CASE Depressed after she says her baby died
Ms. R, age 50, is an African-American woman who presents to a psychiatric hospital under an involuntary commitment executed by local law enforcement. Her sister called the authorities because Ms. R reportedly told her that she is “very depressed” and wants to “end [her] life” by taking an overdose of medications after the death of her newborn 1 week earlier.

Ms. R states that she delivered a child at “full term” in the emergency department of an outside community hospital, and that her current psychiatric symptoms began after the child died from “SIDS” [sudden infant death syndrome] shortly after birth.

Ms. R describes depressive symptoms including depressed mood, anhedonia, decreased energy, feelings of guilt, decreased concentration, poor sleep, and suicidal ideation. She denies substance use or a medical condition that could have induced these symptoms, and denies symptoms of mania, anxiety, or psychosis at admission or during the previous year.

Ms. R reports a history of manic episodes that includes periods of elevated mood or irritability, impulsivity, increased energy, excessive spending despite negative consequences, lack of need for sleep, rapid thoughts, and rapid speech that impaired her social and occupational functioning. Her most recent manic episode was approximately 3 years before this admission. She reports a previous suicide attempt and a history of physical abuse from a former intimate partner.

Neither the findings of a physical examination nor the results of a screening test for serum β-human chorionic gonadotropin (βHCG) are consistent with pregnancy. Ms. R’s medical record reveals that she was hospitalized for a “cardiac workup” a week earlier and requested investigation of possible pregnancy, which was negative. Records also reveal that she had a hysterectomy 10 years earlier.

Although Ms. R’s sister and boyfriend support her claim of pregnancy, the patient’s young adult son refutes it and states that she “does stuff like this for attention.” Her son also reports receiving a forged sonogram picture that his mother found online 1 month earlier. Ms. R presents an obituary from a local newspaper for the child but, on further investigation, the photograph of the infant was discovered to be of another child, also obtained online. Ms. R’s family denies knowledge of potential external reward Ms. R could gain by claiming to be pregnant.

Which of the following diagnoses can be considered after Ms. R’s initial presentation?
   a) somatic symptom disorder
   b) major depressive disorder
   c) bipolar I disorder
   d) delusional disorder

The authors’ observations
Ms. R reported the recent death of a newborn that was incompatible with her medical history. Her family members revealed that Ms. R made an active effort to deceive them about the reported pregnancy. She also exhibited symptoms of a major depressive episode in the context of previous manic episodes and expressed suicidal ideation.

The first step in the diagnostic pathway was to rule out possible medical explanations, including pregnancy, which could account for the patient’s symptoms. Although the serum βHCG level usually returns to non-pregnant levels 2 to 4 weeks after delivery, it can take even longer in some women.¹ The absence of βHCG along with the recorded history of hysterectomy indicated that Ms. R was not pregnant at the time of testing or within the preceding few weeks. Once medical anomalies and substance use were ruled out, further classification of the psychiatric condition was undertaken.

One aspect of establishing a diagnosis for Ms. R is determining the presence of psychosis (eg, delusional thinking) (Table 1). Ms. R deliberately fabricated evidence of her pregnancy and manipulated family members, which indicated a low likelihood of delusions and supported a diagnostic alternative to psychosis.

Ms. R has a well-described history of manic episodes with current symptoms of a major depressive episode. The treatment team makes a diagnosis of bipolar I disorder, most recent episode depressed. The depressive symptoms Ms. R described were consistent with bipolar depression but did not explain her report of a pregnancy that is inconsistent with reality.

As is the case with Ms. R, diagnostic clarity often requires observation and evaluation over time. Building a strong therapeutic relationship with Ms. R in the context of an appropriate treatment plan allows the treatment team to explore the origin, motivations, and evolution of her thought content while managing her illness.

Confronting a patient about her false claims is likely to result in which of the following?
   a) spontaneous resolution of symptoms
   b) improved therapeutic alliance
   c) degradation of the patient’s coping mechanism
   d) violent outbursts by the patient

EVALUATION Confrontation
At admission, Ms. R remains resolute that she was pregnant and is suffering immense psychological distress secondary to the death of her child. Early in the treatment course, she is confronted with evidence indicating that her pregnancy was impossible. Shortly after this interaction, nursing staff alerts the treating physician that Ms. R experienced a “seizure-like spell” characterized by gross non-stereotyped jerking of the upper extremities, intact orientation, retention of bowel and bladder function, and coherent speech consistent with a diagnosis of pseudoseizure.²

Ms. R is transferred to a tertiary care facility for neurologic evaluation and observation. Ms. R repeatedly presents a photograph that she claims to be of her deceased child and implores the allied treatment team to advocate for discharge. Evaluation of Ms. R’s neurologic symptoms revealed no medical explanation for the “seizure-like spell” and she is transferred to the inpatient psychiatric hospital.

Upon return to the inpatient psychiatric unit, Ms. R receives intensive psychological exploration of her symptoms, thought content, and the foundation of her pregnancy claim. Within days, she acknowledges that the pregnancy was “not real” and that she was conscious of this fact in the months prior to hospitalization. She cites turmoil in her romantic relationship as the primary stimulus for her actions.

The authors’ observations
Ms. R’s reported pregnancy was not a delusion, but rather a deceitful exposition constructed with appropriate reality testing and a conscious awareness of the manipulation. This eliminated delusions as the explanation of her pregnancy claim. Although Ms. R initially rejected evidence refuting her belief of pregnancy, she recognized and accepted reality with appropriate intervention.

Factitious disorder vs malingering
Factitious disorder and malingering can present with intentional induction or report of symptoms or signs of a physical abnormality:

Factitious disorder imposed on the self is a willful misrepresentation or fabrication of signs or symptoms of an illness by a person in the absence of obvious personal gain that cannot be explained by a separate physical or mental illness (Table 2).^3,4

Malingering is the intentional production or exaggeration of physical or psychological signs or symptoms with obvious secondary gain.

Malingering can be excluded in Ms. R’s case: She did not gain external reward by falsely reporting pregnancy. Although DSM-IV-TR (Table 2) assumes that the motivation for the patient with factitious disorder is to assume the sick role, DSM-5 merely states that the she (he) should present themselves as ill, impaired, or injured.^3,4

Ms. R’s treatment team diagnosed factitious disorder imposed on self after careful exclusion of other causes for her symptoms. Bipolar I disorder, most recent episode depressed, also was diagnosed after considering Ms. R’s previous history of manic episodes and depressive symptoms at presentation.

Factitious disorder and other psychiatric conditions often are comorbid. Bipolar disorder, as in Ms. R’s case, as well as major depressive disorder commonly are comorbid with factitious disorder. It is also important to note that factitious disorder often occurs in the context of a personality disorder.⁵

Which of the following medications are FDA-approved for treating factitious disorder?
   a) olanzapine-fluoxetine combination
   b) lurasidone
   c) valproic acid
   d) all of the above
   e) no medications are approved for treating factitious disorder

TREATMENT Support, drug therapy
Treatment of Ms. R’s factitious disorder consists of psychological interventions via psychotherapy and strengthening of social support. She participates in daily individual therapy sessions as well as several group therapy activities. Ms. R engages with her social worker to facilitate a successful transition to an appropriate support network and access community resources to aid her wellness.

The treatment team feels that her diagnosis of bipolar I disorder, most recent episode depressed, warrants pharmacologic intervention. Ms. R agrees to begin a mood stabilizer, valproic acid, instead of medications FDA-approved to treat bipolar depression, such as lurasidone or quetiapine, because she reports good efficacy and tolerability when she took it during a major depressive episode approximately 4 years earlier.

Valproic acid is started at 250 mg/d and increased to 1,000 mg/d. Ms. R tolerates the medication without observed or reported adverse effects.

The authors’ observations
Managing factitious disorder can be challenging; patients can evoke strong feelings of countertransference during treatment.^3,6,7 Providers might feel that the patient does not need to be treated, or that the patient is “not really sick.” This may induce anger and animosity toward the patient (therapeutic nihilism).⁸ These negative emotions are likely to disrupt the patient–provider relationship and exacerbate the patient’s symptoms.

It is generally accepted that the patient should be made aware of the treatment plan, in an indirect and tactful way, so that the patient does not feel “outed.” Unmasking the patient—the process of instilling insight—is a delicate step and can be a stressful time for the patient.⁹ A confrontational approach often places the patient’s sick role in doubt and does not address the pathological aspect of the disorder.

It is rare for a patient to admit to fabricating symptoms; confronted, the patient is likely to double their efforts to maintain the rouse of a fictional disease.^10,11 It is important for the treatment team to be aware that patients frequently leave the treatment facility against medical advice, seek a different provider, or even pursue legal action for defamation against the treating physician.

Treating comorbid medical and psychiatric conditions is important for successful management of a patient with factitious disorder. Initiating valproic acid to address Ms. R’s bipolar depression contributed to her overall psychiatric stability. Initial treatment with a medication that is FDA-approved for treating bipolar depression, such as lurasidone, quetiapine, or olanzapine-fluoxetine combination, should be considered as an alternative. We chose valproic acid for Ms. R because of its previous efficacy, good tolerability, and the patient’s high level of comfort with the medication.

Which of the following are risk factors for factitious disorder?
   a) lengthy medical treatments or hospitalizations as a child
   b) female sex
   c) experience as a health care worker
   d) all of the above


OUTCOME Stabilization
Successful treatment during Ms. R’s inpatient psychiatric admission results in improved insight, remission of suicidal ideation, and stabilization of mood lability. She is discharged to the care of her family with a plan to follow up with a psychotherapist and psychiatrist. Continued administration of valproic acid continues to be effective after discharge.

Ms. R engages in frequent follow-up with outpatient psychiatric services. She remains engaged in psychotherapy and psychiatric care 1 year after discharge. Ms. R has made no report of pregnancy or required hospitalization during this time. She expresses trust in the mental health care system and acknowledges the role treatment played in her improvement.

CASE Depressed after she says her baby died
Ms. R, age 50, is an African-American woman who presents to a psychiatric hospital under an involuntary commitment executed by local law enforcement. Her sister called the authorities because Ms. R reportedly told her that she is “very depressed” and wants to “end [her] life” by taking an overdose of medications after the death of her newborn 1 week earlier.

Ms. R states that she delivered a child at “full term” in the emergency department of an outside community hospital, and that her current psychiatric symptoms began after the child died from “SIDS” [sudden infant death syndrome] shortly after birth.

Ms. R describes depressive symptoms including depressed mood, anhedonia, decreased energy, feelings of guilt, decreased concentration, poor sleep, and suicidal ideation. She denies substance use or a medical condition that could have induced these symptoms, and denies symptoms of mania, anxiety, or psychosis at admission or during the previous year.

Ms. R reports a history of manic episodes that includes periods of elevated mood or irritability, impulsivity, increased energy, excessive spending despite negative consequences, lack of need for sleep, rapid thoughts, and rapid speech that impaired her social and occupational functioning. Her most recent manic episode was approximately 3 years before this admission. She reports a previous suicide attempt and a history of physical abuse from a former intimate partner.

Neither the findings of a physical examination nor the results of a screening test for serum β-human chorionic gonadotropin (βHCG) are consistent with pregnancy. Ms. R’s medical record reveals that she was hospitalized for a “cardiac workup” a week earlier and requested investigation of possible pregnancy, which was negative. Records also reveal that she had a hysterectomy 10 years earlier.

Although Ms. R’s sister and boyfriend support her claim of pregnancy, the patient’s young adult son refutes it and states that she “does stuff like this for attention.” Her son also reports receiving a forged sonogram picture that his mother found online 1 month earlier. Ms. R presents an obituary from a local newspaper for the child but, on further investigation, the photograph of the infant was discovered to be of another child, also obtained online. Ms. R’s family denies knowledge of potential external reward Ms. R could gain by claiming to be pregnant.

Which of the following diagnoses can be considered after Ms. R’s initial presentation?
   a) somatic symptom disorder
   b) major depressive disorder
   c) bipolar I disorder
   d) delusional disorder

The authors’ observations
Ms. R reported the recent death of a newborn that was incompatible with her medical history. Her family members revealed that Ms. R made an active effort to deceive them about the reported pregnancy. She also exhibited symptoms of a major depressive episode in the context of previous manic episodes and expressed suicidal ideation.

The first step in the diagnostic pathway was to rule out possible medical explanations, including pregnancy, which could account for the patient’s symptoms. Although the serum βHCG level usually returns to non-pregnant levels 2 to 4 weeks after delivery, it can take even longer in some women.¹ The absence of βHCG along with the recorded history of hysterectomy indicated that Ms. R was not pregnant at the time of testing or within the preceding few weeks. Once medical anomalies and substance use were ruled out, further classification of the psychiatric condition was undertaken.

One aspect of establishing a diagnosis for Ms. R is determining the presence of psychosis (eg, delusional thinking) (Table 1). Ms. R deliberately fabricated evidence of her pregnancy and manipulated family members, which indicated a low likelihood of delusions and supported a diagnostic alternative to psychosis.

Ms. R has a well-described history of manic episodes with current symptoms of a major depressive episode. The treatment team makes a diagnosis of bipolar I disorder, most recent episode depressed. The depressive symptoms Ms. R described were consistent with bipolar depression but did not explain her report of a pregnancy that is inconsistent with reality.

