Reviews

Discuss this article at www.facebook.com/CurrentPsychiatry

Epidemiologic data suggest that people who consume diets rich in omega-3 fatty acids (FAs)—long-chain polyunsaturated FAs such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)—have a decreased risk of major depressive disorder (MDD), postpartum depression, and bipolar disorder (BD).^1-5 Omega-3 FA concentration may impact serotonin and dopamine transmission via effects on cell membrane fluidity.⁶ Therefore, decreased intake may increase the risk of several psychiatric disorders. As the average Western diet has changed over the last 2 centuries, omega-3 FA consumption has decreased.⁷ Omega-3 FAs cannot be synthesized by the body and must come from exogenous sources, such as fish and nuts. For a discussion of different types of dietary fats, see Box 1.⁸

Should we advise our patients to increase their omega-3 FA consumption? The American Psychiatric Association (APA) and the American Heart Association (AHA) recommend omega-3 FA consumption for the general population and in some cases, supplementation for specific disorders (Box 2).^9-12 New data has been published since Current Psychiatry last reviewed the evidence for using omega-3 FAs for psychiatric conditions in 2004.⁸ This article looks at the latest evidence on the use of omega-3 FAs to treat mood disorders, schizophrenia, dementia, and other psychiatric conditions.

Box 1

Box 2

Limitations of the data

Reviewing the literature on omega-3 FAs to treat psychiatric disorders is hampered by several difficulties:¹³

• studies may evaluate the use of EPA alone, EPA combined with DHA, or DHA alone
• the doses of EPA and DHA and ratio of EPA to DHA of the supplements used in clinical trials varies greatly
• patients’ dietary consumption of omega-3 FAs is difficult to control
• DSM diagnostic criteria, as well as severity of illness, differ within studies.

In addition, studies may use omega-3 FAs as monotherapy or as adjuncts. All of these factors lead to difficulty interpreting the literature, as well as trouble in extracting data for meta-analysis.

Omega-3 FAs for mood disorders

MDD and other depressive diagnoses. Several meta-analyses examining the use of omega-3 FAs for treating depressive disorders have had equivocal findings. Variability in results might be partially explained by differences in the severity of baseline depression among diverse study populations, diagnostic variation, differing omega-3 supplementation protocols, or other issues.¹³ In addition, publication bias also may affect results.

In a 2011 literature review and meta-analysis of omega-3 FAs as monotherapy or an adjunct to antidepressants to treat MDD, Bloch and Hannestad⁶ concluded that omega-3 FAs offer a small but nonsignificant benefit in treating MDD. This review suggested that omega-3 FAs may be more effective in patients with more severe depression. The effects of varying levels of EPA vs DHA were not examined.

In a systematic review and meta-analysis, Appleton et al¹⁴ concluded that omega-3 FA supplements have little beneficial effect on depressed mood in individuals who do not have a depressive illness diagnosis (eg, MDD). However, this study did not consider the differential effects of EPA vs DHA on treatment response. Patients diagnosed with a depressive illness received greater benefits from omega-3 FA supplementation, although the patients in this study were heterogeneous. Similar to Bloch and Hannestad, Appleton et al¹⁴ found that omega-3 FA supplementation may be most beneficial for depressed patients with more severe symptoms, but is unlikely to help those with mild-to-moderate symptoms or individuals without symptoms who aim to prevent depression.

A meta-analysis by Martins¹⁵ looked at EPA vs DHA to treat depressive illness and found that only supplements that were mostly or completely EPA effectively treated depressive symptoms. Martins also found that severity of illness is key for positive treatment outcomes; there was a significant relationship between higher baseline depression levels and efficacy.¹⁵ Martins noted that omega-3 FA therapy was more effective as a treatment than a preventive strategy, and that adding omega-3 FAs to antidepressants was more efficacious than omega-3 FAs alone.¹⁵

A meta-analysis of clinical trials of omega-3 FAs for depressive illness suggested EPA should be ≥60% of total EPA + DHA.¹⁶

BD. A recent meta-analysis of 6 randomized controlled trials (RCTs) found that adding omega-3 supplements to mood stabilizers in patients with BD was associated with a statistically significant reduction of depressive symptoms, but was not effective for treating mania.¹⁷ The authors suggested patients with BD—especially those with comorbid cardiovascular or metabolic conditions— increase their dietary consumption of foods containing omega-3 FAs (Table)¹⁸ and, if necessary, take a supplement of 1 to 1.5 g/d of mixed EPA and DHA, with a higher ratio of EPA.¹⁹ See Box 3 for a box on how to read omega-3 supplement labels.

In a small RCT of 51 children and adolescents (age 6 to 17) with symptomatic bipolar I or bipolar II disorder, supplementation with flax oil (alpha-linolenic acid, a polyunsaturated omega-3 FA that is a precursor to EPA and DHA) did not affect symptoms as measured by several rating scales.²⁰

Perinatal and postpartum depression. Omega-3 FAs are considered a safe treatment for depressive disorders during pregnancy because they provide neurodevelopmental benefits for neonates and have few contraindications during pregnancy.²¹ RCTs of omega-3 FA monotherapy for perinatal depression have been small (≤51 patients) and produced mixed findings.²¹ A pilot study (N = 16) of patients with postpartum depression found a significant decrease in depressive symptoms with EPA treatment.²² More research is needed before omega-3 FA supplementation can be recommended during pregnancy.

Table

Foods with healthy fats: From best to worst

Box 3

Selecting an omega-3 supplement: What to tell patients

Because nutritional supplements vary, advise patients to look at the supplement facts on the back of a bottle of omega-3 fatty acids. The American Psychiatric Association recommends patients take a total eicosapentaenoic acid (EPA) + docosahexaenoic acid (DHA) of 1 g/d; EPA should be ≥60% of total EPA + DHA.

This image is an example of a label that would meet the appropriate criteria. Total EPA + DHA = 1,490 mg and EPA is 60% of this combined total.

Source: Sublette ME, Ellis SP, Geant AL, et al. Meta-analysis of the effects of eicosapentaenoic acid (EPA) in clinical trials in depression. J Clin Psychiatry. 2011;72(12):1577-1584

Schizophrenia

In a Cochrane review of 8 studies of patients with schizophrenia, adjunctive treatment with omega-3 FAs led to >25% reduction in the Positive and Negative Syndrome Scale, but this improvement was not statistically significant.²³ Omega-3 FAs did not decrease tardive dyskinesia symptoms as measured by the Abnormal Involuntary Movement Scale. The authors stated that results were inconclusive, and use of omega-3 FAs in patients with schizophrenia remains experimental. In a separate meta-analysis that included 335 patients with schizophrenia, EPA augmentation had no beneficial effect on psychotic symptoms.²⁴

In a double-blind RCT of 81 adolescents and young adults (age 13 to 25) at ultra-high risk of psychotic illness, 5% of patients who received 1.2 g/d of omega-3 FAs developed a psychotic disorder compared with 28% of patients receiving placebo.²⁵ The authors concluded that supplementation with omega-3 FAs may be a safe and effective strategy for young patients with subthreshold psychotic symptoms.

Dementia

Studies evaluating the relationship between omega-3 FAs and dementia risk have revealed mixed findings.^26,27 In a pilot study of 10 geriatric patients with moderately severe dementia related to thrombotic cerebrovascular disorder, DHA supplementation led to improved Hamilton Depression Rating Scale and Mini-Mental State Examination (MMSE) scores compared with controls.²⁸ In another study, administering EPA to 64 patients with Alzheimer’s disease significantly improved MMSE scores, with maximum improvement at 3 months, but this benefit dissipated after 6 months of treatment.²⁹ In a study of 22 patients with various types of dementia, Suzuki et al³⁰ found that DHA supplementation improved scores on a Japanese dementia scale. These studies show promise, but more evidence is necessary before recommendations can be made.

Other psychiatric disorders

Omega-3 FAs as monotherapy or an adjunct to psychostimulants does not seem to improve symptoms in children who meet DSM-IV-TR criteria for attention-deficit/hyperactivity disorder (ADHD).^31-33 Studies of omega-3 FAs as treatment for anxiety and personality disorders are limited. To date, omega-3 FAs as adjunctive treatment in obsessive-compulsive disorder (OCD) and monotherapy in borderline personality disorder have not shown efficacy.^34,35

Using omega-3 FAs in practice

Based on new data and several recent meta-analyses, clinical recommendations have emerged. Sarris et al¹⁷ suggested patients with BD increase dietary intake of omega-3 FAs or take a supplement with 1 to 1.5 g/d of mixed EPA and DHA (with a higher ratio of EPA). In MDD, the type of omega-3 FA supplementation seems to be important; EPA seems to be the primary component for efficacy.^15,19 Additionally, the more severe the depression, the more likely symptoms will respond to omega-3 FAs.^6,14,15 Omega-3 FAs are not effective at preventing depression^14,15 and evidence is equivocal for treating perinatal depression.²¹ Omega-3 FA supplementation has not shown efficacy for patients with schizophrenia,^23,24 although it may prevent transition to psychosis in adolescents and young adults at ultra-high risk for a psychotic disorder.²⁵ Data examining omega-3 FA supplementation in postpartum depression²² and dementia^28,29 are limited but show promise. Omega-3 FAs appear to lack efficacy in ADHD,^31-33 OCD,³⁴ and borderline personality disorder.³⁵

Related Resources

• National Center for Complementary and Alternative Medicine. Omega-3 fatty acids. http://nccam.nih.gov/health/omega3.
• National Institutes of Health. Office of Dietary Supplements. Working group report: Omega-3 fatty acids and cardiovascular disease. http://ods.od.nih.gov/Health_Information/omega_3_fatty_acids.aspx.

Disclosure

Dr. Morreale reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Discuss this article at www.facebook.com/CurrentPsychiatry

Epidemiologic data suggest that people who consume diets rich in omega-3 fatty acids (FAs)—long-chain polyunsaturated FAs such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)—have a decreased risk of major depressive disorder (MDD), postpartum depression, and bipolar disorder (BD).^1-5 Omega-3 FA concentration may impact serotonin and dopamine transmission via effects on cell membrane fluidity.⁶ Therefore, decreased intake may increase the risk of several psychiatric disorders. As the average Western diet has changed over the last 2 centuries, omega-3 FA consumption has decreased.⁷ Omega-3 FAs cannot be synthesized by the body and must come from exogenous sources, such as fish and nuts. For a discussion of different types of dietary fats, see Box 1.⁸

Should we advise our patients to increase their omega-3 FA consumption? The American Psychiatric Association (APA) and the American Heart Association (AHA) recommend omega-3 FA consumption for the general population and in some cases, supplementation for specific disorders (Box 2).^9-12 New data has been published since Current Psychiatry last reviewed the evidence for using omega-3 FAs for psychiatric conditions in 2004.⁸ This article looks at the latest evidence on the use of omega-3 FAs to treat mood disorders, schizophrenia, dementia, and other psychiatric conditions.

Box 1

Box 2

Limitations of the data

Reviewing the literature on omega-3 FAs to treat psychiatric disorders is hampered by several difficulties:¹³

• studies may evaluate the use of EPA alone, EPA combined with DHA, or DHA alone
• the doses of EPA and DHA and ratio of EPA to DHA of the supplements used in clinical trials varies greatly
• patients’ dietary consumption of omega-3 FAs is difficult to control
• DSM diagnostic criteria, as well as severity of illness, differ within studies.

In addition, studies may use omega-3 FAs as monotherapy or as adjuncts. All of these factors lead to difficulty interpreting the literature, as well as trouble in extracting data for meta-analysis.

Omega-3 FAs for mood disorders

MDD and other depressive diagnoses. Several meta-analyses examining the use of omega-3 FAs for treating depressive disorders have had equivocal findings. Variability in results might be partially explained by differences in the severity of baseline depression among diverse study populations, diagnostic variation, differing omega-3 supplementation protocols, or other issues.¹³ In addition, publication bias also may affect results.

In a 2011 literature review and meta-analysis of omega-3 FAs as monotherapy or an adjunct to antidepressants to treat MDD, Bloch and Hannestad⁶ concluded that omega-3 FAs offer a small but nonsignificant benefit in treating MDD. This review suggested that omega-3 FAs may be more effective in patients with more severe depression. The effects of varying levels of EPA vs DHA were not examined.

In a systematic review and meta-analysis, Appleton et al¹⁴ concluded that omega-3 FA supplements have little beneficial effect on depressed mood in individuals who do not have a depressive illness diagnosis (eg, MDD). However, this study did not consider the differential effects of EPA vs DHA on treatment response. Patients diagnosed with a depressive illness received greater benefits from omega-3 FA supplementation, although the patients in this study were heterogeneous. Similar to Bloch and Hannestad, Appleton et al¹⁴ found that omega-3 FA supplementation may be most beneficial for depressed patients with more severe symptoms, but is unlikely to help those with mild-to-moderate symptoms or individuals without symptoms who aim to prevent depression.

A meta-analysis by Martins¹⁵ looked at EPA vs DHA to treat depressive illness and found that only supplements that were mostly or completely EPA effectively treated depressive symptoms. Martins also found that severity of illness is key for positive treatment outcomes; there was a significant relationship between higher baseline depression levels and efficacy.¹⁵ Martins noted that omega-3 FA therapy was more effective as a treatment than a preventive strategy, and that adding omega-3 FAs to antidepressants was more efficacious than omega-3 FAs alone.¹⁵

A meta-analysis of clinical trials of omega-3 FAs for depressive illness suggested EPA should be ≥60% of total EPA + DHA.¹⁶

BD. A recent meta-analysis of 6 randomized controlled trials (RCTs) found that adding omega-3 supplements to mood stabilizers in patients with BD was associated with a statistically significant reduction of depressive symptoms, but was not effective for treating mania.¹⁷ The authors suggested patients with BD—especially those with comorbid cardiovascular or metabolic conditions— increase their dietary consumption of foods containing omega-3 FAs (Table)¹⁸ and, if necessary, take a supplement of 1 to 1.5 g/d of mixed EPA and DHA, with a higher ratio of EPA.¹⁹ See Box 3 for a box on how to read omega-3 supplement labels.

In a small RCT of 51 children and adolescents (age 6 to 17) with symptomatic bipolar I or bipolar II disorder, supplementation with flax oil (alpha-linolenic acid, a polyunsaturated omega-3 FA that is a precursor to EPA and DHA) did not affect symptoms as measured by several rating scales.²⁰

Perinatal and postpartum depression. Omega-3 FAs are considered a safe treatment for depressive disorders during pregnancy because they provide neurodevelopmental benefits for neonates and have few contraindications during pregnancy.²¹ RCTs of omega-3 FA monotherapy for perinatal depression have been small (≤51 patients) and produced mixed findings.²¹ A pilot study (N = 16) of patients with postpartum depression found a significant decrease in depressive symptoms with EPA treatment.²² More research is needed before omega-3 FA supplementation can be recommended during pregnancy.

Table

Foods with healthy fats: From best to worst

Box 3

Selecting an omega-3 supplement: What to tell patients

Because nutritional supplements vary, advise patients to look at the supplement facts on the back of a bottle of omega-3 fatty acids. The American Psychiatric Association recommends patients take a total eicosapentaenoic acid (EPA) + docosahexaenoic acid (DHA) of 1 g/d; EPA should be ≥60% of total EPA + DHA.

This image is an example of a label that would meet the appropriate criteria. Total EPA + DHA = 1,490 mg and EPA is 60% of this combined total.

Source: Sublette ME, Ellis SP, Geant AL, et al. Meta-analysis of the effects of eicosapentaenoic acid (EPA) in clinical trials in depression. J Clin Psychiatry. 2011;72(12):1577-1584

Schizophrenia

In a Cochrane review of 8 studies of patients with schizophrenia, adjunctive treatment with omega-3 FAs led to >25% reduction in the Positive and Negative Syndrome Scale, but this improvement was not statistically significant.²³ Omega-3 FAs did not decrease tardive dyskinesia symptoms as measured by the Abnormal Involuntary Movement Scale. The authors stated that results were inconclusive, and use of omega-3 FAs in patients with schizophrenia remains experimental. In a separate meta-analysis that included 335 patients with schizophrenia, EPA augmentation had no beneficial effect on psychotic symptoms.²⁴

In a double-blind RCT of 81 adolescents and young adults (age 13 to 25) at ultra-high risk of psychotic illness, 5% of patients who received 1.2 g/d of omega-3 FAs developed a psychotic disorder compared with 28% of patients receiving placebo.²⁵ The authors concluded that supplementation with omega-3 FAs may be a safe and effective strategy for young patients with subthreshold psychotic symptoms.

Dementia

Studies evaluating the relationship between omega-3 FAs and dementia risk have revealed mixed findings.^26,27 In a pilot study of 10 geriatric patients with moderately severe dementia related to thrombotic cerebrovascular disorder, DHA supplementation led to improved Hamilton Depression Rating Scale and Mini-Mental State Examination (MMSE) scores compared with controls.²⁸ In another study, administering EPA to 64 patients with Alzheimer’s disease significantly improved MMSE scores, with maximum improvement at 3 months, but this benefit dissipated after 6 months of treatment.²⁹ In a study of 22 patients with various types of dementia, Suzuki et al³⁰ found that DHA supplementation improved scores on a Japanese dementia scale. These studies show promise, but more evidence is necessary before recommendations can be made.

Other psychiatric disorders

Omega-3 FAs as monotherapy or an adjunct to psychostimulants does not seem to improve symptoms in children who meet DSM-IV-TR criteria for attention-deficit/hyperactivity disorder (ADHD).^31-33 Studies of omega-3 FAs as treatment for anxiety and personality disorders are limited. To date, omega-3 FAs as adjunctive treatment in obsessive-compulsive disorder (OCD) and monotherapy in borderline personality disorder have not shown efficacy.^34,35

Using omega-3 FAs in practice

Based on new data and several recent meta-analyses, clinical recommendations have emerged. Sarris et al¹⁷ suggested patients with BD increase dietary intake of omega-3 FAs or take a supplement with 1 to 1.5 g/d of mixed EPA and DHA (with a higher ratio of EPA). In MDD, the type of omega-3 FA supplementation seems to be important; EPA seems to be the primary component for efficacy.^15,19 Additionally, the more severe the depression, the more likely symptoms will respond to omega-3 FAs.^6,14,15 Omega-3 FAs are not effective at preventing depression^14,15 and evidence is equivocal for treating perinatal depression.²¹ Omega-3 FA supplementation has not shown efficacy for patients with schizophrenia,^23,24 although it may prevent transition to psychosis in adolescents and young adults at ultra-high risk for a psychotic disorder.²⁵ Data examining omega-3 FA supplementation in postpartum depression²² and dementia^28,29 are limited but show promise. Omega-3 FAs appear to lack efficacy in ADHD,^31-33 OCD,³⁴ and borderline personality disorder.³⁵

Related Resources

• National Center for Complementary and Alternative Medicine. Omega-3 fatty acids. http://nccam.nih.gov/health/omega3.
• National Institutes of Health. Office of Dietary Supplements. Working group report: Omega-3 fatty acids and cardiovascular disease. http://ods.od.nih.gov/Health_Information/omega_3_fatty_acids.aspx.

