The U.S. Food and Drug Administration has granted breakthrough therapy status to Abeona Therapeutics’s EB-101 gene therapy program for patients with recessive dystrophic epidermolysis bullosa, according to a company statement.

The breakthrough therapy designation will expedite the phase 3 trial, intended to start in 2018, and the approval process and make this therapy available to patients who have few or no other treatment options for this serious and painful condition.

The U.S. Food and Drug Administration has granted breakthrough therapy status to Abeona Therapeutics’s EB-101 gene therapy program for patients with recessive dystrophic epidermolysis bullosa, according to a company statement.

The breakthrough therapy designation will expedite the phase 3 trial, intended to start in 2018, and the approval process and make this therapy available to patients who have few or no other treatment options for this serious and painful condition.

The U.S. Food and Drug Administration has granted breakthrough therapy status to Abeona Therapeutics’s EB-101 gene therapy program for patients with recessive dystrophic epidermolysis bullosa, according to a company statement.

The breakthrough therapy designation will expedite the phase 3 trial, intended to start in 2018, and the approval process and make this therapy available to patients who have few or no other treatment options for this serious and painful condition.

Why do some tumors not respond to immunotherapy? Why do some respond at first and then develop resistance? A National Institutes of Health (NIH) study holds some clues to the answer. Using patient samples from The Cancer Genome Atlas, the researchers found > 100 genes that may help T cells destroy tumors.

Related: Which Acute Myeloid Leukemia Patients Are Good Immunotherapy Candidates?

The researchers used CRISPR, a gene-editing technology that stops the expression of individual genes in cancer cells. By first “knocking out” every known protein-encoding gene in the human genome and then testing the ability of modified melanoma cells to respond to T cells, they identified “candidate” genes.

A number of the genes identified by the CRISPR screen were associated with cytolytic activity. One, APLNR, which produces a protein called the apelin receptor, had been “suspected to contribute” to cancer development—now, the NIH researchers say, they have the first indication of a role in response to T cells. In some patients who were resistant to immunotherapies, the apelin receptor protein was nonfunctional, indicating that the loss of that protein could limit the response to immunotherapy.

Related: First Cancer Treatment Based on Biomarkers Is Approved

“Many more genes than we originally expected play a vital role in dictating the success of cancer immunotherapies,” said Shashank Patel, PhD, first author of the study. Their “gene list” could serve as a blueprint to study the emergence of tumor resistance, the researchers say, and lead to more effective treatments.

Source:

NCI study identifies essential genes for cancer immunotherapy [news release] Bethesda, Maryland:  National Institutes of Health; August 7, 2017. https://www.nih.gov/news-events/news-releases/nci-study-identifies-essential-genes-cancer-immunotherapy. Accessed August 29, 2017.

Why do some tumors not respond to immunotherapy? Why do some respond at first and then develop resistance? A National Institutes of Health (NIH) study holds some clues to the answer. Using patient samples from The Cancer Genome Atlas, the researchers found > 100 genes that may help T cells destroy tumors.

Related: Which Acute Myeloid Leukemia Patients Are Good Immunotherapy Candidates?

The researchers used CRISPR, a gene-editing technology that stops the expression of individual genes in cancer cells. By first “knocking out” every known protein-encoding gene in the human genome and then testing the ability of modified melanoma cells to respond to T cells, they identified “candidate” genes.

A number of the genes identified by the CRISPR screen were associated with cytolytic activity. One, APLNR, which produces a protein called the apelin receptor, had been “suspected to contribute” to cancer development—now, the NIH researchers say, they have the first indication of a role in response to T cells. In some patients who were resistant to immunotherapies, the apelin receptor protein was nonfunctional, indicating that the loss of that protein could limit the response to immunotherapy.

Related: First Cancer Treatment Based on Biomarkers Is Approved

“Many more genes than we originally expected play a vital role in dictating the success of cancer immunotherapies,” said Shashank Patel, PhD, first author of the study. Their “gene list” could serve as a blueprint to study the emergence of tumor resistance, the researchers say, and lead to more effective treatments.

Source:

NCI study identifies essential genes for cancer immunotherapy [news release] Bethesda, Maryland:  National Institutes of Health; August 7, 2017. https://www.nih.gov/news-events/news-releases/nci-study-identifies-essential-genes-cancer-immunotherapy. Accessed August 29, 2017.

Why do some tumors not respond to immunotherapy? Why do some respond at first and then develop resistance? A National Institutes of Health (NIH) study holds some clues to the answer. Using patient samples from The Cancer Genome Atlas, the researchers found > 100 genes that may help T cells destroy tumors.

Related: Which Acute Myeloid Leukemia Patients Are Good Immunotherapy Candidates?

The researchers used CRISPR, a gene-editing technology that stops the expression of individual genes in cancer cells. By first “knocking out” every known protein-encoding gene in the human genome and then testing the ability of modified melanoma cells to respond to T cells, they identified “candidate” genes.

A number of the genes identified by the CRISPR screen were associated with cytolytic activity. One, APLNR, which produces a protein called the apelin receptor, had been “suspected to contribute” to cancer development—now, the NIH researchers say, they have the first indication of a role in response to T cells. In some patients who were resistant to immunotherapies, the apelin receptor protein was nonfunctional, indicating that the loss of that protein could limit the response to immunotherapy.

Related: First Cancer Treatment Based on Biomarkers Is Approved

“Many more genes than we originally expected play a vital role in dictating the success of cancer immunotherapies,” said Shashank Patel, PhD, first author of the study. Their “gene list” could serve as a blueprint to study the emergence of tumor resistance, the researchers say, and lead to more effective treatments.

Source:

NCI study identifies essential genes for cancer immunotherapy [news release] Bethesda, Maryland:  National Institutes of Health; August 7, 2017. https://www.nih.gov/news-events/news-releases/nci-study-identifies-essential-genes-cancer-immunotherapy. Accessed August 29, 2017.

What is “trauma-informed care?” Substance Abuse and Mental Health Services Administration (SAMHSA), HHS, the Administration for Children and Families, and the Administration for Community Living, have put together a guide to explain what it is and why understanding and addressing trauma is important for human services programs. The guide is based on SAMHSA’s definition of a trauma-informed program, organization, or system: Realizing the widespread impact of trauma; recognizing signs and symptoms; responding by fulling integrating knowledge about trauma into policies, procedures, and practices; and seeking to “actively resist re-traumatization.”

The Guide to Trauma-Informed Human Services is a web-linked compilation of resources from a range of HHS agencies, federal partners and respected nongovernmental sources. The site will contain information and resources for leaders at the state, tribal, territorial, and local levels on recent advances in understanding of trauma, toxic stress, and resiliency. The topics include PTSD, how exposure to trauma affects brain development, and how adverse childhood experiences differ from trauma experienced at other times in life.

“We hope it will be both immediately helpful,” the authors say, “and a ‘living’ document to be updated over time as our knowledge and experience grow.”

What is “trauma-informed care?” Substance Abuse and Mental Health Services Administration (SAMHSA), HHS, the Administration for Children and Families, and the Administration for Community Living, have put together a guide to explain what it is and why understanding and addressing trauma is important for human services programs. The guide is based on SAMHSA’s definition of a trauma-informed program, organization, or system: Realizing the widespread impact of trauma; recognizing signs and symptoms; responding by fulling integrating knowledge about trauma into policies, procedures, and practices; and seeking to “actively resist re-traumatization.”

The Guide to Trauma-Informed Human Services is a web-linked compilation of resources from a range of HHS agencies, federal partners and respected nongovernmental sources. The site will contain information and resources for leaders at the state, tribal, territorial, and local levels on recent advances in understanding of trauma, toxic stress, and resiliency. The topics include PTSD, how exposure to trauma affects brain development, and how adverse childhood experiences differ from trauma experienced at other times in life.

“We hope it will be both immediately helpful,” the authors say, “and a ‘living’ document to be updated over time as our knowledge and experience grow.”

What is “trauma-informed care?” Substance Abuse and Mental Health Services Administration (SAMHSA), HHS, the Administration for Children and Families, and the Administration for Community Living, have put together a guide to explain what it is and why understanding and addressing trauma is important for human services programs. The guide is based on SAMHSA’s definition of a trauma-informed program, organization, or system: Realizing the widespread impact of trauma; recognizing signs and symptoms; responding by fulling integrating knowledge about trauma into policies, procedures, and practices; and seeking to “actively resist re-traumatization.”

The Guide to Trauma-Informed Human Services is a web-linked compilation of resources from a range of HHS agencies, federal partners and respected nongovernmental sources. The site will contain information and resources for leaders at the state, tribal, territorial, and local levels on recent advances in understanding of trauma, toxic stress, and resiliency. The topics include PTSD, how exposure to trauma affects brain development, and how adverse childhood experiences differ from trauma experienced at other times in life.

“We hope it will be both immediately helpful,” the authors say, “and a ‘living’ document to be updated over time as our knowledge and experience grow.”

Photo courtesy of Novartis

The US Food and Drug Administration (FDA) has approved the first chimeric antigen receptor (CAR) T-cell therapy, tisagenlecleucel (Kymriah^TM, formerly CTL019).

The therapy is approved for use in children and young adults up to 25 years of age who have B-cell precursor acute lymphoblastic leukemia (ALL) that is refractory or in second or later relapse.

Tisagenlecleucel consists of autologous T cells expressing a CD19-specific CAR.

The therapy was first developed by the University of Pennsylvania. In 2012, the university and Novartis entered into a global collaboration to further research, develop, and commercialize CAR T-cell therapies. Novartis holds the worldwide rights to tisagenlecleucel and other therapies developed through the collaboration.

The application for tisagenlecleucel was supported by results from 3 clinical trials:

• A pilot study presented at the 2015 ASH Annual Meeting
• The phase 2 ENSIGN trial, which was presented at the 2016 ASH Annual Meeting
• The phase 2 ELIANA study, which was recently presented at the 22nd Congress of the European Hematology Association (EHA).

Safety concerns

The prescribing information for tisagenlecleucel includes a boxed warning noting that the treatment poses a risk of cytokine release syndrome (CRS) and neurological toxicity, both of which can be life-threatening.

Because of the risk of CRS, the FDA has expanded the approved use of tocilizumab (Actemra) to include treatment of CAR T-cell-induced severe or life-threatening CRS in patients age 2 and older.

The risk of CRS and neurological toxicity also prompted the FDA to approve tisagenlecleucel with a risk evaluation and mitigation strategy (REMS), which includes elements to assure safe use.

The FDA is requiring that hospitals and their associated clinics that dispense tisagenlecleucel be specially certified. As part of that certification, staff involved in the prescribing, dispensing, or administration of tisagenlecleucel are required to be trained to recognize and manage CRS and neurological events.

Additionally, the certified healthcare settings are required to have protocols in place to ensure that tisagenlecleucel is only given to patients after verifying that tocilizumab is available for immediate administration.

The REMS program specifies that patients be informed of the signs and symptoms of CRS and neurological toxicities following infusion and of the importance of promptly returning to the treatment site if they develop fever or other adverse reactions after receiving tisagenlecleucel.

To further evaluate the long-term safety of tisagenlecleucel, Novartis is required to conduct a post-marketing observational study involving patients who received the treatment.

Access and cost

Tisagenlecleucel will be manufactured for each individual patient at Novartis’s facility in Morris Plains, New Jersey.

Novartis said it has designed a manufacturing and supply chain platform that allows for an individualized treatment approach on a global scale. This process includes cryopreservation of a patient’s harvested cells, providing the flexibility to initiate treatment with tisagenlecleucel based on the individual patient’s condition.

Tisagenlecleucel will reportedly cost $475,000 for a single course of treatment. However, Novartis said it will help patients navigate insurance coverage and provide financial assistance for those who are uninsured or underinsured.

In addition, patients will only be required to pay for tisagenlecleucel if they respond within a month of receiving the treatment. This is a result of a collaboration between Novartis and the US Centers for Medicare and Medicaid Services that is focused on delivering value-based care. The approach is intended to include indication-based pricing for medicines and supports payments for a medicine based on the clinical outcomes achieved.

Photo courtesy of Novartis

The US Food and Drug Administration (FDA) has approved the first chimeric antigen receptor (CAR) T-cell therapy, tisagenlecleucel (Kymriah^TM, formerly CTL019).

The therapy is approved for use in children and young adults up to 25 years of age who have B-cell precursor acute lymphoblastic leukemia (ALL) that is refractory or in second or later relapse.

Tisagenlecleucel consists of autologous T cells expressing a CD19-specific CAR.

The therapy was first developed by the University of Pennsylvania. In 2012, the university and Novartis entered into a global collaboration to further research, develop, and commercialize CAR T-cell therapies. Novartis holds the worldwide rights to tisagenlecleucel and other therapies developed through the collaboration.

The application for tisagenlecleucel was supported by results from 3 clinical trials:

• A pilot study presented at the 2015 ASH Annual Meeting
• The phase 2 ENSIGN trial, which was presented at the 2016 ASH Annual Meeting
• The phase 2 ELIANA study, which was recently presented at the 22nd Congress of the European Hematology Association (EHA).

Safety concerns

The prescribing information for tisagenlecleucel includes a boxed warning noting that the treatment poses a risk of cytokine release syndrome (CRS) and neurological toxicity, both of which can be life-threatening.

Because of the risk of CRS, the FDA has expanded the approved use of tocilizumab (Actemra) to include treatment of CAR T-cell-induced severe or life-threatening CRS in patients age 2 and older.

The risk of CRS and neurological toxicity also prompted the FDA to approve tisagenlecleucel with a risk evaluation and mitigation strategy (REMS), which includes elements to assure safe use.

The FDA is requiring that hospitals and their associated clinics that dispense tisagenlecleucel be specially certified. As part of that certification, staff involved in the prescribing, dispensing, or administration of tisagenlecleucel are required to be trained to recognize and manage CRS and neurological events.

Additionally, the certified healthcare settings are required to have protocols in place to ensure that tisagenlecleucel is only given to patients after verifying that tocilizumab is available for immediate administration.

The REMS program specifies that patients be informed of the signs and symptoms of CRS and neurological toxicities following infusion and of the importance of promptly returning to the treatment site if they develop fever or other adverse reactions after receiving tisagenlecleucel.

To further evaluate the long-term safety of tisagenlecleucel, Novartis is required to conduct a post-marketing observational study involving patients who received the treatment.

Access and cost

Tisagenlecleucel will be manufactured for each individual patient at Novartis’s facility in Morris Plains, New Jersey.

Novartis said it has designed a manufacturing and supply chain platform that allows for an individualized treatment approach on a global scale. This process includes cryopreservation of a patient’s harvested cells, providing the flexibility to initiate treatment with tisagenlecleucel based on the individual patient’s condition.

Tisagenlecleucel will reportedly cost $475,000 for a single course of treatment. However, Novartis said it will help patients navigate insurance coverage and provide financial assistance for those who are uninsured or underinsured.

In addition, patients will only be required to pay for tisagenlecleucel if they respond within a month of receiving the treatment. This is a result of a collaboration between Novartis and the US Centers for Medicare and Medicaid Services that is focused on delivering value-based care. The approach is intended to include indication-based pricing for medicines and supports payments for a medicine based on the clinical outcomes achieved.

Photo courtesy of Novartis

The US Food and Drug Administration (FDA) has approved the first chimeric antigen receptor (CAR) T-cell therapy, tisagenlecleucel (Kymriah^TM, formerly CTL019).

The therapy is approved for use in children and young adults up to 25 years of age who have B-cell precursor acute lymphoblastic leukemia (ALL) that is refractory or in second or later relapse.

Tisagenlecleucel consists of autologous T cells expressing a CD19-specific CAR.

The therapy was first developed by the University of Pennsylvania. In 2012, the university and Novartis entered into a global collaboration to further research, develop, and commercialize CAR T-cell therapies. Novartis holds the worldwide rights to tisagenlecleucel and other therapies developed through the collaboration.

