continued on dexamethasone therapy.

Discussion

Hypoglycemia due to NICTH is rare, with a prevalence of four times less than that of insulinoma.³ In most cases, NICTH occurs in patients with solid tumors of mesenchymal and epithelial origins such as hepatocellular carcinoma, gastric carcinoma or mesothelioma.⁴ In NICTH, the serum levels of insulin, C-peptide, and IGF-1 are usually decreased or undetectable. However, the circulating levels of total IGF2 may be increased, decreased, or normal. Concurrent normal to high morning cortisol and normal response to cosyntropin stimulation can rule out adrenal insufficiency and suggest NICTH. An IGF-2: IGF-1 ratio of >10 is considered to be clinically significant and highly suggestive of NICTH.⁵ Hypoglycemia in NICTH can be managed by administration of oral glucose, intravenous dextrose or glucagon. In some cases, diazoxide, a potent inhibitor of insulin secretion, has been found to be useful.⁶ Diazoxide directly inhibits the release of insulin through stimulation of adrenergic receptors and also has an extra pancreatic hyperglycemic effect, probably by inhibiting cyclic adenosine monophosphate phosphodiesterase, resulting in higher plasma levels of cyclic AMP and enhanced glycogenolysis.

Glucocorticoid therapy has been shown to suppress IGF-2 in a dose dependent manner and also by increasing gluconeogenesis.⁷ Surgical resection of the tumor whenever possible is the treatment of choice followed by radiotherapy and chemotherapy for inoperable disease and if successful, usually results in resolution of hypoglycemia. Imatinib, is the chemotherapeutic drug of choice for metastatic GIST, but many case reports have suggested worsening of hypoglycemia in advanced GIST with the use of the drug.⁸ The patient described in our report was not on any chemotherapy, hence hypoglycemia could not be attributed to it. On the basis of findings among 24 patients with GIST, Rikhof and colleagues have recommended monitoring plasma levels of pro-IGF-IIE to identify patients at high risk for developing hypoglycemia, especially those with progressive disease.⁹ Furthermore, over expression of IGF-2 as a predictor of potential relapse may be an area for potential research and further study.¹⁰

Hypoglycemia, a frequently encountered medical emergency, is usually seen in patients with diabetes, most commonly as a result of iatrogenesis. However, it can also be encountered in nondiabetic patients. Various causes, such as pancreatic islet cell tumors producing insulin, primary or secondary adrenal insufficiency, advanced liver disease, pheochromocytoma and hypothyroidism, have been found to contribute to the condition in the nondiabetic population.¹ In rare cases, an excessive production of insulin-like growth factor (IGF-2) – a condition known as nonislet cell tumor-induced hypoglycemia (NICTH) – has also been found to cause hypoglycemia. Hypoinsulinemic hypoglycemia, with low IGF-1 levels and an IGF-2-IgF1 ratio of greater than 10, is found to be suggestive of NICTH.

Case presentation and summary

An 81-year-old man with a history of diabetes mellitus, systolic heart failure, chronic kidney disease, and metastatic classical gastrointestinal spindle cell sarcoma presented to the emergency department with an acute change in mental status resulting from a new onset hypoglycemia. He was admitted, and during his hospital stay, he experienced severe hypoglycemic episodes with symptomatic presentations of diaphoresis on multiple occasions. A detailed history revealed that for diabetes, the patient had been on insulin for the first 12 years after his diagnosis, after which he was switched to metformin 500 mg twice daily for about 2 years, and as a satisfactory glycemic control was attained, eventually metformin had also been stopped 3 years prior to the current presentation.

The patient’s past medical records were obtained from the hospital at which he had been diagnosed gastrointestinal spindle cell sarcoma. Patient had not received treatment for the cancer as the disease was too widespread to be treated. The gastrointestinal spindle cell sarcoma, which had initially been surgically resected 7 years before the current presentation, had a recurrence 3 years later with abdominal and pulmonary metastasis, but no liver metastasis. No further intervention was carried out because the widely metastasized disease would not have benefited from any more surgical intervention and chemotherapy was not initiated because of the patient’s comorbid illnesses.

A blood sample drawn from the patient at the time of one hypoglycemic event, revealed low serum insulin <0.1 U/ml (normal, 2-19.6 U/ml); low C-peptide level, 0.59 ng/ml (0.8-3.85 ng/ml); low IGF-1, 16 ng/ml (5-4 ng/ml); and IGF-3, 0.9 ng/ml (2.2-4.5 ng/ml). IGF-2 levels were found to be markedly elevated at 945 ng/ml (47-350 ng/ml). The calculated IGF-2-IGF-1 ratio was 59.06 (normal, <10), suggesting NICTH as the etiology for the patient’s hypoglycemia.

