Living in a racially segregated neighborhood can be bad for the blood pressure (BP) if you are a black adult, according to Northwestern University researchers. They found that simply moving away from that neighborhood is enough to reduce systolic blood pressure 1 to 5 points.

In the study, which was partly funded by the NIH, the researchers examined BP readings for 2,280 black adults who participated in the Coronary Artery Risk Development in Young Adults (CARDIA) study. The participants were initially screened in 1985 and 1986 then reexamined several times over the next 25 years. The Northwestern study is the first to look at the longitudinal effects of segregation on BP compare the effect within the same individuals. Previous research had looked at single points in time.

The researchers categorized neighborhood segregation as high, medium, or low, using a scale that compareed the percentage of black residents in a neighborhood to the surrounding area. When neighborhoods were more segregated, the participants had small but statistically significant increases in systolic BP. Less segregation equaled a “notable” drop in BP.

Participants who lived in a highly segregated neighborhood and moved to a less segregated one saw the most significant improvements. Those who moved temporarily saw a 1 mm Hg drop. A permanent move equaled 3 to 5 mm Hg. That’s a “powerful effect,” said lead author Kiarri Kershaw, assistant professor of preventive medicine at Northwestern. Just 1 mm Hg lower at the population level, she notes, could mean “meaningful” reductions in heart attacks, strokes, and heart failure. The associations persisted even after the researchers accounted for marital status, body mass index, smoking history, physical activity, and socioeconomic status of the community.

The changes in blood pressure were not related to poverty or household income. Kershaw says less stress, achieved by reducing exposure to violence and improving opportunities for socioeconomic mobility, is “likely a key factor.” Other factors that could help include improving access to health-promoting resources, such as full-service grocery stores, recreation centers, and health care clinics.

Living in a racially segregated neighborhood can be bad for the blood pressure (BP) if you are a black adult, according to Northwestern University researchers. They found that simply moving away from that neighborhood is enough to reduce systolic blood pressure 1 to 5 points.

In the study, which was partly funded by the NIH, the researchers examined BP readings for 2,280 black adults who participated in the Coronary Artery Risk Development in Young Adults (CARDIA) study. The participants were initially screened in 1985 and 1986 then reexamined several times over the next 25 years. The Northwestern study is the first to look at the longitudinal effects of segregation on BP compare the effect within the same individuals. Previous research had looked at single points in time.

The researchers categorized neighborhood segregation as high, medium, or low, using a scale that compareed the percentage of black residents in a neighborhood to the surrounding area. When neighborhoods were more segregated, the participants had small but statistically significant increases in systolic BP. Less segregation equaled a “notable” drop in BP.

Participants who lived in a highly segregated neighborhood and moved to a less segregated one saw the most significant improvements. Those who moved temporarily saw a 1 mm Hg drop. A permanent move equaled 3 to 5 mm Hg. That’s a “powerful effect,” said lead author Kiarri Kershaw, assistant professor of preventive medicine at Northwestern. Just 1 mm Hg lower at the population level, she notes, could mean “meaningful” reductions in heart attacks, strokes, and heart failure. The associations persisted even after the researchers accounted for marital status, body mass index, smoking history, physical activity, and socioeconomic status of the community.

The changes in blood pressure were not related to poverty or household income. Kershaw says less stress, achieved by reducing exposure to violence and improving opportunities for socioeconomic mobility, is “likely a key factor.” Other factors that could help include improving access to health-promoting resources, such as full-service grocery stores, recreation centers, and health care clinics.

Living in a racially segregated neighborhood can be bad for the blood pressure (BP) if you are a black adult, according to Northwestern University researchers. They found that simply moving away from that neighborhood is enough to reduce systolic blood pressure 1 to 5 points.

In the study, which was partly funded by the NIH, the researchers examined BP readings for 2,280 black adults who participated in the Coronary Artery Risk Development in Young Adults (CARDIA) study. The participants were initially screened in 1985 and 1986 then reexamined several times over the next 25 years. The Northwestern study is the first to look at the longitudinal effects of segregation on BP compare the effect within the same individuals. Previous research had looked at single points in time.

The researchers categorized neighborhood segregation as high, medium, or low, using a scale that compareed the percentage of black residents in a neighborhood to the surrounding area. When neighborhoods were more segregated, the participants had small but statistically significant increases in systolic BP. Less segregation equaled a “notable” drop in BP.

Participants who lived in a highly segregated neighborhood and moved to a less segregated one saw the most significant improvements. Those who moved temporarily saw a 1 mm Hg drop. A permanent move equaled 3 to 5 mm Hg. That’s a “powerful effect,” said lead author Kiarri Kershaw, assistant professor of preventive medicine at Northwestern. Just 1 mm Hg lower at the population level, she notes, could mean “meaningful” reductions in heart attacks, strokes, and heart failure. The associations persisted even after the researchers accounted for marital status, body mass index, smoking history, physical activity, and socioeconomic status of the community.

The changes in blood pressure were not related to poverty or household income. Kershaw says less stress, achieved by reducing exposure to violence and improving opportunities for socioeconomic mobility, is “likely a key factor.” Other factors that could help include improving access to health-promoting resources, such as full-service grocery stores, recreation centers, and health care clinics.

IN THIS ARTICLE

• Diagnostic criteria
• Pharmacologic management
• Patient education

A more severe variant of peptic ulcer disease, Zollinger-Ellison syndrome (ZES) is a rare, chronic, and potentially life-threatening ulcerative disorder. Because the syndrome can be easily misdiagnosed based on clinical presentation alone, primary care clinicians need to be aware of its diagnostic features and know when referral to a gastroenterologist is necessary. Clinicians should suspect ZES in patients with peptic ulcer disease that is refractory to traditional medications.

Caused by a gastrin-secreting neuroendocrine tumor of the pancreas or duodenum called a gastrinoma, ZES can be benign or malignant. It typically manifests in white men ages 30 to 50.¹ Due to the significant number of patients treated for a benign cause of peptic ulcer disease (eg, Helicobacter pylori or NSAID-induced ulcers) who are never tested for ZES, the exact incidence is difficult to determine.² However, it is estimated that approximately 0.1 to 3 people per million develop the disease annually.³

PATHOPHYSIOLOGY

Approximately 80% of gastrinomas occur in the “gastrinoma triangle,” outlined by the hepatic portal vein, neck and body of the pancreas, and latter two-thirds of the duodenum (see Figure).^1,4,5 Most gastrinomas involved in ZES occur sporadically, but there is a hereditary component associated with multiple endocrine neoplasia type 1 (MEN1), an autosomal dominant disorder.⁴

The overproduction and secretion of gastrin by the gastrinoma stimulates hypersecretion of hydrochloric acid.⁴ This is distinguished from high gastrin levels in the setting of fasting hypochlorhydria or achlorhydria, which may be caused by chronic atrophic gastritis, proton pump inhibitor (PPI) use, or pernicious anemia.⁵ The chronic hypersecretion of acid causes ulcerations to form. Most commonly, a single ulcer forms in the first portion of the duodenum.³

CLINICAL PRESENTATION

Patients with ZES often report vague abdominal pain that may mimic peptic ulcer disease on initial presentation. The widespread use of PPIs can mask symptoms, and one-fourth of patients present with no abdominal pain at all.⁶ Patients may also present with symptoms of GERD (ie, heartburn, chest pain, dysphagia).^1,4 Excessive acid production can lead to the development of Barrett esophagus, which can further complicate the management of ZES.⁶ Half of all patients with ZES have diarrhea, which can manifest on its own or be accompanied by other abdominal complaints, and is often attributed to lower GI problems such as Crohn disease.^1,7 Family history of MEN1 should raise suspicion for ZES; however, 80% of ZES cases occur sporadically.³

The physical exam may be within normal limits, and no physical finding is considered pathognomonic for ZES. Findings may include epigastric tenderness; pallor, due to an ulcer-related anemia or GI bleed; jaundice, if there is liver involvement; and esophageal or dental erosions, due to excessive acid.⁸

DIAGNOSIS

Patients with symptoms refractory to medical management should be referred to a specialist for further testing. Once a patient is referred, a gastroenterologist will perform lab tests and imaging studies. In order to be diagnosed with ZES, the patient must exhibit an acidic environment with a pH less than 2 and an inappropriate release of gastrin with a basal acid output greater than 15 mEq/h (or > 5 mEq/h in a patient with prior acid reduction surgery).^5,6

Fasting serum gastrin (FSG) is the initial study of choice, followed by a secretin-stimulating test when necessary.⁹ Diagnosis is established by an FSG level greater than 100 pg/mL; if more than 10-fold the normal level, no further testing is needed. However, results often range from 100 to 1,000 pg/mL.^6,10 At these values, further testing with secretin stimulation is warranted.⁹ The test is performed with an IV injection of secretin, and blood samples are obtained to measure serum gastrin levels.¹⁰ An increase greater than 100 pg/mL is considered positive; one greater than 200 pg/mL is diagnostic.³

Once lab tests have been performed, a series of imaging studies are indicated. Endoscopy is used to identify active ulcers and erosions due to long-term acid secretion.³ CT, MRI, and somatostatin receptor scintigraphy (a specialized form of imaging that is the study of choice for localizing gastrinomas) are performed to localize primary tumors and identify any metastatic disease that may be present.¹⁰ Finally, after lab tests and imaging studies have been completed, genetic screening for MEN1 is used to determine if the patient has a sporadic or hereditary gastrinoma.³

MANAGEMENT

Once ZES has been diagnosed, the specialist will refer the patient for surgical opinion. The main objectives of surgery are to determine whether the tumor is malignant via biopsy, and to resect the tumor to suppress the acid hypersecretion, if indicated in the absence of liver metastasis and large pancreatic tumor size. Medical management should begin immediately to prevent any further damage from prolonged gastric hypersecretion.¹

Pharmacologic options include PPIs, H2-receptor antagonists, and somatostatin analogues; PPIs are considered firstline therapy. Many patients with ZES require a higher dosage than is needed with typical GERD (60-100 mg/d vs 20-40 mg/d). Somatostatin analogues can be used in conjunction with PPIs and have been shown to inhibit tumor growth in patients with malignant ZES.¹

Once a ZES diagnosis has been made, the tumor(s) resected (if appropriate), and vagotomy considered or performed, patients will need routine follow-up with their gastroenterologist and their primary care provider, who can manage medications and recommend any lifestyle changes.⁵

PROGNOSIS

The most important prognostic factor of patients with ZES is whether the gastrinoma is benign or malignant. There are two patterns: aggressive disease (25%) and nonaggressive disease (75%).⁵ At diagnosis, 40% to 70% of patients with sporadic ZES present with lymph node metastases, and 20% to 40% present with liver metastases. Patients with liver metastases have a 10-year survival rate of 30%, compared to a 15-year survival rate of 83% in patients without liver metastases.^11,12

Along with the tumor itself, another prognostic factor to consider is the FSG level at diagnosis. Patients with higher FSG levels have decreased five- and 10-year survival rates compared to patients with lower FSG values. The 10-year survival rate for patients with a lower FSG value (0-499 pg/mL) is 86%, while the 10-year survival rate for those with a greater FSG value (> 1,000 pg/mL) is 73%.^11,12 Overall, the prognosis is good for patients with ZES. The 10-year survival rate is high, and management is possible with medications and surgical resection of the gastrinoma.

PATIENT EDUCATION

Once patients are diagnosed, treatment with PPIs is typically lifelong unless they are considered cured by surgical resection. Patients need to understand that compliance is necessary to properly manage symptoms; certain foods, alcohol, and tobacco can affect the condition, and lifestyle modifications should be made, as they would with typical GERD or peptic ulcer disease.

CONCLUSION

ZES is frequently overlooked, and patients often continue to experience unresolved symptoms related to hypergastrinemia. Due to its complexity and ability to mimic other disorders—as well as the implications of duodenal versus pancreatic location, and other disorders of the kidney or endocrine system suggestive of MEN1—ZES should be ruled out in any patient with unexplained persistent GERD, peptic ulcer disease, elevated FSG, chronic diarrhea, and/or abdominal pain.⁵

The gastrinoma itself is a well-differentiated and slow-growing tumor in the majority of cases, making the prognosis for ZES favorable for long-term survival. Proper pharmacologic management is instrumental for controlling symptoms and decreasing acid production. Surgical resection offers patients the best chance for a complete cure. Clinicians and patients should be well educated about ZES in order to successfully manage the disorder.

IN THIS ARTICLE

• Diagnostic criteria
• Pharmacologic management
• Patient education

A more severe variant of peptic ulcer disease, Zollinger-Ellison syndrome (ZES) is a rare, chronic, and potentially life-threatening ulcerative disorder. Because the syndrome can be easily misdiagnosed based on clinical presentation alone, primary care clinicians need to be aware of its diagnostic features and know when referral to a gastroenterologist is necessary. Clinicians should suspect ZES in patients with peptic ulcer disease that is refractory to traditional medications.

Caused by a gastrin-secreting neuroendocrine tumor of the pancreas or duodenum called a gastrinoma, ZES can be benign or malignant. It typically manifests in white men ages 30 to 50.¹ Due to the significant number of patients treated for a benign cause of peptic ulcer disease (eg, Helicobacter pylori or NSAID-induced ulcers) who are never tested for ZES, the exact incidence is difficult to determine.² However, it is estimated that approximately 0.1 to 3 people per million develop the disease annually.³

PATHOPHYSIOLOGY

Approximately 80% of gastrinomas occur in the “gastrinoma triangle,” outlined by the hepatic portal vein, neck and body of the pancreas, and latter two-thirds of the duodenum (see Figure).^1,4,5 Most gastrinomas involved in ZES occur sporadically, but there is a hereditary component associated with multiple endocrine neoplasia type 1 (MEN1), an autosomal dominant disorder.⁴

The overproduction and secretion of gastrin by the gastrinoma stimulates hypersecretion of hydrochloric acid.⁴ This is distinguished from high gastrin levels in the setting of fasting hypochlorhydria or achlorhydria, which may be caused by chronic atrophic gastritis, proton pump inhibitor (PPI) use, or pernicious anemia.⁵ The chronic hypersecretion of acid causes ulcerations to form. Most commonly, a single ulcer forms in the first portion of the duodenum.³

CLINICAL PRESENTATION

Patients with ZES often report vague abdominal pain that may mimic peptic ulcer disease on initial presentation. The widespread use of PPIs can mask symptoms, and one-fourth of patients present with no abdominal pain at all.⁶ Patients may also present with symptoms of GERD (ie, heartburn, chest pain, dysphagia).^1,4 Excessive acid production can lead to the development of Barrett esophagus, which can further complicate the management of ZES.⁶ Half of all patients with ZES have diarrhea, which can manifest on its own or be accompanied by other abdominal complaints, and is often attributed to lower GI problems such as Crohn disease.^1,7 Family history of MEN1 should raise suspicion for ZES; however, 80% of ZES cases occur sporadically.³

The physical exam may be within normal limits, and no physical finding is considered pathognomonic for ZES. Findings may include epigastric tenderness; pallor, due to an ulcer-related anemia or GI bleed; jaundice, if there is liver involvement; and esophageal or dental erosions, due to excessive acid.⁸

DIAGNOSIS

Patients with symptoms refractory to medical management should be referred to a specialist for further testing. Once a patient is referred, a gastroenterologist will perform lab tests and imaging studies. In order to be diagnosed with ZES, the patient must exhibit an acidic environment with a pH less than 2 and an inappropriate release of gastrin with a basal acid output greater than 15 mEq/h (or > 5 mEq/h in a patient with prior acid reduction surgery).^5,6

Fasting serum gastrin (FSG) is the initial study of choice, followed by a secretin-stimulating test when necessary.⁹ Diagnosis is established by an FSG level greater than 100 pg/mL; if more than 10-fold the normal level, no further testing is needed. However, results often range from 100 to 1,000 pg/mL.^6,10 At these values, further testing with secretin stimulation is warranted.⁹ The test is performed with an IV injection of secretin, and blood samples are obtained to measure serum gastrin levels.¹⁰ An increase greater than 100 pg/mL is considered positive; one greater than 200 pg/mL is diagnostic.³

Once lab tests have been performed, a series of imaging studies are indicated. Endoscopy is used to identify active ulcers and erosions due to long-term acid secretion.³ CT, MRI, and somatostatin receptor scintigraphy (a specialized form of imaging that is the study of choice for localizing gastrinomas) are performed to localize primary tumors and identify any metastatic disease that may be present.¹⁰ Finally, after lab tests and imaging studies have been completed, genetic screening for MEN1 is used to determine if the patient has a sporadic or hereditary gastrinoma.³

MANAGEMENT

Once ZES has been diagnosed, the specialist will refer the patient for surgical opinion. The main objectives of surgery are to determine whether the tumor is malignant via biopsy, and to resect the tumor to suppress the acid hypersecretion, if indicated in the absence of liver metastasis and large pancreatic tumor size. Medical management should begin immediately to prevent any further damage from prolonged gastric hypersecretion.¹

Pharmacologic options include PPIs, H2-receptor antagonists, and somatostatin analogues; PPIs are considered firstline therapy. Many patients with ZES require a higher dosage than is needed with typical GERD (60-100 mg/d vs 20-40 mg/d). Somatostatin analogues can be used in conjunction with PPIs and have been shown to inhibit tumor growth in patients with malignant ZES.¹

Once a ZES diagnosis has been made, the tumor(s) resected (if appropriate), and vagotomy considered or performed, patients will need routine follow-up with their gastroenterologist and their primary care provider, who can manage medications and recommend any lifestyle changes.⁵

PROGNOSIS

The most important prognostic factor of patients with ZES is whether the gastrinoma is benign or malignant. There are two patterns: aggressive disease (25%) and nonaggressive disease (75%).⁵ At diagnosis, 40% to 70% of patients with sporadic ZES present with lymph node metastases, and 20% to 40% present with liver metastases. Patients with liver metastases have a 10-year survival rate of 30%, compared to a 15-year survival rate of 83% in patients without liver metastases.^11,12

Along with the tumor itself, another prognostic factor to consider is the FSG level at diagnosis. Patients with higher FSG levels have decreased five- and 10-year survival rates compared to patients with lower FSG values. The 10-year survival rate for patients with a lower FSG value (0-499 pg/mL) is 86%, while the 10-year survival rate for those with a greater FSG value (> 1,000 pg/mL) is 73%.^11,12 Overall, the prognosis is good for patients with ZES. The 10-year survival rate is high, and management is possible with medications and surgical resection of the gastrinoma.

