With the variety of drugs available for treating depression, choosing one can be daunting. Different agents have characteristics that may make them a better choice for different types of patients, but even so, treating any kind of mental illness often requires an element of trial and error.

Primary care providers are on the frontline of treating mental illness, often evaluating patients before they are seen by a psychiatrist. The purpose of this article is to provide insight into the art of prescribing antidepressants in the primary care setting. We will discuss common patient presentations, including depressed patients without other medical comorbidities as well as those with common comorbidities, with our recommendations for first-line treatment.

We hope our recommendations will help you to navigate the uncertainty more confidently, resulting in more efficient and tailored treatment for your patients.

BASELINE TESTING

When starting a patient on antidepressant drug therapy, we recommend obtaining a set of baseline laboratory tests to rule out underlying medical conditions that may be contributing to the patient’s depression or that may preclude the use of a given drug. (For example, elevation of liver enzymes may preclude the use of duloxetine.) Tests should include:

• A complete blood cell count
• A complete metabolic panel
• A thyroid-stimulating hormone level.

Electrocardiography may also be useful, as some antidepressants can prolong the QT interval or elevate the blood levels of other drugs with this effect.

GENERAL TREATMENT CONSIDERATIONS

There are several classes of antidepressants, and each class has a number of agents. Research has found little difference in efficacy among agents. So to simplify choosing which one to use, we recommend becoming comfortable with an agent from each class, ie:

• A selective serotonin reuptake inhibitor (SSRI)
• A selective serotonin-norepinephrine reuptake inhibitor (SNRI)
• A tricyclic antidepressant (TCA)
• A monoamine oxidase (MAO) inhibitor.

Each class includes generic agents, many of which are on the discount lists of retail pharmacies. Table 1 shows representative drugs from each class, with their relative costs.

Start low and go slow. In general, when starting an antidepressant, consider starting at half the normal dose, titrating upward as tolerated about every 14 days. This approach can minimize side effects. For example, if prescribing fluoxetine, start with 10 mg and titrate every 2 weeks based on tolerance and patient response. That said, each patient may respond differently, requiring perhaps a lower starting dose or a longer titration schedule.

Anticipate side effects. Most of the side effects of an antidepressant drug can be explained by its mechanism of action. Although side effects should certainly be considered when choosing an agent, patients can be reassured that most are transient and benign. A detailed discussion of side effects of antidepressant drugs is beyond the scope of this article, but a review by Khawam et al¹ was published earlier in this journal.

Reassess. If after 4 to 6 weeks the patient has had little or no response, it is reasonable to switch agents. For a patient who was on an SSRI, the change can be to another SSRI or to an SNRI. However, if two SSRIs have already failed, then choose an SNRI. Agents are commonly cross-tapered during the switch to avoid abrupt cessation of one drug or the increased risk of adverse events such as cytochrome P450 interactions, serotonin syndrome, or hypertensive crisis (when switching to an MAO inhibitor).

Beware of interactions. All SSRIs and SNRIs are metabolized through the P450 system in the liver and therefore have the potential for drug-drug interactions. Care must be taken when giving these agents together with drugs whose metabolism can be altered by P450 inhibition. For TCAs, blood levels can be checked if there is concern about toxicity; however, dosing is not strictly based on this level. Great care should be taken if a TCA is given together with an SNRI or an SSRI, as the TCA blood level can become significantly elevated. This may result in QT interval prolongation, as mentioned earlier.

Refer. Referral to a psychiatrist is appropriate for patients for whom multiple classes have failed, for patients who have another psychiatric comorbidity (such as psychosis, hypomania, or mania), or for patients who may need hospitalization. Referral is also appropriate if the physician is concerned about suicide risk.

PATIENTS WITH MAJOR DEPRESSION ONLY

For a patient presenting with depression but no other significant medical comorbidity, the first-line therapy is often an SSRI. Several generic SSRIs are available, and some are on the discount lists at retail pharmacies.

Symptoms should start to improve in about 2 weeks, and the optimal response should be achieved in 4 to 6 weeks of treatment. If this does not occur, consider either adding an augmenting agent or switching to a different antidepressant.

PATIENTS WITH CHRONIC PAIN

Chronic pain and depression often go hand in hand and can potentiate each other. When considering an antidepressant in a patient who has both conditions, the SNRIs and TCAs are typically preferred. Some SNRIs, namely duloxetine and milnacipran, are approved for certain chronic pain conditions, such as fibromyalgia. SNRIs are frequently used off-label for other chronic pain conditions such as headache and neuropathic pain.²

TCAs such as amitriptyline, nortriptyline, and doxepin are also often used in patients with chronic pain. These agents, like the SNRIs, inhibit the reuptake of serotonin and norepinephrine and are used off-label for neuropathic pain,^3,4 migraine, interstitial cystitis,⁵ and other pain conditions.^6–9

For TCAs and SNRIs, the effective dose range for chronic pain overlaps that for depression. However, TCAs are often given at lower doses to patients without depression. We recommend starting at a low dose and slowly titrating upward to an effective dose. SNRIs are often preferred over TCAs because they do not have anticholinergic side effects and because an overdose is much less likely to be lethal.

PATIENTS WITH SEXUAL DYSFUNCTION

One of the more commonly reported side effects of antidepressants is sexual dysfunction, generally in the form of delayed orgasm or decreased libido.¹⁰ Typically, these complaints are attributed to SSRIs and SNRIs; however, TCAs and MAO inhibitors have also been associated wth sexual dysfunction.

Both erectile dysfunction and priapism have been linked to certain antidepressants. In particular, trazodone is a known cause of priapism. Even if using low doses for sleep, male patients should be made aware of this adverse effect.

Switching from one agent to another in the same class is not likely to improve sexual side effects. In particular, all the SSRIs are similar in their likelihood of causing sexual dysfunction. In a patient taking an SSRI who experiences this side effect, switching to bupropion¹¹ or mirtazapine¹² can be quite useful. Bupropion acts primarily on dopamine and norepinephrine, whereas mirtazapine acts on serotonin and norepinephrine but in a different manner from SSRIs and SNRIs.

Adjunctive treatment such as a cholinergic agonist, yohimbine (contraindicated with MAO inhibitors), a serotonergic agent (eg, buspirone), or a drug that acts on nitric oxide (eg, sildenafil, tadalafil) may have some utility but is often ineffective. Dose reduction, if possible, can be of value.

PATIENTS WITH ANXIETY

Many antidepressants are also approved for anxiety disorders, and still more are used off-label for this purpose. Anxiety and depression often occur together, so being able to treat both conditions with one drug can be quite useful.¹³ In general, the antidepressant effects are seen at lower doses of SSRIs and SNRIs, whereas more of the anxiolytic effects are seen at higher doses, particularly for obsessive-compulsive disorder.¹⁴

First-line treatment would be an SSRI or SNRI. Most anxiety disorders respond to either class, but there are some more-specific recommendations. SSRIs are best studied in panic disorder, generalized anxiety disorder, social anxiety disorder, posttraumatic stress disorder, and obsessive-compulsive disorder. Fluoxetine, citalopram, escitalopram, and sertraline¹⁵ can all be effective in both major depressive disorder and generalized anxiety disorder. Panic disorder also tends to respond well to SSRIs. SNRIs have been evaluated primarily in generalized anxiety disorder but may also be useful in many of the other conditions.

Additionally, mirtazapine (used off-label)¹² and the TCAs^16–18 can help treat anxiety. Clomipramine is used to treat obsessive-compulsive disorder.¹⁹ These drugs are especially useful for nighttime anxiety, as they can aid sleep. Of note, the anxiolytic effect of mirtazapine may be greater at higher doses.

MAO inhibitors often go unused because of the dietary and medication restrictions involved. However, very refractory cases of certain anxiety disorders may respond preferentially to these agents.

Bupropion tends to be more activating than other antidepressants, so is often avoided in anxious patients. However, some research suggests this is not always necessary.²⁰ If the anxiety is secondary to depression, it will often improve significantly with this agent.

When starting or increasing the dose of an antidepressant, patients may experience increased anxiety or feel “jittery.” This feeling usually passes within the first week of treatment, and it is important to inform patients about this effect. “Start low and go slow” in patients with significant comorbid anxiety. Temporarily using a benzodiazepine such as clonazepam may make the transition more tolerable.

PATIENTS WITH CHRONIC FATIGUE SYNDROME OR FIBROMYALGIA

Increasing recognition of both chronic fatigue syndrome and fibromyalgia has led to more proactive treatment for these disorders. Depression can go hand in hand with these disorders, and certain antidepressants, namely the SNRIs, can be useful in this population.

More data exist for the treatment of fibromyalgia. Both duloxetine and milnacipran are approved by the US Food and Drug Administration (FDA) for the treatment of fibromyalgia.²¹ Venlafaxine is also used off-label for this purpose. SSRIs such as fluoxetine and citalopram have had mixed results.^21–23 TCAs have been used with some success; however, their side effects and lethal potential are often limiting.^21,24,25 A recent study in Spain also suggested there may be benefit from using MAO inhibitors for fibromyalgia, but data are quite limited.²⁶

The data for treating chronic fatigue syndrome with SSRIs, SNRIs, or MAO inhibitors are conflicting.^27–29 However, managing the co-existing depression may provide some relief in and of itself.

PATIENTS WITH FREQUENT INSOMNIA

Insomnia can be a symptom of depression, but it can also be a side effect of certain antidepressants. The SSRIs and SNRIs can disrupt sleep patterns in some patients by shortening the rapid-eye-movement (REM) stage.^30,31

In patients with severe insomnia, it may be best to first recommend taking the antidepressant in the morning if they notice worsening sleep after initiating treatment. Patients can be told with any antidepressant, “If it makes you tired, take it at night, and if it wakes you up, take it in the morning.” Of note, a recent South African study suggested that escitalopram may be able to improve sleep.³²

If that does not solve the problem, there are other options. For instance, mirtazapine, particularly in doses of 15 mg or 30 mg, aids depression and insomnia. At higher doses (45 mg), the sleep-aiding effect may be reduced. Low doses of TCAs, particularly doxepin, maprotiline (technically speaking, a tetracyclic antidepressant), amitriptyline, and nortriptyline can be effective sleep aids. These agents may be used as an adjunct to another antidepressant to enhance sleep and mood. However, the TCAs also shorten the REM stage of sleep.³³

The previously mentioned drug interactions with SSRIs and SNRIs also need to be considered. Caution should be used when discontinuing these medications, as patients may experience rebound symptoms in the form of much more vivid dreams. MAO inhibitors may worsen insomnia because they suppress REM sleep.³⁴

Trazodone is another agent that at lower doses (25–150 mg) can be an effective, nonaddicting sleep aid. When used as an antidepressant, it is generally prescribed at higher doses (300–400 mg), but its sedating effects can be quite limiting at these levels. It is important to remember the possibility of priapism in male patients.

GERIATRIC PATIENTS

Old age brings its own set of concerns when treating depression. Elderly patients are more susceptible to potential bradycardia caused by SSRIs. The TCAs have the more worrisome cardiac side effect of QTc prolongation. TCAs can slow cognitive function, whereas the SSRIs, bupropion, and the SNRIs tend not to affect cognition. Escitalopram and duloxetine have been suggested to be particularly effective in the elderly.^35,36 A study from the Netherlands linked SSRIs with increased risk of falling in geriatric patients with dementia.³⁷ Constipation, which could lead to ileus, is increased with TCAs and certain other agents (ie, paroxetine) in the geriatric population.

Mirtazapine is often very useful in elderly patients for many reasons: it treats both anxiety and depression, stimulates appetite and weight gain, can help with nausea, and is an effective sleep aid. Concerns about weight, appetite, and sleep are particularly common in the elderly, whereas younger patients can be less tolerant of drugs that make them gain weight and sleep more. Normal age-related changes to the sleep cycle contribute to decreased satisfaction with sleep as we age. In addition, depression often further impairs sleep. So, in the elderly, optimizing sleep is key. Research has also shown mirtazapine to be effective in patients with both Alzheimer dementia and depression.³⁸

DIABETIC PATIENTS

One of the more worrisome side effects of psychiatric medications in diabetic patients is weight gain. Certain antidepressants have a greater propensity for weight gain and should likely be avoided as first-line treatments in this population.¹² Typically, these agents include those that have more antihistamine action such as paroxetine and the TCAs. These agents also may lead to constipation, which could potentially worsen gastroparesis. Mirtazapine and the MAO inhibitors are also known to cause weight gain.

Bupropion and nefazodone are the most weight-neutral of all antidepressants. Nefazodone has fallen out of favor because of its potential to cause fulminant liver failure in rare cases. However, it remains a reasonable option for patients with comorbid anxiety and depression who have significant weight gain with other agents.

SSRIs and MAO inhibitors may improve or be neutral toward glucose metabolism, and some data suggest that SNRIs may impair this process.³⁹

PATIENTS WITH CARDIAC CONDITIONS

Major depression often coexists with cardiac conditions. In particular, many patients develop depression after suffering a myocardial infarction, and increasingly they are being treated for it.⁴⁰ Treatment in this situation is appropriate, since depression, if untreated, can increase the risk of recurrence of myocardial infarction.⁴¹

However, there are many concerns that accompany treating depression in cardiac patients. Therefore, a baseline electrocardiogram should be obtained before starting an antidepressant.

TCAs and tetracyclic agents have a tendency to prolong the QTc interval and potentiate ventricular arrhythmias,⁴² so it may be prudent to avoid these in patients at risk. These agents can also significantly increase the pulse rate. This tachycardia increases the risk of angina or myocardial infarction from the anticholinergic effects of these drugs.

In February 2013, the FDA issued a warning about possible arrhythmias with citalopram at doses greater than 40 mg in adult patients⁴³; however, research has suggested citalopram is effective in treating depression in cardiac patients.⁴⁴ Research has not shown an increase in efficacy at doses greater than 40 mg daily, so we recommend following the black-box warning.

TCAs and MAO inhibitors can also cause orthostatic hypotension. On the other hand, consuming large amounts of tyramine, in foods such as aged cheese, can precipitate a hypertensive crisis in patients taking MAO inhibitors.

Which antidepressants tend to be safer in cardiac patients? Sertraline has been shown to be safe in congestive heart failure and coronary artery disease,^45–47 but the SSRIs are typically safe. Fluoxetine has shown efficacy in patients who have had a myocardial infarction.⁴⁸ Mirtazapine has also been shown to be efficacious in cardiac patients.⁴⁹ Nefazodone, mirtazapine, bupropion, SSRIs, and SNRIs have little or no tendency toward orthostatic hypotension.

With the variety of drugs available for treating depression, choosing one can be daunting. Different agents have characteristics that may make them a better choice for different types of patients, but even so, treating any kind of mental illness often requires an element of trial and error.

Primary care providers are on the frontline of treating mental illness, often evaluating patients before they are seen by a psychiatrist. The purpose of this article is to provide insight into the art of prescribing antidepressants in the primary care setting. We will discuss common patient presentations, including depressed patients without other medical comorbidities as well as those with common comorbidities, with our recommendations for first-line treatment.

We hope our recommendations will help you to navigate the uncertainty more confidently, resulting in more efficient and tailored treatment for your patients.

BASELINE TESTING

When starting a patient on antidepressant drug therapy, we recommend obtaining a set of baseline laboratory tests to rule out underlying medical conditions that may be contributing to the patient’s depression or that may preclude the use of a given drug. (For example, elevation of liver enzymes may preclude the use of duloxetine.) Tests should include:

• A complete blood cell count
• A complete metabolic panel
• A thyroid-stimulating hormone level.

Electrocardiography may also be useful, as some antidepressants can prolong the QT interval or elevate the blood levels of other drugs with this effect.

GENERAL TREATMENT CONSIDERATIONS

There are several classes of antidepressants, and each class has a number of agents. Research has found little difference in efficacy among agents. So to simplify choosing which one to use, we recommend becoming comfortable with an agent from each class, ie:

• A selective serotonin reuptake inhibitor (SSRI)
• A selective serotonin-norepinephrine reuptake inhibitor (SNRI)
• A tricyclic antidepressant (TCA)
• A monoamine oxidase (MAO) inhibitor.

Each class includes generic agents, many of which are on the discount lists of retail pharmacies. Table 1 shows representative drugs from each class, with their relative costs.

Start low and go slow. In general, when starting an antidepressant, consider starting at half the normal dose, titrating upward as tolerated about every 14 days. This approach can minimize side effects. For example, if prescribing fluoxetine, start with 10 mg and titrate every 2 weeks based on tolerance and patient response. That said, each patient may respond differently, requiring perhaps a lower starting dose or a longer titration schedule.

Anticipate side effects. Most of the side effects of an antidepressant drug can be explained by its mechanism of action. Although side effects should certainly be considered when choosing an agent, patients can be reassured that most are transient and benign. A detailed discussion of side effects of antidepressant drugs is beyond the scope of this article, but a review by Khawam et al¹ was published earlier in this journal.

Reassess. If after 4 to 6 weeks the patient has had little or no response, it is reasonable to switch agents. For a patient who was on an SSRI, the change can be to another SSRI or to an SNRI. However, if two SSRIs have already failed, then choose an SNRI. Agents are commonly cross-tapered during the switch to avoid abrupt cessation of one drug or the increased risk of adverse events such as cytochrome P450 interactions, serotonin syndrome, or hypertensive crisis (when switching to an MAO inhibitor).

Beware of interactions. All SSRIs and SNRIs are metabolized through the P450 system in the liver and therefore have the potential for drug-drug interactions. Care must be taken when giving these agents together with drugs whose metabolism can be altered by P450 inhibition. For TCAs, blood levels can be checked if there is concern about toxicity; however, dosing is not strictly based on this level. Great care should be taken if a TCA is given together with an SNRI or an SSRI, as the TCA blood level can become significantly elevated. This may result in QT interval prolongation, as mentioned earlier.

Refer. Referral to a psychiatrist is appropriate for patients for whom multiple classes have failed, for patients who have another psychiatric comorbidity (such as psychosis, hypomania, or mania), or for patients who may need hospitalization. Referral is also appropriate if the physician is concerned about suicide risk.

PATIENTS WITH MAJOR DEPRESSION ONLY

For a patient presenting with depression but no other significant medical comorbidity, the first-line therapy is often an SSRI. Several generic SSRIs are available, and some are on the discount lists at retail pharmacies.

Symptoms should start to improve in about 2 weeks, and the optimal response should be achieved in 4 to 6 weeks of treatment. If this does not occur, consider either adding an augmenting agent or switching to a different antidepressant.

PATIENTS WITH CHRONIC PAIN

Chronic pain and depression often go hand in hand and can potentiate each other. When considering an antidepressant in a patient who has both conditions, the SNRIs and TCAs are typically preferred. Some SNRIs, namely duloxetine and milnacipran, are approved for certain chronic pain conditions, such as fibromyalgia. SNRIs are frequently used off-label for other chronic pain conditions such as headache and neuropathic pain.²

TCAs such as amitriptyline, nortriptyline, and doxepin are also often used in patients with chronic pain. These agents, like the SNRIs, inhibit the reuptake of serotonin and norepinephrine and are used off-label for neuropathic pain,^3,4 migraine, interstitial cystitis,⁵ and other pain conditions.^6–9

For TCAs and SNRIs, the effective dose range for chronic pain overlaps that for depression. However, TCAs are often given at lower doses to patients without depression. We recommend starting at a low dose and slowly titrating upward to an effective dose. SNRIs are often preferred over TCAs because they do not have anticholinergic side effects and because an overdose is much less likely to be lethal.

PATIENTS WITH SEXUAL DYSFUNCTION

One of the more commonly reported side effects of antidepressants is sexual dysfunction, generally in the form of delayed orgasm or decreased libido.¹⁰ Typically, these complaints are attributed to SSRIs and SNRIs; however, TCAs and MAO inhibitors have also been associated wth sexual dysfunction.

Both erectile dysfunction and priapism have been linked to certain antidepressants. In particular, trazodone is a known cause of priapism. Even if using low doses for sleep, male patients should be made aware of this adverse effect.

Switching from one agent to another in the same class is not likely to improve sexual side effects. In particular, all the SSRIs are similar in their likelihood of causing sexual dysfunction. In a patient taking an SSRI who experiences this side effect, switching to bupropion¹¹ or mirtazapine¹² can be quite useful. Bupropion acts primarily on dopamine and norepinephrine, whereas mirtazapine acts on serotonin and norepinephrine but in a different manner from SSRIs and SNRIs.

Adjunctive treatment such as a cholinergic agonist, yohimbine (contraindicated with MAO inhibitors), a serotonergic agent (eg, buspirone), or a drug that acts on nitric oxide (eg, sildenafil, tadalafil) may have some utility but is often ineffective. Dose reduction, if possible, can be of value.

PATIENTS WITH ANXIETY

Many antidepressants are also approved for anxiety disorders, and still more are used off-label for this purpose. Anxiety and depression often occur together, so being able to treat both conditions with one drug can be quite useful.¹³ In general, the antidepressant effects are seen at lower doses of SSRIs and SNRIs, whereas more of the anxiolytic effects are seen at higher doses, particularly for obsessive-compulsive disorder.¹⁴

First-line treatment would be an SSRI or SNRI. Most anxiety disorders respond to either class, but there are some more-specific recommendations. SSRIs are best studied in panic disorder, generalized anxiety disorder, social anxiety disorder, posttraumatic stress disorder, and obsessive-compulsive disorder. Fluoxetine, citalopram, escitalopram, and sertraline¹⁵ can all be effective in both major depressive disorder and generalized anxiety disorder. Panic disorder also tends to respond well to SSRIs. SNRIs have been evaluated primarily in generalized anxiety disorder but may also be useful in many of the other conditions.

Additionally, mirtazapine (used off-label)¹² and the TCAs^16–18 can help treat anxiety. Clomipramine is used to treat obsessive-compulsive disorder.¹⁹ These drugs are especially useful for nighttime anxiety, as they can aid sleep. Of note, the anxiolytic effect of mirtazapine may be greater at higher doses.

MAO inhibitors often go unused because of the dietary and medication restrictions involved. However, very refractory cases of certain anxiety disorders may respond preferentially to these agents.

Bupropion tends to be more activating than other antidepressants, so is often avoided in anxious patients. However, some research suggests this is not always necessary.²⁰ If the anxiety is secondary to depression, it will often improve significantly with this agent.

When starting or increasing the dose of an antidepressant, patients may experience increased anxiety or feel “jittery.” This feeling usually passes within the first week of treatment, and it is important to inform patients about this effect. “Start low and go slow” in patients with significant comorbid anxiety. Temporarily using a benzodiazepine such as clonazepam may make the transition more tolerable.

PATIENTS WITH CHRONIC FATIGUE SYNDROME OR FIBROMYALGIA

Increasing recognition of both chronic fatigue syndrome and fibromyalgia has led to more proactive treatment for these disorders. Depression can go hand in hand with these disorders, and certain antidepressants, namely the SNRIs, can be useful in this population.

More data exist for the treatment of fibromyalgia. Both duloxetine and milnacipran are approved by the US Food and Drug Administration (FDA) for the treatment of fibromyalgia.²¹ Venlafaxine is also used off-label for this purpose. SSRIs such as fluoxetine and citalopram have had mixed results.^21–23 TCAs have been used with some success; however, their side effects and lethal potential are often limiting.^21,24,25 A recent study in Spain also suggested there may be benefit from using MAO inhibitors for fibromyalgia, but data are quite limited.²⁶

The data for treating chronic fatigue syndrome with SSRIs, SNRIs, or MAO inhibitors are conflicting.^27–29 However, managing the co-existing depression may provide some relief in and of itself.