Disclosure

Dr. Morreale reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Discuss this article at www.facebook.com/CurrentPsychiatry

Epidemiologic data suggest that people who consume diets rich in omega-3 fatty acids (FAs)—long-chain polyunsaturated FAs such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)—have a decreased risk of major depressive disorder (MDD), postpartum depression, and bipolar disorder (BD).^1-5 Omega-3 FA concentration may impact serotonin and dopamine transmission via effects on cell membrane fluidity.⁶ Therefore, decreased intake may increase the risk of several psychiatric disorders. As the average Western diet has changed over the last 2 centuries, omega-3 FA consumption has decreased.⁷ Omega-3 FAs cannot be synthesized by the body and must come from exogenous sources, such as fish and nuts. For a discussion of different types of dietary fats, see Box 1.⁸

Should we advise our patients to increase their omega-3 FA consumption? The American Psychiatric Association (APA) and the American Heart Association (AHA) recommend omega-3 FA consumption for the general population and in some cases, supplementation for specific disorders (Box 2).^9-12 New data has been published since Current Psychiatry last reviewed the evidence for using omega-3 FAs for psychiatric conditions in 2004.⁸ This article looks at the latest evidence on the use of omega-3 FAs to treat mood disorders, schizophrenia, dementia, and other psychiatric conditions.

Box 1

Box 2

Limitations of the data

Reviewing the literature on omega-3 FAs to treat psychiatric disorders is hampered by several difficulties:¹³

• studies may evaluate the use of EPA alone, EPA combined with DHA, or DHA alone
• the doses of EPA and DHA and ratio of EPA to DHA of the supplements used in clinical trials varies greatly
• patients’ dietary consumption of omega-3 FAs is difficult to control
• DSM diagnostic criteria, as well as severity of illness, differ within studies.

In addition, studies may use omega-3 FAs as monotherapy or as adjuncts. All of these factors lead to difficulty interpreting the literature, as well as trouble in extracting data for meta-analysis.

Omega-3 FAs for mood disorders

MDD and other depressive diagnoses. Several meta-analyses examining the use of omega-3 FAs for treating depressive disorders have had equivocal findings. Variability in results might be partially explained by differences in the severity of baseline depression among diverse study populations, diagnostic variation, differing omega-3 supplementation protocols, or other issues.¹³ In addition, publication bias also may affect results.

In a 2011 literature review and meta-analysis of omega-3 FAs as monotherapy or an adjunct to antidepressants to treat MDD, Bloch and Hannestad⁶ concluded that omega-3 FAs offer a small but nonsignificant benefit in treating MDD. This review suggested that omega-3 FAs may be more effective in patients with more severe depression. The effects of varying levels of EPA vs DHA were not examined.

In a systematic review and meta-analysis, Appleton et al¹⁴ concluded that omega-3 FA supplements have little beneficial effect on depressed mood in individuals who do not have a depressive illness diagnosis (eg, MDD). However, this study did not consider the differential effects of EPA vs DHA on treatment response. Patients diagnosed with a depressive illness received greater benefits from omega-3 FA supplementation, although the patients in this study were heterogeneous. Similar to Bloch and Hannestad, Appleton et al¹⁴ found that omega-3 FA supplementation may be most beneficial for depressed patients with more severe symptoms, but is unlikely to help those with mild-to-moderate symptoms or individuals without symptoms who aim to prevent depression.

A meta-analysis by Martins¹⁵ looked at EPA vs DHA to treat depressive illness and found that only supplements that were mostly or completely EPA effectively treated depressive symptoms. Martins also found that severity of illness is key for positive treatment outcomes; there was a significant relationship between higher baseline depression levels and efficacy.¹⁵ Martins noted that omega-3 FA therapy was more effective as a treatment than a preventive strategy, and that adding omega-3 FAs to antidepressants was more efficacious than omega-3 FAs alone.¹⁵

A meta-analysis of clinical trials of omega-3 FAs for depressive illness suggested EPA should be ≥60% of total EPA + DHA.¹⁶

BD. A recent meta-analysis of 6 randomized controlled trials (RCTs) found that adding omega-3 supplements to mood stabilizers in patients with BD was associated with a statistically significant reduction of depressive symptoms, but was not effective for treating mania.¹⁷ The authors suggested patients with BD—especially those with comorbid cardiovascular or metabolic conditions— increase their dietary consumption of foods containing omega-3 FAs (Table)¹⁸ and, if necessary, take a supplement of 1 to 1.5 g/d of mixed EPA and DHA, with a higher ratio of EPA.¹⁹ See Box 3 for a box on how to read omega-3 supplement labels.

In a small RCT of 51 children and adolescents (age 6 to 17) with symptomatic bipolar I or bipolar II disorder, supplementation with flax oil (alpha-linolenic acid, a polyunsaturated omega-3 FA that is a precursor to EPA and DHA) did not affect symptoms as measured by several rating scales.²⁰

Perinatal and postpartum depression. Omega-3 FAs are considered a safe treatment for depressive disorders during pregnancy because they provide neurodevelopmental benefits for neonates and have few contraindications during pregnancy.²¹ RCTs of omega-3 FA monotherapy for perinatal depression have been small (≤51 patients) and produced mixed findings.²¹ A pilot study (N = 16) of patients with postpartum depression found a significant decrease in depressive symptoms with EPA treatment.²² More research is needed before omega-3 FA supplementation can be recommended during pregnancy.

Table

Foods with healthy fats: From best to worst

Box 3

Selecting an omega-3 supplement: What to tell patients

Because nutritional supplements vary, advise patients to look at the supplement facts on the back of a bottle of omega-3 fatty acids. The American Psychiatric Association recommends patients take a total eicosapentaenoic acid (EPA) + docosahexaenoic acid (DHA) of 1 g/d; EPA should be ≥60% of total EPA + DHA.

This image is an example of a label that would meet the appropriate criteria. Total EPA + DHA = 1,490 mg and EPA is 60% of this combined total.

Source: Sublette ME, Ellis SP, Geant AL, et al. Meta-analysis of the effects of eicosapentaenoic acid (EPA) in clinical trials in depression. J Clin Psychiatry. 2011;72(12):1577-1584

Schizophrenia

In a Cochrane review of 8 studies of patients with schizophrenia, adjunctive treatment with omega-3 FAs led to >25% reduction in the Positive and Negative Syndrome Scale, but this improvement was not statistically significant.²³ Omega-3 FAs did not decrease tardive dyskinesia symptoms as measured by the Abnormal Involuntary Movement Scale. The authors stated that results were inconclusive, and use of omega-3 FAs in patients with schizophrenia remains experimental. In a separate meta-analysis that included 335 patients with schizophrenia, EPA augmentation had no beneficial effect on psychotic symptoms.²⁴

In a double-blind RCT of 81 adolescents and young adults (age 13 to 25) at ultra-high risk of psychotic illness, 5% of patients who received 1.2 g/d of omega-3 FAs developed a psychotic disorder compared with 28% of patients receiving placebo.²⁵ The authors concluded that supplementation with omega-3 FAs may be a safe and effective strategy for young patients with subthreshold psychotic symptoms.

Dementia

Studies evaluating the relationship between omega-3 FAs and dementia risk have revealed mixed findings.^26,27 In a pilot study of 10 geriatric patients with moderately severe dementia related to thrombotic cerebrovascular disorder, DHA supplementation led to improved Hamilton Depression Rating Scale and Mini-Mental State Examination (MMSE) scores compared with controls.²⁸ In another study, administering EPA to 64 patients with Alzheimer’s disease significantly improved MMSE scores, with maximum improvement at 3 months, but this benefit dissipated after 6 months of treatment.²⁹ In a study of 22 patients with various types of dementia, Suzuki et al³⁰ found that DHA supplementation improved scores on a Japanese dementia scale. These studies show promise, but more evidence is necessary before recommendations can be made.

Other psychiatric disorders

Omega-3 FAs as monotherapy or an adjunct to psychostimulants does not seem to improve symptoms in children who meet DSM-IV-TR criteria for attention-deficit/hyperactivity disorder (ADHD).^31-33 Studies of omega-3 FAs as treatment for anxiety and personality disorders are limited. To date, omega-3 FAs as adjunctive treatment in obsessive-compulsive disorder (OCD) and monotherapy in borderline personality disorder have not shown efficacy.^34,35

Using omega-3 FAs in practice

Based on new data and several recent meta-analyses, clinical recommendations have emerged. Sarris et al¹⁷ suggested patients with BD increase dietary intake of omega-3 FAs or take a supplement with 1 to 1.5 g/d of mixed EPA and DHA (with a higher ratio of EPA). In MDD, the type of omega-3 FA supplementation seems to be important; EPA seems to be the primary component for efficacy.^15,19 Additionally, the more severe the depression, the more likely symptoms will respond to omega-3 FAs.^6,14,15 Omega-3 FAs are not effective at preventing depression^14,15 and evidence is equivocal for treating perinatal depression.²¹ Omega-3 FA supplementation has not shown efficacy for patients with schizophrenia,^23,24 although it may prevent transition to psychosis in adolescents and young adults at ultra-high risk for a psychotic disorder.²⁵ Data examining omega-3 FA supplementation in postpartum depression²² and dementia^28,29 are limited but show promise. Omega-3 FAs appear to lack efficacy in ADHD,^31-33 OCD,³⁴ and borderline personality disorder.³⁵

Related Resources

• National Center for Complementary and Alternative Medicine. Omega-3 fatty acids. http://nccam.nih.gov/health/omega3.
• National Institutes of Health. Office of Dietary Supplements. Working group report: Omega-3 fatty acids and cardiovascular disease. http://ods.od.nih.gov/Health_Information/omega_3_fatty_acids.aspx.

Disclosure

Dr. Morreale reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Recent guidance from the Centers for Medicare and Medicaid Services restricting erythropoiesis-stimulating agents (ESAs) in chemotherapy and cancer-related anemias has resulted in an increase in transfusions. Nine studies, without published contradictory evidence, have shown optimization of the response to ESAs by intravenous (IV) iron when the iron was added to the treatment of chemotherapy-induced anemia. The synergy observed, although greater in iron deficiency, was independent of pretreatment iron parameters. Three studies demonstrated decreased transfusions when IV iron is administered without ESAs. Discordant recommendations regarding IV iron currently exist among the American Society of Hematology/American Society of Clinical Oncology guidelines, the National Comprehensive Cancer Network, and the European Society of Medical Oncology. This discordance is at least partly the result of misconceptions about the clinical nature and incidence of adverse effects with IV iron. Other reasons for this discordance are presented in this review. Based on thousands of studied patients, we conclude that IV iron is safe and probably safer than most physicians realize. Education is needed relating to the interpretation of minor, subclinical infusion reactions that resolve without therapy. IV iron without ESAs may be an effective treatment for chemotherapy-induced anemia and warrants further study. We present evidence supporting the conclusion that baseline serum hepcidin levels may predict responses to IV iron, and we examine the published evidence supporting the conclusion that IV iron should be a standard addition to the management of chemotherapy and cancer-related anemia.

Click on the PDF icon at the top of this introduction to read the full article.

Recent guidance from the Centers for Medicare and Medicaid Services restricting erythropoiesis-stimulating agents (ESAs) in chemotherapy and cancer-related anemias has resulted in an increase in transfusions. Nine studies, without published contradictory evidence, have shown optimization of the response to ESAs by intravenous (IV) iron when the iron was added to the treatment of chemotherapy-induced anemia. The synergy observed, although greater in iron deficiency, was independent of pretreatment iron parameters. Three studies demonstrated decreased transfusions when IV iron is administered without ESAs. Discordant recommendations regarding IV iron currently exist among the American Society of Hematology/American Society of Clinical Oncology guidelines, the National Comprehensive Cancer Network, and the European Society of Medical Oncology. This discordance is at least partly the result of misconceptions about the clinical nature and incidence of adverse effects with IV iron. Other reasons for this discordance are presented in this review. Based on thousands of studied patients, we conclude that IV iron is safe and probably safer than most physicians realize. Education is needed relating to the interpretation of minor, subclinical infusion reactions that resolve without therapy. IV iron without ESAs may be an effective treatment for chemotherapy-induced anemia and warrants further study. We present evidence supporting the conclusion that baseline serum hepcidin levels may predict responses to IV iron, and we examine the published evidence supporting the conclusion that IV iron should be a standard addition to the management of chemotherapy and cancer-related anemia.

Click on the PDF icon at the top of this introduction to read the full article.

Recent guidance from the Centers for Medicare and Medicaid Services restricting erythropoiesis-stimulating agents (ESAs) in chemotherapy and cancer-related anemias has resulted in an increase in transfusions. Nine studies, without published contradictory evidence, have shown optimization of the response to ESAs by intravenous (IV) iron when the iron was added to the treatment of chemotherapy-induced anemia. The synergy observed, although greater in iron deficiency, was independent of pretreatment iron parameters. Three studies demonstrated decreased transfusions when IV iron is administered without ESAs. Discordant recommendations regarding IV iron currently exist among the American Society of Hematology/American Society of Clinical Oncology guidelines, the National Comprehensive Cancer Network, and the European Society of Medical Oncology. This discordance is at least partly the result of misconceptions about the clinical nature and incidence of adverse effects with IV iron. Other reasons for this discordance are presented in this review. Based on thousands of studied patients, we conclude that IV iron is safe and probably safer than most physicians realize. Education is needed relating to the interpretation of minor, subclinical infusion reactions that resolve without therapy. IV iron without ESAs may be an effective treatment for chemotherapy-induced anemia and warrants further study. We present evidence supporting the conclusion that baseline serum hepcidin levels may predict responses to IV iron, and we examine the published evidence supporting the conclusion that IV iron should be a standard addition to the management of chemotherapy and cancer-related anemia.

Click on the PDF icon at the top of this introduction to read the full article.

A 22-year-old man of Turkish ancestry presents to your office for an urgent visit. One day before the visit, he abruptly developed a fever with temperatures as high as 104°F (40°C), abdominal pain, joint pain, and a red rash on the lower right leg. He has no cough, nasal congestion, rhinorrhea, ear or eye pain, oral ulcers, vomiting, or diarrhea. After reviewing his chart, it becomes apparent that he has experienced similar intermittent, random, and self-limited episodes over the last 4 years.

On examination, he is febrile with diffuse abdominal tenderness and guarding. Bowel sounds are normal, and there is no rebound. The left knee is slightly swollen and limited in range of motion, and there is a large, non-palpable, blanching, erythematous lesion over the anterior lower leg.

While pondering diagnostic possibilities, you remember reading about autoinflammatory syndromes that result in recurrent episodes of fever and multisystemic inflammatory symptoms but cannot recall the evaluation and therapeutic options for these conditions.

These syndromes pose diagnostic challenges for physicians. Although these conditions are uncommon and may mimic malignancy or infection, they should be considered in patients who have recurrent febrile illness. While the autoinflammatory syndrome of familial Mediterranean fever (FMF), the diagnosis in the case above, is well known, our growing understanding of genetics and the immune system has unearthed a growing number of autoinflammatory syndromes.

A GENETICALLY DIVERSE BUT CLINICALLY SIMILAR GROUP OF CONDITIONS

The autoinflammatory syndromes are a group of genetically diverse but clinically similar conditions characterized by recurrent attacks of fever, rash, serositis, lymphadenopathy, and musculoskeletal involvement. This category of diseases is rapidly expanding and was built on the discovery of the genetics behind FMF, hyperimmunoglobulin D syndrome (HIDS), tumor necrosis factor receptor-associated periodic syndrome (TRAPS), and the cryopyrin-associated periodic syndromes (CAPS). More recent additions to the list include Blau syndrome and the syndrome of pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA).

In autoinflammatory syndromes, genetic mutations lead to dysregulation of the innate immune system and to episodic manifestations of systemic inflammation. Many patients have first- or second-degree relatives with similar symptoms, reflecting the genetic abnormalities underlying this class of conditions. Unlike patients with other rheumatic diseases, patients with autoinflammatory diseases do not have autoreactive T lymphocytes, and they typically lack pathogenic autoantibodies.

The characterization of genetic autoinflammatory syndromes shows the importance of a well-regulated innate immune system and sheds light on the role of the innate immune system in common medical conditions such as gout and type 2 diabetes (see below).

THE INNATE IMMUNE SYSTEM : OUR FIRST LINE OF DEFENSE

The innate immune system is the first line of immune defense. It is evolutionarily conserved. Unlike the adaptive immune response, the innate immune response is not antigen-specific, and its activation does not produce a memory response. Generally speaking, it is composed of certain white blood cells (neutrophils, dendritic cells, macrophages, natural killer cells), proinflammatory signaling proteins (cytokines), and the complement system. Interleukin 1 (IL-1), interleukin 6 (IL-6), and tumor necrosis factor (TNF) alpha are the critical and most potent proinflammatory cytokines of the innate immune system.

To date, nearly all mutations that have been linked to the autoinflammatory syndromes disrupt regulation of inflammatory signaling within the innate immune system. This disruption generates a proinflammatory state, often leading to a final common pathway ending with activation of the inflammasome.

The inflammasome is a complex of distinct proteins which, when brought together, serve to convert inactive prointerleukin 1 beta to the active proinflammatory cytokine IL-1 beta.¹ Formation of the inflammasome can be mediated by multiple different signals including microbial products, endogenously produced substances such as cholesterol and uric acid, or by proinflammatory cytokines and chemokines (Figure 1).

FAMILIAL MEDITERRANEAN FEVER

FMF is the most common and well characterized autoinflammatory syndrome. Described in 1949, its etiology was not understood until the genetic mutation that causes it was discovered in 1997.^2–4

The Mediterranean fever gene MEFV encodes pyrin, a protein with an important role in controlling IL-1 production. Mutations in MEFV affect pyrin-mediated regulation, and IL-1 production increases.

Classically, FMF is described as autosomal recessive, although many patients have only one abnormal allele.⁵ Possibly, the abnormal allele confers an evolutionary advantage in resisting an endemic pathogen, an idea reflected in the carrier frequencies of different MEFV mutations in certain Mediterranean and Middle Eastern ethnic populations (Sephardic Jews, Turks, Arabs, Armenians).^6,7 Also, carriage of mutations in MEFV in patients with Crohn disease has been associated with a higher risk of extraintestinal manifestations and colonic stricture,⁸ and their carriage in patients with multiple sclerosis has been associated with a rapid progression of that disease.⁹

Although FMF usually presents at ages 5 to 15, about 20% of patients with FMF suffer their first inflammatory attack after age 20 years.