PATIENT EDUCATION

Once patients are diagnosed, treatment with PPIs is typically lifelong unless they are considered cured by surgical resection. Patients need to understand that compliance is necessary to properly manage symptoms; certain foods, alcohol, and tobacco can affect the condition, and lifestyle modifications should be made, as they would with typical GERD or peptic ulcer disease.

CONCLUSION

ZES is frequently overlooked, and patients often continue to experience unresolved symptoms related to hypergastrinemia. Due to its complexity and ability to mimic other disorders—as well as the implications of duodenal versus pancreatic location, and other disorders of the kidney or endocrine system suggestive of MEN1—ZES should be ruled out in any patient with unexplained persistent GERD, peptic ulcer disease, elevated FSG, chronic diarrhea, and/or abdominal pain.⁵

The gastrinoma itself is a well-differentiated and slow-growing tumor in the majority of cases, making the prognosis for ZES favorable for long-term survival. Proper pharmacologic management is instrumental for controlling symptoms and decreasing acid production. Surgical resection offers patients the best chance for a complete cure. Clinicians and patients should be well educated about ZES in order to successfully manage the disorder.

IN THIS ARTICLE

• Diagnostic criteria
• Pharmacologic management
• Patient education

A more severe variant of peptic ulcer disease, Zollinger-Ellison syndrome (ZES) is a rare, chronic, and potentially life-threatening ulcerative disorder. Because the syndrome can be easily misdiagnosed based on clinical presentation alone, primary care clinicians need to be aware of its diagnostic features and know when referral to a gastroenterologist is necessary. Clinicians should suspect ZES in patients with peptic ulcer disease that is refractory to traditional medications.

Caused by a gastrin-secreting neuroendocrine tumor of the pancreas or duodenum called a gastrinoma, ZES can be benign or malignant. It typically manifests in white men ages 30 to 50.¹ Due to the significant number of patients treated for a benign cause of peptic ulcer disease (eg, Helicobacter pylori or NSAID-induced ulcers) who are never tested for ZES, the exact incidence is difficult to determine.² However, it is estimated that approximately 0.1 to 3 people per million develop the disease annually.³

PATHOPHYSIOLOGY

Approximately 80% of gastrinomas occur in the “gastrinoma triangle,” outlined by the hepatic portal vein, neck and body of the pancreas, and latter two-thirds of the duodenum (see Figure).^1,4,5 Most gastrinomas involved in ZES occur sporadically, but there is a hereditary component associated with multiple endocrine neoplasia type 1 (MEN1), an autosomal dominant disorder.⁴

The overproduction and secretion of gastrin by the gastrinoma stimulates hypersecretion of hydrochloric acid.⁴ This is distinguished from high gastrin levels in the setting of fasting hypochlorhydria or achlorhydria, which may be caused by chronic atrophic gastritis, proton pump inhibitor (PPI) use, or pernicious anemia.⁵ The chronic hypersecretion of acid causes ulcerations to form. Most commonly, a single ulcer forms in the first portion of the duodenum.³

CLINICAL PRESENTATION

Patients with ZES often report vague abdominal pain that may mimic peptic ulcer disease on initial presentation. The widespread use of PPIs can mask symptoms, and one-fourth of patients present with no abdominal pain at all.⁶ Patients may also present with symptoms of GERD (ie, heartburn, chest pain, dysphagia).^1,4 Excessive acid production can lead to the development of Barrett esophagus, which can further complicate the management of ZES.⁶ Half of all patients with ZES have diarrhea, which can manifest on its own or be accompanied by other abdominal complaints, and is often attributed to lower GI problems such as Crohn disease.^1,7 Family history of MEN1 should raise suspicion for ZES; however, 80% of ZES cases occur sporadically.³

The physical exam may be within normal limits, and no physical finding is considered pathognomonic for ZES. Findings may include epigastric tenderness; pallor, due to an ulcer-related anemia or GI bleed; jaundice, if there is liver involvement; and esophageal or dental erosions, due to excessive acid.⁸

DIAGNOSIS

Patients with symptoms refractory to medical management should be referred to a specialist for further testing. Once a patient is referred, a gastroenterologist will perform lab tests and imaging studies. In order to be diagnosed with ZES, the patient must exhibit an acidic environment with a pH less than 2 and an inappropriate release of gastrin with a basal acid output greater than 15 mEq/h (or > 5 mEq/h in a patient with prior acid reduction surgery).^5,6

Fasting serum gastrin (FSG) is the initial study of choice, followed by a secretin-stimulating test when necessary.⁹ Diagnosis is established by an FSG level greater than 100 pg/mL; if more than 10-fold the normal level, no further testing is needed. However, results often range from 100 to 1,000 pg/mL.^6,10 At these values, further testing with secretin stimulation is warranted.⁹ The test is performed with an IV injection of secretin, and blood samples are obtained to measure serum gastrin levels.¹⁰ An increase greater than 100 pg/mL is considered positive; one greater than 200 pg/mL is diagnostic.³

Once lab tests have been performed, a series of imaging studies are indicated. Endoscopy is used to identify active ulcers and erosions due to long-term acid secretion.³ CT, MRI, and somatostatin receptor scintigraphy (a specialized form of imaging that is the study of choice for localizing gastrinomas) are performed to localize primary tumors and identify any metastatic disease that may be present.¹⁰ Finally, after lab tests and imaging studies have been completed, genetic screening for MEN1 is used to determine if the patient has a sporadic or hereditary gastrinoma.³

MANAGEMENT

Once ZES has been diagnosed, the specialist will refer the patient for surgical opinion. The main objectives of surgery are to determine whether the tumor is malignant via biopsy, and to resect the tumor to suppress the acid hypersecretion, if indicated in the absence of liver metastasis and large pancreatic tumor size. Medical management should begin immediately to prevent any further damage from prolonged gastric hypersecretion.¹

Pharmacologic options include PPIs, H2-receptor antagonists, and somatostatin analogues; PPIs are considered firstline therapy. Many patients with ZES require a higher dosage than is needed with typical GERD (60-100 mg/d vs 20-40 mg/d). Somatostatin analogues can be used in conjunction with PPIs and have been shown to inhibit tumor growth in patients with malignant ZES.¹

Once a ZES diagnosis has been made, the tumor(s) resected (if appropriate), and vagotomy considered or performed, patients will need routine follow-up with their gastroenterologist and their primary care provider, who can manage medications and recommend any lifestyle changes.⁵

PROGNOSIS

The most important prognostic factor of patients with ZES is whether the gastrinoma is benign or malignant. There are two patterns: aggressive disease (25%) and nonaggressive disease (75%).⁵ At diagnosis, 40% to 70% of patients with sporadic ZES present with lymph node metastases, and 20% to 40% present with liver metastases. Patients with liver metastases have a 10-year survival rate of 30%, compared to a 15-year survival rate of 83% in patients without liver metastases.^11,12

Along with the tumor itself, another prognostic factor to consider is the FSG level at diagnosis. Patients with higher FSG levels have decreased five- and 10-year survival rates compared to patients with lower FSG values. The 10-year survival rate for patients with a lower FSG value (0-499 pg/mL) is 86%, while the 10-year survival rate for those with a greater FSG value (> 1,000 pg/mL) is 73%.^11,12 Overall, the prognosis is good for patients with ZES. The 10-year survival rate is high, and management is possible with medications and surgical resection of the gastrinoma.

PATIENT EDUCATION

Once patients are diagnosed, treatment with PPIs is typically lifelong unless they are considered cured by surgical resection. Patients need to understand that compliance is necessary to properly manage symptoms; certain foods, alcohol, and tobacco can affect the condition, and lifestyle modifications should be made, as they would with typical GERD or peptic ulcer disease.

CONCLUSION

ZES is frequently overlooked, and patients often continue to experience unresolved symptoms related to hypergastrinemia. Due to its complexity and ability to mimic other disorders—as well as the implications of duodenal versus pancreatic location, and other disorders of the kidney or endocrine system suggestive of MEN1—ZES should be ruled out in any patient with unexplained persistent GERD, peptic ulcer disease, elevated FSG, chronic diarrhea, and/or abdominal pain.⁵

The gastrinoma itself is a well-differentiated and slow-growing tumor in the majority of cases, making the prognosis for ZES favorable for long-term survival. Proper pharmacologic management is instrumental for controlling symptoms and decreasing acid production. Surgical resection offers patients the best chance for a complete cure. Clinicians and patients should be well educated about ZES in order to successfully manage the disorder.

CASE An 82-year-old woman with a history of hypertension, diabetes, hyperlipidemia, stage 3 chronic kidney disease, anxiety, urge urinary incontinence, constipation, and bilateral knee osteoarthritis presents to her primary care physician’s office after a fall. She reports that she visited the emergency department (ED) a week ago after falling in the middle of the night on her way to the bathroom. This is the third fall she’s had this year. On chart review, she had a blood pressure (BP) of 112/60 mm Hg and a blood glucose level of 65 mg/dL in the ED. All other testing (head imaging, chest x-ray, urinalysis) was normal. The ED physician recommended that she stop taking her lisinopril-hydrochlorothiazide (HCTZ) and glipizide extended release (XL) until her follow-up appointment. Today, she asks about the need to restart these medications.

Polypharmacy is common among older adults due to a high prevalence of chronic conditions that often require multiple medications for optimal management. Cut points of 5 or 9 medications are frequently used to define polypharmacy. However, some define polypharmacy as taking a medication that lacks an indication, is ineffective, or is duplicating treatment provided by another medication.

Either way, polypharmacy is associated with multiple negative consequences, including an increased risk for adverse drug events (ADEs),^1-4 drug-drug and drug-disease interactions (TABLE 1^5,6),⁷ reduced functional capacity,⁸ multiple geriatric syndromes (TABLE 2^5,9-12), medication non-adherence,¹³ and increased mortality.¹⁴ Polypharmacy also contributes to increased health care costs for both the patient and the health care system.¹⁵

Taking a step back. Polypharmacy often results from prescribing cascades, which occur when an adverse drug effect is misinterpreted as a new medical problem, leading to the prescribing of more medication to treat the initial drug-induced symptom. Potentially inappropriate medications (PIMs), which are medications that should be avoided in older adults and in those with certain conditions, are also more likely to be prescribed in the setting of polypharmacy.¹⁶

Deprescribing is the process of identifying and discontinuing medications that are unnecessary, ineffective, and/or inappropriate in order to reduce polypharmacy and improve health outcomes. Deprescribing is a collaborative process that involves weighing the benefits and harms of medications in the context of a patient’s care goals, current level of functioning, life expectancy, values, and preferences. This article reviews polypharmacy and discusses safe and effective deprescribing strategies for older adults in the primary care setting.

[polldaddy:9781245]

How many people on how many meds?

Polypharmacy often occurs when an adverse drug effect is misinterpreted as a new medical problem, leading to the prescribing of more medication to treat the initial drug-induced symptom.According to a 2016 study, 36% of community-dwelling older adults (ages 62-85 years) were taking 5 or more prescription medications in 2010 to 2011—up from 31% in 2005 to 2006.¹⁷ When one narrows the population to older adults in the United States who are hospitalized, almost half (46%) take 7 or more medications.¹⁸ Among frail, older US veterans at hospital discharge, 40% were prescribed 9 or more medications, with 44% of these patients receiving at least one unnecessary drug.¹⁹

The challenges of multimorbidity

In the United States, 80% of those 65 and older have 2 or more chronic conditions, or multimorbidity.²⁰ Clinical practice guidelines making recommendations for the management of single conditions, such as heart failure, hypertension, or diabetes, often suggest the use of 2 or more medications to achieve optimal management and fail to provide guidance in the setting of multimorbidity. Following treatment recommendations for multiple conditions predictably leads to polypharmacy, with complicated, costly, and burdensome regimens.

Further, the research contributing to the development of clinical practice guidelines frequently excludes older adults and those with multimorbidity, reducing applicability in this population. As a result, many treatment recommendations have uncertain benefit and may be harmful in the multimorbid older patient.²¹

CASE In addition to the patient’s multimorbidity, she had a stroke at age 73 and has some mild residual left-sided weakness. Functionally, she is independent and able to perform her activities of daily living and her instrumental activities of daily living. She lives alone, quit smoking at age 65, and has an occasional glass of wine during family parties. The patient’s daughter and granddaughter live 2 blocks away.

The goal of deprescribing is to reduce polypharmacy and improve health outcomes.

Her current medications include glipizide XL 10 mg/d and lisinopril-HCTZ 20-25 mg/d, which she has temporarily discontinued at the ED doctor’s recommendation, as well as: amlodipine 10 mg/d, metformin 1000 mg BID, senna 8.6 mg/d, docusate 100 mg BID, furosemide 40 mg/d, and ibuprofen 600 mg/d (for knee pain). She reports taking omeprazole 20 mg/d “for almost 20 years,” even though she has not had any reflux symptoms in recent memory. After her stroke, she began taking atorvastatin 10 mg/d, aspirin 81 mg/d, and clopidogrel 75 mg/d, which she continues to take today. About a year ago, she started oxybutynin 5 mg/d for urinary incontinence, but she has not noticed significant relief. Additionally, she takes lorazepam 1 mg for insomnia most nights of the week.

IMAGE: ©BRIAN STAUFER 2017

A review of systems reveals issues with chronic constipation and intermittent dizziness, but is otherwise negative. The physical examination reveals a well-appearing woman with a body mass index of 26. Her temperature is 98.5° F, her heart rate is 78 beats/min and regular, her respirations are 14 breaths/min, and her BP is 117/65 mm Hg. Orthostatic testing is negative. Her heart, lung, and abdominal exams are within normal limits. Her timed up and go test is 14 seconds. Her blood glucose level today in the office after eating breakfast 2 hours ago is 135 mg/dL (normal: <140 mg/dL). Laboratory tests performed at the time of the ED visit show a creatinine level of 1.2 mg/dL (normal range: 0.6 to 1.1 mg/dL), a glomerular filtration rate (GFR) of 44 units (normal range: >60 units), a hemoglobin level of 9.8 g/dL (normal range: 12-15.5 g/dL), and a thyroid stimulating hormone level of 1.4 mIU/L (normal range: 0.5-8.9 mIU/L). A recent hemoglobin A1C is 6.8% (normal: <5.7%), low-density lipoprotein (LDL) level is 103 mg/dL (optimal <100 mg/dL), and high-density lipoprotein (HDL) level is 65 mg/dL (optimal >60 mg/dL). An echocardiogram performed a year ago showed mild aortic stenosis with normal systolic and diastolic function.