The hypoglycemic episodes were initially treated with a continuous dextrose infusion followed by diazoxide treatment. However, diazoxide did not prevent his hypoglycemic episodes, so dexamethasone was considered as an alternative for his condition. The dexamethasone treatment resulted in the normalization of the patient’s serum glucose levels and resolution of his symptoms. The patient was discharged in a satisfactory state few days later and followed up thereafter. No recurrence of hypoglycemic episodes was found, and he was continued on dexamethasone therapy.

Discussion

Hypoglycemia due to NICTH is rare, with a prevalence of four times less than that of insulinoma.³ In most cases, NICTH occurs in patients with solid tumors of mesenchymal and epithelial origins such as hepatocellular carcinoma, gastric carcinoma or mesothelioma.⁴ In NICTH, the serum levels of insulin, C-peptide, and IGF-1 are usually decreased or undetectable. However, the circulating levels of total IGF2 may be increased, decreased, or normal. Concurrent normal to high morning cortisol and normal response to cosyntropin stimulation can rule out adrenal insufficiency and suggest NICTH. An IGF-2: IGF-1 ratio of >10 is considered to be clinically significant and highly suggestive of NICTH.⁵ Hypoglycemia in NICTH can be managed by administration of oral glucose, intravenous dextrose or glucagon. In some cases, diazoxide, a potent inhibitor of insulin secretion, has been found to be useful.⁶ Diazoxide directly inhibits the release of insulin through stimulation of adrenergic receptors and also has an extra pancreatic hyperglycemic effect, probably by inhibiting cyclic adenosine monophosphate phosphodiesterase, resulting in higher plasma levels of cyclic AMP and enhanced glycogenolysis.

Glucocorticoid therapy has been shown to suppress IGF-2 in a dose dependent manner and also by increasing gluconeogenesis.⁷ Surgical resection of the tumor whenever possible is the treatment of choice followed by radiotherapy and chemotherapy for inoperable disease and if successful, usually results in resolution of hypoglycemia. Imatinib, is the chemotherapeutic drug of choice for metastatic GIST, but many case reports have suggested worsening of hypoglycemia in advanced GIST with the use of the drug.⁸ The patient described in our report was not on any chemotherapy, hence hypoglycemia could not be attributed to it. On the basis of findings among 24 patients with GIST, Rikhof and colleagues have recommended monitoring plasma levels of pro-IGF-IIE to identify patients at high risk for developing hypoglycemia, especially those with progressive disease.⁹ Furthermore, over expression of IGF-2 as a predictor of potential relapse may be an area for potential research and further study.¹⁰

MADRID – The rates of both total hip and total knee replacement surgeries dropped among Danish patients with rheumatoid arthritis since the mid-1990s, reductions that were coincident with more widespread use of biologic drugs as well as with other improvements in care, according to analyses of Danish national health records.

“The introduction of guidelines [on biologic drug use] in 2002 and increasing use of biologic drugs [as a result] may have contributed to this positive development,” Lene Dreyer, MD, said at the European Congress of Rheumatology. Other factors that may have also contributed include widespread use of conventional disease-modifying antirheumatic drugs (DMARDs) and adoption of a treat-to-target strategy by many clinicians.

In 1996, the first year studied and before any biologic DMARDs were routinely used for rheumatoid arthritis, the rate of total knee replacement was nearly 6/1,000 person-years among RA patients, compared with a 0.42/1,000 person-years rate in the general adult Danish population, a roughly 14-fold excess among the RA patients, Dr. Dreyer reported. But by 2016, ”this gap had almost disappeared,” she said in a video interview. “It seems like rheumatologists in Denmark are doing a good job” treating RA patients.

That may have been especially true subsequent to 2002, when the Danish Institute for Rational Pharmacotherapy issued recommendations that opened the door to wider use of biologic DMARDs, such as tumor necrosis factor inhibitors, to treat RA patients, noted Dr. Dreyer of Gentofte University Hospital, Copenhagen. During 2003-2011, use of total knee replacement surgery in RA patients fell by an average annualized rate of 0.2 surgeries/1,000 person-years. But among the general Danish population the average annualized rate of knee surgeries rose by 0.08/1,000 person-years.

“This is a very important finding,” commented Robert Landewé, MD, PhD, professor of rheumatology at the Academic Medical Center in Amsterdam. “It is extremely difficult to test the effect of the introduction of the [biologic DMARD] guidelines,” he cautioned. But he highlighted the positive finding that the excess of hip and knee replacement surgeries in patients with RA, compared with the general population, had recently narrowed.

