Barbara Jamieson, MLS

TABLE
Differential diagnosis of hyperandrogenism in PCOS

Evidence summary

Polycystic ovarian syndrome is a condition of unexplained hyperandrogenic chronic anovulation that affects at least 4% of women of reproductive age.¹ Because PCOS is a clinical syndrome, no single diagnostic criterion is sufficient for diagnosis.² Clinical features include menstrual irregularities or infertility, hirsutism, male-pattern balding, acne, ovarian enlargement, and signs of insulin resistance (eg, central obesity, acanthosis nigricans). A 2003 international consensus panel concluded that the presence of 2 of 3 criteria (oligo/anovulation, hyperandrogenism, polycystic ovaries), in the absence of other secondary causes, is sufficient to make the diagnosis.² Evidence for hyperandrogenism includes hirsutism, acne, or elevated total testosterone levels.³ A high luteinizing hormone/follicle-stimulating hormone (LH/FSH) ratio supports the diagnosis. However, because this measure varies considerably in relation to ovulation, body-mass index (BMI), and the particular measurement assay used, the consensus panel recommended against its use as a diagnostic criterion.² Based on optimum receiver operator characteristic curve analyses, ultrasound criteria include the presence of 12 or more follicles in each ovary measuring 2 to 9 mm in diameter (sensitivity=75%, specificity=99%, positive predictive value [PPV]=75%, negative predictive value [NPV]=99%, assuming 4% prevalence) or ovarian volume over 7 mL (sensitivity=67.5%, specificity=91.2%, PPV=24%, NPV 99%).^4,5

PCOS is also a diagnosis of exclusion. Secondary causes of hyperandrogenism may be suggested by clinical findings, including 1) abrupt onset, short duration, or sudden progressive worsening of hirsutism; 2) onset of symptoms in the third decade of life or later; or 3) signs of virilization (deepening voice, clitoromegaly).⁶ The differential diagnosis, clinical features and potentially useful diagnostic tests to rule out secondary causes are shown in the TABLE.

Women with PCOS often experience insulin resistance, and are at increased risk for developing type 2 diabetes, dyslipidemia, and cardiovascular disease. One cross-sectional study⁷ of 122 women with PCOS between 13.5 and 40 years of age found that 35% had impaired glucose tolerance, and another 10% had non-insulindependent diabetes. A prospective case-control study⁸ of young women (aged <35 years) found that compared with age- and BMI-matched controls, those with PCOS had higher levels of fasting glucose, insulin, total and low-density lipoprotein cholesterol, and altered left ventricular mass and cardiac function on echocardiogram. Once PCOS is suspected, the diagnostic work-up should include a 2-hour glucose tolerance test and lipid panel to assess cardiovascular risk, particularly among obese women.

Recommendations from others

A 2002 American College of Obstetricians and Gynecologists guideline⁹ adopted the 1990 National Institutes of Health consensus panel criteria for diagnosing PCOS (ie, chronic anovulation and clinical or biochemical signs of hyperandrogenism, excluding other causes), and recommends that all patients have documentation of elevated testosterone levels; thyroid-stimulating hormone (TSH), prolactin, and 17-hydroxyprogesterone levels to exclude secondary causes of hyperandrogenism; and evaluation for metabolic abnormalities with a 2-hour glucose tolerance test and fasting lipid panel.

TABLE
Differential diagnosis of hyperandrogenism in PCOS

Evidence summary

Polycystic ovarian syndrome is a condition of unexplained hyperandrogenic chronic anovulation that affects at least 4% of women of reproductive age.¹ Because PCOS is a clinical syndrome, no single diagnostic criterion is sufficient for diagnosis.² Clinical features include menstrual irregularities or infertility, hirsutism, male-pattern balding, acne, ovarian enlargement, and signs of insulin resistance (eg, central obesity, acanthosis nigricans). A 2003 international consensus panel concluded that the presence of 2 of 3 criteria (oligo/anovulation, hyperandrogenism, polycystic ovaries), in the absence of other secondary causes, is sufficient to make the diagnosis.² Evidence for hyperandrogenism includes hirsutism, acne, or elevated total testosterone levels.³ A high luteinizing hormone/follicle-stimulating hormone (LH/FSH) ratio supports the diagnosis. However, because this measure varies considerably in relation to ovulation, body-mass index (BMI), and the particular measurement assay used, the consensus panel recommended against its use as a diagnostic criterion.² Based on optimum receiver operator characteristic curve analyses, ultrasound criteria include the presence of 12 or more follicles in each ovary measuring 2 to 9 mm in diameter (sensitivity=75%, specificity=99%, positive predictive value [PPV]=75%, negative predictive value [NPV]=99%, assuming 4% prevalence) or ovarian volume over 7 mL (sensitivity=67.5%, specificity=91.2%, PPV=24%, NPV 99%).^4,5

PCOS is also a diagnosis of exclusion. Secondary causes of hyperandrogenism may be suggested by clinical findings, including 1) abrupt onset, short duration, or sudden progressive worsening of hirsutism; 2) onset of symptoms in the third decade of life or later; or 3) signs of virilization (deepening voice, clitoromegaly).⁶ The differential diagnosis, clinical features and potentially useful diagnostic tests to rule out secondary causes are shown in the TABLE.

Women with PCOS often experience insulin resistance, and are at increased risk for developing type 2 diabetes, dyslipidemia, and cardiovascular disease. One cross-sectional study⁷ of 122 women with PCOS between 13.5 and 40 years of age found that 35% had impaired glucose tolerance, and another 10% had non-insulindependent diabetes. A prospective case-control study⁸ of young women (aged <35 years) found that compared with age- and BMI-matched controls, those with PCOS had higher levels of fasting glucose, insulin, total and low-density lipoprotein cholesterol, and altered left ventricular mass and cardiac function on echocardiogram. Once PCOS is suspected, the diagnostic work-up should include a 2-hour glucose tolerance test and lipid panel to assess cardiovascular risk, particularly among obese women.

Recommendations from others

A 2002 American College of Obstetricians and Gynecologists guideline⁹ adopted the 1990 National Institutes of Health consensus panel criteria for diagnosing PCOS (ie, chronic anovulation and clinical or biochemical signs of hyperandrogenism, excluding other causes), and recommends that all patients have documentation of elevated testosterone levels; thyroid-stimulating hormone (TSH), prolactin, and 17-hydroxyprogesterone levels to exclude secondary causes of hyperandrogenism; and evaluation for metabolic abnormalities with a 2-hour glucose tolerance test and fasting lipid panel.

