Article

Difficulty achieving regular restorative sleep is a common symptom of many psychiatric illnesses and can pose a pharmaceutical challenge, particularly for patients who have contra­indications to benzodiazepines or sedative-hypnotics. Melatonin is commonly used to treat insomnia and circadian rhythm disorders in hospitalized patients because it is largely considered safe, nonhabit forming, unlikely to interact with other medications, and possibly protective against delirium.¹ We support its short-term use in patients with sleep disruption, even if they do not meet the diagnostic criteria for insomnia or a circadian rhythm sleep-wake disorder. However, this use should be guided by consideration of the known physiological actions of melatonin, and not by an assumption that it acts as a simple sedative-hypnotic.

How melatonin works

Melatonin is an endogenous neurohormone involved in circadian rhythm regulation (sleep/wake regulation), a fundamental process in the functioning of the CNS and in the development of psychiatric disorders.² Melatonin is commonly described as a sleep-promoting neurotransmitter, but it is more accurately described as a “darkness hormone.”³ With an onset at dusk and offset at sunrise, melatonin is the signal for biological night, not the signal for sleep. Melanopsin-containing retina neurons sensitive to blue light sense the diminishing light of the evening and communicate this cue to the brain’s master clock in the suprachiasmatic nucleus (SCN) of the hypothalamus (via the retinohypothalamic pathway). The SCN then releases its inhibition on the pineal gland, allowing it to release melatonin into the bloodstream and CSF. The timing of this release is known as the dim-light melatonin onset (DLMO).

Selecting the optimal timing and dose

Studies in laboratory and home settings have consistently shown that the DLMO precedes the onset of sleep by approximately 2 to 4 hours.⁴ Thus, we recommend scheduling melatonin administration for 2 to 4 hours before the intended bedtime.

Lower doses better replicate physiological levels of melatonin. A lower dose is also less likely to lead to a compromise of the entrainment process and the induction of a delayed sleep phase due to the lingering presence of melatonin, or the phase-delaying effects of a strong melatonin signal much later than the ideal DLMO. Giving higher doses at bedtime will induce sleep but may cause a circadian phase delay, effectively “jet lagging” the patient. We recommend prescribing low-dose melatonin (LDM; 0.5 to 1 mg) 2 to 4 hours before the intended bedtime rather than higher doses (≥5 mg) given at bedtime as is common practice and recommended by many melatonin manufacturers. LDM better simulates the natural release and function of melatonin and avoids potential adverse circadian phase delays. The successful use of melatonin in hospitalized patients suggests there is a unique opportunity to use this safe and effective medication with a relatively well-understood mechanism of action for nonhospitalized patients who are having difficulty sleeping. Considering the known physiological actions of melatonin can help guide the optimal timing and dosage of melatonin for this purpose.

Difficulty achieving regular restorative sleep is a common symptom of many psychiatric illnesses and can pose a pharmaceutical challenge, particularly for patients who have contra­indications to benzodiazepines or sedative-hypnotics. Melatonin is commonly used to treat insomnia and circadian rhythm disorders in hospitalized patients because it is largely considered safe, nonhabit forming, unlikely to interact with other medications, and possibly protective against delirium.¹ We support its short-term use in patients with sleep disruption, even if they do not meet the diagnostic criteria for insomnia or a circadian rhythm sleep-wake disorder. However, this use should be guided by consideration of the known physiological actions of melatonin, and not by an assumption that it acts as a simple sedative-hypnotic.

How melatonin works

Melatonin is an endogenous neurohormone involved in circadian rhythm regulation (sleep/wake regulation), a fundamental process in the functioning of the CNS and in the development of psychiatric disorders.² Melatonin is commonly described as a sleep-promoting neurotransmitter, but it is more accurately described as a “darkness hormone.”³ With an onset at dusk and offset at sunrise, melatonin is the signal for biological night, not the signal for sleep. Melanopsin-containing retina neurons sensitive to blue light sense the diminishing light of the evening and communicate this cue to the brain’s master clock in the suprachiasmatic nucleus (SCN) of the hypothalamus (via the retinohypothalamic pathway). The SCN then releases its inhibition on the pineal gland, allowing it to release melatonin into the bloodstream and CSF. The timing of this release is known as the dim-light melatonin onset (DLMO).

Selecting the optimal timing and dose

Studies in laboratory and home settings have consistently shown that the DLMO precedes the onset of sleep by approximately 2 to 4 hours.⁴ Thus, we recommend scheduling melatonin administration for 2 to 4 hours before the intended bedtime.

Lower doses better replicate physiological levels of melatonin. A lower dose is also less likely to lead to a compromise of the entrainment process and the induction of a delayed sleep phase due to the lingering presence of melatonin, or the phase-delaying effects of a strong melatonin signal much later than the ideal DLMO. Giving higher doses at bedtime will induce sleep but may cause a circadian phase delay, effectively “jet lagging” the patient. We recommend prescribing low-dose melatonin (LDM; 0.5 to 1 mg) 2 to 4 hours before the intended bedtime rather than higher doses (≥5 mg) given at bedtime as is common practice and recommended by many melatonin manufacturers. LDM better simulates the natural release and function of melatonin and avoids potential adverse circadian phase delays. The successful use of melatonin in hospitalized patients suggests there is a unique opportunity to use this safe and effective medication with a relatively well-understood mechanism of action for nonhospitalized patients who are having difficulty sleeping. Considering the known physiological actions of melatonin can help guide the optimal timing and dosage of melatonin for this purpose.

Difficulty achieving regular restorative sleep is a common symptom of many psychiatric illnesses and can pose a pharmaceutical challenge, particularly for patients who have contra­indications to benzodiazepines or sedative-hypnotics. Melatonin is commonly used to treat insomnia and circadian rhythm disorders in hospitalized patients because it is largely considered safe, nonhabit forming, unlikely to interact with other medications, and possibly protective against delirium.¹ We support its short-term use in patients with sleep disruption, even if they do not meet the diagnostic criteria for insomnia or a circadian rhythm sleep-wake disorder. However, this use should be guided by consideration of the known physiological actions of melatonin, and not by an assumption that it acts as a simple sedative-hypnotic.

How melatonin works

Melatonin is an endogenous neurohormone involved in circadian rhythm regulation (sleep/wake regulation), a fundamental process in the functioning of the CNS and in the development of psychiatric disorders.² Melatonin is commonly described as a sleep-promoting neurotransmitter, but it is more accurately described as a “darkness hormone.”³ With an onset at dusk and offset at sunrise, melatonin is the signal for biological night, not the signal for sleep. Melanopsin-containing retina neurons sensitive to blue light sense the diminishing light of the evening and communicate this cue to the brain’s master clock in the suprachiasmatic nucleus (SCN) of the hypothalamus (via the retinohypothalamic pathway). The SCN then releases its inhibition on the pineal gland, allowing it to release melatonin into the bloodstream and CSF. The timing of this release is known as the dim-light melatonin onset (DLMO).