Dr. Dreyer and her associates used records from the Danish National Patient Register to compare 29,427 patients with incident RA during 1996-2011 with more than 290,000 matched control individuals. All people studied had not undergone knee or hip replacement surgery prior to their entry into the study. The researchers used an “interrupted time series analysis” to examine the possible impact of the introduction of widespread access to biologic DMARDs starting in 2003.

The analysis showed that the rate of total hip replacements in 1996 was nearly 9 surgeries/1,000 person-years among RA patients and nearly 3/1,000 person-years in the general population, a threefold excess for RA patients. This rate fell by an average annual rate of 0.38/1,000 person-years among RA patients both before and after 2002, so that by 2011 the rate was roughly half the 1996 rate, about 4.5/1,000 patient-years. The rate in the general population rose during 1996-2011, and by 2011 was nearly 4/1,000 person-years and so nearly the same as RA patients. Wider availability of biologic DMARDs for RA patients starting in 2003 did not have an apparent impact on the rate of total hip replacement.

In contrast, wider use of biologic DMARDs appeared to have an effect on the rate of total knee surgeries among RA patients. During 1996-2001, the rate rose by an annual average of 0.19/1,000 person-years, very similar to the 0.21/1,000 person-years annual rise in the general Danish population. However, during 2003-2011, the average annual rate of total knee surgery fell by 0.20/1,000 person-years in the RA patients but continued to rise at an annual average rate of 0.08/1,000 person-years in the general population, Dr. Dreyer reported.

Additional Danish registry data exist for patients who received biologic DMARDs, and Dr. Dreyer said that she and her associates hope to use this to further examine the impact of these drugs on patient outcomes.

Dr. Dreyer has received lecture fees from Merck Sharp & Dohme and UCB. Dr. Landewé has received consulting fees from several drug companies.

[email protected]

On Twitter @mitchelzoler

MADRID – The rates of both total hip and total knee replacement surgeries dropped among Danish patients with rheumatoid arthritis since the mid-1990s, reductions that were coincident with more widespread use of biologic drugs as well as with other improvements in care, according to analyses of Danish national health records.

“The introduction of guidelines [on biologic drug use] in 2002 and increasing use of biologic drugs [as a result] may have contributed to this positive development,” Lene Dreyer, MD, said at the European Congress of Rheumatology. Other factors that may have also contributed include widespread use of conventional disease-modifying antirheumatic drugs (DMARDs) and adoption of a treat-to-target strategy by many clinicians.

In 1996, the first year studied and before any biologic DMARDs were routinely used for rheumatoid arthritis, the rate of total knee replacement was nearly 6/1,000 person-years among RA patients, compared with a 0.42/1,000 person-years rate in the general adult Danish population, a roughly 14-fold excess among the RA patients, Dr. Dreyer reported. But by 2016, ”this gap had almost disappeared,” she said in a video interview. “It seems like rheumatologists in Denmark are doing a good job” treating RA patients.

That may have been especially true subsequent to 2002, when the Danish Institute for Rational Pharmacotherapy issued recommendations that opened the door to wider use of biologic DMARDs, such as tumor necrosis factor inhibitors, to treat RA patients, noted Dr. Dreyer of Gentofte University Hospital, Copenhagen. During 2003-2011, use of total knee replacement surgery in RA patients fell by an average annualized rate of 0.2 surgeries/1,000 person-years. But among the general Danish population the average annualized rate of knee surgeries rose by 0.08/1,000 person-years.

“This is a very important finding,” commented Robert Landewé, MD, PhD, professor of rheumatology at the Academic Medical Center in Amsterdam. “It is extremely difficult to test the effect of the introduction of the [biologic DMARD] guidelines,” he cautioned. But he highlighted the positive finding that the excess of hip and knee replacement surgeries in patients with RA, compared with the general population, had recently narrowed.

Dr. Dreyer and her associates used records from the Danish National Patient Register to compare 29,427 patients with incident RA during 1996-2011 with more than 290,000 matched control individuals. All people studied had not undergone knee or hip replacement surgery prior to their entry into the study. The researchers used an “interrupted time series analysis” to examine the possible impact of the introduction of widespread access to biologic DMARDs starting in 2003.