TABLE
Differential diagnosis of hyperandrogenism in PCOS

Evidence summary

Polycystic ovarian syndrome is a condition of unexplained hyperandrogenic chronic anovulation that affects at least 4% of women of reproductive age.¹ Because PCOS is a clinical syndrome, no single diagnostic criterion is sufficient for diagnosis.² Clinical features include menstrual irregularities or infertility, hirsutism, male-pattern balding, acne, ovarian enlargement, and signs of insulin resistance (eg, central obesity, acanthosis nigricans). A 2003 international consensus panel concluded that the presence of 2 of 3 criteria (oligo/anovulation, hyperandrogenism, polycystic ovaries), in the absence of other secondary causes, is sufficient to make the diagnosis.² Evidence for hyperandrogenism includes hirsutism, acne, or elevated total testosterone levels.³ A high luteinizing hormone/follicle-stimulating hormone (LH/FSH) ratio supports the diagnosis. However, because this measure varies considerably in relation to ovulation, body-mass index (BMI), and the particular measurement assay used, the consensus panel recommended against its use as a diagnostic criterion.² Based on optimum receiver operator characteristic curve analyses, ultrasound criteria include the presence of 12 or more follicles in each ovary measuring 2 to 9 mm in diameter (sensitivity=75%, specificity=99%, positive predictive value [PPV]=75%, negative predictive value [NPV]=99%, assuming 4% prevalence) or ovarian volume over 7 mL (sensitivity=67.5%, specificity=91.2%, PPV=24%, NPV 99%).^4,5

PCOS is also a diagnosis of exclusion. Secondary causes of hyperandrogenism may be suggested by clinical findings, including 1) abrupt onset, short duration, or sudden progressive worsening of hirsutism; 2) onset of symptoms in the third decade of life or later; or 3) signs of virilization (deepening voice, clitoromegaly).⁶ The differential diagnosis, clinical features and potentially useful diagnostic tests to rule out secondary causes are shown in the TABLE.

Women with PCOS often experience insulin resistance, and are at increased risk for developing type 2 diabetes, dyslipidemia, and cardiovascular disease. One cross-sectional study⁷ of 122 women with PCOS between 13.5 and 40 years of age found that 35% had impaired glucose tolerance, and another 10% had non-insulindependent diabetes. A prospective case-control study⁸ of young women (aged <35 years) found that compared with age- and BMI-matched controls, those with PCOS had higher levels of fasting glucose, insulin, total and low-density lipoprotein cholesterol, and altered left ventricular mass and cardiac function on echocardiogram. Once PCOS is suspected, the diagnostic work-up should include a 2-hour glucose tolerance test and lipid panel to assess cardiovascular risk, particularly among obese women.

Recommendations from others

A 2002 American College of Obstetricians and Gynecologists guideline⁹ adopted the 1990 National Institutes of Health consensus panel criteria for diagnosing PCOS (ie, chronic anovulation and clinical or biochemical signs of hyperandrogenism, excluding other causes), and recommends that all patients have documentation of elevated testosterone levels; thyroid-stimulating hormone (TSH), prolactin, and 17-hydroxyprogesterone levels to exclude secondary causes of hyperandrogenism; and evaluation for metabolic abnormalities with a 2-hour glucose tolerance test and fasting lipid panel.

Evidence summary

More than 50 million individuals in the United States have genital herpes. The diagnosis of genital herpes based on clinical history and physical examination is often inaccurate.¹ Clinical suspicion needs to be confirmed by laboratory testing because it has a direct impact on counseling and prognosis.²

Viral culture is still the gold standard test for the detection of HSV; however, the rate of positive cultures depends on the stage of the lesion, the quality of the specimen, and the transport conditions. A British study³ found the rate of virus recovery for early vesicles to be 52% to 93%. This dropped to 41% to 72% if midstage ulcers were present. Finally, the detection for late-stage crusted lesions was only 19% to 27%. Another disadvantage is that culture is labor-intensive. A positive culture takes an average of 3 days to grow, whereas a negative culture must incubate for 10 days.³

PCR techniques are more sensitive and results can be available in less than 4 hours.³ In 110 clinical samples from dermal or genital lesions of patients with suspected HSV infection, the sensitivity of PCR was 98% (positive likelihood ratio [LR+]=∞; negative likelihood ratio [LR–]=0.02) compared with 73% (LR+ = ∞; LR– = 0.27) for culture. The specificities of both were 100%.⁴ In London, 233 samples from patients at a genitourinary medicine clinic were tested with both viral culture and PCR. HSV was detected in 79 samples by culture and 132 samples by PCR. The detection by PCR was higher in early as well as late stages of infection and in both first and recurrent episodes.³ The reference standard for these studies was not an independent standard, but a positive result on both tests or modified versions of the PCR test. The use of a version of the test of interest (PCR) as part of the reference standard, while probably unavoidable in this situation, will tend inflate the sensitivity and specificity.

In another study, daily sampling of lesions in patients with known HSV infections detected HSV DNA on 15 of 17 days with PCR and only 3 of 17 days with culture.¹ This suggests that PCR is more effective in detecting early, as well as late, stages of infection. Currently PCR is more expensive, but it may become cheaper because of decreased labor expense when compared with culture.

Genital herpes may also be detected with enzyme immunoassay testing in as little as 5 hours. In a study⁵ using 275 samples from genital lesions, HSV was detected in 65% of the antigen tests and 53% of the viral cultures. The sensitivity of this method is equal to culture for early lesions, but much higher in late-stage lesions (58% vs 26%).⁵

Serologic tests are often used to detect HSV because they can differentiate between HSV-1 and HSV-2. There is an FDA-approved point-of-care test called POCkit that gives results from capillary blood or serum during an office visit. These tests are 80% to 98% sensitive and more than 96% specific. Unfortunately, they are not readily available in all countries.²

Other detection methods include the Tzanck smear, which is only 40% to 50% sensitive compared with culture, and the Pap smear, which is 60% to 70% sensitive.⁶ These tests should not be the sole method for the diagnosis of HSV. They cannot differentiate between HSV 1 and HSV 2; furthermore, the Tzanck prep will give a positive result if varicella zoster virus is present.⁶ If these tests are positive, confirmatory testing specific for HSV should be performed.