As is the case with Ms. R, diagnostic clarity often requires observation and evaluation over time. Building a strong therapeutic relationship with Ms. R in the context of an appropriate treatment plan allows the treatment team to explore the origin, motivations, and evolution of her thought content while managing her illness.

Confronting a patient about her false claims is likely to result in which of the following?
   a) spontaneous resolution of symptoms
   b) improved therapeutic alliance
   c) degradation of the patient’s coping mechanism
   d) violent outbursts by the patient

EVALUATION Confrontation
At admission, Ms. R remains resolute that she was pregnant and is suffering immense psychological distress secondary to the death of her child. Early in the treatment course, she is confronted with evidence indicating that her pregnancy was impossible. Shortly after this interaction, nursing staff alerts the treating physician that Ms. R experienced a “seizure-like spell” characterized by gross non-stereotyped jerking of the upper extremities, intact orientation, retention of bowel and bladder function, and coherent speech consistent with a diagnosis of pseudoseizure.²

Ms. R is transferred to a tertiary care facility for neurologic evaluation and observation. Ms. R repeatedly presents a photograph that she claims to be of her deceased child and implores the allied treatment team to advocate for discharge. Evaluation of Ms. R’s neurologic symptoms revealed no medical explanation for the “seizure-like spell” and she is transferred to the inpatient psychiatric hospital.

Upon return to the inpatient psychiatric unit, Ms. R receives intensive psychological exploration of her symptoms, thought content, and the foundation of her pregnancy claim. Within days, she acknowledges that the pregnancy was “not real” and that she was conscious of this fact in the months prior to hospitalization. She cites turmoil in her romantic relationship as the primary stimulus for her actions.

The authors’ observations
Ms. R’s reported pregnancy was not a delusion, but rather a deceitful exposition constructed with appropriate reality testing and a conscious awareness of the manipulation. This eliminated delusions as the explanation of her pregnancy claim. Although Ms. R initially rejected evidence refuting her belief of pregnancy, she recognized and accepted reality with appropriate intervention.

Factitious disorder vs malingering
Factitious disorder and malingering can present with intentional induction or report of symptoms or signs of a physical abnormality:

Factitious disorder imposed on the self is a willful misrepresentation or fabrication of signs or symptoms of an illness by a person in the absence of obvious personal gain that cannot be explained by a separate physical or mental illness (Table 2).^3,4

Malingering is the intentional production or exaggeration of physical or psychological signs or symptoms with obvious secondary gain.

Malingering can be excluded in Ms. R’s case: She did not gain external reward by falsely reporting pregnancy. Although DSM-IV-TR (Table 2) assumes that the motivation for the patient with factitious disorder is to assume the sick role, DSM-5 merely states that the she (he) should present themselves as ill, impaired, or injured.^3,4

Ms. R’s treatment team diagnosed factitious disorder imposed on self after careful exclusion of other causes for her symptoms. Bipolar I disorder, most recent episode depressed, also was diagnosed after considering Ms. R’s previous history of manic episodes and depressive symptoms at presentation.

Factitious disorder and other psychiatric conditions often are comorbid. Bipolar disorder, as in Ms. R’s case, as well as major depressive disorder commonly are comorbid with factitious disorder. It is also important to note that factitious disorder often occurs in the context of a personality disorder.⁵

Which of the following medications are FDA-approved for treating factitious disorder?
   a) olanzapine-fluoxetine combination
   b) lurasidone
   c) valproic acid
   d) all of the above
   e) no medications are approved for treating factitious disorder

TREATMENT Support, drug therapy
Treatment of Ms. R’s factitious disorder consists of psychological interventions via psychotherapy and strengthening of social support. She participates in daily individual therapy sessions as well as several group therapy activities. Ms. R engages with her social worker to facilitate a successful transition to an appropriate support network and access community resources to aid her wellness.

The treatment team feels that her diagnosis of bipolar I disorder, most recent episode depressed, warrants pharmacologic intervention. Ms. R agrees to begin a mood stabilizer, valproic acid, instead of medications FDA-approved to treat bipolar depression, such as lurasidone or quetiapine, because she reports good efficacy and tolerability when she took it during a major depressive episode approximately 4 years earlier.

Valproic acid is started at 250 mg/d and increased to 1,000 mg/d. Ms. R tolerates the medication without observed or reported adverse effects.

The authors’ observations
Managing factitious disorder can be challenging; patients can evoke strong feelings of countertransference during treatment.^3,6,7 Providers might feel that the patient does not need to be treated, or that the patient is “not really sick.” This may induce anger and animosity toward the patient (therapeutic nihilism).⁸ These negative emotions are likely to disrupt the patient–provider relationship and exacerbate the patient’s symptoms.

It is generally accepted that the patient should be made aware of the treatment plan, in an indirect and tactful way, so that the patient does not feel “outed.” Unmasking the patient—the process of instilling insight—is a delicate step and can be a stressful time for the patient.⁹ A confrontational approach often places the patient’s sick role in doubt and does not address the pathological aspect of the disorder.

It is rare for a patient to admit to fabricating symptoms; confronted, the patient is likely to double their efforts to maintain the rouse of a fictional disease.^10,11 It is important for the treatment team to be aware that patients frequently leave the treatment facility against medical advice, seek a different provider, or even pursue legal action for defamation against the treating physician.

Treating comorbid medical and psychiatric conditions is important for successful management of a patient with factitious disorder. Initiating valproic acid to address Ms. R’s bipolar depression contributed to her overall psychiatric stability. Initial treatment with a medication that is FDA-approved for treating bipolar depression, such as lurasidone, quetiapine, or olanzapine-fluoxetine combination, should be considered as an alternative. We chose valproic acid for Ms. R because of its previous efficacy, good tolerability, and the patient’s high level of comfort with the medication.

Which of the following are risk factors for factitious disorder?
   a) lengthy medical treatments or hospitalizations as a child
   b) female sex
   c) experience as a health care worker
   d) all of the above


OUTCOME Stabilization
Successful treatment during Ms. R’s inpatient psychiatric admission results in improved insight, remission of suicidal ideation, and stabilization of mood lability. She is discharged to the care of her family with a plan to follow up with a psychotherapist and psychiatrist. Continued administration of valproic acid continues to be effective after discharge.

Ms. R engages in frequent follow-up with outpatient psychiatric services. She remains engaged in psychotherapy and psychiatric care 1 year after discharge. Ms. R has made no report of pregnancy or required hospitalization during this time. She expresses trust in the mental health care system and acknowledges the role treatment played in her improvement.

CASE Depressed after she says her baby died
Ms. R, age 50, is an African-American woman who presents to a psychiatric hospital under an involuntary commitment executed by local law enforcement. Her sister called the authorities because Ms. R reportedly told her that she is “very depressed” and wants to “end [her] life” by taking an overdose of medications after the death of her newborn 1 week earlier.

Ms. R states that she delivered a child at “full term” in the emergency department of an outside community hospital, and that her current psychiatric symptoms began after the child died from “SIDS” [sudden infant death syndrome] shortly after birth.

Ms. R describes depressive symptoms including depressed mood, anhedonia, decreased energy, feelings of guilt, decreased concentration, poor sleep, and suicidal ideation. She denies substance use or a medical condition that could have induced these symptoms, and denies symptoms of mania, anxiety, or psychosis at admission or during the previous year.

Ms. R reports a history of manic episodes that includes periods of elevated mood or irritability, impulsivity, increased energy, excessive spending despite negative consequences, lack of need for sleep, rapid thoughts, and rapid speech that impaired her social and occupational functioning. Her most recent manic episode was approximately 3 years before this admission. She reports a previous suicide attempt and a history of physical abuse from a former intimate partner.

Neither the findings of a physical examination nor the results of a screening test for serum β-human chorionic gonadotropin (βHCG) are consistent with pregnancy. Ms. R’s medical record reveals that she was hospitalized for a “cardiac workup” a week earlier and requested investigation of possible pregnancy, which was negative. Records also reveal that she had a hysterectomy 10 years earlier.

Although Ms. R’s sister and boyfriend support her claim of pregnancy, the patient’s young adult son refutes it and states that she “does stuff like this for attention.” Her son also reports receiving a forged sonogram picture that his mother found online 1 month earlier. Ms. R presents an obituary from a local newspaper for the child but, on further investigation, the photograph of the infant was discovered to be of another child, also obtained online. Ms. R’s family denies knowledge of potential external reward Ms. R could gain by claiming to be pregnant.

Which of the following diagnoses can be considered after Ms. R’s initial presentation?
   a) somatic symptom disorder
   b) major depressive disorder
   c) bipolar I disorder
   d) delusional disorder

The authors’ observations
Ms. R reported the recent death of a newborn that was incompatible with her medical history. Her family members revealed that Ms. R made an active effort to deceive them about the reported pregnancy. She also exhibited symptoms of a major depressive episode in the context of previous manic episodes and expressed suicidal ideation.

The first step in the diagnostic pathway was to rule out possible medical explanations, including pregnancy, which could account for the patient’s symptoms. Although the serum βHCG level usually returns to non-pregnant levels 2 to 4 weeks after delivery, it can take even longer in some women.¹ The absence of βHCG along with the recorded history of hysterectomy indicated that Ms. R was not pregnant at the time of testing or within the preceding few weeks. Once medical anomalies and substance use were ruled out, further classification of the psychiatric condition was undertaken.

One aspect of establishing a diagnosis for Ms. R is determining the presence of psychosis (eg, delusional thinking) (Table 1). Ms. R deliberately fabricated evidence of her pregnancy and manipulated family members, which indicated a low likelihood of delusions and supported a diagnostic alternative to psychosis.

Ms. R has a well-described history of manic episodes with current symptoms of a major depressive episode. The treatment team makes a diagnosis of bipolar I disorder, most recent episode depressed. The depressive symptoms Ms. R described were consistent with bipolar depression but did not explain her report of a pregnancy that is inconsistent with reality.

As is the case with Ms. R, diagnostic clarity often requires observation and evaluation over time. Building a strong therapeutic relationship with Ms. R in the context of an appropriate treatment plan allows the treatment team to explore the origin, motivations, and evolution of her thought content while managing her illness.

Confronting a patient about her false claims is likely to result in which of the following?
   a) spontaneous resolution of symptoms
   b) improved therapeutic alliance
   c) degradation of the patient’s coping mechanism
   d) violent outbursts by the patient

EVALUATION Confrontation
At admission, Ms. R remains resolute that she was pregnant and is suffering immense psychological distress secondary to the death of her child. Early in the treatment course, she is confronted with evidence indicating that her pregnancy was impossible. Shortly after this interaction, nursing staff alerts the treating physician that Ms. R experienced a “seizure-like spell” characterized by gross non-stereotyped jerking of the upper extremities, intact orientation, retention of bowel and bladder function, and coherent speech consistent with a diagnosis of pseudoseizure.²

Ms. R is transferred to a tertiary care facility for neurologic evaluation and observation. Ms. R repeatedly presents a photograph that she claims to be of her deceased child and implores the allied treatment team to advocate for discharge. Evaluation of Ms. R’s neurologic symptoms revealed no medical explanation for the “seizure-like spell” and she is transferred to the inpatient psychiatric hospital.

Upon return to the inpatient psychiatric unit, Ms. R receives intensive psychological exploration of her symptoms, thought content, and the foundation of her pregnancy claim. Within days, she acknowledges that the pregnancy was “not real” and that she was conscious of this fact in the months prior to hospitalization. She cites turmoil in her romantic relationship as the primary stimulus for her actions.

The authors’ observations
Ms. R’s reported pregnancy was not a delusion, but rather a deceitful exposition constructed with appropriate reality testing and a conscious awareness of the manipulation. This eliminated delusions as the explanation of her pregnancy claim. Although Ms. R initially rejected evidence refuting her belief of pregnancy, she recognized and accepted reality with appropriate intervention.

Factitious disorder vs malingering
Factitious disorder and malingering can present with intentional induction or report of symptoms or signs of a physical abnormality:

Factitious disorder imposed on the self is a willful misrepresentation or fabrication of signs or symptoms of an illness by a person in the absence of obvious personal gain that cannot be explained by a separate physical or mental illness (Table 2).^3,4

Malingering is the intentional production or exaggeration of physical or psychological signs or symptoms with obvious secondary gain.

Malingering can be excluded in Ms. R’s case: She did not gain external reward by falsely reporting pregnancy. Although DSM-IV-TR (Table 2) assumes that the motivation for the patient with factitious disorder is to assume the sick role, DSM-5 merely states that the she (he) should present themselves as ill, impaired, or injured.^3,4

Ms. R’s treatment team diagnosed factitious disorder imposed on self after careful exclusion of other causes for her symptoms. Bipolar I disorder, most recent episode depressed, also was diagnosed after considering Ms. R’s previous history of manic episodes and depressive symptoms at presentation.

Factitious disorder and other psychiatric conditions often are comorbid. Bipolar disorder, as in Ms. R’s case, as well as major depressive disorder commonly are comorbid with factitious disorder. It is also important to note that factitious disorder often occurs in the context of a personality disorder.⁵

Which of the following medications are FDA-approved for treating factitious disorder?
   a) olanzapine-fluoxetine combination
   b) lurasidone
   c) valproic acid
   d) all of the above
   e) no medications are approved for treating factitious disorder

TREATMENT Support, drug therapy
Treatment of Ms. R’s factitious disorder consists of psychological interventions via psychotherapy and strengthening of social support. She participates in daily individual therapy sessions as well as several group therapy activities. Ms. R engages with her social worker to facilitate a successful transition to an appropriate support network and access community resources to aid her wellness.