Starting the deprescribing process: Several approaches to choose from

The goal of deprescribing is to reduce polypharmacy and improve health outcomes. It is a process defined as, “reviewing all current medications; identifying medications to be ceased, substituted, or reduced; planning a deprescribing regimen in partnership with the patient; and frequently reviewing and supporting the patient.”²² A medication review should include prescription, over-the-counter (OTC), and complementary/­alternative medicine (CAM) agents.

More than one-third of US men and women ages 62 to 85 years are taking 5 or more prescription medications.Until recently, studies evaluating the process of deprescribing across drug classes and disease conditions were limited, but new research is beginning to show its potential impact. After deprescribing, patients experience fewer falls and show improvements in cognition.²³ While there have not yet been large randomized trials to evaluate deprescribing, a recent systematic review and meta-analysis showed that use of patient-specific deprescribing interventions is associated with improved survival.²⁴ Importantly, there have been no reported adverse drug withdrawal events or deaths associated with deprescribing.²³

Smaller studies have reported additional benefits including decreases in health care costs, reductions in drug-drug interactions and PIMs, improvements in medication adherence, and increases in patient satisfaction.²⁵ In addition, the removal of unnecessary medications may allow for increased consideration of prescribing appropriate medications with known benefit.²⁵

Practically speaking, every encounter between a patient and health care provider is an opportunity to reduce unnecessary medications. Electronic alert systems at pharmacies and those embedded within electronic health record (EHR) systems can also prompt a medication review and an effort to deprescribe.²⁶ Evidence-based tools to identify polypharm­acy and guide appropriate medication use are listed in TABLE 3.^5,6,27-30 In addition, suggested approaches to beginning the deprescribing process are included in TABLE 4.^5,31-33 And a medication class-based approach to deprescribing is provided in TABLE 5.^5,34-45

Although no gold standard process exists for deprescribing, experts suggest that any deprescribing protocol should include the following steps:^32,46

1. Start with a “brown bag” review of the patient’s medications.

Have the patient bring all of his/her medications in a bag to the visit; review them together or have the medication history taken by a pharmacist. Determine and discuss the indication for each medication and its effectiveness for that indication. Consider the potential benefits and harms of each medication in the context of the patient’s care goals and preferences. Assess whether the patient is taking all of the medications that have been prescribed, and identify any reasons for missed pills (eg, adverse effects, dosing regimens, understanding, cognitive issues).

2. Talk to the patient about the deprescribing process.

Talk with the patient about the risks and benefits of deprescribing, and prioritize which medications to address in the process. Prioritize the medications by balancing patient preferences with available pharmacologic evidence. If there is a lack of evidence supporting the benefits for a particular medication, consider known or suspected adverse effects, the ease or burden of the dosing regimen, the patient’s preferences and goals of care, remaining life expectancy, the time until drug benefit is appreciated, and the length of drug benefit after discontinuation.

3. Deprescribe medications.

If you are going to taper a medication, develop a schedule in partnership with the patient. Stop one medication at a time so that you can monitor for withdrawal symptoms or for the return of a condition.

Acknowledging potential barriers to deprescribing may help structure conversations and provide anticipatory guidance to patients and their families. Working to overcome these barriers will help maximize the benefits of deprescribing and help to build trust with patients.

Patient-driven barriers include fear of a condition worsening or returning, lack of a suitable alternative, lack of ongoing support to manage a particular condition, a previous bad experience with medication cessation, and influence from other care providers (eg, family, home caregivers, nurses, specialists, friends). Patients and family members sometimes cling to the hope of future effectiveness of a treatment, especially in the case of medications like donepezil for dementia.⁴⁷ Utilizing a team-based and stepwise patient approach to deprescribing aims to provide hesitant patients with appropriate amounts of education and support to begin to reduce unnecessary medicines.

Provider-driven barriers include feeling uneasy about contradicting a specialist’s recommendations for initiation/continuation of specific medications, fear of causing withdrawal symptoms or disease relapse, and lack of specific data to adequately understand and assess benefits and harms in the older adult population. Primary care physicians have also acknowledged worry about discussing life expectancy and that patients will feel their care is being reduced or “downgraded.”⁴⁸ Finally, there is limited time in which these complex shared decision-making conversations can take place. Thus, if medications are not causing a noticeable problem, it is often easier to just continue them.

Every encounter between a patient and health care provider is an opportunity to reduce unnecessary medications.

One way to overcome some of these concerns is to consider working with a clinical pharmacist. By gaining information regarding medication-specific factors, such as half-life and expected withdrawal patterns, you can feel more confident deprescribing or continuing medications.

Additionally, communicating closely with specialists, ideally with the help of an integra­ted EHR, can allow you to discuss indications for particular medications or concerns about adverse effects, limited benefits, or difficulty with compliance, so that you can develop a collaborative, cohesive, and patient-centered plan. This, in turn, may improve patient understanding and compliance.

4. Create a follow-up plan.

At the time of deprescribing a medication, develop a plan with the patient for monitoring and assessment. Ensure that the patient understands which symptoms may occur in the event of drug withdrawal and which symptoms may suggest the return of a condition. Make sure that other supports are in place if needed (eg, cognitive behavioral therapy, physical therapy, social support or assistance) to help ensure that medication cessation is successful.

CASE During the office visit, you advise the patient that her BP looks normal, her blood sugar is within an appropriate range, and she is lucky to have not sustained any injuries after her most recent fall. In addition to discussing the benefits of some outpatient physical therapy to help with her balance, you ask if she would like to discuss reducing her medications. She is agreeable and asks for your recommendations.

You are aware of several resources that can help you with your recommendations, among them the STOPP/START⁶ and Beers criteria,⁵ as well as the Good Geriatric-Palliative Algorithm.³⁰

If you were to use the STOPP/START and Beers criteria, you might consider stopping:

• lorazepam, which increases the risk of falls and confusion.
• ibuprofen, since this patient has only mild osteoarthritis pain, and ibuprofen has the potential for renal, cardiac, and gastrointestinal toxicities.
• oxybutynin, because it could be contributing to the patient’s constipation and cause confusion and falls.
• furosemide, since the patient has no clinical heart failure.
• omeprazole, since the indication is unknown and the patient has no history of ulceration, esophagitis, or symptomatic gastroesophageal reflux disease.

After reviewing the Good Geriatric-Palliative Algorithm,³⁰ you might consider stopping:

• clopidogrel, as there is no clear indication for this medication in combination with aspirin in this patient.
• glipizide XL, as this patient’s A1c is below goal and this medication puts her at risk of hypoglycemia and its associated morbidities.
• metformin, as it increases her risk of lactic acidosis because her GFR is <45 units.
• docusate, as the evidence to show clear benefit in improving chronic constipation in older adults is lacking.

There have been no reported adverse drug withdrawal events or deaths associated with deprescribing.

You tell your patient that there are multiple medications to consider stopping. In order to monitor any symptoms of withdrawal or return of a condition, it would be best to stop one at a time and follow-up closely. Since she has done well for the past week without the glipizide and lisinopril-HCTZ combination, she can remain off the glipizide and the HCTZ. Lisinopril, however, may provide renal protection in the setting of diabetes and will be continued at this time.

You ask her about adverse effects from her other medications. She indicates that the furosemide makes her run to the bathroom all the time, so she would like to try stopping it. You agree and make a plan for her to monitor her weight, watch for edema, and return in 4 weeks for a follow-up visit.

On follow-up, she is feeling well, has no edema on exam, and is happy to report her urinary incontinence has resolved. You therefore suggest her next deprescribing trial be discontinuation of her oxybutynin. She thanks you for your recommendations about her medications and heads off to her physical therapy appointment.

CORRESPONDENCE
Kathryn McGrath, MD, Department of Family and Community Medicine, Division of Geriatric Medicine and Palliative Care, Thomas Jefferson University, 2422 S Broad St, 2nd Floor, Philadelphia, PA 19145; [email protected].

CASE An 82-year-old woman with a history of hypertension, diabetes, hyperlipidemia, stage 3 chronic kidney disease, anxiety, urge urinary incontinence, constipation, and bilateral knee osteoarthritis presents to her primary care physician’s office after a fall. She reports that she visited the emergency department (ED) a week ago after falling in the middle of the night on her way to the bathroom. This is the third fall she’s had this year. On chart review, she had a blood pressure (BP) of 112/60 mm Hg and a blood glucose level of 65 mg/dL in the ED. All other testing (head imaging, chest x-ray, urinalysis) was normal. The ED physician recommended that she stop taking her lisinopril-hydrochlorothiazide (HCTZ) and glipizide extended release (XL) until her follow-up appointment. Today, she asks about the need to restart these medications.

Polypharmacy is common among older adults due to a high prevalence of chronic conditions that often require multiple medications for optimal management. Cut points of 5 or 9 medications are frequently used to define polypharmacy. However, some define polypharmacy as taking a medication that lacks an indication, is ineffective, or is duplicating treatment provided by another medication.

Either way, polypharmacy is associated with multiple negative consequences, including an increased risk for adverse drug events (ADEs),^1-4 drug-drug and drug-disease interactions (TABLE 1^5,6),⁷ reduced functional capacity,⁸ multiple geriatric syndromes (TABLE 2^5,9-12), medication non-adherence,¹³ and increased mortality.¹⁴ Polypharmacy also contributes to increased health care costs for both the patient and the health care system.¹⁵

Taking a step back. Polypharmacy often results from prescribing cascades, which occur when an adverse drug effect is misinterpreted as a new medical problem, leading to the prescribing of more medication to treat the initial drug-induced symptom. Potentially inappropriate medications (PIMs), which are medications that should be avoided in older adults and in those with certain conditions, are also more likely to be prescribed in the setting of polypharmacy.¹⁶

Deprescribing is the process of identifying and discontinuing medications that are unnecessary, ineffective, and/or inappropriate in order to reduce polypharmacy and improve health outcomes. Deprescribing is a collaborative process that involves weighing the benefits and harms of medications in the context of a patient’s care goals, current level of functioning, life expectancy, values, and preferences. This article reviews polypharmacy and discusses safe and effective deprescribing strategies for older adults in the primary care setting.

[polldaddy:9781245]

How many people on how many meds?

Polypharmacy often occurs when an adverse drug effect is misinterpreted as a new medical problem, leading to the prescribing of more medication to treat the initial drug-induced symptom.According to a 2016 study, 36% of community-dwelling older adults (ages 62-85 years) were taking 5 or more prescription medications in 2010 to 2011—up from 31% in 2005 to 2006.¹⁷ When one narrows the population to older adults in the United States who are hospitalized, almost half (46%) take 7 or more medications.¹⁸ Among frail, older US veterans at hospital discharge, 40% were prescribed 9 or more medications, with 44% of these patients receiving at least one unnecessary drug.¹⁹

The challenges of multimorbidity

In the United States, 80% of those 65 and older have 2 or more chronic conditions, or multimorbidity.²⁰ Clinical practice guidelines making recommendations for the management of single conditions, such as heart failure, hypertension, or diabetes, often suggest the use of 2 or more medications to achieve optimal management and fail to provide guidance in the setting of multimorbidity. Following treatment recommendations for multiple conditions predictably leads to polypharmacy, with complicated, costly, and burdensome regimens.

Further, the research contributing to the development of clinical practice guidelines frequently excludes older adults and those with multimorbidity, reducing applicability in this population. As a result, many treatment recommendations have uncertain benefit and may be harmful in the multimorbid older patient.²¹

CASE In addition to the patient’s multimorbidity, she had a stroke at age 73 and has some mild residual left-sided weakness. Functionally, she is independent and able to perform her activities of daily living and her instrumental activities of daily living. She lives alone, quit smoking at age 65, and has an occasional glass of wine during family parties. The patient’s daughter and granddaughter live 2 blocks away.

The goal of deprescribing is to reduce polypharmacy and improve health outcomes.

Her current medications include glipizide XL 10 mg/d and lisinopril-HCTZ 20-25 mg/d, which she has temporarily discontinued at the ED doctor’s recommendation, as well as: amlodipine 10 mg/d, metformin 1000 mg BID, senna 8.6 mg/d, docusate 100 mg BID, furosemide 40 mg/d, and ibuprofen 600 mg/d (for knee pain). She reports taking omeprazole 20 mg/d “for almost 20 years,” even though she has not had any reflux symptoms in recent memory. After her stroke, she began taking atorvastatin 10 mg/d, aspirin 81 mg/d, and clopidogrel 75 mg/d, which she continues to take today. About a year ago, she started oxybutynin 5 mg/d for urinary incontinence, but she has not noticed significant relief. Additionally, she takes lorazepam 1 mg for insomnia most nights of the week.

IMAGE: ©BRIAN STAUFER 2017

A review of systems reveals issues with chronic constipation and intermittent dizziness, but is otherwise negative. The physical examination reveals a well-appearing woman with a body mass index of 26. Her temperature is 98.5° F, her heart rate is 78 beats/min and regular, her respirations are 14 breaths/min, and her BP is 117/65 mm Hg. Orthostatic testing is negative. Her heart, lung, and abdominal exams are within normal limits. Her timed up and go test is 14 seconds. Her blood glucose level today in the office after eating breakfast 2 hours ago is 135 mg/dL (normal: <140 mg/dL). Laboratory tests performed at the time of the ED visit show a creatinine level of 1.2 mg/dL (normal range: 0.6 to 1.1 mg/dL), a glomerular filtration rate (GFR) of 44 units (normal range: >60 units), a hemoglobin level of 9.8 g/dL (normal range: 12-15.5 g/dL), and a thyroid stimulating hormone level of 1.4 mIU/L (normal range: 0.5-8.9 mIU/L). A recent hemoglobin A1C is 6.8% (normal: <5.7%), low-density lipoprotein (LDL) level is 103 mg/dL (optimal <100 mg/dL), and high-density lipoprotein (HDL) level is 65 mg/dL (optimal >60 mg/dL). An echocardiogram performed a year ago showed mild aortic stenosis with normal systolic and diastolic function.

Starting the deprescribing process: Several approaches to choose from

The goal of deprescribing is to reduce polypharmacy and improve health outcomes. It is a process defined as, “reviewing all current medications; identifying medications to be ceased, substituted, or reduced; planning a deprescribing regimen in partnership with the patient; and frequently reviewing and supporting the patient.”²² A medication review should include prescription, over-the-counter (OTC), and complementary/­alternative medicine (CAM) agents.

More than one-third of US men and women ages 62 to 85 years are taking 5 or more prescription medications.Until recently, studies evaluating the process of deprescribing across drug classes and disease conditions were limited, but new research is beginning to show its potential impact. After deprescribing, patients experience fewer falls and show improvements in cognition.²³ While there have not yet been large randomized trials to evaluate deprescribing, a recent systematic review and meta-analysis showed that use of patient-specific deprescribing interventions is associated with improved survival.²⁴ Importantly, there have been no reported adverse drug withdrawal events or deaths associated with deprescribing.²³

Smaller studies have reported additional benefits including decreases in health care costs, reductions in drug-drug interactions and PIMs, improvements in medication adherence, and increases in patient satisfaction.²⁵ In addition, the removal of unnecessary medications may allow for increased consideration of prescribing appropriate medications with known benefit.²⁵

Practically speaking, every encounter between a patient and health care provider is an opportunity to reduce unnecessary medications. Electronic alert systems at pharmacies and those embedded within electronic health record (EHR) systems can also prompt a medication review and an effort to deprescribe.²⁶ Evidence-based tools to identify polypharm­acy and guide appropriate medication use are listed in TABLE 3.^5,6,27-30 In addition, suggested approaches to beginning the deprescribing process are included in TABLE 4.^5,31-33 And a medication class-based approach to deprescribing is provided in TABLE 5.^5,34-45

Although no gold standard process exists for deprescribing, experts suggest that any deprescribing protocol should include the following steps:^32,46

1. Start with a “brown bag” review of the patient’s medications.

Have the patient bring all of his/her medications in a bag to the visit; review them together or have the medication history taken by a pharmacist. Determine and discuss the indication for each medication and its effectiveness for that indication. Consider the potential benefits and harms of each medication in the context of the patient’s care goals and preferences. Assess whether the patient is taking all of the medications that have been prescribed, and identify any reasons for missed pills (eg, adverse effects, dosing regimens, understanding, cognitive issues).