Selecting the optimal timing and dose

Studies in laboratory and home settings have consistently shown that the DLMO precedes the onset of sleep by approximately 2 to 4 hours.⁴ Thus, we recommend scheduling melatonin administration for 2 to 4 hours before the intended bedtime.

Lower doses better replicate physiological levels of melatonin. A lower dose is also less likely to lead to a compromise of the entrainment process and the induction of a delayed sleep phase due to the lingering presence of melatonin, or the phase-delaying effects of a strong melatonin signal much later than the ideal DLMO. Giving higher doses at bedtime will induce sleep but may cause a circadian phase delay, effectively “jet lagging” the patient. We recommend prescribing low-dose melatonin (LDM; 0.5 to 1 mg) 2 to 4 hours before the intended bedtime rather than higher doses (≥5 mg) given at bedtime as is common practice and recommended by many melatonin manufacturers. LDM better simulates the natural release and function of melatonin and avoids potential adverse circadian phase delays. The successful use of melatonin in hospitalized patients suggests there is a unique opportunity to use this safe and effective medication with a relatively well-understood mechanism of action for nonhospitalized patients who are having difficulty sleeping. Considering the known physiological actions of melatonin can help guide the optimal timing and dosage of melatonin for this purpose.

Editor’s note: Readers’ Forum is a department for correspondence from readers that is not in response to articles published in Current Psychiatry. All submissions to Readers’ Forum undergo peer review and are subject to editing for length and style. For more information, contact let[email protected].

Mr. F, age 42, says he has always been a very anxious person and has chronically found his worrying to negatively affect his life. He says that over the last month his anxiety has been “off the charts” and he is worrying “24/7” due to taking on new responsibilities at his job and his son being diagnosed with lupus. He says his constant worrying is significantly impairing his ability to focus at his job, and he is considering taking a mental health leave from work. His wife reports that she is extremely frustrated because Mr. F has been isolating himself from family and friends; he admits this is true and attributes it to being preoccupied by his worries.

Mr. F endorses chronic insomnia, muscle tension, and irritability associated with anxiety; these have all substantially worsened over the last month. He admits that recently he has occasionally thought it would be easier if he weren’t alive. Mr. F denies having problems with his energy or motivation levels and insists that he generally feels very anxious, but not depressed. He says he drinks 1 alcoholic drink per week and denies any other substance use. Mr. F is overweight and has slightly elevated cholesterol but denies any other health conditions. He takes melatonin to help him sleep but does not take any prescribed medications.

Although this vignette provides limited details, on the surface it appears that Mr. F is experiencing an exacerbation of chronic generalized anxiety disorder (GAD). However, in this article, I propose establishing a new diagnosis: “acute anxiety disorder,” which would encapsulate severe exacerbations of a pre-existing anxiety disorder. Among the patients I have encountered for whom this diagnosis would fit, most have pre-existing GAD or panic disorder.

A look at the differential diagnosis

It is important to determine whether Mr. F is using any substances or has a medical condition that could be contributing to his anxiety. Other psychiatric diagnoses that could be considered include:

Adjustment disorder. This diagnosis would make sense if Mr. F didn’t have an apparent chronic history of symptoms that meet criteria for GAD.

Major depressive disorder with anxious distress. Many patients experiencing a major depressive episode meet the criteria for the specifier “with anxious distress,” even those who do not have a comorbid anxiety disorder.¹ However, it is not evident from this vignette that Mr. F is experiencing a major depressive episode.

Continue to: Panic disorder and GAD...

Panic disorder and GAD. It is possible for a patient with GAD to develop panic disorder, which, at times, occurs after experiencing significant life stressors. Panic disorder requires the presence of recurrent panic attacks. Mr. F describes experiencing chronic, intense symptoms of anxiety rather than the discreet episodes of acute symptoms that characterize panic attacks.

Acute stress disorder. This diagnosis involves psychological symptoms that occur in response to exposure to actual or threatened death, serious injury, or sexual violation. Mr. F was not exposed to any of these stressors.

Why this new diagnosis would be helpful

A new diagnosis, acute anxiety disorder, would indicate that a patient is currently experiencing an acute exacerbation of a chronic anxiety disorder that is leading to a significant decrease in their baseline functioning. My proposed criteria for acute anxiety disorder appear in the Table. Here are some reasons this diagnosis would be helpful:

Signifier of severity. Anxiety disorders such as GAD are generally not considered severe conditions and not considered to fall under the rubric of SPMI (severe and persistent mental illness).² Posttraumatic stress disorder is the anxiety disorder–like condition most often found in the SPMI category. A diagnosis of acute anxiety disorder would indicate a patient is experiencing an episode of anxiety that is distinct from their chronic anxiety condition due to its severe impact on functional capabilities. Acute anxiety disorder would certainly not qualify as a “SPMI diagnosis” that would facilitate someone being considered eligible for supplemental security income, but it might be a legitimate justification for someone to receive short-term disability.

Treatment approach. The pharmacologic treatment of anxiety disorders usually involves a selective serotonin reuptake inhibitor (SSRI) or serotonin-norepinephrine reuptake inhibitor (SNRI). However, these medications can sometimes briefly increase anxiety when they are started. Individuals with acute anxiety are the most vulnerable to the possibility of experiencing increased anxiety when starting an SSRI or SNRI and may benefit from a slower titration of these medications. In light of this and the length of time required for SSRIs or SNRIs to exert a positive effect (typically a few weeks), patients with acute anxiety are best served by treatment with a medication with an immediate onset of action, such as a benzodiazepine or a sleep medication (eg, zolpidem). Benzodiazepines and hypnotics such as zolpidem are best prescribed for as-needed use because they carry a risk of dependence. One might consider prescribing mirtazapine or pregabalin (both of which are used off-label to treat anxiety) because these medications also have a relatively rapid onset of action and can treat both anxiety and insomnia (particularly mirtazapine).

Research considerations. It would be helpful to study which treatments are most effective for the subset of patients who experience acute anxiety disorder as I define it. Perhaps psychotherapy treatment protocols could be adapted or created. Treatment with esketamine or IV ketamine might be further studied as a treatment for acute anxiety because some evidence suggests ketamine is efficacious for this indication.³

Editor’s note: Readers’ Forum is a department for correspondence from readers that is not in response to articles published in Current Psychiatry. All submissions to Readers’ Forum undergo peer review and are subject to editing for length and style. For more information, contact let[email protected].