The treatment team feels that her diagnosis of bipolar I disorder, most recent episode depressed, warrants pharmacologic intervention. Ms. R agrees to begin a mood stabilizer, valproic acid, instead of medications FDA-approved to treat bipolar depression, such as lurasidone or quetiapine, because she reports good efficacy and tolerability when she took it during a major depressive episode approximately 4 years earlier.

Valproic acid is started at 250 mg/d and increased to 1,000 mg/d. Ms. R tolerates the medication without observed or reported adverse effects.

The authors’ observations
Managing factitious disorder can be challenging; patients can evoke strong feelings of countertransference during treatment.^3,6,7 Providers might feel that the patient does not need to be treated, or that the patient is “not really sick.” This may induce anger and animosity toward the patient (therapeutic nihilism).⁸ These negative emotions are likely to disrupt the patient–provider relationship and exacerbate the patient’s symptoms.

It is generally accepted that the patient should be made aware of the treatment plan, in an indirect and tactful way, so that the patient does not feel “outed.” Unmasking the patient—the process of instilling insight—is a delicate step and can be a stressful time for the patient.⁹ A confrontational approach often places the patient’s sick role in doubt and does not address the pathological aspect of the disorder.

It is rare for a patient to admit to fabricating symptoms; confronted, the patient is likely to double their efforts to maintain the rouse of a fictional disease.^10,11 It is important for the treatment team to be aware that patients frequently leave the treatment facility against medical advice, seek a different provider, or even pursue legal action for defamation against the treating physician.

Treating comorbid medical and psychiatric conditions is important for successful management of a patient with factitious disorder. Initiating valproic acid to address Ms. R’s bipolar depression contributed to her overall psychiatric stability. Initial treatment with a medication that is FDA-approved for treating bipolar depression, such as lurasidone, quetiapine, or olanzapine-fluoxetine combination, should be considered as an alternative. We chose valproic acid for Ms. R because of its previous efficacy, good tolerability, and the patient’s high level of comfort with the medication.

Which of the following are risk factors for factitious disorder?
   a) lengthy medical treatments or hospitalizations as a child
   b) female sex
   c) experience as a health care worker
   d) all of the above


OUTCOME Stabilization
Successful treatment during Ms. R’s inpatient psychiatric admission results in improved insight, remission of suicidal ideation, and stabilization of mood lability. She is discharged to the care of her family with a plan to follow up with a psychotherapist and psychiatrist. Continued administration of valproic acid continues to be effective after discharge.

Ms. R engages in frequent follow-up with outpatient psychiatric services. She remains engaged in psychotherapy and psychiatric care 1 year after discharge. Ms. R has made no report of pregnancy or required hospitalization during this time. She expresses trust in the mental health care system and acknowledges the role treatment played in her improvement.

In December 2014, the FDA issued draft guidance for sweeping changes to labeling of pharmaceutical treatments in regard to pregnancy and lactation information. These changes are now in effect for use in practice.¹ The undertaking has been years in the making, and is truly ambitious.

The outdated system of letter categories (A, B, C, D, X) falls short of clinical needs in several ways:

• the quality and volume of data can be lacking
• comparative risk is not described
• using letters can led to oversimplification or, in some cases, exaggeration of risk and safety (Box).

Other drawbacks include infrequent updating of information and omission of information about baseline rates of reproductive-related adverse events, to provide a more meaningful context for risk assessment.

A note before we continue discussion of labeling: Recognize that pregnancy itself is inherently risky; poor outcomes are, regrettably, not uncommon. The rate of birth defects in the United States is approximately 3%, and obstetric complications, such as prematurity, are common.^2,3

New system described
The new labeling content has been described in the FDA’s Pregnancy and Lactation Labeling Rule (also called the “final rule”), issued in December 2014. For each medication, there will be subsections in the labeling:

• Pregnancy
• Lactation
• Females and Males of Reproductive Potential.

In addition, FDA instructions now state that labeling:

• must be updated when new information becomes available
• needs to include evaluation of human data that becomes available mainly after the drug is approved
• needs to include information about the background rates of adverse events related to reproduction.

Labeling in pregnancy. As an example, the “Pregnancy” section of every label contains 3 subsections, all of great clinical importance. First is information about pregnancy exposure registries, with a listing of scientifically acceptable registries (if a registry is available for that drug) and contact information; this section focuses on the high value of data that are systematically and prospectively collected. The second summarizes risk associated with the drug during pregnancy, based on available human, animal, and pharmacologic data. Third is a discussion of clinical considerations.

Need for appropriate controls. Psychiatric disorders increase the risk of pregnancy complications, and often are associated with variables that might increase the risk of a poor pregnancy outcome. For example, a patient who has a psychiatric disorder might be less likely to seek prenatal care, take a prenatal vitamin, and sleep and eat well; she also might use alcohol, tobacco, or other substances of abuse.

The medical literature on the reproductive safety of psychotropic medications is fraught with confounding variables other than the medications themselves. These include variables that, taken alone, might confer a poorer outcome on the fetus or newborn of a pregnant or lactating woman who has a psychiatric illness (to the extent that she uses psychotropics during a pregnancy), compared with what would be seen in (1) a healthy woman who is not taking such medication or (2) the general population.

On the new labels, detailed statements on human data include information from clinical trials, pregnancy exposure registries, and epidemiologic studies. Labels are also to include:

• incidence of adverse events
• effect of dosage
• effect of duration of exposure
• effect of gestational timing of exposure.

The labels emphasize quantifying risk relative to the risk of the same outcome in infants born to women who have not been exposed to the particular drug, but who have the disease or condition for which the drug is indicated (ie, appropriate controls).

Clinical considerations are to include information on the following related to the specific medication (when that information is known):

• more information for prescribers, to further risk-benefit counseling
• disease-associated maternal-fetal risks
• dosage adjustments during pregnancy and postpartum
• maternal adverse reactions
• fetal and neonatal adverse reactions
• labor and delivery.

Clearly, this overdue shift in providing information regarding reproductive safety has the potential to inform clinicians and patients in a meaningful way about the risks and benefits of specific treatments during pregnancy and lactation. Translating that information into practice is daunting, however.

Important aspects of implementation
Pregnancy exposure registries will play a crucial role. For most medications, no systematic registry has been established; to do so, rigorous methodology is required to acquire prospective data and account for confounding variables.⁴ Appropriate control groups also are required to yield data that are useful and interpretable. Primary outcomes require verification, such as review of medical records. Last, registries must be well-conducted and therefore adequately funded, yet labeling changes have not been accompanied by funding requirements set forth by regulators to pharmaceutical manufacturers.

Labeling must be updated continually. Furthermore, it is unclear who will review data for precision and comprehensiveness.

Data need to be understandable to health care providers across disciplines and to patients with varying levels of education for the label to have a meaningful impact on clinical care.

As noted, there is no mandate for funding the meticulous pharmacovigilance required to provide definitive data for labeling. It is unclear if the potential benefits of the new labeling can be reaped without adequate financing of the pharmacovigilance mechanisms required to inform patients adequately.

Role of pregnancy registries
Over the past 2 decades, pregnancy registries have emerged as a rapid, systematic means of collecting important reproductive safety data on the risk for major malformations after prenatal exposure to a medication or a class of medications.^5,6 Such registries enhance the rigor of available cohort studies and other analyses of reproductive safety data that have been derived from large administrative databases.

NPRAA and NPRAD. Recently, the National Pregnancy Registry for Atypical Antipsychotics (NPRAA) and the National Pregnancy Registry for Antidepressants (NPRAD) were established in an effort to obtain reproductive safety data about fetal exposure to second-generation antipsychotics (SGAs) and to newer antidepressants.⁷ Based at Massachusetts General Hospital in Boston, NPRAA and NPRAD systematically and prospectively evaluate the risk of malformations among infants who have been exposed in utero to an SGA or an antidepressant.

The structure of both registries are the same, modeled after the North American Antiepileptic Drug Registry.^5,8 Data are collected prospectively from pregnant women, age 18 to 45, by means of 3 telephone interviews conducted proximate to enrollment, at 7 months’ gestation, and at 2 or 3 months’ postpartum.

Participants include (1) pregnant women who have a history of fetal exposure to an SGA or an antidepressant, or both, and (2) a comparison group of non-exposed pregnant women who have a history of a psychiatric illness. Authorization for release of medical records is obtained for obstetric care, labor and delivery, and neonatal care (≤6 months of age).

Information on the presence of major malformations is abstracted from the medical record, along with other data on neonatal and maternal health outcomes. Identified cases of a congenital malformation are sent to a dysmorphologist, who has been blinded to drug exposure, for final adjudication. Release of findings is dictated by a governing Scientific Advisory Board.

Results so far. Results are available from the NPRAA.⁹ As of December 2014, 487 women were enrolled: 353 who used an SGA and 134 comparison women. Medical records were obtained for 82.2% of participants. A total of 303 women completed the study and were eligible for inclusion in the analysis. Findings include:

• Of 214 live births with first-trimester exposure to an SGA, 3 major malformations were confirmed. In the control group (n = 89), 1 major malformation was confirmed
• The absolute risk of a major malformation was 1.4% for an exposed infant and 1.1% for an unexposed infant
• The odds ratio for a major malformation, comparing exposed infants with unexposed infants, was 1.25 (95% CI, 0.13–12.19).

It is reasonable, therefore, to conclude that, as a class, SGAs are not major teratogens. Although the confidence intervals around the odds ratio estimate remain wide, with the probability for change over the course of the study, it is unlikely that risk will rise to the level of known major teratogens, such as valproate and thalidomide.^10,11

Help with decision-making
Given recent FDA guidance about the importance of pregnancy registries (www.fda.gov/pregnancyregistries), such carefully collected data might help clinicians and patients make informed choices about treatment. Future efforts of NPRAA and NPRAD will focus on sustaining growth in enrollment of participants so that the reproductive safety of SGAs and newer antidepressants can be delineated more clearly.

Last, you can refer potential participants to NPRAA and NPRAD by calling 1-866-961-2388. More information is available at www.womensmentalhealth.org.

In December 2014, the FDA issued draft guidance for sweeping changes to labeling of pharmaceutical treatments in regard to pregnancy and lactation information. These changes are now in effect for use in practice.¹ The undertaking has been years in the making, and is truly ambitious.

The outdated system of letter categories (A, B, C, D, X) falls short of clinical needs in several ways:

• the quality and volume of data can be lacking
• comparative risk is not described
• using letters can led to oversimplification or, in some cases, exaggeration of risk and safety (Box).

Other drawbacks include infrequent updating of information and omission of information about baseline rates of reproductive-related adverse events, to provide a more meaningful context for risk assessment.

A note before we continue discussion of labeling: Recognize that pregnancy itself is inherently risky; poor outcomes are, regrettably, not uncommon. The rate of birth defects in the United States is approximately 3%, and obstetric complications, such as prematurity, are common.^2,3

New system described
The new labeling content has been described in the FDA’s Pregnancy and Lactation Labeling Rule (also called the “final rule”), issued in December 2014. For each medication, there will be subsections in the labeling:

• Pregnancy
• Lactation
• Females and Males of Reproductive Potential.

In addition, FDA instructions now state that labeling:

• must be updated when new information becomes available
• needs to include evaluation of human data that becomes available mainly after the drug is approved
• needs to include information about the background rates of adverse events related to reproduction.

Labeling in pregnancy. As an example, the “Pregnancy” section of every label contains 3 subsections, all of great clinical importance. First is information about pregnancy exposure registries, with a listing of scientifically acceptable registries (if a registry is available for that drug) and contact information; this section focuses on the high value of data that are systematically and prospectively collected. The second summarizes risk associated with the drug during pregnancy, based on available human, animal, and pharmacologic data. Third is a discussion of clinical considerations.

Need for appropriate controls. Psychiatric disorders increase the risk of pregnancy complications, and often are associated with variables that might increase the risk of a poor pregnancy outcome. For example, a patient who has a psychiatric disorder might be less likely to seek prenatal care, take a prenatal vitamin, and sleep and eat well; she also might use alcohol, tobacco, or other substances of abuse.

The medical literature on the reproductive safety of psychotropic medications is fraught with confounding variables other than the medications themselves. These include variables that, taken alone, might confer a poorer outcome on the fetus or newborn of a pregnant or lactating woman who has a psychiatric illness (to the extent that she uses psychotropics during a pregnancy), compared with what would be seen in (1) a healthy woman who is not taking such medication or (2) the general population.

On the new labels, detailed statements on human data include information from clinical trials, pregnancy exposure registries, and epidemiologic studies. Labels are also to include:

• incidence of adverse events
• effect of dosage
• effect of duration of exposure
• effect of gestational timing of exposure.

The labels emphasize quantifying risk relative to the risk of the same outcome in infants born to women who have not been exposed to the particular drug, but who have the disease or condition for which the drug is indicated (ie, appropriate controls).