2. Talk to the patient about the deprescribing process.

Talk with the patient about the risks and benefits of deprescribing, and prioritize which medications to address in the process. Prioritize the medications by balancing patient preferences with available pharmacologic evidence. If there is a lack of evidence supporting the benefits for a particular medication, consider known or suspected adverse effects, the ease or burden of the dosing regimen, the patient’s preferences and goals of care, remaining life expectancy, the time until drug benefit is appreciated, and the length of drug benefit after discontinuation.

3. Deprescribe medications.

If you are going to taper a medication, develop a schedule in partnership with the patient. Stop one medication at a time so that you can monitor for withdrawal symptoms or for the return of a condition.

Acknowledging potential barriers to deprescribing may help structure conversations and provide anticipatory guidance to patients and their families. Working to overcome these barriers will help maximize the benefits of deprescribing and help to build trust with patients.

Patient-driven barriers include fear of a condition worsening or returning, lack of a suitable alternative, lack of ongoing support to manage a particular condition, a previous bad experience with medication cessation, and influence from other care providers (eg, family, home caregivers, nurses, specialists, friends). Patients and family members sometimes cling to the hope of future effectiveness of a treatment, especially in the case of medications like donepezil for dementia.⁴⁷ Utilizing a team-based and stepwise patient approach to deprescribing aims to provide hesitant patients with appropriate amounts of education and support to begin to reduce unnecessary medicines.

Provider-driven barriers include feeling uneasy about contradicting a specialist’s recommendations for initiation/continuation of specific medications, fear of causing withdrawal symptoms or disease relapse, and lack of specific data to adequately understand and assess benefits and harms in the older adult population. Primary care physicians have also acknowledged worry about discussing life expectancy and that patients will feel their care is being reduced or “downgraded.”⁴⁸ Finally, there is limited time in which these complex shared decision-making conversations can take place. Thus, if medications are not causing a noticeable problem, it is often easier to just continue them.

Every encounter between a patient and health care provider is an opportunity to reduce unnecessary medications.

One way to overcome some of these concerns is to consider working with a clinical pharmacist. By gaining information regarding medication-specific factors, such as half-life and expected withdrawal patterns, you can feel more confident deprescribing or continuing medications.

Additionally, communicating closely with specialists, ideally with the help of an integra­ted EHR, can allow you to discuss indications for particular medications or concerns about adverse effects, limited benefits, or difficulty with compliance, so that you can develop a collaborative, cohesive, and patient-centered plan. This, in turn, may improve patient understanding and compliance.

4. Create a follow-up plan.

At the time of deprescribing a medication, develop a plan with the patient for monitoring and assessment. Ensure that the patient understands which symptoms may occur in the event of drug withdrawal and which symptoms may suggest the return of a condition. Make sure that other supports are in place if needed (eg, cognitive behavioral therapy, physical therapy, social support or assistance) to help ensure that medication cessation is successful.

CASE During the office visit, you advise the patient that her BP looks normal, her blood sugar is within an appropriate range, and she is lucky to have not sustained any injuries after her most recent fall. In addition to discussing the benefits of some outpatient physical therapy to help with her balance, you ask if she would like to discuss reducing her medications. She is agreeable and asks for your recommendations.

You are aware of several resources that can help you with your recommendations, among them the STOPP/START⁶ and Beers criteria,⁵ as well as the Good Geriatric-Palliative Algorithm.³⁰

If you were to use the STOPP/START and Beers criteria, you might consider stopping:

• lorazepam, which increases the risk of falls and confusion.
• ibuprofen, since this patient has only mild osteoarthritis pain, and ibuprofen has the potential for renal, cardiac, and gastrointestinal toxicities.
• oxybutynin, because it could be contributing to the patient’s constipation and cause confusion and falls.
• furosemide, since the patient has no clinical heart failure.
• omeprazole, since the indication is unknown and the patient has no history of ulceration, esophagitis, or symptomatic gastroesophageal reflux disease.

After reviewing the Good Geriatric-Palliative Algorithm,³⁰ you might consider stopping:

• clopidogrel, as there is no clear indication for this medication in combination with aspirin in this patient.
• glipizide XL, as this patient’s A1c is below goal and this medication puts her at risk of hypoglycemia and its associated morbidities.
• metformin, as it increases her risk of lactic acidosis because her GFR is <45 units.
• docusate, as the evidence to show clear benefit in improving chronic constipation in older adults is lacking.

There have been no reported adverse drug withdrawal events or deaths associated with deprescribing.

You tell your patient that there are multiple medications to consider stopping. In order to monitor any symptoms of withdrawal or return of a condition, it would be best to stop one at a time and follow-up closely. Since she has done well for the past week without the glipizide and lisinopril-HCTZ combination, she can remain off the glipizide and the HCTZ. Lisinopril, however, may provide renal protection in the setting of diabetes and will be continued at this time.

You ask her about adverse effects from her other medications. She indicates that the furosemide makes her run to the bathroom all the time, so she would like to try stopping it. You agree and make a plan for her to monitor her weight, watch for edema, and return in 4 weeks for a follow-up visit.

On follow-up, she is feeling well, has no edema on exam, and is happy to report her urinary incontinence has resolved. You therefore suggest her next deprescribing trial be discontinuation of her oxybutynin. She thanks you for your recommendations about her medications and heads off to her physical therapy appointment.

CORRESPONDENCE
Kathryn McGrath, MD, Department of Family and Community Medicine, Division of Geriatric Medicine and Palliative Care, Thomas Jefferson University, 2422 S Broad St, 2nd Floor, Philadelphia, PA 19145; [email protected].

CASE An 82-year-old woman with a history of hypertension, diabetes, hyperlipidemia, stage 3 chronic kidney disease, anxiety, urge urinary incontinence, constipation, and bilateral knee osteoarthritis presents to her primary care physician’s office after a fall. She reports that she visited the emergency department (ED) a week ago after falling in the middle of the night on her way to the bathroom. This is the third fall she’s had this year. On chart review, she had a blood pressure (BP) of 112/60 mm Hg and a blood glucose level of 65 mg/dL in the ED. All other testing (head imaging, chest x-ray, urinalysis) was normal. The ED physician recommended that she stop taking her lisinopril-hydrochlorothiazide (HCTZ) and glipizide extended release (XL) until her follow-up appointment. Today, she asks about the need to restart these medications.

Polypharmacy is common among older adults due to a high prevalence of chronic conditions that often require multiple medications for optimal management. Cut points of 5 or 9 medications are frequently used to define polypharmacy. However, some define polypharmacy as taking a medication that lacks an indication, is ineffective, or is duplicating treatment provided by another medication.

Either way, polypharmacy is associated with multiple negative consequences, including an increased risk for adverse drug events (ADEs),^1-4 drug-drug and drug-disease interactions (TABLE 1^5,6),⁷ reduced functional capacity,⁸ multiple geriatric syndromes (TABLE 2^5,9-12), medication non-adherence,¹³ and increased mortality.¹⁴ Polypharmacy also contributes to increased health care costs for both the patient and the health care system.¹⁵

Taking a step back. Polypharmacy often results from prescribing cascades, which occur when an adverse drug effect is misinterpreted as a new medical problem, leading to the prescribing of more medication to treat the initial drug-induced symptom. Potentially inappropriate medications (PIMs), which are medications that should be avoided in older adults and in those with certain conditions, are also more likely to be prescribed in the setting of polypharmacy.¹⁶

Deprescribing is the process of identifying and discontinuing medications that are unnecessary, ineffective, and/or inappropriate in order to reduce polypharmacy and improve health outcomes. Deprescribing is a collaborative process that involves weighing the benefits and harms of medications in the context of a patient’s care goals, current level of functioning, life expectancy, values, and preferences. This article reviews polypharmacy and discusses safe and effective deprescribing strategies for older adults in the primary care setting.

[polldaddy:9781245]

How many people on how many meds?

Polypharmacy often occurs when an adverse drug effect is misinterpreted as a new medical problem, leading to the prescribing of more medication to treat the initial drug-induced symptom.According to a 2016 study, 36% of community-dwelling older adults (ages 62-85 years) were taking 5 or more prescription medications in 2010 to 2011—up from 31% in 2005 to 2006.¹⁷ When one narrows the population to older adults in the United States who are hospitalized, almost half (46%) take 7 or more medications.¹⁸ Among frail, older US veterans at hospital discharge, 40% were prescribed 9 or more medications, with 44% of these patients receiving at least one unnecessary drug.¹⁹

The challenges of multimorbidity

In the United States, 80% of those 65 and older have 2 or more chronic conditions, or multimorbidity.²⁰ Clinical practice guidelines making recommendations for the management of single conditions, such as heart failure, hypertension, or diabetes, often suggest the use of 2 or more medications to achieve optimal management and fail to provide guidance in the setting of multimorbidity. Following treatment recommendations for multiple conditions predictably leads to polypharmacy, with complicated, costly, and burdensome regimens.

Further, the research contributing to the development of clinical practice guidelines frequently excludes older adults and those with multimorbidity, reducing applicability in this population. As a result, many treatment recommendations have uncertain benefit and may be harmful in the multimorbid older patient.²¹

CASE In addition to the patient’s multimorbidity, she had a stroke at age 73 and has some mild residual left-sided weakness. Functionally, she is independent and able to perform her activities of daily living and her instrumental activities of daily living. She lives alone, quit smoking at age 65, and has an occasional glass of wine during family parties. The patient’s daughter and granddaughter live 2 blocks away.

The goal of deprescribing is to reduce polypharmacy and improve health outcomes.

Her current medications include glipizide XL 10 mg/d and lisinopril-HCTZ 20-25 mg/d, which she has temporarily discontinued at the ED doctor’s recommendation, as well as: amlodipine 10 mg/d, metformin 1000 mg BID, senna 8.6 mg/d, docusate 100 mg BID, furosemide 40 mg/d, and ibuprofen 600 mg/d (for knee pain). She reports taking omeprazole 20 mg/d “for almost 20 years,” even though she has not had any reflux symptoms in recent memory. After her stroke, she began taking atorvastatin 10 mg/d, aspirin 81 mg/d, and clopidogrel 75 mg/d, which she continues to take today. About a year ago, she started oxybutynin 5 mg/d for urinary incontinence, but she has not noticed significant relief. Additionally, she takes lorazepam 1 mg for insomnia most nights of the week.

IMAGE: ©BRIAN STAUFER 2017

A review of systems reveals issues with chronic constipation and intermittent dizziness, but is otherwise negative. The physical examination reveals a well-appearing woman with a body mass index of 26. Her temperature is 98.5° F, her heart rate is 78 beats/min and regular, her respirations are 14 breaths/min, and her BP is 117/65 mm Hg. Orthostatic testing is negative. Her heart, lung, and abdominal exams are within normal limits. Her timed up and go test is 14 seconds. Her blood glucose level today in the office after eating breakfast 2 hours ago is 135 mg/dL (normal: <140 mg/dL). Laboratory tests performed at the time of the ED visit show a creatinine level of 1.2 mg/dL (normal range: 0.6 to 1.1 mg/dL), a glomerular filtration rate (GFR) of 44 units (normal range: >60 units), a hemoglobin level of 9.8 g/dL (normal range: 12-15.5 g/dL), and a thyroid stimulating hormone level of 1.4 mIU/L (normal range: 0.5-8.9 mIU/L). A recent hemoglobin A1C is 6.8% (normal: <5.7%), low-density lipoprotein (LDL) level is 103 mg/dL (optimal <100 mg/dL), and high-density lipoprotein (HDL) level is 65 mg/dL (optimal >60 mg/dL). An echocardiogram performed a year ago showed mild aortic stenosis with normal systolic and diastolic function.

Starting the deprescribing process: Several approaches to choose from

The goal of deprescribing is to reduce polypharmacy and improve health outcomes. It is a process defined as, “reviewing all current medications; identifying medications to be ceased, substituted, or reduced; planning a deprescribing regimen in partnership with the patient; and frequently reviewing and supporting the patient.”²² A medication review should include prescription, over-the-counter (OTC), and complementary/­alternative medicine (CAM) agents.

More than one-third of US men and women ages 62 to 85 years are taking 5 or more prescription medications.Until recently, studies evaluating the process of deprescribing across drug classes and disease conditions were limited, but new research is beginning to show its potential impact. After deprescribing, patients experience fewer falls and show improvements in cognition.²³ While there have not yet been large randomized trials to evaluate deprescribing, a recent systematic review and meta-analysis showed that use of patient-specific deprescribing interventions is associated with improved survival.²⁴ Importantly, there have been no reported adverse drug withdrawal events or deaths associated with deprescribing.²³

Smaller studies have reported additional benefits including decreases in health care costs, reductions in drug-drug interactions and PIMs, improvements in medication adherence, and increases in patient satisfaction.²⁵ In addition, the removal of unnecessary medications may allow for increased consideration of prescribing appropriate medications with known benefit.²⁵

Practically speaking, every encounter between a patient and health care provider is an opportunity to reduce unnecessary medications. Electronic alert systems at pharmacies and those embedded within electronic health record (EHR) systems can also prompt a medication review and an effort to deprescribe.²⁶ Evidence-based tools to identify polypharm­acy and guide appropriate medication use are listed in TABLE 3.^5,6,27-30 In addition, suggested approaches to beginning the deprescribing process are included in TABLE 4.^5,31-33 And a medication class-based approach to deprescribing is provided in TABLE 5.^5,34-45

Although no gold standard process exists for deprescribing, experts suggest that any deprescribing protocol should include the following steps:^32,46

1. Start with a “brown bag” review of the patient’s medications.

Have the patient bring all of his/her medications in a bag to the visit; review them together or have the medication history taken by a pharmacist. Determine and discuss the indication for each medication and its effectiveness for that indication. Consider the potential benefits and harms of each medication in the context of the patient’s care goals and preferences. Assess whether the patient is taking all of the medications that have been prescribed, and identify any reasons for missed pills (eg, adverse effects, dosing regimens, understanding, cognitive issues).

2. Talk to the patient about the deprescribing process.

Talk with the patient about the risks and benefits of deprescribing, and prioritize which medications to address in the process. Prioritize the medications by balancing patient preferences with available pharmacologic evidence. If there is a lack of evidence supporting the benefits for a particular medication, consider known or suspected adverse effects, the ease or burden of the dosing regimen, the patient’s preferences and goals of care, remaining life expectancy, the time until drug benefit is appreciated, and the length of drug benefit after discontinuation.

3. Deprescribe medications.

If you are going to taper a medication, develop a schedule in partnership with the patient. Stop one medication at a time so that you can monitor for withdrawal symptoms or for the return of a condition.

Acknowledging potential barriers to deprescribing may help structure conversations and provide anticipatory guidance to patients and their families. Working to overcome these barriers will help maximize the benefits of deprescribing and help to build trust with patients.

Patient-driven barriers include fear of a condition worsening or returning, lack of a suitable alternative, lack of ongoing support to manage a particular condition, a previous bad experience with medication cessation, and influence from other care providers (eg, family, home caregivers, nurses, specialists, friends). Patients and family members sometimes cling to the hope of future effectiveness of a treatment, especially in the case of medications like donepezil for dementia.⁴⁷ Utilizing a team-based and stepwise patient approach to deprescribing aims to provide hesitant patients with appropriate amounts of education and support to begin to reduce unnecessary medicines.

Provider-driven barriers include feeling uneasy about contradicting a specialist’s recommendations for initiation/continuation of specific medications, fear of causing withdrawal symptoms or disease relapse, and lack of specific data to adequately understand and assess benefits and harms in the older adult population. Primary care physicians have also acknowledged worry about discussing life expectancy and that patients will feel their care is being reduced or “downgraded.”⁴⁸ Finally, there is limited time in which these complex shared decision-making conversations can take place. Thus, if medications are not causing a noticeable problem, it is often easier to just continue them.

Every encounter between a patient and health care provider is an opportunity to reduce unnecessary medications.

One way to overcome some of these concerns is to consider working with a clinical pharmacist. By gaining information regarding medication-specific factors, such as half-life and expected withdrawal patterns, you can feel more confident deprescribing or continuing medications.

Additionally, communicating closely with specialists, ideally with the help of an integra­ted EHR, can allow you to discuss indications for particular medications or concerns about adverse effects, limited benefits, or difficulty with compliance, so that you can develop a collaborative, cohesive, and patient-centered plan. This, in turn, may improve patient understanding and compliance.