Mr. F, age 42, says he has always been a very anxious person and has chronically found his worrying to negatively affect his life. He says that over the last month his anxiety has been “off the charts” and he is worrying “24/7” due to taking on new responsibilities at his job and his son being diagnosed with lupus. He says his constant worrying is significantly impairing his ability to focus at his job, and he is considering taking a mental health leave from work. His wife reports that she is extremely frustrated because Mr. F has been isolating himself from family and friends; he admits this is true and attributes it to being preoccupied by his worries.

Mr. F endorses chronic insomnia, muscle tension, and irritability associated with anxiety; these have all substantially worsened over the last month. He admits that recently he has occasionally thought it would be easier if he weren’t alive. Mr. F denies having problems with his energy or motivation levels and insists that he generally feels very anxious, but not depressed. He says he drinks 1 alcoholic drink per week and denies any other substance use. Mr. F is overweight and has slightly elevated cholesterol but denies any other health conditions. He takes melatonin to help him sleep but does not take any prescribed medications.

Although this vignette provides limited details, on the surface it appears that Mr. F is experiencing an exacerbation of chronic generalized anxiety disorder (GAD). However, in this article, I propose establishing a new diagnosis: “acute anxiety disorder,” which would encapsulate severe exacerbations of a pre-existing anxiety disorder. Among the patients I have encountered for whom this diagnosis would fit, most have pre-existing GAD or panic disorder.

A look at the differential diagnosis

It is important to determine whether Mr. F is using any substances or has a medical condition that could be contributing to his anxiety. Other psychiatric diagnoses that could be considered include:

Adjustment disorder. This diagnosis would make sense if Mr. F didn’t have an apparent chronic history of symptoms that meet criteria for GAD.

Major depressive disorder with anxious distress. Many patients experiencing a major depressive episode meet the criteria for the specifier “with anxious distress,” even those who do not have a comorbid anxiety disorder.¹ However, it is not evident from this vignette that Mr. F is experiencing a major depressive episode.

Continue to: Panic disorder and GAD...

Panic disorder and GAD. It is possible for a patient with GAD to develop panic disorder, which, at times, occurs after experiencing significant life stressors. Panic disorder requires the presence of recurrent panic attacks. Mr. F describes experiencing chronic, intense symptoms of anxiety rather than the discreet episodes of acute symptoms that characterize panic attacks.

Acute stress disorder. This diagnosis involves psychological symptoms that occur in response to exposure to actual or threatened death, serious injury, or sexual violation. Mr. F was not exposed to any of these stressors.

Why this new diagnosis would be helpful

A new diagnosis, acute anxiety disorder, would indicate that a patient is currently experiencing an acute exacerbation of a chronic anxiety disorder that is leading to a significant decrease in their baseline functioning. My proposed criteria for acute anxiety disorder appear in the Table. Here are some reasons this diagnosis would be helpful:

Signifier of severity. Anxiety disorders such as GAD are generally not considered severe conditions and not considered to fall under the rubric of SPMI (severe and persistent mental illness).² Posttraumatic stress disorder is the anxiety disorder–like condition most often found in the SPMI category. A diagnosis of acute anxiety disorder would indicate a patient is experiencing an episode of anxiety that is distinct from their chronic anxiety condition due to its severe impact on functional capabilities. Acute anxiety disorder would certainly not qualify as a “SPMI diagnosis” that would facilitate someone being considered eligible for supplemental security income, but it might be a legitimate justification for someone to receive short-term disability.

Treatment approach. The pharmacologic treatment of anxiety disorders usually involves a selective serotonin reuptake inhibitor (SSRI) or serotonin-norepinephrine reuptake inhibitor (SNRI). However, these medications can sometimes briefly increase anxiety when they are started. Individuals with acute anxiety are the most vulnerable to the possibility of experiencing increased anxiety when starting an SSRI or SNRI and may benefit from a slower titration of these medications. In light of this and the length of time required for SSRIs or SNRIs to exert a positive effect (typically a few weeks), patients with acute anxiety are best served by treatment with a medication with an immediate onset of action, such as a benzodiazepine or a sleep medication (eg, zolpidem). Benzodiazepines and hypnotics such as zolpidem are best prescribed for as-needed use because they carry a risk of dependence. One might consider prescribing mirtazapine or pregabalin (both of which are used off-label to treat anxiety) because these medications also have a relatively rapid onset of action and can treat both anxiety and insomnia (particularly mirtazapine).

Research considerations. It would be helpful to study which treatments are most effective for the subset of patients who experience acute anxiety disorder as I define it. Perhaps psychotherapy treatment protocols could be adapted or created. Treatment with esketamine or IV ketamine might be further studied as a treatment for acute anxiety because some evidence suggests ketamine is efficacious for this indication.³

Editor’s note: Readers’ Forum is a department for correspondence from readers that is not in response to articles published in Current Psychiatry. All submissions to Readers’ Forum undergo peer review and are subject to editing for length and style. For more information, contact let[email protected].

Mr. F, age 42, says he has always been a very anxious person and has chronically found his worrying to negatively affect his life. He says that over the last month his anxiety has been “off the charts” and he is worrying “24/7” due to taking on new responsibilities at his job and his son being diagnosed with lupus. He says his constant worrying is significantly impairing his ability to focus at his job, and he is considering taking a mental health leave from work. His wife reports that she is extremely frustrated because Mr. F has been isolating himself from family and friends; he admits this is true and attributes it to being preoccupied by his worries.

Mr. F endorses chronic insomnia, muscle tension, and irritability associated with anxiety; these have all substantially worsened over the last month. He admits that recently he has occasionally thought it would be easier if he weren’t alive. Mr. F denies having problems with his energy or motivation levels and insists that he generally feels very anxious, but not depressed. He says he drinks 1 alcoholic drink per week and denies any other substance use. Mr. F is overweight and has slightly elevated cholesterol but denies any other health conditions. He takes melatonin to help him sleep but does not take any prescribed medications.

Although this vignette provides limited details, on the surface it appears that Mr. F is experiencing an exacerbation of chronic generalized anxiety disorder (GAD). However, in this article, I propose establishing a new diagnosis: “acute anxiety disorder,” which would encapsulate severe exacerbations of a pre-existing anxiety disorder. Among the patients I have encountered for whom this diagnosis would fit, most have pre-existing GAD or panic disorder.

A look at the differential diagnosis

It is important to determine whether Mr. F is using any substances or has a medical condition that could be contributing to his anxiety. Other psychiatric diagnoses that could be considered include:

Adjustment disorder. This diagnosis would make sense if Mr. F didn’t have an apparent chronic history of symptoms that meet criteria for GAD.