The application for tisagenlecleucel was supported by results from 3 clinical trials:

• A pilot study presented at the 2015 ASH Annual Meeting
• The phase 2 ENSIGN trial, which was presented at the 2016 ASH Annual Meeting
• The phase 2 ELIANA study, which was recently presented at the 22nd Congress of the European Hematology Association (EHA).

Safety concerns

The prescribing information for tisagenlecleucel includes a boxed warning noting that the treatment poses a risk of cytokine release syndrome (CRS) and neurological toxicity, both of which can be life-threatening.

Because of the risk of CRS, the FDA has expanded the approved use of tocilizumab (Actemra) to include treatment of CAR T-cell-induced severe or life-threatening CRS in patients age 2 and older.

The risk of CRS and neurological toxicity also prompted the FDA to approve tisagenlecleucel with a risk evaluation and mitigation strategy (REMS), which includes elements to assure safe use.

The FDA is requiring that hospitals and their associated clinics that dispense tisagenlecleucel be specially certified. As part of that certification, staff involved in the prescribing, dispensing, or administration of tisagenlecleucel are required to be trained to recognize and manage CRS and neurological events.

Additionally, the certified healthcare settings are required to have protocols in place to ensure that tisagenlecleucel is only given to patients after verifying that tocilizumab is available for immediate administration.

The REMS program specifies that patients be informed of the signs and symptoms of CRS and neurological toxicities following infusion and of the importance of promptly returning to the treatment site if they develop fever or other adverse reactions after receiving tisagenlecleucel.

To further evaluate the long-term safety of tisagenlecleucel, Novartis is required to conduct a post-marketing observational study involving patients who received the treatment.

Access and cost

Tisagenlecleucel will be manufactured for each individual patient at Novartis’s facility in Morris Plains, New Jersey.

Novartis said it has designed a manufacturing and supply chain platform that allows for an individualized treatment approach on a global scale. This process includes cryopreservation of a patient’s harvested cells, providing the flexibility to initiate treatment with tisagenlecleucel based on the individual patient’s condition.

Tisagenlecleucel will reportedly cost $475,000 for a single course of treatment. However, Novartis said it will help patients navigate insurance coverage and provide financial assistance for those who are uninsured or underinsured.

In addition, patients will only be required to pay for tisagenlecleucel if they respond within a month of receiving the treatment. This is a result of a collaboration between Novartis and the US Centers for Medicare and Medicaid Services that is focused on delivering value-based care. The approach is intended to include indication-based pricing for medicines and supports payments for a medicine based on the clinical outcomes achieved.

The patient was given a diagnosis of tinea capitis (ringworm of the scalp) based on the clinical presentation. (His brother and sister were told that they had tinea corporis and tinea faciei, which our patient also had on his face.)

Tinea capitis is a fungal infection of the scalp that usually starts as flaky and crusty patches of skin, broken-off hair, erythema, scaling, and pustules on the scalp. This can quickly deteriorate into a boggy and pruritic mass of inflamed tissue known as a kerion, which can become severely inflamed and develop regional lymphadenopathy. Hypersensitive and highly inflammatory reactions that look similar to a bacterial infection may be found when the infection is caused by a zoophilic dermatophyte.

Tinea capitis primarily affects children younger than 10 years of age, with a peak incidence among African American boys. Because US public health agencies no longer require physicians to report cases of tinea capitis, its true incidence in the United States is unknown, but it is believed to be increasing.

Tinea capitis is treated with systemic antifungal medication. Oral antifungal agents, such as griseofulvin, itraconazole, terbinafine, and fluconazole, are effective. Oral fluconazole is typically administered at a dosage of 5 to 6 mg/kg/d for 3 to 6 weeks; an alternative regimen, 8 mg/kg once weekly for 8 to 12 weeks, is safe, effective, and associated with high compliance. Short-duration therapy with fluconazole 6 mg/kg/d for 2 weeks is also effective.

This patient was treated with oral fluconazole 50 mg/d for 2 weeks and showed rapid improvement. Fluconazole was continued at 150 mg weekly for another 2 weeks, and at 6 weeks, his scalp lesions had completely resolved. The patient’s siblings were initially treated with topical itraconazole, without effect. They were switched to oral fluconazole 50 mg/d and improved.

Adapted from: Kim K. Inflammatory masses on boy’s scalp. J Fam Pract. 2015;64:367-369

The patient was given a diagnosis of tinea capitis (ringworm of the scalp) based on the clinical presentation. (His brother and sister were told that they had tinea corporis and tinea faciei, which our patient also had on his face.)

Tinea capitis is a fungal infection of the scalp that usually starts as flaky and crusty patches of skin, broken-off hair, erythema, scaling, and pustules on the scalp. This can quickly deteriorate into a boggy and pruritic mass of inflamed tissue known as a kerion, which can become severely inflamed and develop regional lymphadenopathy. Hypersensitive and highly inflammatory reactions that look similar to a bacterial infection may be found when the infection is caused by a zoophilic dermatophyte.

Tinea capitis primarily affects children younger than 10 years of age, with a peak incidence among African American boys. Because US public health agencies no longer require physicians to report cases of tinea capitis, its true incidence in the United States is unknown, but it is believed to be increasing.

Tinea capitis is treated with systemic antifungal medication. Oral antifungal agents, such as griseofulvin, itraconazole, terbinafine, and fluconazole, are effective. Oral fluconazole is typically administered at a dosage of 5 to 6 mg/kg/d for 3 to 6 weeks; an alternative regimen, 8 mg/kg once weekly for 8 to 12 weeks, is safe, effective, and associated with high compliance. Short-duration therapy with fluconazole 6 mg/kg/d for 2 weeks is also effective.

This patient was treated with oral fluconazole 50 mg/d for 2 weeks and showed rapid improvement. Fluconazole was continued at 150 mg weekly for another 2 weeks, and at 6 weeks, his scalp lesions had completely resolved. The patient’s siblings were initially treated with topical itraconazole, without effect. They were switched to oral fluconazole 50 mg/d and improved.

Adapted from: Kim K. Inflammatory masses on boy’s scalp. J Fam Pract. 2015;64:367-369

The patient was given a diagnosis of tinea capitis (ringworm of the scalp) based on the clinical presentation. (His brother and sister were told that they had tinea corporis and tinea faciei, which our patient also had on his face.)

Tinea capitis is a fungal infection of the scalp that usually starts as flaky and crusty patches of skin, broken-off hair, erythema, scaling, and pustules on the scalp. This can quickly deteriorate into a boggy and pruritic mass of inflamed tissue known as a kerion, which can become severely inflamed and develop regional lymphadenopathy. Hypersensitive and highly inflammatory reactions that look similar to a bacterial infection may be found when the infection is caused by a zoophilic dermatophyte.

Tinea capitis primarily affects children younger than 10 years of age, with a peak incidence among African American boys. Because US public health agencies no longer require physicians to report cases of tinea capitis, its true incidence in the United States is unknown, but it is believed to be increasing.

Tinea capitis is treated with systemic antifungal medication. Oral antifungal agents, such as griseofulvin, itraconazole, terbinafine, and fluconazole, are effective. Oral fluconazole is typically administered at a dosage of 5 to 6 mg/kg/d for 3 to 6 weeks; an alternative regimen, 8 mg/kg once weekly for 8 to 12 weeks, is safe, effective, and associated with high compliance. Short-duration therapy with fluconazole 6 mg/kg/d for 2 weeks is also effective.

This patient was treated with oral fluconazole 50 mg/d for 2 weeks and showed rapid improvement. Fluconazole was continued at 150 mg weekly for another 2 weeks, and at 6 weeks, his scalp lesions had completely resolved. The patient’s siblings were initially treated with topical itraconazole, without effect. They were switched to oral fluconazole 50 mg/d and improved.

Adapted from: Kim K. Inflammatory masses on boy’s scalp. J Fam Pract. 2015;64:367-369

Photo courtesy of Roche

The US Food and Drug Administration (FDA) has approved tocilizumab (Actemra®) for the treatment of patients age 2 and older who have severe or life-threatening cytokine release syndrome (CRS) induced by chimeric antigen receptor (CAR) T-cell therapy.

Tocilizumab is a humanized interleukin-6 receptor antagonist.

The drug is also FDA-approved to treat adults with rheumatoid arthritis or giant cell arteritis and patients age 2 and older with polyarticular juvenile idiopathic arthritis or systemic juvenile idiopathic arthritis.

The full prescribing information for tocilizumab, which includes a boxed warning about the risk of serious infections, is available at http://www.actemra.com. The drug is jointly developed by Genentech (a member of the Roche Group) and Chugai Pharmaceutical Co.

The FDA’s latest approval of tocilizumab coincided with the FDA’s approval of the CAR T-cell therapy tisagenlecleucel (Kymriah, formerly CTL019) to treat pediatric and young adult patients with relapsed or refractory B-cell precursor acute lymphoblastic leukemia.

According to Genentech, the FDA’s decision to expand the approval of tocilizumab is based on a retrospective analysis of pooled outcome data from clinical trials of CAR T-cell therapies in patients with hematologic malignancies.

For this analysis, researchers assessed 45 pediatric and adult patients treated with tocilizumab, with or without additional high-dose corticosteroids, for severe or life-threatening CRS.

Thirty-one patients (69%) achieved a response, defined as resolution of CRS within 14 days of the first dose of tocilizumab.

No more than 2 doses of tocilizumab were needed, and no drugs other than tocilizumab and corticosteroids were used for treatment.

No adverse reactions related to tocilizumab were reported.

Photo courtesy of Roche

The US Food and Drug Administration (FDA) has approved tocilizumab (Actemra®) for the treatment of patients age 2 and older who have severe or life-threatening cytokine release syndrome (CRS) induced by chimeric antigen receptor (CAR) T-cell therapy.

Tocilizumab is a humanized interleukin-6 receptor antagonist.

The drug is also FDA-approved to treat adults with rheumatoid arthritis or giant cell arteritis and patients age 2 and older with polyarticular juvenile idiopathic arthritis or systemic juvenile idiopathic arthritis.

The full prescribing information for tocilizumab, which includes a boxed warning about the risk of serious infections, is available at http://www.actemra.com. The drug is jointly developed by Genentech (a member of the Roche Group) and Chugai Pharmaceutical Co.

The FDA’s latest approval of tocilizumab coincided with the FDA’s approval of the CAR T-cell therapy tisagenlecleucel (Kymriah, formerly CTL019) to treat pediatric and young adult patients with relapsed or refractory B-cell precursor acute lymphoblastic leukemia.

According to Genentech, the FDA’s decision to expand the approval of tocilizumab is based on a retrospective analysis of pooled outcome data from clinical trials of CAR T-cell therapies in patients with hematologic malignancies.

For this analysis, researchers assessed 45 pediatric and adult patients treated with tocilizumab, with or without additional high-dose corticosteroids, for severe or life-threatening CRS.

Thirty-one patients (69%) achieved a response, defined as resolution of CRS within 14 days of the first dose of tocilizumab.

No more than 2 doses of tocilizumab were needed, and no drugs other than tocilizumab and corticosteroids were used for treatment.

No adverse reactions related to tocilizumab were reported.

Photo courtesy of Roche

The US Food and Drug Administration (FDA) has approved tocilizumab (Actemra®) for the treatment of patients age 2 and older who have severe or life-threatening cytokine release syndrome (CRS) induced by chimeric antigen receptor (CAR) T-cell therapy.

Tocilizumab is a humanized interleukin-6 receptor antagonist.

The drug is also FDA-approved to treat adults with rheumatoid arthritis or giant cell arteritis and patients age 2 and older with polyarticular juvenile idiopathic arthritis or systemic juvenile idiopathic arthritis.

The full prescribing information for tocilizumab, which includes a boxed warning about the risk of serious infections, is available at http://www.actemra.com. The drug is jointly developed by Genentech (a member of the Roche Group) and Chugai Pharmaceutical Co.

The FDA’s latest approval of tocilizumab coincided with the FDA’s approval of the CAR T-cell therapy tisagenlecleucel (Kymriah, formerly CTL019) to treat pediatric and young adult patients with relapsed or refractory B-cell precursor acute lymphoblastic leukemia.

According to Genentech, the FDA’s decision to expand the approval of tocilizumab is based on a retrospective analysis of pooled outcome data from clinical trials of CAR T-cell therapies in patients with hematologic malignancies.

For this analysis, researchers assessed 45 pediatric and adult patients treated with tocilizumab, with or without additional high-dose corticosteroids, for severe or life-threatening CRS.

Thirty-one patients (69%) achieved a response, defined as resolution of CRS within 14 days of the first dose of tocilizumab.

No more than 2 doses of tocilizumab were needed, and no drugs other than tocilizumab and corticosteroids were used for treatment.

No adverse reactions related to tocilizumab were reported.

CASE 1 An 82-year-old black woman comes in for an annual exam. She has no medical concerns. She volunteers at a hospice, walks daily, and maintains a healthy diet. Her past medical history (PMH) includes osteopenia and osteoarthritis, and her medications include acetaminophen as needed and vitamin D. She has no drug allergies. Her exam reveals a blood pressure (BP) of 148/70 mm Hg, a body mass index of 31, and a heart rate (HR) of 71 beats per minute (bpm). Cardiac and pulmonary exams are normal, and she shows no signs of peripheral edema.

CASE 2 An 88-year-old white man presents to the office for a 3-month follow-up of his hypertension. His systolic BP at home has ranged from 140 to 170 mm Hg. He denies chest pain, shortness of breath, or lower extremity edema. He lives with his wife and frequently swims for exercise. His PMH is significant for depression and degenerative disc disease. His medications include hydrochlorothiazide 12.5 mg/d, sertraline 50 mg/d, and naproxen 250 mg bid. His BP is 160/80 mm Hg and his HR is 70 bpm with normal cardiovascular (CV) and pulmonary exams.

CASE 3 An 80-year-old white man with diabetes mellitus (DM), hypertension, and chronic kidney disease (CKD) presents for a 3-month follow-up visit. His home systolic BP has been in the 140s to 150s. He is functional in all of his activities of daily living (ADLs), but is starting to require assistance with medications, finances, and transportation. He takes aspirin 81 mg/d, chlorthalidone 25 mg/d, and atenolol 50 mg/d. Remarkable laboratory test results include a hemoglobin A1c of 8.6%, a serum creatinine of 1.9 mg/dL (normal range: 0.6-1.2 mg/dL), and an albumin-creatinine ratio of 250 mg/g (normal range: <30 mg/g). During the exam, his BP is 143/70 mm Hg, his HR is 70 bpm, he is alert and oriented to person, place, and time, and he has normal CV and pulmonary exams with no signs of peripheral edema. He has decreased sensation in his feet, but normal reflexes.

How would you proceed with the care of these 3 patients?

Hypertension is the most common diagnosis made during physician office visits in the United States.¹ Nearly one-third of the population has hypertension, and its prevalence increases with age, such that 67% of men and 79% of women ≥75 years of age have the condition.²

Evidence indicates that hypertension is a modifiable risk factor for CV and all-cause mortality (TABLE W1^3-6). All adults ≥75 years of age are at increased CV risk based on Framingham criteria,⁷ making hypertension management paramount. Complicating the situation are findings that indicate nearly half of adults with hypertension have inadequate BP control.²

A systolic BP target of <120 mm Hg is appropriate in community-dwelling, non-diabetic adults ≥75 years of age, but if this places an undue burden on the patient, a goal of <140 mm Hg also provides benefit.

Clinicians require clear direction about optimal BP targets, how best to adjust antihypertensive medications for comorbidities, and how to incorporate frailty and cognitive impairment into management strategies. This article presents recommendations derived from recent evidence and consensus guidelines regarding the management of hypertension in adults ≥75 years of age.