Recommendations from others

The Centers for Disease Control and Prevention⁷ recommends screening with a viral culture when a genital lesion is present, however, the sensitivity declines rapidly within a few days as the lesion begins to heal. To collect a sample the lesion must be unroofed using a Dacron swab, which is then placed in a viral transport medium and processed within 24 hours. Swabs containing calcium agglutinate are toxic to HSV.⁶ Type-specific antibodies develop during the first several weeks and can be detected with serologic tests; however, these may be falsely negative in the early stages of a primary infection.⁷

The US Preventative Services Task Force⁸ recommends against routine serologic screening for HSV in asymptomatic adolescents and adults. They also recommend against routine screening of asymptomatic pregnant women at any time during pregnancy as a way to decrease neonatal transmission.⁸

Evidence summary

More than 50 million individuals in the United States have genital herpes. The diagnosis of genital herpes based on clinical history and physical examination is often inaccurate.¹ Clinical suspicion needs to be confirmed by laboratory testing because it has a direct impact on counseling and prognosis.²

Viral culture is still the gold standard test for the detection of HSV; however, the rate of positive cultures depends on the stage of the lesion, the quality of the specimen, and the transport conditions. A British study³ found the rate of virus recovery for early vesicles to be 52% to 93%. This dropped to 41% to 72% if midstage ulcers were present. Finally, the detection for late-stage crusted lesions was only 19% to 27%. Another disadvantage is that culture is labor-intensive. A positive culture takes an average of 3 days to grow, whereas a negative culture must incubate for 10 days.³

PCR techniques are more sensitive and results can be available in less than 4 hours.³ In 110 clinical samples from dermal or genital lesions of patients with suspected HSV infection, the sensitivity of PCR was 98% (positive likelihood ratio [LR+]=∞; negative likelihood ratio [LR–]=0.02) compared with 73% (LR+ = ∞; LR– = 0.27) for culture. The specificities of both were 100%.⁴ In London, 233 samples from patients at a genitourinary medicine clinic were tested with both viral culture and PCR. HSV was detected in 79 samples by culture and 132 samples by PCR. The detection by PCR was higher in early as well as late stages of infection and in both first and recurrent episodes.³ The reference standard for these studies was not an independent standard, but a positive result on both tests or modified versions of the PCR test. The use of a version of the test of interest (PCR) as part of the reference standard, while probably unavoidable in this situation, will tend inflate the sensitivity and specificity.

In another study, daily sampling of lesions in patients with known HSV infections detected HSV DNA on 15 of 17 days with PCR and only 3 of 17 days with culture.¹ This suggests that PCR is more effective in detecting early, as well as late, stages of infection. Currently PCR is more expensive, but it may become cheaper because of decreased labor expense when compared with culture.

Genital herpes may also be detected with enzyme immunoassay testing in as little as 5 hours. In a study⁵ using 275 samples from genital lesions, HSV was detected in 65% of the antigen tests and 53% of the viral cultures. The sensitivity of this method is equal to culture for early lesions, but much higher in late-stage lesions (58% vs 26%).⁵

Serologic tests are often used to detect HSV because they can differentiate between HSV-1 and HSV-2. There is an FDA-approved point-of-care test called POCkit that gives results from capillary blood or serum during an office visit. These tests are 80% to 98% sensitive and more than 96% specific. Unfortunately, they are not readily available in all countries.²

Other detection methods include the Tzanck smear, which is only 40% to 50% sensitive compared with culture, and the Pap smear, which is 60% to 70% sensitive.⁶ These tests should not be the sole method for the diagnosis of HSV. They cannot differentiate between HSV 1 and HSV 2; furthermore, the Tzanck prep will give a positive result if varicella zoster virus is present.⁶ If these tests are positive, confirmatory testing specific for HSV should be performed.

Recommendations from others

The Centers for Disease Control and Prevention⁷ recommends screening with a viral culture when a genital lesion is present, however, the sensitivity declines rapidly within a few days as the lesion begins to heal. To collect a sample the lesion must be unroofed using a Dacron swab, which is then placed in a viral transport medium and processed within 24 hours. Swabs containing calcium agglutinate are toxic to HSV.⁶ Type-specific antibodies develop during the first several weeks and can be detected with serologic tests; however, these may be falsely negative in the early stages of a primary infection.⁷

The US Preventative Services Task Force⁸ recommends against routine serologic screening for HSV in asymptomatic adolescents and adults. They also recommend against routine screening of asymptomatic pregnant women at any time during pregnancy as a way to decrease neonatal transmission.⁸

Evidence summary

More than 50 million individuals in the United States have genital herpes. The diagnosis of genital herpes based on clinical history and physical examination is often inaccurate.¹ Clinical suspicion needs to be confirmed by laboratory testing because it has a direct impact on counseling and prognosis.²

Viral culture is still the gold standard test for the detection of HSV; however, the rate of positive cultures depends on the stage of the lesion, the quality of the specimen, and the transport conditions. A British study³ found the rate of virus recovery for early vesicles to be 52% to 93%. This dropped to 41% to 72% if midstage ulcers were present. Finally, the detection for late-stage crusted lesions was only 19% to 27%. Another disadvantage is that culture is labor-intensive. A positive culture takes an average of 3 days to grow, whereas a negative culture must incubate for 10 days.³

PCR techniques are more sensitive and results can be available in less than 4 hours.³ In 110 clinical samples from dermal or genital lesions of patients with suspected HSV infection, the sensitivity of PCR was 98% (positive likelihood ratio [LR+]=∞; negative likelihood ratio [LR–]=0.02) compared with 73% (LR+ = ∞; LR– = 0.27) for culture. The specificities of both were 100%.⁴ In London, 233 samples from patients at a genitourinary medicine clinic were tested with both viral culture and PCR. HSV was detected in 79 samples by culture and 132 samples by PCR. The detection by PCR was higher in early as well as late stages of infection and in both first and recurrent episodes.³ The reference standard for these studies was not an independent standard, but a positive result on both tests or modified versions of the PCR test. The use of a version of the test of interest (PCR) as part of the reference standard, while probably unavoidable in this situation, will tend inflate the sensitivity and specificity.