Clinical considerations are to include information on the following related to the specific medication (when that information is known):

• more information for prescribers, to further risk-benefit counseling
• disease-associated maternal-fetal risks
• dosage adjustments during pregnancy and postpartum
• maternal adverse reactions
• fetal and neonatal adverse reactions
• labor and delivery.

Clearly, this overdue shift in providing information regarding reproductive safety has the potential to inform clinicians and patients in a meaningful way about the risks and benefits of specific treatments during pregnancy and lactation. Translating that information into practice is daunting, however.

Important aspects of implementation
Pregnancy exposure registries will play a crucial role. For most medications, no systematic registry has been established; to do so, rigorous methodology is required to acquire prospective data and account for confounding variables.⁴ Appropriate control groups also are required to yield data that are useful and interpretable. Primary outcomes require verification, such as review of medical records. Last, registries must be well-conducted and therefore adequately funded, yet labeling changes have not been accompanied by funding requirements set forth by regulators to pharmaceutical manufacturers.

Labeling must be updated continually. Furthermore, it is unclear who will review data for precision and comprehensiveness.

Data need to be understandable to health care providers across disciplines and to patients with varying levels of education for the label to have a meaningful impact on clinical care.

As noted, there is no mandate for funding the meticulous pharmacovigilance required to provide definitive data for labeling. It is unclear if the potential benefits of the new labeling can be reaped without adequate financing of the pharmacovigilance mechanisms required to inform patients adequately.

Role of pregnancy registries
Over the past 2 decades, pregnancy registries have emerged as a rapid, systematic means of collecting important reproductive safety data on the risk for major malformations after prenatal exposure to a medication or a class of medications.^5,6 Such registries enhance the rigor of available cohort studies and other analyses of reproductive safety data that have been derived from large administrative databases.

NPRAA and NPRAD. Recently, the National Pregnancy Registry for Atypical Antipsychotics (NPRAA) and the National Pregnancy Registry for Antidepressants (NPRAD) were established in an effort to obtain reproductive safety data about fetal exposure to second-generation antipsychotics (SGAs) and to newer antidepressants.⁷ Based at Massachusetts General Hospital in Boston, NPRAA and NPRAD systematically and prospectively evaluate the risk of malformations among infants who have been exposed in utero to an SGA or an antidepressant.

The structure of both registries are the same, modeled after the North American Antiepileptic Drug Registry.^5,8 Data are collected prospectively from pregnant women, age 18 to 45, by means of 3 telephone interviews conducted proximate to enrollment, at 7 months’ gestation, and at 2 or 3 months’ postpartum.

Participants include (1) pregnant women who have a history of fetal exposure to an SGA or an antidepressant, or both, and (2) a comparison group of non-exposed pregnant women who have a history of a psychiatric illness. Authorization for release of medical records is obtained for obstetric care, labor and delivery, and neonatal care (≤6 months of age).

Information on the presence of major malformations is abstracted from the medical record, along with other data on neonatal and maternal health outcomes. Identified cases of a congenital malformation are sent to a dysmorphologist, who has been blinded to drug exposure, for final adjudication. Release of findings is dictated by a governing Scientific Advisory Board.

Results so far. Results are available from the NPRAA.⁹ As of December 2014, 487 women were enrolled: 353 who used an SGA and 134 comparison women. Medical records were obtained for 82.2% of participants. A total of 303 women completed the study and were eligible for inclusion in the analysis. Findings include:

• Of 214 live births with first-trimester exposure to an SGA, 3 major malformations were confirmed. In the control group (n = 89), 1 major malformation was confirmed
• The absolute risk of a major malformation was 1.4% for an exposed infant and 1.1% for an unexposed infant
• The odds ratio for a major malformation, comparing exposed infants with unexposed infants, was 1.25 (95% CI, 0.13–12.19).

It is reasonable, therefore, to conclude that, as a class, SGAs are not major teratogens. Although the confidence intervals around the odds ratio estimate remain wide, with the probability for change over the course of the study, it is unlikely that risk will rise to the level of known major teratogens, such as valproate and thalidomide.^10,11

Help with decision-making
Given recent FDA guidance about the importance of pregnancy registries (www.fda.gov/pregnancyregistries), such carefully collected data might help clinicians and patients make informed choices about treatment. Future efforts of NPRAA and NPRAD will focus on sustaining growth in enrollment of participants so that the reproductive safety of SGAs and newer antidepressants can be delineated more clearly.

Last, you can refer potential participants to NPRAA and NPRAD by calling 1-866-961-2388. More information is available at www.womensmentalhealth.org.

In December 2014, the FDA issued draft guidance for sweeping changes to labeling of pharmaceutical treatments in regard to pregnancy and lactation information. These changes are now in effect for use in practice.¹ The undertaking has been years in the making, and is truly ambitious.

The outdated system of letter categories (A, B, C, D, X) falls short of clinical needs in several ways:

• the quality and volume of data can be lacking
• comparative risk is not described
• using letters can led to oversimplification or, in some cases, exaggeration of risk and safety (Box).

Other drawbacks include infrequent updating of information and omission of information about baseline rates of reproductive-related adverse events, to provide a more meaningful context for risk assessment.

A note before we continue discussion of labeling: Recognize that pregnancy itself is inherently risky; poor outcomes are, regrettably, not uncommon. The rate of birth defects in the United States is approximately 3%, and obstetric complications, such as prematurity, are common.^2,3

New system described
The new labeling content has been described in the FDA’s Pregnancy and Lactation Labeling Rule (also called the “final rule”), issued in December 2014. For each medication, there will be subsections in the labeling:

• Pregnancy
• Lactation
• Females and Males of Reproductive Potential.

In addition, FDA instructions now state that labeling:

• must be updated when new information becomes available
• needs to include evaluation of human data that becomes available mainly after the drug is approved
• needs to include information about the background rates of adverse events related to reproduction.

Labeling in pregnancy. As an example, the “Pregnancy” section of every label contains 3 subsections, all of great clinical importance. First is information about pregnancy exposure registries, with a listing of scientifically acceptable registries (if a registry is available for that drug) and contact information; this section focuses on the high value of data that are systematically and prospectively collected. The second summarizes risk associated with the drug during pregnancy, based on available human, animal, and pharmacologic data. Third is a discussion of clinical considerations.

Need for appropriate controls. Psychiatric disorders increase the risk of pregnancy complications, and often are associated with variables that might increase the risk of a poor pregnancy outcome. For example, a patient who has a psychiatric disorder might be less likely to seek prenatal care, take a prenatal vitamin, and sleep and eat well; she also might use alcohol, tobacco, or other substances of abuse.

The medical literature on the reproductive safety of psychotropic medications is fraught with confounding variables other than the medications themselves. These include variables that, taken alone, might confer a poorer outcome on the fetus or newborn of a pregnant or lactating woman who has a psychiatric illness (to the extent that she uses psychotropics during a pregnancy), compared with what would be seen in (1) a healthy woman who is not taking such medication or (2) the general population.

On the new labels, detailed statements on human data include information from clinical trials, pregnancy exposure registries, and epidemiologic studies. Labels are also to include:

• incidence of adverse events
• effect of dosage
• effect of duration of exposure
• effect of gestational timing of exposure.

The labels emphasize quantifying risk relative to the risk of the same outcome in infants born to women who have not been exposed to the particular drug, but who have the disease or condition for which the drug is indicated (ie, appropriate controls).

Clinical considerations are to include information on the following related to the specific medication (when that information is known):

• more information for prescribers, to further risk-benefit counseling
• disease-associated maternal-fetal risks
• dosage adjustments during pregnancy and postpartum
• maternal adverse reactions
• fetal and neonatal adverse reactions
• labor and delivery.

Clearly, this overdue shift in providing information regarding reproductive safety has the potential to inform clinicians and patients in a meaningful way about the risks and benefits of specific treatments during pregnancy and lactation. Translating that information into practice is daunting, however.

Important aspects of implementation
Pregnancy exposure registries will play a crucial role. For most medications, no systematic registry has been established; to do so, rigorous methodology is required to acquire prospective data and account for confounding variables.⁴ Appropriate control groups also are required to yield data that are useful and interpretable. Primary outcomes require verification, such as review of medical records. Last, registries must be well-conducted and therefore adequately funded, yet labeling changes have not been accompanied by funding requirements set forth by regulators to pharmaceutical manufacturers.

Labeling must be updated continually. Furthermore, it is unclear who will review data for precision and comprehensiveness.

Data need to be understandable to health care providers across disciplines and to patients with varying levels of education for the label to have a meaningful impact on clinical care.

As noted, there is no mandate for funding the meticulous pharmacovigilance required to provide definitive data for labeling. It is unclear if the potential benefits of the new labeling can be reaped without adequate financing of the pharmacovigilance mechanisms required to inform patients adequately.

Role of pregnancy registries
Over the past 2 decades, pregnancy registries have emerged as a rapid, systematic means of collecting important reproductive safety data on the risk for major malformations after prenatal exposure to a medication or a class of medications.^5,6 Such registries enhance the rigor of available cohort studies and other analyses of reproductive safety data that have been derived from large administrative databases.

NPRAA and NPRAD. Recently, the National Pregnancy Registry for Atypical Antipsychotics (NPRAA) and the National Pregnancy Registry for Antidepressants (NPRAD) were established in an effort to obtain reproductive safety data about fetal exposure to second-generation antipsychotics (SGAs) and to newer antidepressants.⁷ Based at Massachusetts General Hospital in Boston, NPRAA and NPRAD systematically and prospectively evaluate the risk of malformations among infants who have been exposed in utero to an SGA or an antidepressant.

The structure of both registries are the same, modeled after the North American Antiepileptic Drug Registry.^5,8 Data are collected prospectively from pregnant women, age 18 to 45, by means of 3 telephone interviews conducted proximate to enrollment, at 7 months’ gestation, and at 2 or 3 months’ postpartum.

Participants include (1) pregnant women who have a history of fetal exposure to an SGA or an antidepressant, or both, and (2) a comparison group of non-exposed pregnant women who have a history of a psychiatric illness. Authorization for release of medical records is obtained for obstetric care, labor and delivery, and neonatal care (≤6 months of age).

Information on the presence of major malformations is abstracted from the medical record, along with other data on neonatal and maternal health outcomes. Identified cases of a congenital malformation are sent to a dysmorphologist, who has been blinded to drug exposure, for final adjudication. Release of findings is dictated by a governing Scientific Advisory Board.

Results so far. Results are available from the NPRAA.⁹ As of December 2014, 487 women were enrolled: 353 who used an SGA and 134 comparison women. Medical records were obtained for 82.2% of participants. A total of 303 women completed the study and were eligible for inclusion in the analysis. Findings include:

• Of 214 live births with first-trimester exposure to an SGA, 3 major malformations were confirmed. In the control group (n = 89), 1 major malformation was confirmed
• The absolute risk of a major malformation was 1.4% for an exposed infant and 1.1% for an unexposed infant
• The odds ratio for a major malformation, comparing exposed infants with unexposed infants, was 1.25 (95% CI, 0.13–12.19).

It is reasonable, therefore, to conclude that, as a class, SGAs are not major teratogens. Although the confidence intervals around the odds ratio estimate remain wide, with the probability for change over the course of the study, it is unlikely that risk will rise to the level of known major teratogens, such as valproate and thalidomide.^10,11

Help with decision-making
Given recent FDA guidance about the importance of pregnancy registries (www.fda.gov/pregnancyregistries), such carefully collected data might help clinicians and patients make informed choices about treatment. Future efforts of NPRAA and NPRAD will focus on sustaining growth in enrollment of participants so that the reproductive safety of SGAs and newer antidepressants can be delineated more clearly.

Last, you can refer potential participants to NPRAA and NPRAD by calling 1-866-961-2388. More information is available at www.womensmentalhealth.org.

Obinutuzumab and bendamustine followed by obinutuzumab maintenance therapy was superior to bendamustine monotherapy based on progression-free survival in rituximab-refractory patients with indolent non-Hodgkin lymphoma, based on a study published online in the Lancet Oncology.

After a median follow-up of 22 months in the obinutuzumab plus bendamustine group and 20 months in the bendamustine monotherapy group, progression-free survival was significantly longer with obinutuzumab plus bendamustine (median not reached; 95% confidence interval, 22.5 months – not estimable) than with bendamustine monotherapy (14.9 months, range, 12.8-16.6; hazard ratio, 0.55; 95% CI 0.40-0.74; P = .0001). About two-thirds of the nearly 400 patients in both study arms had grade 3-5 adverse events.

The anti-CD20 monoclonal antibody obinutuzumab is an option when patients with indolent non-Hodgkin lymphoma relapse or don’t achieve adequate disease control with rituximab-based treatment, wrote Laurie H. Sehn, MD, of the British Columbia Cancer Agency and the University of British Columbia, Vancouver, and her colleagues.

In an open-label, randomized, phase III study called GADOLIN, patients with CD20-positive indolent non-Hodgkin lymphoma were stratified by indolent non-Hodgkin lymphoma subtype, rituximab-refractory type, number of previous therapies, and geographic region.