[polldaddy:9818133]

Diagnosing hypertension

According to the seventh report of the Joint National Committee (JNC 7), hypertension is defined as a systolic BP ≥140 mm Hg and/or a diastolic BP ≥90 mm Hg.⁸ The JNC’s more recent report (JNC 8), however, does not define hypertension; instead, it sets forth treatment thresholds (eg, that there is strong evidence to support treating individuals ≥60 years of age when BP ≥150/90 mm Hg).⁹

It starts with an accurate BP measurement. Ensuring the accuracy of a BP measurement requires multiple readings over time. White coat hypertension and masked hypertension can complicate BP measurement. Home measurements better correlate with atherosclerotic cardiovascular disease (ASCVD) risk than do office measurements.^10-12 In fact, the US Preventive Services Task Force recommends obtaining measurements outside of the clinic setting prior to initiating treatment for hypertension.¹³

Educate staff on the proper technique for obtaining BP measurements in the office (ie, taking measurements using an appropriately sized cuff when patients have been seated for at least 5 minutes with feet uncrossed and with their arm supported at heart level). Cold temperatures, coffee consumption, talking, and recent tobacco use can transiently raise BP. TABLE 1¹⁰ outlines the initial work-up after confirming the diagnosis of hypertension. No other routine tests are recommended for the management of hypertension except those associated with medication monitoring (outlined in TABLE 2^10,11,14,15).

What’s the optimal BP target for older patients? No consensus exists on an optimal BP target for older patients. JNC 8 recommends a target BP <150/90 mm Hg in patients ≥60 years of age.⁹ The American College of Physicians recommends a systolic BP target <140 mm Hg in patients ≥60 years of age with increased stroke or CV risk.¹¹ A subgroup analysis of patients ≥75 years of age from the Systolic BP Intervention Trial (SPRINT)³ was stopped early because of the clear composite CV and mortality benefits associated with targeting a systolic BP <120 mm Hg as compared with <140 mm Hg (TABLE W1^3-6). Although a criticism of this trial and its results is that the researchers included only adults with high CV risk, all adults ≥75 years of age are considered to have high CV risk by the SPRINT study.³ Another criticism is that early suspension of the trial may have exaggerated treatment effects.⁶

Lastly, results were seemingly discrepant from previous trials, most notably, the Action to Control CV Risk in Diabetes (ACCORD) trial.^6,16 However, on closer review, the ACCORD trial¹⁶ included only patients with DM, while the SPRINT³ trial excluded patients with DM, and ACCORD comprised a younger population than the SPRINT subgroup analysis. Also, the ACCORD trial did demonstrate stroke reduction and non-significant reduction in CV events, albeit, at the cost of increased adverse events, such as hypotension, bradycardia, and hypokalemia, with tighter BP control.¹⁶

Common pharmacotherapeutic contributors to uncontrolled BP include NSAIDs, glucocorticoids, high-dose decongestants, and selective norepinephrine reuptake inhibitors.

Population differences presumably explain the discrepancy in results, and a systolic BP target of <120 mm Hg is appropriate in community-dwelling, non-diabetic adults ≥75 years of age. If this target goal cannot be achieved without undue burden (ie, without syncope, hypotension, bradycardia, electrolyte disturbance, renal impairment, or substantial medication burden), a recent meta-analysis found evidence that a systolic BP goal <140 mm Hg also provides benefit.⁶

Initiate treatment, watch for age-related changes

Lifestyle modifications (including appropriate weight loss; reduced caffeine, salt, and alcohol intake; increased physical activity; and smoking cessation) are important in the initial and ongoing management of hypertension.^10,11,17,18 JNC 8 recommends initial treatment with a thiazide-type diuretic, calcium channel blocker (CCB), angiotensin converting enzyme (ACE) inhibitor, or angiotensin receptor blocker (ARB) in the nonblack population, and a CCB or thiazide diuretic in the black population.⁹ Specific initial medication choices for comorbid conditions are outlined in TABLE W2^3,10,17-22. JNC 8 recommends against the use of a beta-blocker or alpha blocker for initial treatment of hypertension.⁹

Start a second drug instead of maximizing the dose of the first

If the target BP cannot be achieved within one month of initiating medication, JNC 8 recommends increasing the dose of the initial drug or adding a second drug without preference for one strategy over the other.⁹ However, a meta-analysis demonstrates that approximately 80% of the antihypertensive effect of a drug can be achieved with half of the standard dose of the medication; this is true for thiazide-type diuretics, ACE inhibitors/ARBs, beta-blockers, and CCBs.²³

Approximately 80% of the antihypertensive effect of a drug can be achieved with half of the standard dose of many medications.

Furthermore, due to fewer adverse effects and positive synergies, studies show that combining low doses of 2 medications is more beneficial than high-dose monotherapy.^19,23,24 Prescribing combination pills can be helpful to limit pill burden. It is appropriate to combine any of the 4 classes of medications recommended as initial therapy by JNC 8 except for an ACE inhibitor combined with an ARB. If the target BP cannot be achieved with 3 drugs in those classes, other medications such as potassium-sparing diuretics or beta-blockers can be added.⁹

Changes associated with aging

Changes associated with aging include atherosclerosis and stiffening of blood vessels, increased systolic BP, widened pulse pressure, reduced glomerular filtration rate, reduced sodium elimination and volume expansion, sinoatrial node cellular dropout, and decreased sensitivity of baroreceptors.¹⁰ Because of these alterations, antihypertensive requirements may change, and resistant hypertension may develop. In addition, older patients may be more susceptible to orthostatic hypotension, heart block, electrolyte derangements, and other antihypertensive adverse effects.

When hypertension is difficult to control. Resistant hypertension is defined as hypertension that cannot be controlled with 3 drugs from 3 different antihypertensive classes, one of which is a diuretic. Cognitive impairment, polypharmacy, and multimorbidity may contribute to difficult-to-control hypertension in older adults and should be assessed prior to work-up for other secondary causes of poorly controlled hypertension.

• Cognitive impairment is often unrecognized and may impact medication adherence, which can masquerade as treatment failure. Assess for cognitive impairment on an ongoing basis with the aging patient, especially when medication adherence appears poor.
• Polypharmacy may also contribute to uncontrolled BP. Common pharmacotherapeutic contributors to uncontrolled BP include nonsteroidal anti-inflammatory drugs (NSAIDs), glucocorticoids, high-dose decongestants, and selective norepinephrine reuptake inhibitors.²⁵
• Multimorbidity describes 2 or more chronic medical conditions in one patient. These patients are medically complex. Comorbidities can increase pill burden and make medication adherence difficult for patients. Other poorly controlled disease states can worsen hypertension (eg, renal dysfunction secondary to diabetes). Optimize treatment of comorbid conditions.

Secondary causes. If resistant hypertension persists despite confirming medication adherence and eliminating offending medications, a work-up should ensue for secondary causes of hypertension, as well as end-organ damage. Causes of secondary hypertension include sleep apnea (see this month's HelpDesk), renal dysfunction (renal artery stenosis), aldosterone-mediated hypertension (often with hypokalemia), and thyroid disease. Evaluation for secondary causes of hypertension and end-organ damage is outlined in TABLE 1.¹⁰ Patients with well-controlled hypertension do not require repeated assessments for end-organ damage unless new symptoms—such as chest pain or edema—develop.

Consider comorbidities

Clinical trials implicitly or explicitly exclude patients with multiple comorbidities. JNC 8 provided minimal guidance for adjusting BP targets based on comorbidity with only nondiabetic CKD and DM specifically addressed.⁹ Guidelines from specialty organizations and recent trials provide some additional guidance in these situations and are outlined in TABLE W2^3,10,17-22.

Heart failure. Hypertension is a major risk factor for heart failure. Long-term treatment of systolic and diastolic hypertension can reduce the incidence of heart failure by approximately half with increased benefit in patients with prior myocardial infarction.²² Research demonstrates clear mortality benefits of certain antihypertensive drug classes, including diuretics, beta-blockers, ACE inhibitors, ARBs, aldosterone antagonists, combination hydralazine and nitrates, and angiotensin receptor-neprilysin inhibitors.^21,22 The overall treatment goal in heart failure is to optimize drugs with mortality benefit, while lowering BP to a goal <130/80 mm Hg in patients ≥75 years of age.²²

Increased risk for CV disease. The SPRINT trial³ defined high risk of CV disease as clinical or subclinical CV disease, CKD, 10-year ASCVD risk of ≥15%, or age ≥75 years. SPRINT supports a systolic BP goal <120 mm Hg, but, as a reminder, SPRINT excluded patients with diabetes. The American College of Cardiology Foundation Task Force and the American Heart Association define high CV risk as a 10-year ASCVD risk ≥10% and recommend a BP goal <130/80 mm Hg.¹⁰

Diabetes mellitus. A BP >115/75 mm Hg is associated with increased CV events and mortality in patients with DM.¹⁸ The American Diabetes Association (ADA) and JNC 8 recommend a BP target <140/90 mm Hg.^9,18 ADA suggests a lower target of 130/80 mm Hg in patients with high CV risk if it is achievable without undue burden.¹⁸

Studies show increased mortality associated with initiating additional treatment once a systolic goal <140 mm Hg has been achieved in patients with DM.²⁶ The ACCORD trial found increased adverse events with aggressive BP lowering to <120/80 mm Hg.¹⁶

For patients with DM requiring more than one antihypertensive agent, there are CV mortality benefits associated with administering at least one antihypertensive drug at night, likely related to the beneficial effect of physiologic nocturnal dipping.²⁷

Chronic kidney disease. JNC 8 specifically recommends an ACE inhibitor or ARB for initial or add-on treatment in patients with CKD and a BP goal <140/90 mm Hg.⁹ The Kidney Disease: Improving Global Outcomes (KDIGO) Blood Pressure Work Group recommends a BP target ≤140/90 mm Hg in patients without albuminuria and ≤130/80 mm Hg in patients with albuminuria to protect against the progression of nephropathy.¹⁷ The SPRINT trial³ included patients with CKD, and KDIGO has not yet updated its guidelines to reflect SPRINT.

Frailty is a clinical syndrome that has been defined as a state of increased vulnerability that is associated with a decline in reserve and function.²⁸ The largest hypertension studies in older adults address frailty, although often the most frail patients are excluded from these studies (TABLE W1^3-6).

The Hypertension in the Very Elderly Trial (HYVET) categorized patients as frail, pre-frail, or robust and found a consistent benefit of antihypertensive treatment on stroke, CV events, and total mortality—regardless of baseline frailty status.²⁹ The SPRINT trial included only community-dwelling adults.³ Other studies suggest that hypertension actually has a protective effect by lowering overall mortality in frail older adults, especially in the frailest and oldest nursing home populations.^30,31

Due to fewer adverse effects and positive synergies, studies show that low doses of 2 drugs is more beneficial than high-dose monotherapy.

Although there is a paucity of data to direct the management of hypertension in frail older patients, physicians should prioritize the condition and focus on adverse events from antihypertensives and on slow titration of medications. The JNC 8 BP target of <150/90 mm Hg is a reasonable BP goal in this population, given the lack of evidence for lower or higher targets.⁹ Many frail patients have one or more of the comorbidities described earlier, and it is reasonable to strive for the comorbidity-specific target, provided it can be achieved without undue burden.

Cognitive impairment and dementia. The association between hypertension and dementia/cognitive impairment is evolving. Hypertension may impact various forms of dementia, such as Alzheimer’s disease (AD) or vascular dementia, differently. There is evidence linking hypertension to AD.³² The relationship between BP and brain perfusion is complex with the potential existence of an age-adjusted relationship such that mid-life hypertension may increase the risk of dementia while late-life hypertension may not.³³

A number of studies reveal the evolving nature of our understanding of these 2 conditions:

• A recent systematic review and meta-analysis examining intensive BP treatments in older adults demonstrated that lower BP targets did not increase cognitive decline.⁶
• HYVET’s cognitive function assessment did not find a significant reduction in the incidence of dementia with BP reduction over a short follow-up period, but when results were combined in a meta-analysis with other placebo-controlled, double-blind trials of antihypertensive treatments, there was significant reduction in incident dementia in patients randomized to antihypertensive treatment.³⁴
• The ACCORD Memory in Diabetes trial (ACCORD-MIND) had the unexpected outcome that intensive lowering of systolic BP to a target <120 mm Hg resulted in a greater decline in total brain volume, compared with the standard BP goal <140 mm Hg. This was measured with magnetic resonance imaging in older adults with type 2 DM.³⁵
• Results from the SPRINT sub-analysis Memory and Cognition in Decreased Hypertension trial are forthcoming and aim to determine the effects of BP reduction on dementia.³⁶

The JNC 8⁹ BP target <150/90 mm Hg or a comorbidity-specific target, if achievable without undue burden, is reasonable in patients with dementia. In a systematic review of observational studies in patients with hypertension and dementia, diuretics, CCBs, ACE inhibitors/ARBs, and beta-blockers were commonly used medications with a trend toward prescribing CCBs and ACE inhibitors/ARBs.³⁷

A BP target <150/90 mm Hg or a comorbidity-specific target, if achievable without undue burden, is reasonable in patients with dementia.

As previously highlighted, cognitive impairment may lead to problems with medication adherence and even inadvertent improper medication use, potentially resulting in adverse events from antihypertensives. If cognitive impairment or dementia is suspected, ensure additional measures (such as medication assistance or supervision) are in place before prescribing antihypertensives.

Certain diseases, such as Parkinson’s-related dementia and multiple system atrophy, can cause autonomic instability, which can increase the risk of falls and complicate hypertension management. Carefully monitor patients for signs of orthostasis.

CASE 1 Repeat the BP measurement in the office once the patient has been seated for ≥5 minutes, and have the patient monitor her BP at home; schedule a follow-up visit in 2 weeks. If hypertension is confirmed with home measurements, then, in addition to lifestyle modifications, initiate treatment with a CCB or thiazide diuretic to achieve a systolic BP goal <120 mm Hg. Titrate medications slowly while monitoring for adverse effects.

CASE 2 Consistent with the office measurement, the patient has home BP readings that are above the BP target (<120 mm Hg systolic). He has been taking a single antihypertensive for longer than one month. Discontinue his NSAID prior to adding any new medications. If his BP is still above target without NSAIDs, then add a second agent, such as a low dose of an ACE inhibitor, ARB, or CCB, rather than maximizing the dose of hydrochlorothiazide.

CASE 3 Given the patient’s diabetes, CKD, and albuminuria, a target BP goal <130/80 mm Hg is reasonable. An ACE inhibitor or ARB is a better medication choice than atenolol in this patient with albuminuria. Because of the deterioration in his ADLs, careful assessment of mobility, functionality, comorbidities, frailty, and cognitive function should take place at each office visit and inform adjustments to the patient’s BP target. Employ cautious medication titration with monitoring for adverse effects, especially hypotension and syncope. If his functional status declines, adverse effects develop, or the medication regimen becomes burdensome, relax the target BP goal to 150/90 mm Hg.

CORRESPONDENCE
Julienne K. Kirk, PharmD, Family and Community Medicine, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157-1084; [email protected].

CASE 1 An 82-year-old black woman comes in for an annual exam. She has no medical concerns. She volunteers at a hospice, walks daily, and maintains a healthy diet. Her past medical history (PMH) includes osteopenia and osteoarthritis, and her medications include acetaminophen as needed and vitamin D. She has no drug allergies. Her exam reveals a blood pressure (BP) of 148/70 mm Hg, a body mass index of 31, and a heart rate (HR) of 71 beats per minute (bpm). Cardiac and pulmonary exams are normal, and she shows no signs of peripheral edema.

CASE 2 An 88-year-old white man presents to the office for a 3-month follow-up of his hypertension. His systolic BP at home has ranged from 140 to 170 mm Hg. He denies chest pain, shortness of breath, or lower extremity edema. He lives with his wife and frequently swims for exercise. His PMH is significant for depression and degenerative disc disease. His medications include hydrochlorothiazide 12.5 mg/d, sertraline 50 mg/d, and naproxen 250 mg bid. His BP is 160/80 mm Hg and his HR is 70 bpm with normal cardiovascular (CV) and pulmonary exams.