Major depressive disorder with anxious distress. Many patients experiencing a major depressive episode meet the criteria for the specifier “with anxious distress,” even those who do not have a comorbid anxiety disorder.¹ However, it is not evident from this vignette that Mr. F is experiencing a major depressive episode.

Continue to: Panic disorder and GAD...

Panic disorder and GAD. It is possible for a patient with GAD to develop panic disorder, which, at times, occurs after experiencing significant life stressors. Panic disorder requires the presence of recurrent panic attacks. Mr. F describes experiencing chronic, intense symptoms of anxiety rather than the discreet episodes of acute symptoms that characterize panic attacks.

Acute stress disorder. This diagnosis involves psychological symptoms that occur in response to exposure to actual or threatened death, serious injury, or sexual violation. Mr. F was not exposed to any of these stressors.

Why this new diagnosis would be helpful

A new diagnosis, acute anxiety disorder, would indicate that a patient is currently experiencing an acute exacerbation of a chronic anxiety disorder that is leading to a significant decrease in their baseline functioning. My proposed criteria for acute anxiety disorder appear in the Table. Here are some reasons this diagnosis would be helpful:

Signifier of severity. Anxiety disorders such as GAD are generally not considered severe conditions and not considered to fall under the rubric of SPMI (severe and persistent mental illness).² Posttraumatic stress disorder is the anxiety disorder–like condition most often found in the SPMI category. A diagnosis of acute anxiety disorder would indicate a patient is experiencing an episode of anxiety that is distinct from their chronic anxiety condition due to its severe impact on functional capabilities. Acute anxiety disorder would certainly not qualify as a “SPMI diagnosis” that would facilitate someone being considered eligible for supplemental security income, but it might be a legitimate justification for someone to receive short-term disability.

Treatment approach. The pharmacologic treatment of anxiety disorders usually involves a selective serotonin reuptake inhibitor (SSRI) or serotonin-norepinephrine reuptake inhibitor (SNRI). However, these medications can sometimes briefly increase anxiety when they are started. Individuals with acute anxiety are the most vulnerable to the possibility of experiencing increased anxiety when starting an SSRI or SNRI and may benefit from a slower titration of these medications. In light of this and the length of time required for SSRIs or SNRIs to exert a positive effect (typically a few weeks), patients with acute anxiety are best served by treatment with a medication with an immediate onset of action, such as a benzodiazepine or a sleep medication (eg, zolpidem). Benzodiazepines and hypnotics such as zolpidem are best prescribed for as-needed use because they carry a risk of dependence. One might consider prescribing mirtazapine or pregabalin (both of which are used off-label to treat anxiety) because these medications also have a relatively rapid onset of action and can treat both anxiety and insomnia (particularly mirtazapine).

Research considerations. It would be helpful to study which treatments are most effective for the subset of patients who experience acute anxiety disorder as I define it. Perhaps psychotherapy treatment protocols could be adapted or created. Treatment with esketamine or IV ketamine might be further studied as a treatment for acute anxiety because some evidence suggests ketamine is efficacious for this indication.³

Obsessive-compulsive disorder (OCD) is typically a severe, chronic illness in which patients have recurrent, unwanted thoughts, urges, and compulsions.¹ It causes significant morbidity and lost potential over time, and is the world’s 10th-most disabling disorder in terms of lost income and decreased quality of life, and the fifth-most disabling mental health condition.² Patients with OCD (and their clinicians) are often desperate for an efficacious treatment, but we must ensure that those who are not helped by traditional psychotherapeutic and/or pharmacologic treatments are appropriate for safe neurosurgical intervention.

Pros and cons of neurosurgical therapies

Most patients with OCD are effectively treated with cognitive-behavioral therapy and pharmacotherapy in the form of selective serotonin reuptake inhibitors, clomipramine, or second-generation antipsychotics. However, up to 5% of individuals with OCD will have symptoms refractory to these traditional therapies.³ These cases require more aggressive forms of therapy, including radiofrequency ablation surgeries and deep brain stimulation (DBS). The efficacy of both therapies is similar at 40% to 60%.^4,5 While these treatments can be life-changing for patients fortunate to receive them, they are not without issue.

Only a limited number of institutions offer these neurosurgical techniques, and for many patients, those locations may be inaccessible. Patients may not experience relief simply due to where they live, difficult logistics, and the high cost requisite to receive care. If fortunate enough to live near a participating institution or have the means to travel to one, the patient and clinician must then choose the best option based on the nuances of the patient’s situation.

Ablation techniques, such as gamma knife or magnetic resonance–guided ultrasound, are simpler and more cost-effective. A drawback of this approach, however, is that it is irreversible. Lesioned structures are irreparable, as are the adverse effects of the surgery, which, while rare, may include a persistent minimally conscious state or necrotic cysts.⁴ A benefit of this approach is that there is no need for lengthy follow-up as seen with DBS.

DBS is more complicated. In addition to having to undergo an open neurosurgical procedure, these patients require long-term follow-up and monitoring. A positive aspect is the device can be turned off or removed. However, the amount of follow-up and adjustments is significant. These patients need access to clinicians skilled in DBS device management.

Finally, we must consider the chronically ill patient’s perspective after successful treatment. While the patient’s symptoms may improve, their lives and identities likely developed around their symptoms. Bosanac et al⁶ describe this reality well in a case study in which a patient with OCD was “burdened with normality” after successful DBS treatment. He was finally able to work, build meaningful relationships, and approach previously unattainable social milestones. This was an overwhelming experience for him, and he and his family needed guidance into the world in which most of us find comfort.

As ablation techniques, DBS, and other cutting-edge therapies for OCD come to the forefront of modern care, clinicians must remember to keep patient safety first. Verify follow-up care before committing patients to invasive and irreversible treatments. While general access is currently poor, participating institutions should consider advertising and communicating that there is an accessible network available for these chronically ill individuals.

Obsessive-compulsive disorder (OCD) is typically a severe, chronic illness in which patients have recurrent, unwanted thoughts, urges, and compulsions.¹ It causes significant morbidity and lost potential over time, and is the world’s 10th-most disabling disorder in terms of lost income and decreased quality of life, and the fifth-most disabling mental health condition.² Patients with OCD (and their clinicians) are often desperate for an efficacious treatment, but we must ensure that those who are not helped by traditional psychotherapeutic and/or pharmacologic treatments are appropriate for safe neurosurgical intervention.

Pros and cons of neurosurgical therapies

Most patients with OCD are effectively treated with cognitive-behavioral therapy and pharmacotherapy in the form of selective serotonin reuptake inhibitors, clomipramine, or second-generation antipsychotics. However, up to 5% of individuals with OCD will have symptoms refractory to these traditional therapies.³ These cases require more aggressive forms of therapy, including radiofrequency ablation surgeries and deep brain stimulation (DBS). The efficacy of both therapies is similar at 40% to 60%.^4,5 While these treatments can be life-changing for patients fortunate to receive them, they are not without issue.