For the study, 194 patients were assigned to obinutuzumab plus bendamustine and 202 to bendamustine monotherapy. Trial participants received six 28-day cycles with either obinutuzumab plus bendamustine (obinutuzumab 1,000 mg on days 1, 8, and 15, cycle 1; and on day 1, cycles 2-6) plus bendamustine (90 mg/m² per day on days 1 and 2, cycles 1-6) or bendamustine monotherapy (120 mg/m² per day on days 1 and 2 of all cycles). Patients in the obinutuzumab plus bendamustine group whose disease did not progress received obinutuzumab maintenance therapy of 1,000 mg once every 2 months for up to 2 years.

Grade 3-5 adverse events occurred in 68% of 194 patients in the obinutuzumab plus bendamustine group and in 62% of 198 patients in the bendamustine monotherapy group. Grade 3 or worse neutropenia affected 33% of the obinutuzumab plus bendamustine group and 26% of the bendamustine monotherapy group. Other grade 3 or worse events included thrombocytopenia in 11% and 16%, anemia in 8% and 10%, and infusion-related reactions in 11% and 6%. Serious adverse events occurred in 38% in the obinutuzumab plus bendamustine group and in 33% in the bendamustine monotherapy group. Adverse events resulted in death in 6% of patients in each group.

The study was funded by Hoffmann-La Roche. Genentech, the maker of obinutuzumab (Gazyva) in the United States, is a wholly owned member of the Roche Group. Dr. Sehn receives honoraria and is a consultant or advisor to Genentech as well as several other drug companies.

[email protected]

On Twitter @maryjodales

Obinutuzumab and bendamustine followed by obinutuzumab maintenance therapy was superior to bendamustine monotherapy based on progression-free survival in rituximab-refractory patients with indolent non-Hodgkin lymphoma, based on a study published online in the Lancet Oncology.

After a median follow-up of 22 months in the obinutuzumab plus bendamustine group and 20 months in the bendamustine monotherapy group, progression-free survival was significantly longer with obinutuzumab plus bendamustine (median not reached; 95% confidence interval, 22.5 months – not estimable) than with bendamustine monotherapy (14.9 months, range, 12.8-16.6; hazard ratio, 0.55; 95% CI 0.40-0.74; P = .0001). About two-thirds of the nearly 400 patients in both study arms had grade 3-5 adverse events.

The anti-CD20 monoclonal antibody obinutuzumab is an option when patients with indolent non-Hodgkin lymphoma relapse or don’t achieve adequate disease control with rituximab-based treatment, wrote Laurie H. Sehn, MD, of the British Columbia Cancer Agency and the University of British Columbia, Vancouver, and her colleagues.

In an open-label, randomized, phase III study called GADOLIN, patients with CD20-positive indolent non-Hodgkin lymphoma were stratified by indolent non-Hodgkin lymphoma subtype, rituximab-refractory type, number of previous therapies, and geographic region.

For the study, 194 patients were assigned to obinutuzumab plus bendamustine and 202 to bendamustine monotherapy. Trial participants received six 28-day cycles with either obinutuzumab plus bendamustine (obinutuzumab 1,000 mg on days 1, 8, and 15, cycle 1; and on day 1, cycles 2-6) plus bendamustine (90 mg/m² per day on days 1 and 2, cycles 1-6) or bendamustine monotherapy (120 mg/m² per day on days 1 and 2 of all cycles). Patients in the obinutuzumab plus bendamustine group whose disease did not progress received obinutuzumab maintenance therapy of 1,000 mg once every 2 months for up to 2 years.

Grade 3-5 adverse events occurred in 68% of 194 patients in the obinutuzumab plus bendamustine group and in 62% of 198 patients in the bendamustine monotherapy group. Grade 3 or worse neutropenia affected 33% of the obinutuzumab plus bendamustine group and 26% of the bendamustine monotherapy group. Other grade 3 or worse events included thrombocytopenia in 11% and 16%, anemia in 8% and 10%, and infusion-related reactions in 11% and 6%. Serious adverse events occurred in 38% in the obinutuzumab plus bendamustine group and in 33% in the bendamustine monotherapy group. Adverse events resulted in death in 6% of patients in each group.

The study was funded by Hoffmann-La Roche. Genentech, the maker of obinutuzumab (Gazyva) in the United States, is a wholly owned member of the Roche Group. Dr. Sehn receives honoraria and is a consultant or advisor to Genentech as well as several other drug companies.

[email protected]

On Twitter @maryjodales

Obinutuzumab and bendamustine followed by obinutuzumab maintenance therapy was superior to bendamustine monotherapy based on progression-free survival in rituximab-refractory patients with indolent non-Hodgkin lymphoma, based on a study published online in the Lancet Oncology.

After a median follow-up of 22 months in the obinutuzumab plus bendamustine group and 20 months in the bendamustine monotherapy group, progression-free survival was significantly longer with obinutuzumab plus bendamustine (median not reached; 95% confidence interval, 22.5 months – not estimable) than with bendamustine monotherapy (14.9 months, range, 12.8-16.6; hazard ratio, 0.55; 95% CI 0.40-0.74; P = .0001). About two-thirds of the nearly 400 patients in both study arms had grade 3-5 adverse events.

The anti-CD20 monoclonal antibody obinutuzumab is an option when patients with indolent non-Hodgkin lymphoma relapse or don’t achieve adequate disease control with rituximab-based treatment, wrote Laurie H. Sehn, MD, of the British Columbia Cancer Agency and the University of British Columbia, Vancouver, and her colleagues.

In an open-label, randomized, phase III study called GADOLIN, patients with CD20-positive indolent non-Hodgkin lymphoma were stratified by indolent non-Hodgkin lymphoma subtype, rituximab-refractory type, number of previous therapies, and geographic region.

For the study, 194 patients were assigned to obinutuzumab plus bendamustine and 202 to bendamustine monotherapy. Trial participants received six 28-day cycles with either obinutuzumab plus bendamustine (obinutuzumab 1,000 mg on days 1, 8, and 15, cycle 1; and on day 1, cycles 2-6) plus bendamustine (90 mg/m² per day on days 1 and 2, cycles 1-6) or bendamustine monotherapy (120 mg/m² per day on days 1 and 2 of all cycles). Patients in the obinutuzumab plus bendamustine group whose disease did not progress received obinutuzumab maintenance therapy of 1,000 mg once every 2 months for up to 2 years.

Grade 3-5 adverse events occurred in 68% of 194 patients in the obinutuzumab plus bendamustine group and in 62% of 198 patients in the bendamustine monotherapy group. Grade 3 or worse neutropenia affected 33% of the obinutuzumab plus bendamustine group and 26% of the bendamustine monotherapy group. Other grade 3 or worse events included thrombocytopenia in 11% and 16%, anemia in 8% and 10%, and infusion-related reactions in 11% and 6%. Serious adverse events occurred in 38% in the obinutuzumab plus bendamustine group and in 33% in the bendamustine monotherapy group. Adverse events resulted in death in 6% of patients in each group.

The study was funded by Hoffmann-La Roche. Genentech, the maker of obinutuzumab (Gazyva) in the United States, is a wholly owned member of the Roche Group. Dr. Sehn receives honoraria and is a consultant or advisor to Genentech as well as several other drug companies.

[email protected]

On Twitter @maryjodales

In early 2014, I decided to use the six state licenses I had obtained as a locum tenens physician to start practicing telemedicine. Since then, I have worked with several telemedicine platforms. I have found that telemedicine companies differ dramatically in their overall ease of use for the provider. Here are my top tips for deciding which telemedicine company to work with.

1. Technology support: Telemedicine is dependent on technology. If it is difficult to get help from tech support, do not credential with the company. Tech support is your lifeline to your patients. Make sure you can get help right away if you are having problems finishing or starting a consult. Companies that send automatic emails saying they will get back to you within 24 hours are the most difficult to work with.
2. Nursing support: All of the telemedicine companies that I have worked with have amazing nurses, but some are overwhelmed with work. Telemedicine nurses are able to connect to your patients via direct callback numbers in a way that you cannot connect. They are able to call in prescriptions to pharmacies if the platform is down or if the patient put in the wrong pharmacy information. Make sure that the company has a nurse that is able to call you back right away. A few telemedicine companies are understaffed with nurses, and it can take hours for a callback. If the key to telemedicine is volume, this is frustrating to deal with.
3. Chief complaints: Many telemedicine companies are moving away from making the “chief complaint” visible to providers before choosing to take the consult. For me, this is a big red flag. It can be as simple as, “I have a cold.” I like this because if I see a patient who says, “I have abdominal pain,” I know to triage them first.
4. Volume: Telemedicine is great for staying connected to outpatient medicine. If you are looking to work on a telemedicine platform for your main source of income, then volume is key. A lot of telemedicine companies will tell you how many calls they get per day; the key question is how many calls they get for the states that you are licensed in and how many providers they have licensed in those states. If you want higher volume, then ask if they will pay for your license in states with higher needs (some will). If you are willing to pay to be licensed in additional states, make sure the volume is high enough to make that extra out-of-pocket cost worth it.
5. Malpractice coverage: Many companies provide malpractice coverage as part of their credentialing package. If they do not, make sure your malpractice coverage covers you for telemedicine.
6. Documentation: Documentation during your telemedicine consult is arguably even more important than in an outpatient visit. Everything is on the phone or by video, so make sure, in the subjective area, that you are quoting what the patient is telling you. You are not able to do a physical exam, so your recommendations will be based on what the patient is saying.

Have fun! Telemedicine has been really enjoyable for me. I like being able to have the time to educate my patients about things like antibiotics. I enjoy the technological aspects and understanding all of the different platforms. Telemedicine gives you a unique opportunity to practice your skills from the comfort of your own home. TH

Geeta Arora, MD, locum tenens hospitalist

In early 2014, I decided to use the six state licenses I had obtained as a locum tenens physician to start practicing telemedicine. Since then, I have worked with several telemedicine platforms. I have found that telemedicine companies differ dramatically in their overall ease of use for the provider. Here are my top tips for deciding which telemedicine company to work with.

1. Technology support: Telemedicine is dependent on technology. If it is difficult to get help from tech support, do not credential with the company. Tech support is your lifeline to your patients. Make sure you can get help right away if you are having problems finishing or starting a consult. Companies that send automatic emails saying they will get back to you within 24 hours are the most difficult to work with.
2. Nursing support: All of the telemedicine companies that I have worked with have amazing nurses, but some are overwhelmed with work. Telemedicine nurses are able to connect to your patients via direct callback numbers in a way that you cannot connect. They are able to call in prescriptions to pharmacies if the platform is down or if the patient put in the wrong pharmacy information. Make sure that the company has a nurse that is able to call you back right away. A few telemedicine companies are understaffed with nurses, and it can take hours for a callback. If the key to telemedicine is volume, this is frustrating to deal with.
3. Chief complaints: Many telemedicine companies are moving away from making the “chief complaint” visible to providers before choosing to take the consult. For me, this is a big red flag. It can be as simple as, “I have a cold.” I like this because if I see a patient who says, “I have abdominal pain,” I know to triage them first.
4. Volume: Telemedicine is great for staying connected to outpatient medicine. If you are looking to work on a telemedicine platform for your main source of income, then volume is key. A lot of telemedicine companies will tell you how many calls they get per day; the key question is how many calls they get for the states that you are licensed in and how many providers they have licensed in those states. If you want higher volume, then ask if they will pay for your license in states with higher needs (some will). If you are willing to pay to be licensed in additional states, make sure the volume is high enough to make that extra out-of-pocket cost worth it.
5. Malpractice coverage: Many companies provide malpractice coverage as part of their credentialing package. If they do not, make sure your malpractice coverage covers you for telemedicine.
6. Documentation: Documentation during your telemedicine consult is arguably even more important than in an outpatient visit. Everything is on the phone or by video, so make sure, in the subjective area, that you are quoting what the patient is telling you. You are not able to do a physical exam, so your recommendations will be based on what the patient is saying.

Have fun! Telemedicine has been really enjoyable for me. I like being able to have the time to educate my patients about things like antibiotics. I enjoy the technological aspects and understanding all of the different platforms. Telemedicine gives you a unique opportunity to practice your skills from the comfort of your own home. TH

Geeta Arora, MD, locum tenens hospitalist

In early 2014, I decided to use the six state licenses I had obtained as a locum tenens physician to start practicing telemedicine. Since then, I have worked with several telemedicine platforms. I have found that telemedicine companies differ dramatically in their overall ease of use for the provider. Here are my top tips for deciding which telemedicine company to work with.

1. Technology support: Telemedicine is dependent on technology. If it is difficult to get help from tech support, do not credential with the company. Tech support is your lifeline to your patients. Make sure you can get help right away if you are having problems finishing or starting a consult. Companies that send automatic emails saying they will get back to you within 24 hours are the most difficult to work with.
2. Nursing support: All of the telemedicine companies that I have worked with have amazing nurses, but some are overwhelmed with work. Telemedicine nurses are able to connect to your patients via direct callback numbers in a way that you cannot connect. They are able to call in prescriptions to pharmacies if the platform is down or if the patient put in the wrong pharmacy information. Make sure that the company has a nurse that is able to call you back right away. A few telemedicine companies are understaffed with nurses, and it can take hours for a callback. If the key to telemedicine is volume, this is frustrating to deal with.
3. Chief complaints: Many telemedicine companies are moving away from making the “chief complaint” visible to providers before choosing to take the consult. For me, this is a big red flag. It can be as simple as, “I have a cold.” I like this because if I see a patient who says, “I have abdominal pain,” I know to triage them first.
4. Volume: Telemedicine is great for staying connected to outpatient medicine. If you are looking to work on a telemedicine platform for your main source of income, then volume is key. A lot of telemedicine companies will tell you how many calls they get per day; the key question is how many calls they get for the states that you are licensed in and how many providers they have licensed in those states. If you want higher volume, then ask if they will pay for your license in states with higher needs (some will). If you are willing to pay to be licensed in additional states, make sure the volume is high enough to make that extra out-of-pocket cost worth it.
5. Malpractice coverage: Many companies provide malpractice coverage as part of their credentialing package. If they do not, make sure your malpractice coverage covers you for telemedicine.
6. Documentation: Documentation during your telemedicine consult is arguably even more important than in an outpatient visit. Everything is on the phone or by video, so make sure, in the subjective area, that you are quoting what the patient is telling you. You are not able to do a physical exam, so your recommendations will be based on what the patient is saying.