4. Create a follow-up plan.

At the time of deprescribing a medication, develop a plan with the patient for monitoring and assessment. Ensure that the patient understands which symptoms may occur in the event of drug withdrawal and which symptoms may suggest the return of a condition. Make sure that other supports are in place if needed (eg, cognitive behavioral therapy, physical therapy, social support or assistance) to help ensure that medication cessation is successful.

CASE During the office visit, you advise the patient that her BP looks normal, her blood sugar is within an appropriate range, and she is lucky to have not sustained any injuries after her most recent fall. In addition to discussing the benefits of some outpatient physical therapy to help with her balance, you ask if she would like to discuss reducing her medications. She is agreeable and asks for your recommendations.

You are aware of several resources that can help you with your recommendations, among them the STOPP/START⁶ and Beers criteria,⁵ as well as the Good Geriatric-Palliative Algorithm.³⁰

If you were to use the STOPP/START and Beers criteria, you might consider stopping:

• lorazepam, which increases the risk of falls and confusion.
• ibuprofen, since this patient has only mild osteoarthritis pain, and ibuprofen has the potential for renal, cardiac, and gastrointestinal toxicities.
• oxybutynin, because it could be contributing to the patient’s constipation and cause confusion and falls.
• furosemide, since the patient has no clinical heart failure.
• omeprazole, since the indication is unknown and the patient has no history of ulceration, esophagitis, or symptomatic gastroesophageal reflux disease.

After reviewing the Good Geriatric-Palliative Algorithm,³⁰ you might consider stopping:

• clopidogrel, as there is no clear indication for this medication in combination with aspirin in this patient.
• glipizide XL, as this patient’s A1c is below goal and this medication puts her at risk of hypoglycemia and its associated morbidities.
• metformin, as it increases her risk of lactic acidosis because her GFR is <45 units.
• docusate, as the evidence to show clear benefit in improving chronic constipation in older adults is lacking.

There have been no reported adverse drug withdrawal events or deaths associated with deprescribing.

You tell your patient that there are multiple medications to consider stopping. In order to monitor any symptoms of withdrawal or return of a condition, it would be best to stop one at a time and follow-up closely. Since she has done well for the past week without the glipizide and lisinopril-HCTZ combination, she can remain off the glipizide and the HCTZ. Lisinopril, however, may provide renal protection in the setting of diabetes and will be continued at this time.

You ask her about adverse effects from her other medications. She indicates that the furosemide makes her run to the bathroom all the time, so she would like to try stopping it. You agree and make a plan for her to monitor her weight, watch for edema, and return in 4 weeks for a follow-up visit.

On follow-up, she is feeling well, has no edema on exam, and is happy to report her urinary incontinence has resolved. You therefore suggest her next deprescribing trial be discontinuation of her oxybutynin. She thanks you for your recommendations about her medications and heads off to her physical therapy appointment.

CORRESPONDENCE
Kathryn McGrath, MD, Department of Family and Community Medicine, Division of Geriatric Medicine and Palliative Care, Thomas Jefferson University, 2422 S Broad St, 2nd Floor, Philadelphia, PA 19145; [email protected].

In the article, “When can infants and children benefit from probiotics?” (J Fam Pract. 2016;65:789-794), Dassow et al recommended probiotics as a therapeutic tool for reducing abdominal pain associated with pediatric irritable bowel syndrome (IBS). There are several types of functional disorders in childhood with related abdominal pain, the most common of which are IBS and functional abdominal pain (FAP).^1,2

Several recent randomized placebo-controlled trials—one of which I led—have shown that Lactobacillus reuteri DSM 17938 is a beneficial treatment for FAP in children.^3-5 When compared with placebo, this probiotic agent significantly reduced the frequency and intensity of FAP in children.

Family physicians should consider this probiotic microorganism as a potential therapeutic tool for IBS, as well as childhood FAP.

Zvi Weizman, MD
Beer-Sheva, Israel

In the article, “When can infants and children benefit from probiotics?” (J Fam Pract. 2016;65:789-794), Dassow et al recommended probiotics as a therapeutic tool for reducing abdominal pain associated with pediatric irritable bowel syndrome (IBS). There are several types of functional disorders in childhood with related abdominal pain, the most common of which are IBS and functional abdominal pain (FAP).^1,2

Several recent randomized placebo-controlled trials—one of which I led—have shown that Lactobacillus reuteri DSM 17938 is a beneficial treatment for FAP in children.^3-5 When compared with placebo, this probiotic agent significantly reduced the frequency and intensity of FAP in children.

Family physicians should consider this probiotic microorganism as a potential therapeutic tool for IBS, as well as childhood FAP.

Zvi Weizman, MD
Beer-Sheva, Israel

In the article, “When can infants and children benefit from probiotics?” (J Fam Pract. 2016;65:789-794), Dassow et al recommended probiotics as a therapeutic tool for reducing abdominal pain associated with pediatric irritable bowel syndrome (IBS). There are several types of functional disorders in childhood with related abdominal pain, the most common of which are IBS and functional abdominal pain (FAP).^1,2

Several recent randomized placebo-controlled trials—one of which I led—have shown that Lactobacillus reuteri DSM 17938 is a beneficial treatment for FAP in children.^3-5 When compared with placebo, this probiotic agent significantly reduced the frequency and intensity of FAP in children.

Family physicians should consider this probiotic microorganism as a potential therapeutic tool for IBS, as well as childhood FAP.

Zvi Weizman, MD
Beer-Sheva, Israel

In the article by Smith et al, “ ‘Cold turkey’ works best for smoking cessation” (J Fam Pract. 2017;66:174-176), the authors highlighted a study by Lindson-Hawley et al showing that abrupt cessation was associated with higher quit rates than gradual cessation.¹

While I agree with Smith et al’s assessment of abrupt cessation for patients in the preparation and action stages of change as created by DiClemente and Prochaska,² most clinical patients are in the pre-contemplative and contemplative stages of change. A bias of the study was that all recruited participants were willing to quit within 2 weeks.

A systematic review by the same authors (Lindson-Hawley et al) compared gradual reduction of smoking with abrupt cessation and found comparable quit rates.³ Smith et al commented that the reason for this conclusion was limitations in the studies, including differences in patient populations, outcome definitions, and types of interventions.

Because a large subset of clinical patients are in the pre-contemplative and contemplative stages of change, I believe gradual cessation remains an important technique to use while patients transition their beliefs.

Jeff Ebel, DO
Toledo, Ohio

Author’s response:

I appreciate Dr. Ebel’s input and perspective. My co-authors and I acknowledge that the previous systematic review noted comparable quit rates, but there were significant limitations to the studies, which Dr. Ebel noted. The highlight from the 2016 randomized, controlled trial by Lindson-Hawley et al is that patients are more likely to quit from abrupt cessation, even if they initially prefer gradual cessation. As Dr. Ebel notes (and we highlighted in the PURL), our role as family physicians is to inform patients of the data, but support them in whatever method of cessation they choose.

Dustin K. Smith, DO
Jacksonville, Fla.

In the article by Smith et al, “ ‘Cold turkey’ works best for smoking cessation” (J Fam Pract. 2017;66:174-176), the authors highlighted a study by Lindson-Hawley et al showing that abrupt cessation was associated with higher quit rates than gradual cessation.¹

While I agree with Smith et al’s assessment of abrupt cessation for patients in the preparation and action stages of change as created by DiClemente and Prochaska,² most clinical patients are in the pre-contemplative and contemplative stages of change. A bias of the study was that all recruited participants were willing to quit within 2 weeks.

A systematic review by the same authors (Lindson-Hawley et al) compared gradual reduction of smoking with abrupt cessation and found comparable quit rates.³ Smith et al commented that the reason for this conclusion was limitations in the studies, including differences in patient populations, outcome definitions, and types of interventions.

Because a large subset of clinical patients are in the pre-contemplative and contemplative stages of change, I believe gradual cessation remains an important technique to use while patients transition their beliefs.

Jeff Ebel, DO
Toledo, Ohio

Author’s response:

I appreciate Dr. Ebel’s input and perspective. My co-authors and I acknowledge that the previous systematic review noted comparable quit rates, but there were significant limitations to the studies, which Dr. Ebel noted. The highlight from the 2016 randomized, controlled trial by Lindson-Hawley et al is that patients are more likely to quit from abrupt cessation, even if they initially prefer gradual cessation. As Dr. Ebel notes (and we highlighted in the PURL), our role as family physicians is to inform patients of the data, but support them in whatever method of cessation they choose.

Dustin K. Smith, DO
Jacksonville, Fla.

In the article by Smith et al, “ ‘Cold turkey’ works best for smoking cessation” (J Fam Pract. 2017;66:174-176), the authors highlighted a study by Lindson-Hawley et al showing that abrupt cessation was associated with higher quit rates than gradual cessation.¹

While I agree with Smith et al’s assessment of abrupt cessation for patients in the preparation and action stages of change as created by DiClemente and Prochaska,² most clinical patients are in the pre-contemplative and contemplative stages of change. A bias of the study was that all recruited participants were willing to quit within 2 weeks.

A systematic review by the same authors (Lindson-Hawley et al) compared gradual reduction of smoking with abrupt cessation and found comparable quit rates.³ Smith et al commented that the reason for this conclusion was limitations in the studies, including differences in patient populations, outcome definitions, and types of interventions.

Because a large subset of clinical patients are in the pre-contemplative and contemplative stages of change, I believe gradual cessation remains an important technique to use while patients transition their beliefs.

Jeff Ebel, DO
Toledo, Ohio

Author’s response:

I appreciate Dr. Ebel’s input and perspective. My co-authors and I acknowledge that the previous systematic review noted comparable quit rates, but there were significant limitations to the studies, which Dr. Ebel noted. The highlight from the 2016 randomized, controlled trial by Lindson-Hawley et al is that patients are more likely to quit from abrupt cessation, even if they initially prefer gradual cessation. As Dr. Ebel notes (and we highlighted in the PURL), our role as family physicians is to inform patients of the data, but support them in whatever method of cessation they choose.

Dustin K. Smith, DO
Jacksonville, Fla.

EVIDENCE SUMMARY

A large systematic review of prospective and retrospective cohort studies found little or no effect of maternal marijuana use on birth weight, stillbirths, preterm births, or congenital anomalies (TABLE^1-8). Some studies found lower birth weights and some found higher birth weights. The authors couldn’t perform a meta-analysis because of heterogeneity, but estimated a clinically insignificant difference of 100 g. Most studies were limited by failure to account for concurrent maternal tobacco smoking.

Moreover, all studies used interview data to determine maternal prenatal marijuana use, which can be subject to large recall bias. A multicenter prospective study of 585 pregnant women that compared interview data with serum screening to identify tetrahydrocannabinol (THC) found poor correlation between history and laboratory validation, for example.¹ Only 31% of pregnant women with positive THC testing self-reported marijuana use (31% sensitivity), and only 43% of women who reported marijuana use had a positive THC screen (43% specificity). Most studies didn’t quantify marijuana use well and didn’t associate use with trimester of exposure.

The authors also point out that marijuana potency has increased substantially since the 1980s when many of the studies were done (THC content was 3.2% in 1983 and 13% in 2008); prenatal marijuana use in the present day may expose the fetus to larger amounts of THC.¹

A 2016 retrospective cohort study of 56 mothers who reported prenatal marijuana use found no differences in preterm birth, low birth weight, or Apgar scores.²

Neurodevelopmental effects on infants, long-term effects on children, teens

Three prospective cohort studies evaluated neurodevelopmental outcomes in neonates and infants, and 2 studies continued to follow children into adolescence.^1,3 All found essentially no differences associated with prenatal marijuana at birth, throughout infancy, and through age 3 years. The studies had the same limitations as those described previously (potential recall bias for identifying which children were exposed to marijuana prenatally and poorly quantified marijuana use not well-associated with trimester of exposure).

The Ottawa Prenatal Prospective Study (OPPS) examined 140 low-risk pregnancies in white women of higher socioeconomic status who used marijuana during pregnancy.^1,3-7 Investigators considered: socioeconomic status, standard demographics, obstetric history, and use of other drugs, tobacco, and alcohol. Using a standardized newborn assessment scale, they found subtle behavioral differences at one week but not 9 days. Investigators evaluated children again at 3 years of age, school entry (5 or 6 years), and 9 to 12 years.

The Maternal Health Practices and Child Development study (MHPCD) of 564 high-risk pregnancies in predominantly minority women of low socioeconomic status followed infants from birth through 14 years of age.^1,3-5,7,8 It found some small differences in outcomes among children exposed to marijuana prenatally. Of note, when investigators evaluated marijuana use at age 14 years, they compared adolescent self-report history with urine THC testing (specificity 78%).

The MHPCD study was limited because, compared with the nonusing group, mothers who used marijuana were also 20% to 25% more likely to be single and poor, to live in poorer quality homes, and to use alcohol, tobacco, and other drugs. Investigators used statistical modeling to account for these environmental differences and estimated that 10% of the difference in outcomes was attributable to prenatal marijuana exposure.

Marijuana potency has increased substantially since the 1980s, when many of the studies were done. (THC content was 3.2% in 1983 and 13% in 2008.)

The Generation R study (Gen R) enrolled 220 lower-risk pregnancies in multiethnic European women of higher socioeconomic status, followed children to 3 years of age, and found no marijuana-associated differences in any parameter.^1,3,4 The final assessment included only 51 children.

RECOMMENDATIONS

The American College of Obstetricians and Gynecologists (ACOG) recommends screening all women for tobacco, alcohol, and drug use (including marijuana) during early pregnancy.⁹ Women who report marijuana use should be counseled regarding potential adverse consequences to fetal health and be encouraged to discontinue use.

ACOG says that insufficient data exist to evaluate the effects of marijuana use on infants during lactation and breastfeeding and recommends against it.

The American Society of Addiction Medicine also recommends screening pregnant women for drug use and making appropriate referrals for substance use treatment.¹⁰

EVIDENCE SUMMARY

A large systematic review of prospective and retrospective cohort studies found little or no effect of maternal marijuana use on birth weight, stillbirths, preterm births, or congenital anomalies (TABLE^1-8). Some studies found lower birth weights and some found higher birth weights. The authors couldn’t perform a meta-analysis because of heterogeneity, but estimated a clinically insignificant difference of 100 g. Most studies were limited by failure to account for concurrent maternal tobacco smoking.

Moreover, all studies used interview data to determine maternal prenatal marijuana use, which can be subject to large recall bias. A multicenter prospective study of 585 pregnant women that compared interview data with serum screening to identify tetrahydrocannabinol (THC) found poor correlation between history and laboratory validation, for example.¹ Only 31% of pregnant women with positive THC testing self-reported marijuana use (31% sensitivity), and only 43% of women who reported marijuana use had a positive THC screen (43% specificity). Most studies didn’t quantify marijuana use well and didn’t associate use with trimester of exposure.

The authors also point out that marijuana potency has increased substantially since the 1980s when many of the studies were done (THC content was 3.2% in 1983 and 13% in 2008); prenatal marijuana use in the present day may expose the fetus to larger amounts of THC.¹

A 2016 retrospective cohort study of 56 mothers who reported prenatal marijuana use found no differences in preterm birth, low birth weight, or Apgar scores.²

Neurodevelopmental effects on infants, long-term effects on children, teens

Three prospective cohort studies evaluated neurodevelopmental outcomes in neonates and infants, and 2 studies continued to follow children into adolescence.^1,3 All found essentially no differences associated with prenatal marijuana at birth, throughout infancy, and through age 3 years. The studies had the same limitations as those described previously (potential recall bias for identifying which children were exposed to marijuana prenatally and poorly quantified marijuana use not well-associated with trimester of exposure).

The Ottawa Prenatal Prospective Study (OPPS) examined 140 low-risk pregnancies in white women of higher socioeconomic status who used marijuana during pregnancy.^1,3-7 Investigators considered: socioeconomic status, standard demographics, obstetric history, and use of other drugs, tobacco, and alcohol. Using a standardized newborn assessment scale, they found subtle behavioral differences at one week but not 9 days. Investigators evaluated children again at 3 years of age, school entry (5 or 6 years), and 9 to 12 years.

The Maternal Health Practices and Child Development study (MHPCD) of 564 high-risk pregnancies in predominantly minority women of low socioeconomic status followed infants from birth through 14 years of age.^1,3-5,7,8 It found some small differences in outcomes among children exposed to marijuana prenatally. Of note, when investigators evaluated marijuana use at age 14 years, they compared adolescent self-report history with urine THC testing (specificity 78%).