Attacks are characterized by brief episodes of fever with temperatures higher than 102°F (38.9°C), lasting less than 72 hours, accompanied by intense serositis. Abdominal serositis may be severe enough to mimic appendicitis and lead to exploratory surgery.

About 70% of patients experience arthritis (predominantly in the legs), and 40% develop erysipeloid erythema, an intensely erythematous, warm, tender, and plaque-like lesion on the lower extremities. Biopsy of involved skin shows a diffuse, primarily neutrophilic, inflammatory cell infiltrate.

Laboratory examination reveals marked elevation of acute-phase reactants, which may normalize between episodes. The diagnosis can be made using a combination of clinical suspicion, sequencing of the MEFV gene, and a positive response to a trial of colchicine (Colcrys).

Without treatment, repetitive attacks of inflammation may result in amyloidosis of the kidneys or liver. The risk of amyloidosis is related to several discrete risk factors, such as country of residence, MEFV genotype, and serum amyloid A genotype.^10–12 Patients should be monitored for physical manifestations of amyloidosis at least annually.

FMF patients have also been described who develop vasculitides such as Henoch-Schönlein purpura, polyarteritis nodosa, or Behçet disease.

Colchicine is the mainstay of FMF treatment

Colchicine has been the mainstay of therapy for patients with FMF for almost 40 years.^13–15 Its benefits in FMF are clear: symptoms cease in nearly 70% of patients treated with colchicine, and an additional 25% have a reduction in the severity and frequency of attacks.

Only 5% to 10% of patients have no response to colchicine; this may be partially due to individual dose limitations imposed by common drug-associated gastrointestinal side effects.^16–18 For these patients, newer biologic drugs that inhibit IL-1 activity, such as anakinra (Kineret) and rilonacept (Arcalyst), offer great promise.

Typically, FMF attacks become less frequent and less severe with age. However, the overall prognosis in FMF is related mainly to the individual’s genotype and the associated risk of amyloidosis.¹⁹

HYPERIMMUNOGLOBULIN D SYNDROME

HIDS is another autosomal recessive autoinflammatory syndrome.²⁰

The genetic defect underlying HIDS lies within the mevalonate kinase gene MVK.²¹ Mevalonate kinase, an enzyme, plays an important role in the cholesterol biosynthesis pathway, following the initial step by 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase. Mutations are primarily missense mutations in highly conserved areas of protein that result in decreased MVK activity (1% to 5% of normal).^22,23 Decreased production of geranylgeranyl pyrophosphate resulting from disruption in the HMG-CoA reductase pathway subsequently leads to increased release of IL-1 beta from peripheral blood mononuclear cells and triggers inflammatory symptoms.²⁴

Attacks of HIDS begin early in life

HIDS attacks begin early in life, with more than 70% of patients suffering their first attack before age 2, but adult-onset disease has been reported. Patients may report that routine childhood vaccinations triggered attacks, a historical finding unique to HIDS.

Attacks typically last 4 days; a longer duration can help the clinician differentiate HIDS from FMF.

More than 90% of patients have cervical lymphadenopathy, and 80% have an erythematous rash characteristically located on the palms and soles. About 70% of patients have headache, arthritis, and abdominal pain.

During attacks, laboratory examination reveals elevated acute inflammatory reactants. As the name implies, serum levels of immunoglobulin D (IgD) are elevated. However, this finding is not specific to HIDS and may also be found in patients with Still disease or FMF or in those who smoke cigarettes. Serum IgD levels fluctuate throughout life, and the sensitivity of commercially available IgD test kits is variable.

Assessment of mevalonic acid levels in the urine during febrile attacks offers a more sensitive, specific, and reliable diagnostic test for HIDS.²⁵ While genetic sequencing is the gold standard of diagnostic testing, close to 30% of patients meeting clinical criteria for HIDS have no definable mutation.²⁶

Treatment of HIDS can be challenging

Oral corticosteroids are effective in HIDS, but their long-term side effects are undesirable. Patients rarely respond to colchicine, differentiating them from FMF patients.

Etanercept (Enbrel), a fusion protein composed of the soluble TNF receptor and the Fc portion of the human IgG1 protein, has been efficacious in some patients.^27,28 IL-1 inhibitors have also been used with increasing efficacy in the treatment of HIDS attacks.^29,30

Although the frequency of attacks decreases with age, long-term follow-up of 28 Dutch HIDS patients found that their quality of life was still lower than that in country-matched controls.³¹

TUMOR NECROSIS FACTOR RECEPTOR-ASSOCIATED PERIODIC SYNDROME

In 1982, a large multiplex family from Scotland and Ireland was described who had a newly recognized syndrome termed familial Hibernian fever, characterized by recurrent fever, rash, and abdominal pain.³² In 1998, the genetics of this autosomal dominant condition were characterized,^33–35 and it is now known by the acronym TRAPS.

TRAPS has a variable presentation owing to a variety of mutations in the gene encoding the cell surface receptor for TNF (TNFRSF1A). TNFRSF1A mutations affecting conserved cysteine residues important for protein folding correspond to severe disease phenotypes.

The R92Q mutation has an allele frequency of up to 4% of the population. It has no impact on the structure and function of the TNF receptor protein and is associated with a heterogeneous disease course. In contrast, the P46L mutation has an allele frequency of 1% of the population and typically is associated with a milder disease course characterized by older age of onset, shorter episodes, and a low frequency of amyloidosis.^36–39

The R92Q and T61I mutations, which have low penetrance, have been increasingly reported in adult patients with the autoimmune diseases systemic lupus erythematosus, rheumatoid arthritis, and multiple sclerosis.^40–42 Their influence is believed to contribute to proinflammatory responses but not to provide additional genetic susceptibility as provided by human leukocyte antigen (HLA) genotypes for susceptibility for these autoimmune diseases.

TRAPS attacks last longer than FMF and HIDS attacks

TRAPS attacks last 7 days or more, differentiating TRAPS from FMF and HIDS. Patients may present from infancy into adulthood, but more typically present in the toddler period.

Most patients experience intense myalgia as well as abdominal and pleuritic chest pain. A single-center series in 2002 described close to half of patients diagnosed with TRAPS as having had an intra-abdominal surgical procedure; in 10% necrotic bowel was identified, yet the biopsy typically revealed only a serosal mononuclear infiltrate.⁴³

Like FMF and HIDS, TRAPS can cause an erythematous rash. The rash usually appears on an extremity, is centrifugal, and travels proximal-to-distal in concert with symptoms of myalgia. Deep tissue biopsy often demonstrates an intense, neutrophilic fasciitis sparing the underlying musculature. Painful conjunctivitis with periorbital edema also may occur.

Laboratory values reflecting widespread systemic inflammation and elevated acute-phase reactants are encountered during attacks and in some cases may persist between episodes.

Genetic testing can be used to confirm the diagnosis. The probability of finding a mutation in TNFRSF1A depends highly on whether the patient has affected relatives. In a series of 28 patients with recurrent inflammatory syndromes and TNFRSF1A mutations, 9 (32%) had a family history of recurrent inflammatory syndromes, while in 176 patients with sporadic, nonfamilial “TRAPS-like” symptoms, TNFRSF1A mutations were uncommon.^37,38

Etanercept is effective for TRAPS

Systemic corticosteroids may be effective for treating TRAPS, but ever-increasing doses are often required.

Etanercept’s ability to bind both soluble and bound TNF explains its relative efficacy in treating TRAPS even though other TNF inhibitors have proven ineffective.^44,45 With etanercept, the prognosis of TRAPS patients is typically good. Etanercept has even been effective in treating cases of renal amyloidosis from long-standing TRAPS, although it has not been shown to facilitate regression of renal amyloid mass.^46,47 However, responses to treatment with etanercept may wane with time, and resistant cases have been reported.

IL-1 blockade with anakinra has been shown to be effective in the short term and long term in small case series, providing a reasonable alternative for patients who are difficult to manage.

CRYOPYRIN-ASSOCIATED PERIODIC SYNDROMES

• Perhaps the most clinically diverse hereditary autoinflammatory syndromes are the cryopyrin-associated periodic syndromes (CAPS). There are three overlapping phenotypes: Familial cold autoinflammatory syndrome (FCAS)
• Muckle-Wells syndrome (MWS)
• Neonatal-onset multisystemic inflammatory disorder (NOMID).

Mutations in NLRP3

CAPS symptoms stem from mutations within the NLRP3 gene (NOD-like receptor family, pyrin domain), which encodes the protein, cyropyrin.⁴⁸NLRP3 mutations result in an abnormal cryopyrin structure, abnormal inflammasome activity, and increased IL-1 beta production.^49,50

There is poor genotype-phenotype association in CAPS; the same NLRP3 point mutation can result in variable features, typically of either FCAS and MWS or MWS and NOMID overlapping phenotypes, supporting the hypothesis that modifier genes play a role in phenotypic expression.

Inheritance patterns in CAPS are autosomal dominant, but spontaneous mutations are also common. In fact, approximately two-thirds of patients with mutation-negative NOMID have somatic NLRP3 mutations, indicating that somatic NLRP3 mosaicism contributes to the clinical syndrome.⁵¹

Clinical features of the CAPS

The hallmarks of the CAPS include recurrent fevers, urticarial rash, and central nervous system inflammation. Characteristically, CAPS patients present in the neonatal period through early childhood, but adult-onset cases, which may have less typical features, have been reported.

Patients with FCAS develop brief episodes (< 24 hours) of fever, joint pain, and urticarial rash when exposed to sudden drops in ambient temperature.

Patients with MWS have more frequent, prolonged attacks, which may or may not be related to changes in ambient temperature. They also develop fever and urticarial rash and may develop arthritis and headaches from aseptic meningitis.

Patients with NOMID often present with fever and persistent urticarial rash shortly after birth and suffer from chronic aseptic meningitis, which can lead to papilledema and optic nerve atrophy. Frontal bossing of the skull and overgrowth of the epiphyseal regions of long bones with accompanying growth delay are also characteristic of NOMID.

IL-1 antagonists offer relief from CAPS

Many patients with FCAS do not require treatment and may move to a warmer climate to avoid rapid swings in ambient temperature. Otherwise, control of IL-1 beta activity is essential to the successful treatment of CAPS. Patients with MWS and NOMID require treatment with IL-1 antagonists, and the biologic drugs anakinra, rilonacept, and canakinumab (Ilaris) offer the possibility of symptomatic relief and long-term control of the disease.^52–54

Prognosis depends on the phenotype

The overall prognosis for patients with CAPS largely depends on phenotype.

Patients with FCAS generally have progressive improvement in attack frequency and severity over time and are at minimal risk of amyloidosis.

Patients with MWS have a relatively good prognosis when treated with IL-1 antagonists, making them at low risk of amyloidosis and sensorineural hearing loss.

However, patients with NOMID are at high risk of sensorineural hearing loss, growth delay, and amyloidosis unless the condition is recognized and treated early in its course. Mortality rates historically are as high as 20% in untreated patients with NOMID.⁵⁵

OTHER AUTOINFLAMMATORY SYNDROMES

More recently, other autoinflammatory syndromes of known genetic etiology have been described.

NLRP12-associated autoinflammatory disorders

A subset of patients with clinical manifestations attributable to CAPS but without mutations at the NLRP3 locus have mutations in another NLRP family member expressed in peripheral blood mononuclear cells on the NLRP12 gene. They are therefore labeled as having an NLRP12-associated autoinflammatory disorder.^56,57

Deficiency of interleukin 1 receptor antagonist

IL-1 receptor antagonist is a naturally occurring antagonist of IL-1 alpha and IL-1 beta. In patients with deficiency of IL-1 receptor antagonist (DIRA), the action of these potent proinflammatory proteins is unopposed, leading to severe pustular rash and osteitis.^58,59

Pyogenic arthritis, pyoderma gangrenosum, and acne syndrome

Patients with PAPA syndrome also have increased IL-1 production, in this case due to a mutation in the cytoplasmic adapter protein proline-serine-threonine phosphatase-interacting protein (PSTPIP1) gene, leading to the development of the symptoms included in the PAPA acronym.⁶⁰

Majeed syndrome

Majeed syndrome is caused by a mutation in the LPIN2 gene, resulting in the early onset of chronic recurrent multifocal osteomyelitis, neutrophilic dermatosis, and dyserythropoietic anemia.⁶¹

Blau syndrome

Some patients with Blau syndrome (granulomatosis, arthritis, and uveitis) have NOD2/CARD15 gene mutations.⁶² Cases of DIRA, PAPA, and Blau syndrome have been reported that responded favorably to treatment with IL-1 antagonists.

Periodic fever, aphthous stomatitis, pharyngitis, and adenopathy syndrome

Although symptoms of the periodic fever, aphthous stomatitis, pharyngitis, and adenopathy (PFAPA) syndrome typically begin in childhood, adult-onset cases have been reported.⁶³

Patients with PFAPA syndrome develop predictable, stereotypic febrile attacks that last on average 5 days and occur approximately every 4 weeks. Between attacks, patients are healthy; during attacks, they may experience oral ulceration (aphthous stomatitis), exudative or nonexudative pharyngitis, and enlarged and tender cervical lymph nodes. Up to 60% of PFAPA patients also experience abdominal pain.

No single genetic mutation has been identified, although it has been shown that 45% of PFAPA patients have a parent or sibling with recurrent fever and 12% have a parent or sibling with a PFAPA-like phenotype, suggesting that the disease has a genetic basis.⁶⁴ Recent studies have demonstrated that T-cell–regulated complement activation and IL-1 production are altered in PFAPA patients, thus supporting the hypothesis that PFAPA is an autoinflammatory syndrome.⁶⁵

Treatment. In view of the syndrome’s self-limited nature, treatment is reserved for patients with a severe presentation or for patients whose condition is especially burdensome.

The fever’s height may partially respond to nonsteroidal anti-inflammatory drugs, but these drugs have little effect on the duration or frequency of fever.

One or two doses of prednisone (1 mg/kg) within 6 hours of fever onset is effective in aborting the febrile episode in 90% of patients; however, up to 50% of patients may experience an increased frequency of attacks after treatment with systemic corticosteroids.^66,67

Additional options include daily colchicine, which may lengthen the time between attacks, and cimetidine (Tagamet), which has been shown to prevent PFAPA attacks in approximately one-third of patients.^67–69

The prognosis of PFAPA is quite favorable, and without intervention 40% of patients experience a significant reduction in the severity and frequency of fever attacks within 5 years of diagnosis. To date, there have been no reports of amyloidosis or hearing loss in PFAPA patients.

DIAGNOSTIC EVALUATION OF SUSPECTED AUTOINFLAMMATORY DISEASE

The autoinflammatory syndromes pose a true diagnostic challenge for physicians. Tremendous advances have been made in molecular and genetic testing. Nevertheless, the history and careful physical examination can lead the astute clinician to the proper diagnosis when evaluating a patient with a suspected autoinflammatory syndrome.

Critical elements in the history include age at the onset of attacks, duration of attacks, associated symptoms (serositis, adenopathy, myalgias, arthralgias, arthritis, ocular symptoms, central nervous system symptoms, rash), family members with similar symptoms, and ethnic background.

Internists should remember that autoinflammatory syndromes are part of the differential diagnosis in adult patients with a recurrent febrile illness. A vigorous search for malignancy and infection (especially tuberculosis) should be conducted in all patients. However, the repetitive, stereotypic nature of autoinflammatory syndromes differentiates them from typical confounders.

The utility of acute-phase reactants in the diagnostic evaluation is limited, as many conditions result in abnormal values. However, serial monitoring of inflammatory markers such as the erythrocyte sedimentation rate and C-reactive protein level in patients with a formally diagnosed autoinflammatory syndrome can be useful in tracking disease activity, identifying flares, and monitoring the efficacy of therapy.

In cases of suspected HIDS, assessment of IgD levels is not recommended, since IgD can be elevated in a number of autoinflammatory and rheumatologic conditions. Instead, preference should be given to testing mevalonic acid levels in the urine in patients with HIDS or suspected HIDS.

Patients with central nervous system symptoms should undergo a thorough examination, including a formal ophthalmologic evaluation, imaging, and possibly lumbar puncture to assess intracranial pressure and inflammatory changes in the cerebrospinal fluid.

Dermatologic manifestations should be examined firsthand and assessed as needed with magnetic resonance imaging to elucidate fascial inflammation or with full-thickness biopsy.

Gross bony abnormalities should be evaluated with plain radiography.

Audiologic testing may be indicated in the diagnostic evaluation of patients with recurrent fever.

Renal or hepatic biopsy may be indicated in the evaluation for amyloidosis; amyloid deposition has been reported in patients with TRAPS and clinical FMF not presenting with fever.^70,71

Genetic testing is commercially available for patients with suspected hereditary autoinflammatory syndromes. However, clinicians should be cautioned that up to 30% of patients with phenotypic manifestations characteristic of a given autoinflammatory syndrome have normal results on genetic testing. In addition, the results of genetic testing may take several months to return and may cost patients and families up to several thousand dollars, as some insurers refuse to cover this procedure. Genetic testing may ultimately be indicated for proper counseling of reproductive risk.

Responses to short courses of medications such as colchicine, prednisone, and IL-1 receptor antagonists also represent diagnostic tools.

NEW INSIGHT INTO MORE COMMON CONDITIONS

Advances in the understanding of the autoinflammatory syndromes have provided new insight into the role of the innate immune system in other, more common conditions.⁷² Indeed, abnormal regulation of the innate inflammatory pathway has been implicated in the pathogenesis of conditions as phenotypically diverse as gout, type 2 diabetes, atherosclerosis, and epilepsy.^73,74

Table 2 presents examples of the innate immune system’s involvement in the pathogenesis of several common chronic conditions.

Further study of autoinflammatory syndromes will add to our understanding of the innate immune system. These advances will lead to continued improvement in the care we give patients, both for the classic autoinflammatory syndromes and for other, more common, genetically complex conditions.

Our 22-year-old patient’s fever, abdominal pain (presumed peritonitis), erysipelas-like skin lesion, and arthritis are typical of FMF. Therefore, genetic testing was performed, which revealed a single MEFV gene mutation (M694V). Colchicine has been efficacious in preventing flares of his disease.

A 22-year-old man of Turkish ancestry presents to your office for an urgent visit. One day before the visit, he abruptly developed a fever with temperatures as high as 104°F (40°C), abdominal pain, joint pain, and a red rash on the lower right leg. He has no cough, nasal congestion, rhinorrhea, ear or eye pain, oral ulcers, vomiting, or diarrhea. After reviewing his chart, it becomes apparent that he has experienced similar intermittent, random, and self-limited episodes over the last 4 years.

On examination, he is febrile with diffuse abdominal tenderness and guarding. Bowel sounds are normal, and there is no rebound. The left knee is slightly swollen and limited in range of motion, and there is a large, non-palpable, blanching, erythematous lesion over the anterior lower leg.