CASE 3 An 80-year-old white man with diabetes mellitus (DM), hypertension, and chronic kidney disease (CKD) presents for a 3-month follow-up visit. His home systolic BP has been in the 140s to 150s. He is functional in all of his activities of daily living (ADLs), but is starting to require assistance with medications, finances, and transportation. He takes aspirin 81 mg/d, chlorthalidone 25 mg/d, and atenolol 50 mg/d. Remarkable laboratory test results include a hemoglobin A1c of 8.6%, a serum creatinine of 1.9 mg/dL (normal range: 0.6-1.2 mg/dL), and an albumin-creatinine ratio of 250 mg/g (normal range: <30 mg/g). During the exam, his BP is 143/70 mm Hg, his HR is 70 bpm, he is alert and oriented to person, place, and time, and he has normal CV and pulmonary exams with no signs of peripheral edema. He has decreased sensation in his feet, but normal reflexes.

How would you proceed with the care of these 3 patients?

Hypertension is the most common diagnosis made during physician office visits in the United States.¹ Nearly one-third of the population has hypertension, and its prevalence increases with age, such that 67% of men and 79% of women ≥75 years of age have the condition.²

Evidence indicates that hypertension is a modifiable risk factor for CV and all-cause mortality (TABLE W1^3-6). All adults ≥75 years of age are at increased CV risk based on Framingham criteria,⁷ making hypertension management paramount. Complicating the situation are findings that indicate nearly half of adults with hypertension have inadequate BP control.²

A systolic BP target of <120 mm Hg is appropriate in community-dwelling, non-diabetic adults ≥75 years of age, but if this places an undue burden on the patient, a goal of <140 mm Hg also provides benefit.

Clinicians require clear direction about optimal BP targets, how best to adjust antihypertensive medications for comorbidities, and how to incorporate frailty and cognitive impairment into management strategies. This article presents recommendations derived from recent evidence and consensus guidelines regarding the management of hypertension in adults ≥75 years of age.

[polldaddy:9818133]

Diagnosing hypertension

According to the seventh report of the Joint National Committee (JNC 7), hypertension is defined as a systolic BP ≥140 mm Hg and/or a diastolic BP ≥90 mm Hg.⁸ The JNC’s more recent report (JNC 8), however, does not define hypertension; instead, it sets forth treatment thresholds (eg, that there is strong evidence to support treating individuals ≥60 years of age when BP ≥150/90 mm Hg).⁹

It starts with an accurate BP measurement. Ensuring the accuracy of a BP measurement requires multiple readings over time. White coat hypertension and masked hypertension can complicate BP measurement. Home measurements better correlate with atherosclerotic cardiovascular disease (ASCVD) risk than do office measurements.^10-12 In fact, the US Preventive Services Task Force recommends obtaining measurements outside of the clinic setting prior to initiating treatment for hypertension.¹³

Educate staff on the proper technique for obtaining BP measurements in the office (ie, taking measurements using an appropriately sized cuff when patients have been seated for at least 5 minutes with feet uncrossed and with their arm supported at heart level). Cold temperatures, coffee consumption, talking, and recent tobacco use can transiently raise BP. TABLE 1¹⁰ outlines the initial work-up after confirming the diagnosis of hypertension. No other routine tests are recommended for the management of hypertension except those associated with medication monitoring (outlined in TABLE 2^10,11,14,15).

What’s the optimal BP target for older patients? No consensus exists on an optimal BP target for older patients. JNC 8 recommends a target BP <150/90 mm Hg in patients ≥60 years of age.⁹ The American College of Physicians recommends a systolic BP target <140 mm Hg in patients ≥60 years of age with increased stroke or CV risk.¹¹ A subgroup analysis of patients ≥75 years of age from the Systolic BP Intervention Trial (SPRINT)³ was stopped early because of the clear composite CV and mortality benefits associated with targeting a systolic BP <120 mm Hg as compared with <140 mm Hg (TABLE W1^3-6). Although a criticism of this trial and its results is that the researchers included only adults with high CV risk, all adults ≥75 years of age are considered to have high CV risk by the SPRINT study.³ Another criticism is that early suspension of the trial may have exaggerated treatment effects.⁶

Lastly, results were seemingly discrepant from previous trials, most notably, the Action to Control CV Risk in Diabetes (ACCORD) trial.^6,16 However, on closer review, the ACCORD trial¹⁶ included only patients with DM, while the SPRINT³ trial excluded patients with DM, and ACCORD comprised a younger population than the SPRINT subgroup analysis. Also, the ACCORD trial did demonstrate stroke reduction and non-significant reduction in CV events, albeit, at the cost of increased adverse events, such as hypotension, bradycardia, and hypokalemia, with tighter BP control.¹⁶

Common pharmacotherapeutic contributors to uncontrolled BP include NSAIDs, glucocorticoids, high-dose decongestants, and selective norepinephrine reuptake inhibitors.

Population differences presumably explain the discrepancy in results, and a systolic BP target of <120 mm Hg is appropriate in community-dwelling, non-diabetic adults ≥75 years of age. If this target goal cannot be achieved without undue burden (ie, without syncope, hypotension, bradycardia, electrolyte disturbance, renal impairment, or substantial medication burden), a recent meta-analysis found evidence that a systolic BP goal <140 mm Hg also provides benefit.⁶

Initiate treatment, watch for age-related changes

Lifestyle modifications (including appropriate weight loss; reduced caffeine, salt, and alcohol intake; increased physical activity; and smoking cessation) are important in the initial and ongoing management of hypertension.^10,11,17,18 JNC 8 recommends initial treatment with a thiazide-type diuretic, calcium channel blocker (CCB), angiotensin converting enzyme (ACE) inhibitor, or angiotensin receptor blocker (ARB) in the nonblack population, and a CCB or thiazide diuretic in the black population.⁹ Specific initial medication choices for comorbid conditions are outlined in TABLE W2^3,10,17-22. JNC 8 recommends against the use of a beta-blocker or alpha blocker for initial treatment of hypertension.⁹

Start a second drug instead of maximizing the dose of the first

If the target BP cannot be achieved within one month of initiating medication, JNC 8 recommends increasing the dose of the initial drug or adding a second drug without preference for one strategy over the other.⁹ However, a meta-analysis demonstrates that approximately 80% of the antihypertensive effect of a drug can be achieved with half of the standard dose of the medication; this is true for thiazide-type diuretics, ACE inhibitors/ARBs, beta-blockers, and CCBs.²³

Approximately 80% of the antihypertensive effect of a drug can be achieved with half of the standard dose of many medications.

Furthermore, due to fewer adverse effects and positive synergies, studies show that combining low doses of 2 medications is more beneficial than high-dose monotherapy.^19,23,24 Prescribing combination pills can be helpful to limit pill burden. It is appropriate to combine any of the 4 classes of medications recommended as initial therapy by JNC 8 except for an ACE inhibitor combined with an ARB. If the target BP cannot be achieved with 3 drugs in those classes, other medications such as potassium-sparing diuretics or beta-blockers can be added.⁹

Changes associated with aging

Changes associated with aging include atherosclerosis and stiffening of blood vessels, increased systolic BP, widened pulse pressure, reduced glomerular filtration rate, reduced sodium elimination and volume expansion, sinoatrial node cellular dropout, and decreased sensitivity of baroreceptors.¹⁰ Because of these alterations, antihypertensive requirements may change, and resistant hypertension may develop. In addition, older patients may be more susceptible to orthostatic hypotension, heart block, electrolyte derangements, and other antihypertensive adverse effects.

When hypertension is difficult to control. Resistant hypertension is defined as hypertension that cannot be controlled with 3 drugs from 3 different antihypertensive classes, one of which is a diuretic. Cognitive impairment, polypharmacy, and multimorbidity may contribute to difficult-to-control hypertension in older adults and should be assessed prior to work-up for other secondary causes of poorly controlled hypertension.

• Cognitive impairment is often unrecognized and may impact medication adherence, which can masquerade as treatment failure. Assess for cognitive impairment on an ongoing basis with the aging patient, especially when medication adherence appears poor.
• Polypharmacy may also contribute to uncontrolled BP. Common pharmacotherapeutic contributors to uncontrolled BP include nonsteroidal anti-inflammatory drugs (NSAIDs), glucocorticoids, high-dose decongestants, and selective norepinephrine reuptake inhibitors.²⁵
• Multimorbidity describes 2 or more chronic medical conditions in one patient. These patients are medically complex. Comorbidities can increase pill burden and make medication adherence difficult for patients. Other poorly controlled disease states can worsen hypertension (eg, renal dysfunction secondary to diabetes). Optimize treatment of comorbid conditions.

Secondary causes. If resistant hypertension persists despite confirming medication adherence and eliminating offending medications, a work-up should ensue for secondary causes of hypertension, as well as end-organ damage. Causes of secondary hypertension include sleep apnea (see this month's HelpDesk), renal dysfunction (renal artery stenosis), aldosterone-mediated hypertension (often with hypokalemia), and thyroid disease. Evaluation for secondary causes of hypertension and end-organ damage is outlined in TABLE 1.¹⁰ Patients with well-controlled hypertension do not require repeated assessments for end-organ damage unless new symptoms—such as chest pain or edema—develop.

Consider comorbidities

Clinical trials implicitly or explicitly exclude patients with multiple comorbidities. JNC 8 provided minimal guidance for adjusting BP targets based on comorbidity with only nondiabetic CKD and DM specifically addressed.⁹ Guidelines from specialty organizations and recent trials provide some additional guidance in these situations and are outlined in TABLE W2^3,10,17-22.

Heart failure. Hypertension is a major risk factor for heart failure. Long-term treatment of systolic and diastolic hypertension can reduce the incidence of heart failure by approximately half with increased benefit in patients with prior myocardial infarction.²² Research demonstrates clear mortality benefits of certain antihypertensive drug classes, including diuretics, beta-blockers, ACE inhibitors, ARBs, aldosterone antagonists, combination hydralazine and nitrates, and angiotensin receptor-neprilysin inhibitors.^21,22 The overall treatment goal in heart failure is to optimize drugs with mortality benefit, while lowering BP to a goal <130/80 mm Hg in patients ≥75 years of age.²²

Increased risk for CV disease. The SPRINT trial³ defined high risk of CV disease as clinical or subclinical CV disease, CKD, 10-year ASCVD risk of ≥15%, or age ≥75 years. SPRINT supports a systolic BP goal <120 mm Hg, but, as a reminder, SPRINT excluded patients with diabetes. The American College of Cardiology Foundation Task Force and the American Heart Association define high CV risk as a 10-year ASCVD risk ≥10% and recommend a BP goal <130/80 mm Hg.¹⁰

Diabetes mellitus. A BP >115/75 mm Hg is associated with increased CV events and mortality in patients with DM.¹⁸ The American Diabetes Association (ADA) and JNC 8 recommend a BP target <140/90 mm Hg.^9,18 ADA suggests a lower target of 130/80 mm Hg in patients with high CV risk if it is achievable without undue burden.¹⁸

Studies show increased mortality associated with initiating additional treatment once a systolic goal <140 mm Hg has been achieved in patients with DM.²⁶ The ACCORD trial found increased adverse events with aggressive BP lowering to <120/80 mm Hg.¹⁶

For patients with DM requiring more than one antihypertensive agent, there are CV mortality benefits associated with administering at least one antihypertensive drug at night, likely related to the beneficial effect of physiologic nocturnal dipping.²⁷

Chronic kidney disease. JNC 8 specifically recommends an ACE inhibitor or ARB for initial or add-on treatment in patients with CKD and a BP goal <140/90 mm Hg.⁹ The Kidney Disease: Improving Global Outcomes (KDIGO) Blood Pressure Work Group recommends a BP target ≤140/90 mm Hg in patients without albuminuria and ≤130/80 mm Hg in patients with albuminuria to protect against the progression of nephropathy.¹⁷ The SPRINT trial³ included patients with CKD, and KDIGO has not yet updated its guidelines to reflect SPRINT.

Frailty is a clinical syndrome that has been defined as a state of increased vulnerability that is associated with a decline in reserve and function.²⁸ The largest hypertension studies in older adults address frailty, although often the most frail patients are excluded from these studies (TABLE W1^3-6).

The Hypertension in the Very Elderly Trial (HYVET) categorized patients as frail, pre-frail, or robust and found a consistent benefit of antihypertensive treatment on stroke, CV events, and total mortality—regardless of baseline frailty status.²⁹ The SPRINT trial included only community-dwelling adults.³ Other studies suggest that hypertension actually has a protective effect by lowering overall mortality in frail older adults, especially in the frailest and oldest nursing home populations.^30,31

Due to fewer adverse effects and positive synergies, studies show that low doses of 2 drugs is more beneficial than high-dose monotherapy.

Although there is a paucity of data to direct the management of hypertension in frail older patients, physicians should prioritize the condition and focus on adverse events from antihypertensives and on slow titration of medications. The JNC 8 BP target of <150/90 mm Hg is a reasonable BP goal in this population, given the lack of evidence for lower or higher targets.⁹ Many frail patients have one or more of the comorbidities described earlier, and it is reasonable to strive for the comorbidity-specific target, provided it can be achieved without undue burden.

Cognitive impairment and dementia. The association between hypertension and dementia/cognitive impairment is evolving. Hypertension may impact various forms of dementia, such as Alzheimer’s disease (AD) or vascular dementia, differently. There is evidence linking hypertension to AD.³² The relationship between BP and brain perfusion is complex with the potential existence of an age-adjusted relationship such that mid-life hypertension may increase the risk of dementia while late-life hypertension may not.³³

A number of studies reveal the evolving nature of our understanding of these 2 conditions:

• A recent systematic review and meta-analysis examining intensive BP treatments in older adults demonstrated that lower BP targets did not increase cognitive decline.⁶
• HYVET’s cognitive function assessment did not find a significant reduction in the incidence of dementia with BP reduction over a short follow-up period, but when results were combined in a meta-analysis with other placebo-controlled, double-blind trials of antihypertensive treatments, there was significant reduction in incident dementia in patients randomized to antihypertensive treatment.³⁴
• The ACCORD Memory in Diabetes trial (ACCORD-MIND) had the unexpected outcome that intensive lowering of systolic BP to a target <120 mm Hg resulted in a greater decline in total brain volume, compared with the standard BP goal <140 mm Hg. This was measured with magnetic resonance imaging in older adults with type 2 DM.³⁵
• Results from the SPRINT sub-analysis Memory and Cognition in Decreased Hypertension trial are forthcoming and aim to determine the effects of BP reduction on dementia.³⁶

The JNC 8⁹ BP target <150/90 mm Hg or a comorbidity-specific target, if achievable without undue burden, is reasonable in patients with dementia. In a systematic review of observational studies in patients with hypertension and dementia, diuretics, CCBs, ACE inhibitors/ARBs, and beta-blockers were commonly used medications with a trend toward prescribing CCBs and ACE inhibitors/ARBs.³⁷

A BP target <150/90 mm Hg or a comorbidity-specific target, if achievable without undue burden, is reasonable in patients with dementia.

As previously highlighted, cognitive impairment may lead to problems with medication adherence and even inadvertent improper medication use, potentially resulting in adverse events from antihypertensives. If cognitive impairment or dementia is suspected, ensure additional measures (such as medication assistance or supervision) are in place before prescribing antihypertensives.

Certain diseases, such as Parkinson’s-related dementia and multiple system atrophy, can cause autonomic instability, which can increase the risk of falls and complicate hypertension management. Carefully monitor patients for signs of orthostasis.

CASE 1 Repeat the BP measurement in the office once the patient has been seated for ≥5 minutes, and have the patient monitor her BP at home; schedule a follow-up visit in 2 weeks. If hypertension is confirmed with home measurements, then, in addition to lifestyle modifications, initiate treatment with a CCB or thiazide diuretic to achieve a systolic BP goal <120 mm Hg. Titrate medications slowly while monitoring for adverse effects.