Only a limited number of institutions offer these neurosurgical techniques, and for many patients, those locations may be inaccessible. Patients may not experience relief simply due to where they live, difficult logistics, and the high cost requisite to receive care. If fortunate enough to live near a participating institution or have the means to travel to one, the patient and clinician must then choose the best option based on the nuances of the patient’s situation.

Ablation techniques, such as gamma knife or magnetic resonance–guided ultrasound, are simpler and more cost-effective. A drawback of this approach, however, is that it is irreversible. Lesioned structures are irreparable, as are the adverse effects of the surgery, which, while rare, may include a persistent minimally conscious state or necrotic cysts.⁴ A benefit of this approach is that there is no need for lengthy follow-up as seen with DBS.

DBS is more complicated. In addition to having to undergo an open neurosurgical procedure, these patients require long-term follow-up and monitoring. A positive aspect is the device can be turned off or removed. However, the amount of follow-up and adjustments is significant. These patients need access to clinicians skilled in DBS device management.

Finally, we must consider the chronically ill patient’s perspective after successful treatment. While the patient’s symptoms may improve, their lives and identities likely developed around their symptoms. Bosanac et al⁶ describe this reality well in a case study in which a patient with OCD was “burdened with normality” after successful DBS treatment. He was finally able to work, build meaningful relationships, and approach previously unattainable social milestones. This was an overwhelming experience for him, and he and his family needed guidance into the world in which most of us find comfort.

As ablation techniques, DBS, and other cutting-edge therapies for OCD come to the forefront of modern care, clinicians must remember to keep patient safety first. Verify follow-up care before committing patients to invasive and irreversible treatments. While general access is currently poor, participating institutions should consider advertising and communicating that there is an accessible network available for these chronically ill individuals.

Obsessive-compulsive disorder (OCD) is typically a severe, chronic illness in which patients have recurrent, unwanted thoughts, urges, and compulsions.¹ It causes significant morbidity and lost potential over time, and is the world’s 10th-most disabling disorder in terms of lost income and decreased quality of life, and the fifth-most disabling mental health condition.² Patients with OCD (and their clinicians) are often desperate for an efficacious treatment, but we must ensure that those who are not helped by traditional psychotherapeutic and/or pharmacologic treatments are appropriate for safe neurosurgical intervention.

Pros and cons of neurosurgical therapies

Most patients with OCD are effectively treated with cognitive-behavioral therapy and pharmacotherapy in the form of selective serotonin reuptake inhibitors, clomipramine, or second-generation antipsychotics. However, up to 5% of individuals with OCD will have symptoms refractory to these traditional therapies.³ These cases require more aggressive forms of therapy, including radiofrequency ablation surgeries and deep brain stimulation (DBS). The efficacy of both therapies is similar at 40% to 60%.^4,5 While these treatments can be life-changing for patients fortunate to receive them, they are not without issue.

Only a limited number of institutions offer these neurosurgical techniques, and for many patients, those locations may be inaccessible. Patients may not experience relief simply due to where they live, difficult logistics, and the high cost requisite to receive care. If fortunate enough to live near a participating institution or have the means to travel to one, the patient and clinician must then choose the best option based on the nuances of the patient’s situation.

Ablation techniques, such as gamma knife or magnetic resonance–guided ultrasound, are simpler and more cost-effective. A drawback of this approach, however, is that it is irreversible. Lesioned structures are irreparable, as are the adverse effects of the surgery, which, while rare, may include a persistent minimally conscious state or necrotic cysts.⁴ A benefit of this approach is that there is no need for lengthy follow-up as seen with DBS.

DBS is more complicated. In addition to having to undergo an open neurosurgical procedure, these patients require long-term follow-up and monitoring. A positive aspect is the device can be turned off or removed. However, the amount of follow-up and adjustments is significant. These patients need access to clinicians skilled in DBS device management.

Finally, we must consider the chronically ill patient’s perspective after successful treatment. While the patient’s symptoms may improve, their lives and identities likely developed around their symptoms. Bosanac et al⁶ describe this reality well in a case study in which a patient with OCD was “burdened with normality” after successful DBS treatment. He was finally able to work, build meaningful relationships, and approach previously unattainable social milestones. This was an overwhelming experience for him, and he and his family needed guidance into the world in which most of us find comfort.

As ablation techniques, DBS, and other cutting-edge therapies for OCD come to the forefront of modern care, clinicians must remember to keep patient safety first. Verify follow-up care before committing patients to invasive and irreversible treatments. While general access is currently poor, participating institutions should consider advertising and communicating that there is an accessible network available for these chronically ill individuals.

Recent publications on psoriatic arthritis (PsA) have focused on targeted therapies, particularly those targeting interleukin (IL) 17 and 23. Bimekizumab is a novel biologic that dually inhibits IL-17A and IL-17F. Coates and colleagues reported 3-year results from the phase 2b BE ACTIVE trial that included 206 adults with active PsA randomly assigned to receive bimekizumab or placebo for 48 weeks, of which 184 patients were enrolled in the open-label extension phase for a further 104 weeks of treatment. They report that at least 20% improvement in American College of Rheumatology score was maintained by 64.1% of patients at week 152 compared with 72.3% of patients at week 48. By week 152, 89.3% of patients had reported one or more treatment-emergent adverse event (TEAE), with serious TEAE being reported by 10.7% of patients. Fungal infections are of special interest when inhibiting both IL-17A and IL-17F. It was observed that 9.7% had fungal infections (all mild-to-moderate and localized), of which 4.6% had candidiasis. Thus, bimekizumab shows promise as a new therapy for PsA.

In addition to improving signs and symptoms, clinically meaningful improvement in health-related quality of life is an important goal of treatment. Two studies reported improvement in patient reported outcomes on treatment with IL-23 inhibitors.

An analysis of data from the phase 3 DISCOVER 2 trial included 738 biologic-naive patients with active PsA and inadequate response to standard treatments. These patients were randomly assigned to receive 100 mg guselkumab every 4 weeks (Q4W) or every 8 weeks (Q8W) or placebo. Curtis and colleagues showed that a significantly higher proportion of patients receiving guselkumab Q4W/Q8W vs placebo reported achieving minimally important differences (MID) in the EuroQol 5-Dimension 5-Level (EQ-5D-5L) Index (56.0%/56.0% vs 43.4%; P < .006) and Visual Analog Scale (EQ-VAS) score (62.8%/63.5% vs 44.4%; P < .0001) at week 24, with more than 60% of patients reporting improvements at week 52.