While pondering diagnostic possibilities, you remember reading about autoinflammatory syndromes that result in recurrent episodes of fever and multisystemic inflammatory symptoms but cannot recall the evaluation and therapeutic options for these conditions.

These syndromes pose diagnostic challenges for physicians. Although these conditions are uncommon and may mimic malignancy or infection, they should be considered in patients who have recurrent febrile illness. While the autoinflammatory syndrome of familial Mediterranean fever (FMF), the diagnosis in the case above, is well known, our growing understanding of genetics and the immune system has unearthed a growing number of autoinflammatory syndromes.

A GENETICALLY DIVERSE BUT CLINICALLY SIMILAR GROUP OF CONDITIONS

The autoinflammatory syndromes are a group of genetically diverse but clinically similar conditions characterized by recurrent attacks of fever, rash, serositis, lymphadenopathy, and musculoskeletal involvement. This category of diseases is rapidly expanding and was built on the discovery of the genetics behind FMF, hyperimmunoglobulin D syndrome (HIDS), tumor necrosis factor receptor-associated periodic syndrome (TRAPS), and the cryopyrin-associated periodic syndromes (CAPS). More recent additions to the list include Blau syndrome and the syndrome of pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA).

In autoinflammatory syndromes, genetic mutations lead to dysregulation of the innate immune system and to episodic manifestations of systemic inflammation. Many patients have first- or second-degree relatives with similar symptoms, reflecting the genetic abnormalities underlying this class of conditions. Unlike patients with other rheumatic diseases, patients with autoinflammatory diseases do not have autoreactive T lymphocytes, and they typically lack pathogenic autoantibodies.

The characterization of genetic autoinflammatory syndromes shows the importance of a well-regulated innate immune system and sheds light on the role of the innate immune system in common medical conditions such as gout and type 2 diabetes (see below).

THE INNATE IMMUNE SYSTEM : OUR FIRST LINE OF DEFENSE

The innate immune system is the first line of immune defense. It is evolutionarily conserved. Unlike the adaptive immune response, the innate immune response is not antigen-specific, and its activation does not produce a memory response. Generally speaking, it is composed of certain white blood cells (neutrophils, dendritic cells, macrophages, natural killer cells), proinflammatory signaling proteins (cytokines), and the complement system. Interleukin 1 (IL-1), interleukin 6 (IL-6), and tumor necrosis factor (TNF) alpha are the critical and most potent proinflammatory cytokines of the innate immune system.

To date, nearly all mutations that have been linked to the autoinflammatory syndromes disrupt regulation of inflammatory signaling within the innate immune system. This disruption generates a proinflammatory state, often leading to a final common pathway ending with activation of the inflammasome.

The inflammasome is a complex of distinct proteins which, when brought together, serve to convert inactive prointerleukin 1 beta to the active proinflammatory cytokine IL-1 beta.¹ Formation of the inflammasome can be mediated by multiple different signals including microbial products, endogenously produced substances such as cholesterol and uric acid, or by proinflammatory cytokines and chemokines (Figure 1).

FAMILIAL MEDITERRANEAN FEVER

FMF is the most common and well characterized autoinflammatory syndrome. Described in 1949, its etiology was not understood until the genetic mutation that causes it was discovered in 1997.^2–4

The Mediterranean fever gene MEFV encodes pyrin, a protein with an important role in controlling IL-1 production. Mutations in MEFV affect pyrin-mediated regulation, and IL-1 production increases.

Classically, FMF is described as autosomal recessive, although many patients have only one abnormal allele.⁵ Possibly, the abnormal allele confers an evolutionary advantage in resisting an endemic pathogen, an idea reflected in the carrier frequencies of different MEFV mutations in certain Mediterranean and Middle Eastern ethnic populations (Sephardic Jews, Turks, Arabs, Armenians).^6,7 Also, carriage of mutations in MEFV in patients with Crohn disease has been associated with a higher risk of extraintestinal manifestations and colonic stricture,⁸ and their carriage in patients with multiple sclerosis has been associated with a rapid progression of that disease.⁹

Although FMF usually presents at ages 5 to 15, about 20% of patients with FMF suffer their first inflammatory attack after age 20 years.

Attacks are characterized by brief episodes of fever with temperatures higher than 102°F (38.9°C), lasting less than 72 hours, accompanied by intense serositis. Abdominal serositis may be severe enough to mimic appendicitis and lead to exploratory surgery.

About 70% of patients experience arthritis (predominantly in the legs), and 40% develop erysipeloid erythema, an intensely erythematous, warm, tender, and plaque-like lesion on the lower extremities. Biopsy of involved skin shows a diffuse, primarily neutrophilic, inflammatory cell infiltrate.

Laboratory examination reveals marked elevation of acute-phase reactants, which may normalize between episodes. The diagnosis can be made using a combination of clinical suspicion, sequencing of the MEFV gene, and a positive response to a trial of colchicine (Colcrys).

Without treatment, repetitive attacks of inflammation may result in amyloidosis of the kidneys or liver. The risk of amyloidosis is related to several discrete risk factors, such as country of residence, MEFV genotype, and serum amyloid A genotype.^10–12 Patients should be monitored for physical manifestations of amyloidosis at least annually.

FMF patients have also been described who develop vasculitides such as Henoch-Schönlein purpura, polyarteritis nodosa, or Behçet disease.

Colchicine is the mainstay of FMF treatment

Colchicine has been the mainstay of therapy for patients with FMF for almost 40 years.^13–15 Its benefits in FMF are clear: symptoms cease in nearly 70% of patients treated with colchicine, and an additional 25% have a reduction in the severity and frequency of attacks.

Only 5% to 10% of patients have no response to colchicine; this may be partially due to individual dose limitations imposed by common drug-associated gastrointestinal side effects.^16–18 For these patients, newer biologic drugs that inhibit IL-1 activity, such as anakinra (Kineret) and rilonacept (Arcalyst), offer great promise.

Typically, FMF attacks become less frequent and less severe with age. However, the overall prognosis in FMF is related mainly to the individual’s genotype and the associated risk of amyloidosis.¹⁹

HYPERIMMUNOGLOBULIN D SYNDROME

HIDS is another autosomal recessive autoinflammatory syndrome.²⁰

The genetic defect underlying HIDS lies within the mevalonate kinase gene MVK.²¹ Mevalonate kinase, an enzyme, plays an important role in the cholesterol biosynthesis pathway, following the initial step by 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase. Mutations are primarily missense mutations in highly conserved areas of protein that result in decreased MVK activity (1% to 5% of normal).^22,23 Decreased production of geranylgeranyl pyrophosphate resulting from disruption in the HMG-CoA reductase pathway subsequently leads to increased release of IL-1 beta from peripheral blood mononuclear cells and triggers inflammatory symptoms.²⁴

Attacks of HIDS begin early in life

HIDS attacks begin early in life, with more than 70% of patients suffering their first attack before age 2, but adult-onset disease has been reported. Patients may report that routine childhood vaccinations triggered attacks, a historical finding unique to HIDS.

Attacks typically last 4 days; a longer duration can help the clinician differentiate HIDS from FMF.

More than 90% of patients have cervical lymphadenopathy, and 80% have an erythematous rash characteristically located on the palms and soles. About 70% of patients have headache, arthritis, and abdominal pain.

During attacks, laboratory examination reveals elevated acute inflammatory reactants. As the name implies, serum levels of immunoglobulin D (IgD) are elevated. However, this finding is not specific to HIDS and may also be found in patients with Still disease or FMF or in those who smoke cigarettes. Serum IgD levels fluctuate throughout life, and the sensitivity of commercially available IgD test kits is variable.

Assessment of mevalonic acid levels in the urine during febrile attacks offers a more sensitive, specific, and reliable diagnostic test for HIDS.²⁵ While genetic sequencing is the gold standard of diagnostic testing, close to 30% of patients meeting clinical criteria for HIDS have no definable mutation.²⁶

Treatment of HIDS can be challenging

Oral corticosteroids are effective in HIDS, but their long-term side effects are undesirable. Patients rarely respond to colchicine, differentiating them from FMF patients.

Etanercept (Enbrel), a fusion protein composed of the soluble TNF receptor and the Fc portion of the human IgG1 protein, has been efficacious in some patients.^27,28 IL-1 inhibitors have also been used with increasing efficacy in the treatment of HIDS attacks.^29,30

Although the frequency of attacks decreases with age, long-term follow-up of 28 Dutch HIDS patients found that their quality of life was still lower than that in country-matched controls.³¹

TUMOR NECROSIS FACTOR RECEPTOR-ASSOCIATED PERIODIC SYNDROME

In 1982, a large multiplex family from Scotland and Ireland was described who had a newly recognized syndrome termed familial Hibernian fever, characterized by recurrent fever, rash, and abdominal pain.³² In 1998, the genetics of this autosomal dominant condition were characterized,^33–35 and it is now known by the acronym TRAPS.

TRAPS has a variable presentation owing to a variety of mutations in the gene encoding the cell surface receptor for TNF (TNFRSF1A). TNFRSF1A mutations affecting conserved cysteine residues important for protein folding correspond to severe disease phenotypes.

The R92Q mutation has an allele frequency of up to 4% of the population. It has no impact on the structure and function of the TNF receptor protein and is associated with a heterogeneous disease course. In contrast, the P46L mutation has an allele frequency of 1% of the population and typically is associated with a milder disease course characterized by older age of onset, shorter episodes, and a low frequency of amyloidosis.^36–39

The R92Q and T61I mutations, which have low penetrance, have been increasingly reported in adult patients with the autoimmune diseases systemic lupus erythematosus, rheumatoid arthritis, and multiple sclerosis.^40–42 Their influence is believed to contribute to proinflammatory responses but not to provide additional genetic susceptibility as provided by human leukocyte antigen (HLA) genotypes for susceptibility for these autoimmune diseases.

TRAPS attacks last longer than FMF and HIDS attacks

TRAPS attacks last 7 days or more, differentiating TRAPS from FMF and HIDS. Patients may present from infancy into adulthood, but more typically present in the toddler period.

Most patients experience intense myalgia as well as abdominal and pleuritic chest pain. A single-center series in 2002 described close to half of patients diagnosed with TRAPS as having had an intra-abdominal surgical procedure; in 10% necrotic bowel was identified, yet the biopsy typically revealed only a serosal mononuclear infiltrate.⁴³

Like FMF and HIDS, TRAPS can cause an erythematous rash. The rash usually appears on an extremity, is centrifugal, and travels proximal-to-distal in concert with symptoms of myalgia. Deep tissue biopsy often demonstrates an intense, neutrophilic fasciitis sparing the underlying musculature. Painful conjunctivitis with periorbital edema also may occur.

Laboratory values reflecting widespread systemic inflammation and elevated acute-phase reactants are encountered during attacks and in some cases may persist between episodes.

Genetic testing can be used to confirm the diagnosis. The probability of finding a mutation in TNFRSF1A depends highly on whether the patient has affected relatives. In a series of 28 patients with recurrent inflammatory syndromes and TNFRSF1A mutations, 9 (32%) had a family history of recurrent inflammatory syndromes, while in 176 patients with sporadic, nonfamilial “TRAPS-like” symptoms, TNFRSF1A mutations were uncommon.^37,38

Etanercept is effective for TRAPS

Systemic corticosteroids may be effective for treating TRAPS, but ever-increasing doses are often required.

Etanercept’s ability to bind both soluble and bound TNF explains its relative efficacy in treating TRAPS even though other TNF inhibitors have proven ineffective.^44,45 With etanercept, the prognosis of TRAPS patients is typically good. Etanercept has even been effective in treating cases of renal amyloidosis from long-standing TRAPS, although it has not been shown to facilitate regression of renal amyloid mass.^46,47 However, responses to treatment with etanercept may wane with time, and resistant cases have been reported.

IL-1 blockade with anakinra has been shown to be effective in the short term and long term in small case series, providing a reasonable alternative for patients who are difficult to manage.

CRYOPYRIN-ASSOCIATED PERIODIC SYNDROMES

• Perhaps the most clinically diverse hereditary autoinflammatory syndromes are the cryopyrin-associated periodic syndromes (CAPS). There are three overlapping phenotypes: Familial cold autoinflammatory syndrome (FCAS)
• Muckle-Wells syndrome (MWS)
• Neonatal-onset multisystemic inflammatory disorder (NOMID).

Mutations in NLRP3

CAPS symptoms stem from mutations within the NLRP3 gene (NOD-like receptor family, pyrin domain), which encodes the protein, cyropyrin.⁴⁸NLRP3 mutations result in an abnormal cryopyrin structure, abnormal inflammasome activity, and increased IL-1 beta production.^49,50

There is poor genotype-phenotype association in CAPS; the same NLRP3 point mutation can result in variable features, typically of either FCAS and MWS or MWS and NOMID overlapping phenotypes, supporting the hypothesis that modifier genes play a role in phenotypic expression.

Inheritance patterns in CAPS are autosomal dominant, but spontaneous mutations are also common. In fact, approximately two-thirds of patients with mutation-negative NOMID have somatic NLRP3 mutations, indicating that somatic NLRP3 mosaicism contributes to the clinical syndrome.⁵¹

Clinical features of the CAPS

The hallmarks of the CAPS include recurrent fevers, urticarial rash, and central nervous system inflammation. Characteristically, CAPS patients present in the neonatal period through early childhood, but adult-onset cases, which may have less typical features, have been reported.

Patients with FCAS develop brief episodes (< 24 hours) of fever, joint pain, and urticarial rash when exposed to sudden drops in ambient temperature.

Patients with MWS have more frequent, prolonged attacks, which may or may not be related to changes in ambient temperature. They also develop fever and urticarial rash and may develop arthritis and headaches from aseptic meningitis.

Patients with NOMID often present with fever and persistent urticarial rash shortly after birth and suffer from chronic aseptic meningitis, which can lead to papilledema and optic nerve atrophy. Frontal bossing of the skull and overgrowth of the epiphyseal regions of long bones with accompanying growth delay are also characteristic of NOMID.

IL-1 antagonists offer relief from CAPS

Many patients with FCAS do not require treatment and may move to a warmer climate to avoid rapid swings in ambient temperature. Otherwise, control of IL-1 beta activity is essential to the successful treatment of CAPS. Patients with MWS and NOMID require treatment with IL-1 antagonists, and the biologic drugs anakinra, rilonacept, and canakinumab (Ilaris) offer the possibility of symptomatic relief and long-term control of the disease.^52–54

Prognosis depends on the phenotype

The overall prognosis for patients with CAPS largely depends on phenotype.

Patients with FCAS generally have progressive improvement in attack frequency and severity over time and are at minimal risk of amyloidosis.

Patients with MWS have a relatively good prognosis when treated with IL-1 antagonists, making them at low risk of amyloidosis and sensorineural hearing loss.

However, patients with NOMID are at high risk of sensorineural hearing loss, growth delay, and amyloidosis unless the condition is recognized and treated early in its course. Mortality rates historically are as high as 20% in untreated patients with NOMID.⁵⁵

OTHER AUTOINFLAMMATORY SYNDROMES

More recently, other autoinflammatory syndromes of known genetic etiology have been described.

NLRP12-associated autoinflammatory disorders

A subset of patients with clinical manifestations attributable to CAPS but without mutations at the NLRP3 locus have mutations in another NLRP family member expressed in peripheral blood mononuclear cells on the NLRP12 gene. They are therefore labeled as having an NLRP12-associated autoinflammatory disorder.^56,57

Deficiency of interleukin 1 receptor antagonist

IL-1 receptor antagonist is a naturally occurring antagonist of IL-1 alpha and IL-1 beta. In patients with deficiency of IL-1 receptor antagonist (DIRA), the action of these potent proinflammatory proteins is unopposed, leading to severe pustular rash and osteitis.^58,59

Pyogenic arthritis, pyoderma gangrenosum, and acne syndrome

Patients with PAPA syndrome also have increased IL-1 production, in this case due to a mutation in the cytoplasmic adapter protein proline-serine-threonine phosphatase-interacting protein (PSTPIP1) gene, leading to the development of the symptoms included in the PAPA acronym.⁶⁰

Majeed syndrome

Majeed syndrome is caused by a mutation in the LPIN2 gene, resulting in the early onset of chronic recurrent multifocal osteomyelitis, neutrophilic dermatosis, and dyserythropoietic anemia.⁶¹

Blau syndrome

Some patients with Blau syndrome (granulomatosis, arthritis, and uveitis) have NOD2/CARD15 gene mutations.⁶² Cases of DIRA, PAPA, and Blau syndrome have been reported that responded favorably to treatment with IL-1 antagonists.

Periodic fever, aphthous stomatitis, pharyngitis, and adenopathy syndrome

Although symptoms of the periodic fever, aphthous stomatitis, pharyngitis, and adenopathy (PFAPA) syndrome typically begin in childhood, adult-onset cases have been reported.⁶³

Patients with PFAPA syndrome develop predictable, stereotypic febrile attacks that last on average 5 days and occur approximately every 4 weeks. Between attacks, patients are healthy; during attacks, they may experience oral ulceration (aphthous stomatitis), exudative or nonexudative pharyngitis, and enlarged and tender cervical lymph nodes. Up to 60% of PFAPA patients also experience abdominal pain.

No single genetic mutation has been identified, although it has been shown that 45% of PFAPA patients have a parent or sibling with recurrent fever and 12% have a parent or sibling with a PFAPA-like phenotype, suggesting that the disease has a genetic basis.⁶⁴ Recent studies have demonstrated that T-cell–regulated complement activation and IL-1 production are altered in PFAPA patients, thus supporting the hypothesis that PFAPA is an autoinflammatory syndrome.⁶⁵

Treatment. In view of the syndrome’s self-limited nature, treatment is reserved for patients with a severe presentation or for patients whose condition is especially burdensome.

The fever’s height may partially respond to nonsteroidal anti-inflammatory drugs, but these drugs have little effect on the duration or frequency of fever.

One or two doses of prednisone (1 mg/kg) within 6 hours of fever onset is effective in aborting the febrile episode in 90% of patients; however, up to 50% of patients may experience an increased frequency of attacks after treatment with systemic corticosteroids.^66,67

Additional options include daily colchicine, which may lengthen the time between attacks, and cimetidine (Tagamet), which has been shown to prevent PFAPA attacks in approximately one-third of patients.^67–69

The prognosis of PFAPA is quite favorable, and without intervention 40% of patients experience a significant reduction in the severity and frequency of fever attacks within 5 years of diagnosis. To date, there have been no reports of amyloidosis or hearing loss in PFAPA patients.

DIAGNOSTIC EVALUATION OF SUSPECTED AUTOINFLAMMATORY DISEASE

The autoinflammatory syndromes pose a true diagnostic challenge for physicians. Tremendous advances have been made in molecular and genetic testing. Nevertheless, the history and careful physical examination can lead the astute clinician to the proper diagnosis when evaluating a patient with a suspected autoinflammatory syndrome.