PATIENTS WITH FREQUENT INSOMNIA

Insomnia can be a symptom of depression, but it can also be a side effect of certain antidepressants. The SSRIs and SNRIs can disrupt sleep patterns in some patients by shortening the rapid-eye-movement (REM) stage.^30,31

In patients with severe insomnia, it may be best to first recommend taking the antidepressant in the morning if they notice worsening sleep after initiating treatment. Patients can be told with any antidepressant, “If it makes you tired, take it at night, and if it wakes you up, take it in the morning.” Of note, a recent South African study suggested that escitalopram may be able to improve sleep.³²

If that does not solve the problem, there are other options. For instance, mirtazapine, particularly in doses of 15 mg or 30 mg, aids depression and insomnia. At higher doses (45 mg), the sleep-aiding effect may be reduced. Low doses of TCAs, particularly doxepin, maprotiline (technically speaking, a tetracyclic antidepressant), amitriptyline, and nortriptyline can be effective sleep aids. These agents may be used as an adjunct to another antidepressant to enhance sleep and mood. However, the TCAs also shorten the REM stage of sleep.³³

The previously mentioned drug interactions with SSRIs and SNRIs also need to be considered. Caution should be used when discontinuing these medications, as patients may experience rebound symptoms in the form of much more vivid dreams. MAO inhibitors may worsen insomnia because they suppress REM sleep.³⁴

Trazodone is another agent that at lower doses (25–150 mg) can be an effective, nonaddicting sleep aid. When used as an antidepressant, it is generally prescribed at higher doses (300–400 mg), but its sedating effects can be quite limiting at these levels. It is important to remember the possibility of priapism in male patients.

GERIATRIC PATIENTS

Old age brings its own set of concerns when treating depression. Elderly patients are more susceptible to potential bradycardia caused by SSRIs. The TCAs have the more worrisome cardiac side effect of QTc prolongation. TCAs can slow cognitive function, whereas the SSRIs, bupropion, and the SNRIs tend not to affect cognition. Escitalopram and duloxetine have been suggested to be particularly effective in the elderly.^35,36 A study from the Netherlands linked SSRIs with increased risk of falling in geriatric patients with dementia.³⁷ Constipation, which could lead to ileus, is increased with TCAs and certain other agents (ie, paroxetine) in the geriatric population.

Mirtazapine is often very useful in elderly patients for many reasons: it treats both anxiety and depression, stimulates appetite and weight gain, can help with nausea, and is an effective sleep aid. Concerns about weight, appetite, and sleep are particularly common in the elderly, whereas younger patients can be less tolerant of drugs that make them gain weight and sleep more. Normal age-related changes to the sleep cycle contribute to decreased satisfaction with sleep as we age. In addition, depression often further impairs sleep. So, in the elderly, optimizing sleep is key. Research has also shown mirtazapine to be effective in patients with both Alzheimer dementia and depression.³⁸

DIABETIC PATIENTS

One of the more worrisome side effects of psychiatric medications in diabetic patients is weight gain. Certain antidepressants have a greater propensity for weight gain and should likely be avoided as first-line treatments in this population.¹² Typically, these agents include those that have more antihistamine action such as paroxetine and the TCAs. These agents also may lead to constipation, which could potentially worsen gastroparesis. Mirtazapine and the MAO inhibitors are also known to cause weight gain.

Bupropion and nefazodone are the most weight-neutral of all antidepressants. Nefazodone has fallen out of favor because of its potential to cause fulminant liver failure in rare cases. However, it remains a reasonable option for patients with comorbid anxiety and depression who have significant weight gain with other agents.

SSRIs and MAO inhibitors may improve or be neutral toward glucose metabolism, and some data suggest that SNRIs may impair this process.³⁹

PATIENTS WITH CARDIAC CONDITIONS

Major depression often coexists with cardiac conditions. In particular, many patients develop depression after suffering a myocardial infarction, and increasingly they are being treated for it.⁴⁰ Treatment in this situation is appropriate, since depression, if untreated, can increase the risk of recurrence of myocardial infarction.⁴¹

However, there are many concerns that accompany treating depression in cardiac patients. Therefore, a baseline electrocardiogram should be obtained before starting an antidepressant.

TCAs and tetracyclic agents have a tendency to prolong the QTc interval and potentiate ventricular arrhythmias,⁴² so it may be prudent to avoid these in patients at risk. These agents can also significantly increase the pulse rate. This tachycardia increases the risk of angina or myocardial infarction from the anticholinergic effects of these drugs.

In February 2013, the FDA issued a warning about possible arrhythmias with citalopram at doses greater than 40 mg in adult patients⁴³; however, research has suggested citalopram is effective in treating depression in cardiac patients.⁴⁴ Research has not shown an increase in efficacy at doses greater than 40 mg daily, so we recommend following the black-box warning.

TCAs and MAO inhibitors can also cause orthostatic hypotension. On the other hand, consuming large amounts of tyramine, in foods such as aged cheese, can precipitate a hypertensive crisis in patients taking MAO inhibitors.

Which antidepressants tend to be safer in cardiac patients? Sertraline has been shown to be safe in congestive heart failure and coronary artery disease,^45–47 but the SSRIs are typically safe. Fluoxetine has shown efficacy in patients who have had a myocardial infarction.⁴⁸ Mirtazapine has also been shown to be efficacious in cardiac patients.⁴⁹ Nefazodone, mirtazapine, bupropion, SSRIs, and SNRIs have little or no tendency toward orthostatic hypotension.

With the variety of drugs available for treating depression, choosing one can be daunting. Different agents have characteristics that may make them a better choice for different types of patients, but even so, treating any kind of mental illness often requires an element of trial and error.

Primary care providers are on the frontline of treating mental illness, often evaluating patients before they are seen by a psychiatrist. The purpose of this article is to provide insight into the art of prescribing antidepressants in the primary care setting. We will discuss common patient presentations, including depressed patients without other medical comorbidities as well as those with common comorbidities, with our recommendations for first-line treatment.

We hope our recommendations will help you to navigate the uncertainty more confidently, resulting in more efficient and tailored treatment for your patients.

BASELINE TESTING

When starting a patient on antidepressant drug therapy, we recommend obtaining a set of baseline laboratory tests to rule out underlying medical conditions that may be contributing to the patient’s depression or that may preclude the use of a given drug. (For example, elevation of liver enzymes may preclude the use of duloxetine.) Tests should include:

• A complete blood cell count
• A complete metabolic panel
• A thyroid-stimulating hormone level.

Electrocardiography may also be useful, as some antidepressants can prolong the QT interval or elevate the blood levels of other drugs with this effect.

GENERAL TREATMENT CONSIDERATIONS

There are several classes of antidepressants, and each class has a number of agents. Research has found little difference in efficacy among agents. So to simplify choosing which one to use, we recommend becoming comfortable with an agent from each class, ie:

• A selective serotonin reuptake inhibitor (SSRI)
• A selective serotonin-norepinephrine reuptake inhibitor (SNRI)
• A tricyclic antidepressant (TCA)
• A monoamine oxidase (MAO) inhibitor.

Each class includes generic agents, many of which are on the discount lists of retail pharmacies. Table 1 shows representative drugs from each class, with their relative costs.

Start low and go slow. In general, when starting an antidepressant, consider starting at half the normal dose, titrating upward as tolerated about every 14 days. This approach can minimize side effects. For example, if prescribing fluoxetine, start with 10 mg and titrate every 2 weeks based on tolerance and patient response. That said, each patient may respond differently, requiring perhaps a lower starting dose or a longer titration schedule.

Anticipate side effects. Most of the side effects of an antidepressant drug can be explained by its mechanism of action. Although side effects should certainly be considered when choosing an agent, patients can be reassured that most are transient and benign. A detailed discussion of side effects of antidepressant drugs is beyond the scope of this article, but a review by Khawam et al¹ was published earlier in this journal.

Reassess. If after 4 to 6 weeks the patient has had little or no response, it is reasonable to switch agents. For a patient who was on an SSRI, the change can be to another SSRI or to an SNRI. However, if two SSRIs have already failed, then choose an SNRI. Agents are commonly cross-tapered during the switch to avoid abrupt cessation of one drug or the increased risk of adverse events such as cytochrome P450 interactions, serotonin syndrome, or hypertensive crisis (when switching to an MAO inhibitor).

Beware of interactions. All SSRIs and SNRIs are metabolized through the P450 system in the liver and therefore have the potential for drug-drug interactions. Care must be taken when giving these agents together with drugs whose metabolism can be altered by P450 inhibition. For TCAs, blood levels can be checked if there is concern about toxicity; however, dosing is not strictly based on this level. Great care should be taken if a TCA is given together with an SNRI or an SSRI, as the TCA blood level can become significantly elevated. This may result in QT interval prolongation, as mentioned earlier.

Refer. Referral to a psychiatrist is appropriate for patients for whom multiple classes have failed, for patients who have another psychiatric comorbidity (such as psychosis, hypomania, or mania), or for patients who may need hospitalization. Referral is also appropriate if the physician is concerned about suicide risk.

PATIENTS WITH MAJOR DEPRESSION ONLY

For a patient presenting with depression but no other significant medical comorbidity, the first-line therapy is often an SSRI. Several generic SSRIs are available, and some are on the discount lists at retail pharmacies.

Symptoms should start to improve in about 2 weeks, and the optimal response should be achieved in 4 to 6 weeks of treatment. If this does not occur, consider either adding an augmenting agent or switching to a different antidepressant.

PATIENTS WITH CHRONIC PAIN

Chronic pain and depression often go hand in hand and can potentiate each other. When considering an antidepressant in a patient who has both conditions, the SNRIs and TCAs are typically preferred. Some SNRIs, namely duloxetine and milnacipran, are approved for certain chronic pain conditions, such as fibromyalgia. SNRIs are frequently used off-label for other chronic pain conditions such as headache and neuropathic pain.²

TCAs such as amitriptyline, nortriptyline, and doxepin are also often used in patients with chronic pain. These agents, like the SNRIs, inhibit the reuptake of serotonin and norepinephrine and are used off-label for neuropathic pain,^3,4 migraine, interstitial cystitis,⁵ and other pain conditions.^6–9

For TCAs and SNRIs, the effective dose range for chronic pain overlaps that for depression. However, TCAs are often given at lower doses to patients without depression. We recommend starting at a low dose and slowly titrating upward to an effective dose. SNRIs are often preferred over TCAs because they do not have anticholinergic side effects and because an overdose is much less likely to be lethal.

PATIENTS WITH SEXUAL DYSFUNCTION

One of the more commonly reported side effects of antidepressants is sexual dysfunction, generally in the form of delayed orgasm or decreased libido.¹⁰ Typically, these complaints are attributed to SSRIs and SNRIs; however, TCAs and MAO inhibitors have also been associated wth sexual dysfunction.

Both erectile dysfunction and priapism have been linked to certain antidepressants. In particular, trazodone is a known cause of priapism. Even if using low doses for sleep, male patients should be made aware of this adverse effect.

Switching from one agent to another in the same class is not likely to improve sexual side effects. In particular, all the SSRIs are similar in their likelihood of causing sexual dysfunction. In a patient taking an SSRI who experiences this side effect, switching to bupropion¹¹ or mirtazapine¹² can be quite useful. Bupropion acts primarily on dopamine and norepinephrine, whereas mirtazapine acts on serotonin and norepinephrine but in a different manner from SSRIs and SNRIs.

Adjunctive treatment such as a cholinergic agonist, yohimbine (contraindicated with MAO inhibitors), a serotonergic agent (eg, buspirone), or a drug that acts on nitric oxide (eg, sildenafil, tadalafil) may have some utility but is often ineffective. Dose reduction, if possible, can be of value.

PATIENTS WITH ANXIETY

Many antidepressants are also approved for anxiety disorders, and still more are used off-label for this purpose. Anxiety and depression often occur together, so being able to treat both conditions with one drug can be quite useful.¹³ In general, the antidepressant effects are seen at lower doses of SSRIs and SNRIs, whereas more of the anxiolytic effects are seen at higher doses, particularly for obsessive-compulsive disorder.¹⁴

First-line treatment would be an SSRI or SNRI. Most anxiety disorders respond to either class, but there are some more-specific recommendations. SSRIs are best studied in panic disorder, generalized anxiety disorder, social anxiety disorder, posttraumatic stress disorder, and obsessive-compulsive disorder. Fluoxetine, citalopram, escitalopram, and sertraline¹⁵ can all be effective in both major depressive disorder and generalized anxiety disorder. Panic disorder also tends to respond well to SSRIs. SNRIs have been evaluated primarily in generalized anxiety disorder but may also be useful in many of the other conditions.

Additionally, mirtazapine (used off-label)¹² and the TCAs^16–18 can help treat anxiety. Clomipramine is used to treat obsessive-compulsive disorder.¹⁹ These drugs are especially useful for nighttime anxiety, as they can aid sleep. Of note, the anxiolytic effect of mirtazapine may be greater at higher doses.

MAO inhibitors often go unused because of the dietary and medication restrictions involved. However, very refractory cases of certain anxiety disorders may respond preferentially to these agents.

Bupropion tends to be more activating than other antidepressants, so is often avoided in anxious patients. However, some research suggests this is not always necessary.²⁰ If the anxiety is secondary to depression, it will often improve significantly with this agent.

When starting or increasing the dose of an antidepressant, patients may experience increased anxiety or feel “jittery.” This feeling usually passes within the first week of treatment, and it is important to inform patients about this effect. “Start low and go slow” in patients with significant comorbid anxiety. Temporarily using a benzodiazepine such as clonazepam may make the transition more tolerable.

PATIENTS WITH CHRONIC FATIGUE SYNDROME OR FIBROMYALGIA

Increasing recognition of both chronic fatigue syndrome and fibromyalgia has led to more proactive treatment for these disorders. Depression can go hand in hand with these disorders, and certain antidepressants, namely the SNRIs, can be useful in this population.

More data exist for the treatment of fibromyalgia. Both duloxetine and milnacipran are approved by the US Food and Drug Administration (FDA) for the treatment of fibromyalgia.²¹ Venlafaxine is also used off-label for this purpose. SSRIs such as fluoxetine and citalopram have had mixed results.^21–23 TCAs have been used with some success; however, their side effects and lethal potential are often limiting.^21,24,25 A recent study in Spain also suggested there may be benefit from using MAO inhibitors for fibromyalgia, but data are quite limited.²⁶

The data for treating chronic fatigue syndrome with SSRIs, SNRIs, or MAO inhibitors are conflicting.^27–29 However, managing the co-existing depression may provide some relief in and of itself.

PATIENTS WITH FREQUENT INSOMNIA

Insomnia can be a symptom of depression, but it can also be a side effect of certain antidepressants. The SSRIs and SNRIs can disrupt sleep patterns in some patients by shortening the rapid-eye-movement (REM) stage.^30,31

In patients with severe insomnia, it may be best to first recommend taking the antidepressant in the morning if they notice worsening sleep after initiating treatment. Patients can be told with any antidepressant, “If it makes you tired, take it at night, and if it wakes you up, take it in the morning.” Of note, a recent South African study suggested that escitalopram may be able to improve sleep.³²

If that does not solve the problem, there are other options. For instance, mirtazapine, particularly in doses of 15 mg or 30 mg, aids depression and insomnia. At higher doses (45 mg), the sleep-aiding effect may be reduced. Low doses of TCAs, particularly doxepin, maprotiline (technically speaking, a tetracyclic antidepressant), amitriptyline, and nortriptyline can be effective sleep aids. These agents may be used as an adjunct to another antidepressant to enhance sleep and mood. However, the TCAs also shorten the REM stage of sleep.³³

The previously mentioned drug interactions with SSRIs and SNRIs also need to be considered. Caution should be used when discontinuing these medications, as patients may experience rebound symptoms in the form of much more vivid dreams. MAO inhibitors may worsen insomnia because they suppress REM sleep.³⁴

Trazodone is another agent that at lower doses (25–150 mg) can be an effective, nonaddicting sleep aid. When used as an antidepressant, it is generally prescribed at higher doses (300–400 mg), but its sedating effects can be quite limiting at these levels. It is important to remember the possibility of priapism in male patients.

GERIATRIC PATIENTS

Old age brings its own set of concerns when treating depression. Elderly patients are more susceptible to potential bradycardia caused by SSRIs. The TCAs have the more worrisome cardiac side effect of QTc prolongation. TCAs can slow cognitive function, whereas the SSRIs, bupropion, and the SNRIs tend not to affect cognition. Escitalopram and duloxetine have been suggested to be particularly effective in the elderly.^35,36 A study from the Netherlands linked SSRIs with increased risk of falling in geriatric patients with dementia.³⁷ Constipation, which could lead to ileus, is increased with TCAs and certain other agents (ie, paroxetine) in the geriatric population.

Mirtazapine is often very useful in elderly patients for many reasons: it treats both anxiety and depression, stimulates appetite and weight gain, can help with nausea, and is an effective sleep aid. Concerns about weight, appetite, and sleep are particularly common in the elderly, whereas younger patients can be less tolerant of drugs that make them gain weight and sleep more. Normal age-related changes to the sleep cycle contribute to decreased satisfaction with sleep as we age. In addition, depression often further impairs sleep. So, in the elderly, optimizing sleep is key. Research has also shown mirtazapine to be effective in patients with both Alzheimer dementia and depression.³⁸

DIABETIC PATIENTS

One of the more worrisome side effects of psychiatric medications in diabetic patients is weight gain. Certain antidepressants have a greater propensity for weight gain and should likely be avoided as first-line treatments in this population.¹² Typically, these agents include those that have more antihistamine action such as paroxetine and the TCAs. These agents also may lead to constipation, which could potentially worsen gastroparesis. Mirtazapine and the MAO inhibitors are also known to cause weight gain.

Bupropion and nefazodone are the most weight-neutral of all antidepressants. Nefazodone has fallen out of favor because of its potential to cause fulminant liver failure in rare cases. However, it remains a reasonable option for patients with comorbid anxiety and depression who have significant weight gain with other agents.

SSRIs and MAO inhibitors may improve or be neutral toward glucose metabolism, and some data suggest that SNRIs may impair this process.³⁹

PATIENTS WITH CARDIAC CONDITIONS

Major depression often coexists with cardiac conditions. In particular, many patients develop depression after suffering a myocardial infarction, and increasingly they are being treated for it.⁴⁰ Treatment in this situation is appropriate, since depression, if untreated, can increase the risk of recurrence of myocardial infarction.⁴¹

However, there are many concerns that accompany treating depression in cardiac patients. Therefore, a baseline electrocardiogram should be obtained before starting an antidepressant.

TCAs and tetracyclic agents have a tendency to prolong the QTc interval and potentiate ventricular arrhythmias,⁴² so it may be prudent to avoid these in patients at risk. These agents can also significantly increase the pulse rate. This tachycardia increases the risk of angina or myocardial infarction from the anticholinergic effects of these drugs.

In February 2013, the FDA issued a warning about possible arrhythmias with citalopram at doses greater than 40 mg in adult patients⁴³; however, research has suggested citalopram is effective in treating depression in cardiac patients.⁴⁴ Research has not shown an increase in efficacy at doses greater than 40 mg daily, so we recommend following the black-box warning.

TCAs and MAO inhibitors can also cause orthostatic hypotension. On the other hand, consuming large amounts of tyramine, in foods such as aged cheese, can precipitate a hypertensive crisis in patients taking MAO inhibitors.

Which antidepressants tend to be safer in cardiac patients? Sertraline has been shown to be safe in congestive heart failure and coronary artery disease,^45–47 but the SSRIs are typically safe. Fluoxetine has shown efficacy in patients who have had a myocardial infarction.⁴⁸ Mirtazapine has also been shown to be efficacious in cardiac patients.⁴⁹ Nefazodone, mirtazapine, bupropion, SSRIs, and SNRIs have little or no tendency toward orthostatic hypotension.

An 82-year-old woman was admitted to the hospital with dyspnea and chest discomfort over the past 24 hours. She was known to have paroxysmal atrial fibrillation and was taking warfarin, but that had been stopped 2 weeks earlier because of an acute ischemic stroke.

At the time of admission, she had no fever, cough, orthopnea, or leg swelling. Her physical activity was restricted, with residual right-sided weakness after her stroke. Her heart rate was 125 bpm; her oxygen saturation level was 98% on 2 L of oxygen per minute via nasal cannula. She had an irregularly irregular rhythm, a jugular venous pressure of 7 cm H₂O, and no cardiac murmurs. Lung sounds were reduced at the bases, with faint crepitations.

Her hemoglobin concentration and white blood cell count were normal. Her brain-natriuretic peptide level was elevated at 2,648 pg/mL (reference range < 167), but cardiac enzyme levels were normal.

Electrocardiography showed atrial fibrillation with rapid ventricular response.

Plain chest radiography showed a 3-cm wedge-shaped opacity in the right mid-thorax (Figure 1), a finding known as the Hampton hump—a sign of pulmonary infarction caused by embolism.

Contrast-enhanced computed tomography (CT) of the chest showed acute thromboembolism in the right interlobar artery and wedge-shaped consolidation in the right-middle lobe (Figure 2), indicating pulmonary infarction.

Brain CT showed a stable infarction. Anticoagulation was restarted, and the patient was discharged in stable condition.

THE HAMPTON HUMP IN PULMONARY EMBOLISM

Because the lungs have a dual blood supply, pulmonary infarction is seen in only a minority of cases of pulmonary embolism. Infarction is more common in patients with peripheral pulmonary embolism, owing to the rapid inflow of bronchial blood, and in patients with medical comorbidities such as heart failure and chronic lung disease.²

The Hampton hump, first described by Aubrey Otis Hampton in 1940, is a peripheral (pleural-based) opacity that represents alveolar hemorrhage from underlying pulmonary infarction. It is one of several radiographic features that have been associated with pulmonary embolism; another is the Westermark sign, indicating oligemia.³

Worsley et al⁴ examined the diagnostic value of these radiographic features and found that the Hampton hump had a sensitivity of 22% and a specificity of 82% for detecting pulmonary embolism in the right hemithorax, and 24% and 82%, respectively, in the left hemithorax. The prevalence of pleural-based opacities was not significantly different in patients with or without pulmonary embolism. The authors concluded that chest radiography has limited diagnostic value in excluding or diagnosing pulmonary embolism.

In contrast, computed tomographic pulmonary angiography is the first-line imaging test in patients with suspected pulmonary embolism, because of its high sensitivity and specificity.¹

We were not specifically looking for a pulmonary embolism when we found this new opacity on our patient’s radiograph, but this prompted further imaging, which led to the diagnosis. Although a near-normal chest radiograph is the most common radiologic finding in pulmonary embolism, this case shows how careful observation can detect unusual signs.

An 82-year-old woman was admitted to the hospital with dyspnea and chest discomfort over the past 24 hours. She was known to have paroxysmal atrial fibrillation and was taking warfarin, but that had been stopped 2 weeks earlier because of an acute ischemic stroke.

At the time of admission, she had no fever, cough, orthopnea, or leg swelling. Her physical activity was restricted, with residual right-sided weakness after her stroke. Her heart rate was 125 bpm; her oxygen saturation level was 98% on 2 L of oxygen per minute via nasal cannula. She had an irregularly irregular rhythm, a jugular venous pressure of 7 cm H₂O, and no cardiac murmurs. Lung sounds were reduced at the bases, with faint crepitations.

Her hemoglobin concentration and white blood cell count were normal. Her brain-natriuretic peptide level was elevated at 2,648 pg/mL (reference range < 167), but cardiac enzyme levels were normal.

Electrocardiography showed atrial fibrillation with rapid ventricular response.

Plain chest radiography showed a 3-cm wedge-shaped opacity in the right mid-thorax (Figure 1), a finding known as the Hampton hump—a sign of pulmonary infarction caused by embolism.

Contrast-enhanced computed tomography (CT) of the chest showed acute thromboembolism in the right interlobar artery and wedge-shaped consolidation in the right-middle lobe (Figure 2), indicating pulmonary infarction.

Brain CT showed a stable infarction. Anticoagulation was restarted, and the patient was discharged in stable condition.

THE HAMPTON HUMP IN PULMONARY EMBOLISM

Because the lungs have a dual blood supply, pulmonary infarction is seen in only a minority of cases of pulmonary embolism. Infarction is more common in patients with peripheral pulmonary embolism, owing to the rapid inflow of bronchial blood, and in patients with medical comorbidities such as heart failure and chronic lung disease.²

The Hampton hump, first described by Aubrey Otis Hampton in 1940, is a peripheral (pleural-based) opacity that represents alveolar hemorrhage from underlying pulmonary infarction. It is one of several radiographic features that have been associated with pulmonary embolism; another is the Westermark sign, indicating oligemia.³

Worsley et al⁴ examined the diagnostic value of these radiographic features and found that the Hampton hump had a sensitivity of 22% and a specificity of 82% for detecting pulmonary embolism in the right hemithorax, and 24% and 82%, respectively, in the left hemithorax. The prevalence of pleural-based opacities was not significantly different in patients with or without pulmonary embolism. The authors concluded that chest radiography has limited diagnostic value in excluding or diagnosing pulmonary embolism.