CASE 2 Consistent with the office measurement, the patient has home BP readings that are above the BP target (<120 mm Hg systolic). He has been taking a single antihypertensive for longer than one month. Discontinue his NSAID prior to adding any new medications. If his BP is still above target without NSAIDs, then add a second agent, such as a low dose of an ACE inhibitor, ARB, or CCB, rather than maximizing the dose of hydrochlorothiazide.

CASE 3 Given the patient’s diabetes, CKD, and albuminuria, a target BP goal <130/80 mm Hg is reasonable. An ACE inhibitor or ARB is a better medication choice than atenolol in this patient with albuminuria. Because of the deterioration in his ADLs, careful assessment of mobility, functionality, comorbidities, frailty, and cognitive function should take place at each office visit and inform adjustments to the patient’s BP target. Employ cautious medication titration with monitoring for adverse effects, especially hypotension and syncope. If his functional status declines, adverse effects develop, or the medication regimen becomes burdensome, relax the target BP goal to 150/90 mm Hg.

CORRESPONDENCE
Julienne K. Kirk, PharmD, Family and Community Medicine, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157-1084; [email protected].

CASE 1 An 82-year-old black woman comes in for an annual exam. She has no medical concerns. She volunteers at a hospice, walks daily, and maintains a healthy diet. Her past medical history (PMH) includes osteopenia and osteoarthritis, and her medications include acetaminophen as needed and vitamin D. She has no drug allergies. Her exam reveals a blood pressure (BP) of 148/70 mm Hg, a body mass index of 31, and a heart rate (HR) of 71 beats per minute (bpm). Cardiac and pulmonary exams are normal, and she shows no signs of peripheral edema.

CASE 2 An 88-year-old white man presents to the office for a 3-month follow-up of his hypertension. His systolic BP at home has ranged from 140 to 170 mm Hg. He denies chest pain, shortness of breath, or lower extremity edema. He lives with his wife and frequently swims for exercise. His PMH is significant for depression and degenerative disc disease. His medications include hydrochlorothiazide 12.5 mg/d, sertraline 50 mg/d, and naproxen 250 mg bid. His BP is 160/80 mm Hg and his HR is 70 bpm with normal cardiovascular (CV) and pulmonary exams.

CASE 3 An 80-year-old white man with diabetes mellitus (DM), hypertension, and chronic kidney disease (CKD) presents for a 3-month follow-up visit. His home systolic BP has been in the 140s to 150s. He is functional in all of his activities of daily living (ADLs), but is starting to require assistance with medications, finances, and transportation. He takes aspirin 81 mg/d, chlorthalidone 25 mg/d, and atenolol 50 mg/d. Remarkable laboratory test results include a hemoglobin A1c of 8.6%, a serum creatinine of 1.9 mg/dL (normal range: 0.6-1.2 mg/dL), and an albumin-creatinine ratio of 250 mg/g (normal range: <30 mg/g). During the exam, his BP is 143/70 mm Hg, his HR is 70 bpm, he is alert and oriented to person, place, and time, and he has normal CV and pulmonary exams with no signs of peripheral edema. He has decreased sensation in his feet, but normal reflexes.

How would you proceed with the care of these 3 patients?

Hypertension is the most common diagnosis made during physician office visits in the United States.¹ Nearly one-third of the population has hypertension, and its prevalence increases with age, such that 67% of men and 79% of women ≥75 years of age have the condition.²

Evidence indicates that hypertension is a modifiable risk factor for CV and all-cause mortality (TABLE W1^3-6). All adults ≥75 years of age are at increased CV risk based on Framingham criteria,⁷ making hypertension management paramount. Complicating the situation are findings that indicate nearly half of adults with hypertension have inadequate BP control.²

A systolic BP target of <120 mm Hg is appropriate in community-dwelling, non-diabetic adults ≥75 years of age, but if this places an undue burden on the patient, a goal of <140 mm Hg also provides benefit.

Clinicians require clear direction about optimal BP targets, how best to adjust antihypertensive medications for comorbidities, and how to incorporate frailty and cognitive impairment into management strategies. This article presents recommendations derived from recent evidence and consensus guidelines regarding the management of hypertension in adults ≥75 years of age.

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Diagnosing hypertension

According to the seventh report of the Joint National Committee (JNC 7), hypertension is defined as a systolic BP ≥140 mm Hg and/or a diastolic BP ≥90 mm Hg.⁸ The JNC’s more recent report (JNC 8), however, does not define hypertension; instead, it sets forth treatment thresholds (eg, that there is strong evidence to support treating individuals ≥60 years of age when BP ≥150/90 mm Hg).⁹

It starts with an accurate BP measurement. Ensuring the accuracy of a BP measurement requires multiple readings over time. White coat hypertension and masked hypertension can complicate BP measurement. Home measurements better correlate with atherosclerotic cardiovascular disease (ASCVD) risk than do office measurements.^10-12 In fact, the US Preventive Services Task Force recommends obtaining measurements outside of the clinic setting prior to initiating treatment for hypertension.¹³

Educate staff on the proper technique for obtaining BP measurements in the office (ie, taking measurements using an appropriately sized cuff when patients have been seated for at least 5 minutes with feet uncrossed and with their arm supported at heart level). Cold temperatures, coffee consumption, talking, and recent tobacco use can transiently raise BP. TABLE 1¹⁰ outlines the initial work-up after confirming the diagnosis of hypertension. No other routine tests are recommended for the management of hypertension except those associated with medication monitoring (outlined in TABLE 2^10,11,14,15).

What’s the optimal BP target for older patients? No consensus exists on an optimal BP target for older patients. JNC 8 recommends a target BP <150/90 mm Hg in patients ≥60 years of age.⁹ The American College of Physicians recommends a systolic BP target <140 mm Hg in patients ≥60 years of age with increased stroke or CV risk.¹¹ A subgroup analysis of patients ≥75 years of age from the Systolic BP Intervention Trial (SPRINT)³ was stopped early because of the clear composite CV and mortality benefits associated with targeting a systolic BP <120 mm Hg as compared with <140 mm Hg (TABLE W1^3-6). Although a criticism of this trial and its results is that the researchers included only adults with high CV risk, all adults ≥75 years of age are considered to have high CV risk by the SPRINT study.³ Another criticism is that early suspension of the trial may have exaggerated treatment effects.⁶

Lastly, results were seemingly discrepant from previous trials, most notably, the Action to Control CV Risk in Diabetes (ACCORD) trial.^6,16 However, on closer review, the ACCORD trial¹⁶ included only patients with DM, while the SPRINT³ trial excluded patients with DM, and ACCORD comprised a younger population than the SPRINT subgroup analysis. Also, the ACCORD trial did demonstrate stroke reduction and non-significant reduction in CV events, albeit, at the cost of increased adverse events, such as hypotension, bradycardia, and hypokalemia, with tighter BP control.¹⁶

Common pharmacotherapeutic contributors to uncontrolled BP include NSAIDs, glucocorticoids, high-dose decongestants, and selective norepinephrine reuptake inhibitors.

Population differences presumably explain the discrepancy in results, and a systolic BP target of <120 mm Hg is appropriate in community-dwelling, non-diabetic adults ≥75 years of age. If this target goal cannot be achieved without undue burden (ie, without syncope, hypotension, bradycardia, electrolyte disturbance, renal impairment, or substantial medication burden), a recent meta-analysis found evidence that a systolic BP goal <140 mm Hg also provides benefit.⁶

Initiate treatment, watch for age-related changes

Lifestyle modifications (including appropriate weight loss; reduced caffeine, salt, and alcohol intake; increased physical activity; and smoking cessation) are important in the initial and ongoing management of hypertension.^10,11,17,18 JNC 8 recommends initial treatment with a thiazide-type diuretic, calcium channel blocker (CCB), angiotensin converting enzyme (ACE) inhibitor, or angiotensin receptor blocker (ARB) in the nonblack population, and a CCB or thiazide diuretic in the black population.⁹ Specific initial medication choices for comorbid conditions are outlined in TABLE W2^3,10,17-22. JNC 8 recommends against the use of a beta-blocker or alpha blocker for initial treatment of hypertension.⁹

Start a second drug instead of maximizing the dose of the first

If the target BP cannot be achieved within one month of initiating medication, JNC 8 recommends increasing the dose of the initial drug or adding a second drug without preference for one strategy over the other.⁹ However, a meta-analysis demonstrates that approximately 80% of the antihypertensive effect of a drug can be achieved with half of the standard dose of the medication; this is true for thiazide-type diuretics, ACE inhibitors/ARBs, beta-blockers, and CCBs.²³

Approximately 80% of the antihypertensive effect of a drug can be achieved with half of the standard dose of many medications.

Furthermore, due to fewer adverse effects and positive synergies, studies show that combining low doses of 2 medications is more beneficial than high-dose monotherapy.^19,23,24 Prescribing combination pills can be helpful to limit pill burden. It is appropriate to combine any of the 4 classes of medications recommended as initial therapy by JNC 8 except for an ACE inhibitor combined with an ARB. If the target BP cannot be achieved with 3 drugs in those classes, other medications such as potassium-sparing diuretics or beta-blockers can be added.⁹

Changes associated with aging

Changes associated with aging include atherosclerosis and stiffening of blood vessels, increased systolic BP, widened pulse pressure, reduced glomerular filtration rate, reduced sodium elimination and volume expansion, sinoatrial node cellular dropout, and decreased sensitivity of baroreceptors.¹⁰ Because of these alterations, antihypertensive requirements may change, and resistant hypertension may develop. In addition, older patients may be more susceptible to orthostatic hypotension, heart block, electrolyte derangements, and other antihypertensive adverse effects.

When hypertension is difficult to control. Resistant hypertension is defined as hypertension that cannot be controlled with 3 drugs from 3 different antihypertensive classes, one of which is a diuretic. Cognitive impairment, polypharmacy, and multimorbidity may contribute to difficult-to-control hypertension in older adults and should be assessed prior to work-up for other secondary causes of poorly controlled hypertension.

• Cognitive impairment is often unrecognized and may impact medication adherence, which can masquerade as treatment failure. Assess for cognitive impairment on an ongoing basis with the aging patient, especially when medication adherence appears poor.
• Polypharmacy may also contribute to uncontrolled BP. Common pharmacotherapeutic contributors to uncontrolled BP include nonsteroidal anti-inflammatory drugs (NSAIDs), glucocorticoids, high-dose decongestants, and selective norepinephrine reuptake inhibitors.²⁵
• Multimorbidity describes 2 or more chronic medical conditions in one patient. These patients are medically complex. Comorbidities can increase pill burden and make medication adherence difficult for patients. Other poorly controlled disease states can worsen hypertension (eg, renal dysfunction secondary to diabetes). Optimize treatment of comorbid conditions.

Secondary causes. If resistant hypertension persists despite confirming medication adherence and eliminating offending medications, a work-up should ensue for secondary causes of hypertension, as well as end-organ damage. Causes of secondary hypertension include sleep apnea (see this month's HelpDesk), renal dysfunction (renal artery stenosis), aldosterone-mediated hypertension (often with hypokalemia), and thyroid disease. Evaluation for secondary causes of hypertension and end-organ damage is outlined in TABLE 1.¹⁰ Patients with well-controlled hypertension do not require repeated assessments for end-organ damage unless new symptoms—such as chest pain or edema—develop.

Consider comorbidities

Clinical trials implicitly or explicitly exclude patients with multiple comorbidities. JNC 8 provided minimal guidance for adjusting BP targets based on comorbidity with only nondiabetic CKD and DM specifically addressed.⁹ Guidelines from specialty organizations and recent trials provide some additional guidance in these situations and are outlined in TABLE W2^3,10,17-22.

Heart failure. Hypertension is a major risk factor for heart failure. Long-term treatment of systolic and diastolic hypertension can reduce the incidence of heart failure by approximately half with increased benefit in patients with prior myocardial infarction.²² Research demonstrates clear mortality benefits of certain antihypertensive drug classes, including diuretics, beta-blockers, ACE inhibitors, ARBs, aldosterone antagonists, combination hydralazine and nitrates, and angiotensin receptor-neprilysin inhibitors.^21,22 The overall treatment goal in heart failure is to optimize drugs with mortality benefit, while lowering BP to a goal <130/80 mm Hg in patients ≥75 years of age.²²

Increased risk for CV disease. The SPRINT trial³ defined high risk of CV disease as clinical or subclinical CV disease, CKD, 10-year ASCVD risk of ≥15%, or age ≥75 years. SPRINT supports a systolic BP goal <120 mm Hg, but, as a reminder, SPRINT excluded patients with diabetes. The American College of Cardiology Foundation Task Force and the American Heart Association define high CV risk as a 10-year ASCVD risk ≥10% and recommend a BP goal <130/80 mm Hg.¹⁰

Diabetes mellitus. A BP >115/75 mm Hg is associated with increased CV events and mortality in patients with DM.¹⁸ The American Diabetes Association (ADA) and JNC 8 recommend a BP target <140/90 mm Hg.^9,18 ADA suggests a lower target of 130/80 mm Hg in patients with high CV risk if it is achievable without undue burden.¹⁸

Studies show increased mortality associated with initiating additional treatment once a systolic goal <140 mm Hg has been achieved in patients with DM.²⁶ The ACCORD trial found increased adverse events with aggressive BP lowering to <120/80 mm Hg.¹⁶

For patients with DM requiring more than one antihypertensive agent, there are CV mortality benefits associated with administering at least one antihypertensive drug at night, likely related to the beneficial effect of physiologic nocturnal dipping.²⁷

Chronic kidney disease. JNC 8 specifically recommends an ACE inhibitor or ARB for initial or add-on treatment in patients with CKD and a BP goal <140/90 mm Hg.⁹ The Kidney Disease: Improving Global Outcomes (KDIGO) Blood Pressure Work Group recommends a BP target ≤140/90 mm Hg in patients without albuminuria and ≤130/80 mm Hg in patients with albuminuria to protect against the progression of nephropathy.¹⁷ The SPRINT trial³ included patients with CKD, and KDIGO has not yet updated its guidelines to reflect SPRINT.

Frailty is a clinical syndrome that has been defined as a state of increased vulnerability that is associated with a decline in reserve and function.²⁸ The largest hypertension studies in older adults address frailty, although often the most frail patients are excluded from these studies (TABLE W1^3-6).

The Hypertension in the Very Elderly Trial (HYVET) categorized patients as frail, pre-frail, or robust and found a consistent benefit of antihypertensive treatment on stroke, CV events, and total mortality—regardless of baseline frailty status.²⁹ The SPRINT trial included only community-dwelling adults.³ Other studies suggest that hypertension actually has a protective effect by lowering overall mortality in frail older adults, especially in the frailest and oldest nursing home populations.^30,31

Due to fewer adverse effects and positive synergies, studies show that low doses of 2 drugs is more beneficial than high-dose monotherapy.

Although there is a paucity of data to direct the management of hypertension in frail older patients, physicians should prioritize the condition and focus on adverse events from antihypertensives and on slow titration of medications. The JNC 8 BP target of <150/90 mm Hg is a reasonable BP goal in this population, given the lack of evidence for lower or higher targets.⁹ Many frail patients have one or more of the comorbidities described earlier, and it is reasonable to strive for the comorbidity-specific target, provided it can be achieved without undue burden.