Critical elements in the history include age at the onset of attacks, duration of attacks, associated symptoms (serositis, adenopathy, myalgias, arthralgias, arthritis, ocular symptoms, central nervous system symptoms, rash), family members with similar symptoms, and ethnic background.

Internists should remember that autoinflammatory syndromes are part of the differential diagnosis in adult patients with a recurrent febrile illness. A vigorous search for malignancy and infection (especially tuberculosis) should be conducted in all patients. However, the repetitive, stereotypic nature of autoinflammatory syndromes differentiates them from typical confounders.

The utility of acute-phase reactants in the diagnostic evaluation is limited, as many conditions result in abnormal values. However, serial monitoring of inflammatory markers such as the erythrocyte sedimentation rate and C-reactive protein level in patients with a formally diagnosed autoinflammatory syndrome can be useful in tracking disease activity, identifying flares, and monitoring the efficacy of therapy.

In cases of suspected HIDS, assessment of IgD levels is not recommended, since IgD can be elevated in a number of autoinflammatory and rheumatologic conditions. Instead, preference should be given to testing mevalonic acid levels in the urine in patients with HIDS or suspected HIDS.

Patients with central nervous system symptoms should undergo a thorough examination, including a formal ophthalmologic evaluation, imaging, and possibly lumbar puncture to assess intracranial pressure and inflammatory changes in the cerebrospinal fluid.

Dermatologic manifestations should be examined firsthand and assessed as needed with magnetic resonance imaging to elucidate fascial inflammation or with full-thickness biopsy.

Gross bony abnormalities should be evaluated with plain radiography.

Audiologic testing may be indicated in the diagnostic evaluation of patients with recurrent fever.

Renal or hepatic biopsy may be indicated in the evaluation for amyloidosis; amyloid deposition has been reported in patients with TRAPS and clinical FMF not presenting with fever.^70,71

Genetic testing is commercially available for patients with suspected hereditary autoinflammatory syndromes. However, clinicians should be cautioned that up to 30% of patients with phenotypic manifestations characteristic of a given autoinflammatory syndrome have normal results on genetic testing. In addition, the results of genetic testing may take several months to return and may cost patients and families up to several thousand dollars, as some insurers refuse to cover this procedure. Genetic testing may ultimately be indicated for proper counseling of reproductive risk.

Responses to short courses of medications such as colchicine, prednisone, and IL-1 receptor antagonists also represent diagnostic tools.

NEW INSIGHT INTO MORE COMMON CONDITIONS

Advances in the understanding of the autoinflammatory syndromes have provided new insight into the role of the innate immune system in other, more common conditions.⁷² Indeed, abnormal regulation of the innate inflammatory pathway has been implicated in the pathogenesis of conditions as phenotypically diverse as gout, type 2 diabetes, atherosclerosis, and epilepsy.^73,74

Table 2 presents examples of the innate immune system’s involvement in the pathogenesis of several common chronic conditions.

Further study of autoinflammatory syndromes will add to our understanding of the innate immune system. These advances will lead to continued improvement in the care we give patients, both for the classic autoinflammatory syndromes and for other, more common, genetically complex conditions.

Our 22-year-old patient’s fever, abdominal pain (presumed peritonitis), erysipelas-like skin lesion, and arthritis are typical of FMF. Therefore, genetic testing was performed, which revealed a single MEFV gene mutation (M694V). Colchicine has been efficacious in preventing flares of his disease.

A 22-year-old man of Turkish ancestry presents to your office for an urgent visit. One day before the visit, he abruptly developed a fever with temperatures as high as 104°F (40°C), abdominal pain, joint pain, and a red rash on the lower right leg. He has no cough, nasal congestion, rhinorrhea, ear or eye pain, oral ulcers, vomiting, or diarrhea. After reviewing his chart, it becomes apparent that he has experienced similar intermittent, random, and self-limited episodes over the last 4 years.

On examination, he is febrile with diffuse abdominal tenderness and guarding. Bowel sounds are normal, and there is no rebound. The left knee is slightly swollen and limited in range of motion, and there is a large, non-palpable, blanching, erythematous lesion over the anterior lower leg.

While pondering diagnostic possibilities, you remember reading about autoinflammatory syndromes that result in recurrent episodes of fever and multisystemic inflammatory symptoms but cannot recall the evaluation and therapeutic options for these conditions.

These syndromes pose diagnostic challenges for physicians. Although these conditions are uncommon and may mimic malignancy or infection, they should be considered in patients who have recurrent febrile illness. While the autoinflammatory syndrome of familial Mediterranean fever (FMF), the diagnosis in the case above, is well known, our growing understanding of genetics and the immune system has unearthed a growing number of autoinflammatory syndromes.

A GENETICALLY DIVERSE BUT CLINICALLY SIMILAR GROUP OF CONDITIONS

The autoinflammatory syndromes are a group of genetically diverse but clinically similar conditions characterized by recurrent attacks of fever, rash, serositis, lymphadenopathy, and musculoskeletal involvement. This category of diseases is rapidly expanding and was built on the discovery of the genetics behind FMF, hyperimmunoglobulin D syndrome (HIDS), tumor necrosis factor receptor-associated periodic syndrome (TRAPS), and the cryopyrin-associated periodic syndromes (CAPS). More recent additions to the list include Blau syndrome and the syndrome of pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA).

In autoinflammatory syndromes, genetic mutations lead to dysregulation of the innate immune system and to episodic manifestations of systemic inflammation. Many patients have first- or second-degree relatives with similar symptoms, reflecting the genetic abnormalities underlying this class of conditions. Unlike patients with other rheumatic diseases, patients with autoinflammatory diseases do not have autoreactive T lymphocytes, and they typically lack pathogenic autoantibodies.

The characterization of genetic autoinflammatory syndromes shows the importance of a well-regulated innate immune system and sheds light on the role of the innate immune system in common medical conditions such as gout and type 2 diabetes (see below).

THE INNATE IMMUNE SYSTEM : OUR FIRST LINE OF DEFENSE

The innate immune system is the first line of immune defense. It is evolutionarily conserved. Unlike the adaptive immune response, the innate immune response is not antigen-specific, and its activation does not produce a memory response. Generally speaking, it is composed of certain white blood cells (neutrophils, dendritic cells, macrophages, natural killer cells), proinflammatory signaling proteins (cytokines), and the complement system. Interleukin 1 (IL-1), interleukin 6 (IL-6), and tumor necrosis factor (TNF) alpha are the critical and most potent proinflammatory cytokines of the innate immune system.

To date, nearly all mutations that have been linked to the autoinflammatory syndromes disrupt regulation of inflammatory signaling within the innate immune system. This disruption generates a proinflammatory state, often leading to a final common pathway ending with activation of the inflammasome.

The inflammasome is a complex of distinct proteins which, when brought together, serve to convert inactive prointerleukin 1 beta to the active proinflammatory cytokine IL-1 beta.¹ Formation of the inflammasome can be mediated by multiple different signals including microbial products, endogenously produced substances such as cholesterol and uric acid, or by proinflammatory cytokines and chemokines (Figure 1).

FAMILIAL MEDITERRANEAN FEVER

FMF is the most common and well characterized autoinflammatory syndrome. Described in 1949, its etiology was not understood until the genetic mutation that causes it was discovered in 1997.^2–4

The Mediterranean fever gene MEFV encodes pyrin, a protein with an important role in controlling IL-1 production. Mutations in MEFV affect pyrin-mediated regulation, and IL-1 production increases.

Classically, FMF is described as autosomal recessive, although many patients have only one abnormal allele.⁵ Possibly, the abnormal allele confers an evolutionary advantage in resisting an endemic pathogen, an idea reflected in the carrier frequencies of different MEFV mutations in certain Mediterranean and Middle Eastern ethnic populations (Sephardic Jews, Turks, Arabs, Armenians).^6,7 Also, carriage of mutations in MEFV in patients with Crohn disease has been associated with a higher risk of extraintestinal manifestations and colonic stricture,⁸ and their carriage in patients with multiple sclerosis has been associated with a rapid progression of that disease.⁹

Although FMF usually presents at ages 5 to 15, about 20% of patients with FMF suffer their first inflammatory attack after age 20 years.

Attacks are characterized by brief episodes of fever with temperatures higher than 102°F (38.9°C), lasting less than 72 hours, accompanied by intense serositis. Abdominal serositis may be severe enough to mimic appendicitis and lead to exploratory surgery.

About 70% of patients experience arthritis (predominantly in the legs), and 40% develop erysipeloid erythema, an intensely erythematous, warm, tender, and plaque-like lesion on the lower extremities. Biopsy of involved skin shows a diffuse, primarily neutrophilic, inflammatory cell infiltrate.

Laboratory examination reveals marked elevation of acute-phase reactants, which may normalize between episodes. The diagnosis can be made using a combination of clinical suspicion, sequencing of the MEFV gene, and a positive response to a trial of colchicine (Colcrys).

Without treatment, repetitive attacks of inflammation may result in amyloidosis of the kidneys or liver. The risk of amyloidosis is related to several discrete risk factors, such as country of residence, MEFV genotype, and serum amyloid A genotype.^10–12 Patients should be monitored for physical manifestations of amyloidosis at least annually.

FMF patients have also been described who develop vasculitides such as Henoch-Schönlein purpura, polyarteritis nodosa, or Behçet disease.

Colchicine is the mainstay of FMF treatment

Colchicine has been the mainstay of therapy for patients with FMF for almost 40 years.^13–15 Its benefits in FMF are clear: symptoms cease in nearly 70% of patients treated with colchicine, and an additional 25% have a reduction in the severity and frequency of attacks.

Only 5% to 10% of patients have no response to colchicine; this may be partially due to individual dose limitations imposed by common drug-associated gastrointestinal side effects.^16–18 For these patients, newer biologic drugs that inhibit IL-1 activity, such as anakinra (Kineret) and rilonacept (Arcalyst), offer great promise.

Typically, FMF attacks become less frequent and less severe with age. However, the overall prognosis in FMF is related mainly to the individual’s genotype and the associated risk of amyloidosis.¹⁹

HYPERIMMUNOGLOBULIN D SYNDROME

HIDS is another autosomal recessive autoinflammatory syndrome.²⁰

The genetic defect underlying HIDS lies within the mevalonate kinase gene MVK.²¹ Mevalonate kinase, an enzyme, plays an important role in the cholesterol biosynthesis pathway, following the initial step by 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase. Mutations are primarily missense mutations in highly conserved areas of protein that result in decreased MVK activity (1% to 5% of normal).^22,23 Decreased production of geranylgeranyl pyrophosphate resulting from disruption in the HMG-CoA reductase pathway subsequently leads to increased release of IL-1 beta from peripheral blood mononuclear cells and triggers inflammatory symptoms.²⁴

Attacks of HIDS begin early in life

HIDS attacks begin early in life, with more than 70% of patients suffering their first attack before age 2, but adult-onset disease has been reported. Patients may report that routine childhood vaccinations triggered attacks, a historical finding unique to HIDS.

Attacks typically last 4 days; a longer duration can help the clinician differentiate HIDS from FMF.

More than 90% of patients have cervical lymphadenopathy, and 80% have an erythematous rash characteristically located on the palms and soles. About 70% of patients have headache, arthritis, and abdominal pain.

During attacks, laboratory examination reveals elevated acute inflammatory reactants. As the name implies, serum levels of immunoglobulin D (IgD) are elevated. However, this finding is not specific to HIDS and may also be found in patients with Still disease or FMF or in those who smoke cigarettes. Serum IgD levels fluctuate throughout life, and the sensitivity of commercially available IgD test kits is variable.

Assessment of mevalonic acid levels in the urine during febrile attacks offers a more sensitive, specific, and reliable diagnostic test for HIDS.²⁵ While genetic sequencing is the gold standard of diagnostic testing, close to 30% of patients meeting clinical criteria for HIDS have no definable mutation.²⁶

Treatment of HIDS can be challenging

Oral corticosteroids are effective in HIDS, but their long-term side effects are undesirable. Patients rarely respond to colchicine, differentiating them from FMF patients.

Etanercept (Enbrel), a fusion protein composed of the soluble TNF receptor and the Fc portion of the human IgG1 protein, has been efficacious in some patients.^27,28 IL-1 inhibitors have also been used with increasing efficacy in the treatment of HIDS attacks.^29,30

Although the frequency of attacks decreases with age, long-term follow-up of 28 Dutch HIDS patients found that their quality of life was still lower than that in country-matched controls.³¹

TUMOR NECROSIS FACTOR RECEPTOR-ASSOCIATED PERIODIC SYNDROME

In 1982, a large multiplex family from Scotland and Ireland was described who had a newly recognized syndrome termed familial Hibernian fever, characterized by recurrent fever, rash, and abdominal pain.³² In 1998, the genetics of this autosomal dominant condition were characterized,^33–35 and it is now known by the acronym TRAPS.

TRAPS has a variable presentation owing to a variety of mutations in the gene encoding the cell surface receptor for TNF (TNFRSF1A). TNFRSF1A mutations affecting conserved cysteine residues important for protein folding correspond to severe disease phenotypes.

The R92Q mutation has an allele frequency of up to 4% of the population. It has no impact on the structure and function of the TNF receptor protein and is associated with a heterogeneous disease course. In contrast, the P46L mutation has an allele frequency of 1% of the population and typically is associated with a milder disease course characterized by older age of onset, shorter episodes, and a low frequency of amyloidosis.^36–39

The R92Q and T61I mutations, which have low penetrance, have been increasingly reported in adult patients with the autoimmune diseases systemic lupus erythematosus, rheumatoid arthritis, and multiple sclerosis.^40–42 Their influence is believed to contribute to proinflammatory responses but not to provide additional genetic susceptibility as provided by human leukocyte antigen (HLA) genotypes for susceptibility for these autoimmune diseases.

TRAPS attacks last longer than FMF and HIDS attacks

TRAPS attacks last 7 days or more, differentiating TRAPS from FMF and HIDS. Patients may present from infancy into adulthood, but more typically present in the toddler period.

Most patients experience intense myalgia as well as abdominal and pleuritic chest pain. A single-center series in 2002 described close to half of patients diagnosed with TRAPS as having had an intra-abdominal surgical procedure; in 10% necrotic bowel was identified, yet the biopsy typically revealed only a serosal mononuclear infiltrate.⁴³

Like FMF and HIDS, TRAPS can cause an erythematous rash. The rash usually appears on an extremity, is centrifugal, and travels proximal-to-distal in concert with symptoms of myalgia. Deep tissue biopsy often demonstrates an intense, neutrophilic fasciitis sparing the underlying musculature. Painful conjunctivitis with periorbital edema also may occur.

Laboratory values reflecting widespread systemic inflammation and elevated acute-phase reactants are encountered during attacks and in some cases may persist between episodes.

Genetic testing can be used to confirm the diagnosis. The probability of finding a mutation in TNFRSF1A depends highly on whether the patient has affected relatives. In a series of 28 patients with recurrent inflammatory syndromes and TNFRSF1A mutations, 9 (32%) had a family history of recurrent inflammatory syndromes, while in 176 patients with sporadic, nonfamilial “TRAPS-like” symptoms, TNFRSF1A mutations were uncommon.^37,38

Etanercept is effective for TRAPS

Systemic corticosteroids may be effective for treating TRAPS, but ever-increasing doses are often required.

Etanercept’s ability to bind both soluble and bound TNF explains its relative efficacy in treating TRAPS even though other TNF inhibitors have proven ineffective.^44,45 With etanercept, the prognosis of TRAPS patients is typically good. Etanercept has even been effective in treating cases of renal amyloidosis from long-standing TRAPS, although it has not been shown to facilitate regression of renal amyloid mass.^46,47 However, responses to treatment with etanercept may wane with time, and resistant cases have been reported.

IL-1 blockade with anakinra has been shown to be effective in the short term and long term in small case series, providing a reasonable alternative for patients who are difficult to manage.

CRYOPYRIN-ASSOCIATED PERIODIC SYNDROMES

• Perhaps the most clinically diverse hereditary autoinflammatory syndromes are the cryopyrin-associated periodic syndromes (CAPS). There are three overlapping phenotypes: Familial cold autoinflammatory syndrome (FCAS)
• Muckle-Wells syndrome (MWS)
• Neonatal-onset multisystemic inflammatory disorder (NOMID).

Mutations in NLRP3

CAPS symptoms stem from mutations within the NLRP3 gene (NOD-like receptor family, pyrin domain), which encodes the protein, cyropyrin.⁴⁸NLRP3 mutations result in an abnormal cryopyrin structure, abnormal inflammasome activity, and increased IL-1 beta production.^49,50

There is poor genotype-phenotype association in CAPS; the same NLRP3 point mutation can result in variable features, typically of either FCAS and MWS or MWS and NOMID overlapping phenotypes, supporting the hypothesis that modifier genes play a role in phenotypic expression.

Inheritance patterns in CAPS are autosomal dominant, but spontaneous mutations are also common. In fact, approximately two-thirds of patients with mutation-negative NOMID have somatic NLRP3 mutations, indicating that somatic NLRP3 mosaicism contributes to the clinical syndrome.⁵¹

Clinical features of the CAPS

The hallmarks of the CAPS include recurrent fevers, urticarial rash, and central nervous system inflammation. Characteristically, CAPS patients present in the neonatal period through early childhood, but adult-onset cases, which may have less typical features, have been reported.

Patients with FCAS develop brief episodes (< 24 hours) of fever, joint pain, and urticarial rash when exposed to sudden drops in ambient temperature.

Patients with MWS have more frequent, prolonged attacks, which may or may not be related to changes in ambient temperature. They also develop fever and urticarial rash and may develop arthritis and headaches from aseptic meningitis.

Patients with NOMID often present with fever and persistent urticarial rash shortly after birth and suffer from chronic aseptic meningitis, which can lead to papilledema and optic nerve atrophy. Frontal bossing of the skull and overgrowth of the epiphyseal regions of long bones with accompanying growth delay are also characteristic of NOMID.

IL-1 antagonists offer relief from CAPS

Many patients with FCAS do not require treatment and may move to a warmer climate to avoid rapid swings in ambient temperature. Otherwise, control of IL-1 beta activity is essential to the successful treatment of CAPS. Patients with MWS and NOMID require treatment with IL-1 antagonists, and the biologic drugs anakinra, rilonacept, and canakinumab (Ilaris) offer the possibility of symptomatic relief and long-term control of the disease.^52–54

Prognosis depends on the phenotype

The overall prognosis for patients with CAPS largely depends on phenotype.

Patients with FCAS generally have progressive improvement in attack frequency and severity over time and are at minimal risk of amyloidosis.

Patients with MWS have a relatively good prognosis when treated with IL-1 antagonists, making them at low risk of amyloidosis and sensorineural hearing loss.