In another study, daily sampling of lesions in patients with known HSV infections detected HSV DNA on 15 of 17 days with PCR and only 3 of 17 days with culture.¹ This suggests that PCR is more effective in detecting early, as well as late, stages of infection. Currently PCR is more expensive, but it may become cheaper because of decreased labor expense when compared with culture.

Genital herpes may also be detected with enzyme immunoassay testing in as little as 5 hours. In a study⁵ using 275 samples from genital lesions, HSV was detected in 65% of the antigen tests and 53% of the viral cultures. The sensitivity of this method is equal to culture for early lesions, but much higher in late-stage lesions (58% vs 26%).⁵

Serologic tests are often used to detect HSV because they can differentiate between HSV-1 and HSV-2. There is an FDA-approved point-of-care test called POCkit that gives results from capillary blood or serum during an office visit. These tests are 80% to 98% sensitive and more than 96% specific. Unfortunately, they are not readily available in all countries.²

Other detection methods include the Tzanck smear, which is only 40% to 50% sensitive compared with culture, and the Pap smear, which is 60% to 70% sensitive.⁶ These tests should not be the sole method for the diagnosis of HSV. They cannot differentiate between HSV 1 and HSV 2; furthermore, the Tzanck prep will give a positive result if varicella zoster virus is present.⁶ If these tests are positive, confirmatory testing specific for HSV should be performed.

Recommendations from others

The Centers for Disease Control and Prevention⁷ recommends screening with a viral culture when a genital lesion is present, however, the sensitivity declines rapidly within a few days as the lesion begins to heal. To collect a sample the lesion must be unroofed using a Dacron swab, which is then placed in a viral transport medium and processed within 24 hours. Swabs containing calcium agglutinate are toxic to HSV.⁶ Type-specific antibodies develop during the first several weeks and can be detected with serologic tests; however, these may be falsely negative in the early stages of a primary infection.⁷

The US Preventative Services Task Force⁸ recommends against routine serologic screening for HSV in asymptomatic adolescents and adults. They also recommend against routine screening of asymptomatic pregnant women at any time during pregnancy as a way to decrease neonatal transmission.⁸

TABLE
Primary therapies for Raynaud’s phenomenon

Evidence summary

Raynaud’s phenomenon is diagnosed by a history of cold temperatures or emotional stress precipitating episodic digital artery vasospasm, according to expert opinion. This presents as well-demarcated digital pallor and cyanosis, often followed by reactive hyperemia occurring 15 to 20 minutes after rewarming.^1,2 No reliable office test confirms the diagnosis. By definition, primary Raynaud’s phenomenon occurs in the absence of associated diseases and is considered an exaggerated vasoconstrictive response to cold. It must be distinguished from normal mottling of the digits in response to cold temperatures, effects of vasoconstrictive medications, environmental injury (frostbite, use of vibrating tools), neuropathy, and thoracic outlet syndrome.^1,2 Experts differ on whether laboratory evaluation with erythrocyte sedimentation rate and an antinuclear antibody test is necessary for patients with primary Raynaud’s phenomenon.^1,3

Patients with secondary Raynaud’s phenomenon have an underlying cause or disease, such as scleroderma or systemic lupus erythematosis.² The finding of distorted capillaries in the nail folds using an ophthalmoscope set at 40+ diopter magnification is the best predictor of an associated connective-tissue disease.⁴ A cold-water challenge to trigger an attack of Raynaud’s phenomenon produces inconsistent results and is not recommended. Research tools such as thermographic and laser Doppler imaging can measure digital artery blood flow but are rarely used clinically.^1,5 Patients with secondary Raynaud’s phenomenon should have a complete blood count, biochemistry profile, and urinalysis. They may need additional tests as determined by the nature of their underlying disease.¹

Conservative management is helpful for all patients with Raynaud’s phenomenon, and may be the only treatment needed. Experts advise dressing warmly, wearing gloves when appropriate, using abortive strategies such as placing the hands into warm water, and avoiding sudden cold exposure, emotional stress, and vasoconstrictive agents such as nicotine.⁶

Medication may be helpful for patients whose symptoms are not controlled with conservative measures. Six randomized, placebo-controlled trials involving 451 people with primary Raynaud’s phenomenon demonstrated that nifedipine decreases the mean frequency of vasospastic attacks. Three of these trials also showed subjective improvement in symptom severity with nifedipine vs placebo.⁷ A meta-analysis of 6 randomized crossover studies compared nifedipine or nicardipine with placebo in 59 patients with secondary Raynaud’s phenomenon and underlying systemic sclerosis. Nifedipine significantly decreased the frequency and severity of attacks. Nicardipine showed a trend towards reduced symptoms in 1 trial with only 15 patients.⁸ Another randomized trial comparing sustained-release nifedipine to placebo showed a 66% reduction in the number of attacks in the treatment group at 1 year; 19 of the 77 people in the nifedipine group dropped out of the study, as did 24 of the 81 people in the placebo group.⁹

A systematic review of 2 randomized controlled trials with a total of 40 patients found prazosin modestly effective in secondary Raynaud’s phenomenon, but it was less well-tolerated than calcium channel blockers.¹⁰ Single, small randomized crossover trials showed improved responses to both fluoxetine¹¹ and losartan¹² when compared with nifedipine. In general, these medications appear to reduce attacks by 30% to 40%.

Small, prospective studies of low-level laser irradiation, palmar sympathectomy, and endoscopic thoracic sympathectomy show some benefit for patients with digital ulcers.^13-15 A randomized controlled trial showed biofeedback was ineffective for voluntary control of digital blood flow for patients with Raynaud’s phenomenon.⁹

Recommendations from others

The American College of Rheumatology does not offer recommendations for the diagnosis or treatment of Raynaud’s phenomenon. UpToDate recommends treatment with conservative measures; sustained-release nifedipine or amlodipine may be used if these are insufficient. Other vasodilators may be added or substituted in the event of an adverse reaction or poor response to the calciumchannel blocker.¹⁶