The analysis showed that the rate of total hip replacements in 1996 was nearly 9 surgeries/1,000 person-years among RA patients and nearly 3/1,000 person-years in the general population, a threefold excess for RA patients. This rate fell by an average annual rate of 0.38/1,000 person-years among RA patients both before and after 2002, so that by 2011 the rate was roughly half the 1996 rate, about 4.5/1,000 patient-years. The rate in the general population rose during 1996-2011, and by 2011 was nearly 4/1,000 person-years and so nearly the same as RA patients. Wider availability of biologic DMARDs for RA patients starting in 2003 did not have an apparent impact on the rate of total hip replacement.

In contrast, wider use of biologic DMARDs appeared to have an effect on the rate of total knee surgeries among RA patients. During 1996-2001, the rate rose by an annual average of 0.19/1,000 person-years, very similar to the 0.21/1,000 person-years annual rise in the general Danish population. However, during 2003-2011, the average annual rate of total knee surgery fell by 0.20/1,000 person-years in the RA patients but continued to rise at an annual average rate of 0.08/1,000 person-years in the general population, Dr. Dreyer reported.

Additional Danish registry data exist for patients who received biologic DMARDs, and Dr. Dreyer said that she and her associates hope to use this to further examine the impact of these drugs on patient outcomes.

Dr. Dreyer has received lecture fees from Merck Sharp & Dohme and UCB. Dr. Landewé has received consulting fees from several drug companies.

[email protected]

On Twitter @mitchelzoler

MADRID – The rates of both total hip and total knee replacement surgeries dropped among Danish patients with rheumatoid arthritis since the mid-1990s, reductions that were coincident with more widespread use of biologic drugs as well as with other improvements in care, according to analyses of Danish national health records.

“The introduction of guidelines [on biologic drug use] in 2002 and increasing use of biologic drugs [as a result] may have contributed to this positive development,” Lene Dreyer, MD, said at the European Congress of Rheumatology. Other factors that may have also contributed include widespread use of conventional disease-modifying antirheumatic drugs (DMARDs) and adoption of a treat-to-target strategy by many clinicians.

In 1996, the first year studied and before any biologic DMARDs were routinely used for rheumatoid arthritis, the rate of total knee replacement was nearly 6/1,000 person-years among RA patients, compared with a 0.42/1,000 person-years rate in the general adult Danish population, a roughly 14-fold excess among the RA patients, Dr. Dreyer reported. But by 2016, ”this gap had almost disappeared,” she said in a video interview. “It seems like rheumatologists in Denmark are doing a good job” treating RA patients.

That may have been especially true subsequent to 2002, when the Danish Institute for Rational Pharmacotherapy issued recommendations that opened the door to wider use of biologic DMARDs, such as tumor necrosis factor inhibitors, to treat RA patients, noted Dr. Dreyer of Gentofte University Hospital, Copenhagen. During 2003-2011, use of total knee replacement surgery in RA patients fell by an average annualized rate of 0.2 surgeries/1,000 person-years. But among the general Danish population the average annualized rate of knee surgeries rose by 0.08/1,000 person-years.

“This is a very important finding,” commented Robert Landewé, MD, PhD, professor of rheumatology at the Academic Medical Center in Amsterdam. “It is extremely difficult to test the effect of the introduction of the [biologic DMARD] guidelines,” he cautioned. But he highlighted the positive finding that the excess of hip and knee replacement surgeries in patients with RA, compared with the general population, had recently narrowed.

Dr. Dreyer and her associates used records from the Danish National Patient Register to compare 29,427 patients with incident RA during 1996-2011 with more than 290,000 matched control individuals. All people studied had not undergone knee or hip replacement surgery prior to their entry into the study. The researchers used an “interrupted time series analysis” to examine the possible impact of the introduction of widespread access to biologic DMARDs starting in 2003.

The analysis showed that the rate of total hip replacements in 1996 was nearly 9 surgeries/1,000 person-years among RA patients and nearly 3/1,000 person-years in the general population, a threefold excess for RA patients. This rate fell by an average annual rate of 0.38/1,000 person-years among RA patients both before and after 2002, so that by 2011 the rate was roughly half the 1996 rate, about 4.5/1,000 patient-years. The rate in the general population rose during 1996-2011, and by 2011 was nearly 4/1,000 person-years and so nearly the same as RA patients. Wider availability of biologic DMARDs for RA patients starting in 2003 did not have an apparent impact on the rate of total hip replacement.

In contrast, wider use of biologic DMARDs appeared to have an effect on the rate of total knee surgeries among RA patients. During 1996-2001, the rate rose by an annual average of 0.19/1,000 person-years, very similar to the 0.21/1,000 person-years annual rise in the general Danish population. However, during 2003-2011, the average annual rate of total knee surgery fell by 0.20/1,000 person-years in the RA patients but continued to rise at an annual average rate of 0.08/1,000 person-years in the general population, Dr. Dreyer reported.