Have fun! Telemedicine has been really enjoyable for me. I like being able to have the time to educate my patients about things like antibiotics. I enjoy the technological aspects and understanding all of the different platforms. Telemedicine gives you a unique opportunity to practice your skills from the comfort of your own home. TH

Geeta Arora, MD, locum tenens hospitalist

Micrograph showing CLL

Researchers say they have performed the first large-scale analysis of the chromatin landscape in chronic lymphocytic leukemia (CLL).

And, in doing so, they have identified shared gene regulatory networks as well as heterogeneity between patients and CLL subtypes.

The group says this work should enable deeper investigation into chromatin regulation in CLL and the identification of therapeutically relevant mechanisms of disease.

The work has been published in Nature Communications.

The researchers performed chromatin accessibility mapping—via the assay for transposase-accessible chromatin using sequencing (ATAC-seq)—on 88 CLL samples from 55 patients.

For 10 of the samples, the team also established histone profiles using ChIPmentation for 3 histone marks (H3K4me1, H3K27ac, and H3K27me3) and transcriptome profiles using RNA sequencing.

The researchers then developed a bioinformatic method for linking the chromatin profiles to clinical annotations and molecular diagnostics data, and they analyzed gene regulatory networks that underlie the major disease subtypes of CLL.

The work revealed a “shared core” of regulatory regions in CLL patients as well as variations between the samples.

Furthermore, the chromatin profiles and gene regulatory networks accurately predicted IGHV mutation status and pinpointed differences between IGVH-mutated and IGVH-unmutated CLL.

“Our study has been able to dissect the variability that exists in the epigenome of CLL patients and helped to identify disease-specific changes, which will hopefully be informative for distinguishing disease subtypes or identifying suitable treatments,” said study author Jonathan Strefford, PhD, of the University of Southampton in the UK.

“Epigenetics can offer a useful doorway into ways of improving disease diagnosis and more personalized treatment choices for patients.”

Micrograph showing CLL

Researchers say they have performed the first large-scale analysis of the chromatin landscape in chronic lymphocytic leukemia (CLL).

And, in doing so, they have identified shared gene regulatory networks as well as heterogeneity between patients and CLL subtypes.

The group says this work should enable deeper investigation into chromatin regulation in CLL and the identification of therapeutically relevant mechanisms of disease.

The work has been published in Nature Communications.

The researchers performed chromatin accessibility mapping—via the assay for transposase-accessible chromatin using sequencing (ATAC-seq)—on 88 CLL samples from 55 patients.

For 10 of the samples, the team also established histone profiles using ChIPmentation for 3 histone marks (H3K4me1, H3K27ac, and H3K27me3) and transcriptome profiles using RNA sequencing.

The researchers then developed a bioinformatic method for linking the chromatin profiles to clinical annotations and molecular diagnostics data, and they analyzed gene regulatory networks that underlie the major disease subtypes of CLL.

The work revealed a “shared core” of regulatory regions in CLL patients as well as variations between the samples.

Furthermore, the chromatin profiles and gene regulatory networks accurately predicted IGHV mutation status and pinpointed differences between IGVH-mutated and IGVH-unmutated CLL.

“Our study has been able to dissect the variability that exists in the epigenome of CLL patients and helped to identify disease-specific changes, which will hopefully be informative for distinguishing disease subtypes or identifying suitable treatments,” said study author Jonathan Strefford, PhD, of the University of Southampton in the UK.

“Epigenetics can offer a useful doorway into ways of improving disease diagnosis and more personalized treatment choices for patients.”

Micrograph showing CLL

Researchers say they have performed the first large-scale analysis of the chromatin landscape in chronic lymphocytic leukemia (CLL).

And, in doing so, they have identified shared gene regulatory networks as well as heterogeneity between patients and CLL subtypes.

The group says this work should enable deeper investigation into chromatin regulation in CLL and the identification of therapeutically relevant mechanisms of disease.

The work has been published in Nature Communications.

The researchers performed chromatin accessibility mapping—via the assay for transposase-accessible chromatin using sequencing (ATAC-seq)—on 88 CLL samples from 55 patients.

For 10 of the samples, the team also established histone profiles using ChIPmentation for 3 histone marks (H3K4me1, H3K27ac, and H3K27me3) and transcriptome profiles using RNA sequencing.

The researchers then developed a bioinformatic method for linking the chromatin profiles to clinical annotations and molecular diagnostics data, and they analyzed gene regulatory networks that underlie the major disease subtypes of CLL.

The work revealed a “shared core” of regulatory regions in CLL patients as well as variations between the samples.

Furthermore, the chromatin profiles and gene regulatory networks accurately predicted IGHV mutation status and pinpointed differences between IGVH-mutated and IGVH-unmutated CLL.

“Our study has been able to dissect the variability that exists in the epigenome of CLL patients and helped to identify disease-specific changes, which will hopefully be informative for distinguishing disease subtypes or identifying suitable treatments,” said study author Jonathan Strefford, PhD, of the University of Southampton in the UK.

“Epigenetics can offer a useful doorway into ways of improving disease diagnosis and more personalized treatment choices for patients.”

An EBV-infected cell (green/red)

among uninfected cells (blue)

Image courtesy of Benjamin

Chaigne-Delalande

A cytotoxic T-lymphocyte product that targets Epstein-Barr virus (EBV-CTLs) has been classified as an advanced therapy medicinal product (ATMP) by the European Medicines Agency (EMA).

The EBV-CTLs are being developed by Atara Biotherapeutics, Inc., to treat patients with EBV post-transplant lymphoproliferative disorder (EBV-PTLD).

ATMP classification was established to regulate cell and gene therapy and tissue-engineered medicinal products, support the development of these products, and provide a benchmark for the level of quality compliance for pharmaceutical practices.

ATMP classification can provide developers with scientific regulatory guidance, help clarify the applicable regulatory framework and development path, and provide access to all relevant services and incentives offered by the EMA. It can also be advantageous when submitting clinical trial dossiers to national regulatory authorities within the European Union.

About EBV-CTLs

Atara Bio’s EBV-CTL product utilizes a technology in which T cells are collected from the blood of third-party donors and then exposed to EBV antigens. The activated T cells are then expanded, characterized, and stored for future use in a partially HLA-matched patient.

In the context of EBV-PTLD, the EBV-CTLs find the cancer cells expressing EBV and kill them.

Atara Bio’s EBV-CTL product is currently being studied in phase 2 trials of patients with EBV-associated cancers, including PTLD and nasopharyngeal carcinoma.

Results of a phase 1/2 study of EBV-CTLs were presented at the APHON 37th Annual Conference and Exhibit and the 2015 ASCO Annual Meeting.

Atara Bio’s EBV-CTL product has orphan designation in the European Union and the US, as well as breakthrough designation in the US.

An EBV-infected cell (green/red)

among uninfected cells (blue)

Image courtesy of Benjamin

Chaigne-Delalande

A cytotoxic T-lymphocyte product that targets Epstein-Barr virus (EBV-CTLs) has been classified as an advanced therapy medicinal product (ATMP) by the European Medicines Agency (EMA).

The EBV-CTLs are being developed by Atara Biotherapeutics, Inc., to treat patients with EBV post-transplant lymphoproliferative disorder (EBV-PTLD).

ATMP classification was established to regulate cell and gene therapy and tissue-engineered medicinal products, support the development of these products, and provide a benchmark for the level of quality compliance for pharmaceutical practices.

ATMP classification can provide developers with scientific regulatory guidance, help clarify the applicable regulatory framework and development path, and provide access to all relevant services and incentives offered by the EMA. It can also be advantageous when submitting clinical trial dossiers to national regulatory authorities within the European Union.

About EBV-CTLs

Atara Bio’s EBV-CTL product utilizes a technology in which T cells are collected from the blood of third-party donors and then exposed to EBV antigens. The activated T cells are then expanded, characterized, and stored for future use in a partially HLA-matched patient.

In the context of EBV-PTLD, the EBV-CTLs find the cancer cells expressing EBV and kill them.

Atara Bio’s EBV-CTL product is currently being studied in phase 2 trials of patients with EBV-associated cancers, including PTLD and nasopharyngeal carcinoma.

Results of a phase 1/2 study of EBV-CTLs were presented at the APHON 37th Annual Conference and Exhibit and the 2015 ASCO Annual Meeting.

Atara Bio’s EBV-CTL product has orphan designation in the European Union and the US, as well as breakthrough designation in the US.

An EBV-infected cell (green/red)

among uninfected cells (blue)

Image courtesy of Benjamin

Chaigne-Delalande

A cytotoxic T-lymphocyte product that targets Epstein-Barr virus (EBV-CTLs) has been classified as an advanced therapy medicinal product (ATMP) by the European Medicines Agency (EMA).

The EBV-CTLs are being developed by Atara Biotherapeutics, Inc., to treat patients with EBV post-transplant lymphoproliferative disorder (EBV-PTLD).

ATMP classification was established to regulate cell and gene therapy and tissue-engineered medicinal products, support the development of these products, and provide a benchmark for the level of quality compliance for pharmaceutical practices.

ATMP classification can provide developers with scientific regulatory guidance, help clarify the applicable regulatory framework and development path, and provide access to all relevant services and incentives offered by the EMA. It can also be advantageous when submitting clinical trial dossiers to national regulatory authorities within the European Union.

About EBV-CTLs

Atara Bio’s EBV-CTL product utilizes a technology in which T cells are collected from the blood of third-party donors and then exposed to EBV antigens. The activated T cells are then expanded, characterized, and stored for future use in a partially HLA-matched patient.

In the context of EBV-PTLD, the EBV-CTLs find the cancer cells expressing EBV and kill them.

Atara Bio’s EBV-CTL product is currently being studied in phase 2 trials of patients with EBV-associated cancers, including PTLD and nasopharyngeal carcinoma.

Results of a phase 1/2 study of EBV-CTLs were presented at the APHON 37th Annual Conference and Exhibit and the 2015 ASCO Annual Meeting.

Atara Bio’s EBV-CTL product has orphan designation in the European Union and the US, as well as breakthrough designation in the US.

Blood smear showing

Plasmodium vivax

Image by Mae Melvin

Genomic research suggests the malaria parasite Plasmodium vivax is evolving rapidly to adapt to conditions in different geographic locations.

Researchers studied more than 200 parasite samples from across the Asia-Pacific region and found that P vivax has evolved differently in different areas.

The team identified substantial differences in the frequency of copy number variations (CNVs) in samples from western Thailand, western Cambodia, and Papua Indonesia.

They believe this is a result of the different antimalarial drugs used in these regions.

The researchers described this work in Nature Genetics.

“For so long, it’s not been possible to study P vivax genomes in detail, on a large-scale, but now we can, and we’re seeing the effect that drug use has on how parasites are evolving,” said study author Dominic Kwiatkowski, of the Wellcome Trust Sanger Institute in the UK.

He and his colleagues studied the genomes of 228 parasite samples, identifying the strains carried by each patient and revealing their infection history. Most samples came from Southeast Asia (Thailand, Cambodia, Vietnam, Laos, Myanmar, and Malaysia) and Oceania (Papua Indonesia and Papua New Guinea), but the team also studied samples from China, India, Sri Lanka, Brazil, and Madagascar.

The researchers performed detailed population genetic analyses using 148 samples from western Thailand, western Cambodia, and Papua Indonesia. This revealed CNVs in 9 regions of the core genome, and the frequency of the 4 most common CNVs varied greatly according to geographical location.

The first common CNV was a 9-kb deletion on chromosome 8 that includes the first 3 exons of a gene encoding a cytoadherence-linked asexual protein. The CNV was present in 73% of Papua Indonesia samples, 6% of western Cambodia samples, and 3% of western Thailand samples.

The second common CNV was a 7-kb duplication on chromosome 6 that encompasses pvdbp, the gene that encodes the Duffy-binding protein, which mediates P vivax’s invasion of erythrocytes. It was present in 5% of Papua Indonesia samples, 35% of western Cambodia samples, and 25% of western Thailand samples.

The third common CNV was a 37-kb duplication on chromosome 10 that includes pvmdr1, which has been associated with resistance to mefloquine and is homologous to the pfmdr1 amplification responsible for mefloquine resistance in P falciparum. This CNV was only present in samples from western Thailand.

The fourth common CNV was a 3-kb duplication on chromosome 14 that includes the gene PVX_101445. It was found only in Papua Indonesia samples.