Similarly, analyses of data by Kristensen and colleagues from two phase 3 trials, KEEPsAKE-1 and KEEPsAKE-2, included adults with PsA and inadequate response/intolerance to disease-modifying antirheumatic drugs or biologics. The patients were randomly assigned to receive risankizumab or placebo for 24 weeks and only risankizumab during weeks 24-52. At week 24, patients receiving risankizumab vs placebo were significantly more likely to report achieving MID in Patient's Global Assessment of Disease Activity (PtGA) in both KEEPsAKE-1 (odds ratio [OR] 2.0; P < .001) and KEEPsAKE-2 (OR 1.9; P < .01) studies, with further improvement at week 52. Improvement was also seen on the Patient's Assessment of Pain, Health Assessment Questionnaire – Disability Index, Short-Form 36 Physical and Mental Component Summary scores, EQ-5D-5L, Functional Assessment of Chronic Illness Therapy – Fatigue, and Work Productivity and Activity Impairment.

An interesting insight from two studies showed the importance of nail disease in predicting treatment response. A post hoc analysis by Helliwell and colleagues of the phase 3 SEAM-PsA trial of 851 biologic/methotrexate-naive patients with active PsA who were randomly assigned to receive methotrexate monotherapy, etanercept monotherapy, or methotrexate + etanercept combination therapy showed that the presence of both dactylitis and nail disease at baseline were significantly associated with the achievement of minimal disease activity (OR 1.4; P = .0457; and OR 1.8; P = .0233, respectively), as well as low PsA Disease Activity Score (OR 1.8; P = .0014; and OR 1.8; P = .0168, respectively).

Similarly, a post hoc analysis by Baraliakos and colleagues of the phase 3b MAXIMISE trial of 473 adult patients with PsA and axial manifestations who were randomly assigned to receive secukinumab (150 or 300 mg) or placebo showed that the presence vs the absence of nail dystrophy was associated with the achievement of significantly better Assessment of SpondyloArthritis International Society 20 response in the 300 mg secukinumab group (OR 5.0; 95% CI 1.47-17.19).

Recent publications on psoriatic arthritis (PsA) have focused on targeted therapies, particularly those targeting interleukin (IL) 17 and 23. Bimekizumab is a novel biologic that dually inhibits IL-17A and IL-17F. Coates and colleagues reported 3-year results from the phase 2b BE ACTIVE trial that included 206 adults with active PsA randomly assigned to receive bimekizumab or placebo for 48 weeks, of which 184 patients were enrolled in the open-label extension phase for a further 104 weeks of treatment. They report that at least 20% improvement in American College of Rheumatology score was maintained by 64.1% of patients at week 152 compared with 72.3% of patients at week 48. By week 152, 89.3% of patients had reported one or more treatment-emergent adverse event (TEAE), with serious TEAE being reported by 10.7% of patients. Fungal infections are of special interest when inhibiting both IL-17A and IL-17F. It was observed that 9.7% had fungal infections (all mild-to-moderate and localized), of which 4.6% had candidiasis. Thus, bimekizumab shows promise as a new therapy for PsA.

In addition to improving signs and symptoms, clinically meaningful improvement in health-related quality of life is an important goal of treatment. Two studies reported improvement in patient reported outcomes on treatment with IL-23 inhibitors.

An analysis of data from the phase 3 DISCOVER 2 trial included 738 biologic-naive patients with active PsA and inadequate response to standard treatments. These patients were randomly assigned to receive 100 mg guselkumab every 4 weeks (Q4W) or every 8 weeks (Q8W) or placebo. Curtis and colleagues showed that a significantly higher proportion of patients receiving guselkumab Q4W/Q8W vs placebo reported achieving minimally important differences (MID) in the EuroQol 5-Dimension 5-Level (EQ-5D-5L) Index (56.0%/56.0% vs 43.4%; P < .006) and Visual Analog Scale (EQ-VAS) score (62.8%/63.5% vs 44.4%; P < .0001) at week 24, with more than 60% of patients reporting improvements at week 52.

Similarly, analyses of data by Kristensen and colleagues from two phase 3 trials, KEEPsAKE-1 and KEEPsAKE-2, included adults with PsA and inadequate response/intolerance to disease-modifying antirheumatic drugs or biologics. The patients were randomly assigned to receive risankizumab or placebo for 24 weeks and only risankizumab during weeks 24-52. At week 24, patients receiving risankizumab vs placebo were significantly more likely to report achieving MID in Patient's Global Assessment of Disease Activity (PtGA) in both KEEPsAKE-1 (odds ratio [OR] 2.0; P < .001) and KEEPsAKE-2 (OR 1.9; P < .01) studies, with further improvement at week 52. Improvement was also seen on the Patient's Assessment of Pain, Health Assessment Questionnaire – Disability Index, Short-Form 36 Physical and Mental Component Summary scores, EQ-5D-5L, Functional Assessment of Chronic Illness Therapy – Fatigue, and Work Productivity and Activity Impairment.

An interesting insight from two studies showed the importance of nail disease in predicting treatment response. A post hoc analysis by Helliwell and colleagues of the phase 3 SEAM-PsA trial of 851 biologic/methotrexate-naive patients with active PsA who were randomly assigned to receive methotrexate monotherapy, etanercept monotherapy, or methotrexate + etanercept combination therapy showed that the presence of both dactylitis and nail disease at baseline were significantly associated with the achievement of minimal disease activity (OR 1.4; P = .0457; and OR 1.8; P = .0233, respectively), as well as low PsA Disease Activity Score (OR 1.8; P = .0014; and OR 1.8; P = .0168, respectively).

Similarly, a post hoc analysis by Baraliakos and colleagues of the phase 3b MAXIMISE trial of 473 adult patients with PsA and axial manifestations who were randomly assigned to receive secukinumab (150 or 300 mg) or placebo showed that the presence vs the absence of nail dystrophy was associated with the achievement of significantly better Assessment of SpondyloArthritis International Society 20 response in the 300 mg secukinumab group (OR 5.0; 95% CI 1.47-17.19).

Recent publications on psoriatic arthritis (PsA) have focused on targeted therapies, particularly those targeting interleukin (IL) 17 and 23. Bimekizumab is a novel biologic that dually inhibits IL-17A and IL-17F. Coates and colleagues reported 3-year results from the phase 2b BE ACTIVE trial that included 206 adults with active PsA randomly assigned to receive bimekizumab or placebo for 48 weeks, of which 184 patients were enrolled in the open-label extension phase for a further 104 weeks of treatment. They report that at least 20% improvement in American College of Rheumatology score was maintained by 64.1% of patients at week 152 compared with 72.3% of patients at week 48. By week 152, 89.3% of patients had reported one or more treatment-emergent adverse event (TEAE), with serious TEAE being reported by 10.7% of patients. Fungal infections are of special interest when inhibiting both IL-17A and IL-17F. It was observed that 9.7% had fungal infections (all mild-to-moderate and localized), of which 4.6% had candidiasis. Thus, bimekizumab shows promise as a new therapy for PsA.