TABLE
Primary therapies for Raynaud’s phenomenon

Evidence summary

Raynaud’s phenomenon is diagnosed by a history of cold temperatures or emotional stress precipitating episodic digital artery vasospasm, according to expert opinion. This presents as well-demarcated digital pallor and cyanosis, often followed by reactive hyperemia occurring 15 to 20 minutes after rewarming.^1,2 No reliable office test confirms the diagnosis. By definition, primary Raynaud’s phenomenon occurs in the absence of associated diseases and is considered an exaggerated vasoconstrictive response to cold. It must be distinguished from normal mottling of the digits in response to cold temperatures, effects of vasoconstrictive medications, environmental injury (frostbite, use of vibrating tools), neuropathy, and thoracic outlet syndrome.^1,2 Experts differ on whether laboratory evaluation with erythrocyte sedimentation rate and an antinuclear antibody test is necessary for patients with primary Raynaud’s phenomenon.^1,3

Patients with secondary Raynaud’s phenomenon have an underlying cause or disease, such as scleroderma or systemic lupus erythematosis.² The finding of distorted capillaries in the nail folds using an ophthalmoscope set at 40+ diopter magnification is the best predictor of an associated connective-tissue disease.⁴ A cold-water challenge to trigger an attack of Raynaud’s phenomenon produces inconsistent results and is not recommended. Research tools such as thermographic and laser Doppler imaging can measure digital artery blood flow but are rarely used clinically.^1,5 Patients with secondary Raynaud’s phenomenon should have a complete blood count, biochemistry profile, and urinalysis. They may need additional tests as determined by the nature of their underlying disease.¹

Conservative management is helpful for all patients with Raynaud’s phenomenon, and may be the only treatment needed. Experts advise dressing warmly, wearing gloves when appropriate, using abortive strategies such as placing the hands into warm water, and avoiding sudden cold exposure, emotional stress, and vasoconstrictive agents such as nicotine.⁶

Medication may be helpful for patients whose symptoms are not controlled with conservative measures. Six randomized, placebo-controlled trials involving 451 people with primary Raynaud’s phenomenon demonstrated that nifedipine decreases the mean frequency of vasospastic attacks. Three of these trials also showed subjective improvement in symptom severity with nifedipine vs placebo.⁷ A meta-analysis of 6 randomized crossover studies compared nifedipine or nicardipine with placebo in 59 patients with secondary Raynaud’s phenomenon and underlying systemic sclerosis. Nifedipine significantly decreased the frequency and severity of attacks. Nicardipine showed a trend towards reduced symptoms in 1 trial with only 15 patients.⁸ Another randomized trial comparing sustained-release nifedipine to placebo showed a 66% reduction in the number of attacks in the treatment group at 1 year; 19 of the 77 people in the nifedipine group dropped out of the study, as did 24 of the 81 people in the placebo group.⁹

A systematic review of 2 randomized controlled trials with a total of 40 patients found prazosin modestly effective in secondary Raynaud’s phenomenon, but it was less well-tolerated than calcium channel blockers.¹⁰ Single, small randomized crossover trials showed improved responses to both fluoxetine¹¹ and losartan¹² when compared with nifedipine. In general, these medications appear to reduce attacks by 30% to 40%.

Small, prospective studies of low-level laser irradiation, palmar sympathectomy, and endoscopic thoracic sympathectomy show some benefit for patients with digital ulcers.^13-15 A randomized controlled trial showed biofeedback was ineffective for voluntary control of digital blood flow for patients with Raynaud’s phenomenon.⁹

Recommendations from others

The American College of Rheumatology does not offer recommendations for the diagnosis or treatment of Raynaud’s phenomenon. UpToDate recommends treatment with conservative measures; sustained-release nifedipine or amlodipine may be used if these are insufficient. Other vasodilators may be added or substituted in the event of an adverse reaction or poor response to the calciumchannel blocker.¹⁶

TABLE
Primary therapies for Raynaud’s phenomenon

Evidence summary

Raynaud’s phenomenon is diagnosed by a history of cold temperatures or emotional stress precipitating episodic digital artery vasospasm, according to expert opinion. This presents as well-demarcated digital pallor and cyanosis, often followed by reactive hyperemia occurring 15 to 20 minutes after rewarming.^1,2 No reliable office test confirms the diagnosis. By definition, primary Raynaud’s phenomenon occurs in the absence of associated diseases and is considered an exaggerated vasoconstrictive response to cold. It must be distinguished from normal mottling of the digits in response to cold temperatures, effects of vasoconstrictive medications, environmental injury (frostbite, use of vibrating tools), neuropathy, and thoracic outlet syndrome.^1,2 Experts differ on whether laboratory evaluation with erythrocyte sedimentation rate and an antinuclear antibody test is necessary for patients with primary Raynaud’s phenomenon.^1,3

Patients with secondary Raynaud’s phenomenon have an underlying cause or disease, such as scleroderma or systemic lupus erythematosis.² The finding of distorted capillaries in the nail folds using an ophthalmoscope set at 40+ diopter magnification is the best predictor of an associated connective-tissue disease.⁴ A cold-water challenge to trigger an attack of Raynaud’s phenomenon produces inconsistent results and is not recommended. Research tools such as thermographic and laser Doppler imaging can measure digital artery blood flow but are rarely used clinically.^1,5 Patients with secondary Raynaud’s phenomenon should have a complete blood count, biochemistry profile, and urinalysis. They may need additional tests as determined by the nature of their underlying disease.¹

Conservative management is helpful for all patients with Raynaud’s phenomenon, and may be the only treatment needed. Experts advise dressing warmly, wearing gloves when appropriate, using abortive strategies such as placing the hands into warm water, and avoiding sudden cold exposure, emotional stress, and vasoconstrictive agents such as nicotine.⁶

Medication may be helpful for patients whose symptoms are not controlled with conservative measures. Six randomized, placebo-controlled trials involving 451 people with primary Raynaud’s phenomenon demonstrated that nifedipine decreases the mean frequency of vasospastic attacks. Three of these trials also showed subjective improvement in symptom severity with nifedipine vs placebo.⁷ A meta-analysis of 6 randomized crossover studies compared nifedipine or nicardipine with placebo in 59 patients with secondary Raynaud’s phenomenon and underlying systemic sclerosis. Nifedipine significantly decreased the frequency and severity of attacks. Nicardipine showed a trend towards reduced symptoms in 1 trial with only 15 patients.⁸ Another randomized trial comparing sustained-release nifedipine to placebo showed a 66% reduction in the number of attacks in the treatment group at 1 year; 19 of the 77 people in the nifedipine group dropped out of the study, as did 24 of the 81 people in the placebo group.⁹

A systematic review of 2 randomized controlled trials with a total of 40 patients found prazosin modestly effective in secondary Raynaud’s phenomenon, but it was less well-tolerated than calcium channel blockers.¹⁰ Single, small randomized crossover trials showed improved responses to both fluoxetine¹¹ and losartan¹² when compared with nifedipine. In general, these medications appear to reduce attacks by 30% to 40%.