However, patients with NOMID are at high risk of sensorineural hearing loss, growth delay, and amyloidosis unless the condition is recognized and treated early in its course. Mortality rates historically are as high as 20% in untreated patients with NOMID.⁵⁵

OTHER AUTOINFLAMMATORY SYNDROMES

More recently, other autoinflammatory syndromes of known genetic etiology have been described.

NLRP12-associated autoinflammatory disorders

A subset of patients with clinical manifestations attributable to CAPS but without mutations at the NLRP3 locus have mutations in another NLRP family member expressed in peripheral blood mononuclear cells on the NLRP12 gene. They are therefore labeled as having an NLRP12-associated autoinflammatory disorder.^56,57

Deficiency of interleukin 1 receptor antagonist

IL-1 receptor antagonist is a naturally occurring antagonist of IL-1 alpha and IL-1 beta. In patients with deficiency of IL-1 receptor antagonist (DIRA), the action of these potent proinflammatory proteins is unopposed, leading to severe pustular rash and osteitis.^58,59

Pyogenic arthritis, pyoderma gangrenosum, and acne syndrome

Patients with PAPA syndrome also have increased IL-1 production, in this case due to a mutation in the cytoplasmic adapter protein proline-serine-threonine phosphatase-interacting protein (PSTPIP1) gene, leading to the development of the symptoms included in the PAPA acronym.⁶⁰

Majeed syndrome

Majeed syndrome is caused by a mutation in the LPIN2 gene, resulting in the early onset of chronic recurrent multifocal osteomyelitis, neutrophilic dermatosis, and dyserythropoietic anemia.⁶¹

Blau syndrome

Some patients with Blau syndrome (granulomatosis, arthritis, and uveitis) have NOD2/CARD15 gene mutations.⁶² Cases of DIRA, PAPA, and Blau syndrome have been reported that responded favorably to treatment with IL-1 antagonists.

Periodic fever, aphthous stomatitis, pharyngitis, and adenopathy syndrome

Although symptoms of the periodic fever, aphthous stomatitis, pharyngitis, and adenopathy (PFAPA) syndrome typically begin in childhood, adult-onset cases have been reported.⁶³

Patients with PFAPA syndrome develop predictable, stereotypic febrile attacks that last on average 5 days and occur approximately every 4 weeks. Between attacks, patients are healthy; during attacks, they may experience oral ulceration (aphthous stomatitis), exudative or nonexudative pharyngitis, and enlarged and tender cervical lymph nodes. Up to 60% of PFAPA patients also experience abdominal pain.

No single genetic mutation has been identified, although it has been shown that 45% of PFAPA patients have a parent or sibling with recurrent fever and 12% have a parent or sibling with a PFAPA-like phenotype, suggesting that the disease has a genetic basis.⁶⁴ Recent studies have demonstrated that T-cell–regulated complement activation and IL-1 production are altered in PFAPA patients, thus supporting the hypothesis that PFAPA is an autoinflammatory syndrome.⁶⁵

Treatment. In view of the syndrome’s self-limited nature, treatment is reserved for patients with a severe presentation or for patients whose condition is especially burdensome.

The fever’s height may partially respond to nonsteroidal anti-inflammatory drugs, but these drugs have little effect on the duration or frequency of fever.

One or two doses of prednisone (1 mg/kg) within 6 hours of fever onset is effective in aborting the febrile episode in 90% of patients; however, up to 50% of patients may experience an increased frequency of attacks after treatment with systemic corticosteroids.^66,67

Additional options include daily colchicine, which may lengthen the time between attacks, and cimetidine (Tagamet), which has been shown to prevent PFAPA attacks in approximately one-third of patients.^67–69

The prognosis of PFAPA is quite favorable, and without intervention 40% of patients experience a significant reduction in the severity and frequency of fever attacks within 5 years of diagnosis. To date, there have been no reports of amyloidosis or hearing loss in PFAPA patients.

DIAGNOSTIC EVALUATION OF SUSPECTED AUTOINFLAMMATORY DISEASE

The autoinflammatory syndromes pose a true diagnostic challenge for physicians. Tremendous advances have been made in molecular and genetic testing. Nevertheless, the history and careful physical examination can lead the astute clinician to the proper diagnosis when evaluating a patient with a suspected autoinflammatory syndrome.

Critical elements in the history include age at the onset of attacks, duration of attacks, associated symptoms (serositis, adenopathy, myalgias, arthralgias, arthritis, ocular symptoms, central nervous system symptoms, rash), family members with similar symptoms, and ethnic background.

Internists should remember that autoinflammatory syndromes are part of the differential diagnosis in adult patients with a recurrent febrile illness. A vigorous search for malignancy and infection (especially tuberculosis) should be conducted in all patients. However, the repetitive, stereotypic nature of autoinflammatory syndromes differentiates them from typical confounders.

The utility of acute-phase reactants in the diagnostic evaluation is limited, as many conditions result in abnormal values. However, serial monitoring of inflammatory markers such as the erythrocyte sedimentation rate and C-reactive protein level in patients with a formally diagnosed autoinflammatory syndrome can be useful in tracking disease activity, identifying flares, and monitoring the efficacy of therapy.

In cases of suspected HIDS, assessment of IgD levels is not recommended, since IgD can be elevated in a number of autoinflammatory and rheumatologic conditions. Instead, preference should be given to testing mevalonic acid levels in the urine in patients with HIDS or suspected HIDS.

Patients with central nervous system symptoms should undergo a thorough examination, including a formal ophthalmologic evaluation, imaging, and possibly lumbar puncture to assess intracranial pressure and inflammatory changes in the cerebrospinal fluid.

Dermatologic manifestations should be examined firsthand and assessed as needed with magnetic resonance imaging to elucidate fascial inflammation or with full-thickness biopsy.

Gross bony abnormalities should be evaluated with plain radiography.

Audiologic testing may be indicated in the diagnostic evaluation of patients with recurrent fever.

Renal or hepatic biopsy may be indicated in the evaluation for amyloidosis; amyloid deposition has been reported in patients with TRAPS and clinical FMF not presenting with fever.^70,71

Genetic testing is commercially available for patients with suspected hereditary autoinflammatory syndromes. However, clinicians should be cautioned that up to 30% of patients with phenotypic manifestations characteristic of a given autoinflammatory syndrome have normal results on genetic testing. In addition, the results of genetic testing may take several months to return and may cost patients and families up to several thousand dollars, as some insurers refuse to cover this procedure. Genetic testing may ultimately be indicated for proper counseling of reproductive risk.

Responses to short courses of medications such as colchicine, prednisone, and IL-1 receptor antagonists also represent diagnostic tools.

NEW INSIGHT INTO MORE COMMON CONDITIONS

Advances in the understanding of the autoinflammatory syndromes have provided new insight into the role of the innate immune system in other, more common conditions.⁷² Indeed, abnormal regulation of the innate inflammatory pathway has been implicated in the pathogenesis of conditions as phenotypically diverse as gout, type 2 diabetes, atherosclerosis, and epilepsy.^73,74

Table 2 presents examples of the innate immune system’s involvement in the pathogenesis of several common chronic conditions.

Further study of autoinflammatory syndromes will add to our understanding of the innate immune system. These advances will lead to continued improvement in the care we give patients, both for the classic autoinflammatory syndromes and for other, more common, genetically complex conditions.

Our 22-year-old patient’s fever, abdominal pain (presumed peritonitis), erysipelas-like skin lesion, and arthritis are typical of FMF. Therefore, genetic testing was performed, which revealed a single MEFV gene mutation (M694V). Colchicine has been efficacious in preventing flares of his disease.

More than 10% of patients labeled as having cellulitis do not have cellulitis.¹ This is unfortunate, as it leads to excessive and incorrect use of antibiotics and to delays in appropriate therapy.² However, it is not surprising, given the number of conditions that bear a striking similarity to cellulitis. A familiarity with the features of true cellulitis and with the handful of conditions that can bear a striking similarity to it is the way out of this potential diagnostic quagmire.

WHAT CELLULITIS IS—AND IS NOT

The key characteristics of cellulitis are redness, warmth, tenderness, and swelling of the skin. A history of trauma and pain in the affected area and evidence of leukocytosis³ suggest cellulitis. A symmetric or diffusely scattered pattern indicates a condition other than cellulitis, which is overwhelmingly unilateral, with smooth, indistinct borders^4,5 Other factors pointing to cellulitis are underlying immunosuppression, a more rapid progression, previous episodes, systemic symptoms (eg, fever, leukocytosis), new medications, new travel or outdoor exposure, and comorbidities such as diabetes and peripheral vascular disease. A long-standing, slowly progressive course and a history of unsuccessful treatment with antibiotics are strong indicators of a condition other than cellulitis.

Consultation with a dermatologist is recommended to narrow the differential diagnosis. The dermatologist can determine if biopsy is necessary, as many dermatoses that mimic cellulitis can be diagnosed by visual recognition alone.

STASIS DERMATITIS

The most common mimic of cellulitis is stasis dermatitis (Figure 1).² Patients can present with ill-defined, bilateral, pitting edema of the lower extremities, typically with erythema, hyperpigmentation, serous drainage, and superficial desquamation.^3,6,7

The inciting factor is chronic venous insufficiency, leading to interstitial edema, extravasation of red blood cells, and decreased tissue oxygenation. This process causes micro-vascular changes and microthrombi that up-regulate transforming growth factor beta and fibroblastic growth factor.⁷ If the process is allowed to continue, stasis dermatitis may progress to lipodermatosclerosis.

Tip: Stasis dermatitis is generally bilateral, the process will have been ongoing for years, there is often pitting edema, and the legs should be nontender.

LIPODERMATOSCLEROSIS

Lipodermatosclerosis is a sclerosing panniculitis classically described as an “inverted champagne bottle” or “inverted bowling pin” appearance of the leg, ie, the diameter of the leg is sharply narrowed directly below the calf (Figure 2).

There is an acute and a chronic phase. The acute phase is characterized by inflammation and erythema, and the chronic phase is characterized by fibrosis.⁸ The acute phase presents with severe lower-extremity pain above the medial malleolus, erythema, edema, and warmth; there is no sharp demarcation between affected and unaffected skin.^9,10 This phase can be difficult to distinguish from cellulitis, so the history plays a key role. Known venous insufficiency, cutaneous changes of stasis dermatitis, and the absence of systemic symptoms all point to lipodermatosclerosis.

The chronic phase is characterized by unilateral or bilateral, indurated, sclerotic plaques with a “bound-down” appearance (ie, they appear as if tethered—or bound—to the subcutaneous tissue) affecting the skin from below the knee to the ankle; there is a sharp demarcation between affected and unaffected skin.^9–11 The skin is often bronze or brown secondary to hemosiderin deposits. There can be prominent varicosities and scattered ulcerations depending on the course of the disease.

This condition is thought to be the result of long-standing chronic venous insufficiency.^7,8,9,11 It is proposed that venous incompetence leads to extravasation of interstitial fluid and red blood cells, decreased diffusion of oxygen to the tissues, and eventual tissue and endothelial damage. As the endothelium is damaged, microthrombi formation and infarction ensue, stimulating fibroblasts to form granulation tissue.

Tip: The history helps to distinguish acute lipodermatosclerosis from cellulitis. Chroniclipodermatoslcerosis will have been ongoing for years, the legs should be nontender, the skin will be bound-down, and the diameter of the leg will sharply decrease from knee to ankle.

CONTACT DERMATITIS

Allergic and irritant forms of contact dermatitis are often mistaken for cellulitis. Irritant contact dermatitis (Figure 3) presents with erythematous patches and plaques with well-defined borders, often in a geometric distribution where the skin was exposed to an irritant.¹² Allergic contact dermatitis is a delayed hypersensitivity dermatitis that can be secondary to something ingested, applied to the skin, or airborne (Figure 4). It presents as erythematous macules, papules, and plaques that may have serous drainage or vesiculation. Lesions of allergic contact dermatitis are usually confined to the site of contact with the allergen, but they can infrequently be found at distant sites, in which case it is considered systemic contact dermatitis.^3,5 Depending on the severity of the allergy, patients may complain of intense pain and pruritus.³

Additionally, chronic, nonhealing leg ulcers may have a confounding allergic contact dermatitis.⁷ Although patients may believe they are helping the ulcer heal by applying topical antibiotics or other lubricants, they may in fact be impeding the healing process. Always inquire as to what the patient is applying if he or she has leg ulceration with surrounding edema and erythema that has not resolved with conventional treatments.^13,14

Tip: The key to distinguishing contact dermatitis from cellulitis is the history. For example, ask about recent changes in medications, soaps, and laundry detergents, new hobbies, or recent surgeries. The involved site is often confined to the area where the allergen contacted the skin, except in cases of exposure to an airborne allergen.

LYMPHEDEMA

Lymphedema is characterized by localized edema of an affected extremity, with induration, erythema, and secondary cutaneous changes such as hyperkeratosis, dyspigmentation, and wart-like architecture (Figure 5).

Primary lymphedema appears in the setting of congenital abnormalities, whereas secondary lymphedema results from an interruption of a previously functioning lymphatic system (eg, after radical mastectomy).

Patients often present with unilateral nonpitting edema and erythema in the absence of systemic symptoms.¹² Many patients presenting with lower-extremity lymphedema are overweight or obese, as the weight they carry causes obstruction of the inguinal lymphatics.⁶

The pathophysiology is not clearly delineated but is thought to be a consequence of decreased oxygenation of tissue secondary to extravasated lymph. As the oxygen is compromised, macrophages and fibroblasts are recruited, resulting in fibrosis.⁶

Patients with lymphedema are more susceptible to superficial and deep skin infections, as the natural defense system in the epidermis and papillary dermis is compromised by impaired lymphatic drainage.¹⁵

To differentiate uncomplicated lymphedema from a secondary cutaneous infection, the clinician should take into account the presence or absence of warmth, pain, increased erythema, and systemic symptoms (Figure 6).

Tip: Primary lymphedema will most likely present in childhood with no inciting factors and will require a full workup. Obtaining a history should make secondary lymphedema a relatively straightforward diagnosis: Has the patient undergone lymph node dissection? Has the patient had an injury in the affected leg? Lymphedema is overwhelmingly unilateral and nonpitting, and is often seen in overweight people (if no precipitating factor is present).

EOSINOPHILIC CELLULITIS

Eosinophilic cellulitis, or Wells syndrome, was first described in 1971 as a granulomatous dermatitis.¹⁶ It is a recurrent hypersensitivity reaction to a drug, to a vaccine, or to an insect bite, or to a viral or fungal infection that presents on the extremities as localized erythema, edema, and induration with sharp borders and a green or gray hue (Figure 7).^17–19 The lesions commonly progress to firm, indurated plaques that resemble morphea. The plaques may take weeks or years to resolve, but they do so without scarring.^12,17,20,21

As patients tend to have recurrent bouts of eosinophilic cellulitis, they may have lesions in different stages of healing. Patients tend to report itching and burning that precedes the onset of plaques.²² The complete blood count typically shows a transient hypereosinophilia.^{12,16,17,23–25}

Tip: This diagnosis often requires biopsy for confirmation, but helpful clues are a history of recurrent episodes, the color of the lesions, and peripheral eosinophilia.

PAPULAR URTICARIA

Papular urticaria is a dermal hypersensitivity reaction to an insect bite, most commonly from a flea or mosquito.²⁶ Patients are often children, as their immune system may be hypersensitive. But children often develop tolerance before puberty.²⁷

The presentation may vary, from numerous urticarial papules near the site of a bite, to generalized, large, indurated, erythematous plaques reminiscent of cellulitis (Figure 8).^5,26 The lesions usually develop within hours of a bite and persist for an average of 1 to 2 weeks.²⁸ The areas typically affected are the head and neck or the upper or lower extremities; the palms, soles, and trunk are usually spared.²⁷

Patients most often complain of intense itching.¹² The pathogenesis is proposed to be mediated by the immune complex, and tissue biopsy study shows increased eosinophils. The eosinophils stimulate mast cells, causing release of histamine, leading to increased vascular permeability, edema, and erythema.^28,29

Tip: Biopsy may be necessary to confirm the diagnosis, though often the history may be sufficient. The patient may or may not recall a bite, so probe into recent activities such as outdoor sports or contact with a new pet. The papules and plaques are generally very pruritic but not painful.

DERMATOLOGY CONSULT

If the clinical presentation and history do not correlate, or if the skin condition has been treated with antibiotics yet has failed to respond, the possibility of other cutaneous dermatoses should be entertained. A dermatology consult can help determine the diagnosis, the need for further evaluation, and the best treatment course.

More than 10% of patients labeled as having cellulitis do not have cellulitis.¹ This is unfortunate, as it leads to excessive and incorrect use of antibiotics and to delays in appropriate therapy.² However, it is not surprising, given the number of conditions that bear a striking similarity to cellulitis. A familiarity with the features of true cellulitis and with the handful of conditions that can bear a striking similarity to it is the way out of this potential diagnostic quagmire.

WHAT CELLULITIS IS—AND IS NOT

The key characteristics of cellulitis are redness, warmth, tenderness, and swelling of the skin. A history of trauma and pain in the affected area and evidence of leukocytosis³ suggest cellulitis. A symmetric or diffusely scattered pattern indicates a condition other than cellulitis, which is overwhelmingly unilateral, with smooth, indistinct borders^4,5 Other factors pointing to cellulitis are underlying immunosuppression, a more rapid progression, previous episodes, systemic symptoms (eg, fever, leukocytosis), new medications, new travel or outdoor exposure, and comorbidities such as diabetes and peripheral vascular disease. A long-standing, slowly progressive course and a history of unsuccessful treatment with antibiotics are strong indicators of a condition other than cellulitis.

Consultation with a dermatologist is recommended to narrow the differential diagnosis. The dermatologist can determine if biopsy is necessary, as many dermatoses that mimic cellulitis can be diagnosed by visual recognition alone.

STASIS DERMATITIS

The most common mimic of cellulitis is stasis dermatitis (Figure 1).² Patients can present with ill-defined, bilateral, pitting edema of the lower extremities, typically with erythema, hyperpigmentation, serous drainage, and superficial desquamation.^3,6,7

The inciting factor is chronic venous insufficiency, leading to interstitial edema, extravasation of red blood cells, and decreased tissue oxygenation. This process causes micro-vascular changes and microthrombi that up-regulate transforming growth factor beta and fibroblastic growth factor.⁷ If the process is allowed to continue, stasis dermatitis may progress to lipodermatosclerosis.

Tip: Stasis dermatitis is generally bilateral, the process will have been ongoing for years, there is often pitting edema, and the legs should be nontender.

LIPODERMATOSCLEROSIS

Lipodermatosclerosis is a sclerosing panniculitis classically described as an “inverted champagne bottle” or “inverted bowling pin” appearance of the leg, ie, the diameter of the leg is sharply narrowed directly below the calf (Figure 2).