Additional Danish registry data exist for patients who received biologic DMARDs, and Dr. Dreyer said that she and her associates hope to use this to further examine the impact of these drugs on patient outcomes.

Dr. Dreyer has received lecture fees from Merck Sharp & Dohme and UCB. Dr. Landewé has received consulting fees from several drug companies.

[email protected]

On Twitter @mitchelzoler

MADRID – Obese patients with axial spondyloarthritis were substantially less responsive to treatment with a tumor necrosis factor inhibitor than were healthy-weight patients in a multicenter Swiss study with 531 patients.

In a multivariate analysis that controlled for several demographic and clinical factors, including baseline disease severity, obese patients with axial spondyloarthritis (SpA) were 70% less likely to achieve a 40% or better improvement in their Assessment in SpondyloArthritis International Society improvement criteria (ASAS 40) when compared with patients with a healthy body mass index (BMI), Raphael Micheroli, MD, reported in a poster at the European Congress of Rheumatology.

Mitchel L. Zoler/Frontline Medical News

[email protected]

On Twitter @mitchelzoler

MADRID – Obese patients with axial spondyloarthritis were substantially less responsive to treatment with a tumor necrosis factor inhibitor than were healthy-weight patients in a multicenter Swiss study with 531 patients.

In a multivariate analysis that controlled for several demographic and clinical factors, including baseline disease severity, obese patients with axial spondyloarthritis (SpA) were 70% less likely to achieve a 40% or better improvement in their Assessment in SpondyloArthritis International Society improvement criteria (ASAS 40) when compared with patients with a healthy body mass index (BMI), Raphael Micheroli, MD, reported in a poster at the European Congress of Rheumatology.

Mitchel L. Zoler/Frontline Medical News

[email protected]

On Twitter @mitchelzoler

MADRID – Obese patients with axial spondyloarthritis were substantially less responsive to treatment with a tumor necrosis factor inhibitor than were healthy-weight patients in a multicenter Swiss study with 531 patients.

In a multivariate analysis that controlled for several demographic and clinical factors, including baseline disease severity, obese patients with axial spondyloarthritis (SpA) were 70% less likely to achieve a 40% or better improvement in their Assessment in SpondyloArthritis International Society improvement criteria (ASAS 40) when compared with patients with a healthy body mass index (BMI), Raphael Micheroli, MD, reported in a poster at the European Congress of Rheumatology.

Mitchel L. Zoler/Frontline Medical News

[email protected]

On Twitter @mitchelzoler

Transcranial direct-current stimulation did not show noninferiority to escitalopram for major depressive disorder in a single-center trial. The results were published online June 29.

The randomized double-blind placebo-controlled noninferiority study involved 245 adults with moderate to severe depression, many of whom had coexisting anxiety disorder. This “reflects a typical clinical population in which treatment for depression is indicated,” said André R. Brunoni, MD, PhD, of the Service of Interdisciplinary Neuromodulation, Institute of Psychiatry and Laboratory of Neurosciences, University of São Paulo, Brazil, and his associates.

A total of 94 patients were assigned to receive active tDCS plus oral placebo (tDCS group), 91 to receive sham tDCS plus escitalopram (escitalopram group), and 60 to receive sham tDCS plus oral placebo (placebo group) for 10 weeks. The primary outcome – decrease in mean depression score on the 17-item Hamilton Depression Rating Scale – was 9.0 points with tDCS, 11.3 points with escitalopram, and 5.8 points with placebo. Thus, tDCS did not achieve noninferiority to escitalopram, the investigators said (N Engl J Med. 2017 June 29. doi: 10.1056/NEJMoa1612999).

Although tDCS was superior to placebo in some secondary outcomes, including rate of clinical response (defined as a reduction of 50% or more in the Hamilton or the Montgomery-Åsberg Depression Rating Scale), it was associated with significantly more adverse events. The tDCS group reported more tinnitus, more nervousness, and more itching, tingling, burning, and skin redness at the electrode sites than did the other study groups. The escitalopram group reported higher rates of sleepiness and obstipation than did the other study groups.

One concerning finding was that two patients in the tDCS group developed new-onset mania during treatment, Dr. Brunoni and his associates noted.

“Future studies of tDCS could investigate different total doses of electrical stimulation in patients with major depressive disorder,” they wrote.