Cognitive impairment and dementia. The association between hypertension and dementia/cognitive impairment is evolving. Hypertension may impact various forms of dementia, such as Alzheimer’s disease (AD) or vascular dementia, differently. There is evidence linking hypertension to AD.³² The relationship between BP and brain perfusion is complex with the potential existence of an age-adjusted relationship such that mid-life hypertension may increase the risk of dementia while late-life hypertension may not.³³

A number of studies reveal the evolving nature of our understanding of these 2 conditions:

• A recent systematic review and meta-analysis examining intensive BP treatments in older adults demonstrated that lower BP targets did not increase cognitive decline.⁶
• HYVET’s cognitive function assessment did not find a significant reduction in the incidence of dementia with BP reduction over a short follow-up period, but when results were combined in a meta-analysis with other placebo-controlled, double-blind trials of antihypertensive treatments, there was significant reduction in incident dementia in patients randomized to antihypertensive treatment.³⁴
• The ACCORD Memory in Diabetes trial (ACCORD-MIND) had the unexpected outcome that intensive lowering of systolic BP to a target <120 mm Hg resulted in a greater decline in total brain volume, compared with the standard BP goal <140 mm Hg. This was measured with magnetic resonance imaging in older adults with type 2 DM.³⁵
• Results from the SPRINT sub-analysis Memory and Cognition in Decreased Hypertension trial are forthcoming and aim to determine the effects of BP reduction on dementia.³⁶

The JNC 8⁹ BP target <150/90 mm Hg or a comorbidity-specific target, if achievable without undue burden, is reasonable in patients with dementia. In a systematic review of observational studies in patients with hypertension and dementia, diuretics, CCBs, ACE inhibitors/ARBs, and beta-blockers were commonly used medications with a trend toward prescribing CCBs and ACE inhibitors/ARBs.³⁷

A BP target <150/90 mm Hg or a comorbidity-specific target, if achievable without undue burden, is reasonable in patients with dementia.

As previously highlighted, cognitive impairment may lead to problems with medication adherence and even inadvertent improper medication use, potentially resulting in adverse events from antihypertensives. If cognitive impairment or dementia is suspected, ensure additional measures (such as medication assistance or supervision) are in place before prescribing antihypertensives.

Certain diseases, such as Parkinson’s-related dementia and multiple system atrophy, can cause autonomic instability, which can increase the risk of falls and complicate hypertension management. Carefully monitor patients for signs of orthostasis.

CASE 1 Repeat the BP measurement in the office once the patient has been seated for ≥5 minutes, and have the patient monitor her BP at home; schedule a follow-up visit in 2 weeks. If hypertension is confirmed with home measurements, then, in addition to lifestyle modifications, initiate treatment with a CCB or thiazide diuretic to achieve a systolic BP goal <120 mm Hg. Titrate medications slowly while monitoring for adverse effects.

CASE 2 Consistent with the office measurement, the patient has home BP readings that are above the BP target (<120 mm Hg systolic). He has been taking a single antihypertensive for longer than one month. Discontinue his NSAID prior to adding any new medications. If his BP is still above target without NSAIDs, then add a second agent, such as a low dose of an ACE inhibitor, ARB, or CCB, rather than maximizing the dose of hydrochlorothiazide.

CASE 3 Given the patient’s diabetes, CKD, and albuminuria, a target BP goal <130/80 mm Hg is reasonable. An ACE inhibitor or ARB is a better medication choice than atenolol in this patient with albuminuria. Because of the deterioration in his ADLs, careful assessment of mobility, functionality, comorbidities, frailty, and cognitive function should take place at each office visit and inform adjustments to the patient’s BP target. Employ cautious medication titration with monitoring for adverse effects, especially hypotension and syncope. If his functional status declines, adverse effects develop, or the medication regimen becomes burdensome, relax the target BP goal to 150/90 mm Hg.

CORRESPONDENCE
Julienne K. Kirk, PharmD, Family and Community Medicine, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157-1084; [email protected].

Photo by Chad McNeeley

New research published in The Journal of Clinical Investigation suggests the protein Del-1 regulates the hematopoietic stem cell (HSC) niche.

Researchers therefore believe that targeting Del-1 could be an effective way to improve HSC transplants (HSCTs) for donors and recipients.

There may also be ways to modulate levels of Del-1 to enhance immune cell production in patients with certain hematologic malignancies.

“Because the hematopoietic stem cell niche is so important for the creation of bone marrow and blood cells and because Del-1 is a soluble protein and is easily manipulated, one can see that it could be a target in many potential applications,” said study author George Hajishengallis, DDS, PhD, of the University of Pennsylvania School of Dental Medicine in Philadelphia.

“I think that Del-1 represents a major regulator of the hematopoietic stem cell niche,” added study author Triantafyllos Chavakis, MD, PhD, of the Technical University of Dresden in Germany. “It will be worthwhile to study its expression in the context of hematopoietic malignancy.”

This research began when Drs Hajishengallis and Chavakis identified Del-1 as a potential drug target for gum disease. They found the protein prevents inflammatory cells from moving into the gums.

Both researchers and their labs also discovered that Del-1 was expressed in the bone marrow as well. So the researchers began following up to determine the protein’s function there.

“In the beginning, I thought it would have a simple function, like regulating the exit of mature leukocytes from the marrow into the periphery, something analogous to what it was doing in the gingiva,” Dr Hajishengallis said. “But it turned out it had a much more important and global role than what I had imagined.”

The researchers’ investigations revealed that Del-1 was expressed by at least 3 cell types that support HSCs: arteriolar endothelial cells, CXCL12-abundant reticular cells, and cells of the osteoblastic lineage.

Using mice deficient in Del-1, the researchers found the protein promotes proliferation and differentiation of HSCs, sending more progenitor cells down a path toward becoming myeloid cells rather than lymphocytes.

In HSCT experiments, the team discovered the presence of Del-1 in recipient bone marrow is required for the transplanted HSCs to engraft in the recipient and to facilitate the process of myelopoiesis.

When the researchers mimicked a systemic infection in mice, animals deficient in Del-1 were slower to begin making myeloid cells again compared to mice with normal Del-1 levels.

“We saw roles for Del-1 in both steady-state and emergency conditions,” Dr Hajishengallis said.

He and his colleagues also identified the protein with which Del-1 interacts, the ß3 integrin, perhaps pointing to a target for therapeutic interventions down the line.

The researchers see potential applications in HSCTs, for both donors and recipients.

In donors, blocking the interaction between Del-1 and HSCs could enhance the mobilization of those progenitors into the bloodstream. This could be helpful for increasing donor cell numbers for transplantation.

HSCT recipients, on the other hand, may need enhanced Del-1 interaction to ensure the transplanted cells engraft and begin making new blood cells more rapidly.

In addition, people undergoing chemotherapy who develop febrile neutropenia might benefit from the role of Del-1 in supporting the production of immune-related blood cells such as neutrophils.

“It’s easy to think of practical applications for these findings,” Dr Hajishengallis said. “Now, we need to find out whether it works in practice, so our studies continue.”

Photo by Chad McNeeley

New research published in The Journal of Clinical Investigation suggests the protein Del-1 regulates the hematopoietic stem cell (HSC) niche.

Researchers therefore believe that targeting Del-1 could be an effective way to improve HSC transplants (HSCTs) for donors and recipients.

There may also be ways to modulate levels of Del-1 to enhance immune cell production in patients with certain hematologic malignancies.

“Because the hematopoietic stem cell niche is so important for the creation of bone marrow and blood cells and because Del-1 is a soluble protein and is easily manipulated, one can see that it could be a target in many potential applications,” said study author George Hajishengallis, DDS, PhD, of the University of Pennsylvania School of Dental Medicine in Philadelphia.

“I think that Del-1 represents a major regulator of the hematopoietic stem cell niche,” added study author Triantafyllos Chavakis, MD, PhD, of the Technical University of Dresden in Germany. “It will be worthwhile to study its expression in the context of hematopoietic malignancy.”

This research began when Drs Hajishengallis and Chavakis identified Del-1 as a potential drug target for gum disease. They found the protein prevents inflammatory cells from moving into the gums.

Both researchers and their labs also discovered that Del-1 was expressed in the bone marrow as well. So the researchers began following up to determine the protein’s function there.

“In the beginning, I thought it would have a simple function, like regulating the exit of mature leukocytes from the marrow into the periphery, something analogous to what it was doing in the gingiva,” Dr Hajishengallis said. “But it turned out it had a much more important and global role than what I had imagined.”

The researchers’ investigations revealed that Del-1 was expressed by at least 3 cell types that support HSCs: arteriolar endothelial cells, CXCL12-abundant reticular cells, and cells of the osteoblastic lineage.

Using mice deficient in Del-1, the researchers found the protein promotes proliferation and differentiation of HSCs, sending more progenitor cells down a path toward becoming myeloid cells rather than lymphocytes.

In HSCT experiments, the team discovered the presence of Del-1 in recipient bone marrow is required for the transplanted HSCs to engraft in the recipient and to facilitate the process of myelopoiesis.

When the researchers mimicked a systemic infection in mice, animals deficient in Del-1 were slower to begin making myeloid cells again compared to mice with normal Del-1 levels.

“We saw roles for Del-1 in both steady-state and emergency conditions,” Dr Hajishengallis said.

He and his colleagues also identified the protein with which Del-1 interacts, the ß3 integrin, perhaps pointing to a target for therapeutic interventions down the line.

The researchers see potential applications in HSCTs, for both donors and recipients.

In donors, blocking the interaction between Del-1 and HSCs could enhance the mobilization of those progenitors into the bloodstream. This could be helpful for increasing donor cell numbers for transplantation.

HSCT recipients, on the other hand, may need enhanced Del-1 interaction to ensure the transplanted cells engraft and begin making new blood cells more rapidly.

In addition, people undergoing chemotherapy who develop febrile neutropenia might benefit from the role of Del-1 in supporting the production of immune-related blood cells such as neutrophils.

“It’s easy to think of practical applications for these findings,” Dr Hajishengallis said. “Now, we need to find out whether it works in practice, so our studies continue.”

Photo by Chad McNeeley

New research published in The Journal of Clinical Investigation suggests the protein Del-1 regulates the hematopoietic stem cell (HSC) niche.

Researchers therefore believe that targeting Del-1 could be an effective way to improve HSC transplants (HSCTs) for donors and recipients.

There may also be ways to modulate levels of Del-1 to enhance immune cell production in patients with certain hematologic malignancies.

“Because the hematopoietic stem cell niche is so important for the creation of bone marrow and blood cells and because Del-1 is a soluble protein and is easily manipulated, one can see that it could be a target in many potential applications,” said study author George Hajishengallis, DDS, PhD, of the University of Pennsylvania School of Dental Medicine in Philadelphia.

“I think that Del-1 represents a major regulator of the hematopoietic stem cell niche,” added study author Triantafyllos Chavakis, MD, PhD, of the Technical University of Dresden in Germany. “It will be worthwhile to study its expression in the context of hematopoietic malignancy.”

This research began when Drs Hajishengallis and Chavakis identified Del-1 as a potential drug target for gum disease. They found the protein prevents inflammatory cells from moving into the gums.

Both researchers and their labs also discovered that Del-1 was expressed in the bone marrow as well. So the researchers began following up to determine the protein’s function there.

“In the beginning, I thought it would have a simple function, like regulating the exit of mature leukocytes from the marrow into the periphery, something analogous to what it was doing in the gingiva,” Dr Hajishengallis said. “But it turned out it had a much more important and global role than what I had imagined.”

The researchers’ investigations revealed that Del-1 was expressed by at least 3 cell types that support HSCs: arteriolar endothelial cells, CXCL12-abundant reticular cells, and cells of the osteoblastic lineage.

Using mice deficient in Del-1, the researchers found the protein promotes proliferation and differentiation of HSCs, sending more progenitor cells down a path toward becoming myeloid cells rather than lymphocytes.

In HSCT experiments, the team discovered the presence of Del-1 in recipient bone marrow is required for the transplanted HSCs to engraft in the recipient and to facilitate the process of myelopoiesis.

When the researchers mimicked a systemic infection in mice, animals deficient in Del-1 were slower to begin making myeloid cells again compared to mice with normal Del-1 levels.

“We saw roles for Del-1 in both steady-state and emergency conditions,” Dr Hajishengallis said.

He and his colleagues also identified the protein with which Del-1 interacts, the ß3 integrin, perhaps pointing to a target for therapeutic interventions down the line.

The researchers see potential applications in HSCTs, for both donors and recipients.

In donors, blocking the interaction between Del-1 and HSCs could enhance the mobilization of those progenitors into the bloodstream. This could be helpful for increasing donor cell numbers for transplantation.

HSCT recipients, on the other hand, may need enhanced Del-1 interaction to ensure the transplanted cells engraft and begin making new blood cells more rapidly.

In addition, people undergoing chemotherapy who develop febrile neutropenia might benefit from the role of Del-1 in supporting the production of immune-related blood cells such as neutrophils.

“It’s easy to think of practical applications for these findings,” Dr Hajishengallis said. “Now, we need to find out whether it works in practice, so our studies continue.”

THE CASE

A 34-year-old Eritrean man presented to the emergency department with complaints of diffuse abdominal pain and distention. He had emigrated to the United States 3 months earlier, following 5 years in a refugee camp in Ethiopia. Two weeks earlier, the patient sought care at his primary care clinic and was diagnosed with post-operative urinary retention and constipation following a recent hemorrhoidectomy. A Foley catheter was inserted and provided a short period of relief.

Following the visit, however, his abdominal pain worsened. He also experienced increasing abdominal distention, a declining appetite, and persistent nausea. The patient said that he was unable to urinate and had not had a bowel movement in 6 days. He also described fevers, drenching night sweats, chills, and a 4-kg weight loss over 2 months.

On physical examination, the patient had a wasted appearance. He was afebrile, alert, and oriented, but anxious and writhing in pain. An abdominal examination revealed some distention, generalized guarding, and tenderness. There was dullness to percussion in all regions without rebound, and no caput medusa was noted. The remainder of the physical examination was unremarkable.

Pertinent laboratory values included negative screens for human immunodeficiency virus (HIV) 1 and 2, and a purified protein derivative test that produced 10 mm of induration at 48 hours. An interferon-gamma release assay was not performed following these results. A computerized tomography (CT) scan of the abdomen and pelvis with intravenous and oral contrast revealed thickening of the peritoneal lining with infiltration of the mesenteric fat and large loculated fluid collections in the abdominal cavity (FIGURE). A CT scan of the patient’s lungs showed some mild atelectasis with left-sided effusion.

After hospital admission, the patient spiked fevers as high as 103.3° F and developed progressively worsening ascites. An ultrasound-guided paracentesis was performed, during which almost 2 liters of yellow, hazy fluid was removed. Fluid and blood cultures were negative.

THE DIAGNOSIS

With a high clinical suspicion for tuberculosis (TB) peritonitis, we requested a surgical consultation and a peritoneal biopsy was performed. The patient was started on ethambutol, isoniazid, pyrazinamide, pyridoxine, and rifampin while the biopsy results were pending.

Pathology subsequently confirmed a diagnosis of TB peritonitis, reporting dense fibroconnective tissue with areas of chronic inflammation and occasional accumulations of histiocytes with multinucleated giant cells showing granulomatous inflammation. An acid-fast (AF) bacilli stain for Mycobacteria showed a single curved bacillus compatible with Mycobacterium tuberculosis.

The patient was discharged following a 3-week hospital stay. At his follow-up visit several weeks later, the patient reported marked improvement and increasing exercise tolerance. He had gained weight, and the abdominal distention and tenderness had resolved.

DISCUSSION

Worldwide, TB is one of the top 10 causes of death. The World Health Organization estimates that there were 1.4 million TB deaths globally in 2015.¹ And while rates of TB are decreasing in the United States, there was a resurgence from 1985 to 1992.² This was attributable to the HIV/acquired immunodeficiency syndrome epidemic, increased immigration from countries endemic for TB, and deterioration of the TB public health infrastructure.³

Transmission. M tuberculosis is a rod-shaped, nonspore-forming AF bacillus that typically infects the lungs, but may infect other areas of the body. Transmission typically occurs via airborne spread of droplets from an infected individual. Possible other methods of disease dissemination include ingestion of infected sputum, hematogenous spread from active pulmonary TB, or ingestion of contaminated milk or food.