Small, prospective studies of low-level laser irradiation, palmar sympathectomy, and endoscopic thoracic sympathectomy show some benefit for patients with digital ulcers.^13-15 A randomized controlled trial showed biofeedback was ineffective for voluntary control of digital blood flow for patients with Raynaud’s phenomenon.⁹

Recommendations from others

The American College of Rheumatology does not offer recommendations for the diagnosis or treatment of Raynaud’s phenomenon. UpToDate recommends treatment with conservative measures; sustained-release nifedipine or amlodipine may be used if these are insufficient. Other vasodilators may be added or substituted in the event of an adverse reaction or poor response to the calciumchannel blocker.¹⁶

Evidence summary

A Cochrane review of Pap smear sampling devices for nonpregnant women concludes that the cervical brush with spatula is more effective at collecting endocervical cells and producing adequate Pap smears.¹ Based on more limited evidence, the higher rate of adequate smears is associated with the detection of more cytologic abnormalities. However, the manufacturer of Cytobrush (Medscand) recommends that the device not be used after the first 10 weeks of pregnancy, raising issues of both effectiveness and safety in this population.

Upon review of the literature, these concerns appear to be unfounded. In multiple studies involving more than 25,000 pregnant and nonpregnant patients, the brush was consistently shown to be the method obtaining the highest rate of adequate smears—ie, those containing endocervical cells.^2-10 Furthermore, in studies including about 1900 pregnant patients, the brush with spatula caused no significantly increased risk of serious adverse outcomes, nor any trend in that direction.^5-7,9-11 The device did cause a slight increase in self-limited vaginal spotting.

In theory, a more accurate Pap smear could lead to patient-oriented outcomes, such as less need for procedures to diagnose and treat cervical cytologic abnormalities, reduced incidence of invasive cervical cancer, and fewer patient deaths from cervical cancer. No data on these outcomes is available. Some studies did look for differences in the detection of cytologic abnormalities between the brush with spatula and the swab with spatula methods. Most small studies and a meta-analysis showed no difference.^2,3,8,9 One study showed a trend towards improved yield; in another study, the brush with spatula significantly improved the ability to detect cytologic abnormalities in pregnant patients.^7,10

Three studies addressed cost-effectiveness of the brush in pregnancy.^3,9,12 Especially when including the cost of repeat Pap smears for inadequate specimens, the brush with spatula was rated most cost-effective in all 3 studies.

Comparison of the use of conventional Pap smear collection techniques with newer liquid-based cytology or human papilloma virus (HPV) typing has not yet been addressed in the literature.

Recommendations from others

“The Working Group’s Recommendations for Women in Low Risk Pregnancy” through the Veterans Health Administration lists use of a nylon cervical brush—no type is specified—as the appropriate sampling device in the late first trimester of pregnancy.¹³ No recommendations specific to the Cytobrush were found.

The following organizations have made no recommendations for or against the use of the Cytobrush in pregnancy: US Preventive Services Task Force, American College of Obstetricians and Gynecologists, American Academy of Family Physicians, or the American Academy of Nurse-Midwives.

Evidence summary

A Cochrane review of Pap smear sampling devices for nonpregnant women concludes that the cervical brush with spatula is more effective at collecting endocervical cells and producing adequate Pap smears.¹ Based on more limited evidence, the higher rate of adequate smears is associated with the detection of more cytologic abnormalities. However, the manufacturer of Cytobrush (Medscand) recommends that the device not be used after the first 10 weeks of pregnancy, raising issues of both effectiveness and safety in this population.

Upon review of the literature, these concerns appear to be unfounded. In multiple studies involving more than 25,000 pregnant and nonpregnant patients, the brush was consistently shown to be the method obtaining the highest rate of adequate smears—ie, those containing endocervical cells.^2-10 Furthermore, in studies including about 1900 pregnant patients, the brush with spatula caused no significantly increased risk of serious adverse outcomes, nor any trend in that direction.^5-7,9-11 The device did cause a slight increase in self-limited vaginal spotting.

In theory, a more accurate Pap smear could lead to patient-oriented outcomes, such as less need for procedures to diagnose and treat cervical cytologic abnormalities, reduced incidence of invasive cervical cancer, and fewer patient deaths from cervical cancer. No data on these outcomes is available. Some studies did look for differences in the detection of cytologic abnormalities between the brush with spatula and the swab with spatula methods. Most small studies and a meta-analysis showed no difference.^2,3,8,9 One study showed a trend towards improved yield; in another study, the brush with spatula significantly improved the ability to detect cytologic abnormalities in pregnant patients.^7,10

Three studies addressed cost-effectiveness of the brush in pregnancy.^3,9,12 Especially when including the cost of repeat Pap smears for inadequate specimens, the brush with spatula was rated most cost-effective in all 3 studies.

Comparison of the use of conventional Pap smear collection techniques with newer liquid-based cytology or human papilloma virus (HPV) typing has not yet been addressed in the literature.

Recommendations from others

“The Working Group’s Recommendations for Women in Low Risk Pregnancy” through the Veterans Health Administration lists use of a nylon cervical brush—no type is specified—as the appropriate sampling device in the late first trimester of pregnancy.¹³ No recommendations specific to the Cytobrush were found.

The following organizations have made no recommendations for or against the use of the Cytobrush in pregnancy: US Preventive Services Task Force, American College of Obstetricians and Gynecologists, American Academy of Family Physicians, or the American Academy of Nurse-Midwives.

Evidence summary

A Cochrane review of Pap smear sampling devices for nonpregnant women concludes that the cervical brush with spatula is more effective at collecting endocervical cells and producing adequate Pap smears.¹ Based on more limited evidence, the higher rate of adequate smears is associated with the detection of more cytologic abnormalities. However, the manufacturer of Cytobrush (Medscand) recommends that the device not be used after the first 10 weeks of pregnancy, raising issues of both effectiveness and safety in this population.