In contrast, computed tomographic pulmonary angiography is the first-line imaging test in patients with suspected pulmonary embolism, because of its high sensitivity and specificity.¹

We were not specifically looking for a pulmonary embolism when we found this new opacity on our patient’s radiograph, but this prompted further imaging, which led to the diagnosis. Although a near-normal chest radiograph is the most common radiologic finding in pulmonary embolism, this case shows how careful observation can detect unusual signs.

An 82-year-old woman was admitted to the hospital with dyspnea and chest discomfort over the past 24 hours. She was known to have paroxysmal atrial fibrillation and was taking warfarin, but that had been stopped 2 weeks earlier because of an acute ischemic stroke.

At the time of admission, she had no fever, cough, orthopnea, or leg swelling. Her physical activity was restricted, with residual right-sided weakness after her stroke. Her heart rate was 125 bpm; her oxygen saturation level was 98% on 2 L of oxygen per minute via nasal cannula. She had an irregularly irregular rhythm, a jugular venous pressure of 7 cm H₂O, and no cardiac murmurs. Lung sounds were reduced at the bases, with faint crepitations.

Her hemoglobin concentration and white blood cell count were normal. Her brain-natriuretic peptide level was elevated at 2,648 pg/mL (reference range < 167), but cardiac enzyme levels were normal.

Electrocardiography showed atrial fibrillation with rapid ventricular response.

Plain chest radiography showed a 3-cm wedge-shaped opacity in the right mid-thorax (Figure 1), a finding known as the Hampton hump—a sign of pulmonary infarction caused by embolism.

Contrast-enhanced computed tomography (CT) of the chest showed acute thromboembolism in the right interlobar artery and wedge-shaped consolidation in the right-middle lobe (Figure 2), indicating pulmonary infarction.

Brain CT showed a stable infarction. Anticoagulation was restarted, and the patient was discharged in stable condition.

THE HAMPTON HUMP IN PULMONARY EMBOLISM

Because the lungs have a dual blood supply, pulmonary infarction is seen in only a minority of cases of pulmonary embolism. Infarction is more common in patients with peripheral pulmonary embolism, owing to the rapid inflow of bronchial blood, and in patients with medical comorbidities such as heart failure and chronic lung disease.²

The Hampton hump, first described by Aubrey Otis Hampton in 1940, is a peripheral (pleural-based) opacity that represents alveolar hemorrhage from underlying pulmonary infarction. It is one of several radiographic features that have been associated with pulmonary embolism; another is the Westermark sign, indicating oligemia.³

Worsley et al⁴ examined the diagnostic value of these radiographic features and found that the Hampton hump had a sensitivity of 22% and a specificity of 82% for detecting pulmonary embolism in the right hemithorax, and 24% and 82%, respectively, in the left hemithorax. The prevalence of pleural-based opacities was not significantly different in patients with or without pulmonary embolism. The authors concluded that chest radiography has limited diagnostic value in excluding or diagnosing pulmonary embolism.

In contrast, computed tomographic pulmonary angiography is the first-line imaging test in patients with suspected pulmonary embolism, because of its high sensitivity and specificity.¹

We were not specifically looking for a pulmonary embolism when we found this new opacity on our patient’s radiograph, but this prompted further imaging, which led to the diagnosis. Although a near-normal chest radiograph is the most common radiologic finding in pulmonary embolism, this case shows how careful observation can detect unusual signs.

Pneumonia was once considered the “old man’s friend,” but in the modern world, has it become the physician’s?

See related editorial

The definition of pneumonia has increasingly been stretched, and physicians occasionally make the diagnosis without canonical signs or symptoms, or even with negative chest radiography. The hallmark of overdiagnosis is identifying illness for which treatment is not needed or is not helpful, and some cases of pneumonia likely fit this description. Empirical evidence over the last 3 decades shows a sustained increase in the diagnosis of pneumonia, but little evidence of a decrease in the rates of pneumonia morbidity and mortality. The central problem with pneumonia is one common to many diagnoses, such as pulmonary embolism, coronary artery disease, and infectious conditions—diagnostic criteria remain divorced from outcomes data. Linking the two has the potential to improve the evidence base of medicine.

Like many long-recognized diagnoses, pneumonia lacks a standardized definition. Most physicians believe that although fever, cough, sputum production, dyspnea, and pleurisy are hallmark symptoms, confirmatory chest radiography is needed to cement the diagnosis.¹ But what if a patient has only a fever, cough, and infiltrate? What if the infiltrate is not visible on radiography, but only on computed tomography (CT)? And what if the patient has a cough but is afebrile and has nonspecific findings on CT?

THE RATE OF HOSPITAL ADMISSIONS FOR PNEUMONIA IS RISING

In current clinical practice, any or all of the above cases are called pneumonia. The pneumonia label, once applied, justifies the use of antibiotics, which patients or physicians may overtly desire. One prospective observational study of six hospitals found that 21% of patients admitted with pneumonia and 43% of those treated as outpatients had negative chest radiographs.² Empirical evidence suggests that the incidence of these “soft” diagnoses may be growing in number.

In the United States, hospitalizations with discharge codes listing pneumonia increased 20% from the late 1980s to the early 2000s.³ The rates of hospitalization for the 10 other most frequent causes of admission did not change significantly over this same period, suggesting a selective increase in hospital admissions for pneumonia.

This focus on pneumonia would be justified if it led to a proportionate benefit for pneumonia outcomes. However, in the same data set, the risk of death from pneumonia did not improve more than that from the other 10 common conditions—all improved similarly—and the rate of discharge from the hospital to a long-term care facility was unchanged. We are hospitalizing more patients with pneumonia, but this has not improved outcomes beyond global trends in mortality.

Data from England suggest that overdiagnosis may be a worldwide phenomenon. Between 1997 and 2005, hospitalization rates in England for pneumonia, adjusted for age, increased 34% from 1.48 to 1.98 per 1,000 persons.⁴ The 30-day in-hospital death rate for pneumonia remained about the same over this period. In the absence of a paradigm-shifting technology, one that would alter hospitalization practices, or an environmental cause of increased incidence—and with pneumonia there has been neither—the most likely explanation for these documented trends is that hospitals are admitting patients with pneumonia that is less severe.

Finally, data from the 2000s that at first seemed to reverse the trend of increasing hospitalizations for pneumonia have been reanalyzed to account for alternative coding.⁵ For instance, a pneumonia admission may be coded with respiratory failure as the primary diagnosis and pneumonia as the secondary diagnosis. Examining data from large populations from 2002 to 2009, and correcting as such, shows that the incidence of pneumonia has reached a plateau or has declined only slightly from the elevated rates of the early 2000s. The death rate remains unchanged.

PNEUMONIA: A DIAGNOSIS IN THE EYE OF THE BEHOLDER

Apparently, when it comes to pneumonia, the diagnosis is in the eye of the beholder. Different physicians have different thresholds for applying the label. In the wake of quality efforts to ensure that emergency physicians deliver antibiotics within 4 hours, emergency doctors have been shown to have worse accuracy in diagnosing pneumonia.¹ But worse accuracy compared with what standard?

In an investigation by Welker et al,¹ the standard definition of pneumonia was based on the one favored by the US Food and Drug Administration for clinical trials. Patients had to have all of the following:

• A new or increasing infiltrate on radiography or CT
• A fever, an elevated white blood cell count, or a shift to immature polymorphonuclear leukocytes
• At least two signs or symptoms of the condition (eg, cough, dyspnea, egophany).

Although this definition is reasonable and ensures homogeneity in clinical trials, it is not steadfastly adhered to in clinical practice and has never been shown to cleanly delineate a population that benefits from antibiotics.

Another challenge to devising a perfect definition of pneumonia is the lack of a pathologic gold standard. Based on a review of 17,340 Medicare patients hospitalized for community-acquired pneumonia, microbial confirmation is often of little assistance, and a probable pathogen is identified in only 7.6% of cases.⁶

RATES OF OUTPATIENT DIAGNOSIS ARE LIKELY SIMILAR

Thus far, we have examined trends in inpatient diagnosis but not those of outpatient diagnosis. There is no well-done observational study that documents outpatient trends, but there is little reason to suppose the trends are different. Risk-scoring systems in pneumonia, such as the PORT⁷ and the CURB-65,⁸ have been designed to decrease unnecessary inpatient admissions, but they do not lend clarity to the diagnosis itself.

The central problem with pneumonia, as with many long-recognized clinical conditions, is that the diagnosis is separated from the treatment. In other words, although physicians are confident that antibiotics benefit patients who have what Sir William Osler would have called pneumonia (elevated white blood cell count, fever, cough, dyspnea, pleurisy, egophany, lobular infiltrate), we don’t know whether the treatment benefits patients whose pneumonia would have been unrecognizable decades ago (with cough, low-grade fever, and infiltrate on CT alone). Improvements in imaging may exacerbate the problem. In this sense, pneumonia exists on a spectrum, as do many medical diagnoses. Not all cases are equally severe, and some may not deserve to be labeled as pneumonia.

No randomized trial has compared antibiotics against supportive care in pneumonia, and, likely, no such trial is needed for clear cases. However, with the growing number of soft diagnoses, randomized trials are desperately needed to delineate where harms outweigh benefits, and where the fuzzy edge of the pneumonia diagnosis must end. And as is always the case with studies that challenge a standard of care, null results should prompt further trials.

WELL-DESIGNED TRIALS COULD END THE UNCERTAINTY

In the next few years, clinical trials, rationally planned, may end most of the uncertainty regarding pneumonia.

Existing observational data may be used to identify groups of patients who, in today’s world, are diagnosed with pneumonia but who do exceptionally well (eg, younger patients with fewer comorbidities, who present with low-grade fever but no signs of consolidation on physical examination, and with dubious results on chest radiography). These are patients for whom equipoise exists, and randomized trials should compare a strategy of antibiotics with a strategy of best supportive care. Trials should be powered for patient-centered outcomes, such as the duration and the complications of illness. The death rate should be scrupulously recorded.

Patients whose pneumonia would have been unrecognizable decades ago should be another target population for the trials I propose.

In a short time, pneumonia may become synonymous with a set of factors for lung infection that predict who will benefit from antibiotics, and who can be safely followed. Already, we are moving toward this standard in other diseases.⁹ For pulmonary embolism, ongoing trials are testing if anticoagulation can be safely omitted in patients with subsegmental clots (clinicaltrials.gov identifier NCT01455818). Such trials are, at last, translating old diagnoses into the language of evidence-based medicine.

For patients with pneumonia who are not hospitalized, the current outpatient therapy is based on data from studies that show a low rate of failure with empiric treatment based on consideration of the common pathogens for this condition, with few patients subsequently requiring hospitalization. Today, this reasoning is inadequate. The basis for any therapy must be proven benefit for patients with a defined condition compared with a lesser strategy. Data already demonstrate that a short course of antibiotics is no worse than a long course for many hospitalized and outpatients with pneumonia,^10,11 but many other patients may require no treatment at all. The time has come to find out.

Pneumonia was once considered the “old man’s friend,” but in the modern world, has it become the physician’s?

See related editorial

The definition of pneumonia has increasingly been stretched, and physicians occasionally make the diagnosis without canonical signs or symptoms, or even with negative chest radiography. The hallmark of overdiagnosis is identifying illness for which treatment is not needed or is not helpful, and some cases of pneumonia likely fit this description. Empirical evidence over the last 3 decades shows a sustained increase in the diagnosis of pneumonia, but little evidence of a decrease in the rates of pneumonia morbidity and mortality. The central problem with pneumonia is one common to many diagnoses, such as pulmonary embolism, coronary artery disease, and infectious conditions—diagnostic criteria remain divorced from outcomes data. Linking the two has the potential to improve the evidence base of medicine.

Like many long-recognized diagnoses, pneumonia lacks a standardized definition. Most physicians believe that although fever, cough, sputum production, dyspnea, and pleurisy are hallmark symptoms, confirmatory chest radiography is needed to cement the diagnosis.¹ But what if a patient has only a fever, cough, and infiltrate? What if the infiltrate is not visible on radiography, but only on computed tomography (CT)? And what if the patient has a cough but is afebrile and has nonspecific findings on CT?

THE RATE OF HOSPITAL ADMISSIONS FOR PNEUMONIA IS RISING

In current clinical practice, any or all of the above cases are called pneumonia. The pneumonia label, once applied, justifies the use of antibiotics, which patients or physicians may overtly desire. One prospective observational study of six hospitals found that 21% of patients admitted with pneumonia and 43% of those treated as outpatients had negative chest radiographs.² Empirical evidence suggests that the incidence of these “soft” diagnoses may be growing in number.

In the United States, hospitalizations with discharge codes listing pneumonia increased 20% from the late 1980s to the early 2000s.³ The rates of hospitalization for the 10 other most frequent causes of admission did not change significantly over this same period, suggesting a selective increase in hospital admissions for pneumonia.

This focus on pneumonia would be justified if it led to a proportionate benefit for pneumonia outcomes. However, in the same data set, the risk of death from pneumonia did not improve more than that from the other 10 common conditions—all improved similarly—and the rate of discharge from the hospital to a long-term care facility was unchanged. We are hospitalizing more patients with pneumonia, but this has not improved outcomes beyond global trends in mortality.

Data from England suggest that overdiagnosis may be a worldwide phenomenon. Between 1997 and 2005, hospitalization rates in England for pneumonia, adjusted for age, increased 34% from 1.48 to 1.98 per 1,000 persons.⁴ The 30-day in-hospital death rate for pneumonia remained about the same over this period. In the absence of a paradigm-shifting technology, one that would alter hospitalization practices, or an environmental cause of increased incidence—and with pneumonia there has been neither—the most likely explanation for these documented trends is that hospitals are admitting patients with pneumonia that is less severe.

Finally, data from the 2000s that at first seemed to reverse the trend of increasing hospitalizations for pneumonia have been reanalyzed to account for alternative coding.⁵ For instance, a pneumonia admission may be coded with respiratory failure as the primary diagnosis and pneumonia as the secondary diagnosis. Examining data from large populations from 2002 to 2009, and correcting as such, shows that the incidence of pneumonia has reached a plateau or has declined only slightly from the elevated rates of the early 2000s. The death rate remains unchanged.

PNEUMONIA: A DIAGNOSIS IN THE EYE OF THE BEHOLDER

Apparently, when it comes to pneumonia, the diagnosis is in the eye of the beholder. Different physicians have different thresholds for applying the label. In the wake of quality efforts to ensure that emergency physicians deliver antibiotics within 4 hours, emergency doctors have been shown to have worse accuracy in diagnosing pneumonia.¹ But worse accuracy compared with what standard?

In an investigation by Welker et al,¹ the standard definition of pneumonia was based on the one favored by the US Food and Drug Administration for clinical trials. Patients had to have all of the following:

• A new or increasing infiltrate on radiography or CT
• A fever, an elevated white blood cell count, or a shift to immature polymorphonuclear leukocytes
• At least two signs or symptoms of the condition (eg, cough, dyspnea, egophany).

Although this definition is reasonable and ensures homogeneity in clinical trials, it is not steadfastly adhered to in clinical practice and has never been shown to cleanly delineate a population that benefits from antibiotics.

Another challenge to devising a perfect definition of pneumonia is the lack of a pathologic gold standard. Based on a review of 17,340 Medicare patients hospitalized for community-acquired pneumonia, microbial confirmation is often of little assistance, and a probable pathogen is identified in only 7.6% of cases.⁶

RATES OF OUTPATIENT DIAGNOSIS ARE LIKELY SIMILAR

Thus far, we have examined trends in inpatient diagnosis but not those of outpatient diagnosis. There is no well-done observational study that documents outpatient trends, but there is little reason to suppose the trends are different. Risk-scoring systems in pneumonia, such as the PORT⁷ and the CURB-65,⁸ have been designed to decrease unnecessary inpatient admissions, but they do not lend clarity to the diagnosis itself.

The central problem with pneumonia, as with many long-recognized clinical conditions, is that the diagnosis is separated from the treatment. In other words, although physicians are confident that antibiotics benefit patients who have what Sir William Osler would have called pneumonia (elevated white blood cell count, fever, cough, dyspnea, pleurisy, egophany, lobular infiltrate), we don’t know whether the treatment benefits patients whose pneumonia would have been unrecognizable decades ago (with cough, low-grade fever, and infiltrate on CT alone). Improvements in imaging may exacerbate the problem. In this sense, pneumonia exists on a spectrum, as do many medical diagnoses. Not all cases are equally severe, and some may not deserve to be labeled as pneumonia.

No randomized trial has compared antibiotics against supportive care in pneumonia, and, likely, no such trial is needed for clear cases. However, with the growing number of soft diagnoses, randomized trials are desperately needed to delineate where harms outweigh benefits, and where the fuzzy edge of the pneumonia diagnosis must end. And as is always the case with studies that challenge a standard of care, null results should prompt further trials.

WELL-DESIGNED TRIALS COULD END THE UNCERTAINTY

In the next few years, clinical trials, rationally planned, may end most of the uncertainty regarding pneumonia.

Existing observational data may be used to identify groups of patients who, in today’s world, are diagnosed with pneumonia but who do exceptionally well (eg, younger patients with fewer comorbidities, who present with low-grade fever but no signs of consolidation on physical examination, and with dubious results on chest radiography). These are patients for whom equipoise exists, and randomized trials should compare a strategy of antibiotics with a strategy of best supportive care. Trials should be powered for patient-centered outcomes, such as the duration and the complications of illness. The death rate should be scrupulously recorded.

Patients whose pneumonia would have been unrecognizable decades ago should be another target population for the trials I propose.

In a short time, pneumonia may become synonymous with a set of factors for lung infection that predict who will benefit from antibiotics, and who can be safely followed. Already, we are moving toward this standard in other diseases.⁹ For pulmonary embolism, ongoing trials are testing if anticoagulation can be safely omitted in patients with subsegmental clots (clinicaltrials.gov identifier NCT01455818). Such trials are, at last, translating old diagnoses into the language of evidence-based medicine.

For patients with pneumonia who are not hospitalized, the current outpatient therapy is based on data from studies that show a low rate of failure with empiric treatment based on consideration of the common pathogens for this condition, with few patients subsequently requiring hospitalization. Today, this reasoning is inadequate. The basis for any therapy must be proven benefit for patients with a defined condition compared with a lesser strategy. Data already demonstrate that a short course of antibiotics is no worse than a long course for many hospitalized and outpatients with pneumonia,^10,11 but many other patients may require no treatment at all. The time has come to find out.

Pneumonia was once considered the “old man’s friend,” but in the modern world, has it become the physician’s?

See related editorial

The definition of pneumonia has increasingly been stretched, and physicians occasionally make the diagnosis without canonical signs or symptoms, or even with negative chest radiography. The hallmark of overdiagnosis is identifying illness for which treatment is not needed or is not helpful, and some cases of pneumonia likely fit this description. Empirical evidence over the last 3 decades shows a sustained increase in the diagnosis of pneumonia, but little evidence of a decrease in the rates of pneumonia morbidity and mortality. The central problem with pneumonia is one common to many diagnoses, such as pulmonary embolism, coronary artery disease, and infectious conditions—diagnostic criteria remain divorced from outcomes data. Linking the two has the potential to improve the evidence base of medicine.

Like many long-recognized diagnoses, pneumonia lacks a standardized definition. Most physicians believe that although fever, cough, sputum production, dyspnea, and pleurisy are hallmark symptoms, confirmatory chest radiography is needed to cement the diagnosis.¹ But what if a patient has only a fever, cough, and infiltrate? What if the infiltrate is not visible on radiography, but only on computed tomography (CT)? And what if the patient has a cough but is afebrile and has nonspecific findings on CT?

THE RATE OF HOSPITAL ADMISSIONS FOR PNEUMONIA IS RISING

In current clinical practice, any or all of the above cases are called pneumonia. The pneumonia label, once applied, justifies the use of antibiotics, which patients or physicians may overtly desire. One prospective observational study of six hospitals found that 21% of patients admitted with pneumonia and 43% of those treated as outpatients had negative chest radiographs.² Empirical evidence suggests that the incidence of these “soft” diagnoses may be growing in number.

In the United States, hospitalizations with discharge codes listing pneumonia increased 20% from the late 1980s to the early 2000s.³ The rates of hospitalization for the 10 other most frequent causes of admission did not change significantly over this same period, suggesting a selective increase in hospital admissions for pneumonia.

This focus on pneumonia would be justified if it led to a proportionate benefit for pneumonia outcomes. However, in the same data set, the risk of death from pneumonia did not improve more than that from the other 10 common conditions—all improved similarly—and the rate of discharge from the hospital to a long-term care facility was unchanged. We are hospitalizing more patients with pneumonia, but this has not improved outcomes beyond global trends in mortality.

Data from England suggest that overdiagnosis may be a worldwide phenomenon. Between 1997 and 2005, hospitalization rates in England for pneumonia, adjusted for age, increased 34% from 1.48 to 1.98 per 1,000 persons.⁴ The 30-day in-hospital death rate for pneumonia remained about the same over this period. In the absence of a paradigm-shifting technology, one that would alter hospitalization practices, or an environmental cause of increased incidence—and with pneumonia there has been neither—the most likely explanation for these documented trends is that hospitals are admitting patients with pneumonia that is less severe.

Finally, data from the 2000s that at first seemed to reverse the trend of increasing hospitalizations for pneumonia have been reanalyzed to account for alternative coding.⁵ For instance, a pneumonia admission may be coded with respiratory failure as the primary diagnosis and pneumonia as the secondary diagnosis. Examining data from large populations from 2002 to 2009, and correcting as such, shows that the incidence of pneumonia has reached a plateau or has declined only slightly from the elevated rates of the early 2000s. The death rate remains unchanged.

PNEUMONIA: A DIAGNOSIS IN THE EYE OF THE BEHOLDER

Apparently, when it comes to pneumonia, the diagnosis is in the eye of the beholder. Different physicians have different thresholds for applying the label. In the wake of quality efforts to ensure that emergency physicians deliver antibiotics within 4 hours, emergency doctors have been shown to have worse accuracy in diagnosing pneumonia.¹ But worse accuracy compared with what standard?

In an investigation by Welker et al,¹ the standard definition of pneumonia was based on the one favored by the US Food and Drug Administration for clinical trials. Patients had to have all of the following:

• A new or increasing infiltrate on radiography or CT
• A fever, an elevated white blood cell count, or a shift to immature polymorphonuclear leukocytes
• At least two signs or symptoms of the condition (eg, cough, dyspnea, egophany).

Although this definition is reasonable and ensures homogeneity in clinical trials, it is not steadfastly adhered to in clinical practice and has never been shown to cleanly delineate a population that benefits from antibiotics.

Another challenge to devising a perfect definition of pneumonia is the lack of a pathologic gold standard. Based on a review of 17,340 Medicare patients hospitalized for community-acquired pneumonia, microbial confirmation is often of little assistance, and a probable pathogen is identified in only 7.6% of cases.⁶

RATES OF OUTPATIENT DIAGNOSIS ARE LIKELY SIMILAR

Thus far, we have examined trends in inpatient diagnosis but not those of outpatient diagnosis. There is no well-done observational study that documents outpatient trends, but there is little reason to suppose the trends are different. Risk-scoring systems in pneumonia, such as the PORT⁷ and the CURB-65,⁸ have been designed to decrease unnecessary inpatient admissions, but they do not lend clarity to the diagnosis itself.