“Our study shows that the strongest evidence of evolution is in Papua, Indonesia, where resistance of P vivax to chloroquine is now rampant,” said Ric Price, MD, of the University of Oxford in the UK.

“These data provide crucial information from which we can start to identify the mechanisms of drug resistance in P vivax.”

“We can see in the genome that drug resistance is a huge driver for evolution,” added Richard Pearson, PhD, of the Wellcome Trust Sanger Institute.

“Intriguingly, in some places, this process appears to be happening in response to drugs used primarily to treat a different malaria parasite, P falciparum. Although the exact cause isn’t known, this is a worrying sign that drug resistance is becoming deeply entrenched in the parasite population.”

The researchers said there are a few possible reasons why P vivax may be evolving to evade drugs used against P falciparum.

Many people carry mixed infections of both species of parasite, so, in treating one species, the other automatically gets exposed to the drug. Another culprit may be unsupervised drug use—where many people take the most readily available, rather than the most suitable, antimalarial drug.

Another finding from this study was that, when the researchers identified patients who were carrying multiple strains of parasite, the genomic data made it possible to determine how closely the different strains were related to one another.

“This means that we can now start to pull apart the genetic complexity of individual Plasmodium vivax infections and work out whether the parasites came from one or more mosquito bites,” Kwiatkowski said. “It provides a way of addressing fundamental questions about how P vivax is transmitted and how it persists within a community and, in particular, about the biology of relapsing infections.”

Blood smear showing

Plasmodium vivax

Image by Mae Melvin

Genomic research suggests the malaria parasite Plasmodium vivax is evolving rapidly to adapt to conditions in different geographic locations.

Researchers studied more than 200 parasite samples from across the Asia-Pacific region and found that P vivax has evolved differently in different areas.

The team identified substantial differences in the frequency of copy number variations (CNVs) in samples from western Thailand, western Cambodia, and Papua Indonesia.

They believe this is a result of the different antimalarial drugs used in these regions.

The researchers described this work in Nature Genetics.

“For so long, it’s not been possible to study P vivax genomes in detail, on a large-scale, but now we can, and we’re seeing the effect that drug use has on how parasites are evolving,” said study author Dominic Kwiatkowski, of the Wellcome Trust Sanger Institute in the UK.

He and his colleagues studied the genomes of 228 parasite samples, identifying the strains carried by each patient and revealing their infection history. Most samples came from Southeast Asia (Thailand, Cambodia, Vietnam, Laos, Myanmar, and Malaysia) and Oceania (Papua Indonesia and Papua New Guinea), but the team also studied samples from China, India, Sri Lanka, Brazil, and Madagascar.

The researchers performed detailed population genetic analyses using 148 samples from western Thailand, western Cambodia, and Papua Indonesia. This revealed CNVs in 9 regions of the core genome, and the frequency of the 4 most common CNVs varied greatly according to geographical location.

The first common CNV was a 9-kb deletion on chromosome 8 that includes the first 3 exons of a gene encoding a cytoadherence-linked asexual protein. The CNV was present in 73% of Papua Indonesia samples, 6% of western Cambodia samples, and 3% of western Thailand samples.

The second common CNV was a 7-kb duplication on chromosome 6 that encompasses pvdbp, the gene that encodes the Duffy-binding protein, which mediates P vivax’s invasion of erythrocytes. It was present in 5% of Papua Indonesia samples, 35% of western Cambodia samples, and 25% of western Thailand samples.

The third common CNV was a 37-kb duplication on chromosome 10 that includes pvmdr1, which has been associated with resistance to mefloquine and is homologous to the pfmdr1 amplification responsible for mefloquine resistance in P falciparum. This CNV was only present in samples from western Thailand.

The fourth common CNV was a 3-kb duplication on chromosome 14 that includes the gene PVX_101445. It was found only in Papua Indonesia samples.

“Our study shows that the strongest evidence of evolution is in Papua, Indonesia, where resistance of P vivax to chloroquine is now rampant,” said Ric Price, MD, of the University of Oxford in the UK.

“These data provide crucial information from which we can start to identify the mechanisms of drug resistance in P vivax.”

“We can see in the genome that drug resistance is a huge driver for evolution,” added Richard Pearson, PhD, of the Wellcome Trust Sanger Institute.

“Intriguingly, in some places, this process appears to be happening in response to drugs used primarily to treat a different malaria parasite, P falciparum. Although the exact cause isn’t known, this is a worrying sign that drug resistance is becoming deeply entrenched in the parasite population.”

The researchers said there are a few possible reasons why P vivax may be evolving to evade drugs used against P falciparum.

Many people carry mixed infections of both species of parasite, so, in treating one species, the other automatically gets exposed to the drug. Another culprit may be unsupervised drug use—where many people take the most readily available, rather than the most suitable, antimalarial drug.

Another finding from this study was that, when the researchers identified patients who were carrying multiple strains of parasite, the genomic data made it possible to determine how closely the different strains were related to one another.

“This means that we can now start to pull apart the genetic complexity of individual Plasmodium vivax infections and work out whether the parasites came from one or more mosquito bites,” Kwiatkowski said. “It provides a way of addressing fundamental questions about how P vivax is transmitted and how it persists within a community and, in particular, about the biology of relapsing infections.”

Blood smear showing

Plasmodium vivax

Image by Mae Melvin

Genomic research suggests the malaria parasite Plasmodium vivax is evolving rapidly to adapt to conditions in different geographic locations.

Researchers studied more than 200 parasite samples from across the Asia-Pacific region and found that P vivax has evolved differently in different areas.

The team identified substantial differences in the frequency of copy number variations (CNVs) in samples from western Thailand, western Cambodia, and Papua Indonesia.

They believe this is a result of the different antimalarial drugs used in these regions.

The researchers described this work in Nature Genetics.

“For so long, it’s not been possible to study P vivax genomes in detail, on a large-scale, but now we can, and we’re seeing the effect that drug use has on how parasites are evolving,” said study author Dominic Kwiatkowski, of the Wellcome Trust Sanger Institute in the UK.

He and his colleagues studied the genomes of 228 parasite samples, identifying the strains carried by each patient and revealing their infection history. Most samples came from Southeast Asia (Thailand, Cambodia, Vietnam, Laos, Myanmar, and Malaysia) and Oceania (Papua Indonesia and Papua New Guinea), but the team also studied samples from China, India, Sri Lanka, Brazil, and Madagascar.

The researchers performed detailed population genetic analyses using 148 samples from western Thailand, western Cambodia, and Papua Indonesia. This revealed CNVs in 9 regions of the core genome, and the frequency of the 4 most common CNVs varied greatly according to geographical location.

The first common CNV was a 9-kb deletion on chromosome 8 that includes the first 3 exons of a gene encoding a cytoadherence-linked asexual protein. The CNV was present in 73% of Papua Indonesia samples, 6% of western Cambodia samples, and 3% of western Thailand samples.

The second common CNV was a 7-kb duplication on chromosome 6 that encompasses pvdbp, the gene that encodes the Duffy-binding protein, which mediates P vivax’s invasion of erythrocytes. It was present in 5% of Papua Indonesia samples, 35% of western Cambodia samples, and 25% of western Thailand samples.

The third common CNV was a 37-kb duplication on chromosome 10 that includes pvmdr1, which has been associated with resistance to mefloquine and is homologous to the pfmdr1 amplification responsible for mefloquine resistance in P falciparum. This CNV was only present in samples from western Thailand.

The fourth common CNV was a 3-kb duplication on chromosome 14 that includes the gene PVX_101445. It was found only in Papua Indonesia samples.

“Our study shows that the strongest evidence of evolution is in Papua, Indonesia, where resistance of P vivax to chloroquine is now rampant,” said Ric Price, MD, of the University of Oxford in the UK.

“These data provide crucial information from which we can start to identify the mechanisms of drug resistance in P vivax.”

“We can see in the genome that drug resistance is a huge driver for evolution,” added Richard Pearson, PhD, of the Wellcome Trust Sanger Institute.

“Intriguingly, in some places, this process appears to be happening in response to drugs used primarily to treat a different malaria parasite, P falciparum. Although the exact cause isn’t known, this is a worrying sign that drug resistance is becoming deeply entrenched in the parasite population.”

The researchers said there are a few possible reasons why P vivax may be evolving to evade drugs used against P falciparum.

Many people carry mixed infections of both species of parasite, so, in treating one species, the other automatically gets exposed to the drug. Another culprit may be unsupervised drug use—where many people take the most readily available, rather than the most suitable, antimalarial drug.

Another finding from this study was that, when the researchers identified patients who were carrying multiple strains of parasite, the genomic data made it possible to determine how closely the different strains were related to one another.

“This means that we can now start to pull apart the genetic complexity of individual Plasmodium vivax infections and work out whether the parasites came from one or more mosquito bites,” Kwiatkowski said. “It provides a way of addressing fundamental questions about how P vivax is transmitted and how it persists within a community and, in particular, about the biology of relapsing infections.”

Vials of drug

Photo by Bill Branson

Several case reports have suggested that cancer patients taking the immunotherapy drugs nivolumab and ipilimumab may have a higher-than-normal risk of developing rheumatic diseases.

Between 2012 and 2016, 13 patients at the Johns Hopkins Kimmel Cancer Center who were taking one or both drugs developed inflammatory arthritis or sicca syndrome, a set of autoimmune conditions causing dry eyes and mouth.

The cases were described in Annals of Rheumatic Diseases.

Nivolumab and ipilimumab are both designed to turn off the molecular “checkpoints” some cancers—including lymphoma—use to evade the immune system. When the drugs work, they allow the immune system to detect and attack tumor cells. However, they also turn up the activity of the immune system as a whole and can therefore trigger immune-related side effects.

Clinical trials of ipilimumab and nivolumab have indicated that the drugs confer an increased risk of inflammatory bowel diseases, lung inflammation, autoimmune thyroid disease, and pituitary gland inflammation.

However, those trials were designed primarily to determine efficacy against cancer and not to fully examine all features of rheumatologic side effects, said Laura C. Cappelli, MD, of the Johns Hopkins University School of Medicine in Baltimore, Maryland.

With this in mind, she and her colleagues decided to take a closer look at 13 adults (older than 18) who were treated at the Johns Hopkins Kimmel Cancer Center and reported rheumatologic symptoms after their treatment with nivolumab and/or ipilimumab.

Eight patients were taking both ipilimumab and nivolumab, and 5 were taking 1 of the 2 drugs. They were receiving the drugs to treat melanoma (n=6), non-small-cell lung cancer (n=5), small-cell lung cancer (n=1), and renal cell carcinoma (n=1).

Nine of the patients developed inflammatory arthritis—4 with synovitis confirmed via imaging and 4 with inflammatory synovial fluid—and the remaining 4 patients were diagnosed with sicca syndrome. Other immune-related adverse events included pneumonitis, colitis, interstitial nephritis, and thyroiditis.

The researchers said this is the largest published case series showing a link between checkpoint inhibitors and rheumatic diseases.

The patients described in this case report make up about 1.3% of all patients treated with the drugs—singly or in combination—at The Johns Hopkins Hospital from 2012 to 2016. However, the researchers believe that rate is likely an underestimation of how common rheumatic diseases are in patients taking immune checkpoint inhibitors.

“We keep having referrals coming in from our oncologists as more patients are treated with these drugs,” said Clifton Bingham, MD, of the Johns Hopkins University School of Medicine.

“In particular, as more patients are treated with combinations of multiple immunotherapies, we expect the rate to go up.”

Dr Cappelli said she wants the case report to raise awareness among patients and clinicians that rheumatologic side effects may occur with checkpoint inhibitors.

“It is important when weighing the risk-benefit ratio of prescribing these drugs,” she said. “And it’s important for people to be on the lookout for symptoms so they can see a rheumatologist early in an effort to prevent or limit joint damage.”

Drs Cappelli and Bingham and their colleagues are planning further collaboration with Johns Hopkins oncologists to better track the incidence of rheumatic disease in patients taking immunotherapy drugs and determine whether any particular characteristics put cancer patients at higher risk of such complications.

Vials of drug

Photo by Bill Branson

Several case reports have suggested that cancer patients taking the immunotherapy drugs nivolumab and ipilimumab may have a higher-than-normal risk of developing rheumatic diseases.

Between 2012 and 2016, 13 patients at the Johns Hopkins Kimmel Cancer Center who were taking one or both drugs developed inflammatory arthritis or sicca syndrome, a set of autoimmune conditions causing dry eyes and mouth.

The cases were described in Annals of Rheumatic Diseases.

Nivolumab and ipilimumab are both designed to turn off the molecular “checkpoints” some cancers—including lymphoma—use to evade the immune system. When the drugs work, they allow the immune system to detect and attack tumor cells. However, they also turn up the activity of the immune system as a whole and can therefore trigger immune-related side effects.

Clinical trials of ipilimumab and nivolumab have indicated that the drugs confer an increased risk of inflammatory bowel diseases, lung inflammation, autoimmune thyroid disease, and pituitary gland inflammation.

However, those trials were designed primarily to determine efficacy against cancer and not to fully examine all features of rheumatologic side effects, said Laura C. Cappelli, MD, of the Johns Hopkins University School of Medicine in Baltimore, Maryland.