In addition to improving signs and symptoms, clinically meaningful improvement in health-related quality of life is an important goal of treatment. Two studies reported improvement in patient reported outcomes on treatment with IL-23 inhibitors.

An analysis of data from the phase 3 DISCOVER 2 trial included 738 biologic-naive patients with active PsA and inadequate response to standard treatments. These patients were randomly assigned to receive 100 mg guselkumab every 4 weeks (Q4W) or every 8 weeks (Q8W) or placebo. Curtis and colleagues showed that a significantly higher proportion of patients receiving guselkumab Q4W/Q8W vs placebo reported achieving minimally important differences (MID) in the EuroQol 5-Dimension 5-Level (EQ-5D-5L) Index (56.0%/56.0% vs 43.4%; P < .006) and Visual Analog Scale (EQ-VAS) score (62.8%/63.5% vs 44.4%; P < .0001) at week 24, with more than 60% of patients reporting improvements at week 52.

Similarly, analyses of data by Kristensen and colleagues from two phase 3 trials, KEEPsAKE-1 and KEEPsAKE-2, included adults with PsA and inadequate response/intolerance to disease-modifying antirheumatic drugs or biologics. The patients were randomly assigned to receive risankizumab or placebo for 24 weeks and only risankizumab during weeks 24-52. At week 24, patients receiving risankizumab vs placebo were significantly more likely to report achieving MID in Patient's Global Assessment of Disease Activity (PtGA) in both KEEPsAKE-1 (odds ratio [OR] 2.0; P < .001) and KEEPsAKE-2 (OR 1.9; P < .01) studies, with further improvement at week 52. Improvement was also seen on the Patient's Assessment of Pain, Health Assessment Questionnaire – Disability Index, Short-Form 36 Physical and Mental Component Summary scores, EQ-5D-5L, Functional Assessment of Chronic Illness Therapy – Fatigue, and Work Productivity and Activity Impairment.

An interesting insight from two studies showed the importance of nail disease in predicting treatment response. A post hoc analysis by Helliwell and colleagues of the phase 3 SEAM-PsA trial of 851 biologic/methotrexate-naive patients with active PsA who were randomly assigned to receive methotrexate monotherapy, etanercept monotherapy, or methotrexate + etanercept combination therapy showed that the presence of both dactylitis and nail disease at baseline were significantly associated with the achievement of minimal disease activity (OR 1.4; P = .0457; and OR 1.8; P = .0233, respectively), as well as low PsA Disease Activity Score (OR 1.8; P = .0014; and OR 1.8; P = .0168, respectively).

Similarly, a post hoc analysis by Baraliakos and colleagues of the phase 3b MAXIMISE trial of 473 adult patients with PsA and axial manifestations who were randomly assigned to receive secukinumab (150 or 300 mg) or placebo showed that the presence vs the absence of nail dystrophy was associated with the achievement of significantly better Assessment of SpondyloArthritis International Society 20 response in the 300 mg secukinumab group (OR 5.0; 95% CI 1.47-17.19).

The potential to prevent clinical rheumatoid arthritis (RA) in patients at risk of developing arthritis is of long-standing interest in the rheumatology community. Other studies have addressed the potential for early treatment with glucocorticoids, hydroxychloroquine, or biologics to prevent arthritis, with mixed results. Few published studies have assessed the efficacy of methotrexate in the prevention of arthritis. A randomized controlled trial by Krijbolder and colleagues of adults with arthralgias deemed to be at risk for progression to RA evaluated the use of a single intramuscular steroid injection combined with 1 year of oral methotrexate, compared with placebo, for preventing the development of RA according to the 2010 American College of Rheumatology classification criteria. Although no difference was seen between the groups in development of RA, those treated with methotrexate did have lower levels of joint inflammation seen on MRI and better functional status as per Health Assessment Questionnaire score.

Su and colleagues also looked at the impact of different medications on the development of RA. Using a national health insurance database in Taiwan (between 1997 and 2013), they studied the use of biguanides and sulfonylureas in patients with diabetes and the risk for incident RA. In over 90,000 patients with diabetes, a longer duration of sulfonylurea or biguanide prescription within the first 3 years of diabetes diagnosis was associated with a lower risk for RA compared with non-use. However, use of any antihyperglycemic agents was also associated with lower risk for RA incidence. Limited information is available on both the severity of diabetes and activity of RA, so even a potential mechanism in terms of reduction of blood glucose or inflammation is hard to determine, and more detailed studies are needed.

The safety of different treatments during pregnancy, as well as the effect of both RA and its treatment on pregnancy outcomes, have been areas of research interest in terms of counseling patients with RA about pregnancy planning and management of medications. Gerardi and colleagues followed 63 patients with RA prospectively during pregnancy. They found that although the general understanding is that inflammatory arthritis improves during pregnancy, the percentage of patients with moderate and high disease activity increased slightly, and 37% of patients experienced a flare. Flares were associated with elevated C-reactive protein (CRP) levels and use of multiple prior biologic disease-modifying antirheumatic drugs (bDMARD) (suggesting overall more active arthritis), as well as bDMARD discontinuation in early pregnancy. Similarly, preterm delivery was associated with elevated CRP, higher Disease Activity Score-28 scores, and flares. The study findings provide further support for the importance of controlling maternal disease activity in favoring a better RA course as well as better pregnancy outcomes.

Smeele and colleagues recently published an analysis of the PreCARA cohort study looking at birthweight in pregnant patients with RA. RA is associated with children being born small for gestational age. In this cohort study of 188 pregnant patients with RA, the treatment protocol before pregnancy included hydroxychloroquine, sulfasalazine, prednisone, and anti–tumor necrosis factor (TNF) agents (adalimumab, infliximab, etanercept, and certolizumab). Anti-TNF medications were stopped at 20, 20, 28, or 38 weeks, respectively, according to the European Alliance of Associations for Rheumatology (EULAR) recommendations. In terms of gestational age at delivery and congenital malformations, no difference was seen between patients who used anti-TNF agents during pregnancy and those who did not. Anti-TNF use during pregnancy was associated, however, with increased birthweight and a lower percentage of infants who were small for gestational age. These findings are in keeping with those of prior studies, although larger studies would be helpful in determining whether there are critical periods during pregnancy that have a significant effect on birthweight or whether overall control of inflammation is the predominant factor.