There is an acute and a chronic phase. The acute phase is characterized by inflammation and erythema, and the chronic phase is characterized by fibrosis.⁸ The acute phase presents with severe lower-extremity pain above the medial malleolus, erythema, edema, and warmth; there is no sharp demarcation between affected and unaffected skin.^9,10 This phase can be difficult to distinguish from cellulitis, so the history plays a key role. Known venous insufficiency, cutaneous changes of stasis dermatitis, and the absence of systemic symptoms all point to lipodermatosclerosis.

The chronic phase is characterized by unilateral or bilateral, indurated, sclerotic plaques with a “bound-down” appearance (ie, they appear as if tethered—or bound—to the subcutaneous tissue) affecting the skin from below the knee to the ankle; there is a sharp demarcation between affected and unaffected skin.^9–11 The skin is often bronze or brown secondary to hemosiderin deposits. There can be prominent varicosities and scattered ulcerations depending on the course of the disease.

This condition is thought to be the result of long-standing chronic venous insufficiency.^7,8,9,11 It is proposed that venous incompetence leads to extravasation of interstitial fluid and red blood cells, decreased diffusion of oxygen to the tissues, and eventual tissue and endothelial damage. As the endothelium is damaged, microthrombi formation and infarction ensue, stimulating fibroblasts to form granulation tissue.

Tip: The history helps to distinguish acute lipodermatosclerosis from cellulitis. Chroniclipodermatoslcerosis will have been ongoing for years, the legs should be nontender, the skin will be bound-down, and the diameter of the leg will sharply decrease from knee to ankle.

CONTACT DERMATITIS

Allergic and irritant forms of contact dermatitis are often mistaken for cellulitis. Irritant contact dermatitis (Figure 3) presents with erythematous patches and plaques with well-defined borders, often in a geometric distribution where the skin was exposed to an irritant.¹² Allergic contact dermatitis is a delayed hypersensitivity dermatitis that can be secondary to something ingested, applied to the skin, or airborne (Figure 4). It presents as erythematous macules, papules, and plaques that may have serous drainage or vesiculation. Lesions of allergic contact dermatitis are usually confined to the site of contact with the allergen, but they can infrequently be found at distant sites, in which case it is considered systemic contact dermatitis.^3,5 Depending on the severity of the allergy, patients may complain of intense pain and pruritus.³

Additionally, chronic, nonhealing leg ulcers may have a confounding allergic contact dermatitis.⁷ Although patients may believe they are helping the ulcer heal by applying topical antibiotics or other lubricants, they may in fact be impeding the healing process. Always inquire as to what the patient is applying if he or she has leg ulceration with surrounding edema and erythema that has not resolved with conventional treatments.^13,14

Tip: The key to distinguishing contact dermatitis from cellulitis is the history. For example, ask about recent changes in medications, soaps, and laundry detergents, new hobbies, or recent surgeries. The involved site is often confined to the area where the allergen contacted the skin, except in cases of exposure to an airborne allergen.

LYMPHEDEMA

Lymphedema is characterized by localized edema of an affected extremity, with induration, erythema, and secondary cutaneous changes such as hyperkeratosis, dyspigmentation, and wart-like architecture (Figure 5).

Primary lymphedema appears in the setting of congenital abnormalities, whereas secondary lymphedema results from an interruption of a previously functioning lymphatic system (eg, after radical mastectomy).

Patients often present with unilateral nonpitting edema and erythema in the absence of systemic symptoms.¹² Many patients presenting with lower-extremity lymphedema are overweight or obese, as the weight they carry causes obstruction of the inguinal lymphatics.⁶

The pathophysiology is not clearly delineated but is thought to be a consequence of decreased oxygenation of tissue secondary to extravasated lymph. As the oxygen is compromised, macrophages and fibroblasts are recruited, resulting in fibrosis.⁶

Patients with lymphedema are more susceptible to superficial and deep skin infections, as the natural defense system in the epidermis and papillary dermis is compromised by impaired lymphatic drainage.¹⁵

To differentiate uncomplicated lymphedema from a secondary cutaneous infection, the clinician should take into account the presence or absence of warmth, pain, increased erythema, and systemic symptoms (Figure 6).

Tip: Primary lymphedema will most likely present in childhood with no inciting factors and will require a full workup. Obtaining a history should make secondary lymphedema a relatively straightforward diagnosis: Has the patient undergone lymph node dissection? Has the patient had an injury in the affected leg? Lymphedema is overwhelmingly unilateral and nonpitting, and is often seen in overweight people (if no precipitating factor is present).

EOSINOPHILIC CELLULITIS

Eosinophilic cellulitis, or Wells syndrome, was first described in 1971 as a granulomatous dermatitis.¹⁶ It is a recurrent hypersensitivity reaction to a drug, to a vaccine, or to an insect bite, or to a viral or fungal infection that presents on the extremities as localized erythema, edema, and induration with sharp borders and a green or gray hue (Figure 7).^17–19 The lesions commonly progress to firm, indurated plaques that resemble morphea. The plaques may take weeks or years to resolve, but they do so without scarring.^12,17,20,21

As patients tend to have recurrent bouts of eosinophilic cellulitis, they may have lesions in different stages of healing. Patients tend to report itching and burning that precedes the onset of plaques.²² The complete blood count typically shows a transient hypereosinophilia.^{12,16,17,23–25}

Tip: This diagnosis often requires biopsy for confirmation, but helpful clues are a history of recurrent episodes, the color of the lesions, and peripheral eosinophilia.

PAPULAR URTICARIA

Papular urticaria is a dermal hypersensitivity reaction to an insect bite, most commonly from a flea or mosquito.²⁶ Patients are often children, as their immune system may be hypersensitive. But children often develop tolerance before puberty.²⁷

The presentation may vary, from numerous urticarial papules near the site of a bite, to generalized, large, indurated, erythematous plaques reminiscent of cellulitis (Figure 8).^5,26 The lesions usually develop within hours of a bite and persist for an average of 1 to 2 weeks.²⁸ The areas typically affected are the head and neck or the upper or lower extremities; the palms, soles, and trunk are usually spared.²⁷

Patients most often complain of intense itching.¹² The pathogenesis is proposed to be mediated by the immune complex, and tissue biopsy study shows increased eosinophils. The eosinophils stimulate mast cells, causing release of histamine, leading to increased vascular permeability, edema, and erythema.^28,29

Tip: Biopsy may be necessary to confirm the diagnosis, though often the history may be sufficient. The patient may or may not recall a bite, so probe into recent activities such as outdoor sports or contact with a new pet. The papules and plaques are generally very pruritic but not painful.

DERMATOLOGY CONSULT

If the clinical presentation and history do not correlate, or if the skin condition has been treated with antibiotics yet has failed to respond, the possibility of other cutaneous dermatoses should be entertained. A dermatology consult can help determine the diagnosis, the need for further evaluation, and the best treatment course.

More than 10% of patients labeled as having cellulitis do not have cellulitis.¹ This is unfortunate, as it leads to excessive and incorrect use of antibiotics and to delays in appropriate therapy.² However, it is not surprising, given the number of conditions that bear a striking similarity to cellulitis. A familiarity with the features of true cellulitis and with the handful of conditions that can bear a striking similarity to it is the way out of this potential diagnostic quagmire.

WHAT CELLULITIS IS—AND IS NOT

The key characteristics of cellulitis are redness, warmth, tenderness, and swelling of the skin. A history of trauma and pain in the affected area and evidence of leukocytosis³ suggest cellulitis. A symmetric or diffusely scattered pattern indicates a condition other than cellulitis, which is overwhelmingly unilateral, with smooth, indistinct borders^4,5 Other factors pointing to cellulitis are underlying immunosuppression, a more rapid progression, previous episodes, systemic symptoms (eg, fever, leukocytosis), new medications, new travel or outdoor exposure, and comorbidities such as diabetes and peripheral vascular disease. A long-standing, slowly progressive course and a history of unsuccessful treatment with antibiotics are strong indicators of a condition other than cellulitis.

Consultation with a dermatologist is recommended to narrow the differential diagnosis. The dermatologist can determine if biopsy is necessary, as many dermatoses that mimic cellulitis can be diagnosed by visual recognition alone.

STASIS DERMATITIS

The most common mimic of cellulitis is stasis dermatitis (Figure 1).² Patients can present with ill-defined, bilateral, pitting edema of the lower extremities, typically with erythema, hyperpigmentation, serous drainage, and superficial desquamation.^3,6,7

The inciting factor is chronic venous insufficiency, leading to interstitial edema, extravasation of red blood cells, and decreased tissue oxygenation. This process causes micro-vascular changes and microthrombi that up-regulate transforming growth factor beta and fibroblastic growth factor.⁷ If the process is allowed to continue, stasis dermatitis may progress to lipodermatosclerosis.

Tip: Stasis dermatitis is generally bilateral, the process will have been ongoing for years, there is often pitting edema, and the legs should be nontender.

LIPODERMATOSCLEROSIS

Lipodermatosclerosis is a sclerosing panniculitis classically described as an “inverted champagne bottle” or “inverted bowling pin” appearance of the leg, ie, the diameter of the leg is sharply narrowed directly below the calf (Figure 2).

There is an acute and a chronic phase. The acute phase is characterized by inflammation and erythema, and the chronic phase is characterized by fibrosis.⁸ The acute phase presents with severe lower-extremity pain above the medial malleolus, erythema, edema, and warmth; there is no sharp demarcation between affected and unaffected skin.^9,10 This phase can be difficult to distinguish from cellulitis, so the history plays a key role. Known venous insufficiency, cutaneous changes of stasis dermatitis, and the absence of systemic symptoms all point to lipodermatosclerosis.

The chronic phase is characterized by unilateral or bilateral, indurated, sclerotic plaques with a “bound-down” appearance (ie, they appear as if tethered—or bound—to the subcutaneous tissue) affecting the skin from below the knee to the ankle; there is a sharp demarcation between affected and unaffected skin.^9–11 The skin is often bronze or brown secondary to hemosiderin deposits. There can be prominent varicosities and scattered ulcerations depending on the course of the disease.

This condition is thought to be the result of long-standing chronic venous insufficiency.^7,8,9,11 It is proposed that venous incompetence leads to extravasation of interstitial fluid and red blood cells, decreased diffusion of oxygen to the tissues, and eventual tissue and endothelial damage. As the endothelium is damaged, microthrombi formation and infarction ensue, stimulating fibroblasts to form granulation tissue.

Tip: The history helps to distinguish acute lipodermatosclerosis from cellulitis. Chroniclipodermatoslcerosis will have been ongoing for years, the legs should be nontender, the skin will be bound-down, and the diameter of the leg will sharply decrease from knee to ankle.

CONTACT DERMATITIS

Allergic and irritant forms of contact dermatitis are often mistaken for cellulitis. Irritant contact dermatitis (Figure 3) presents with erythematous patches and plaques with well-defined borders, often in a geometric distribution where the skin was exposed to an irritant.¹² Allergic contact dermatitis is a delayed hypersensitivity dermatitis that can be secondary to something ingested, applied to the skin, or airborne (Figure 4). It presents as erythematous macules, papules, and plaques that may have serous drainage or vesiculation. Lesions of allergic contact dermatitis are usually confined to the site of contact with the allergen, but they can infrequently be found at distant sites, in which case it is considered systemic contact dermatitis.^3,5 Depending on the severity of the allergy, patients may complain of intense pain and pruritus.³

Additionally, chronic, nonhealing leg ulcers may have a confounding allergic contact dermatitis.⁷ Although patients may believe they are helping the ulcer heal by applying topical antibiotics or other lubricants, they may in fact be impeding the healing process. Always inquire as to what the patient is applying if he or she has leg ulceration with surrounding edema and erythema that has not resolved with conventional treatments.^13,14

Tip: The key to distinguishing contact dermatitis from cellulitis is the history. For example, ask about recent changes in medications, soaps, and laundry detergents, new hobbies, or recent surgeries. The involved site is often confined to the area where the allergen contacted the skin, except in cases of exposure to an airborne allergen.

LYMPHEDEMA

Lymphedema is characterized by localized edema of an affected extremity, with induration, erythema, and secondary cutaneous changes such as hyperkeratosis, dyspigmentation, and wart-like architecture (Figure 5).

Primary lymphedema appears in the setting of congenital abnormalities, whereas secondary lymphedema results from an interruption of a previously functioning lymphatic system (eg, after radical mastectomy).

Patients often present with unilateral nonpitting edema and erythema in the absence of systemic symptoms.¹² Many patients presenting with lower-extremity lymphedema are overweight or obese, as the weight they carry causes obstruction of the inguinal lymphatics.⁶

The pathophysiology is not clearly delineated but is thought to be a consequence of decreased oxygenation of tissue secondary to extravasated lymph. As the oxygen is compromised, macrophages and fibroblasts are recruited, resulting in fibrosis.⁶

Patients with lymphedema are more susceptible to superficial and deep skin infections, as the natural defense system in the epidermis and papillary dermis is compromised by impaired lymphatic drainage.¹⁵

To differentiate uncomplicated lymphedema from a secondary cutaneous infection, the clinician should take into account the presence or absence of warmth, pain, increased erythema, and systemic symptoms (Figure 6).

Tip: Primary lymphedema will most likely present in childhood with no inciting factors and will require a full workup. Obtaining a history should make secondary lymphedema a relatively straightforward diagnosis: Has the patient undergone lymph node dissection? Has the patient had an injury in the affected leg? Lymphedema is overwhelmingly unilateral and nonpitting, and is often seen in overweight people (if no precipitating factor is present).

EOSINOPHILIC CELLULITIS

Eosinophilic cellulitis, or Wells syndrome, was first described in 1971 as a granulomatous dermatitis.¹⁶ It is a recurrent hypersensitivity reaction to a drug, to a vaccine, or to an insect bite, or to a viral or fungal infection that presents on the extremities as localized erythema, edema, and induration with sharp borders and a green or gray hue (Figure 7).^17–19 The lesions commonly progress to firm, indurated plaques that resemble morphea. The plaques may take weeks or years to resolve, but they do so without scarring.^12,17,20,21

As patients tend to have recurrent bouts of eosinophilic cellulitis, they may have lesions in different stages of healing. Patients tend to report itching and burning that precedes the onset of plaques.²² The complete blood count typically shows a transient hypereosinophilia.^{12,16,17,23–25}

Tip: This diagnosis often requires biopsy for confirmation, but helpful clues are a history of recurrent episodes, the color of the lesions, and peripheral eosinophilia.

PAPULAR URTICARIA

Papular urticaria is a dermal hypersensitivity reaction to an insect bite, most commonly from a flea or mosquito.²⁶ Patients are often children, as their immune system may be hypersensitive. But children often develop tolerance before puberty.²⁷

The presentation may vary, from numerous urticarial papules near the site of a bite, to generalized, large, indurated, erythematous plaques reminiscent of cellulitis (Figure 8).^5,26 The lesions usually develop within hours of a bite and persist for an average of 1 to 2 weeks.²⁸ The areas typically affected are the head and neck or the upper or lower extremities; the palms, soles, and trunk are usually spared.²⁷

Patients most often complain of intense itching.¹² The pathogenesis is proposed to be mediated by the immune complex, and tissue biopsy study shows increased eosinophils. The eosinophils stimulate mast cells, causing release of histamine, leading to increased vascular permeability, edema, and erythema.^28,29

Tip: Biopsy may be necessary to confirm the diagnosis, though often the history may be sufficient. The patient may or may not recall a bite, so probe into recent activities such as outdoor sports or contact with a new pet. The papules and plaques are generally very pruritic but not painful.

DERMATOLOGY CONSULT

If the clinical presentation and history do not correlate, or if the skin condition has been treated with antibiotics yet has failed to respond, the possibility of other cutaneous dermatoses should be entertained. A dermatology consult can help determine the diagnosis, the need for further evaluation, and the best treatment course.

Prolonged delivery: child with cerebral palsy   awarded $70M

AFTER MORE THAN 4 HOURS of second-stage labor followed by prolonged pushing and crowning, the baby was born depressed. Later, the child was found to have cerebral palsy.

PARENTS’ CLAIM The ObGyn was negligent in failing to perform an episiotomy, not attempting vacuum extraction, and not using forceps to assist delivery. Although fetal heart-rate monitoring results deteriorated, the ObGyn did not assess contractions for 30 minutes at one point. Hospital staff members were unable to adequately intubate or ventilate the newborn. The hospital staff disposed of the baby’s cord blood. Records were altered.

The parents’ counsel proposed that the defendants’ insurance company refused all settlement efforts prior to trial because the case venue was known to be conservative regarding jury verdicts.

DEFENDANTS’ DEFENSE The hospital and the ObGyn were not negligent; the mother and baby received proper care. Hospital staff acted appropriately.

VERDICT During the trial, the hospital settled for an undisclosed amount. An additional $2 million was offered on behalf of the ObGyn later in the trial, but the parents refused settlement at that time.

A California jury returned a $74.525 million verdict against the ObGyn. The child was awarded $70.725 million for medical expenses, lost earnings, and damages. The parents were awarded $3.8 million for emotional distress.

Was ectopic pregnancy missed?

A WOMAN IN SEVERE ABDOMINAL PAIN saw her internist. CT scans revealed a right ovarian cyst. When pain continued, she saw her ObGyn 3 weeks later, and her bowel was full of hard stool. Ultrasonography (US) showed a multicystic right ovary and a thin endometrial stripe. She was taking birth control pills and her husband had a vasectomy. She was told her abdominal pain was from constipation and ovarian cysts. A week later, she had laparoscopic surgery to remove an ectopic pregnancy.

PATIENT’S CLAIM The ObGyn did not perform a pregnancy test, and did not diagnose an ectopic pregnancy in a timely manner. An earlier diagnosis would have allowed medical rather than surgical resolution.

PHYSICIAN’S DEFENSE It was too early to determine if the pregnancy was intrauterine or ectopic. An earlier diagnosis would have resulted in laparoscopic surgery rather than medical treatment, as the medication (methotrexate) can cause increased pain.

VERDICT An Illinois defense verdict was returned.

Foreshortened vagina inhibits intercourse

A 65-YEAR-OLD WOMAN underwent anterior and posterior colphorrhaphy to repair a cystocele and rectocele, sacrospinous ligament fixation for vaginal prolapse, and a TVT mid-urethral suspension procedure to correct stress urinary incontinence. During two follow-up visits, the gynecologist determined that she was healing normally.

Within the next few weeks, the patient came to believe that her vagina had been sewn shut. She did not return to her gynecologist, but sought treatment with another physician 6 months later. It was determined that she had a stenotic and foreshortened vagina.

PATIENT’S CLAIM Too much vaginal tissue was removed during surgery.