M tuberculosis elicits a proinflammatory phase, which facilitates the formation of a granuloma within the host tissues. The host’s immune response to M tuberculosis plays a role in the risk of developing this type of TB.³

TB presentation is classified as pulmonary, extrapulmonary, or both. Clinicians are generally attentive to the classic symptoms of pulmonary TB: cough, weight loss, night sweats, and fever. Presentation of extrapulmonary TB, however, may vary.⁴

Black patients have a significantly higher incidence of extrapulmonary tuberculosis than nonblack counterparts.

According to one study, the most common presenting symptoms for peritoneal TB are weight loss, abdominal pain, and/or fever, all of which our patient experienced.⁵ In addition, our patient was an immigrant from Africa, and black patients have been shown to have a significantly higher incidence of extrapulmonary TB than their nonblack counterparts.⁶ Although our patient was HIV-negative, a recent meta-analysis confirmed the strong association between extrapulmonary TB and HIV, emphasizing the importance of including HIV screens in the standard work-up for TB.⁷

Other symptoms may include microcytosis, anemia, thrombocytosis, and an elevated erythrocyte sedimentation rate. Although a chest x-ray is often negative, advanced imaging, such as CT or magnetic resonance imaging, is often abnormal and may point to the diagnosis.⁵

Treatment of extrapulmonary TB is generally the same as that for pulmonary TB and, interestingly, the incidence of multi-drug resistant extrapulmonary TB is not necessarily higher than it is for pulmonary TB (<1% vs 1.6%).^3,7 In light of this, a standard regimen—like the one our patient received—is generally utilized for 6 to 9 months. Nonetheless, resistance testing should still be performed.^3,4

THE TAKEAWAY

While considered uncommon, more than 20% of TB cases in the United States are extrapulmonary (the most common form is TB lymphadenitis).^7,8 It is imperative to identify appropriate risk factors, including associated comorbidities, patient characteristics, and population/endemic differences in immigrant populations.

In this case, although the symptom combination of persistent abdominal pain, fever, and weight loss may not trigger suspicion of a TB diagnosis in isolation, combining the symptoms with knowledge of the patient’s immigration status should at least raise an eyebrow. Given their nonpulmonary symptoms, many of these patients will not present to pulmonologists, making diagnosis particularly relevant to primary care.

THE CASE

A 34-year-old Eritrean man presented to the emergency department with complaints of diffuse abdominal pain and distention. He had emigrated to the United States 3 months earlier, following 5 years in a refugee camp in Ethiopia. Two weeks earlier, the patient sought care at his primary care clinic and was diagnosed with post-operative urinary retention and constipation following a recent hemorrhoidectomy. A Foley catheter was inserted and provided a short period of relief.

Following the visit, however, his abdominal pain worsened. He also experienced increasing abdominal distention, a declining appetite, and persistent nausea. The patient said that he was unable to urinate and had not had a bowel movement in 6 days. He also described fevers, drenching night sweats, chills, and a 4-kg weight loss over 2 months.

On physical examination, the patient had a wasted appearance. He was afebrile, alert, and oriented, but anxious and writhing in pain. An abdominal examination revealed some distention, generalized guarding, and tenderness. There was dullness to percussion in all regions without rebound, and no caput medusa was noted. The remainder of the physical examination was unremarkable.

Pertinent laboratory values included negative screens for human immunodeficiency virus (HIV) 1 and 2, and a purified protein derivative test that produced 10 mm of induration at 48 hours. An interferon-gamma release assay was not performed following these results. A computerized tomography (CT) scan of the abdomen and pelvis with intravenous and oral contrast revealed thickening of the peritoneal lining with infiltration of the mesenteric fat and large loculated fluid collections in the abdominal cavity (FIGURE). A CT scan of the patient’s lungs showed some mild atelectasis with left-sided effusion.

After hospital admission, the patient spiked fevers as high as 103.3° F and developed progressively worsening ascites. An ultrasound-guided paracentesis was performed, during which almost 2 liters of yellow, hazy fluid was removed. Fluid and blood cultures were negative.

THE DIAGNOSIS

With a high clinical suspicion for tuberculosis (TB) peritonitis, we requested a surgical consultation and a peritoneal biopsy was performed. The patient was started on ethambutol, isoniazid, pyrazinamide, pyridoxine, and rifampin while the biopsy results were pending.

Pathology subsequently confirmed a diagnosis of TB peritonitis, reporting dense fibroconnective tissue with areas of chronic inflammation and occasional accumulations of histiocytes with multinucleated giant cells showing granulomatous inflammation. An acid-fast (AF) bacilli stain for Mycobacteria showed a single curved bacillus compatible with Mycobacterium tuberculosis.

The patient was discharged following a 3-week hospital stay. At his follow-up visit several weeks later, the patient reported marked improvement and increasing exercise tolerance. He had gained weight, and the abdominal distention and tenderness had resolved.

DISCUSSION

Worldwide, TB is one of the top 10 causes of death. The World Health Organization estimates that there were 1.4 million TB deaths globally in 2015.¹ And while rates of TB are decreasing in the United States, there was a resurgence from 1985 to 1992.² This was attributable to the HIV/acquired immunodeficiency syndrome epidemic, increased immigration from countries endemic for TB, and deterioration of the TB public health infrastructure.³

Transmission. M tuberculosis is a rod-shaped, nonspore-forming AF bacillus that typically infects the lungs, but may infect other areas of the body. Transmission typically occurs via airborne spread of droplets from an infected individual. Possible other methods of disease dissemination include ingestion of infected sputum, hematogenous spread from active pulmonary TB, or ingestion of contaminated milk or food.

M tuberculosis elicits a proinflammatory phase, which facilitates the formation of a granuloma within the host tissues. The host’s immune response to M tuberculosis plays a role in the risk of developing this type of TB.³

TB presentation is classified as pulmonary, extrapulmonary, or both. Clinicians are generally attentive to the classic symptoms of pulmonary TB: cough, weight loss, night sweats, and fever. Presentation of extrapulmonary TB, however, may vary.⁴

Black patients have a significantly higher incidence of extrapulmonary tuberculosis than nonblack counterparts.

According to one study, the most common presenting symptoms for peritoneal TB are weight loss, abdominal pain, and/or fever, all of which our patient experienced.⁵ In addition, our patient was an immigrant from Africa, and black patients have been shown to have a significantly higher incidence of extrapulmonary TB than their nonblack counterparts.⁶ Although our patient was HIV-negative, a recent meta-analysis confirmed the strong association between extrapulmonary TB and HIV, emphasizing the importance of including HIV screens in the standard work-up for TB.⁷

Other symptoms may include microcytosis, anemia, thrombocytosis, and an elevated erythrocyte sedimentation rate. Although a chest x-ray is often negative, advanced imaging, such as CT or magnetic resonance imaging, is often abnormal and may point to the diagnosis.⁵

Treatment of extrapulmonary TB is generally the same as that for pulmonary TB and, interestingly, the incidence of multi-drug resistant extrapulmonary TB is not necessarily higher than it is for pulmonary TB (<1% vs 1.6%).^3,7 In light of this, a standard regimen—like the one our patient received—is generally utilized for 6 to 9 months. Nonetheless, resistance testing should still be performed.^3,4

THE TAKEAWAY

While considered uncommon, more than 20% of TB cases in the United States are extrapulmonary (the most common form is TB lymphadenitis).^7,8 It is imperative to identify appropriate risk factors, including associated comorbidities, patient characteristics, and population/endemic differences in immigrant populations.

In this case, although the symptom combination of persistent abdominal pain, fever, and weight loss may not trigger suspicion of a TB diagnosis in isolation, combining the symptoms with knowledge of the patient’s immigration status should at least raise an eyebrow. Given their nonpulmonary symptoms, many of these patients will not present to pulmonologists, making diagnosis particularly relevant to primary care.

THE CASE

A 34-year-old Eritrean man presented to the emergency department with complaints of diffuse abdominal pain and distention. He had emigrated to the United States 3 months earlier, following 5 years in a refugee camp in Ethiopia. Two weeks earlier, the patient sought care at his primary care clinic and was diagnosed with post-operative urinary retention and constipation following a recent hemorrhoidectomy. A Foley catheter was inserted and provided a short period of relief.

Following the visit, however, his abdominal pain worsened. He also experienced increasing abdominal distention, a declining appetite, and persistent nausea. The patient said that he was unable to urinate and had not had a bowel movement in 6 days. He also described fevers, drenching night sweats, chills, and a 4-kg weight loss over 2 months.

On physical examination, the patient had a wasted appearance. He was afebrile, alert, and oriented, but anxious and writhing in pain. An abdominal examination revealed some distention, generalized guarding, and tenderness. There was dullness to percussion in all regions without rebound, and no caput medusa was noted. The remainder of the physical examination was unremarkable.

Pertinent laboratory values included negative screens for human immunodeficiency virus (HIV) 1 and 2, and a purified protein derivative test that produced 10 mm of induration at 48 hours. An interferon-gamma release assay was not performed following these results. A computerized tomography (CT) scan of the abdomen and pelvis with intravenous and oral contrast revealed thickening of the peritoneal lining with infiltration of the mesenteric fat and large loculated fluid collections in the abdominal cavity (FIGURE). A CT scan of the patient’s lungs showed some mild atelectasis with left-sided effusion.

After hospital admission, the patient spiked fevers as high as 103.3° F and developed progressively worsening ascites. An ultrasound-guided paracentesis was performed, during which almost 2 liters of yellow, hazy fluid was removed. Fluid and blood cultures were negative.

THE DIAGNOSIS

With a high clinical suspicion for tuberculosis (TB) peritonitis, we requested a surgical consultation and a peritoneal biopsy was performed. The patient was started on ethambutol, isoniazid, pyrazinamide, pyridoxine, and rifampin while the biopsy results were pending.

Pathology subsequently confirmed a diagnosis of TB peritonitis, reporting dense fibroconnective tissue with areas of chronic inflammation and occasional accumulations of histiocytes with multinucleated giant cells showing granulomatous inflammation. An acid-fast (AF) bacilli stain for Mycobacteria showed a single curved bacillus compatible with Mycobacterium tuberculosis.

The patient was discharged following a 3-week hospital stay. At his follow-up visit several weeks later, the patient reported marked improvement and increasing exercise tolerance. He had gained weight, and the abdominal distention and tenderness had resolved.

DISCUSSION

Worldwide, TB is one of the top 10 causes of death. The World Health Organization estimates that there were 1.4 million TB deaths globally in 2015.¹ And while rates of TB are decreasing in the United States, there was a resurgence from 1985 to 1992.² This was attributable to the HIV/acquired immunodeficiency syndrome epidemic, increased immigration from countries endemic for TB, and deterioration of the TB public health infrastructure.³

Transmission. M tuberculosis is a rod-shaped, nonspore-forming AF bacillus that typically infects the lungs, but may infect other areas of the body. Transmission typically occurs via airborne spread of droplets from an infected individual. Possible other methods of disease dissemination include ingestion of infected sputum, hematogenous spread from active pulmonary TB, or ingestion of contaminated milk or food.

M tuberculosis elicits a proinflammatory phase, which facilitates the formation of a granuloma within the host tissues. The host’s immune response to M tuberculosis plays a role in the risk of developing this type of TB.³

TB presentation is classified as pulmonary, extrapulmonary, or both. Clinicians are generally attentive to the classic symptoms of pulmonary TB: cough, weight loss, night sweats, and fever. Presentation of extrapulmonary TB, however, may vary.⁴

Black patients have a significantly higher incidence of extrapulmonary tuberculosis than nonblack counterparts.

According to one study, the most common presenting symptoms for peritoneal TB are weight loss, abdominal pain, and/or fever, all of which our patient experienced.⁵ In addition, our patient was an immigrant from Africa, and black patients have been shown to have a significantly higher incidence of extrapulmonary TB than their nonblack counterparts.⁶ Although our patient was HIV-negative, a recent meta-analysis confirmed the strong association between extrapulmonary TB and HIV, emphasizing the importance of including HIV screens in the standard work-up for TB.⁷

Other symptoms may include microcytosis, anemia, thrombocytosis, and an elevated erythrocyte sedimentation rate. Although a chest x-ray is often negative, advanced imaging, such as CT or magnetic resonance imaging, is often abnormal and may point to the diagnosis.⁵

Treatment of extrapulmonary TB is generally the same as that for pulmonary TB and, interestingly, the incidence of multi-drug resistant extrapulmonary TB is not necessarily higher than it is for pulmonary TB (<1% vs 1.6%).^3,7 In light of this, a standard regimen—like the one our patient received—is generally utilized for 6 to 9 months. Nonetheless, resistance testing should still be performed.^3,4

THE TAKEAWAY

While considered uncommon, more than 20% of TB cases in the United States are extrapulmonary (the most common form is TB lymphadenitis).^7,8 It is imperative to identify appropriate risk factors, including associated comorbidities, patient characteristics, and population/endemic differences in immigrant populations.

In this case, although the symptom combination of persistent abdominal pain, fever, and weight loss may not trigger suspicion of a TB diagnosis in isolation, combining the symptoms with knowledge of the patient’s immigration status should at least raise an eyebrow. Given their nonpulmonary symptoms, many of these patients will not present to pulmonologists, making diagnosis particularly relevant to primary care.

Over the course of a month, this 34-year-old woman had sought care at our facility—and another—on 3 separate occasions for painful bruises (visits #1 and #3) and deep vein thrombosis (DVT; visit #2). The bruises first appeared acutely on her arms (FIGURE 1A), prompting her first visit to our ED and leading to a hospital stay. Several weeks later, the patient developed new bruise-like lesions on her earlobes (FIGURE 1B), face, trunk, and lower extremities. In between these 2 visits, the patient was seen in another ED (and admitted) for right upper extremity DVT and was started on enoxaparin, followed by warfarin.

The patient had no history of trauma, but did have a 7-year history of cocaine abuse. The initial bruises appeared one week after using cocaine from a different dealer.

On her most recent visit, her vitals and physical examination were unremarkable, apart from the skin findings. Her complete blood count, complete metabolic panel, and urinalysis were unremarkable. On her previous admissions, the patient’s urine drug test had been positive for cocaine. She’d also tested positive for cytoplasmic antineutrophil cytoplasmic antibodies (c-ANCA), antinuclear antibodies (ANA), anti-double stranded DNA (anti-dsDNA), and anticardiolipin IgM.

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

Diagnosis: Levamisole-induced cutaneous vasculopathy

The patient was given a diagnosis of levamisole-induced cutaneous vasculopathy based on her history of cocaine use; the typical, painful palpable purpura with angulated borders and a necrotic center (retiform purpura); and positive immunologic markers.^1-5 DVT has also been reported in association with levamisole-induced vasculopathy.⁶

Intended for livestock. Levamisole is a pharmaceutical agent typically used as an anthelmintic in livestock, but, since 2007, it has increasingly been found as an adulterant in cocaine.⁷ According to the Drug Enforcement Administration, 71% of cocaine tested in 2009 contained levamisole.⁷

While levamisole is a pharmaceutical agent typically used as an anthelmintic in livestock, it has increasingly been found as an adulterant in cocaine.

Experts speculate that levamisole is used in the production process of cocaine to increase its volume and enhance its psychoactive effects.^1-4 In humans, levamisole’s immunomodulatory properties were once used to treat various cancers and immunologic conditions, but it was withdrawn from the US market in 2000 due to adverse effects.^1,2,4 Severe adverse reactions associated with levamisole include agranulocytosis, vascular occlusive disease, and thrombotic vasculopathy with or without vasculitis.^1,2

The incidence of levamisole-induced cutaneous vasculopathy is unknown. That said, it’s important to suspect the condition in cocaine users who present with retiform purpura. Earlobe lesions are characteristic, while involvement of other areas is variable.^2-4

Differential includes other causes of purpura

A number of conditions make up the differential. While each of these presents with areas of skin necrosis or purpura, a thorough history can be revealing. Factors such as substance abuse, recent treatment with a vitamin K antagonist, or even a recent infection can be the key to making the diagnosis.