The potential to prevent clinical rheumatoid arthritis (RA) in patients at risk of developing arthritis is of long-standing interest in the rheumatology community. Other studies have addressed the potential for early treatment with glucocorticoids, hydroxychloroquine, or biologics to prevent arthritis, with mixed results. Few published studies have assessed the efficacy of methotrexate in the prevention of arthritis. A randomized controlled trial by Krijbolder and colleagues of adults with arthralgias deemed to be at risk for progression to RA evaluated the use of a single intramuscular steroid injection combined with 1 year of oral methotrexate, compared with placebo, for preventing the development of RA according to the 2010 American College of Rheumatology classification criteria. Although no difference was seen between the groups in development of RA, those treated with methotrexate did have lower levels of joint inflammation seen on MRI and better functional status as per Health Assessment Questionnaire score.

Su and colleagues also looked at the impact of different medications on the development of RA. Using a national health insurance database in Taiwan (between 1997 and 2013), they studied the use of biguanides and sulfonylureas in patients with diabetes and the risk for incident RA. In over 90,000 patients with diabetes, a longer duration of sulfonylurea or biguanide prescription within the first 3 years of diabetes diagnosis was associated with a lower risk for RA compared with non-use. However, use of any antihyperglycemic agents was also associated with lower risk for RA incidence. Limited information is available on both the severity of diabetes and activity of RA, so even a potential mechanism in terms of reduction of blood glucose or inflammation is hard to determine, and more detailed studies are needed.

The safety of different treatments during pregnancy, as well as the effect of both RA and its treatment on pregnancy outcomes, have been areas of research interest in terms of counseling patients with RA about pregnancy planning and management of medications. Gerardi and colleagues followed 63 patients with RA prospectively during pregnancy. They found that although the general understanding is that inflammatory arthritis improves during pregnancy, the percentage of patients with moderate and high disease activity increased slightly, and 37% of patients experienced a flare. Flares were associated with elevated C-reactive protein (CRP) levels and use of multiple prior biologic disease-modifying antirheumatic drugs (bDMARD) (suggesting overall more active arthritis), as well as bDMARD discontinuation in early pregnancy. Similarly, preterm delivery was associated with elevated CRP, higher Disease Activity Score-28 scores, and flares. The study findings provide further support for the importance of controlling maternal disease activity in favoring a better RA course as well as better pregnancy outcomes.

Smeele and colleagues recently published an analysis of the PreCARA cohort study looking at birthweight in pregnant patients with RA. RA is associated with children being born small for gestational age. In this cohort study of 188 pregnant patients with RA, the treatment protocol before pregnancy included hydroxychloroquine, sulfasalazine, prednisone, and anti–tumor necrosis factor (TNF) agents (adalimumab, infliximab, etanercept, and certolizumab). Anti-TNF medications were stopped at 20, 20, 28, or 38 weeks, respectively, according to the European Alliance of Associations for Rheumatology (EULAR) recommendations. In terms of gestational age at delivery and congenital malformations, no difference was seen between patients who used anti-TNF agents during pregnancy and those who did not. Anti-TNF use during pregnancy was associated, however, with increased birthweight and a lower percentage of infants who were small for gestational age. These findings are in keeping with those of prior studies, although larger studies would be helpful in determining whether there are critical periods during pregnancy that have a significant effect on birthweight or whether overall control of inflammation is the predominant factor.

The potential to prevent clinical rheumatoid arthritis (RA) in patients at risk of developing arthritis is of long-standing interest in the rheumatology community. Other studies have addressed the potential for early treatment with glucocorticoids, hydroxychloroquine, or biologics to prevent arthritis, with mixed results. Few published studies have assessed the efficacy of methotrexate in the prevention of arthritis. A randomized controlled trial by Krijbolder and colleagues of adults with arthralgias deemed to be at risk for progression to RA evaluated the use of a single intramuscular steroid injection combined with 1 year of oral methotrexate, compared with placebo, for preventing the development of RA according to the 2010 American College of Rheumatology classification criteria. Although no difference was seen between the groups in development of RA, those treated with methotrexate did have lower levels of joint inflammation seen on MRI and better functional status as per Health Assessment Questionnaire score.

Su and colleagues also looked at the impact of different medications on the development of RA. Using a national health insurance database in Taiwan (between 1997 and 2013), they studied the use of biguanides and sulfonylureas in patients with diabetes and the risk for incident RA. In over 90,000 patients with diabetes, a longer duration of sulfonylurea or biguanide prescription within the first 3 years of diabetes diagnosis was associated with a lower risk for RA compared with non-use. However, use of any antihyperglycemic agents was also associated with lower risk for RA incidence. Limited information is available on both the severity of diabetes and activity of RA, so even a potential mechanism in terms of reduction of blood glucose or inflammation is hard to determine, and more detailed studies are needed.

The safety of different treatments during pregnancy, as well as the effect of both RA and its treatment on pregnancy outcomes, have been areas of research interest in terms of counseling patients with RA about pregnancy planning and management of medications. Gerardi and colleagues followed 63 patients with RA prospectively during pregnancy. They found that although the general understanding is that inflammatory arthritis improves during pregnancy, the percentage of patients with moderate and high disease activity increased slightly, and 37% of patients experienced a flare. Flares were associated with elevated C-reactive protein (CRP) levels and use of multiple prior biologic disease-modifying antirheumatic drugs (bDMARD) (suggesting overall more active arthritis), as well as bDMARD discontinuation in early pregnancy. Similarly, preterm delivery was associated with elevated CRP, higher Disease Activity Score-28 scores, and flares. The study findings provide further support for the importance of controlling maternal disease activity in favoring a better RA course as well as better pregnancy outcomes.

Smeele and colleagues recently published an analysis of the PreCARA cohort study looking at birthweight in pregnant patients with RA. RA is associated with children being born small for gestational age. In this cohort study of 188 pregnant patients with RA, the treatment protocol before pregnancy included hydroxychloroquine, sulfasalazine, prednisone, and anti–tumor necrosis factor (TNF) agents (adalimumab, infliximab, etanercept, and certolizumab). Anti-TNF medications were stopped at 20, 20, 28, or 38 weeks, respectively, according to the European Alliance of Associations for Rheumatology (EULAR) recommendations. In terms of gestational age at delivery and congenital malformations, no difference was seen between patients who used anti-TNF agents during pregnancy and those who did not. Anti-TNF use during pregnancy was associated, however, with increased birthweight and a lower percentage of infants who were small for gestational age. These findings are in keeping with those of prior studies, although larger studies would be helpful in determining whether there are critical periods during pregnancy that have a significant effect on birthweight or whether overall control of inflammation is the predominant factor.