The central problem with pneumonia, as with many long-recognized clinical conditions, is that the diagnosis is separated from the treatment. In other words, although physicians are confident that antibiotics benefit patients who have what Sir William Osler would have called pneumonia (elevated white blood cell count, fever, cough, dyspnea, pleurisy, egophany, lobular infiltrate), we don’t know whether the treatment benefits patients whose pneumonia would have been unrecognizable decades ago (with cough, low-grade fever, and infiltrate on CT alone). Improvements in imaging may exacerbate the problem. In this sense, pneumonia exists on a spectrum, as do many medical diagnoses. Not all cases are equally severe, and some may not deserve to be labeled as pneumonia.

No randomized trial has compared antibiotics against supportive care in pneumonia, and, likely, no such trial is needed for clear cases. However, with the growing number of soft diagnoses, randomized trials are desperately needed to delineate where harms outweigh benefits, and where the fuzzy edge of the pneumonia diagnosis must end. And as is always the case with studies that challenge a standard of care, null results should prompt further trials.

WELL-DESIGNED TRIALS COULD END THE UNCERTAINTY

In the next few years, clinical trials, rationally planned, may end most of the uncertainty regarding pneumonia.

Existing observational data may be used to identify groups of patients who, in today’s world, are diagnosed with pneumonia but who do exceptionally well (eg, younger patients with fewer comorbidities, who present with low-grade fever but no signs of consolidation on physical examination, and with dubious results on chest radiography). These are patients for whom equipoise exists, and randomized trials should compare a strategy of antibiotics with a strategy of best supportive care. Trials should be powered for patient-centered outcomes, such as the duration and the complications of illness. The death rate should be scrupulously recorded.

Patients whose pneumonia would have been unrecognizable decades ago should be another target population for the trials I propose.

In a short time, pneumonia may become synonymous with a set of factors for lung infection that predict who will benefit from antibiotics, and who can be safely followed. Already, we are moving toward this standard in other diseases.⁹ For pulmonary embolism, ongoing trials are testing if anticoagulation can be safely omitted in patients with subsegmental clots (clinicaltrials.gov identifier NCT01455818). Such trials are, at last, translating old diagnoses into the language of evidence-based medicine.

For patients with pneumonia who are not hospitalized, the current outpatient therapy is based on data from studies that show a low rate of failure with empiric treatment based on consideration of the common pathogens for this condition, with few patients subsequently requiring hospitalization. Today, this reasoning is inadequate. The basis for any therapy must be proven benefit for patients with a defined condition compared with a lesser strategy. Data already demonstrate that a short course of antibiotics is no worse than a long course for many hospitalized and outpatients with pneumonia,^10,11 but many other patients may require no treatment at all. The time has come to find out.

In his commentary in this issue, Dr. Vinay Prasad provides a well-supported perspective on the overdiagnosis of pneumonia.

Although I agree that there can be a tendency to overdiagnose pneumonia, we must not overlook the fact that pneumonia is still a leading cause of death in the United States.

See related commentary

The number of cases of invasive pneumococcal disease (mostly bacteremic pneumonia) in people over age 65 has increased over the past decade.¹ This increase is not the result of overdiagnosis, since the diagnosis relies on the well-established US Centers for Disease Control and Prevention (CDC) surveillance system, which requires a positive culture from a sterile site. However, to an extent, the increase can be explained by the increasing age of our population and by the associated comorbidities.² These comorbidities increase the predisposition to and the severity of pneumonia and adversely affect the outcome—which may also explain why we have seen no significant decrease in the death rate for patients admitted to the hospital.

In addition, a 2012 report³ that drew data from a variety of sources, including the CDC, projected that between 2004 and 2040, the US population would increase by 38% and at the same time pneumococcal pneumonia hospitalizations would increase by 96%, since population growth is fastest in older age groups, who have the highest rates of disease.³

Thus, I believe that pneumonia will continue to be a big problem and that we should pursue efforts to prevent it (including vaccinating more people against it) and to better manage it.

I agree that “over-calling” acute respiratory infections as pneumonia is often the result of imprecise diagnosis. Clinical criteria, even a combination of symptoms (cough) and signs (fever, tachycardia, and crackles), are not reliably predictive when using chest radiography as the standard.⁴ This can lead to the overuse of antimicrobials.

The Centers for Medicare and Medicaid Services used to call for starting the first dose of antibiotics within a specified time (at one time it was 4 hours, subsequently it became 6 hours) of presentation to the hospital with community-acquired pneumonia. Although the actual effect was uncertain, many feared that this performance measure would unintentionally lead to the indiscriminate use of antimicrobials to achieve high rates of compliance in patients who have little evidence of pneumonia, in order to not miss a possible case.^5,6 However, it is important to be aware that this measure was retired in 2012 and is no longer in effect.

WE NEED BETTER ASSESSMENTS AND TREATMENTS

We need better ways to assess and manage patients with pneumonia. I believe part of the solution to better assessment lies in improved diagnostic tools, and these are now becoming available.

As Dr. Prasad notes, the causative pathogen is rarely identified using standard diagnostic methods. However, polymerase chain reaction testing and measurement of the biomarker procalcitonin may improve our diagnostic accuracy and, hopefully, lead to better outcomes.⁷ The results of these tests can be rapidly available and thus may aid the point-of-care decision to treat or not to treat with antimicrobials and to allow for therapy to be started within an acceptable period. In addition, procalcitonin testing has been shown to help differentiate viral from bacterial causes of respiratory tract infection.

Dr. Prasad states that no randomized trial has compared antibiotics with supportive care in pneumonia. Although this is true for recent trials, historical studies demonstrate that antibiotics reduce death rates in patients with pneumonia.⁸ Indeed, these are the basis for the recent changes in the US Food and Drug Administration guidance for clinical trials of pneumonia.⁹

Treatment is best when it is directed at the pathogen, but there is little consensus on the practicality of achieving this goal at the primary point of care. A study funded by the National Institutes of Health is about to start enrollment to compare the effect of narrow-spectrum therapy vs the standard of care based on rapid diagnostics.¹⁰ Identification of a specific pathogen will allow directed therapy without the need for a broad-spectrum empiric regimen. In contrast, finding a viral cause without an accompanying bacterial cause will prevent the unnecessary use of antibacterials in many cases. A significant percent of cases of pneumonia in adults are caused by viruses alone.⁶

Thus, the question will not be, “Should we treat community-acquired pneumonia with antibacterials” but rather, “What is the optimal treatment for pneumonia with a defined cause?” This is a major change from an empirical broad-spectrum regimen (treat all likely pathogens) to a more specific approach that has several potential benefits, including better patient outcomes and less emergence of resistance. To paraphrase Dr. Prasad, the time has come to find this out.

In his commentary in this issue, Dr. Vinay Prasad provides a well-supported perspective on the overdiagnosis of pneumonia.

Although I agree that there can be a tendency to overdiagnose pneumonia, we must not overlook the fact that pneumonia is still a leading cause of death in the United States.

See related commentary

The number of cases of invasive pneumococcal disease (mostly bacteremic pneumonia) in people over age 65 has increased over the past decade.¹ This increase is not the result of overdiagnosis, since the diagnosis relies on the well-established US Centers for Disease Control and Prevention (CDC) surveillance system, which requires a positive culture from a sterile site. However, to an extent, the increase can be explained by the increasing age of our population and by the associated comorbidities.² These comorbidities increase the predisposition to and the severity of pneumonia and adversely affect the outcome—which may also explain why we have seen no significant decrease in the death rate for patients admitted to the hospital.

In addition, a 2012 report³ that drew data from a variety of sources, including the CDC, projected that between 2004 and 2040, the US population would increase by 38% and at the same time pneumococcal pneumonia hospitalizations would increase by 96%, since population growth is fastest in older age groups, who have the highest rates of disease.³

Thus, I believe that pneumonia will continue to be a big problem and that we should pursue efforts to prevent it (including vaccinating more people against it) and to better manage it.

I agree that “over-calling” acute respiratory infections as pneumonia is often the result of imprecise diagnosis. Clinical criteria, even a combination of symptoms (cough) and signs (fever, tachycardia, and crackles), are not reliably predictive when using chest radiography as the standard.⁴ This can lead to the overuse of antimicrobials.

The Centers for Medicare and Medicaid Services used to call for starting the first dose of antibiotics within a specified time (at one time it was 4 hours, subsequently it became 6 hours) of presentation to the hospital with community-acquired pneumonia. Although the actual effect was uncertain, many feared that this performance measure would unintentionally lead to the indiscriminate use of antimicrobials to achieve high rates of compliance in patients who have little evidence of pneumonia, in order to not miss a possible case.^5,6 However, it is important to be aware that this measure was retired in 2012 and is no longer in effect.

WE NEED BETTER ASSESSMENTS AND TREATMENTS

We need better ways to assess and manage patients with pneumonia. I believe part of the solution to better assessment lies in improved diagnostic tools, and these are now becoming available.

As Dr. Prasad notes, the causative pathogen is rarely identified using standard diagnostic methods. However, polymerase chain reaction testing and measurement of the biomarker procalcitonin may improve our diagnostic accuracy and, hopefully, lead to better outcomes.⁷ The results of these tests can be rapidly available and thus may aid the point-of-care decision to treat or not to treat with antimicrobials and to allow for therapy to be started within an acceptable period. In addition, procalcitonin testing has been shown to help differentiate viral from bacterial causes of respiratory tract infection.

Dr. Prasad states that no randomized trial has compared antibiotics with supportive care in pneumonia. Although this is true for recent trials, historical studies demonstrate that antibiotics reduce death rates in patients with pneumonia.⁸ Indeed, these are the basis for the recent changes in the US Food and Drug Administration guidance for clinical trials of pneumonia.⁹

Treatment is best when it is directed at the pathogen, but there is little consensus on the practicality of achieving this goal at the primary point of care. A study funded by the National Institutes of Health is about to start enrollment to compare the effect of narrow-spectrum therapy vs the standard of care based on rapid diagnostics.¹⁰ Identification of a specific pathogen will allow directed therapy without the need for a broad-spectrum empiric regimen. In contrast, finding a viral cause without an accompanying bacterial cause will prevent the unnecessary use of antibacterials in many cases. A significant percent of cases of pneumonia in adults are caused by viruses alone.⁶

Thus, the question will not be, “Should we treat community-acquired pneumonia with antibacterials” but rather, “What is the optimal treatment for pneumonia with a defined cause?” This is a major change from an empirical broad-spectrum regimen (treat all likely pathogens) to a more specific approach that has several potential benefits, including better patient outcomes and less emergence of resistance. To paraphrase Dr. Prasad, the time has come to find this out.

In his commentary in this issue, Dr. Vinay Prasad provides a well-supported perspective on the overdiagnosis of pneumonia.

Although I agree that there can be a tendency to overdiagnose pneumonia, we must not overlook the fact that pneumonia is still a leading cause of death in the United States.

See related commentary

The number of cases of invasive pneumococcal disease (mostly bacteremic pneumonia) in people over age 65 has increased over the past decade.¹ This increase is not the result of overdiagnosis, since the diagnosis relies on the well-established US Centers for Disease Control and Prevention (CDC) surveillance system, which requires a positive culture from a sterile site. However, to an extent, the increase can be explained by the increasing age of our population and by the associated comorbidities.² These comorbidities increase the predisposition to and the severity of pneumonia and adversely affect the outcome—which may also explain why we have seen no significant decrease in the death rate for patients admitted to the hospital.

In addition, a 2012 report³ that drew data from a variety of sources, including the CDC, projected that between 2004 and 2040, the US population would increase by 38% and at the same time pneumococcal pneumonia hospitalizations would increase by 96%, since population growth is fastest in older age groups, who have the highest rates of disease.³

Thus, I believe that pneumonia will continue to be a big problem and that we should pursue efforts to prevent it (including vaccinating more people against it) and to better manage it.

I agree that “over-calling” acute respiratory infections as pneumonia is often the result of imprecise diagnosis. Clinical criteria, even a combination of symptoms (cough) and signs (fever, tachycardia, and crackles), are not reliably predictive when using chest radiography as the standard.⁴ This can lead to the overuse of antimicrobials.

The Centers for Medicare and Medicaid Services used to call for starting the first dose of antibiotics within a specified time (at one time it was 4 hours, subsequently it became 6 hours) of presentation to the hospital with community-acquired pneumonia. Although the actual effect was uncertain, many feared that this performance measure would unintentionally lead to the indiscriminate use of antimicrobials to achieve high rates of compliance in patients who have little evidence of pneumonia, in order to not miss a possible case.^5,6 However, it is important to be aware that this measure was retired in 2012 and is no longer in effect.

WE NEED BETTER ASSESSMENTS AND TREATMENTS

We need better ways to assess and manage patients with pneumonia. I believe part of the solution to better assessment lies in improved diagnostic tools, and these are now becoming available.

As Dr. Prasad notes, the causative pathogen is rarely identified using standard diagnostic methods. However, polymerase chain reaction testing and measurement of the biomarker procalcitonin may improve our diagnostic accuracy and, hopefully, lead to better outcomes.⁷ The results of these tests can be rapidly available and thus may aid the point-of-care decision to treat or not to treat with antimicrobials and to allow for therapy to be started within an acceptable period. In addition, procalcitonin testing has been shown to help differentiate viral from bacterial causes of respiratory tract infection.

Dr. Prasad states that no randomized trial has compared antibiotics with supportive care in pneumonia. Although this is true for recent trials, historical studies demonstrate that antibiotics reduce death rates in patients with pneumonia.⁸ Indeed, these are the basis for the recent changes in the US Food and Drug Administration guidance for clinical trials of pneumonia.⁹

Treatment is best when it is directed at the pathogen, but there is little consensus on the practicality of achieving this goal at the primary point of care. A study funded by the National Institutes of Health is about to start enrollment to compare the effect of narrow-spectrum therapy vs the standard of care based on rapid diagnostics.¹⁰ Identification of a specific pathogen will allow directed therapy without the need for a broad-spectrum empiric regimen. In contrast, finding a viral cause without an accompanying bacterial cause will prevent the unnecessary use of antibacterials in many cases. A significant percent of cases of pneumonia in adults are caused by viruses alone.⁶

Thus, the question will not be, “Should we treat community-acquired pneumonia with antibacterials” but rather, “What is the optimal treatment for pneumonia with a defined cause?” This is a major change from an empirical broad-spectrum regimen (treat all likely pathogens) to a more specific approach that has several potential benefits, including better patient outcomes and less emergence of resistance. To paraphrase Dr. Prasad, the time has come to find this out.

No. in general, the decision to treat portal vein thrombosis with anticoagulant drugs is complex and depends on whether the thrombosis is acute or chronic, and whether the cause is a local factor, cirrhosis of the liver, or a systemic condition (Table 1). A “one-size-fits-all” approach should be avoided (Figure 1).

ACUTE PORTAL VEIN THROMBOSIS WITHOUT CIRRHOSIS

No randomized controlled trial has yet evaluated anticoagulation in acute portal vein thrombosis. But a prospective study published in 2010 showed that the portal vein and its left or right branch were patent in 39% of anticoagulated patients (vs 13% initially), the splenic vein in 80% (vs 57% initially), and the superior mesenteric vein in 73% (vs 42% initially).¹ Further, there appears to be a 20% reduction in the overall mortality rate associated with anticoagulation for acute portal vein thrombosis in retrospective studies.²

In the absence of contraindications, anticoagulation with heparin or low-molecular-weight heparin is recommended, with complete bridging to oral anticoagulation with a vitamin K antagonist. Anticoagulation should be continued for at least 3 months, and indefinitely in patients with permanent hypercoaguable risk factors.³

CHRONIC PORTAL VEIN THROMBOSIS WITHOUT CIRRHOSIS

All patients with chronic portal vein thrombosis should undergo esophagogastroduodenoscopy to evaluate for varices. Patients with large varices should be treated orally with a nonselective beta-adrenergic blocker or endoscopically. Though no prospective study has validated this practice, a retrospective analysis showed a decreased risk of first or recurrent bleeding.⁴

In 2007, a retrospective study showed a lower rate of death in patients with portomesenteric venous thrombosis treated with an oral vitamin K antagonist.⁵ Patients with chronic portal vein thrombosis with ongoing thrombotic risk factors should be treated with long-term anticoagulation after screening for varices, and if varices are present, primary prophylaxis should be started.³ With this approach, less than 5% of patients died from classic complications of portal vein thrombosis at 5 years of follow-up.⁴

ACUTE OR CHRONIC PORTAL VEIN THROMBOSIS WITH CIRRHOSIS

Portal vein thrombosis is common in patients with underlying cirrhosis. The risk in patients with cirrhosis significantly increases as liver function worsens. In patients with well-compensated cirrhosis, the risk is less than 1% vs 8% to 25% in those with advanced cirrhosis.⁶

In patients awaiting liver transplantation, a large retrospective study⁷ showed that the rate of partial or complete recanalization of the splanchnic veins was significantly higher in those who received anticoagulation (8 of 19) than in those who did not (0 of 10, P = .002). The rate of survival was significantly lower in those who had complete thrombotic obstruction of the portal vein at the time of surgery (P = .04). However, there was no difference in survival rates between those with partial obstruction who received anticoagulation and those with a patent portal vein.⁷

A later retrospective study⁸ showed no significant benefit in the rate of transplantation-free survival or survival after liver transplantation in patients with or without chronic portal vein thrombosis.⁸

Unfortunately, we have no data from prospective controlled trials and only limited data from retrospective studies to make a strong recommendation for or against anticoagulation in either acute and chronic portal vein thrombosis associated with cirrhosis. As such, each case must be evaluated on an individual basis in association with expert consultation.

In our experience, the risk of bleeding in patients with liver cirrhosis is substantial because of the decreased synthesis of coagulation factors and the presence of varices, whereas the efficacy and the benefits of recanalizing the portal vein in asymptomatic patients with liver cirrhosis and portal vein thrombosis are unknown. Therefore, unless the thrombosis extends into the mesenteric vein, thus posing a risk of mesenteric ischemia, we do not generally recommend anticoagulation in asymptomatic portal vein thrombosis in patients with cirrhosis.

No. in general, the decision to treat portal vein thrombosis with anticoagulant drugs is complex and depends on whether the thrombosis is acute or chronic, and whether the cause is a local factor, cirrhosis of the liver, or a systemic condition (Table 1). A “one-size-fits-all” approach should be avoided (Figure 1).

ACUTE PORTAL VEIN THROMBOSIS WITHOUT CIRRHOSIS

No randomized controlled trial has yet evaluated anticoagulation in acute portal vein thrombosis. But a prospective study published in 2010 showed that the portal vein and its left or right branch were patent in 39% of anticoagulated patients (vs 13% initially), the splenic vein in 80% (vs 57% initially), and the superior mesenteric vein in 73% (vs 42% initially).¹ Further, there appears to be a 20% reduction in the overall mortality rate associated with anticoagulation for acute portal vein thrombosis in retrospective studies.²

In the absence of contraindications, anticoagulation with heparin or low-molecular-weight heparin is recommended, with complete bridging to oral anticoagulation with a vitamin K antagonist. Anticoagulation should be continued for at least 3 months, and indefinitely in patients with permanent hypercoaguable risk factors.³

CHRONIC PORTAL VEIN THROMBOSIS WITHOUT CIRRHOSIS

All patients with chronic portal vein thrombosis should undergo esophagogastroduodenoscopy to evaluate for varices. Patients with large varices should be treated orally with a nonselective beta-adrenergic blocker or endoscopically. Though no prospective study has validated this practice, a retrospective analysis showed a decreased risk of first or recurrent bleeding.⁴

In 2007, a retrospective study showed a lower rate of death in patients with portomesenteric venous thrombosis treated with an oral vitamin K antagonist.⁵ Patients with chronic portal vein thrombosis with ongoing thrombotic risk factors should be treated with long-term anticoagulation after screening for varices, and if varices are present, primary prophylaxis should be started.³ With this approach, less than 5% of patients died from classic complications of portal vein thrombosis at 5 years of follow-up.⁴

ACUTE OR CHRONIC PORTAL VEIN THROMBOSIS WITH CIRRHOSIS

Portal vein thrombosis is common in patients with underlying cirrhosis. The risk in patients with cirrhosis significantly increases as liver function worsens. In patients with well-compensated cirrhosis, the risk is less than 1% vs 8% to 25% in those with advanced cirrhosis.⁶

In patients awaiting liver transplantation, a large retrospective study⁷ showed that the rate of partial or complete recanalization of the splanchnic veins was significantly higher in those who received anticoagulation (8 of 19) than in those who did not (0 of 10, P = .002). The rate of survival was significantly lower in those who had complete thrombotic obstruction of the portal vein at the time of surgery (P = .04). However, there was no difference in survival rates between those with partial obstruction who received anticoagulation and those with a patent portal vein.⁷

A later retrospective study⁸ showed no significant benefit in the rate of transplantation-free survival or survival after liver transplantation in patients with or without chronic portal vein thrombosis.⁸

Unfortunately, we have no data from prospective controlled trials and only limited data from retrospective studies to make a strong recommendation for or against anticoagulation in either acute and chronic portal vein thrombosis associated with cirrhosis. As such, each case must be evaluated on an individual basis in association with expert consultation.

In our experience, the risk of bleeding in patients with liver cirrhosis is substantial because of the decreased synthesis of coagulation factors and the presence of varices, whereas the efficacy and the benefits of recanalizing the portal vein in asymptomatic patients with liver cirrhosis and portal vein thrombosis are unknown. Therefore, unless the thrombosis extends into the mesenteric vein, thus posing a risk of mesenteric ischemia, we do not generally recommend anticoagulation in asymptomatic portal vein thrombosis in patients with cirrhosis.

No. in general, the decision to treat portal vein thrombosis with anticoagulant drugs is complex and depends on whether the thrombosis is acute or chronic, and whether the cause is a local factor, cirrhosis of the liver, or a systemic condition (Table 1). A “one-size-fits-all” approach should be avoided (Figure 1).

ACUTE PORTAL VEIN THROMBOSIS WITHOUT CIRRHOSIS

No randomized controlled trial has yet evaluated anticoagulation in acute portal vein thrombosis. But a prospective study published in 2010 showed that the portal vein and its left or right branch were patent in 39% of anticoagulated patients (vs 13% initially), the splenic vein in 80% (vs 57% initially), and the superior mesenteric vein in 73% (vs 42% initially).¹ Further, there appears to be a 20% reduction in the overall mortality rate associated with anticoagulation for acute portal vein thrombosis in retrospective studies.²

In the absence of contraindications, anticoagulation with heparin or low-molecular-weight heparin is recommended, with complete bridging to oral anticoagulation with a vitamin K antagonist. Anticoagulation should be continued for at least 3 months, and indefinitely in patients with permanent hypercoaguable risk factors.³

CHRONIC PORTAL VEIN THROMBOSIS WITHOUT CIRRHOSIS

All patients with chronic portal vein thrombosis should undergo esophagogastroduodenoscopy to evaluate for varices. Patients with large varices should be treated orally with a nonselective beta-adrenergic blocker or endoscopically. Though no prospective study has validated this practice, a retrospective analysis showed a decreased risk of first or recurrent bleeding.⁴

In 2007, a retrospective study showed a lower rate of death in patients with portomesenteric venous thrombosis treated with an oral vitamin K antagonist.⁵ Patients with chronic portal vein thrombosis with ongoing thrombotic risk factors should be treated with long-term anticoagulation after screening for varices, and if varices are present, primary prophylaxis should be started.³ With this approach, less than 5% of patients died from classic complications of portal vein thrombosis at 5 years of follow-up.⁴

ACUTE OR CHRONIC PORTAL VEIN THROMBOSIS WITH CIRRHOSIS

Portal vein thrombosis is common in patients with underlying cirrhosis. The risk in patients with cirrhosis significantly increases as liver function worsens. In patients with well-compensated cirrhosis, the risk is less than 1% vs 8% to 25% in those with advanced cirrhosis.⁶

In patients awaiting liver transplantation, a large retrospective study⁷ showed that the rate of partial or complete recanalization of the splanchnic veins was significantly higher in those who received anticoagulation (8 of 19) than in those who did not (0 of 10, P = .002). The rate of survival was significantly lower in those who had complete thrombotic obstruction of the portal vein at the time of surgery (P = .04). However, there was no difference in survival rates between those with partial obstruction who received anticoagulation and those with a patent portal vein.⁷

A later retrospective study⁸ showed no significant benefit in the rate of transplantation-free survival or survival after liver transplantation in patients with or without chronic portal vein thrombosis.⁸

Unfortunately, we have no data from prospective controlled trials and only limited data from retrospective studies to make a strong recommendation for or against anticoagulation in either acute and chronic portal vein thrombosis associated with cirrhosis. As such, each case must be evaluated on an individual basis in association with expert consultation.