The MHPCD study was limited because, compared with the nonusing group, mothers who used marijuana were also 20% to 25% more likely to be single and poor, to live in poorer quality homes, and to use alcohol, tobacco, and other drugs. Investigators used statistical modeling to account for these environmental differences and estimated that 10% of the difference in outcomes was attributable to prenatal marijuana exposure.

Marijuana potency has increased substantially since the 1980s, when many of the studies were done. (THC content was 3.2% in 1983 and 13% in 2008.)

The Generation R study (Gen R) enrolled 220 lower-risk pregnancies in multiethnic European women of higher socioeconomic status, followed children to 3 years of age, and found no marijuana-associated differences in any parameter.^1,3,4 The final assessment included only 51 children.

RECOMMENDATIONS

The American College of Obstetricians and Gynecologists (ACOG) recommends screening all women for tobacco, alcohol, and drug use (including marijuana) during early pregnancy.⁹ Women who report marijuana use should be counseled regarding potential adverse consequences to fetal health and be encouraged to discontinue use.

ACOG says that insufficient data exist to evaluate the effects of marijuana use on infants during lactation and breastfeeding and recommends against it.

The American Society of Addiction Medicine also recommends screening pregnant women for drug use and making appropriate referrals for substance use treatment.¹⁰

EVIDENCE SUMMARY

A large systematic review of prospective and retrospective cohort studies found little or no effect of maternal marijuana use on birth weight, stillbirths, preterm births, or congenital anomalies (TABLE^1-8). Some studies found lower birth weights and some found higher birth weights. The authors couldn’t perform a meta-analysis because of heterogeneity, but estimated a clinically insignificant difference of 100 g. Most studies were limited by failure to account for concurrent maternal tobacco smoking.

Moreover, all studies used interview data to determine maternal prenatal marijuana use, which can be subject to large recall bias. A multicenter prospective study of 585 pregnant women that compared interview data with serum screening to identify tetrahydrocannabinol (THC) found poor correlation between history and laboratory validation, for example.¹ Only 31% of pregnant women with positive THC testing self-reported marijuana use (31% sensitivity), and only 43% of women who reported marijuana use had a positive THC screen (43% specificity). Most studies didn’t quantify marijuana use well and didn’t associate use with trimester of exposure.

The authors also point out that marijuana potency has increased substantially since the 1980s when many of the studies were done (THC content was 3.2% in 1983 and 13% in 2008); prenatal marijuana use in the present day may expose the fetus to larger amounts of THC.¹

A 2016 retrospective cohort study of 56 mothers who reported prenatal marijuana use found no differences in preterm birth, low birth weight, or Apgar scores.²

Neurodevelopmental effects on infants, long-term effects on children, teens

Three prospective cohort studies evaluated neurodevelopmental outcomes in neonates and infants, and 2 studies continued to follow children into adolescence.^1,3 All found essentially no differences associated with prenatal marijuana at birth, throughout infancy, and through age 3 years. The studies had the same limitations as those described previously (potential recall bias for identifying which children were exposed to marijuana prenatally and poorly quantified marijuana use not well-associated with trimester of exposure).

The Ottawa Prenatal Prospective Study (OPPS) examined 140 low-risk pregnancies in white women of higher socioeconomic status who used marijuana during pregnancy.^1,3-7 Investigators considered: socioeconomic status, standard demographics, obstetric history, and use of other drugs, tobacco, and alcohol. Using a standardized newborn assessment scale, they found subtle behavioral differences at one week but not 9 days. Investigators evaluated children again at 3 years of age, school entry (5 or 6 years), and 9 to 12 years.

The Maternal Health Practices and Child Development study (MHPCD) of 564 high-risk pregnancies in predominantly minority women of low socioeconomic status followed infants from birth through 14 years of age.^1,3-5,7,8 It found some small differences in outcomes among children exposed to marijuana prenatally. Of note, when investigators evaluated marijuana use at age 14 years, they compared adolescent self-report history with urine THC testing (specificity 78%).

The MHPCD study was limited because, compared with the nonusing group, mothers who used marijuana were also 20% to 25% more likely to be single and poor, to live in poorer quality homes, and to use alcohol, tobacco, and other drugs. Investigators used statistical modeling to account for these environmental differences and estimated that 10% of the difference in outcomes was attributable to prenatal marijuana exposure.

Marijuana potency has increased substantially since the 1980s, when many of the studies were done. (THC content was 3.2% in 1983 and 13% in 2008.)

The Generation R study (Gen R) enrolled 220 lower-risk pregnancies in multiethnic European women of higher socioeconomic status, followed children to 3 years of age, and found no marijuana-associated differences in any parameter.^1,3,4 The final assessment included only 51 children.

RECOMMENDATIONS

The American College of Obstetricians and Gynecologists (ACOG) recommends screening all women for tobacco, alcohol, and drug use (including marijuana) during early pregnancy.⁹ Women who report marijuana use should be counseled regarding potential adverse consequences to fetal health and be encouraged to discontinue use.

ACOG says that insufficient data exist to evaluate the effects of marijuana use on infants during lactation and breastfeeding and recommends against it.

The American Society of Addiction Medicine also recommends screening pregnant women for drug use and making appropriate referrals for substance use treatment.¹⁰

Drugs are valuable when they effectively relieve symptoms or prevent illness, but we all know they are double-edged swords when it comes to cost, adverse effects, and drug interactions. This “downside” is not lost on older Americans—especially when you consider that more than a third of Americans, ages 62 to 85 years, take 5 or more prescription medications daily.¹

Too often patients take prescription drugs that they either don’t need or that are harming them. That’s where deprescribing comes in. As this month’s feature article by McGrath and colleagues explains, deprescribing is the process of reducing or stopping unnecessary prescription medications.

The power of deprescribing. About a decade ago, a geriatrician/family physician friend of mine took over as medical director of a 160-bed nursing home. He lamented that the average number of prescription medications taken by the patients in the nursing home was 9.5. He and his team went to work deprescribing, and one year later, the average number of prescription medications per patient was 5.3. As far as he and the nursing staff could tell, the patients were doing just fine and were more alert and functional.

With a blood pressure consistently around 105/50 mm Hg, it was an easy decision to stop one of the patient’s 3 antihypertensive medications.

Another specialist, another Rx. In clinic, I saw a 54-year-old woman with the chief complaint of chronic, dry cough for which she had been on a specialist pilgrimage. A GI specialist prescribed omeprazole, an ENT physician prescribed fluticasone nasal spray and cetirizine, and a pulmonologist added an inhaled corticosteroid to the mix. (I’m not making this up!) I reviewed her medication list carefully and noted she had been placed on amitriptyline for insomnia shortly before the cough began. I was suspicious because the properties of anticholinergics can contribute to a cough. At my suggestion, she agreed to stop the amitriptyline (and endure some sleeplessness). Two weeks later, she returned with no cough. Over the next month, she stopped all 4 other medications, and the cough did not return.

Today in the office, a 64-year-old man complained of lightheadedness and fatigue and told me his blood pressure on home monitoring was consistently around 105/50 mm Hg. In addition to taking 3 antihypertensive medications, I discovered he had been prescribed doxazosin—an alpha blocker, which also lowers blood pressure—for symptoms of benign prostatic hypertrophy. It was an easy decision to stop one of his 3 antihypertensive medications.

I’m certain that you, too, have stories of successful deprescribing. Let’s remain alert to the problem of polypharmacy, keep meticulous medication lists, and deprescribe whenever it makes good sense. Doing so is essential to our roles as family physicians.

Drugs are valuable when they effectively relieve symptoms or prevent illness, but we all know they are double-edged swords when it comes to cost, adverse effects, and drug interactions. This “downside” is not lost on older Americans—especially when you consider that more than a third of Americans, ages 62 to 85 years, take 5 or more prescription medications daily.¹

Too often patients take prescription drugs that they either don’t need or that are harming them. That’s where deprescribing comes in. As this month’s feature article by McGrath and colleagues explains, deprescribing is the process of reducing or stopping unnecessary prescription medications.

The power of deprescribing. About a decade ago, a geriatrician/family physician friend of mine took over as medical director of a 160-bed nursing home. He lamented that the average number of prescription medications taken by the patients in the nursing home was 9.5. He and his team went to work deprescribing, and one year later, the average number of prescription medications per patient was 5.3. As far as he and the nursing staff could tell, the patients were doing just fine and were more alert and functional.

With a blood pressure consistently around 105/50 mm Hg, it was an easy decision to stop one of the patient’s 3 antihypertensive medications.

Another specialist, another Rx. In clinic, I saw a 54-year-old woman with the chief complaint of chronic, dry cough for which she had been on a specialist pilgrimage. A GI specialist prescribed omeprazole, an ENT physician prescribed fluticasone nasal spray and cetirizine, and a pulmonologist added an inhaled corticosteroid to the mix. (I’m not making this up!) I reviewed her medication list carefully and noted she had been placed on amitriptyline for insomnia shortly before the cough began. I was suspicious because the properties of anticholinergics can contribute to a cough. At my suggestion, she agreed to stop the amitriptyline (and endure some sleeplessness). Two weeks later, she returned with no cough. Over the next month, she stopped all 4 other medications, and the cough did not return.

Today in the office, a 64-year-old man complained of lightheadedness and fatigue and told me his blood pressure on home monitoring was consistently around 105/50 mm Hg. In addition to taking 3 antihypertensive medications, I discovered he had been prescribed doxazosin—an alpha blocker, which also lowers blood pressure—for symptoms of benign prostatic hypertrophy. It was an easy decision to stop one of his 3 antihypertensive medications.

I’m certain that you, too, have stories of successful deprescribing. Let’s remain alert to the problem of polypharmacy, keep meticulous medication lists, and deprescribe whenever it makes good sense. Doing so is essential to our roles as family physicians.

Drugs are valuable when they effectively relieve symptoms or prevent illness, but we all know they are double-edged swords when it comes to cost, adverse effects, and drug interactions. This “downside” is not lost on older Americans—especially when you consider that more than a third of Americans, ages 62 to 85 years, take 5 or more prescription medications daily.¹

Too often patients take prescription drugs that they either don’t need or that are harming them. That’s where deprescribing comes in. As this month’s feature article by McGrath and colleagues explains, deprescribing is the process of reducing or stopping unnecessary prescription medications.

The power of deprescribing. About a decade ago, a geriatrician/family physician friend of mine took over as medical director of a 160-bed nursing home. He lamented that the average number of prescription medications taken by the patients in the nursing home was 9.5. He and his team went to work deprescribing, and one year later, the average number of prescription medications per patient was 5.3. As far as he and the nursing staff could tell, the patients were doing just fine and were more alert and functional.

With a blood pressure consistently around 105/50 mm Hg, it was an easy decision to stop one of the patient’s 3 antihypertensive medications.

Another specialist, another Rx. In clinic, I saw a 54-year-old woman with the chief complaint of chronic, dry cough for which she had been on a specialist pilgrimage. A GI specialist prescribed omeprazole, an ENT physician prescribed fluticasone nasal spray and cetirizine, and a pulmonologist added an inhaled corticosteroid to the mix. (I’m not making this up!) I reviewed her medication list carefully and noted she had been placed on amitriptyline for insomnia shortly before the cough began. I was suspicious because the properties of anticholinergics can contribute to a cough. At my suggestion, she agreed to stop the amitriptyline (and endure some sleeplessness). Two weeks later, she returned with no cough. Over the next month, she stopped all 4 other medications, and the cough did not return.

Today in the office, a 64-year-old man complained of lightheadedness and fatigue and told me his blood pressure on home monitoring was consistently around 105/50 mm Hg. In addition to taking 3 antihypertensive medications, I discovered he had been prescribed doxazosin—an alpha blocker, which also lowers blood pressure—for symptoms of benign prostatic hypertrophy. It was an easy decision to stop one of his 3 antihypertensive medications.

I’m certain that you, too, have stories of successful deprescribing. Let’s remain alert to the problem of polypharmacy, keep meticulous medication lists, and deprescribe whenever it makes good sense. Doing so is essential to our roles as family physicians.

Between 2009 and 2014, hepatitis C virus (HCV) infection among women giving birth rose 89%, from 1.8 to 3.4 per live births, according to a study published in Morbidity and Mortality Weekly Report. The researchers say, geographically, the increase in maternal HCV infection mirrors increases in HCV incidence among adults. The highest infection rate was in West Virginia, which had 22.6 per 1,000 live births. Next was Tennessee with 10.1. State infection rates varied widely: Hawaii had the lowest rate, of 0.7.

In Tennessee, the prevalence of maternal HCV infection increased 163%, from 3.8 per 1,000 in 2009 to 10 in 2014. But even among the 95 Tennessee counties, rates varied substantially. The highest rates were in the 52 Appalachian counties. Campbell County had 78 per 1,000 births. Compared with women in urban areas, pregnant women from rural areas had triple the odds of HCV infection. The rise in infection among pregnant women coincides with the rises in heroin and prescription opioid epidemics, which also disproportionately affect rural populations.

Analyzing the Tennessee births, researchers found that the odds of HCV infection were about 5 times higher among women who smoked cigarettes during pregnancy. Concurrent infections were another serious risk factor, with hepatitis B virus infection boosting the odds of HCV infection by nearly 17 times.

HCV infection is a growing—but modifiable—threat among pregnant women, the researchers say. The rise in infection is “particularly concerning,” in light of recent research that has found poor follow-up of HCV-exposed infants. The researchers cite a Philadelphia study that found only 16% of HCV-exposed infants were appropriately followed. That could mean that infected infants are going undetected, the researchers say. The rate of transmission from mothers to infants is estimated at 6%; it’s important for exposed infants to be followed for evidence of seroconversion. But anti-HCV antibody tests can’t be completed until 18 months because passively acquired maternal antibodies can persist. Testing for HCV ribonucleic acid can be performed earlier.

The CDC and the American College of Obstetricians and Gynecologists recommend selective screening of pregnant women at high risk for HCV infection, particularly those with a history of injection drug use or long-term hemodialysis.

Between 2009 and 2014, hepatitis C virus (HCV) infection among women giving birth rose 89%, from 1.8 to 3.4 per live births, according to a study published in Morbidity and Mortality Weekly Report. The researchers say, geographically, the increase in maternal HCV infection mirrors increases in HCV incidence among adults. The highest infection rate was in West Virginia, which had 22.6 per 1,000 live births. Next was Tennessee with 10.1. State infection rates varied widely: Hawaii had the lowest rate, of 0.7.

In Tennessee, the prevalence of maternal HCV infection increased 163%, from 3.8 per 1,000 in 2009 to 10 in 2014. But even among the 95 Tennessee counties, rates varied substantially. The highest rates were in the 52 Appalachian counties. Campbell County had 78 per 1,000 births. Compared with women in urban areas, pregnant women from rural areas had triple the odds of HCV infection. The rise in infection among pregnant women coincides with the rises in heroin and prescription opioid epidemics, which also disproportionately affect rural populations.

Analyzing the Tennessee births, researchers found that the odds of HCV infection were about 5 times higher among women who smoked cigarettes during pregnancy. Concurrent infections were another serious risk factor, with hepatitis B virus infection boosting the odds of HCV infection by nearly 17 times.

HCV infection is a growing—but modifiable—threat among pregnant women, the researchers say. The rise in infection is “particularly concerning,” in light of recent research that has found poor follow-up of HCV-exposed infants. The researchers cite a Philadelphia study that found only 16% of HCV-exposed infants were appropriately followed. That could mean that infected infants are going undetected, the researchers say. The rate of transmission from mothers to infants is estimated at 6%; it’s important for exposed infants to be followed for evidence of seroconversion. But anti-HCV antibody tests can’t be completed until 18 months because passively acquired maternal antibodies can persist. Testing for HCV ribonucleic acid can be performed earlier.

The CDC and the American College of Obstetricians and Gynecologists recommend selective screening of pregnant women at high risk for HCV infection, particularly those with a history of injection drug use or long-term hemodialysis.

Between 2009 and 2014, hepatitis C virus (HCV) infection among women giving birth rose 89%, from 1.8 to 3.4 per live births, according to a study published in Morbidity and Mortality Weekly Report. The researchers say, geographically, the increase in maternal HCV infection mirrors increases in HCV incidence among adults. The highest infection rate was in West Virginia, which had 22.6 per 1,000 live births. Next was Tennessee with 10.1. State infection rates varied widely: Hawaii had the lowest rate, of 0.7.