Warfarin-induced skin necrosis presents with large, irregular bullae that eventually become necrotic. It appears one to 10 days after treatment with a vitamin K antagonist and typically affects areas of the body with greater subcutaneous adipose tissue, including the breasts, thighs, buttocks, and penis. Microscopic examination reveals bland thrombi with no inflammation of the vessel wall.⁵

ANCA-associated small-vessel vasculitis includes microscopic polyangiitis, Wegner’s granulomatosis, and Churg-Strauss syndrome. With these conditions, palpable purpuras are more commonly seen in areas that are dependent on, or affected by, venous stasis. Microscopic evaluation reveals leukocytoclastic vasculitis. Perinuclear ANCA is more often positive than c-ANCA.⁵

Purpura fulminans is a medical emergency characterized by skin necrosis and disseminated intravascular coagulation. It can rapidly lead to multi-organ failure. Microscopic evaluation reveals thrombotic occlusion of small- and medium-sized vessels. It affects neonates and children, and is associated with severe sepsis or an autoimmune response to an otherwise benign childhood infection. It may also be a symptom of hereditary protein C or protein S deficiency.⁸

Cholesterol emboli are more common in men ages 50 and older with atherosclerotic disease, hypertension, or tobacco use. Abrupt onset of livedo reticularis may be followed by retiform purpura, ulcers, nodules, and gangrene. Lesions most often appear on the distal lower extremities and buttocks. Systemic symptoms may include fever, weight loss, myalgia, and altered mental status. Multiple organ systems may be involved. Frozen sections reveal needle-shaped clefts and doubly-refractile crystals.⁵

Evolving skin lesions, relevant lab findings

Initially, patients with levamisole-induced cutaneous vasculopathy will develop painful, palpable purpura with angulated borders and a necrotic center. The lesions can progress, though, to bullae, necrosis, or eschar formation.^1,3,4

Patients with this condition frequently test positive for ANCA and, even more frequently, for c-ANCA, ANA, antiphospholipid antibodies, leukopenia, and neutropenia. Other immunologic markers for which patients may test positive include anti-cardiolipin antibodies, lupus anticoagulant, anti-dsDNA, myeloperoxidase, and anti-Sjögren’s-syndrome-related antigen A (also known as anti-Ro) antibodies.^1-4

Natural progression of levamisole-induced cutaneous vasculopathy is generally benign. Most clinical signs and symptoms—as well as serologic manifestations—resolve without intervention after cessation of cocaine use. However, signs and symptoms may recur with subsequent exposure.

There is no specific therapy for levamisole-induced cutaneous vasculopathy, but prednisone and other immunosuppressive agents can be used in patients with severe or systemic symptoms.^1-4 Necrotic lesions and eschar formation may be complicated by infection and require debridement and/or skin grafts.

Our patient was discharged after a brief hospital stay, as she had no indication of systemic involvement and no new or worsening skin lesions. She was given wound care instructions and advised to stop using cocaine. The patient was counseled at bedside by a physician and given information on community resources (outpatient treatment, support groups, etc) by social services. However, the patient continued to use the substance and had several readmissions with worsening skin lesions complicated by secondary bacterial infection. She did not have systemic complications, but required antibiotics, multiple wound debridement sessions, and subsequent skin grafts.

CORRESPONDENCE
Yu Wah, MD, ABIHM, University of Texas Health Science Center at Houston, 6431 Fannin Street, Suite JJL 308, Houston, TX 77030; [email protected].

Over the course of a month, this 34-year-old woman had sought care at our facility—and another—on 3 separate occasions for painful bruises (visits #1 and #3) and deep vein thrombosis (DVT; visit #2). The bruises first appeared acutely on her arms (FIGURE 1A), prompting her first visit to our ED and leading to a hospital stay. Several weeks later, the patient developed new bruise-like lesions on her earlobes (FIGURE 1B), face, trunk, and lower extremities. In between these 2 visits, the patient was seen in another ED (and admitted) for right upper extremity DVT and was started on enoxaparin, followed by warfarin.

The patient had no history of trauma, but did have a 7-year history of cocaine abuse. The initial bruises appeared one week after using cocaine from a different dealer.

On her most recent visit, her vitals and physical examination were unremarkable, apart from the skin findings. Her complete blood count, complete metabolic panel, and urinalysis were unremarkable. On her previous admissions, the patient’s urine drug test had been positive for cocaine. She’d also tested positive for cytoplasmic antineutrophil cytoplasmic antibodies (c-ANCA), antinuclear antibodies (ANA), anti-double stranded DNA (anti-dsDNA), and anticardiolipin IgM.

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

Diagnosis: Levamisole-induced cutaneous vasculopathy

The patient was given a diagnosis of levamisole-induced cutaneous vasculopathy based on her history of cocaine use; the typical, painful palpable purpura with angulated borders and a necrotic center (retiform purpura); and positive immunologic markers.^1-5 DVT has also been reported in association with levamisole-induced vasculopathy.⁶

Intended for livestock. Levamisole is a pharmaceutical agent typically used as an anthelmintic in livestock, but, since 2007, it has increasingly been found as an adulterant in cocaine.⁷ According to the Drug Enforcement Administration, 71% of cocaine tested in 2009 contained levamisole.⁷

While levamisole is a pharmaceutical agent typically used as an anthelmintic in livestock, it has increasingly been found as an adulterant in cocaine.

Experts speculate that levamisole is used in the production process of cocaine to increase its volume and enhance its psychoactive effects.^1-4 In humans, levamisole’s immunomodulatory properties were once used to treat various cancers and immunologic conditions, but it was withdrawn from the US market in 2000 due to adverse effects.^1,2,4 Severe adverse reactions associated with levamisole include agranulocytosis, vascular occlusive disease, and thrombotic vasculopathy with or without vasculitis.^1,2

The incidence of levamisole-induced cutaneous vasculopathy is unknown. That said, it’s important to suspect the condition in cocaine users who present with retiform purpura. Earlobe lesions are characteristic, while involvement of other areas is variable.^2-4

Differential includes other causes of purpura

A number of conditions make up the differential. While each of these presents with areas of skin necrosis or purpura, a thorough history can be revealing. Factors such as substance abuse, recent treatment with a vitamin K antagonist, or even a recent infection can be the key to making the diagnosis.

Warfarin-induced skin necrosis presents with large, irregular bullae that eventually become necrotic. It appears one to 10 days after treatment with a vitamin K antagonist and typically affects areas of the body with greater subcutaneous adipose tissue, including the breasts, thighs, buttocks, and penis. Microscopic examination reveals bland thrombi with no inflammation of the vessel wall.⁵

ANCA-associated small-vessel vasculitis includes microscopic polyangiitis, Wegner’s granulomatosis, and Churg-Strauss syndrome. With these conditions, palpable purpuras are more commonly seen in areas that are dependent on, or affected by, venous stasis. Microscopic evaluation reveals leukocytoclastic vasculitis. Perinuclear ANCA is more often positive than c-ANCA.⁵

Purpura fulminans is a medical emergency characterized by skin necrosis and disseminated intravascular coagulation. It can rapidly lead to multi-organ failure. Microscopic evaluation reveals thrombotic occlusion of small- and medium-sized vessels. It affects neonates and children, and is associated with severe sepsis or an autoimmune response to an otherwise benign childhood infection. It may also be a symptom of hereditary protein C or protein S deficiency.⁸

Cholesterol emboli are more common in men ages 50 and older with atherosclerotic disease, hypertension, or tobacco use. Abrupt onset of livedo reticularis may be followed by retiform purpura, ulcers, nodules, and gangrene. Lesions most often appear on the distal lower extremities and buttocks. Systemic symptoms may include fever, weight loss, myalgia, and altered mental status. Multiple organ systems may be involved. Frozen sections reveal needle-shaped clefts and doubly-refractile crystals.⁵

Evolving skin lesions, relevant lab findings

Initially, patients with levamisole-induced cutaneous vasculopathy will develop painful, palpable purpura with angulated borders and a necrotic center. The lesions can progress, though, to bullae, necrosis, or eschar formation.^1,3,4

Patients with this condition frequently test positive for ANCA and, even more frequently, for c-ANCA, ANA, antiphospholipid antibodies, leukopenia, and neutropenia. Other immunologic markers for which patients may test positive include anti-cardiolipin antibodies, lupus anticoagulant, anti-dsDNA, myeloperoxidase, and anti-Sjögren’s-syndrome-related antigen A (also known as anti-Ro) antibodies.^1-4

Natural progression of levamisole-induced cutaneous vasculopathy is generally benign. Most clinical signs and symptoms—as well as serologic manifestations—resolve without intervention after cessation of cocaine use. However, signs and symptoms may recur with subsequent exposure.

There is no specific therapy for levamisole-induced cutaneous vasculopathy, but prednisone and other immunosuppressive agents can be used in patients with severe or systemic symptoms.^1-4 Necrotic lesions and eschar formation may be complicated by infection and require debridement and/or skin grafts.

Our patient was discharged after a brief hospital stay, as she had no indication of systemic involvement and no new or worsening skin lesions. She was given wound care instructions and advised to stop using cocaine. The patient was counseled at bedside by a physician and given information on community resources (outpatient treatment, support groups, etc) by social services. However, the patient continued to use the substance and had several readmissions with worsening skin lesions complicated by secondary bacterial infection. She did not have systemic complications, but required antibiotics, multiple wound debridement sessions, and subsequent skin grafts.

CORRESPONDENCE
Yu Wah, MD, ABIHM, University of Texas Health Science Center at Houston, 6431 Fannin Street, Suite JJL 308, Houston, TX 77030; [email protected].

Over the course of a month, this 34-year-old woman had sought care at our facility—and another—on 3 separate occasions for painful bruises (visits #1 and #3) and deep vein thrombosis (DVT; visit #2). The bruises first appeared acutely on her arms (FIGURE 1A), prompting her first visit to our ED and leading to a hospital stay. Several weeks later, the patient developed new bruise-like lesions on her earlobes (FIGURE 1B), face, trunk, and lower extremities. In between these 2 visits, the patient was seen in another ED (and admitted) for right upper extremity DVT and was started on enoxaparin, followed by warfarin.

The patient had no history of trauma, but did have a 7-year history of cocaine abuse. The initial bruises appeared one week after using cocaine from a different dealer.

On her most recent visit, her vitals and physical examination were unremarkable, apart from the skin findings. Her complete blood count, complete metabolic panel, and urinalysis were unremarkable. On her previous admissions, the patient’s urine drug test had been positive for cocaine. She’d also tested positive for cytoplasmic antineutrophil cytoplasmic antibodies (c-ANCA), antinuclear antibodies (ANA), anti-double stranded DNA (anti-dsDNA), and anticardiolipin IgM.

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

Diagnosis: Levamisole-induced cutaneous vasculopathy

The patient was given a diagnosis of levamisole-induced cutaneous vasculopathy based on her history of cocaine use; the typical, painful palpable purpura with angulated borders and a necrotic center (retiform purpura); and positive immunologic markers.^1-5 DVT has also been reported in association with levamisole-induced vasculopathy.⁶

Intended for livestock. Levamisole is a pharmaceutical agent typically used as an anthelmintic in livestock, but, since 2007, it has increasingly been found as an adulterant in cocaine.⁷ According to the Drug Enforcement Administration, 71% of cocaine tested in 2009 contained levamisole.⁷

While levamisole is a pharmaceutical agent typically used as an anthelmintic in livestock, it has increasingly been found as an adulterant in cocaine.

Experts speculate that levamisole is used in the production process of cocaine to increase its volume and enhance its psychoactive effects.^1-4 In humans, levamisole’s immunomodulatory properties were once used to treat various cancers and immunologic conditions, but it was withdrawn from the US market in 2000 due to adverse effects.^1,2,4 Severe adverse reactions associated with levamisole include agranulocytosis, vascular occlusive disease, and thrombotic vasculopathy with or without vasculitis.^1,2

The incidence of levamisole-induced cutaneous vasculopathy is unknown. That said, it’s important to suspect the condition in cocaine users who present with retiform purpura. Earlobe lesions are characteristic, while involvement of other areas is variable.^2-4

Differential includes other causes of purpura

A number of conditions make up the differential. While each of these presents with areas of skin necrosis or purpura, a thorough history can be revealing. Factors such as substance abuse, recent treatment with a vitamin K antagonist, or even a recent infection can be the key to making the diagnosis.

Warfarin-induced skin necrosis presents with large, irregular bullae that eventually become necrotic. It appears one to 10 days after treatment with a vitamin K antagonist and typically affects areas of the body with greater subcutaneous adipose tissue, including the breasts, thighs, buttocks, and penis. Microscopic examination reveals bland thrombi with no inflammation of the vessel wall.⁵

ANCA-associated small-vessel vasculitis includes microscopic polyangiitis, Wegner’s granulomatosis, and Churg-Strauss syndrome. With these conditions, palpable purpuras are more commonly seen in areas that are dependent on, or affected by, venous stasis. Microscopic evaluation reveals leukocytoclastic vasculitis. Perinuclear ANCA is more often positive than c-ANCA.⁵

Purpura fulminans is a medical emergency characterized by skin necrosis and disseminated intravascular coagulation. It can rapidly lead to multi-organ failure. Microscopic evaluation reveals thrombotic occlusion of small- and medium-sized vessels. It affects neonates and children, and is associated with severe sepsis or an autoimmune response to an otherwise benign childhood infection. It may also be a symptom of hereditary protein C or protein S deficiency.⁸

Cholesterol emboli are more common in men ages 50 and older with atherosclerotic disease, hypertension, or tobacco use. Abrupt onset of livedo reticularis may be followed by retiform purpura, ulcers, nodules, and gangrene. Lesions most often appear on the distal lower extremities and buttocks. Systemic symptoms may include fever, weight loss, myalgia, and altered mental status. Multiple organ systems may be involved. Frozen sections reveal needle-shaped clefts and doubly-refractile crystals.⁵

Evolving skin lesions, relevant lab findings

Initially, patients with levamisole-induced cutaneous vasculopathy will develop painful, palpable purpura with angulated borders and a necrotic center. The lesions can progress, though, to bullae, necrosis, or eschar formation.^1,3,4

Patients with this condition frequently test positive for ANCA and, even more frequently, for c-ANCA, ANA, antiphospholipid antibodies, leukopenia, and neutropenia. Other immunologic markers for which patients may test positive include anti-cardiolipin antibodies, lupus anticoagulant, anti-dsDNA, myeloperoxidase, and anti-Sjögren’s-syndrome-related antigen A (also known as anti-Ro) antibodies.^1-4

Natural progression of levamisole-induced cutaneous vasculopathy is generally benign. Most clinical signs and symptoms—as well as serologic manifestations—resolve without intervention after cessation of cocaine use. However, signs and symptoms may recur with subsequent exposure.

There is no specific therapy for levamisole-induced cutaneous vasculopathy, but prednisone and other immunosuppressive agents can be used in patients with severe or systemic symptoms.^1-4 Necrotic lesions and eschar formation may be complicated by infection and require debridement and/or skin grafts.

Our patient was discharged after a brief hospital stay, as she had no indication of systemic involvement and no new or worsening skin lesions. She was given wound care instructions and advised to stop using cocaine. The patient was counseled at bedside by a physician and given information on community resources (outpatient treatment, support groups, etc) by social services. However, the patient continued to use the substance and had several readmissions with worsening skin lesions complicated by secondary bacterial infection. She did not have systemic complications, but required antibiotics, multiple wound debridement sessions, and subsequent skin grafts.

CORRESPONDENCE
Yu Wah, MD, ABIHM, University of Texas Health Science Center at Houston, 6431 Fannin Street, Suite JJL 308, Houston, TX 77030; [email protected].