In our experience, the risk of bleeding in patients with liver cirrhosis is substantial because of the decreased synthesis of coagulation factors and the presence of varices, whereas the efficacy and the benefits of recanalizing the portal vein in asymptomatic patients with liver cirrhosis and portal vein thrombosis are unknown. Therefore, unless the thrombosis extends into the mesenteric vein, thus posing a risk of mesenteric ischemia, we do not generally recommend anticoagulation in asymptomatic portal vein thrombosis in patients with cirrhosis.

In this issue of the Journal, Dr. Soumya Chatterjee and colleagues discuss the antisynthetase syndrome. Although uncommon, this syndrome is important for internists and subspecialists to be aware of. Patients present in several different ways, and potentially life-threatening organ involvement may initially not be recognized or may not be linked with other components of the syndrome, such as involvement of the lungs, muscles, heart, and esophagus and fever.

I am currently on our inpatient rheumatology consultation service, and so I am reminded daily of the challenges hospitalists and subspecialists confront in ordering tests while trying to balance limiting length of stay with cost-efficiency and the desire to obtain a correct diagnosis. And I am repeatedly sensitized to several common test-ordering pitfalls intrinsic to the evaluation of patients with multisystem disease, including myositis. Most have a shared theme—limited time is spent in thoughtful reflection before ordering.

Patients with myositis rarely present with the textbook description of proximal muscle weakness. They describe fatigue, malaise, and sometimes a generalized sense of weakness. It is the probing questioning of their functional capacity and focused examination that reveal that the weakness is characterized by difficulty getting up off the floor, out of a low chair, or off the toilet. Then, with further questioning, some patients note that their fatigue and tiredness may also include getting winded easily with exertion, such as when climbing stairs, thus raising the question of cardiac dysfunction, pulmonary hypertension, or interstitial lung disease.

The responses to those probing questions and the subsequent examination should transform the interpretation of elevated aminotransferase levels (“liver tests”: AST and ALT) from liver disease into suspicion of muscle disease and the appropriate ordering of the creatine kinase level (avoiding liver imaging and hepatology consultation). The carefully repeated and now focused neurologic examination distinguishes the initial “poor cooperation” from the proximal weakness of myopathy. The probing interview leads to the performance of a focused physical examination that frames the appropriate interpretation of the routinely obtained “admission lab studies”!

The thoughtful history and examination are the basic stuff of clinical medicine that can easily be pushed aside by any of us as we deal with the tensions of high-volume, “high-throughput” medical care. It is a low-resistance path from hearing the symptom of fatigue with elevated “liver enzymes” to immediately checking ferritin, ceruloplasmin, and a hepatitis screen in preparation for getting a liver biopsy. It is easy to go through the motions without reflection. Easy, but sometimes wrong. And it is just as easy (but likely to be costly and unhelpful) to identify a patient prematurely with “possible autoimmune disease” and to immediately order a panoply of antinuclear and autoimmune serologies, including the Jo-1 autoantibody test.

As Dr. Chatterjee et al point out, we must continuously reflect on our diagnoses, for even after we navigate the pitfalls and avoid missing the diagnosis of myositis, if we don’t continuously assess all the patient’s symptoms, repeat the examination in a directed manner, and then look for circulating Jo-1 antibody when appropriate, we may well miss the opportunity to recognize that our patient’s ongoing fatigue with exertion is a reflection of the well-described association of myositis with interstitial lung disease (which may warrant a change in therapy), and not steroid myopathy or just poor conditioning.

Alternatively, in evaluating a patient who describes a year of feeling tired, suffering generalized muscle pains with low-grade fevers with temperatures of 99.8°F, and total exhaustion for 3 days after cleaning the oven, testing for antinuclear antibodies, extractable nuclear antigen antibodies, and a “vasculitis panel” in anticipation of a rheumatology consultation is not likely to be useful therapeutically or diagnostically.

Despite the daily pressures, we need to keep ourselves grounded in the fundamentals of clinical care: careful listening, purposeful examination, and directed use of laboratory tests and imaging. The downstream consequences of ordering tests for the sake of efficient throughput are quite real, and thoughtful test ordering is one step toward quality care, as well as cost-effective care.

In future months, the Journal will delve more deeply into test ordering when, in a joint effort with the American College of Physicians, we will be discussing the use and misuse of specific tests.

In this issue of the Journal, Dr. Soumya Chatterjee and colleagues discuss the antisynthetase syndrome. Although uncommon, this syndrome is important for internists and subspecialists to be aware of. Patients present in several different ways, and potentially life-threatening organ involvement may initially not be recognized or may not be linked with other components of the syndrome, such as involvement of the lungs, muscles, heart, and esophagus and fever.

I am currently on our inpatient rheumatology consultation service, and so I am reminded daily of the challenges hospitalists and subspecialists confront in ordering tests while trying to balance limiting length of stay with cost-efficiency and the desire to obtain a correct diagnosis. And I am repeatedly sensitized to several common test-ordering pitfalls intrinsic to the evaluation of patients with multisystem disease, including myositis. Most have a shared theme—limited time is spent in thoughtful reflection before ordering.

Patients with myositis rarely present with the textbook description of proximal muscle weakness. They describe fatigue, malaise, and sometimes a generalized sense of weakness. It is the probing questioning of their functional capacity and focused examination that reveal that the weakness is characterized by difficulty getting up off the floor, out of a low chair, or off the toilet. Then, with further questioning, some patients note that their fatigue and tiredness may also include getting winded easily with exertion, such as when climbing stairs, thus raising the question of cardiac dysfunction, pulmonary hypertension, or interstitial lung disease.

The responses to those probing questions and the subsequent examination should transform the interpretation of elevated aminotransferase levels (“liver tests”: AST and ALT) from liver disease into suspicion of muscle disease and the appropriate ordering of the creatine kinase level (avoiding liver imaging and hepatology consultation). The carefully repeated and now focused neurologic examination distinguishes the initial “poor cooperation” from the proximal weakness of myopathy. The probing interview leads to the performance of a focused physical examination that frames the appropriate interpretation of the routinely obtained “admission lab studies”!

The thoughtful history and examination are the basic stuff of clinical medicine that can easily be pushed aside by any of us as we deal with the tensions of high-volume, “high-throughput” medical care. It is a low-resistance path from hearing the symptom of fatigue with elevated “liver enzymes” to immediately checking ferritin, ceruloplasmin, and a hepatitis screen in preparation for getting a liver biopsy. It is easy to go through the motions without reflection. Easy, but sometimes wrong. And it is just as easy (but likely to be costly and unhelpful) to identify a patient prematurely with “possible autoimmune disease” and to immediately order a panoply of antinuclear and autoimmune serologies, including the Jo-1 autoantibody test.

As Dr. Chatterjee et al point out, we must continuously reflect on our diagnoses, for even after we navigate the pitfalls and avoid missing the diagnosis of myositis, if we don’t continuously assess all the patient’s symptoms, repeat the examination in a directed manner, and then look for circulating Jo-1 antibody when appropriate, we may well miss the opportunity to recognize that our patient’s ongoing fatigue with exertion is a reflection of the well-described association of myositis with interstitial lung disease (which may warrant a change in therapy), and not steroid myopathy or just poor conditioning.

Alternatively, in evaluating a patient who describes a year of feeling tired, suffering generalized muscle pains with low-grade fevers with temperatures of 99.8°F, and total exhaustion for 3 days after cleaning the oven, testing for antinuclear antibodies, extractable nuclear antigen antibodies, and a “vasculitis panel” in anticipation of a rheumatology consultation is not likely to be useful therapeutically or diagnostically.

Despite the daily pressures, we need to keep ourselves grounded in the fundamentals of clinical care: careful listening, purposeful examination, and directed use of laboratory tests and imaging. The downstream consequences of ordering tests for the sake of efficient throughput are quite real, and thoughtful test ordering is one step toward quality care, as well as cost-effective care.

In future months, the Journal will delve more deeply into test ordering when, in a joint effort with the American College of Physicians, we will be discussing the use and misuse of specific tests.

In this issue of the Journal, Dr. Soumya Chatterjee and colleagues discuss the antisynthetase syndrome. Although uncommon, this syndrome is important for internists and subspecialists to be aware of. Patients present in several different ways, and potentially life-threatening organ involvement may initially not be recognized or may not be linked with other components of the syndrome, such as involvement of the lungs, muscles, heart, and esophagus and fever.

I am currently on our inpatient rheumatology consultation service, and so I am reminded daily of the challenges hospitalists and subspecialists confront in ordering tests while trying to balance limiting length of stay with cost-efficiency and the desire to obtain a correct diagnosis. And I am repeatedly sensitized to several common test-ordering pitfalls intrinsic to the evaluation of patients with multisystem disease, including myositis. Most have a shared theme—limited time is spent in thoughtful reflection before ordering.

Patients with myositis rarely present with the textbook description of proximal muscle weakness. They describe fatigue, malaise, and sometimes a generalized sense of weakness. It is the probing questioning of their functional capacity and focused examination that reveal that the weakness is characterized by difficulty getting up off the floor, out of a low chair, or off the toilet. Then, with further questioning, some patients note that their fatigue and tiredness may also include getting winded easily with exertion, such as when climbing stairs, thus raising the question of cardiac dysfunction, pulmonary hypertension, or interstitial lung disease.

The responses to those probing questions and the subsequent examination should transform the interpretation of elevated aminotransferase levels (“liver tests”: AST and ALT) from liver disease into suspicion of muscle disease and the appropriate ordering of the creatine kinase level (avoiding liver imaging and hepatology consultation). The carefully repeated and now focused neurologic examination distinguishes the initial “poor cooperation” from the proximal weakness of myopathy. The probing interview leads to the performance of a focused physical examination that frames the appropriate interpretation of the routinely obtained “admission lab studies”!

The thoughtful history and examination are the basic stuff of clinical medicine that can easily be pushed aside by any of us as we deal with the tensions of high-volume, “high-throughput” medical care. It is a low-resistance path from hearing the symptom of fatigue with elevated “liver enzymes” to immediately checking ferritin, ceruloplasmin, and a hepatitis screen in preparation for getting a liver biopsy. It is easy to go through the motions without reflection. Easy, but sometimes wrong. And it is just as easy (but likely to be costly and unhelpful) to identify a patient prematurely with “possible autoimmune disease” and to immediately order a panoply of antinuclear and autoimmune serologies, including the Jo-1 autoantibody test.

As Dr. Chatterjee et al point out, we must continuously reflect on our diagnoses, for even after we navigate the pitfalls and avoid missing the diagnosis of myositis, if we don’t continuously assess all the patient’s symptoms, repeat the examination in a directed manner, and then look for circulating Jo-1 antibody when appropriate, we may well miss the opportunity to recognize that our patient’s ongoing fatigue with exertion is a reflection of the well-described association of myositis with interstitial lung disease (which may warrant a change in therapy), and not steroid myopathy or just poor conditioning.

Alternatively, in evaluating a patient who describes a year of feeling tired, suffering generalized muscle pains with low-grade fevers with temperatures of 99.8°F, and total exhaustion for 3 days after cleaning the oven, testing for antinuclear antibodies, extractable nuclear antigen antibodies, and a “vasculitis panel” in anticipation of a rheumatology consultation is not likely to be useful therapeutically or diagnostically.

Despite the daily pressures, we need to keep ourselves grounded in the fundamentals of clinical care: careful listening, purposeful examination, and directed use of laboratory tests and imaging. The downstream consequences of ordering tests for the sake of efficient throughput are quite real, and thoughtful test ordering is one step toward quality care, as well as cost-effective care.

In future months, the Journal will delve more deeply into test ordering when, in a joint effort with the American College of Physicians, we will be discussing the use and misuse of specific tests.

A 66-year-old man was initially seen in clinic in March 2004 with a 5-month history of polyarthritis (affecting the finger joints, wrists, and knees) and several hours of morning stiffness. He also had significant proximal muscle weakness, progressive exertional dyspnea, and a nonproductive cough. There was no history of fever, chills, rash, dysphagia, or sicca symptoms. Findings on initial tests:

• His creatine kinase level was 700 U/L (reference range 30–220), which later rose to 1,664 U/L.
• He was positive for antinuclear antibody with a 5.7 optical density ratio (normal < 1.5) and for anti-Jo-1 antibody.
• An electromyogram was consistent with a necrotizing myopathy. Left rectus femoris biopsy revealed scattered degenerating and regenerating muscle fibers but no evidence of endomysial inflammation.
• On pulmonary function testing, his forced vital capacity was 80% of predicted, and his carbon monoxide diffusion capacity was 67% of predicted.
• High-resolution computed tomography revealed evidence of interstitial lung disease, characterized by bilateral patchy ground-glass opacities suggestive of active alveolitis, most extensive at the lung bases.
• Bronchoalveolar lavage indicated alveolitis, and transbronchial biopsy revealed pathologic changes consistent with cryptogenic organizing pneumonia. All cultures were negative.

This constellation of clinical manifestations, including myositis, interstitial lung disease, and polyarthritis, along with positive anti-Jo-1 antibody, confirmed the diagnosis of antisynthetase syndrome.

In June 2004, for his interstitial lung disease, he was started on daily oral cyclophosphamide along with high-dose oral prednisone. Three months later the skin of the tips and radial margins of his fingers started thickening and cracking, the appearance of which is classically described as “mechanic’s hands,” a well-described manifestation of antisynthetase syndrome (Figure 1).

Cyclophosphamide was continued for about a year. Subsequently, along with prednisone, he sequentially received various other immunosuppressive medications (methotrexate, tacrolimus, mycophenolate mofetil, and rituximab) over the next few years in an attempt to control his progressive interstitial lung disease. All of these agents were only partially and temporarily effective. Ultimately, despite all of these therapies, as his interstitial lung disease progressed, he needed supplemental oxygen and enrollment in a pulmonary rehabilitation program.

In March 2010, he was admitted with worsening dyspnea and significant peripheral edema and was found to have severe pulmonary arterial hypertension. He was started on bosentan. Eight months later sildenafil was added for progressive pulmonary arterial hypertension. However, his oxygenation status continued to decline.

In July 2011, he presented with chills, increasing shortness of breath, and a mild productive cough. As he was severely hypoxic, he was admitted to the intensive care unit and started on mechanical ventilation and broad-spectrum antibiotics. Despite escalation of oxygen therapy, his respiratory status rapidly deteriorated, and he developed hypotension requiring vasopressors. He ultimately died of cardiac arrest secondary to respiratory failure.

A CONSTELLATION OF MANIFESTATIONS

Antisynthetase syndrome, associated with anti-aminoacyl-transfer RNA (tRNA) synthetase antibodies, is characterized by a constellation of manifestations that include myositis, interstitial lung disease, mechanic’s hands, fever, Raynaud phenomenon, and nonerosive symmetric polyarthritis of the small joints.¹

Anti-Jo-1 antibody (anti-histidyl-tRNA synthetase) is the most common of the antibodies and also was the first one to be identified (Table 1). It was named after John P, a patient with polymyositis and interstitial lung disease, in whom it was first detected in 1980.² The onset of the syndrome associated with anti-Jo-1 antibody is often acute, and the myositis is usually steroid-responsive. However, not uncommonly, severe disease can develop over time, with a tendency to relapse and with a poor long-term prognosis.

RARE BUT UNDERRECOGNIZED

The true population prevalence of antisynthetase syndrome is unknown. Because this syndrome is rare, comprehensive epidemiologic studies are difficult to perform.

In several retrospective studies, the annual incidence of idiopathic inflammatory myopathies has been reported to be 2 to 10 new cases per million adults per year.³ Antisynthetase antibodies are detected in 20% to 40% of such cases.^4–6 The disease is two to three times more common in women than in men.⁷

Early diagnosis is difficult because the clinical presentation is varied and often nonspecific, clinically milder disease may escape detection, and many general practitioners lack familiarity with this syndrome and consequently do not recognize it. Moreover, tests for myositis-specific antibodies (including antisynthetase antibodies) are often not ordered in the evaluation of myositis, and hence the diagnosis of antisynthetase syndrome cannot be substantiated. Furthermore, interstitial lung disease can predominate or can be the sole manifestation in the absence of clinically apparent myositis,^8–10 and patients can be misdiagnosed as having idiopathic pulmonary fibrosis when underlying antisynthetase syndrome is not suspected. This distinction may be important because these conditions differ in their pathology and treatment. Histologically, the predominant pattern of lung injury in idiopathic pulmonary fibrosis is “usual interstitial pneumonia” which does not respond to immunosuppressive therapy, and hence lung transplantation is the only therapeutic option. On the other hand, in antisynthetase syndrome, the usual pattern of lung injury is “nonspecific interstitial pneumonia,” in which immunosuppressive therapy has a role.

Anti-Jo-1 antibody is detected in 15% to 25% of patients with polymyositis and in up to 70% of myositis patients with concomitant interstitial lung disease.¹¹ Autoantibodies to seven other, less frequently targeted, aminoacyl tRNA synthetases have also been described in patients with polymyositis and interstitial lung disease (Table 1).^11,12 In addition, an autoantibody to a 48-kDa transfer RNA-related protein (Wa) has been described.¹³ These non-Jo-1 antisynthetase antibodies are detected in only about 3% of myositis patients.¹⁴

ROLE OF ANTISYNTHETASE ANTIBODIES

Synthetases play a central role in protein synthesis by catalyzing the acetylation of tRNAs. The propensity of organ involvement in antisynthetase syndrome suggests that tissue-specific changes in muscle or lung lead to the production of unique forms of target autoantigens, the aminoacyl-tRNA synthetases. There is evidence that these enzymes themselves may be involved in recruiting both antigen-presenting and inflammatory cells to the site of muscle or lung injury.¹⁵ However, the molecular pathway that initiates and propagates this autoimmune response and the specific role of the antisynthetase antibodies in the pathogenesis of this syndrome are presently unknown.

SIX SALIENT CLINICAL FEATURES

There are six predominant clinical manifestations, which may be present at disease onset or appear later as the disease progresses:

• Fever
• Myositis
• Interstitial lung disease
• Mechanic’s hands
• Raynaud phenomenon
• Inflammatory polyarthritis.

There is considerable clinical heterogeneity, and one or other manifestation can predominate or can be the only expression of the syndrome. Furthermore, in the same patient, the individual features can prevail at different times and may develop years after onset of the disease. Therefore, in addition to patients with myositis, it would be important to suspect antisynthetase syndrome in patients presenting with isolated lung involvement (amyopathic interstitial lung disease), as there are therapeutic implications. Studies have demonstrated the efficacy of immunosuppressive agents in interstitial lung disease associated with antisynthetase syndrome (where the predominant pattern of lung injury is “nonspecific interstitial pneumonitis”), whereas lung transplantation has so far been the only treatment option in idiopathic pulmonary fibrosis.

Fever

About 20% of patients have a fever at disease onset or associated with relapses. Sometimes the fever can persist until treatment of antisynthetase syndrome is started.

Myositis

Muscle disease is seen in more than 90% of patients with anti-Jo-1 antisynthetase syndrome. It can be subclinical (in the absence of proximal myopathy), manifested by transient creatine kinase elevation only, which may normalize after therapy is initiated.

However, more commonly, patients develop profound proximal muscle weakness and sometimes muscle pain (Table 2). Weakness of the striated muscles of the upper esophagus, cricopharyngeus, and hypopharynx may cause dysphagia and makes these patients susceptible to aspiration pneumonia. Diaphragmatic and intercostal muscle weakness can contribute to shortness of breath in some patients. Myocarditis has also been reported.

Pulmonary disease

Interstitial lung disease develops in most patients with anti-Jo-1 antisynthetase syndrome, with a reported prevalence of about 90% in one series.¹⁶ Patients often present with acute, subacute, or insidious onset of exertional dyspnea. Sometimes there is an intractable nonproductive cough.

At the outset of antisynthetase syndrome, if the patient is profoundly weak because of myopathy or has inflammatory polyarthritis, mobility is significantly compromised, and exertional dyspnea may not be experienced. However, as the interstitial lung disease progresses, shortness of breath becomes overt, more so when the patient’s level of activity improves with treatment of myositis.

Inspiratory crackles on auscultation of the lung bases or changes on chest radiography are relatively insensitive findings and can miss early interstitial lung disease. Therefore, if antisynthetase syndrome is suspected or diagnosed, a baseline pulmonary function test (spirometry and carbon monoxide diffusion capacity) is indicated. It will often detect occult interstitial lung disease, and the diagnosis can then be confirmed with thoracic high-resolution computed tomography (Figure 2).

Pulmonary hypertension. Recent studies indicate that, similar to patients with other autoimmune rheumatic diseases, pulmonary hypertension can develop in patients with antisynthetase syndrome, with or without concomitant interstitial lung disease.^17,18 This complication occurred in the case presented here. It has been found that when pulmonary hypertension coexists with interstitial lung disease, its degree may not correlate with the severity of the latter.¹⁷ Additionally, pulmonary hypertension, when present, has been found to contribute independently to prognosis and survival.

In about 30% of patients, the skin of the tips and margins of the fingers becomes thickened, hyperkeratotic, and fissured, the appearance of which is classically described as mechanic’s hands. It is a common manifestation of antisynthetase syndrome and is particularly prominent on the radial side of the index fingers (Figure 1). Biopsy of affected skin shows an interface psoriasiform dermatitis.¹⁹ In addition, some dermatomyositis patients with Gottron papules and a heliotrope rash have antisynthetase antibodies.

Raynaud phenomenon

Raynaud phenomenon develops in about 40% of patients. Some have nailfold capillary abnormalities.²⁰ However, persistent or severe digital ischemia leading to digital ulceration or infarction is uncommon.²¹

Inflammatory arthritis

Arthralgias and arthritis are common (50%), the most common form being a symmetric polyarthritis of the small joints of the hands and feet. It is typically nonerosive but can sometimes be erosive and destructive.²⁰

Because inflammatory arthritis mimics rheumatoid arthritis, antisynthetase syndrome should be considered in rheumatoid factor-negative patients presenting with polyarthritis.

ASSOCIATION WITH MALIGNANCY

Traditional teaching has been that antisynthetase antibody is protective against an underlying malignancy.^22,23 However, several recently published case studies have reported various malignancies occurring within 6 to 12 months of the diagnosis of antisynthetase syndrome.^7,24 The debate as to whether these are chance associations or causal (a paraneoplastic phenomenon) has not been resolved at this time.²⁴

It is now recommended that patients with antisynthetase syndrome be screened for malignancies as appropriate for the patient’s age and sex. Screening should include a careful history and physical examination, complete blood cell count, comprehensive metabolic panel, chest radiography, mammography, and a gynecologic examination for women.²⁵ If abnormalities are found, a more thorough evaluation for cancer is appropriate.

DIAGNOSIS

Muscle enzyme levels are often elevated

Muscle enzymes (creatine kinase and aldolase) are often elevated. Serum creatine kinase levels can range between 5 to 50 times the upper limit of normal. In an established case, creatine kinase levels along with careful manual muscle strength testing may help evaluate myositis activity. However, in chronic and advanced disease, creatine kinase may be within the normal range despite active myositis, partly because of extensive loss of muscle mass. In myositis, it may be prudent to check both creatine kinase and aldolase; sometimes only serum aldolase level rises, when immune-mediated injury predominantly affects the early regenerative myocytes.²⁶

Judicious use of autoantibody testing

The characteristic clinical presentation is the initial clue to the diagnosis of antisynthetase syndrome, which is then supported by serologic testing.

Injudicious testing for a long list of antibodies should be avoided, as the cost is considerable and it does not influence further management. However, ordering an anti-Jo-1 antibody test in the correct clinical setting is appropriate, as it has high specificity,^27,28 and thus can help establish or refute the clinical suspicion of antisynthetase syndrome.