PHYSICIAN’S DEFENSE The stenotic and foreshortened vagina was an unexpected result of the healing process after surgery.

VERDICT An Illinois defense verdict was returned.

Hydrocephalus in utero not seen until too late

A WOMAN HAD PRENATAL TREATMENT at a federally funded health clinic. A certified nurse midwife (CNM) ordered second-trimester US, with normal results. During the third trimester, the mother switched to a private ObGyn who ordered testing. US indicated the fetus was hydrocephalic. The child was born with cognitive disabilities and will need lifelong care.

PARENTS’ CLAIM The CNM ordered US too early in the pregnancy to be of diagnostic value; no further testing was undertaken. When hydrocephalus was seen, an abortion was not legally available because of fetal age.

DEFENDANT’S DEFENSE Even if US had been performed later in the second trimester, the defect would not have shown.

VERDICT A $4 million New Jersey settlement was reached.

Severe brachial plexus injury

WHEN SHOULDER DYSTOCIA WAS ENCOUNTERED, the ObGyn used standard maneuvers to deliver the child. The baby suffered a severe brachial plexus injury with rupture of C7 nerve and avulsions at C8 and T1.

Nerve-graft surgery at 6 months and tendon transfer surgery at 2 years resulted in recovery of good shoulder and elbow function, but the child has inadequate use of his wrist and hand. Additional surgeries are planned.

PARENTS’ CLAIM The ObGyn did not inform the mother that she was at risk for shoulder dystocia, nor did he discuss cesarean delivery. The mother’s risk factors included short stature, gestational diabetes, excessive weight gain during pregnancy, and two previous deliveries that involved vacuum assistance and a broken clavicle. The ObGyn applied excessive traction to the fetal head during delivery.

PHYSICIAN’S DEFENSE The mother’s risk factors were not severe enough to consider the chance of shoulder dystocia. The baby’s injuries were due to the normal forces of labor. Traction placed on the baby’s head during delivery was gentle and appropriate.

VERDICT A $5.5 million Iowa verdict was returned.

Faulty testing: baby has Down syndrome

AT 13 WEEKS’ GESTATION, a 34-year-old woman underwent chorionic villus sampling (CVS) at a maternal-fetal medicine center. Results showed a normal chromosomal profile. Later, two sonograms indicated possible Down syndrome. The parents were assured that the baby did not have a genetic disorder; amniocentesis was never suggested.

A week before the baby’s birth, the parents were told the child has Down syndrome.

PARENTS’ CLAIM Maternal tissue, not fetal tissue, had been removed and tested during CVS. The parents would have aborted the fetus had they known she had Down syndrome.

DEFENDANTS’ DEFENSE CVS was properly administered.

VERDICT A $3 million Missouri verdict was returned against the center where the testing was performed.

Why did the uterus seem to be growing?

A 52-YEAR-OLD WOMAN’S UTERUS was larger than normal in February 2007. By November 2008, her uterus was the size of a 14-week gestation. In September 2009, she complained of abdominal discomfort. Her uterus was larger than at the previous visit. The gynecologist suggested a hysterectomy, but nothing was scheduled.

In November 2009, she reported increasing pelvic pressure; her uterus was the size of an 18-week gestation. US and MRI showed large masses on both ovaries although the uterus had no masses or fibroids within it. A gynecologic oncologist performed abdominal hysterectomy with bilateral salpingo-oophorectomy and bilateral peri-aortic lymph node dissection. Pathology returned a diagnosis of ovarian cancer. The patient underwent chemotherapy.

PATIENT’S CLAIM The gynecologist was negligent in not ordering testing in 2007 when the larger-than-normal uterus was first detected, or in subsequent visits through September 2009. A more timely reaction would have given her an opportunity to treat the cancer at an earlier stage.

PHYSICIAN’S DEFENSE The case was settled before trial.

VERDICT A $650,000 Maryland settlement was reached.

Erb’s palsy after shoulder dystocia

DURING VAGINAL DELIVERY, the ObGyn encountered shoulder dystocia. The child suffered a brachial plexus injury and has Erb’s palsy. There was some improvement after two operations, but she still has muscle weakness, arm-length discrepancy, and limited range of motion.

PARENTS’ CLAIM The ObGyn applied excessive downward traction on the baby’s head when her left shoulder could not pass under the pubic bone.

PHYSICIAN’S DEFENSE The injury was caused by uterine contractions and maternal pushing. Proper maneuvers and gentle pressure were used.

VERDICT A $1.34 million New Jersey verdict was returned.

Prolonged delivery: child with cerebral palsy   awarded $70M

AFTER MORE THAN 4 HOURS of second-stage labor followed by prolonged pushing and crowning, the baby was born depressed. Later, the child was found to have cerebral palsy.

PARENTS’ CLAIM The ObGyn was negligent in failing to perform an episiotomy, not attempting vacuum extraction, and not using forceps to assist delivery. Although fetal heart-rate monitoring results deteriorated, the ObGyn did not assess contractions for 30 minutes at one point. Hospital staff members were unable to adequately intubate or ventilate the newborn. The hospital staff disposed of the baby’s cord blood. Records were altered.

The parents’ counsel proposed that the defendants’ insurance company refused all settlement efforts prior to trial because the case venue was known to be conservative regarding jury verdicts.

DEFENDANTS’ DEFENSE The hospital and the ObGyn were not negligent; the mother and baby received proper care. Hospital staff acted appropriately.

VERDICT During the trial, the hospital settled for an undisclosed amount. An additional $2 million was offered on behalf of the ObGyn later in the trial, but the parents refused settlement at that time.

A California jury returned a $74.525 million verdict against the ObGyn. The child was awarded $70.725 million for medical expenses, lost earnings, and damages. The parents were awarded $3.8 million for emotional distress.

Was ectopic pregnancy missed?

A WOMAN IN SEVERE ABDOMINAL PAIN saw her internist. CT scans revealed a right ovarian cyst. When pain continued, she saw her ObGyn 3 weeks later, and her bowel was full of hard stool. Ultrasonography (US) showed a multicystic right ovary and a thin endometrial stripe. She was taking birth control pills and her husband had a vasectomy. She was told her abdominal pain was from constipation and ovarian cysts. A week later, she had laparoscopic surgery to remove an ectopic pregnancy.

PATIENT’S CLAIM The ObGyn did not perform a pregnancy test, and did not diagnose an ectopic pregnancy in a timely manner. An earlier diagnosis would have allowed medical rather than surgical resolution.

PHYSICIAN’S DEFENSE It was too early to determine if the pregnancy was intrauterine or ectopic. An earlier diagnosis would have resulted in laparoscopic surgery rather than medical treatment, as the medication (methotrexate) can cause increased pain.

VERDICT An Illinois defense verdict was returned.

Foreshortened vagina inhibits intercourse

A 65-YEAR-OLD WOMAN underwent anterior and posterior colphorrhaphy to repair a cystocele and rectocele, sacrospinous ligament fixation for vaginal prolapse, and a TVT mid-urethral suspension procedure to correct stress urinary incontinence. During two follow-up visits, the gynecologist determined that she was healing normally.

Within the next few weeks, the patient came to believe that her vagina had been sewn shut. She did not return to her gynecologist, but sought treatment with another physician 6 months later. It was determined that she had a stenotic and foreshortened vagina.

PATIENT’S CLAIM Too much vaginal tissue was removed during surgery.

PHYSICIAN’S DEFENSE The stenotic and foreshortened vagina was an unexpected result of the healing process after surgery.

VERDICT An Illinois defense verdict was returned.

Hydrocephalus in utero not seen until too late

A WOMAN HAD PRENATAL TREATMENT at a federally funded health clinic. A certified nurse midwife (CNM) ordered second-trimester US, with normal results. During the third trimester, the mother switched to a private ObGyn who ordered testing. US indicated the fetus was hydrocephalic. The child was born with cognitive disabilities and will need lifelong care.

PARENTS’ CLAIM The CNM ordered US too early in the pregnancy to be of diagnostic value; no further testing was undertaken. When hydrocephalus was seen, an abortion was not legally available because of fetal age.

DEFENDANT’S DEFENSE Even if US had been performed later in the second trimester, the defect would not have shown.

VERDICT A $4 million New Jersey settlement was reached.

Severe brachial plexus injury

WHEN SHOULDER DYSTOCIA WAS ENCOUNTERED, the ObGyn used standard maneuvers to deliver the child. The baby suffered a severe brachial plexus injury with rupture of C7 nerve and avulsions at C8 and T1.

Nerve-graft surgery at 6 months and tendon transfer surgery at 2 years resulted in recovery of good shoulder and elbow function, but the child has inadequate use of his wrist and hand. Additional surgeries are planned.

PARENTS’ CLAIM The ObGyn did not inform the mother that she was at risk for shoulder dystocia, nor did he discuss cesarean delivery. The mother’s risk factors included short stature, gestational diabetes, excessive weight gain during pregnancy, and two previous deliveries that involved vacuum assistance and a broken clavicle. The ObGyn applied excessive traction to the fetal head during delivery.

PHYSICIAN’S DEFENSE The mother’s risk factors were not severe enough to consider the chance of shoulder dystocia. The baby’s injuries were due to the normal forces of labor. Traction placed on the baby’s head during delivery was gentle and appropriate.

VERDICT A $5.5 million Iowa verdict was returned.

Faulty testing: baby has Down syndrome

AT 13 WEEKS’ GESTATION, a 34-year-old woman underwent chorionic villus sampling (CVS) at a maternal-fetal medicine center. Results showed a normal chromosomal profile. Later, two sonograms indicated possible Down syndrome. The parents were assured that the baby did not have a genetic disorder; amniocentesis was never suggested.

A week before the baby’s birth, the parents were told the child has Down syndrome.

PARENTS’ CLAIM Maternal tissue, not fetal tissue, had been removed and tested during CVS. The parents would have aborted the fetus had they known she had Down syndrome.

DEFENDANTS’ DEFENSE CVS was properly administered.

VERDICT A $3 million Missouri verdict was returned against the center where the testing was performed.

Why did the uterus seem to be growing?

A 52-YEAR-OLD WOMAN’S UTERUS was larger than normal in February 2007. By November 2008, her uterus was the size of a 14-week gestation. In September 2009, she complained of abdominal discomfort. Her uterus was larger than at the previous visit. The gynecologist suggested a hysterectomy, but nothing was scheduled.

In November 2009, she reported increasing pelvic pressure; her uterus was the size of an 18-week gestation. US and MRI showed large masses on both ovaries although the uterus had no masses or fibroids within it. A gynecologic oncologist performed abdominal hysterectomy with bilateral salpingo-oophorectomy and bilateral peri-aortic lymph node dissection. Pathology returned a diagnosis of ovarian cancer. The patient underwent chemotherapy.

PATIENT’S CLAIM The gynecologist was negligent in not ordering testing in 2007 when the larger-than-normal uterus was first detected, or in subsequent visits through September 2009. A more timely reaction would have given her an opportunity to treat the cancer at an earlier stage.

PHYSICIAN’S DEFENSE The case was settled before trial.

VERDICT A $650,000 Maryland settlement was reached.

Erb’s palsy after shoulder dystocia

DURING VAGINAL DELIVERY, the ObGyn encountered shoulder dystocia. The child suffered a brachial plexus injury and has Erb’s palsy. There was some improvement after two operations, but she still has muscle weakness, arm-length discrepancy, and limited range of motion.

PARENTS’ CLAIM The ObGyn applied excessive downward traction on the baby’s head when her left shoulder could not pass under the pubic bone.

PHYSICIAN’S DEFENSE The injury was caused by uterine contractions and maternal pushing. Proper maneuvers and gentle pressure were used.

VERDICT A $1.34 million New Jersey verdict was returned.

Prolonged delivery: child with cerebral palsy   awarded $70M

AFTER MORE THAN 4 HOURS of second-stage labor followed by prolonged pushing and crowning, the baby was born depressed. Later, the child was found to have cerebral palsy.

PARENTS’ CLAIM The ObGyn was negligent in failing to perform an episiotomy, not attempting vacuum extraction, and not using forceps to assist delivery. Although fetal heart-rate monitoring results deteriorated, the ObGyn did not assess contractions for 30 minutes at one point. Hospital staff members were unable to adequately intubate or ventilate the newborn. The hospital staff disposed of the baby’s cord blood. Records were altered.

The parents’ counsel proposed that the defendants’ insurance company refused all settlement efforts prior to trial because the case venue was known to be conservative regarding jury verdicts.

DEFENDANTS’ DEFENSE The hospital and the ObGyn were not negligent; the mother and baby received proper care. Hospital staff acted appropriately.

VERDICT During the trial, the hospital settled for an undisclosed amount. An additional $2 million was offered on behalf of the ObGyn later in the trial, but the parents refused settlement at that time.

A California jury returned a $74.525 million verdict against the ObGyn. The child was awarded $70.725 million for medical expenses, lost earnings, and damages. The parents were awarded $3.8 million for emotional distress.

Was ectopic pregnancy missed?

A WOMAN IN SEVERE ABDOMINAL PAIN saw her internist. CT scans revealed a right ovarian cyst. When pain continued, she saw her ObGyn 3 weeks later, and her bowel was full of hard stool. Ultrasonography (US) showed a multicystic right ovary and a thin endometrial stripe. She was taking birth control pills and her husband had a vasectomy. She was told her abdominal pain was from constipation and ovarian cysts. A week later, she had laparoscopic surgery to remove an ectopic pregnancy.

PATIENT’S CLAIM The ObGyn did not perform a pregnancy test, and did not diagnose an ectopic pregnancy in a timely manner. An earlier diagnosis would have allowed medical rather than surgical resolution.

PHYSICIAN’S DEFENSE It was too early to determine if the pregnancy was intrauterine or ectopic. An earlier diagnosis would have resulted in laparoscopic surgery rather than medical treatment, as the medication (methotrexate) can cause increased pain.

VERDICT An Illinois defense verdict was returned.

Foreshortened vagina inhibits intercourse

A 65-YEAR-OLD WOMAN underwent anterior and posterior colphorrhaphy to repair a cystocele and rectocele, sacrospinous ligament fixation for vaginal prolapse, and a TVT mid-urethral suspension procedure to correct stress urinary incontinence. During two follow-up visits, the gynecologist determined that she was healing normally.

Within the next few weeks, the patient came to believe that her vagina had been sewn shut. She did not return to her gynecologist, but sought treatment with another physician 6 months later. It was determined that she had a stenotic and foreshortened vagina.

PATIENT’S CLAIM Too much vaginal tissue was removed during surgery.

PHYSICIAN’S DEFENSE The stenotic and foreshortened vagina was an unexpected result of the healing process after surgery.

VERDICT An Illinois defense verdict was returned.

Hydrocephalus in utero not seen until too late

A WOMAN HAD PRENATAL TREATMENT at a federally funded health clinic. A certified nurse midwife (CNM) ordered second-trimester US, with normal results. During the third trimester, the mother switched to a private ObGyn who ordered testing. US indicated the fetus was hydrocephalic. The child was born with cognitive disabilities and will need lifelong care.

PARENTS’ CLAIM The CNM ordered US too early in the pregnancy to be of diagnostic value; no further testing was undertaken. When hydrocephalus was seen, an abortion was not legally available because of fetal age.

DEFENDANT’S DEFENSE Even if US had been performed later in the second trimester, the defect would not have shown.

VERDICT A $4 million New Jersey settlement was reached.

Severe brachial plexus injury

WHEN SHOULDER DYSTOCIA WAS ENCOUNTERED, the ObGyn used standard maneuvers to deliver the child. The baby suffered a severe brachial plexus injury with rupture of C7 nerve and avulsions at C8 and T1.

Nerve-graft surgery at 6 months and tendon transfer surgery at 2 years resulted in recovery of good shoulder and elbow function, but the child has inadequate use of his wrist and hand. Additional surgeries are planned.

PARENTS’ CLAIM The ObGyn did not inform the mother that she was at risk for shoulder dystocia, nor did he discuss cesarean delivery. The mother’s risk factors included short stature, gestational diabetes, excessive weight gain during pregnancy, and two previous deliveries that involved vacuum assistance and a broken clavicle. The ObGyn applied excessive traction to the fetal head during delivery.

PHYSICIAN’S DEFENSE The mother’s risk factors were not severe enough to consider the chance of shoulder dystocia. The baby’s injuries were due to the normal forces of labor. Traction placed on the baby’s head during delivery was gentle and appropriate.

VERDICT A $5.5 million Iowa verdict was returned.

Faulty testing: baby has Down syndrome

AT 13 WEEKS’ GESTATION, a 34-year-old woman underwent chorionic villus sampling (CVS) at a maternal-fetal medicine center. Results showed a normal chromosomal profile. Later, two sonograms indicated possible Down syndrome. The parents were assured that the baby did not have a genetic disorder; amniocentesis was never suggested.

A week before the baby’s birth, the parents were told the child has Down syndrome.

PARENTS’ CLAIM Maternal tissue, not fetal tissue, had been removed and tested during CVS. The parents would have aborted the fetus had they known she had Down syndrome.

DEFENDANTS’ DEFENSE CVS was properly administered.

VERDICT A $3 million Missouri verdict was returned against the center where the testing was performed.

Why did the uterus seem to be growing?

A 52-YEAR-OLD WOMAN’S UTERUS was larger than normal in February 2007. By November 2008, her uterus was the size of a 14-week gestation. In September 2009, she complained of abdominal discomfort. Her uterus was larger than at the previous visit. The gynecologist suggested a hysterectomy, but nothing was scheduled.

In November 2009, she reported increasing pelvic pressure; her uterus was the size of an 18-week gestation. US and MRI showed large masses on both ovaries although the uterus had no masses or fibroids within it. A gynecologic oncologist performed abdominal hysterectomy with bilateral salpingo-oophorectomy and bilateral peri-aortic lymph node dissection. Pathology returned a diagnosis of ovarian cancer. The patient underwent chemotherapy.

PATIENT’S CLAIM The gynecologist was negligent in not ordering testing in 2007 when the larger-than-normal uterus was first detected, or in subsequent visits through September 2009. A more timely reaction would have given her an opportunity to treat the cancer at an earlier stage.

PHYSICIAN’S DEFENSE The case was settled before trial.

VERDICT A $650,000 Maryland settlement was reached.

Erb’s palsy after shoulder dystocia

DURING VAGINAL DELIVERY, the ObGyn encountered shoulder dystocia. The child suffered a brachial plexus injury and has Erb’s palsy. There was some improvement after two operations, but she still has muscle weakness, arm-length discrepancy, and limited range of motion.

PARENTS’ CLAIM The ObGyn applied excessive downward traction on the baby’s head when her left shoulder could not pass under the pubic bone.

PHYSICIAN’S DEFENSE The injury was caused by uterine contractions and maternal pushing. Proper maneuvers and gentle pressure were used.

VERDICT A $1.34 million New Jersey verdict was returned.