Upon review of the literature, these concerns appear to be unfounded. In multiple studies involving more than 25,000 pregnant and nonpregnant patients, the brush was consistently shown to be the method obtaining the highest rate of adequate smears—ie, those containing endocervical cells.^2-10 Furthermore, in studies including about 1900 pregnant patients, the brush with spatula caused no significantly increased risk of serious adverse outcomes, nor any trend in that direction.^5-7,9-11 The device did cause a slight increase in self-limited vaginal spotting.

In theory, a more accurate Pap smear could lead to patient-oriented outcomes, such as less need for procedures to diagnose and treat cervical cytologic abnormalities, reduced incidence of invasive cervical cancer, and fewer patient deaths from cervical cancer. No data on these outcomes is available. Some studies did look for differences in the detection of cytologic abnormalities between the brush with spatula and the swab with spatula methods. Most small studies and a meta-analysis showed no difference.^2,3,8,9 One study showed a trend towards improved yield; in another study, the brush with spatula significantly improved the ability to detect cytologic abnormalities in pregnant patients.^7,10

Three studies addressed cost-effectiveness of the brush in pregnancy.^3,9,12 Especially when including the cost of repeat Pap smears for inadequate specimens, the brush with spatula was rated most cost-effective in all 3 studies.

Comparison of the use of conventional Pap smear collection techniques with newer liquid-based cytology or human papilloma virus (HPV) typing has not yet been addressed in the literature.

Recommendations from others

“The Working Group’s Recommendations for Women in Low Risk Pregnancy” through the Veterans Health Administration lists use of a nylon cervical brush—no type is specified—as the appropriate sampling device in the late first trimester of pregnancy.¹³ No recommendations specific to the Cytobrush were found.

The following organizations have made no recommendations for or against the use of the Cytobrush in pregnancy: US Preventive Services Task Force, American College of Obstetricians and Gynecologists, American Academy of Family Physicians, or the American Academy of Nurse-Midwives.

Evidence summary

Based on the advantage of nocturnal sedation of first-generation antihistamines, clinicians frequently use these agents to treat pruritus. Evidence is lacking to support this intuitive approach. Furthermore, not all pruritus can be lumped into a single category, as distinct treatment recommendations exist for different categories.

The best evidence supporting antihistamines is for the treatment of urticarial pruritus. A Medline-based review found 7 double-blind, placebo-controlled trials that compared the benefit of first- and second-generation antihistamines in 720 patients with chronic idiopathic urticaria. Hydroxyzine was used in 682 patients, while the remainder took clemastine. Second-generation agents included cetirizine, loratadine, or acrivastine. The researchers qualitatively summarized outcomes and concluded that the treatment benefits were equivalent and superior to placebo.¹ The clinical practice of doubling the dose of second-generation agents for initial treatment failures was not recommended, due to absence of supporting data for this approach.

A recent review of therapies for urticarial itch concluded that second-generation antihista mines were preferred.² However, the methodology failed to use a systematic search technique. The conclusion was based upon a single double-blind placebo-controlled study of 188 patients at least 12 years of age. They received cetirizine 10 mg daily, hydroxyzine 25 mg 3 times daily, or placebo. This study found both agents produced significant, and equivalent, pruritus reduction relative to placebo.³

In contrast to urticarial itch, pruritus from atopic dermatitis does not improve with antihistamines. An NHS Centre narrative review on relieving pruritus in atopic dermatitis concluded that there was little objective evidence to support the efficacy of first- or second-generation antihistamines; 803 participants from 16 case series and reports were included. There were no large RCTs. Results were not pooled or tested for heterogeneity, so they should be interpreted cautiously.^4,5

Another systematic review focusing on pediatric patients concluded oral antihistamines are not beneficial for pruritus from atopic dermatitis. A search of Cochrane and PubMed revealed only 2 relevant RCTs involving 177 children. Cetirizine and chlorpheniramine were each compared with placebo, and no statistically significant reduction in symptoms was found.⁶

Vigilance must be exercised when interpreting pruritus literature. Many studies are pharmacodynamic only, omit appropriate statistical information, and measure surrogate outcomes in healthy volunteers, such as wheal and flare suppression to injected histamine. Such disease-oriented evidence has filtered into clinical recommendations.

One recent nonsystematic, narrative review of pruritic dermatoses concluded second-generation antihistamines appear to be more effective.⁷ This conclusion was largely based on a study of 14 young, healthy, “light-skinned” Canadian men. No placebo control was used. Seven received fexofenadine 120 mg; the other 7 took diphenhydramine 50 mg. Primary outcomes were concentrations of drug in skin punch biopsies and plasma samples, plus degree of wheal and flare suppression to histamine. In this study, fexofenadine showed statistically significant disease-oriented results.⁸

Recommendations from others

No evidence-based guidelines or consensus statements were found that address antihistamine preference in the treatment of pruritus. Although use of non-antihistamine agents is beyond the scope of this inquiry, an excellent topical review of pruritus was recently published that comprehensively outlined the Twycross classification system and detailed the evidence for usual and nontraditional treatments.⁹ Since antihistamines do not benefit atopic-related pruritus, other options include emollients, counterirritants such as menthol/camphor or capsaicin, EMLA cream, topical pramoxine, topical corticosteroids, topical doxepin, topical immunomodulators such as pimecrolimus or tacrolimus, topical aspirin, and phototherapy with psoralen ultraviolet A-range (PUVA).

Acknowledgments

The opinions and assertions contained herein are the private views of the author and are not to be construed as official, or as reflecting the views of the US Air Force medical department or the US Air Force at large.

Evidence summary

Based on the advantage of nocturnal sedation of first-generation antihistamines, clinicians frequently use these agents to treat pruritus. Evidence is lacking to support this intuitive approach. Furthermore, not all pruritus can be lumped into a single category, as distinct treatment recommendations exist for different categories.

The best evidence supporting antihistamines is for the treatment of urticarial pruritus. A Medline-based review found 7 double-blind, placebo-controlled trials that compared the benefit of first- and second-generation antihistamines in 720 patients with chronic idiopathic urticaria. Hydroxyzine was used in 682 patients, while the remainder took clemastine. Second-generation agents included cetirizine, loratadine, or acrivastine. The researchers qualitatively summarized outcomes and concluded that the treatment benefits were equivalent and superior to placebo.¹ The clinical practice of doubling the dose of second-generation agents for initial treatment failures was not recommended, due to absence of supporting data for this approach.