In Tennessee, the prevalence of maternal HCV infection increased 163%, from 3.8 per 1,000 in 2009 to 10 in 2014. But even among the 95 Tennessee counties, rates varied substantially. The highest rates were in the 52 Appalachian counties. Campbell County had 78 per 1,000 births. Compared with women in urban areas, pregnant women from rural areas had triple the odds of HCV infection. The rise in infection among pregnant women coincides with the rises in heroin and prescription opioid epidemics, which also disproportionately affect rural populations.

Analyzing the Tennessee births, researchers found that the odds of HCV infection were about 5 times higher among women who smoked cigarettes during pregnancy. Concurrent infections were another serious risk factor, with hepatitis B virus infection boosting the odds of HCV infection by nearly 17 times.

HCV infection is a growing—but modifiable—threat among pregnant women, the researchers say. The rise in infection is “particularly concerning,” in light of recent research that has found poor follow-up of HCV-exposed infants. The researchers cite a Philadelphia study that found only 16% of HCV-exposed infants were appropriately followed. That could mean that infected infants are going undetected, the researchers say. The rate of transmission from mothers to infants is estimated at 6%; it’s important for exposed infants to be followed for evidence of seroconversion. But anti-HCV antibody tests can’t be completed until 18 months because passively acquired maternal antibodies can persist. Testing for HCV ribonucleic acid can be performed earlier.

The CDC and the American College of Obstetricians and Gynecologists recommend selective screening of pregnant women at high risk for HCV infection, particularly those with a history of injection drug use or long-term hemodialysis.

BCP-ALL

The European Commission (EC) has approved inotuzumab ozogamicin (BESPONSA®) as monotherapy for adults with relapsed or refractory, CD22-positive B-cell precursor acute lymphoblastic leukemia (BCP-ALL).

Adults with Philadelphia chromosome-positive, relapsed/refractory, CD22-positive BCP-ALL should have failed treatment with at least one tyrosine kinase inhibitor before receiving inotuzumab ozogamicin.

Inotuzumab ozogamicin is an antibody-drug conjugate that consists of a monoclonal antibody targeting CD22 and a cytotoxic agent known as calicheamicin.

The product originates from a collaboration between Pfizer and Celltech (now UCB), but Pfizer has sole responsibility for all manufacturing and clinical development activities.

The EC’s approval of inotuzumab ozogamicin is supported by results from a phase 3 trial, which were published in NEJM in June 2016.

The trial enrolled 326 adult patients with relapsed or refractory BCP-ALL and compared inotuzumab ozogamicin to standard of care chemotherapy.

The rate of complete remission, including incomplete hematologic recovery, was 80.7% in the inotuzumab ozogamicin arm and 29.4% in the chemotherapy arm (P<0.001). The median duration of remission was 4.6 months and 3.1 months, respectively (P=0.03).

Forty-one percent of patients treated with inotuzumab ozogamicin and 11% of those who received chemotherapy proceeded to stem cell transplant directly after treatment (P<0.001).

The median progression-free survival was 5.0 months in the inotuzumab ozogamicin arm and 1.8 months in the chemotherapy arm (P<0.001).

The median overall survival was 7.7 months and 6.7 months, respectively (P=0.04). This did not meet the prespecified boundary of significance (P=0.0208).

Liver-related adverse events were more common in the inotuzumab ozogamicin arm than the chemotherapy arm. The most frequent of these were increased aspartate aminotransferase level (20% vs 10%), hyperbilirubinemia (15% vs 10%), and increased alanine aminotransferase level (14% vs 11%).

Veno-occlusive liver disease occurred in 11% of patients in the inotuzumab ozogamicin arm and 1% in the chemotherapy arm.

There were 17 deaths during treatment in the inotuzumab ozogamicin arm and 11 in the chemotherapy arm. Four deaths were considered related to inotuzumab ozogamicin, and 2 were thought to be related to chemotherapy.

BCP-ALL

The European Commission (EC) has approved inotuzumab ozogamicin (BESPONSA®) as monotherapy for adults with relapsed or refractory, CD22-positive B-cell precursor acute lymphoblastic leukemia (BCP-ALL).

Adults with Philadelphia chromosome-positive, relapsed/refractory, CD22-positive BCP-ALL should have failed treatment with at least one tyrosine kinase inhibitor before receiving inotuzumab ozogamicin.

Inotuzumab ozogamicin is an antibody-drug conjugate that consists of a monoclonal antibody targeting CD22 and a cytotoxic agent known as calicheamicin.

The product originates from a collaboration between Pfizer and Celltech (now UCB), but Pfizer has sole responsibility for all manufacturing and clinical development activities.

The EC’s approval of inotuzumab ozogamicin is supported by results from a phase 3 trial, which were published in NEJM in June 2016.

The trial enrolled 326 adult patients with relapsed or refractory BCP-ALL and compared inotuzumab ozogamicin to standard of care chemotherapy.

The rate of complete remission, including incomplete hematologic recovery, was 80.7% in the inotuzumab ozogamicin arm and 29.4% in the chemotherapy arm (P<0.001). The median duration of remission was 4.6 months and 3.1 months, respectively (P=0.03).

Forty-one percent of patients treated with inotuzumab ozogamicin and 11% of those who received chemotherapy proceeded to stem cell transplant directly after treatment (P<0.001).

The median progression-free survival was 5.0 months in the inotuzumab ozogamicin arm and 1.8 months in the chemotherapy arm (P<0.001).

The median overall survival was 7.7 months and 6.7 months, respectively (P=0.04). This did not meet the prespecified boundary of significance (P=0.0208).

Liver-related adverse events were more common in the inotuzumab ozogamicin arm than the chemotherapy arm. The most frequent of these were increased aspartate aminotransferase level (20% vs 10%), hyperbilirubinemia (15% vs 10%), and increased alanine aminotransferase level (14% vs 11%).

Veno-occlusive liver disease occurred in 11% of patients in the inotuzumab ozogamicin arm and 1% in the chemotherapy arm.

There were 17 deaths during treatment in the inotuzumab ozogamicin arm and 11 in the chemotherapy arm. Four deaths were considered related to inotuzumab ozogamicin, and 2 were thought to be related to chemotherapy.

BCP-ALL

The European Commission (EC) has approved inotuzumab ozogamicin (BESPONSA®) as monotherapy for adults with relapsed or refractory, CD22-positive B-cell precursor acute lymphoblastic leukemia (BCP-ALL).

Adults with Philadelphia chromosome-positive, relapsed/refractory, CD22-positive BCP-ALL should have failed treatment with at least one tyrosine kinase inhibitor before receiving inotuzumab ozogamicin.

Inotuzumab ozogamicin is an antibody-drug conjugate that consists of a monoclonal antibody targeting CD22 and a cytotoxic agent known as calicheamicin.

The product originates from a collaboration between Pfizer and Celltech (now UCB), but Pfizer has sole responsibility for all manufacturing and clinical development activities.

The EC’s approval of inotuzumab ozogamicin is supported by results from a phase 3 trial, which were published in NEJM in June 2016.

The trial enrolled 326 adult patients with relapsed or refractory BCP-ALL and compared inotuzumab ozogamicin to standard of care chemotherapy.

The rate of complete remission, including incomplete hematologic recovery, was 80.7% in the inotuzumab ozogamicin arm and 29.4% in the chemotherapy arm (P<0.001). The median duration of remission was 4.6 months and 3.1 months, respectively (P=0.03).

Forty-one percent of patients treated with inotuzumab ozogamicin and 11% of those who received chemotherapy proceeded to stem cell transplant directly after treatment (P<0.001).

The median progression-free survival was 5.0 months in the inotuzumab ozogamicin arm and 1.8 months in the chemotherapy arm (P<0.001).

The median overall survival was 7.7 months and 6.7 months, respectively (P=0.04). This did not meet the prespecified boundary of significance (P=0.0208).

Liver-related adverse events were more common in the inotuzumab ozogamicin arm than the chemotherapy arm. The most frequent of these were increased aspartate aminotransferase level (20% vs 10%), hyperbilirubinemia (15% vs 10%), and increased alanine aminotransferase level (14% vs 11%).

Veno-occlusive liver disease occurred in 11% of patients in the inotuzumab ozogamicin arm and 1% in the chemotherapy arm.

There were 17 deaths during treatment in the inotuzumab ozogamicin arm and 11 in the chemotherapy arm. Four deaths were considered related to inotuzumab ozogamicin, and 2 were thought to be related to chemotherapy.

A 25-year-old college student with no medical history sought care at our hospital for a nonproductive cough, subjective fevers, myalgia, and malaise that he’d developed 10 days earlier. The day before his visit, he’d also developed scratchy red eyes and a sore throat. He said he’d taken an over-the-counter cough suppressant to help with the cough, but his eyes and lips developed further redness and irritation.

On examination, the patient demonstra­ted conjunctival suffusion, periorbital edema, diffuse oral stomatitis with pseudomembranous crusting, and nasal crusting (FIGURE 1). His vital signs were within normal limits, and he had no epithelial skin eruptions or erosions in any other mucosal regions.

The patient was not currently sexually active and had one lifetime female sexual partner. He had no history of sexually transmitted infections or cold sores, and was not taking any medications, herbs, or supplements. During the initial 24 hours of admission, he developed 4 to 5 red targetoid papules on each hand (FIGURE 2).

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

Diagnosis: M pneumoniae-associated mucositis

The patient was admitted for observation to rule out Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN). We felt that the degree of mucositis (extensive) compared to the number of targetoid papules on the hands (minimal) suggested a diagnosis of Mycoplasma pneumoniae-associated mucositis (MPAM), a subtype of erythema multiforme (EM) major. The patient’s prodrome of fever, cough, and malaise also supported a “walking pneumonia” diagnosis, such as MPAM.

Further testing. The patient had a normal chest x-ray and a negative respiratory virus polymerase chain reaction (PCR), but IgM serologies for Mycoplasma were elevated. Although the patient developed targetoid lesions on his hands during his first 24 hours in the hospital, he felt his constitutional symptoms had improved.

Exposure to Mycoplasma leads to an immune response

MPAM (also known as Fuchs’ syndrome and mycoplasma-associated mucositis with minimal skin manifestations) appears at some point during infection with M pneumoniae and causes severe ocular, oral, and sometimes genital symptoms with minimal skin manifestations.

The degree of mucositis (extensive) compared to the number of targetoid papules on the patient’s hands (minimal) suggested Mycoplasma pneumoniae-associated mucositis.

MPAM is primarily seen in young males. In one systemic review of 202 cases, the average age of the patients was 11.9 years and 66% were male.¹ Exposure to M pneumoniae is theorized to result in the production of autoantibodies to mycoplasma p1-adhesion molecules and to molecular mimicry of keratinocyte antigens located in the mucosa.^1-3

Mycoplasma organisms have not been isolated from the cutaneous lesions of patients with MPAM; they have only been isolated from the respiratory tract, supporting the theory that MPAM is the body’s immune response to Mycoplasma, rather than a direct pathologic effect.⁴ This pathogenesis is distinct from that of SJS/TEN, which is thought to involve CD8+ T-cell-mediated keratinocyte apoptosis (programed cell death). In addition, SJS/TEN is almost always drug induced.

First up in the differential: Rule out SJS/TEN

When evaluating a patient like ours with a blistering eruption, the most important diagnosis to exclude is SJS/TEN. This condition is usually triggered by a medication, which was absent in this case. SJS/TEN begins with a host of constitutional symptoms and an erythematous blistering eruption, which may be preceded by atypical targetoid (2-zoned) flat papules along with erosions on 2 or more mucosal surfaces.

Patients with SJS/TEN are usually critically ill and may have a guarded prognosis. Patients with MPAM have a more favorable prognosis and are unlikely to be critically ill—as was the case with our patient.

EM major is often associated with Mycoplasma infections. Patients with EM major may have fever and arthralgias, as well as extensive mucous membrane involvement including that of the lips/mouth, eyes, and genitals.

Experts agree that EM is separate from the SJS/TEN continuum, and that patients with EM major, including those with MPAM, are not at risk of developing SJS/TEN.⁵ EM is characterized by the presence of the more characteristic ‘target’ or ‘iris’ 3-zoned lesion—a central dusky purpura, surrounded by an elevated edematous pale ring, rimmed by a red macular outer ring. EM major is defined as EM along with involvement of one or more mucosal regions.

In this case, the patient had acral target lesions and oral and ocular mucosal involvement characteristic of EM major, without widespread skin erosions or sloughing commonly seen with SJS/TEN.

Kawasaki’s disease occurs in young children and presents with conjunctivitis and oral changes. However, patients with Kawasaki’s disease generally have a fever for >5 days, a strawberry tongue (not a part of the morphology of EM major or MPAM), and palmoplantar erythema and desquamation that are not common with EM major or MPAM.¹

Pemphigus vulgaris is uncommon in children and young adults. The disease does not present with diffuse mucositis nor diffuse blistering of the skin, but rather with discrete shallow erosions on the mucosa and the trunk along with flaccid bullae and erosions on the skin.

The morphologies of a fixed drug eruption (round purpuric patch) and toxic shock syndrome (diffuse macular erythema and widespread skin sloughing) are inconsistent with this patient’s diffuse mucositis, conjunctivitis, and targetoid lesions.

Confirm exposure to M pneumoniae

Testing with the purpose of ruling in MPAM is directed toward proving that the patient has been exposed to M pneumoniae. (Of note: M pneumoniae cannot be detected via routine commercial blood cultures.)

Serologic testing for elevated IgM antibodies to Mycoplasma is the most specific method. Various studies have found it to be positive in 100% of cases, but detection may be delayed for a couple of weeks while the body develops the requisite antibodies.⁴

Respiratory PCR for Mycoplasma is rapid and usu­ally appropriately positive, but may be negative in cases where the patient has spontaneously cleared the infection or has been exposed to antibiotics before development of the eruption.⁴ An infiltrate on chest imaging is supportive of the diagnosis.

Skin biopsy will demonstrate either mucositis and necrosis of keratinocytes or EM-like necrosis, but does not suggest an etiology.

Strikingly different paths of care

Distinguishing between SJS/TEN and EM major (including MPAM) is crucial to guiding management. Patients with SJS/TEN need critical care, particularly of their eyes and genitourinary and respiratory systems. Specialist consultation is often required.

Patients with erythema multiforme, including those with Mycoplasma pneumoniae-associated mucositis, are not at risk of developing Stevens-Johnson syndrome/toxic epidermal necrolysis.

For EM major, patients require supportive care along with ongoing assurances that the eruption has a benign prognosis. Hospital admission is not mandatory as long as adequate supportive care and symptom control can be provided on an outpatient basis. Early consultation with Ophthalmology, Oral Medicine, and Urology may also be key.

Keep in mind that patients may have severe stomatitis and pain that alter their ability to eat and perform normal activities. Thus, managing pain and ensuring adequate nutrition are crucial for successful support. While antibiotics treat active Mycoplasma infection, there is no clear evidence that antibiotics alter the course of the eruption, which is also consistent with the hypothesized pathogenesis.^3,4

While there is no clear statistical evidence that systemic immune suppression alters the disease course, a large proportion (31%) of patients in a recent systematic review of MPAM were treated with corticosteroids, and a smaller, but noteworthy, percentage (9%) were treated with intravenous immunoglobulins (IVIG).⁴ There are reports of severe stomatitis that didn’t improve with supportive care, but that showed dramatic improvement with IVIG treatment.^6,7

Our patient had difficulty controlling secretions and managing the painful mucositis of his mouth; he was initially unable to tolerate solid foods. Topical lidocaine solution for his mucositis caused burning and more discomfort, but acetaminophen-hydrocodone 300 mg-5 mg every 6 hours did relieve his pain. Wound care with a bland emollient and the application of non-stick dressings to his lips at night also helped to relieve some of the pain.

Because the patient’s oropharyngeal swelling made it hard for him to swallow, he received oral prednisone 0.5 mg/kg/d, which provided him with relief within 24 hours. The acute inflammation and eruption also subsided within 48 hours and the patient was discharged after 5 days of being hospitalized. He continued to recover as an outpatient, seeing his primary care physician within 2 weeks for final nutrition and wound care support. Two weeks after that, he had a dermatology appointment, and all of his lesions had re-epithelialized.