Screening pulmonary function testing and thoracic high-resolution computed tomography for all patients with polymyositis or dermatomyositis is not considered “standard of care” and will likely not be reimbursed by third-party payers. However, in a patient with symptoms and signs of myositis, the presence of an antisynthetase antibody should prompt screening for occult interstitial lung disease, even in the absence of symptoms. As lung disease ultimately determines the prognosis in antisynthetase syndrome, early diagnosis and management is the key. Therefore, these tests would likely be approved to establish the diagnosis of interstitial lung disease and evaluate its severity.

If a myositis patient is also found to have interstitial lung disease or develops mechanic’s hands, the likely diagnosis is antisynthetase syndrome, which can be confirmed by serologic testing for antisynthetase antibodies. Interstitial lung disease in antisynthetase syndrome is often from “nonspecific interstitial pneumonitis”; therefore, medications tested and proven effective for this condition should be approved and reimbursed by payers.^29–32

The coexistence of myositis and interstitial lung disease increases the sensitivity of anti-Jo-1 antibody.¹¹ Thus, the clinician can have more confidence in early recognition and initiation of aggressive but targeted disease-modifying therapy.

Various methods can be used for detecting antisynthetase antibodies, with comparable results.²⁸ Anti-Jo-1 antibody testing costs about $140. If that test is negative and antisynthetase syndrome is still suspected, then testing for the non-Jo-1 antisynthetase antibodies may be justified (Table 1). Though the cost of this panel of autoantibodies is about $300, it helps to confirm the diagnosis, and it influences the choice of second-line immunosuppressive agents such as tacrolimus²⁹ and rituximab³² in patients resistant to conventional immunosuppressive agents such as azathioprine and methotrexate.

Often, anti-Ro52 SS-A antibodies are present concurrently in patients with anti-Jo-1 syndrome.³³ In observational studies in patients with anti-Jo-1 antibody-associated interstitial lung disease, coexistence of anti-Ro52 SS-A antibody tended to predict a worse pulmonary outcome than in those with anti-Jo-1 antibody alone.^34,35

Electromyography

Electromyography not only helps differentiate between myopathic and neuropathic weakness, but it may also support the diagnosis of “inflammatory” myopathy as suggested by prominent muscle membrane irritability (fibrillations, positive sharp waves) and abnormal motor unit action potentials (spontaneous activity showing small, short, polyphasic potentials and early recruitment). However, the findings can be nonspecific, and may even be normal in 10% to 15% of patients.³⁶ Electromyographic abnormalities are most consistently observed in weak proximal muscles, and electromyography is also helpful in selecting a muscle for biopsy. Although no single electromyographic pattern is considered diagnostic for inflammatory myopathy, abnormalities are present in around 90% of patients (Table 2).³

Magnetic resonance imaging

Magnetic resonance imaging may show increased signal intensity in the affected muscles and surrounding tissues (Figure 3).³⁷ Because it lacks sensitivity and specificity, magnetic resonance imaging is not helpful in diagnosing the disease. However, in the correct clinical setting, it may be used to guide muscle biopsy, and it can help in monitoring the disease progress.³⁸

Muscle histopathology

Muscle biopsy, though often helpful, is not always diagnostic, and antisynthetase syndrome should still be suspected in the right clinical context, even in the absence of characteristic pathologic changes.

Biopsy of sites recently studied by electromyography should be avoided, and if the patient has undergone electromyography recently, the contralateral side should be selected for biopsy.

Reports of histopathologic findings in muscle biopsies in patients with antisynthetase syndrome document inflammatory myopathic features (Figure 4). In a series of patients with anti-Jo-1 syndrome, inflammation was noted in all cases, predominantly perimysial in location, with occasional endomysial and perivascular inflammation.³⁹ Many of the inflammatory cells seen were macrophages and lymphocytes, in contrast to the predominantly lymphocytic infiltrates described in classic polymyositis and dermatomyositis. Perifascicular atrophy, similar to what is seen in dermatomyositis, was encountered; however, vascular changes, typical of dermatomyositis, were absent. Occasional degenerating and regenerating muscle fibers were also observed in most cases. Additionally, a characteristic perimysial connective tissue fragmentation was described, a feature less often seen in classic polymyositis and dermatomyositis.³⁹

If antisynthetase syndrome is suspected or diagnosed, baseline pulmonary function testing (spirometry and carbon monoxide diffusion capacity) is indicated. It will often detect occult interstitial lung disease (reduced forced vital capacity and carbon monoxide diffusion capacity), and the diagnosis will be substantiated on thoracic high-resolution computed tomography. Respiratory muscle weakness can be detected with upright and supine spirometry.⁴⁰ Weakness of these muscles contributes to shortness of breath, and patients may need ventilatory support.

Thoracic high-resolution computed tomography

Different patterns of lung injury can be seen in antisynthetase syndrome. Diffuse ground-glass opacification may suggest a nonspecific interstitial pneumonitis pattern, which is the most common form of interstitial lung disease (Figure 2), whereas coarse reticulation or honeycombing correlates with a usual interstitial pneumonitis pattern. Patchy consolidation or air-space disease can occur if cryptogenic organizing pneumonia is the predominant pattern of lung injury.

Swallowing evaluation

A comprehensive swallowing evaluation by a speech therapist may be necessary for evaluation of dysphagia (from oropharyngeal and striated esophageal muscle weakness) and determination of aspiration risk (Table 2).

Lung histopathology

If necessary, a surgical lung biopsy is needed to document the pathologic pattern of injury, including the amount of fibrosis in the lung. Historically, in idiopathic inflammatory myopathy patients in general, this has taken the form of usual interstitial pneumonia, organizing pneumonia, or diffuse alveolar damage.⁴¹ With the emergence of the definition of nonspecific interstitial pneumonitis and fibrosis as a documented and accepted pattern, more studies have found this to be the most common pattern of lung injury.¹⁶ It is characterized by diffuse involvement of the lung by an interstitial chronic inflammatory infiltrate, a cellular type of nonspecific interstitial pneumonitis that progresses in a uniform pattern to a fibrotic type (Figure 5). This form of fibrosis rarely results in significant remodeling, so-called honeycomb changes. In addition, anti-Jo-1 antibody patients may also have an increased incidence of acute lung injury, including acute diffuse alveolar damage that is often superimposed on the underlying chronic lung disease.⁴²

In patients with pulmonary hypertension, histopathologic studies of the muscular pulmonary arteries often show moderate intimal fibroplasia, suggesting that a pulmonary arteriopathy with intimal thickening and luminal narrowing develops in some of these patients (Figure 5), independent of chronic hypoxic pulmonary vasoconstriction or vascular obstruction due to its entrapment within fibrotic lung tissue.¹⁷

TREATMENT

Glucocorticoids are the mainstay

Glucocorticoids are considered the mainstay of treatment. Patients should be advised that long-term use of glucocorticoids is necessary, though the response is variable. It is also important to discuss possible side effects of long-term glucocorticoid use.

Standard practice is to initiate treatment with high doses for the first 4 to 6 weeks to achieve disease control, followed by a slow taper over the next 9 to 12 months to the lowest effective dose to maintain remission. If the patient is profoundly weak, especially with respiratory muscle weakness or significant dysphagia and aspiration risk, hospital admission for intravenous methylprednisolone 1,000 mg daily for 3 to 5 days may be necessary. Otherwise, oral prednisone 1 mg/kg/day would be the usual starting dose.

If the patient’s muscle strength initially improves and then declines weeks to months later despite adequate therapy, glucocorticoid-induced myopathy should be suspected, especially if the muscle enzymes are within the reference range. This is more likely to occur if high-dose prednisone is continued for more than 6 to 8 weeks.

Improvement in muscle strength, which can take several weeks to several months, is a more reliable indicator of response to therapy than the serum creatine kinase level, which may take much longer to normalize. Relying on normalization of the creatine kinase level alone may lead to unnecessary prolongation of high-dose glucocorticoid therapy. It may take several months for the muscle enzymes to normalize, and there is usually a time lag between normalization of muscle enzymes and complete recovery of muscle strength.

Long-term use of high-dose prednisone leads to glucocorticoid-induced osteoporosis. Therefore, patients should receive osteoporosis prophylaxis including antiresorptive therapy with a bisphosphonate. In addition, prophylaxis against Pneumocystis jirovecii is indicated for patients treated with high-dose glucocorticoids.

Although glucocorticoids are considered the mainstay of treatment, additional immunosuppressive agents such as azathioprine and methotrexate are often required, both as glucocorticoid-sparing agents and to achieve adequate disease control.¹⁰ Addition of such agents from the outset is particularly necessary in patients with profound muscle weakness or those who have concomitant symptomatic interstitial lung disease.

No randomized controlled trial comparing azathioprine and methotrexate has been conducted to date. Therefore, the choice is based on patient preference, presence of coexisting interstitial lung disease or liver disease, commitment to limit alcohol consumption, and thiopurine methyltransferase status. Most patients need prolonged therapy.

In a randomized clinical trial, concomitant therapy with prednisone and azathioprine resulted in better functional outcomes and a significantly lower prednisone dose requirement for maintenance therapy at 3 years than with prednisone alone.^43,44 Although no such randomized study has been conducted using methotrexate, several retrospective studies have demonstrated 70% to 80% response rates, including those for whom monotherapy with glucocorticoids had failed.^45,46 The combination of methotrexate and azathioprine may be beneficial in patients who previously had inadequate responses to either of these agents alone.⁴⁷

For severe pulmonary involvement associated with antisynthetase syndrome, monthly intravenous infusion of cyclophosphamide has been shown to be effective.^48,49

Some recent studies established the role of tacrolimus in the treatment of both interstitial lung disease and myositis associated with antisynthetase syndrome.²⁹ Cyclosporine has also been successfully used in a case of interstitial lung disease associated with anti Jo-1 syndrome.³⁰

Rituximab, a monoclonal antibody to Blymphocyte antigen CD20, can also be used successfully in refractory disease,³¹ including refractory interstitial lung disease.³²

In an open-label prospective study, polymyositis refractory to glucocorticoids and multiple conventional immunosuppressive agents responded well to high-dose intravenous immune globulin in the short term.⁵⁰ However, the antisynthetase antibody status in this cohort was unknown; therefore, no definite conclusion could be drawn about the efficacy of intravenous immune globulin specifically in antisynthetase syndrome.

General measures

In patients with profound muscle weakness, physical therapy and rehabilitation should begin early. The goal is to reduce further muscle wasting from disuse and prevent muscle contractures. Patients with oropharyngeal and esophageal dysmotility should be advised about aspiration precautions and may need a swallow evaluation by a speech therapist; some may need temporary parenteral hyper-alimentation or J-tube insertion.

PROGNOSIS

If skeletal muscle involvement is the sole manifestation of antisynthetase syndrome, patients usually respond to glucocorticoids and immunosuppressive therapy and do fairly well. However, the outcome is not so promising when patients also develop interstitial lung disease, and the severity and type of lung injury usually determine the prognosis. As expected, patients with a progressive course of interstitial lung disease fare poorly, whereas those with a nonprogressive course tend to do relatively better. Older age at onset (> 60 years), presence of a malignancy, and a negative antinuclear antibody test are associated with a poor prognosis.⁷

Acknowledgment: The authors are grateful to Dr. Stephen Hatem, MD, staff radiologist, musculoskeletal radiology, Cleveland Clinic Imaging Institute, for help in the preparation of the magnetic resonance images. We also thank Dr. Steven Shook, MD, staff neurologist, Cleveland Clinic Neurological Institute, for help in summarizing the EMG findings.

A 66-year-old man was initially seen in clinic in March 2004 with a 5-month history of polyarthritis (affecting the finger joints, wrists, and knees) and several hours of morning stiffness. He also had significant proximal muscle weakness, progressive exertional dyspnea, and a nonproductive cough. There was no history of fever, chills, rash, dysphagia, or sicca symptoms. Findings on initial tests:

• His creatine kinase level was 700 U/L (reference range 30–220), which later rose to 1,664 U/L.
• He was positive for antinuclear antibody with a 5.7 optical density ratio (normal < 1.5) and for anti-Jo-1 antibody.
• An electromyogram was consistent with a necrotizing myopathy. Left rectus femoris biopsy revealed scattered degenerating and regenerating muscle fibers but no evidence of endomysial inflammation.
• On pulmonary function testing, his forced vital capacity was 80% of predicted, and his carbon monoxide diffusion capacity was 67% of predicted.
• High-resolution computed tomography revealed evidence of interstitial lung disease, characterized by bilateral patchy ground-glass opacities suggestive of active alveolitis, most extensive at the lung bases.
• Bronchoalveolar lavage indicated alveolitis, and transbronchial biopsy revealed pathologic changes consistent with cryptogenic organizing pneumonia. All cultures were negative.

This constellation of clinical manifestations, including myositis, interstitial lung disease, and polyarthritis, along with positive anti-Jo-1 antibody, confirmed the diagnosis of antisynthetase syndrome.

In June 2004, for his interstitial lung disease, he was started on daily oral cyclophosphamide along with high-dose oral prednisone. Three months later the skin of the tips and radial margins of his fingers started thickening and cracking, the appearance of which is classically described as “mechanic’s hands,” a well-described manifestation of antisynthetase syndrome (Figure 1).

Cyclophosphamide was continued for about a year. Subsequently, along with prednisone, he sequentially received various other immunosuppressive medications (methotrexate, tacrolimus, mycophenolate mofetil, and rituximab) over the next few years in an attempt to control his progressive interstitial lung disease. All of these agents were only partially and temporarily effective. Ultimately, despite all of these therapies, as his interstitial lung disease progressed, he needed supplemental oxygen and enrollment in a pulmonary rehabilitation program.

In March 2010, he was admitted with worsening dyspnea and significant peripheral edema and was found to have severe pulmonary arterial hypertension. He was started on bosentan. Eight months later sildenafil was added for progressive pulmonary arterial hypertension. However, his oxygenation status continued to decline.

In July 2011, he presented with chills, increasing shortness of breath, and a mild productive cough. As he was severely hypoxic, he was admitted to the intensive care unit and started on mechanical ventilation and broad-spectrum antibiotics. Despite escalation of oxygen therapy, his respiratory status rapidly deteriorated, and he developed hypotension requiring vasopressors. He ultimately died of cardiac arrest secondary to respiratory failure.

A CONSTELLATION OF MANIFESTATIONS

Antisynthetase syndrome, associated with anti-aminoacyl-transfer RNA (tRNA) synthetase antibodies, is characterized by a constellation of manifestations that include myositis, interstitial lung disease, mechanic’s hands, fever, Raynaud phenomenon, and nonerosive symmetric polyarthritis of the small joints.¹

Anti-Jo-1 antibody (anti-histidyl-tRNA synthetase) is the most common of the antibodies and also was the first one to be identified (Table 1). It was named after John P, a patient with polymyositis and interstitial lung disease, in whom it was first detected in 1980.² The onset of the syndrome associated with anti-Jo-1 antibody is often acute, and the myositis is usually steroid-responsive. However, not uncommonly, severe disease can develop over time, with a tendency to relapse and with a poor long-term prognosis.

RARE BUT UNDERRECOGNIZED

The true population prevalence of antisynthetase syndrome is unknown. Because this syndrome is rare, comprehensive epidemiologic studies are difficult to perform.

In several retrospective studies, the annual incidence of idiopathic inflammatory myopathies has been reported to be 2 to 10 new cases per million adults per year.³ Antisynthetase antibodies are detected in 20% to 40% of such cases.^4–6 The disease is two to three times more common in women than in men.⁷

Early diagnosis is difficult because the clinical presentation is varied and often nonspecific, clinically milder disease may escape detection, and many general practitioners lack familiarity with this syndrome and consequently do not recognize it. Moreover, tests for myositis-specific antibodies (including antisynthetase antibodies) are often not ordered in the evaluation of myositis, and hence the diagnosis of antisynthetase syndrome cannot be substantiated. Furthermore, interstitial lung disease can predominate or can be the sole manifestation in the absence of clinically apparent myositis,^8–10 and patients can be misdiagnosed as having idiopathic pulmonary fibrosis when underlying antisynthetase syndrome is not suspected. This distinction may be important because these conditions differ in their pathology and treatment. Histologically, the predominant pattern of lung injury in idiopathic pulmonary fibrosis is “usual interstitial pneumonia” which does not respond to immunosuppressive therapy, and hence lung transplantation is the only therapeutic option. On the other hand, in antisynthetase syndrome, the usual pattern of lung injury is “nonspecific interstitial pneumonia,” in which immunosuppressive therapy has a role.

Anti-Jo-1 antibody is detected in 15% to 25% of patients with polymyositis and in up to 70% of myositis patients with concomitant interstitial lung disease.¹¹ Autoantibodies to seven other, less frequently targeted, aminoacyl tRNA synthetases have also been described in patients with polymyositis and interstitial lung disease (Table 1).^11,12 In addition, an autoantibody to a 48-kDa transfer RNA-related protein (Wa) has been described.¹³ These non-Jo-1 antisynthetase antibodies are detected in only about 3% of myositis patients.¹⁴

ROLE OF ANTISYNTHETASE ANTIBODIES

Synthetases play a central role in protein synthesis by catalyzing the acetylation of tRNAs. The propensity of organ involvement in antisynthetase syndrome suggests that tissue-specific changes in muscle or lung lead to the production of unique forms of target autoantigens, the aminoacyl-tRNA synthetases. There is evidence that these enzymes themselves may be involved in recruiting both antigen-presenting and inflammatory cells to the site of muscle or lung injury.¹⁵ However, the molecular pathway that initiates and propagates this autoimmune response and the specific role of the antisynthetase antibodies in the pathogenesis of this syndrome are presently unknown.

SIX SALIENT CLINICAL FEATURES

There are six predominant clinical manifestations, which may be present at disease onset or appear later as the disease progresses:

• Fever
• Myositis
• Interstitial lung disease
• Mechanic’s hands
• Raynaud phenomenon
• Inflammatory polyarthritis.

There is considerable clinical heterogeneity, and one or other manifestation can predominate or can be the only expression of the syndrome. Furthermore, in the same patient, the individual features can prevail at different times and may develop years after onset of the disease. Therefore, in addition to patients with myositis, it would be important to suspect antisynthetase syndrome in patients presenting with isolated lung involvement (amyopathic interstitial lung disease), as there are therapeutic implications. Studies have demonstrated the efficacy of immunosuppressive agents in interstitial lung disease associated with antisynthetase syndrome (where the predominant pattern of lung injury is “nonspecific interstitial pneumonitis”), whereas lung transplantation has so far been the only treatment option in idiopathic pulmonary fibrosis.

Fever

About 20% of patients have a fever at disease onset or associated with relapses. Sometimes the fever can persist until treatment of antisynthetase syndrome is started.

Myositis

Muscle disease is seen in more than 90% of patients with anti-Jo-1 antisynthetase syndrome. It can be subclinical (in the absence of proximal myopathy), manifested by transient creatine kinase elevation only, which may normalize after therapy is initiated.

However, more commonly, patients develop profound proximal muscle weakness and sometimes muscle pain (Table 2). Weakness of the striated muscles of the upper esophagus, cricopharyngeus, and hypopharynx may cause dysphagia and makes these patients susceptible to aspiration pneumonia. Diaphragmatic and intercostal muscle weakness can contribute to shortness of breath in some patients. Myocarditis has also been reported.

Pulmonary disease

Interstitial lung disease develops in most patients with anti-Jo-1 antisynthetase syndrome, with a reported prevalence of about 90% in one series.¹⁶ Patients often present with acute, subacute, or insidious onset of exertional dyspnea. Sometimes there is an intractable nonproductive cough.

At the outset of antisynthetase syndrome, if the patient is profoundly weak because of myopathy or has inflammatory polyarthritis, mobility is significantly compromised, and exertional dyspnea may not be experienced. However, as the interstitial lung disease progresses, shortness of breath becomes overt, more so when the patient’s level of activity improves with treatment of myositis.

Inspiratory crackles on auscultation of the lung bases or changes on chest radiography are relatively insensitive findings and can miss early interstitial lung disease. Therefore, if antisynthetase syndrome is suspected or diagnosed, a baseline pulmonary function test (spirometry and carbon monoxide diffusion capacity) is indicated. It will often detect occult interstitial lung disease, and the diagnosis can then be confirmed with thoracic high-resolution computed tomography (Figure 2).

Pulmonary hypertension. Recent studies indicate that, similar to patients with other autoimmune rheumatic diseases, pulmonary hypertension can develop in patients with antisynthetase syndrome, with or without concomitant interstitial lung disease.^17,18 This complication occurred in the case presented here. It has been found that when pulmonary hypertension coexists with interstitial lung disease, its degree may not correlate with the severity of the latter.¹⁷ Additionally, pulmonary hypertension, when present, has been found to contribute independently to prognosis and survival.

In about 30% of patients, the skin of the tips and margins of the fingers becomes thickened, hyperkeratotic, and fissured, the appearance of which is classically described as mechanic’s hands. It is a common manifestation of antisynthetase syndrome and is particularly prominent on the radial side of the index fingers (Figure 1). Biopsy of affected skin shows an interface psoriasiform dermatitis.¹⁹ In addition, some dermatomyositis patients with Gottron papules and a heliotrope rash have antisynthetase antibodies.

Raynaud phenomenon

Raynaud phenomenon develops in about 40% of patients. Some have nailfold capillary abnormalities.²⁰ However, persistent or severe digital ischemia leading to digital ulceration or infarction is uncommon.²¹

Inflammatory arthritis

Arthralgias and arthritis are common (50%), the most common form being a symmetric polyarthritis of the small joints of the hands and feet. It is typically nonerosive but can sometimes be erosive and destructive.²⁰

Because inflammatory arthritis mimics rheumatoid arthritis, antisynthetase syndrome should be considered in rheumatoid factor-negative patients presenting with polyarthritis.

ASSOCIATION WITH MALIGNANCY

Traditional teaching has been that antisynthetase antibody is protective against an underlying malignancy.^22,23 However, several recently published case studies have reported various malignancies occurring within 6 to 12 months of the diagnosis of antisynthetase syndrome.^7,24 The debate as to whether these are chance associations or causal (a paraneoplastic phenomenon) has not been resolved at this time.²⁴

It is now recommended that patients with antisynthetase syndrome be screened for malignancies as appropriate for the patient’s age and sex. Screening should include a careful history and physical examination, complete blood cell count, comprehensive metabolic panel, chest radiography, mammography, and a gynecologic examination for women.²⁵ If abnormalities are found, a more thorough evaluation for cancer is appropriate.

DIAGNOSIS

Muscle enzyme levels are often elevated

Muscle enzymes (creatine kinase and aldolase) are often elevated. Serum creatine kinase levels can range between 5 to 50 times the upper limit of normal. In an established case, creatine kinase levels along with careful manual muscle strength testing may help evaluate myositis activity. However, in chronic and advanced disease, creatine kinase may be within the normal range despite active myositis, partly because of extensive loss of muscle mass. In myositis, it may be prudent to check both creatine kinase and aldolase; sometimes only serum aldolase level rises, when immune-mediated injury predominantly affects the early regenerative myocytes.²⁶

Judicious use of autoantibody testing

The characteristic clinical presentation is the initial clue to the diagnosis of antisynthetase syndrome, which is then supported by serologic testing.

Injudicious testing for a long list of antibodies should be avoided, as the cost is considerable and it does not influence further management. However, ordering an anti-Jo-1 antibody test in the correct clinical setting is appropriate, as it has high specificity,^27,28 and thus can help establish or refute the clinical suspicion of antisynthetase syndrome.

Screening pulmonary function testing and thoracic high-resolution computed tomography for all patients with polymyositis or dermatomyositis is not considered “standard of care” and will likely not be reimbursed by third-party payers. However, in a patient with symptoms and signs of myositis, the presence of an antisynthetase antibody should prompt screening for occult interstitial lung disease, even in the absence of symptoms. As lung disease ultimately determines the prognosis in antisynthetase syndrome, early diagnosis and management is the key. Therefore, these tests would likely be approved to establish the diagnosis of interstitial lung disease and evaluate its severity.