With this in mind, she and her colleagues decided to take a closer look at 13 adults (older than 18) who were treated at the Johns Hopkins Kimmel Cancer Center and reported rheumatologic symptoms after their treatment with nivolumab and/or ipilimumab.

Eight patients were taking both ipilimumab and nivolumab, and 5 were taking 1 of the 2 drugs. They were receiving the drugs to treat melanoma (n=6), non-small-cell lung cancer (n=5), small-cell lung cancer (n=1), and renal cell carcinoma (n=1).

Nine of the patients developed inflammatory arthritis—4 with synovitis confirmed via imaging and 4 with inflammatory synovial fluid—and the remaining 4 patients were diagnosed with sicca syndrome. Other immune-related adverse events included pneumonitis, colitis, interstitial nephritis, and thyroiditis.

The researchers said this is the largest published case series showing a link between checkpoint inhibitors and rheumatic diseases.

The patients described in this case report make up about 1.3% of all patients treated with the drugs—singly or in combination—at The Johns Hopkins Hospital from 2012 to 2016. However, the researchers believe that rate is likely an underestimation of how common rheumatic diseases are in patients taking immune checkpoint inhibitors.

“We keep having referrals coming in from our oncologists as more patients are treated with these drugs,” said Clifton Bingham, MD, of the Johns Hopkins University School of Medicine.

“In particular, as more patients are treated with combinations of multiple immunotherapies, we expect the rate to go up.”

Dr Cappelli said she wants the case report to raise awareness among patients and clinicians that rheumatologic side effects may occur with checkpoint inhibitors.

“It is important when weighing the risk-benefit ratio of prescribing these drugs,” she said. “And it’s important for people to be on the lookout for symptoms so they can see a rheumatologist early in an effort to prevent or limit joint damage.”

Drs Cappelli and Bingham and their colleagues are planning further collaboration with Johns Hopkins oncologists to better track the incidence of rheumatic disease in patients taking immunotherapy drugs and determine whether any particular characteristics put cancer patients at higher risk of such complications.

Vials of drug

Photo by Bill Branson

Several case reports have suggested that cancer patients taking the immunotherapy drugs nivolumab and ipilimumab may have a higher-than-normal risk of developing rheumatic diseases.

Between 2012 and 2016, 13 patients at the Johns Hopkins Kimmel Cancer Center who were taking one or both drugs developed inflammatory arthritis or sicca syndrome, a set of autoimmune conditions causing dry eyes and mouth.

The cases were described in Annals of Rheumatic Diseases.

Nivolumab and ipilimumab are both designed to turn off the molecular “checkpoints” some cancers—including lymphoma—use to evade the immune system. When the drugs work, they allow the immune system to detect and attack tumor cells. However, they also turn up the activity of the immune system as a whole and can therefore trigger immune-related side effects.

Clinical trials of ipilimumab and nivolumab have indicated that the drugs confer an increased risk of inflammatory bowel diseases, lung inflammation, autoimmune thyroid disease, and pituitary gland inflammation.

However, those trials were designed primarily to determine efficacy against cancer and not to fully examine all features of rheumatologic side effects, said Laura C. Cappelli, MD, of the Johns Hopkins University School of Medicine in Baltimore, Maryland.

With this in mind, she and her colleagues decided to take a closer look at 13 adults (older than 18) who were treated at the Johns Hopkins Kimmel Cancer Center and reported rheumatologic symptoms after their treatment with nivolumab and/or ipilimumab.

Eight patients were taking both ipilimumab and nivolumab, and 5 were taking 1 of the 2 drugs. They were receiving the drugs to treat melanoma (n=6), non-small-cell lung cancer (n=5), small-cell lung cancer (n=1), and renal cell carcinoma (n=1).

Nine of the patients developed inflammatory arthritis—4 with synovitis confirmed via imaging and 4 with inflammatory synovial fluid—and the remaining 4 patients were diagnosed with sicca syndrome. Other immune-related adverse events included pneumonitis, colitis, interstitial nephritis, and thyroiditis.

The researchers said this is the largest published case series showing a link between checkpoint inhibitors and rheumatic diseases.

The patients described in this case report make up about 1.3% of all patients treated with the drugs—singly or in combination—at The Johns Hopkins Hospital from 2012 to 2016. However, the researchers believe that rate is likely an underestimation of how common rheumatic diseases are in patients taking immune checkpoint inhibitors.

“We keep having referrals coming in from our oncologists as more patients are treated with these drugs,” said Clifton Bingham, MD, of the Johns Hopkins University School of Medicine.

“In particular, as more patients are treated with combinations of multiple immunotherapies, we expect the rate to go up.”

Dr Cappelli said she wants the case report to raise awareness among patients and clinicians that rheumatologic side effects may occur with checkpoint inhibitors.

“It is important when weighing the risk-benefit ratio of prescribing these drugs,” she said. “And it’s important for people to be on the lookout for symptoms so they can see a rheumatologist early in an effort to prevent or limit joint damage.”

Drs Cappelli and Bingham and their colleagues are planning further collaboration with Johns Hopkins oncologists to better track the incidence of rheumatic disease in patients taking immunotherapy drugs and determine whether any particular characteristics put cancer patients at higher risk of such complications.

Premenopausal risk-reducing salpingo-oophorectomy becomes cost-effective in women who have a 4% or greater lifetime risk of ovarian cancer, according to a modeling study published online in the Journal of Medical Genetics.

The procedure, which is usually undertaken in women aged over 35 years who have completed their families, is available in the United Kingdom to women with a greater than 10% lifetime risk of ovarian cancer. However, the researchers, led by Dr. Ranjit Manchanda of Barts Cancer Institute at Queen Mary University of London, suggested that this threshold has not been tested for cost-effectiveness.

The decision analysis model evaluated lifetime costs as well as the effects of risk-reducing salpingo-oophorectomy in 40-year-old premenopausal women by comparing it with no procedure in women whose lifetime ovarian cancer risk ranged from 2%-10%. The final outcomes were development of breast cancer, ovarian cancer, and excess deaths from coronary heart disease, while cost-effectiveness was judged against the National Institute for Health and Care Excellence threshold of £20,000-£30,000 per quality-adjusted life-years (QALY).

Researchers found that premenopausal risk-reducing salpingo-oophorectomy was cost-effective in women with a 4% or greater lifetime risk of ovarian cancer, largely because of the reduction in their risk of breast cancer. At this level of risk, surgery gained 42.7 days of life-expectancy, with an incremental cost-effectiveness ratio of £19,536($26,186)/QALY.

Premenopausal risk-reducing salpingo-oophorectomy was not cost-effective at the baseline risk rate of 2%, with an incremental cost-effectiveness ratio of £46,480($62,267)/QALY and 19.9 days gain in life expectancy (J Med Genetics 2016 June 27. doi: 10.1136/jmedgenet-2016-103800).

The cost-effectiveness was predicated on the assumption of at least an 80% compliance rate with hormone therapy (HT) in women who underwent the procedure; without HT, the cost-effectiveness threshold increased to a lifetime risk of over 8.2%.

“Our results are of major significance for clinical practice and risk management in view of declining genetic testing costs and the improvements in estimating an individual’s OC risk,” the authors wrote.

“With routine clinical testing for certain moderate penetrance genes around the corner and lack of an effective OC screening programme, these findings are timely as it provides evidence supporting a surgical prevention strategy for ‘lower-risk’ (lifetime risk less than 10%) individuals,” noted Dr. Manchanda and colleagues.

They stressed that symptom levels after salpingo-oophorectomy, particularly for sexual function, were still higher even in women taking HT compared to those who hadn’t undergone salpingo-oophorectomy.

“This limitation needs to be discussed as part of informed consent for the surgical procedure and incorporated into [the risk-reducing salpingo-oophorectomy] decision-making process,” they wrote.

One author declared a financial interest in Abcodia, which has an interest in ovarian cancer screening and biomarkers for screening and risk prediction. No other conflicts of interest were declared.

Premenopausal risk-reducing salpingo-oophorectomy becomes cost-effective in women who have a 4% or greater lifetime risk of ovarian cancer, according to a modeling study published online in the Journal of Medical Genetics.

The procedure, which is usually undertaken in women aged over 35 years who have completed their families, is available in the United Kingdom to women with a greater than 10% lifetime risk of ovarian cancer. However, the researchers, led by Dr. Ranjit Manchanda of Barts Cancer Institute at Queen Mary University of London, suggested that this threshold has not been tested for cost-effectiveness.

The decision analysis model evaluated lifetime costs as well as the effects of risk-reducing salpingo-oophorectomy in 40-year-old premenopausal women by comparing it with no procedure in women whose lifetime ovarian cancer risk ranged from 2%-10%. The final outcomes were development of breast cancer, ovarian cancer, and excess deaths from coronary heart disease, while cost-effectiveness was judged against the National Institute for Health and Care Excellence threshold of £20,000-£30,000 per quality-adjusted life-years (QALY).

Researchers found that premenopausal risk-reducing salpingo-oophorectomy was cost-effective in women with a 4% or greater lifetime risk of ovarian cancer, largely because of the reduction in their risk of breast cancer. At this level of risk, surgery gained 42.7 days of life-expectancy, with an incremental cost-effectiveness ratio of £19,536($26,186)/QALY.

Premenopausal risk-reducing salpingo-oophorectomy was not cost-effective at the baseline risk rate of 2%, with an incremental cost-effectiveness ratio of £46,480($62,267)/QALY and 19.9 days gain in life expectancy (J Med Genetics 2016 June 27. doi: 10.1136/jmedgenet-2016-103800).

The cost-effectiveness was predicated on the assumption of at least an 80% compliance rate with hormone therapy (HT) in women who underwent the procedure; without HT, the cost-effectiveness threshold increased to a lifetime risk of over 8.2%.

“Our results are of major significance for clinical practice and risk management in view of declining genetic testing costs and the improvements in estimating an individual’s OC risk,” the authors wrote.

“With routine clinical testing for certain moderate penetrance genes around the corner and lack of an effective OC screening programme, these findings are timely as it provides evidence supporting a surgical prevention strategy for ‘lower-risk’ (lifetime risk less than 10%) individuals,” noted Dr. Manchanda and colleagues.

They stressed that symptom levels after salpingo-oophorectomy, particularly for sexual function, were still higher even in women taking HT compared to those who hadn’t undergone salpingo-oophorectomy.

“This limitation needs to be discussed as part of informed consent for the surgical procedure and incorporated into [the risk-reducing salpingo-oophorectomy] decision-making process,” they wrote.

One author declared a financial interest in Abcodia, which has an interest in ovarian cancer screening and biomarkers for screening and risk prediction. No other conflicts of interest were declared.

Premenopausal risk-reducing salpingo-oophorectomy becomes cost-effective in women who have a 4% or greater lifetime risk of ovarian cancer, according to a modeling study published online in the Journal of Medical Genetics.

The procedure, which is usually undertaken in women aged over 35 years who have completed their families, is available in the United Kingdom to women with a greater than 10% lifetime risk of ovarian cancer. However, the researchers, led by Dr. Ranjit Manchanda of Barts Cancer Institute at Queen Mary University of London, suggested that this threshold has not been tested for cost-effectiveness.

The decision analysis model evaluated lifetime costs as well as the effects of risk-reducing salpingo-oophorectomy in 40-year-old premenopausal women by comparing it with no procedure in women whose lifetime ovarian cancer risk ranged from 2%-10%. The final outcomes were development of breast cancer, ovarian cancer, and excess deaths from coronary heart disease, while cost-effectiveness was judged against the National Institute for Health and Care Excellence threshold of £20,000-£30,000 per quality-adjusted life-years (QALY).

Researchers found that premenopausal risk-reducing salpingo-oophorectomy was cost-effective in women with a 4% or greater lifetime risk of ovarian cancer, largely because of the reduction in their risk of breast cancer. At this level of risk, surgery gained 42.7 days of life-expectancy, with an incremental cost-effectiveness ratio of £19,536($26,186)/QALY.

Premenopausal risk-reducing salpingo-oophorectomy was not cost-effective at the baseline risk rate of 2%, with an incremental cost-effectiveness ratio of £46,480($62,267)/QALY and 19.9 days gain in life expectancy (J Med Genetics 2016 June 27. doi: 10.1136/jmedgenet-2016-103800).

The cost-effectiveness was predicated on the assumption of at least an 80% compliance rate with hormone therapy (HT) in women who underwent the procedure; without HT, the cost-effectiveness threshold increased to a lifetime risk of over 8.2%.

“Our results are of major significance for clinical practice and risk management in view of declining genetic testing costs and the improvements in estimating an individual’s OC risk,” the authors wrote.

“With routine clinical testing for certain moderate penetrance genes around the corner and lack of an effective OC screening programme, these findings are timely as it provides evidence supporting a surgical prevention strategy for ‘lower-risk’ (lifetime risk less than 10%) individuals,” noted Dr. Manchanda and colleagues.

They stressed that symptom levels after salpingo-oophorectomy, particularly for sexual function, were still higher even in women taking HT compared to those who hadn’t undergone salpingo-oophorectomy.

“This limitation needs to be discussed as part of informed consent for the surgical procedure and incorporated into [the risk-reducing salpingo-oophorectomy] decision-making process,” they wrote.

One author declared a financial interest in Abcodia, which has an interest in ovarian cancer screening and biomarkers for screening and risk prediction. No other conflicts of interest were declared.