CORRESPONDENCE
Sahand Rahnama-Moghadam, MD, MS, University of Texas Health Science Center at San Antonio, 7323 Snowden Road, Apt. 1205, San Antonio, TX 78240; [email protected].

A 25-year-old college student with no medical history sought care at our hospital for a nonproductive cough, subjective fevers, myalgia, and malaise that he’d developed 10 days earlier. The day before his visit, he’d also developed scratchy red eyes and a sore throat. He said he’d taken an over-the-counter cough suppressant to help with the cough, but his eyes and lips developed further redness and irritation.

On examination, the patient demonstra­ted conjunctival suffusion, periorbital edema, diffuse oral stomatitis with pseudomembranous crusting, and nasal crusting (FIGURE 1). His vital signs were within normal limits, and he had no epithelial skin eruptions or erosions in any other mucosal regions.

The patient was not currently sexually active and had one lifetime female sexual partner. He had no history of sexually transmitted infections or cold sores, and was not taking any medications, herbs, or supplements. During the initial 24 hours of admission, he developed 4 to 5 red targetoid papules on each hand (FIGURE 2).

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

Diagnosis: M pneumoniae-associated mucositis

The patient was admitted for observation to rule out Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN). We felt that the degree of mucositis (extensive) compared to the number of targetoid papules on the hands (minimal) suggested a diagnosis of Mycoplasma pneumoniae-associated mucositis (MPAM), a subtype of erythema multiforme (EM) major. The patient’s prodrome of fever, cough, and malaise also supported a “walking pneumonia” diagnosis, such as MPAM.

Further testing. The patient had a normal chest x-ray and a negative respiratory virus polymerase chain reaction (PCR), but IgM serologies for Mycoplasma were elevated. Although the patient developed targetoid lesions on his hands during his first 24 hours in the hospital, he felt his constitutional symptoms had improved.

Exposure to Mycoplasma leads to an immune response

MPAM (also known as Fuchs’ syndrome and mycoplasma-associated mucositis with minimal skin manifestations) appears at some point during infection with M pneumoniae and causes severe ocular, oral, and sometimes genital symptoms with minimal skin manifestations.

The degree of mucositis (extensive) compared to the number of targetoid papules on the patient’s hands (minimal) suggested Mycoplasma pneumoniae-associated mucositis.

MPAM is primarily seen in young males. In one systemic review of 202 cases, the average age of the patients was 11.9 years and 66% were male.¹ Exposure to M pneumoniae is theorized to result in the production of autoantibodies to mycoplasma p1-adhesion molecules and to molecular mimicry of keratinocyte antigens located in the mucosa.^1-3

Mycoplasma organisms have not been isolated from the cutaneous lesions of patients with MPAM; they have only been isolated from the respiratory tract, supporting the theory that MPAM is the body’s immune response to Mycoplasma, rather than a direct pathologic effect.⁴ This pathogenesis is distinct from that of SJS/TEN, which is thought to involve CD8+ T-cell-mediated keratinocyte apoptosis (programed cell death). In addition, SJS/TEN is almost always drug induced.

First up in the differential: Rule out SJS/TEN

When evaluating a patient like ours with a blistering eruption, the most important diagnosis to exclude is SJS/TEN. This condition is usually triggered by a medication, which was absent in this case. SJS/TEN begins with a host of constitutional symptoms and an erythematous blistering eruption, which may be preceded by atypical targetoid (2-zoned) flat papules along with erosions on 2 or more mucosal surfaces.

Patients with SJS/TEN are usually critically ill and may have a guarded prognosis. Patients with MPAM have a more favorable prognosis and are unlikely to be critically ill—as was the case with our patient.

EM major is often associated with Mycoplasma infections. Patients with EM major may have fever and arthralgias, as well as extensive mucous membrane involvement including that of the lips/mouth, eyes, and genitals.

Experts agree that EM is separate from the SJS/TEN continuum, and that patients with EM major, including those with MPAM, are not at risk of developing SJS/TEN.⁵ EM is characterized by the presence of the more characteristic ‘target’ or ‘iris’ 3-zoned lesion—a central dusky purpura, surrounded by an elevated edematous pale ring, rimmed by a red macular outer ring. EM major is defined as EM along with involvement of one or more mucosal regions.

In this case, the patient had acral target lesions and oral and ocular mucosal involvement characteristic of EM major, without widespread skin erosions or sloughing commonly seen with SJS/TEN.

Kawasaki’s disease occurs in young children and presents with conjunctivitis and oral changes. However, patients with Kawasaki’s disease generally have a fever for >5 days, a strawberry tongue (not a part of the morphology of EM major or MPAM), and palmoplantar erythema and desquamation that are not common with EM major or MPAM.¹

Pemphigus vulgaris is uncommon in children and young adults. The disease does not present with diffuse mucositis nor diffuse blistering of the skin, but rather with discrete shallow erosions on the mucosa and the trunk along with flaccid bullae and erosions on the skin.

The morphologies of a fixed drug eruption (round purpuric patch) and toxic shock syndrome (diffuse macular erythema and widespread skin sloughing) are inconsistent with this patient’s diffuse mucositis, conjunctivitis, and targetoid lesions.

Confirm exposure to M pneumoniae

Testing with the purpose of ruling in MPAM is directed toward proving that the patient has been exposed to M pneumoniae. (Of note: M pneumoniae cannot be detected via routine commercial blood cultures.)

Serologic testing for elevated IgM antibodies to Mycoplasma is the most specific method. Various studies have found it to be positive in 100% of cases, but detection may be delayed for a couple of weeks while the body develops the requisite antibodies.⁴

Respiratory PCR for Mycoplasma is rapid and usu­ally appropriately positive, but may be negative in cases where the patient has spontaneously cleared the infection or has been exposed to antibiotics before development of the eruption.⁴ An infiltrate on chest imaging is supportive of the diagnosis.

Skin biopsy will demonstrate either mucositis and necrosis of keratinocytes or EM-like necrosis, but does not suggest an etiology.

Strikingly different paths of care

Distinguishing between SJS/TEN and EM major (including MPAM) is crucial to guiding management. Patients with SJS/TEN need critical care, particularly of their eyes and genitourinary and respiratory systems. Specialist consultation is often required.

Patients with erythema multiforme, including those with Mycoplasma pneumoniae-associated mucositis, are not at risk of developing Stevens-Johnson syndrome/toxic epidermal necrolysis.

For EM major, patients require supportive care along with ongoing assurances that the eruption has a benign prognosis. Hospital admission is not mandatory as long as adequate supportive care and symptom control can be provided on an outpatient basis. Early consultation with Ophthalmology, Oral Medicine, and Urology may also be key.

Keep in mind that patients may have severe stomatitis and pain that alter their ability to eat and perform normal activities. Thus, managing pain and ensuring adequate nutrition are crucial for successful support. While antibiotics treat active Mycoplasma infection, there is no clear evidence that antibiotics alter the course of the eruption, which is also consistent with the hypothesized pathogenesis.^3,4

While there is no clear statistical evidence that systemic immune suppression alters the disease course, a large proportion (31%) of patients in a recent systematic review of MPAM were treated with corticosteroids, and a smaller, but noteworthy, percentage (9%) were treated with intravenous immunoglobulins (IVIG).⁴ There are reports of severe stomatitis that didn’t improve with supportive care, but that showed dramatic improvement with IVIG treatment.^6,7

Our patient had difficulty controlling secretions and managing the painful mucositis of his mouth; he was initially unable to tolerate solid foods. Topical lidocaine solution for his mucositis caused burning and more discomfort, but acetaminophen-hydrocodone 300 mg-5 mg every 6 hours did relieve his pain. Wound care with a bland emollient and the application of non-stick dressings to his lips at night also helped to relieve some of the pain.

Because the patient’s oropharyngeal swelling made it hard for him to swallow, he received oral prednisone 0.5 mg/kg/d, which provided him with relief within 24 hours. The acute inflammation and eruption also subsided within 48 hours and the patient was discharged after 5 days of being hospitalized. He continued to recover as an outpatient, seeing his primary care physician within 2 weeks for final nutrition and wound care support. Two weeks after that, he had a dermatology appointment, and all of his lesions had re-epithelialized.

CORRESPONDENCE
Sahand Rahnama-Moghadam, MD, MS, University of Texas Health Science Center at San Antonio, 7323 Snowden Road, Apt. 1205, San Antonio, TX 78240; [email protected].

A 25-year-old college student with no medical history sought care at our hospital for a nonproductive cough, subjective fevers, myalgia, and malaise that he’d developed 10 days earlier. The day before his visit, he’d also developed scratchy red eyes and a sore throat. He said he’d taken an over-the-counter cough suppressant to help with the cough, but his eyes and lips developed further redness and irritation.

On examination, the patient demonstra­ted conjunctival suffusion, periorbital edema, diffuse oral stomatitis with pseudomembranous crusting, and nasal crusting (FIGURE 1). His vital signs were within normal limits, and he had no epithelial skin eruptions or erosions in any other mucosal regions.

The patient was not currently sexually active and had one lifetime female sexual partner. He had no history of sexually transmitted infections or cold sores, and was not taking any medications, herbs, or supplements. During the initial 24 hours of admission, he developed 4 to 5 red targetoid papules on each hand (FIGURE 2).

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

Diagnosis: M pneumoniae-associated mucositis

The patient was admitted for observation to rule out Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN). We felt that the degree of mucositis (extensive) compared to the number of targetoid papules on the hands (minimal) suggested a diagnosis of Mycoplasma pneumoniae-associated mucositis (MPAM), a subtype of erythema multiforme (EM) major. The patient’s prodrome of fever, cough, and malaise also supported a “walking pneumonia” diagnosis, such as MPAM.

Further testing. The patient had a normal chest x-ray and a negative respiratory virus polymerase chain reaction (PCR), but IgM serologies for Mycoplasma were elevated. Although the patient developed targetoid lesions on his hands during his first 24 hours in the hospital, he felt his constitutional symptoms had improved.

Exposure to Mycoplasma leads to an immune response

MPAM (also known as Fuchs’ syndrome and mycoplasma-associated mucositis with minimal skin manifestations) appears at some point during infection with M pneumoniae and causes severe ocular, oral, and sometimes genital symptoms with minimal skin manifestations.

The degree of mucositis (extensive) compared to the number of targetoid papules on the patient’s hands (minimal) suggested Mycoplasma pneumoniae-associated mucositis.

MPAM is primarily seen in young males. In one systemic review of 202 cases, the average age of the patients was 11.9 years and 66% were male.¹ Exposure to M pneumoniae is theorized to result in the production of autoantibodies to mycoplasma p1-adhesion molecules and to molecular mimicry of keratinocyte antigens located in the mucosa.^1-3

Mycoplasma organisms have not been isolated from the cutaneous lesions of patients with MPAM; they have only been isolated from the respiratory tract, supporting the theory that MPAM is the body’s immune response to Mycoplasma, rather than a direct pathologic effect.⁴ This pathogenesis is distinct from that of SJS/TEN, which is thought to involve CD8+ T-cell-mediated keratinocyte apoptosis (programed cell death). In addition, SJS/TEN is almost always drug induced.

First up in the differential: Rule out SJS/TEN

When evaluating a patient like ours with a blistering eruption, the most important diagnosis to exclude is SJS/TEN. This condition is usually triggered by a medication, which was absent in this case. SJS/TEN begins with a host of constitutional symptoms and an erythematous blistering eruption, which may be preceded by atypical targetoid (2-zoned) flat papules along with erosions on 2 or more mucosal surfaces.

Patients with SJS/TEN are usually critically ill and may have a guarded prognosis. Patients with MPAM have a more favorable prognosis and are unlikely to be critically ill—as was the case with our patient.

EM major is often associated with Mycoplasma infections. Patients with EM major may have fever and arthralgias, as well as extensive mucous membrane involvement including that of the lips/mouth, eyes, and genitals.

Experts agree that EM is separate from the SJS/TEN continuum, and that patients with EM major, including those with MPAM, are not at risk of developing SJS/TEN.⁵ EM is characterized by the presence of the more characteristic ‘target’ or ‘iris’ 3-zoned lesion—a central dusky purpura, surrounded by an elevated edematous pale ring, rimmed by a red macular outer ring. EM major is defined as EM along with involvement of one or more mucosal regions.

In this case, the patient had acral target lesions and oral and ocular mucosal involvement characteristic of EM major, without widespread skin erosions or sloughing commonly seen with SJS/TEN.

Kawasaki’s disease occurs in young children and presents with conjunctivitis and oral changes. However, patients with Kawasaki’s disease generally have a fever for >5 days, a strawberry tongue (not a part of the morphology of EM major or MPAM), and palmoplantar erythema and desquamation that are not common with EM major or MPAM.¹

Pemphigus vulgaris is uncommon in children and young adults. The disease does not present with diffuse mucositis nor diffuse blistering of the skin, but rather with discrete shallow erosions on the mucosa and the trunk along with flaccid bullae and erosions on the skin.

The morphologies of a fixed drug eruption (round purpuric patch) and toxic shock syndrome (diffuse macular erythema and widespread skin sloughing) are inconsistent with this patient’s diffuse mucositis, conjunctivitis, and targetoid lesions.

Confirm exposure to M pneumoniae

Testing with the purpose of ruling in MPAM is directed toward proving that the patient has been exposed to M pneumoniae. (Of note: M pneumoniae cannot be detected via routine commercial blood cultures.)

Serologic testing for elevated IgM antibodies to Mycoplasma is the most specific method. Various studies have found it to be positive in 100% of cases, but detection may be delayed for a couple of weeks while the body develops the requisite antibodies.⁴

Respiratory PCR for Mycoplasma is rapid and usu­ally appropriately positive, but may be negative in cases where the patient has spontaneously cleared the infection or has been exposed to antibiotics before development of the eruption.⁴ An infiltrate on chest imaging is supportive of the diagnosis.

Skin biopsy will demonstrate either mucositis and necrosis of keratinocytes or EM-like necrosis, but does not suggest an etiology.

Strikingly different paths of care

Distinguishing between SJS/TEN and EM major (including MPAM) is crucial to guiding management. Patients with SJS/TEN need critical care, particularly of their eyes and genitourinary and respiratory systems. Specialist consultation is often required.

Patients with erythema multiforme, including those with Mycoplasma pneumoniae-associated mucositis, are not at risk of developing Stevens-Johnson syndrome/toxic epidermal necrolysis.

For EM major, patients require supportive care along with ongoing assurances that the eruption has a benign prognosis. Hospital admission is not mandatory as long as adequate supportive care and symptom control can be provided on an outpatient basis. Early consultation with Ophthalmology, Oral Medicine, and Urology may also be key.

Keep in mind that patients may have severe stomatitis and pain that alter their ability to eat and perform normal activities. Thus, managing pain and ensuring adequate nutrition are crucial for successful support. While antibiotics treat active Mycoplasma infection, there is no clear evidence that antibiotics alter the course of the eruption, which is also consistent with the hypothesized pathogenesis.^3,4

While there is no clear statistical evidence that systemic immune suppression alters the disease course, a large proportion (31%) of patients in a recent systematic review of MPAM were treated with corticosteroids, and a smaller, but noteworthy, percentage (9%) were treated with intravenous immunoglobulins (IVIG).⁴ There are reports of severe stomatitis that didn’t improve with supportive care, but that showed dramatic improvement with IVIG treatment.^6,7

Our patient had difficulty controlling secretions and managing the painful mucositis of his mouth; he was initially unable to tolerate solid foods. Topical lidocaine solution for his mucositis caused burning and more discomfort, but acetaminophen-hydrocodone 300 mg-5 mg every 6 hours did relieve his pain. Wound care with a bland emollient and the application of non-stick dressings to his lips at night also helped to relieve some of the pain.

Because the patient’s oropharyngeal swelling made it hard for him to swallow, he received oral prednisone 0.5 mg/kg/d, which provided him with relief within 24 hours. The acute inflammation and eruption also subsided within 48 hours and the patient was discharged after 5 days of being hospitalized. He continued to recover as an outpatient, seeing his primary care physician within 2 weeks for final nutrition and wound care support. Two weeks after that, he had a dermatology appointment, and all of his lesions had re-epithelialized.

CORRESPONDENCE
Sahand Rahnama-Moghadam, MD, MS, University of Texas Health Science Center at San Antonio, 7323 Snowden Road, Apt. 1205, San Antonio, TX 78240; [email protected].