This trial was supported by the Fundacão de Amparo à Pesquisa do Estado de São Paulo, the Brain and Behavior Research Foundation, the Sao Paulo State Foundation, the National Council for Scientific and Technological Development, the Associacao Beneficente Alzira Denise Hertzog de Silva, and the Brazilian Coordination for the Improvement of Higher Education Personnel. Soterix Medical supplied the tDCS devices, and Libbs Laboratory supplied the escitalopram used in this study free of charge. Dr. Brunoni reported ties to Soterix Medical, Libbs Laboratory, and Delta Medical. His associates reported ties to numerous industry sources.

Transcranial direct-current stimulation did not show noninferiority to escitalopram for major depressive disorder in a single-center trial. The results were published online June 29.

The randomized double-blind placebo-controlled noninferiority study involved 245 adults with moderate to severe depression, many of whom had coexisting anxiety disorder. This “reflects a typical clinical population in which treatment for depression is indicated,” said André R. Brunoni, MD, PhD, of the Service of Interdisciplinary Neuromodulation, Institute of Psychiatry and Laboratory of Neurosciences, University of São Paulo, Brazil, and his associates.

A total of 94 patients were assigned to receive active tDCS plus oral placebo (tDCS group), 91 to receive sham tDCS plus escitalopram (escitalopram group), and 60 to receive sham tDCS plus oral placebo (placebo group) for 10 weeks. The primary outcome – decrease in mean depression score on the 17-item Hamilton Depression Rating Scale – was 9.0 points with tDCS, 11.3 points with escitalopram, and 5.8 points with placebo. Thus, tDCS did not achieve noninferiority to escitalopram, the investigators said (N Engl J Med. 2017 June 29. doi: 10.1056/NEJMoa1612999).

Although tDCS was superior to placebo in some secondary outcomes, including rate of clinical response (defined as a reduction of 50% or more in the Hamilton or the Montgomery-Åsberg Depression Rating Scale), it was associated with significantly more adverse events. The tDCS group reported more tinnitus, more nervousness, and more itching, tingling, burning, and skin redness at the electrode sites than did the other study groups. The escitalopram group reported higher rates of sleepiness and obstipation than did the other study groups.

One concerning finding was that two patients in the tDCS group developed new-onset mania during treatment, Dr. Brunoni and his associates noted.

“Future studies of tDCS could investigate different total doses of electrical stimulation in patients with major depressive disorder,” they wrote.

This trial was supported by the Fundacão de Amparo à Pesquisa do Estado de São Paulo, the Brain and Behavior Research Foundation, the Sao Paulo State Foundation, the National Council for Scientific and Technological Development, the Associacao Beneficente Alzira Denise Hertzog de Silva, and the Brazilian Coordination for the Improvement of Higher Education Personnel. Soterix Medical supplied the tDCS devices, and Libbs Laboratory supplied the escitalopram used in this study free of charge. Dr. Brunoni reported ties to Soterix Medical, Libbs Laboratory, and Delta Medical. His associates reported ties to numerous industry sources.

Transcranial direct-current stimulation did not show noninferiority to escitalopram for major depressive disorder in a single-center trial. The results were published online June 29.

The randomized double-blind placebo-controlled noninferiority study involved 245 adults with moderate to severe depression, many of whom had coexisting anxiety disorder. This “reflects a typical clinical population in which treatment for depression is indicated,” said André R. Brunoni, MD, PhD, of the Service of Interdisciplinary Neuromodulation, Institute of Psychiatry and Laboratory of Neurosciences, University of São Paulo, Brazil, and his associates.

A total of 94 patients were assigned to receive active tDCS plus oral placebo (tDCS group), 91 to receive sham tDCS plus escitalopram (escitalopram group), and 60 to receive sham tDCS plus oral placebo (placebo group) for 10 weeks. The primary outcome – decrease in mean depression score on the 17-item Hamilton Depression Rating Scale – was 9.0 points with tDCS, 11.3 points with escitalopram, and 5.8 points with placebo. Thus, tDCS did not achieve noninferiority to escitalopram, the investigators said (N Engl J Med. 2017 June 29. doi: 10.1056/NEJMoa1612999).

Although tDCS was superior to placebo in some secondary outcomes, including rate of clinical response (defined as a reduction of 50% or more in the Hamilton or the Montgomery-Åsberg Depression Rating Scale), it was associated with significantly more adverse events. The tDCS group reported more tinnitus, more nervousness, and more itching, tingling, burning, and skin redness at the electrode sites than did the other study groups. The escitalopram group reported higher rates of sleepiness and obstipation than did the other study groups.