If a myositis patient is also found to have interstitial lung disease or develops mechanic’s hands, the likely diagnosis is antisynthetase syndrome, which can be confirmed by serologic testing for antisynthetase antibodies. Interstitial lung disease in antisynthetase syndrome is often from “nonspecific interstitial pneumonitis”; therefore, medications tested and proven effective for this condition should be approved and reimbursed by payers.^29–32

The coexistence of myositis and interstitial lung disease increases the sensitivity of anti-Jo-1 antibody.¹¹ Thus, the clinician can have more confidence in early recognition and initiation of aggressive but targeted disease-modifying therapy.

Various methods can be used for detecting antisynthetase antibodies, with comparable results.²⁸ Anti-Jo-1 antibody testing costs about $140. If that test is negative and antisynthetase syndrome is still suspected, then testing for the non-Jo-1 antisynthetase antibodies may be justified (Table 1). Though the cost of this panel of autoantibodies is about $300, it helps to confirm the diagnosis, and it influences the choice of second-line immunosuppressive agents such as tacrolimus²⁹ and rituximab³² in patients resistant to conventional immunosuppressive agents such as azathioprine and methotrexate.

Often, anti-Ro52 SS-A antibodies are present concurrently in patients with anti-Jo-1 syndrome.³³ In observational studies in patients with anti-Jo-1 antibody-associated interstitial lung disease, coexistence of anti-Ro52 SS-A antibody tended to predict a worse pulmonary outcome than in those with anti-Jo-1 antibody alone.^34,35

Electromyography

Electromyography not only helps differentiate between myopathic and neuropathic weakness, but it may also support the diagnosis of “inflammatory” myopathy as suggested by prominent muscle membrane irritability (fibrillations, positive sharp waves) and abnormal motor unit action potentials (spontaneous activity showing small, short, polyphasic potentials and early recruitment). However, the findings can be nonspecific, and may even be normal in 10% to 15% of patients.³⁶ Electromyographic abnormalities are most consistently observed in weak proximal muscles, and electromyography is also helpful in selecting a muscle for biopsy. Although no single electromyographic pattern is considered diagnostic for inflammatory myopathy, abnormalities are present in around 90% of patients (Table 2).³

Magnetic resonance imaging

Magnetic resonance imaging may show increased signal intensity in the affected muscles and surrounding tissues (Figure 3).³⁷ Because it lacks sensitivity and specificity, magnetic resonance imaging is not helpful in diagnosing the disease. However, in the correct clinical setting, it may be used to guide muscle biopsy, and it can help in monitoring the disease progress.³⁸

Muscle histopathology

Muscle biopsy, though often helpful, is not always diagnostic, and antisynthetase syndrome should still be suspected in the right clinical context, even in the absence of characteristic pathologic changes.

Biopsy of sites recently studied by electromyography should be avoided, and if the patient has undergone electromyography recently, the contralateral side should be selected for biopsy.

Reports of histopathologic findings in muscle biopsies in patients with antisynthetase syndrome document inflammatory myopathic features (Figure 4). In a series of patients with anti-Jo-1 syndrome, inflammation was noted in all cases, predominantly perimysial in location, with occasional endomysial and perivascular inflammation.³⁹ Many of the inflammatory cells seen were macrophages and lymphocytes, in contrast to the predominantly lymphocytic infiltrates described in classic polymyositis and dermatomyositis. Perifascicular atrophy, similar to what is seen in dermatomyositis, was encountered; however, vascular changes, typical of dermatomyositis, were absent. Occasional degenerating and regenerating muscle fibers were also observed in most cases. Additionally, a characteristic perimysial connective tissue fragmentation was described, a feature less often seen in classic polymyositis and dermatomyositis.³⁹

If antisynthetase syndrome is suspected or diagnosed, baseline pulmonary function testing (spirometry and carbon monoxide diffusion capacity) is indicated. It will often detect occult interstitial lung disease (reduced forced vital capacity and carbon monoxide diffusion capacity), and the diagnosis will be substantiated on thoracic high-resolution computed tomography. Respiratory muscle weakness can be detected with upright and supine spirometry.⁴⁰ Weakness of these muscles contributes to shortness of breath, and patients may need ventilatory support.

Thoracic high-resolution computed tomography

Different patterns of lung injury can be seen in antisynthetase syndrome. Diffuse ground-glass opacification may suggest a nonspecific interstitial pneumonitis pattern, which is the most common form of interstitial lung disease (Figure 2), whereas coarse reticulation or honeycombing correlates with a usual interstitial pneumonitis pattern. Patchy consolidation or air-space disease can occur if cryptogenic organizing pneumonia is the predominant pattern of lung injury.

Swallowing evaluation

A comprehensive swallowing evaluation by a speech therapist may be necessary for evaluation of dysphagia (from oropharyngeal and striated esophageal muscle weakness) and determination of aspiration risk (Table 2).

Lung histopathology

If necessary, a surgical lung biopsy is needed to document the pathologic pattern of injury, including the amount of fibrosis in the lung. Historically, in idiopathic inflammatory myopathy patients in general, this has taken the form of usual interstitial pneumonia, organizing pneumonia, or diffuse alveolar damage.⁴¹ With the emergence of the definition of nonspecific interstitial pneumonitis and fibrosis as a documented and accepted pattern, more studies have found this to be the most common pattern of lung injury.¹⁶ It is characterized by diffuse involvement of the lung by an interstitial chronic inflammatory infiltrate, a cellular type of nonspecific interstitial pneumonitis that progresses in a uniform pattern to a fibrotic type (Figure 5). This form of fibrosis rarely results in significant remodeling, so-called honeycomb changes. In addition, anti-Jo-1 antibody patients may also have an increased incidence of acute lung injury, including acute diffuse alveolar damage that is often superimposed on the underlying chronic lung disease.⁴²

In patients with pulmonary hypertension, histopathologic studies of the muscular pulmonary arteries often show moderate intimal fibroplasia, suggesting that a pulmonary arteriopathy with intimal thickening and luminal narrowing develops in some of these patients (Figure 5), independent of chronic hypoxic pulmonary vasoconstriction or vascular obstruction due to its entrapment within fibrotic lung tissue.¹⁷

TREATMENT

Glucocorticoids are the mainstay

Glucocorticoids are considered the mainstay of treatment. Patients should be advised that long-term use of glucocorticoids is necessary, though the response is variable. It is also important to discuss possible side effects of long-term glucocorticoid use.

Standard practice is to initiate treatment with high doses for the first 4 to 6 weeks to achieve disease control, followed by a slow taper over the next 9 to 12 months to the lowest effective dose to maintain remission. If the patient is profoundly weak, especially with respiratory muscle weakness or significant dysphagia and aspiration risk, hospital admission for intravenous methylprednisolone 1,000 mg daily for 3 to 5 days may be necessary. Otherwise, oral prednisone 1 mg/kg/day would be the usual starting dose.

If the patient’s muscle strength initially improves and then declines weeks to months later despite adequate therapy, glucocorticoid-induced myopathy should be suspected, especially if the muscle enzymes are within the reference range. This is more likely to occur if high-dose prednisone is continued for more than 6 to 8 weeks.

Improvement in muscle strength, which can take several weeks to several months, is a more reliable indicator of response to therapy than the serum creatine kinase level, which may take much longer to normalize. Relying on normalization of the creatine kinase level alone may lead to unnecessary prolongation of high-dose glucocorticoid therapy. It may take several months for the muscle enzymes to normalize, and there is usually a time lag between normalization of muscle enzymes and complete recovery of muscle strength.

Long-term use of high-dose prednisone leads to glucocorticoid-induced osteoporosis. Therefore, patients should receive osteoporosis prophylaxis including antiresorptive therapy with a bisphosphonate. In addition, prophylaxis against Pneumocystis jirovecii is indicated for patients treated with high-dose glucocorticoids.

Although glucocorticoids are considered the mainstay of treatment, additional immunosuppressive agents such as azathioprine and methotrexate are often required, both as glucocorticoid-sparing agents and to achieve adequate disease control.¹⁰ Addition of such agents from the outset is particularly necessary in patients with profound muscle weakness or those who have concomitant symptomatic interstitial lung disease.

No randomized controlled trial comparing azathioprine and methotrexate has been conducted to date. Therefore, the choice is based on patient preference, presence of coexisting interstitial lung disease or liver disease, commitment to limit alcohol consumption, and thiopurine methyltransferase status. Most patients need prolonged therapy.

In a randomized clinical trial, concomitant therapy with prednisone and azathioprine resulted in better functional outcomes and a significantly lower prednisone dose requirement for maintenance therapy at 3 years than with prednisone alone.^43,44 Although no such randomized study has been conducted using methotrexate, several retrospective studies have demonstrated 70% to 80% response rates, including those for whom monotherapy with glucocorticoids had failed.^45,46 The combination of methotrexate and azathioprine may be beneficial in patients who previously had inadequate responses to either of these agents alone.⁴⁷

For severe pulmonary involvement associated with antisynthetase syndrome, monthly intravenous infusion of cyclophosphamide has been shown to be effective.^48,49

Some recent studies established the role of tacrolimus in the treatment of both interstitial lung disease and myositis associated with antisynthetase syndrome.²⁹ Cyclosporine has also been successfully used in a case of interstitial lung disease associated with anti Jo-1 syndrome.³⁰

Rituximab, a monoclonal antibody to Blymphocyte antigen CD20, can also be used successfully in refractory disease,³¹ including refractory interstitial lung disease.³²

In an open-label prospective study, polymyositis refractory to glucocorticoids and multiple conventional immunosuppressive agents responded well to high-dose intravenous immune globulin in the short term.⁵⁰ However, the antisynthetase antibody status in this cohort was unknown; therefore, no definite conclusion could be drawn about the efficacy of intravenous immune globulin specifically in antisynthetase syndrome.

General measures

In patients with profound muscle weakness, physical therapy and rehabilitation should begin early. The goal is to reduce further muscle wasting from disuse and prevent muscle contractures. Patients with oropharyngeal and esophageal dysmotility should be advised about aspiration precautions and may need a swallow evaluation by a speech therapist; some may need temporary parenteral hyper-alimentation or J-tube insertion.

PROGNOSIS

If skeletal muscle involvement is the sole manifestation of antisynthetase syndrome, patients usually respond to glucocorticoids and immunosuppressive therapy and do fairly well. However, the outcome is not so promising when patients also develop interstitial lung disease, and the severity and type of lung injury usually determine the prognosis. As expected, patients with a progressive course of interstitial lung disease fare poorly, whereas those with a nonprogressive course tend to do relatively better. Older age at onset (> 60 years), presence of a malignancy, and a negative antinuclear antibody test are associated with a poor prognosis.⁷

Acknowledgment: The authors are grateful to Dr. Stephen Hatem, MD, staff radiologist, musculoskeletal radiology, Cleveland Clinic Imaging Institute, for help in the preparation of the magnetic resonance images. We also thank Dr. Steven Shook, MD, staff neurologist, Cleveland Clinic Neurological Institute, for help in summarizing the EMG findings.

A 66-year-old man was initially seen in clinic in March 2004 with a 5-month history of polyarthritis (affecting the finger joints, wrists, and knees) and several hours of morning stiffness. He also had significant proximal muscle weakness, progressive exertional dyspnea, and a nonproductive cough. There was no history of fever, chills, rash, dysphagia, or sicca symptoms. Findings on initial tests:

• His creatine kinase level was 700 U/L (reference range 30–220), which later rose to 1,664 U/L.
• He was positive for antinuclear antibody with a 5.7 optical density ratio (normal < 1.5) and for anti-Jo-1 antibody.
• An electromyogram was consistent with a necrotizing myopathy. Left rectus femoris biopsy revealed scattered degenerating and regenerating muscle fibers but no evidence of endomysial inflammation.
• On pulmonary function testing, his forced vital capacity was 80% of predicted, and his carbon monoxide diffusion capacity was 67% of predicted.
• High-resolution computed tomography revealed evidence of interstitial lung disease, characterized by bilateral patchy ground-glass opacities suggestive of active alveolitis, most extensive at the lung bases.
• Bronchoalveolar lavage indicated alveolitis, and transbronchial biopsy revealed pathologic changes consistent with cryptogenic organizing pneumonia. All cultures were negative.

This constellation of clinical manifestations, including myositis, interstitial lung disease, and polyarthritis, along with positive anti-Jo-1 antibody, confirmed the diagnosis of antisynthetase syndrome.

In June 2004, for his interstitial lung disease, he was started on daily oral cyclophosphamide along with high-dose oral prednisone. Three months later the skin of the tips and radial margins of his fingers started thickening and cracking, the appearance of which is classically described as “mechanic’s hands,” a well-described manifestation of antisynthetase syndrome (Figure 1).

Cyclophosphamide was continued for about a year. Subsequently, along with prednisone, he sequentially received various other immunosuppressive medications (methotrexate, tacrolimus, mycophenolate mofetil, and rituximab) over the next few years in an attempt to control his progressive interstitial lung disease. All of these agents were only partially and temporarily effective. Ultimately, despite all of these therapies, as his interstitial lung disease progressed, he needed supplemental oxygen and enrollment in a pulmonary rehabilitation program.

In March 2010, he was admitted with worsening dyspnea and significant peripheral edema and was found to have severe pulmonary arterial hypertension. He was started on bosentan. Eight months later sildenafil was added for progressive pulmonary arterial hypertension. However, his oxygenation status continued to decline.

In July 2011, he presented with chills, increasing shortness of breath, and a mild productive cough. As he was severely hypoxic, he was admitted to the intensive care unit and started on mechanical ventilation and broad-spectrum antibiotics. Despite escalation of oxygen therapy, his respiratory status rapidly deteriorated, and he developed hypotension requiring vasopressors. He ultimately died of cardiac arrest secondary to respiratory failure.

A CONSTELLATION OF MANIFESTATIONS

Antisynthetase syndrome, associated with anti-aminoacyl-transfer RNA (tRNA) synthetase antibodies, is characterized by a constellation of manifestations that include myositis, interstitial lung disease, mechanic’s hands, fever, Raynaud phenomenon, and nonerosive symmetric polyarthritis of the small joints.¹

Anti-Jo-1 antibody (anti-histidyl-tRNA synthetase) is the most common of the antibodies and also was the first one to be identified (Table 1). It was named after John P, a patient with polymyositis and interstitial lung disease, in whom it was first detected in 1980.² The onset of the syndrome associated with anti-Jo-1 antibody is often acute, and the myositis is usually steroid-responsive. However, not uncommonly, severe disease can develop over time, with a tendency to relapse and with a poor long-term prognosis.

RARE BUT UNDERRECOGNIZED

The true population prevalence of antisynthetase syndrome is unknown. Because this syndrome is rare, comprehensive epidemiologic studies are difficult to perform.

In several retrospective studies, the annual incidence of idiopathic inflammatory myopathies has been reported to be 2 to 10 new cases per million adults per year.³ Antisynthetase antibodies are detected in 20% to 40% of such cases.^4–6 The disease is two to three times more common in women than in men.⁷

Early diagnosis is difficult because the clinical presentation is varied and often nonspecific, clinically milder disease may escape detection, and many general practitioners lack familiarity with this syndrome and consequently do not recognize it. Moreover, tests for myositis-specific antibodies (including antisynthetase antibodies) are often not ordered in the evaluation of myositis, and hence the diagnosis of antisynthetase syndrome cannot be substantiated. Furthermore, interstitial lung disease can predominate or can be the sole manifestation in the absence of clinically apparent myositis,^8–10 and patients can be misdiagnosed as having idiopathic pulmonary fibrosis when underlying antisynthetase syndrome is not suspected. This distinction may be important because these conditions differ in their pathology and treatment. Histologically, the predominant pattern of lung injury in idiopathic pulmonary fibrosis is “usual interstitial pneumonia” which does not respond to immunosuppressive therapy, and hence lung transplantation is the only therapeutic option. On the other hand, in antisynthetase syndrome, the usual pattern of lung injury is “nonspecific interstitial pneumonia,” in which immunosuppressive therapy has a role.

Anti-Jo-1 antibody is detected in 15% to 25% of patients with polymyositis and in up to 70% of myositis patients with concomitant interstitial lung disease.¹¹ Autoantibodies to seven other, less frequently targeted, aminoacyl tRNA synthetases have also been described in patients with polymyositis and interstitial lung disease (Table 1).^11,12 In addition, an autoantibody to a 48-kDa transfer RNA-related protein (Wa) has been described.¹³ These non-Jo-1 antisynthetase antibodies are detected in only about 3% of myositis patients.¹⁴

ROLE OF ANTISYNTHETASE ANTIBODIES

Synthetases play a central role in protein synthesis by catalyzing the acetylation of tRNAs. The propensity of organ involvement in antisynthetase syndrome suggests that tissue-specific changes in muscle or lung lead to the production of unique forms of target autoantigens, the aminoacyl-tRNA synthetases. There is evidence that these enzymes themselves may be involved in recruiting both antigen-presenting and inflammatory cells to the site of muscle or lung injury.¹⁵ However, the molecular pathway that initiates and propagates this autoimmune response and the specific role of the antisynthetase antibodies in the pathogenesis of this syndrome are presently unknown.

SIX SALIENT CLINICAL FEATURES

There are six predominant clinical manifestations, which may be present at disease onset or appear later as the disease progresses:

• Fever
• Myositis
• Interstitial lung disease
• Mechanic’s hands
• Raynaud phenomenon
• Inflammatory polyarthritis.

There is considerable clinical heterogeneity, and one or other manifestation can predominate or can be the only expression of the syndrome. Furthermore, in the same patient, the individual features can prevail at different times and may develop years after onset of the disease. Therefore, in addition to patients with myositis, it would be important to suspect antisynthetase syndrome in patients presenting with isolated lung involvement (amyopathic interstitial lung disease), as there are therapeutic implications. Studies have demonstrated the efficacy of immunosuppressive agents in interstitial lung disease associated with antisynthetase syndrome (where the predominant pattern of lung injury is “nonspecific interstitial pneumonitis”), whereas lung transplantation has so far been the only treatment option in idiopathic pulmonary fibrosis.

Fever

About 20% of patients have a fever at disease onset or associated with relapses. Sometimes the fever can persist until treatment of antisynthetase syndrome is started.

Myositis

Muscle disease is seen in more than 90% of patients with anti-Jo-1 antisynthetase syndrome. It can be subclinical (in the absence of proximal myopathy), manifested by transient creatine kinase elevation only, which may normalize after therapy is initiated.

However, more commonly, patients develop profound proximal muscle weakness and sometimes muscle pain (Table 2). Weakness of the striated muscles of the upper esophagus, cricopharyngeus, and hypopharynx may cause dysphagia and makes these patients susceptible to aspiration pneumonia. Diaphragmatic and intercostal muscle weakness can contribute to shortness of breath in some patients. Myocarditis has also been reported.

Pulmonary disease

Interstitial lung disease develops in most patients with anti-Jo-1 antisynthetase syndrome, with a reported prevalence of about 90% in one series.¹⁶ Patients often present with acute, subacute, or insidious onset of exertional dyspnea. Sometimes there is an intractable nonproductive cough.

At the outset of antisynthetase syndrome, if the patient is profoundly weak because of myopathy or has inflammatory polyarthritis, mobility is significantly compromised, and exertional dyspnea may not be experienced. However, as the interstitial lung disease progresses, shortness of breath becomes overt, more so when the patient’s level of activity improves with treatment of myositis.

Inspiratory crackles on auscultation of the lung bases or changes on chest radiography are relatively insensitive findings and can miss early interstitial lung disease. Therefore, if antisynthetase syndrome is suspected or diagnosed, a baseline pulmonary function test (spirometry and carbon monoxide diffusion capacity) is indicated. It will often detect occult interstitial lung disease, and the diagnosis can then be confirmed with thoracic high-resolution computed tomography (Figure 2).

Pulmonary hypertension. Recent studies indicate that, similar to patients with other autoimmune rheumatic diseases, pulmonary hypertension can develop in patients with antisynthetase syndrome, with or without concomitant interstitial lung disease.^17,18 This complication occurred in the case presented here. It has been found that when pulmonary hypertension coexists with interstitial lung disease, its degree may not correlate with the severity of the latter.¹⁷ Additionally, pulmonary hypertension, when present, has been found to contribute independently to prognosis and survival.

In about 30% of patients, the skin of the tips and margins of the fingers becomes thickened, hyperkeratotic, and fissured, the appearance of which is classically described as mechanic’s hands. It is a common manifestation of antisynthetase syndrome and is particularly prominent on the radial side of the index fingers (Figure 1). Biopsy of affected skin shows an interface psoriasiform dermatitis.¹⁹ In addition, some dermatomyositis patients with Gottron papules and a heliotrope rash have antisynthetase antibodies.

Raynaud phenomenon

Raynaud phenomenon develops in about 40% of patients. Some have nailfold capillary abnormalities.²⁰ However, persistent or severe digital ischemia leading to digital ulceration or infarction is uncommon.²¹

Inflammatory arthritis

Arthralgias and arthritis are common (50%), the most common form being a symmetric polyarthritis of the small joints of the hands and feet. It is typically nonerosive but can sometimes be erosive and destructive.²⁰

Because inflammatory arthritis mimics rheumatoid arthritis, antisynthetase syndrome should be considered in rheumatoid factor-negative patients presenting with polyarthritis.

ASSOCIATION WITH MALIGNANCY

Traditional teaching has been that antisynthetase antibody is protective against an underlying malignancy.^22,23 However, several recently published case studies have reported various malignancies occurring within 6 to 12 months of the diagnosis of antisynthetase syndrome.^7,24 The debate as to whether these are chance associations or causal (a paraneoplastic phenomenon) has not been resolved at this time.²⁴

It is now recommended that patients with antisynthetase syndrome be screened for malignancies as appropriate for the patient’s age and sex. Screening should include a careful history and physical examination, complete blood cell count, comprehensive metabolic panel, chest radiography, mammography, and a gynecologic examination for women.²⁵ If abnormalities are found, a more thorough evaluation for cancer is appropriate.

DIAGNOSIS

Muscle enzyme levels are often elevated

Muscle enzymes (creatine kinase and aldolase) are often elevated. Serum creatine kinase levels can range between 5 to 50 times the upper limit of normal. In an established case, creatine kinase levels along with careful manual muscle strength testing may help evaluate myositis activity. However, in chronic and advanced disease, creatine kinase may be within the normal range despite active myositis, partly because of extensive loss of muscle mass. In myositis, it may be prudent to check both creatine kinase and aldolase; sometimes only serum aldolase level rises, when immune-mediated injury predominantly affects the early regenerative myocytes.²⁶

Judicious use of autoantibody testing

The characteristic clinical presentation is the initial clue to the diagnosis of antisynthetase syndrome, which is then supported by serologic testing.

Injudicious testing for a long list of antibodies should be avoided, as the cost is considerable and it does not influence further management. However, ordering an anti-Jo-1 antibody test in the correct clinical setting is appropriate, as it has high specificity,^27,28 and thus can help establish or refute the clinical suspicion of antisynthetase syndrome.

Screening pulmonary function testing and thoracic high-resolution computed tomography for all patients with polymyositis or dermatomyositis is not considered “standard of care” and will likely not be reimbursed by third-party payers. However, in a patient with symptoms and signs of myositis, the presence of an antisynthetase antibody should prompt screening for occult interstitial lung disease, even in the absence of symptoms. As lung disease ultimately determines the prognosis in antisynthetase syndrome, early diagnosis and management is the key. Therefore, these tests would likely be approved to establish the diagnosis of interstitial lung disease and evaluate its severity.

If a myositis patient is also found to have interstitial lung disease or develops mechanic’s hands, the likely diagnosis is antisynthetase syndrome, which can be confirmed by serologic testing for antisynthetase antibodies. Interstitial lung disease in antisynthetase syndrome is often from “nonspecific interstitial pneumonitis”; therefore, medications tested and proven effective for this condition should be approved and reimbursed by payers.^29–32

The coexistence of myositis and interstitial lung disease increases the sensitivity of anti-Jo-1 antibody.¹¹ Thus, the clinician can have more confidence in early recognition and initiation of aggressive but targeted disease-modifying therapy.