A recent review of therapies for urticarial itch concluded that second-generation antihista mines were preferred.² However, the methodology failed to use a systematic search technique. The conclusion was based upon a single double-blind placebo-controlled study of 188 patients at least 12 years of age. They received cetirizine 10 mg daily, hydroxyzine 25 mg 3 times daily, or placebo. This study found both agents produced significant, and equivalent, pruritus reduction relative to placebo.³

In contrast to urticarial itch, pruritus from atopic dermatitis does not improve with antihistamines. An NHS Centre narrative review on relieving pruritus in atopic dermatitis concluded that there was little objective evidence to support the efficacy of first- or second-generation antihistamines; 803 participants from 16 case series and reports were included. There were no large RCTs. Results were not pooled or tested for heterogeneity, so they should be interpreted cautiously.^4,5

Another systematic review focusing on pediatric patients concluded oral antihistamines are not beneficial for pruritus from atopic dermatitis. A search of Cochrane and PubMed revealed only 2 relevant RCTs involving 177 children. Cetirizine and chlorpheniramine were each compared with placebo, and no statistically significant reduction in symptoms was found.⁶

Vigilance must be exercised when interpreting pruritus literature. Many studies are pharmacodynamic only, omit appropriate statistical information, and measure surrogate outcomes in healthy volunteers, such as wheal and flare suppression to injected histamine. Such disease-oriented evidence has filtered into clinical recommendations.

One recent nonsystematic, narrative review of pruritic dermatoses concluded second-generation antihistamines appear to be more effective.⁷ This conclusion was largely based on a study of 14 young, healthy, “light-skinned” Canadian men. No placebo control was used. Seven received fexofenadine 120 mg; the other 7 took diphenhydramine 50 mg. Primary outcomes were concentrations of drug in skin punch biopsies and plasma samples, plus degree of wheal and flare suppression to histamine. In this study, fexofenadine showed statistically significant disease-oriented results.⁸

Recommendations from others

No evidence-based guidelines or consensus statements were found that address antihistamine preference in the treatment of pruritus. Although use of non-antihistamine agents is beyond the scope of this inquiry, an excellent topical review of pruritus was recently published that comprehensively outlined the Twycross classification system and detailed the evidence for usual and nontraditional treatments.⁹ Since antihistamines do not benefit atopic-related pruritus, other options include emollients, counterirritants such as menthol/camphor or capsaicin, EMLA cream, topical pramoxine, topical corticosteroids, topical doxepin, topical immunomodulators such as pimecrolimus or tacrolimus, topical aspirin, and phototherapy with psoralen ultraviolet A-range (PUVA).

Acknowledgments

The opinions and assertions contained herein are the private views of the author and are not to be construed as official, or as reflecting the views of the US Air Force medical department or the US Air Force at large.

Evidence summary

Based on the advantage of nocturnal sedation of first-generation antihistamines, clinicians frequently use these agents to treat pruritus. Evidence is lacking to support this intuitive approach. Furthermore, not all pruritus can be lumped into a single category, as distinct treatment recommendations exist for different categories.

The best evidence supporting antihistamines is for the treatment of urticarial pruritus. A Medline-based review found 7 double-blind, placebo-controlled trials that compared the benefit of first- and second-generation antihistamines in 720 patients with chronic idiopathic urticaria. Hydroxyzine was used in 682 patients, while the remainder took clemastine. Second-generation agents included cetirizine, loratadine, or acrivastine. The researchers qualitatively summarized outcomes and concluded that the treatment benefits were equivalent and superior to placebo.¹ The clinical practice of doubling the dose of second-generation agents for initial treatment failures was not recommended, due to absence of supporting data for this approach.

A recent review of therapies for urticarial itch concluded that second-generation antihista mines were preferred.² However, the methodology failed to use a systematic search technique. The conclusion was based upon a single double-blind placebo-controlled study of 188 patients at least 12 years of age. They received cetirizine 10 mg daily, hydroxyzine 25 mg 3 times daily, or placebo. This study found both agents produced significant, and equivalent, pruritus reduction relative to placebo.³

In contrast to urticarial itch, pruritus from atopic dermatitis does not improve with antihistamines. An NHS Centre narrative review on relieving pruritus in atopic dermatitis concluded that there was little objective evidence to support the efficacy of first- or second-generation antihistamines; 803 participants from 16 case series and reports were included. There were no large RCTs. Results were not pooled or tested for heterogeneity, so they should be interpreted cautiously.^4,5

Another systematic review focusing on pediatric patients concluded oral antihistamines are not beneficial for pruritus from atopic dermatitis. A search of Cochrane and PubMed revealed only 2 relevant RCTs involving 177 children. Cetirizine and chlorpheniramine were each compared with placebo, and no statistically significant reduction in symptoms was found.⁶

Vigilance must be exercised when interpreting pruritus literature. Many studies are pharmacodynamic only, omit appropriate statistical information, and measure surrogate outcomes in healthy volunteers, such as wheal and flare suppression to injected histamine. Such disease-oriented evidence has filtered into clinical recommendations.

One recent nonsystematic, narrative review of pruritic dermatoses concluded second-generation antihistamines appear to be more effective.⁷ This conclusion was largely based on a study of 14 young, healthy, “light-skinned” Canadian men. No placebo control was used. Seven received fexofenadine 120 mg; the other 7 took diphenhydramine 50 mg. Primary outcomes were concentrations of drug in skin punch biopsies and plasma samples, plus degree of wheal and flare suppression to histamine. In this study, fexofenadine showed statistically significant disease-oriented results.⁸

Recommendations from others

No evidence-based guidelines or consensus statements were found that address antihistamine preference in the treatment of pruritus. Although use of non-antihistamine agents is beyond the scope of this inquiry, an excellent topical review of pruritus was recently published that comprehensively outlined the Twycross classification system and detailed the evidence for usual and nontraditional treatments.⁹ Since antihistamines do not benefit atopic-related pruritus, other options include emollients, counterirritants such as menthol/camphor or capsaicin, EMLA cream, topical pramoxine, topical corticosteroids, topical doxepin, topical immunomodulators such as pimecrolimus or tacrolimus, topical aspirin, and phototherapy with psoralen ultraviolet A-range (PUVA).

Acknowledgments

The opinions and assertions contained herein are the private views of the author and are not to be construed as official, or as reflecting the views of the US Air Force medical department or the US Air Force at large.