One concerning finding was that two patients in the tDCS group developed new-onset mania during treatment, Dr. Brunoni and his associates noted.

“Future studies of tDCS could investigate different total doses of electrical stimulation in patients with major depressive disorder,” they wrote.

This trial was supported by the Fundacão de Amparo à Pesquisa do Estado de São Paulo, the Brain and Behavior Research Foundation, the Sao Paulo State Foundation, the National Council for Scientific and Technological Development, the Associacao Beneficente Alzira Denise Hertzog de Silva, and the Brazilian Coordination for the Improvement of Higher Education Personnel. Soterix Medical supplied the tDCS devices, and Libbs Laboratory supplied the escitalopram used in this study free of charge. Dr. Brunoni reported ties to Soterix Medical, Libbs Laboratory, and Delta Medical. His associates reported ties to numerous industry sources.

For patients who have a single, small skin abscess, the addition of oral antibiotics to standard incision and drainage of the lesion improves cure rates and decreases recurrence rates, according to a study published online June 28 in the New England Journal of Medicine.

The results of this multicenter prospective randomized double-blind placebo-controlled trial, taken together with those of another recent large study, “call into question the perception – largely based on expert opinion or smaller, underpowered, and lower-quality noninferiority trials – that cure rates do not improve with the addition of systemic antibiotic treatment after incision and drainage,” said Robert S. Daum, MD, professor of pediatrics at the University of Chicago, and his associates.

The trial involved 786 patients of all ages (64% were adults and 36% were children; mean age was 25.5 years) who had a single, uncomplicated skin abscess of 5 cm or smaller and were treated at the University of Chicago; San Francisco General Hospital; Harbor-UCLA Medical Center; Vanderbilt University Medical Center, Nashville; Washington University, St. Louis; or Emory University, Atlanta. A total of 266 patients were assigned to receive oral clindamycin, 263 to receive oral trimethoprim–sulfamethoxazole (TMP-SMX), and 257 to receive matching placebo for 10 days after the lesions were incised and drained.

At follow-up 7-10 days following the conclusion of treatment, the rates of clinical cure were 83.1% with clindamycin and 81.7% with TMP-SMX, both significantly greater than the 68.9% cure rate with placebo (P less than .001 for both comparisons). Similarly, at 1-month follow-up, 78.6% of the clindamycin group and 73.0% of the TMP-SMX group “remained cured,” compared with 62.6% of the placebo group (N Engl J Med. 2017 June 28. doi: 10.1056/NEJMoa1607033).

Among those with cultures positive for Staphylococcus aureus, cure rates 7-10 days after treatment ended were 83.5% and 83.2% in the clindamycin and TMP-SMX groups, respectively, significantly higher than in the placebo group (63.8%). Among those positive for methicillin-resistant S. aureus, cure rates were 81.7% and 84.6% in the clindamycin and TMP-SMX groups, respectively, significantly higher than in the placebo group (62.9%).

The rate of treatment-associated adverse events was higher with clindamycin (21.9%) than with TMP-SMX (11.1%) or with placebo (12.5%). The most common adverse events were diarrhea and nausea, which were mild to moderate in severity and resolved with sequelae. There were no cases of Clostridium difficile–associated diarrhea or severe allergic reactions. One patient had a hypersensitivity reaction that was considered to be related to TMP-SMX, which involved fever, rash, thrombocytopenia, and hepatitis and which resolved without sequelae.

The National Institute of Allergy and Infectious Diseases and the National Center for Research Resources supported the study. Dr. Daum reported ties to Pfizer, Dynavax, Theravance, and Merck, and his associates reported ties to numerous industry sources.

For patients who have a single, small skin abscess, the addition of oral antibiotics to standard incision and drainage of the lesion improves cure rates and decreases recurrence rates, according to a study published online June 28 in the New England Journal of Medicine.

The results of this multicenter prospective randomized double-blind placebo-controlled trial, taken together with those of another recent large study, “call into question the perception – largely based on expert opinion or smaller, underpowered, and lower-quality noninferiority trials – that cure rates do not improve with the addition of systemic antibiotic treatment after incision and drainage,” said Robert S. Daum, MD, professor of pediatrics at the University of Chicago, and his associates.

The trial involved 786 patients of all ages (64% were adults and 36% were children; mean age was 25.5 years) who had a single, uncomplicated skin abscess of 5 cm or smaller and were treated at the University of Chicago; San Francisco General Hospital; Harbor-UCLA Medical Center; Vanderbilt University Medical Center, Nashville; Washington University, St. Louis; or Emory University, Atlanta. A total of 266 patients were assigned to receive oral clindamycin, 263 to receive oral trimethoprim–sulfamethoxazole (TMP-SMX), and 257 to receive matching placebo for 10 days after the lesions were incised and drained.