Various methods can be used for detecting antisynthetase antibodies, with comparable results.²⁸ Anti-Jo-1 antibody testing costs about $140. If that test is negative and antisynthetase syndrome is still suspected, then testing for the non-Jo-1 antisynthetase antibodies may be justified (Table 1). Though the cost of this panel of autoantibodies is about $300, it helps to confirm the diagnosis, and it influences the choice of second-line immunosuppressive agents such as tacrolimus²⁹ and rituximab³² in patients resistant to conventional immunosuppressive agents such as azathioprine and methotrexate.

Often, anti-Ro52 SS-A antibodies are present concurrently in patients with anti-Jo-1 syndrome.³³ In observational studies in patients with anti-Jo-1 antibody-associated interstitial lung disease, coexistence of anti-Ro52 SS-A antibody tended to predict a worse pulmonary outcome than in those with anti-Jo-1 antibody alone.^34,35

Electromyography

Electromyography not only helps differentiate between myopathic and neuropathic weakness, but it may also support the diagnosis of “inflammatory” myopathy as suggested by prominent muscle membrane irritability (fibrillations, positive sharp waves) and abnormal motor unit action potentials (spontaneous activity showing small, short, polyphasic potentials and early recruitment). However, the findings can be nonspecific, and may even be normal in 10% to 15% of patients.³⁶ Electromyographic abnormalities are most consistently observed in weak proximal muscles, and electromyography is also helpful in selecting a muscle for biopsy. Although no single electromyographic pattern is considered diagnostic for inflammatory myopathy, abnormalities are present in around 90% of patients (Table 2).³

Magnetic resonance imaging

Magnetic resonance imaging may show increased signal intensity in the affected muscles and surrounding tissues (Figure 3).³⁷ Because it lacks sensitivity and specificity, magnetic resonance imaging is not helpful in diagnosing the disease. However, in the correct clinical setting, it may be used to guide muscle biopsy, and it can help in monitoring the disease progress.³⁸

Muscle histopathology

Muscle biopsy, though often helpful, is not always diagnostic, and antisynthetase syndrome should still be suspected in the right clinical context, even in the absence of characteristic pathologic changes.

Biopsy of sites recently studied by electromyography should be avoided, and if the patient has undergone electromyography recently, the contralateral side should be selected for biopsy.

Reports of histopathologic findings in muscle biopsies in patients with antisynthetase syndrome document inflammatory myopathic features (Figure 4). In a series of patients with anti-Jo-1 syndrome, inflammation was noted in all cases, predominantly perimysial in location, with occasional endomysial and perivascular inflammation.³⁹ Many of the inflammatory cells seen were macrophages and lymphocytes, in contrast to the predominantly lymphocytic infiltrates described in classic polymyositis and dermatomyositis. Perifascicular atrophy, similar to what is seen in dermatomyositis, was encountered; however, vascular changes, typical of dermatomyositis, were absent. Occasional degenerating and regenerating muscle fibers were also observed in most cases. Additionally, a characteristic perimysial connective tissue fragmentation was described, a feature less often seen in classic polymyositis and dermatomyositis.³⁹

If antisynthetase syndrome is suspected or diagnosed, baseline pulmonary function testing (spirometry and carbon monoxide diffusion capacity) is indicated. It will often detect occult interstitial lung disease (reduced forced vital capacity and carbon monoxide diffusion capacity), and the diagnosis will be substantiated on thoracic high-resolution computed tomography. Respiratory muscle weakness can be detected with upright and supine spirometry.⁴⁰ Weakness of these muscles contributes to shortness of breath, and patients may need ventilatory support.

Thoracic high-resolution computed tomography

Different patterns of lung injury can be seen in antisynthetase syndrome. Diffuse ground-glass opacification may suggest a nonspecific interstitial pneumonitis pattern, which is the most common form of interstitial lung disease (Figure 2), whereas coarse reticulation or honeycombing correlates with a usual interstitial pneumonitis pattern. Patchy consolidation or air-space disease can occur if cryptogenic organizing pneumonia is the predominant pattern of lung injury.

Swallowing evaluation

A comprehensive swallowing evaluation by a speech therapist may be necessary for evaluation of dysphagia (from oropharyngeal and striated esophageal muscle weakness) and determination of aspiration risk (Table 2).

Lung histopathology

If necessary, a surgical lung biopsy is needed to document the pathologic pattern of injury, including the amount of fibrosis in the lung. Historically, in idiopathic inflammatory myopathy patients in general, this has taken the form of usual interstitial pneumonia, organizing pneumonia, or diffuse alveolar damage.⁴¹ With the emergence of the definition of nonspecific interstitial pneumonitis and fibrosis as a documented and accepted pattern, more studies have found this to be the most common pattern of lung injury.¹⁶ It is characterized by diffuse involvement of the lung by an interstitial chronic inflammatory infiltrate, a cellular type of nonspecific interstitial pneumonitis that progresses in a uniform pattern to a fibrotic type (Figure 5). This form of fibrosis rarely results in significant remodeling, so-called honeycomb changes. In addition, anti-Jo-1 antibody patients may also have an increased incidence of acute lung injury, including acute diffuse alveolar damage that is often superimposed on the underlying chronic lung disease.⁴²

In patients with pulmonary hypertension, histopathologic studies of the muscular pulmonary arteries often show moderate intimal fibroplasia, suggesting that a pulmonary arteriopathy with intimal thickening and luminal narrowing develops in some of these patients (Figure 5), independent of chronic hypoxic pulmonary vasoconstriction or vascular obstruction due to its entrapment within fibrotic lung tissue.¹⁷

TREATMENT

Glucocorticoids are the mainstay

Glucocorticoids are considered the mainstay of treatment. Patients should be advised that long-term use of glucocorticoids is necessary, though the response is variable. It is also important to discuss possible side effects of long-term glucocorticoid use.

Standard practice is to initiate treatment with high doses for the first 4 to 6 weeks to achieve disease control, followed by a slow taper over the next 9 to 12 months to the lowest effective dose to maintain remission. If the patient is profoundly weak, especially with respiratory muscle weakness or significant dysphagia and aspiration risk, hospital admission for intravenous methylprednisolone 1,000 mg daily for 3 to 5 days may be necessary. Otherwise, oral prednisone 1 mg/kg/day would be the usual starting dose.

If the patient’s muscle strength initially improves and then declines weeks to months later despite adequate therapy, glucocorticoid-induced myopathy should be suspected, especially if the muscle enzymes are within the reference range. This is more likely to occur if high-dose prednisone is continued for more than 6 to 8 weeks.

Improvement in muscle strength, which can take several weeks to several months, is a more reliable indicator of response to therapy than the serum creatine kinase level, which may take much longer to normalize. Relying on normalization of the creatine kinase level alone may lead to unnecessary prolongation of high-dose glucocorticoid therapy. It may take several months for the muscle enzymes to normalize, and there is usually a time lag between normalization of muscle enzymes and complete recovery of muscle strength.

Long-term use of high-dose prednisone leads to glucocorticoid-induced osteoporosis. Therefore, patients should receive osteoporosis prophylaxis including antiresorptive therapy with a bisphosphonate. In addition, prophylaxis against Pneumocystis jirovecii is indicated for patients treated with high-dose glucocorticoids.

Although glucocorticoids are considered the mainstay of treatment, additional immunosuppressive agents such as azathioprine and methotrexate are often required, both as glucocorticoid-sparing agents and to achieve adequate disease control.¹⁰ Addition of such agents from the outset is particularly necessary in patients with profound muscle weakness or those who have concomitant symptomatic interstitial lung disease.

No randomized controlled trial comparing azathioprine and methotrexate has been conducted to date. Therefore, the choice is based on patient preference, presence of coexisting interstitial lung disease or liver disease, commitment to limit alcohol consumption, and thiopurine methyltransferase status. Most patients need prolonged therapy.

In a randomized clinical trial, concomitant therapy with prednisone and azathioprine resulted in better functional outcomes and a significantly lower prednisone dose requirement for maintenance therapy at 3 years than with prednisone alone.^43,44 Although no such randomized study has been conducted using methotrexate, several retrospective studies have demonstrated 70% to 80% response rates, including those for whom monotherapy with glucocorticoids had failed.^45,46 The combination of methotrexate and azathioprine may be beneficial in patients who previously had inadequate responses to either of these agents alone.⁴⁷

For severe pulmonary involvement associated with antisynthetase syndrome, monthly intravenous infusion of cyclophosphamide has been shown to be effective.^48,49

Some recent studies established the role of tacrolimus in the treatment of both interstitial lung disease and myositis associated with antisynthetase syndrome.²⁹ Cyclosporine has also been successfully used in a case of interstitial lung disease associated with anti Jo-1 syndrome.³⁰

Rituximab, a monoclonal antibody to Blymphocyte antigen CD20, can also be used successfully in refractory disease,³¹ including refractory interstitial lung disease.³²

In an open-label prospective study, polymyositis refractory to glucocorticoids and multiple conventional immunosuppressive agents responded well to high-dose intravenous immune globulin in the short term.⁵⁰ However, the antisynthetase antibody status in this cohort was unknown; therefore, no definite conclusion could be drawn about the efficacy of intravenous immune globulin specifically in antisynthetase syndrome.

General measures

In patients with profound muscle weakness, physical therapy and rehabilitation should begin early. The goal is to reduce further muscle wasting from disuse and prevent muscle contractures. Patients with oropharyngeal and esophageal dysmotility should be advised about aspiration precautions and may need a swallow evaluation by a speech therapist; some may need temporary parenteral hyper-alimentation or J-tube insertion.

PROGNOSIS

If skeletal muscle involvement is the sole manifestation of antisynthetase syndrome, patients usually respond to glucocorticoids and immunosuppressive therapy and do fairly well. However, the outcome is not so promising when patients also develop interstitial lung disease, and the severity and type of lung injury usually determine the prognosis. As expected, patients with a progressive course of interstitial lung disease fare poorly, whereas those with a nonprogressive course tend to do relatively better. Older age at onset (> 60 years), presence of a malignancy, and a negative antinuclear antibody test are associated with a poor prognosis.⁷

Acknowledgment: The authors are grateful to Dr. Stephen Hatem, MD, staff radiologist, musculoskeletal radiology, Cleveland Clinic Imaging Institute, for help in the preparation of the magnetic resonance images. We also thank Dr. Steven Shook, MD, staff neurologist, Cleveland Clinic Neurological Institute, for help in summarizing the EMG findings.

Mycoplasma pneumoniae is a cell wall–deficient pleomorphic bacterium and well-reported cause of respiratory tract infection in the school-aged child. Symptoms are variable, and clinical presentations run the gamut from upper respiratory (usually self-limited) and lower respiratory tract involvement (pneumonia) to unusual manifestations including nervous system disease (encephalitis, cerebellar ataxia, transverse myelitis), hemolytic anemia, Stevens-Johnson syndrome, and myocarditis/pericarditis.

Pneumonia occurs in 10% of infected school-aged children, and cough can persist for 3-4 weeks; some children wheeze in the setting of Mycoplasma infection. Radiographic patterns of disease are variable; patchy alveolar infiltrates with small pleural effusions are often described. Consolidated pneumonia, large effusions, and hilar adenopathy are uncommonly reported, and severe disease has been described in certain patient populations, including those with sickle cell disease, children with Down syndrome, and those with immunodeficiencies. The acute chest presentation has been associated with M. pneumoniae in children with sickle cell anemia and prolonged hospitalizations (mean, 10 days), and the need for transfusion and mechanical ventilation was noted in 82% and 6%, respectively, in one study (Pediatrics 2003;112(1 Pt 1):87-95). Community clusters of pneumonia are reported in school-aged children, and in Rhode Island, an outbreak was reported in children from four schools; 76 had pneumonia and 3 had encephalitis (J. Infect. Dis. 2008;198:1365-74).

Considering this is a common pathogen, there are a number of questions regarding the scope of disease and impact of treatment that are incompletely answered. The first problem is that it is hard to confirm diagnostically. Culture is technically difficult, the organism takes up to 3 weeks to grow, and the diagnostic test is offered in very few labs. The old-fashioned cold agglutinin test has a low sensitivity and specificity; an increase in titers can be seen during a variety of viral infections. Polymerase chain reaction (PCR) on respiratory secretions is increasingly available; sensitivity and specificity are said to be 80% and 100%, respectively. The organism can persist in the respiratory tract for several weeks though, even after treatment, so PCR can remain positive for 2-3 weeks. This makes it hard to use PCR to confirm M. pneumoniae as the etiologic agent, especially in the setting of unusual clinical presentations. Serologic testing is often ordered and hard to interpret. False positive IgM antibody tests are not uncommon, and IgM antibody can persist for months. Outside of PCR and culture, acute and convalescent specimens can be used diagnostically, and a fourfold IgG antibody rise is consistent with acute infection.

Macrolides are regarded as the preferred treatment for M. pneumoniae pneumonia, but several studies question whether treatment impacts the clinical course. This may be due to the inherent difficulty of confirming M. pneumoniae as the etiologic agent, as most studies used serology to confirm the diagnosis. In countries outside the United States, macrolide resistance is well reported, and this may be underappreciated in the United States. We recently cared for a teenager with Down syndrome with pneumonia caused by M. pneumoniae who had a protracted clinical course. Fever and hypoxemia were persistent over a several-week period despite two courses of azithromycin and exclusion of virus, bacteria, and fungal pathogens. Bronchoalveolar lavage was performed, M. pneumoniae was detected by PCR, and macrolide resistance was confirmed. Levofloxacin was given, and she recovered over the next week.

Macrolide resistance is commonly reported outside the United States; rates in China are reported to be greater than 90%, in Japan 80%, and in Europe, between 15% and 25%. A recent study from Greg Storch and his colleagues (Pediatr. Infect. Dis. J. 2012;31:409-10) documented macrolide resistance in 8% of respiratory samples collected between 2007 and 2010 (49 patients; mean age, 10 years), noting the resistance rate was 3% in 2007-2008 and 15% in 2009-2010. A recently published study of data from Canada reported that 12.1% of M. pneumoniae–positive specimens collected between 2010 and January 2012 carried nucleotide mutations associated with macrolide resistance in the 23S rRNA gene (Emerg. Infect. Dis. 2013 September [doi: 10.3201/eid1909.121466]). Anecdotal studies suggest that patients with macrolide-resistant M. pneumoniae infection clinically improve when given doxycycline (or minocycline) or levofloxacin.

A number of clinical questions regarding M. pneumoniae may be answered more definitively in the future, but we need more easily available diagnostics (PCR is a good start), routinely accessible susceptibility data, and a good randomized controlled study to investigate the question of whether treatment shortens the course of disease.

Dr. Jackson is chief of pediatric infectious diseases at Children’s Mercy Hospital, Kansas City, Mo., and professor of pediatrics at the University of Missouri-Kansas City. She said she has no conflicts of interest to disclose. E-mail her at [email protected].

Mycoplasma pneumoniae is a cell wall–deficient pleomorphic bacterium and well-reported cause of respiratory tract infection in the school-aged child. Symptoms are variable, and clinical presentations run the gamut from upper respiratory (usually self-limited) and lower respiratory tract involvement (pneumonia) to unusual manifestations including nervous system disease (encephalitis, cerebellar ataxia, transverse myelitis), hemolytic anemia, Stevens-Johnson syndrome, and myocarditis/pericarditis.

Pneumonia occurs in 10% of infected school-aged children, and cough can persist for 3-4 weeks; some children wheeze in the setting of Mycoplasma infection. Radiographic patterns of disease are variable; patchy alveolar infiltrates with small pleural effusions are often described. Consolidated pneumonia, large effusions, and hilar adenopathy are uncommonly reported, and severe disease has been described in certain patient populations, including those with sickle cell disease, children with Down syndrome, and those with immunodeficiencies. The acute chest presentation has been associated with M. pneumoniae in children with sickle cell anemia and prolonged hospitalizations (mean, 10 days), and the need for transfusion and mechanical ventilation was noted in 82% and 6%, respectively, in one study (Pediatrics 2003;112(1 Pt 1):87-95). Community clusters of pneumonia are reported in school-aged children, and in Rhode Island, an outbreak was reported in children from four schools; 76 had pneumonia and 3 had encephalitis (J. Infect. Dis. 2008;198:1365-74).

Considering this is a common pathogen, there are a number of questions regarding the scope of disease and impact of treatment that are incompletely answered. The first problem is that it is hard to confirm diagnostically. Culture is technically difficult, the organism takes up to 3 weeks to grow, and the diagnostic test is offered in very few labs. The old-fashioned cold agglutinin test has a low sensitivity and specificity; an increase in titers can be seen during a variety of viral infections. Polymerase chain reaction (PCR) on respiratory secretions is increasingly available; sensitivity and specificity are said to be 80% and 100%, respectively. The organism can persist in the respiratory tract for several weeks though, even after treatment, so PCR can remain positive for 2-3 weeks. This makes it hard to use PCR to confirm M. pneumoniae as the etiologic agent, especially in the setting of unusual clinical presentations. Serologic testing is often ordered and hard to interpret. False positive IgM antibody tests are not uncommon, and IgM antibody can persist for months. Outside of PCR and culture, acute and convalescent specimens can be used diagnostically, and a fourfold IgG antibody rise is consistent with acute infection.

Macrolides are regarded as the preferred treatment for M. pneumoniae pneumonia, but several studies question whether treatment impacts the clinical course. This may be due to the inherent difficulty of confirming M. pneumoniae as the etiologic agent, as most studies used serology to confirm the diagnosis. In countries outside the United States, macrolide resistance is well reported, and this may be underappreciated in the United States. We recently cared for a teenager with Down syndrome with pneumonia caused by M. pneumoniae who had a protracted clinical course. Fever and hypoxemia were persistent over a several-week period despite two courses of azithromycin and exclusion of virus, bacteria, and fungal pathogens. Bronchoalveolar lavage was performed, M. pneumoniae was detected by PCR, and macrolide resistance was confirmed. Levofloxacin was given, and she recovered over the next week.

Macrolide resistance is commonly reported outside the United States; rates in China are reported to be greater than 90%, in Japan 80%, and in Europe, between 15% and 25%. A recent study from Greg Storch and his colleagues (Pediatr. Infect. Dis. J. 2012;31:409-10) documented macrolide resistance in 8% of respiratory samples collected between 2007 and 2010 (49 patients; mean age, 10 years), noting the resistance rate was 3% in 2007-2008 and 15% in 2009-2010. A recently published study of data from Canada reported that 12.1% of M. pneumoniae–positive specimens collected between 2010 and January 2012 carried nucleotide mutations associated with macrolide resistance in the 23S rRNA gene (Emerg. Infect. Dis. 2013 September [doi: 10.3201/eid1909.121466]). Anecdotal studies suggest that patients with macrolide-resistant M. pneumoniae infection clinically improve when given doxycycline (or minocycline) or levofloxacin.

A number of clinical questions regarding M. pneumoniae may be answered more definitively in the future, but we need more easily available diagnostics (PCR is a good start), routinely accessible susceptibility data, and a good randomized controlled study to investigate the question of whether treatment shortens the course of disease.

Dr. Jackson is chief of pediatric infectious diseases at Children’s Mercy Hospital, Kansas City, Mo., and professor of pediatrics at the University of Missouri-Kansas City. She said she has no conflicts of interest to disclose. E-mail her at [email protected].

Mycoplasma pneumoniae is a cell wall–deficient pleomorphic bacterium and well-reported cause of respiratory tract infection in the school-aged child. Symptoms are variable, and clinical presentations run the gamut from upper respiratory (usually self-limited) and lower respiratory tract involvement (pneumonia) to unusual manifestations including nervous system disease (encephalitis, cerebellar ataxia, transverse myelitis), hemolytic anemia, Stevens-Johnson syndrome, and myocarditis/pericarditis.

Pneumonia occurs in 10% of infected school-aged children, and cough can persist for 3-4 weeks; some children wheeze in the setting of Mycoplasma infection. Radiographic patterns of disease are variable; patchy alveolar infiltrates with small pleural effusions are often described. Consolidated pneumonia, large effusions, and hilar adenopathy are uncommonly reported, and severe disease has been described in certain patient populations, including those with sickle cell disease, children with Down syndrome, and those with immunodeficiencies. The acute chest presentation has been associated with M. pneumoniae in children with sickle cell anemia and prolonged hospitalizations (mean, 10 days), and the need for transfusion and mechanical ventilation was noted in 82% and 6%, respectively, in one study (Pediatrics 2003;112(1 Pt 1):87-95). Community clusters of pneumonia are reported in school-aged children, and in Rhode Island, an outbreak was reported in children from four schools; 76 had pneumonia and 3 had encephalitis (J. Infect. Dis. 2008;198:1365-74).

Considering this is a common pathogen, there are a number of questions regarding the scope of disease and impact of treatment that are incompletely answered. The first problem is that it is hard to confirm diagnostically. Culture is technically difficult, the organism takes up to 3 weeks to grow, and the diagnostic test is offered in very few labs. The old-fashioned cold agglutinin test has a low sensitivity and specificity; an increase in titers can be seen during a variety of viral infections. Polymerase chain reaction (PCR) on respiratory secretions is increasingly available; sensitivity and specificity are said to be 80% and 100%, respectively. The organism can persist in the respiratory tract for several weeks though, even after treatment, so PCR can remain positive for 2-3 weeks. This makes it hard to use PCR to confirm M. pneumoniae as the etiologic agent, especially in the setting of unusual clinical presentations. Serologic testing is often ordered and hard to interpret. False positive IgM antibody tests are not uncommon, and IgM antibody can persist for months. Outside of PCR and culture, acute and convalescent specimens can be used diagnostically, and a fourfold IgG antibody rise is consistent with acute infection.

Macrolides are regarded as the preferred treatment for M. pneumoniae pneumonia, but several studies question whether treatment impacts the clinical course. This may be due to the inherent difficulty of confirming M. pneumoniae as the etiologic agent, as most studies used serology to confirm the diagnosis. In countries outside the United States, macrolide resistance is well reported, and this may be underappreciated in the United States. We recently cared for a teenager with Down syndrome with pneumonia caused by M. pneumoniae who had a protracted clinical course. Fever and hypoxemia were persistent over a several-week period despite two courses of azithromycin and exclusion of virus, bacteria, and fungal pathogens. Bronchoalveolar lavage was performed, M. pneumoniae was detected by PCR, and macrolide resistance was confirmed. Levofloxacin was given, and she recovered over the next week.

Macrolide resistance is commonly reported outside the United States; rates in China are reported to be greater than 90%, in Japan 80%, and in Europe, between 15% and 25%. A recent study from Greg Storch and his colleagues (Pediatr. Infect. Dis. J. 2012;31:409-10) documented macrolide resistance in 8% of respiratory samples collected between 2007 and 2010 (49 patients; mean age, 10 years), noting the resistance rate was 3% in 2007-2008 and 15% in 2009-2010. A recently published study of data from Canada reported that 12.1% of M. pneumoniae–positive specimens collected between 2010 and January 2012 carried nucleotide mutations associated with macrolide resistance in the 23S rRNA gene (Emerg. Infect. Dis. 2013 September [doi: 10.3201/eid1909.121466]). Anecdotal studies suggest that patients with macrolide-resistant M. pneumoniae infection clinically improve when given doxycycline (or minocycline) or levofloxacin.

A number of clinical questions regarding M. pneumoniae may be answered more definitively in the future, but we need more easily available diagnostics (PCR is a good start), routinely accessible susceptibility data, and a good randomized controlled study to investigate the question of whether treatment shortens the course of disease.

Dr. Jackson is chief of pediatric infectious diseases at Children’s Mercy Hospital, Kansas City, Mo., and professor of pediatrics at the University of Missouri-Kansas City. She said she has no conflicts of interest to disclose. E-mail her at [email protected].

Bipolar disorder is characterized by the cyclical occurrence of elevated (manic or hypomanic) and depressed mood states. The illness, which includes the bipolar I and bipolar II subtypes, exacts a heavy toll in terms of quality of life, functioning, morbidity, comorbidity, and mortality.¹ Depressive episodes and symptoms deserve particular attention: Not only do they dominate the long-term course of the illness; they are associated with similar or greater psychosocial impairment than corresponding levels of manic or hypomanic symptoms.¹