At follow-up 7-10 days following the conclusion of treatment, the rates of clinical cure were 83.1% with clindamycin and 81.7% with TMP-SMX, both significantly greater than the 68.9% cure rate with placebo (P less than .001 for both comparisons). Similarly, at 1-month follow-up, 78.6% of the clindamycin group and 73.0% of the TMP-SMX group “remained cured,” compared with 62.6% of the placebo group (N Engl J Med. 2017 June 28. doi: 10.1056/NEJMoa1607033).

Among those with cultures positive for Staphylococcus aureus, cure rates 7-10 days after treatment ended were 83.5% and 83.2% in the clindamycin and TMP-SMX groups, respectively, significantly higher than in the placebo group (63.8%). Among those positive for methicillin-resistant S. aureus, cure rates were 81.7% and 84.6% in the clindamycin and TMP-SMX groups, respectively, significantly higher than in the placebo group (62.9%).

The rate of treatment-associated adverse events was higher with clindamycin (21.9%) than with TMP-SMX (11.1%) or with placebo (12.5%). The most common adverse events were diarrhea and nausea, which were mild to moderate in severity and resolved with sequelae. There were no cases of Clostridium difficile–associated diarrhea or severe allergic reactions. One patient had a hypersensitivity reaction that was considered to be related to TMP-SMX, which involved fever, rash, thrombocytopenia, and hepatitis and which resolved without sequelae.

The National Institute of Allergy and Infectious Diseases and the National Center for Research Resources supported the study. Dr. Daum reported ties to Pfizer, Dynavax, Theravance, and Merck, and his associates reported ties to numerous industry sources.

For patients who have a single, small skin abscess, the addition of oral antibiotics to standard incision and drainage of the lesion improves cure rates and decreases recurrence rates, according to a study published online June 28 in the New England Journal of Medicine.

The results of this multicenter prospective randomized double-blind placebo-controlled trial, taken together with those of another recent large study, “call into question the perception – largely based on expert opinion or smaller, underpowered, and lower-quality noninferiority trials – that cure rates do not improve with the addition of systemic antibiotic treatment after incision and drainage,” said Robert S. Daum, MD, professor of pediatrics at the University of Chicago, and his associates.

The trial involved 786 patients of all ages (64% were adults and 36% were children; mean age was 25.5 years) who had a single, uncomplicated skin abscess of 5 cm or smaller and were treated at the University of Chicago; San Francisco General Hospital; Harbor-UCLA Medical Center; Vanderbilt University Medical Center, Nashville; Washington University, St. Louis; or Emory University, Atlanta. A total of 266 patients were assigned to receive oral clindamycin, 263 to receive oral trimethoprim–sulfamethoxazole (TMP-SMX), and 257 to receive matching placebo for 10 days after the lesions were incised and drained.

At follow-up 7-10 days following the conclusion of treatment, the rates of clinical cure were 83.1% with clindamycin and 81.7% with TMP-SMX, both significantly greater than the 68.9% cure rate with placebo (P less than .001 for both comparisons). Similarly, at 1-month follow-up, 78.6% of the clindamycin group and 73.0% of the TMP-SMX group “remained cured,” compared with 62.6% of the placebo group (N Engl J Med. 2017 June 28. doi: 10.1056/NEJMoa1607033).

Among those with cultures positive for Staphylococcus aureus, cure rates 7-10 days after treatment ended were 83.5% and 83.2% in the clindamycin and TMP-SMX groups, respectively, significantly higher than in the placebo group (63.8%). Among those positive for methicillin-resistant S. aureus, cure rates were 81.7% and 84.6% in the clindamycin and TMP-SMX groups, respectively, significantly higher than in the placebo group (62.9%).

The rate of treatment-associated adverse events was higher with clindamycin (21.9%) than with TMP-SMX (11.1%) or with placebo (12.5%). The most common adverse events were diarrhea and nausea, which were mild to moderate in severity and resolved with sequelae. There were no cases of Clostridium difficile–associated diarrhea or severe allergic reactions. One patient had a hypersensitivity reaction that was considered to be related to TMP-SMX, which involved fever, rash, thrombocytopenia, and hepatitis and which resolved without sequelae.

The National Institute of Allergy and Infectious Diseases and the National Center for Research Resources supported the study. Dr. Daum reported ties to Pfizer, Dynavax, Theravance, and Merck, and his associates reported ties to numerous industry sources.