Hyperglycemia and diabetes mellitus are very common in hospitalized patients. Although more data are available on the prevalence of this problem and on how to manage it in the intensive care unit (ICU) than on regular hospital floors, the situation is changing. Information is emerging on the prevalence and impact of hyperglycemia and diabetes in the non-ICU setting, which is the focus of this paper.

HYPERGLYCEMIA IS COMMON AND PREDICTS POOR OUTCOMES

Cook et al,¹ in a survey of 126 US hospitals, found that the prevalence of hyperglycemia (blood glucose > 180 mg/dL) was 46% in the ICU and 32% in regular wards.

Kosiborod et al² reported that hyperglycemia (blood glucose > 140 mg/dL) was present in 78% of diabetic patients hospitalized with acute coronary syndrome and 26% of similar hospitalized nondiabetic patients.

Hyperglycemia is a common comorbidity in medical-surgical patients in community hospitals. Our group³ found that, in our hospital, 62% of patients were normoglycemic (ie, had a fasting blood glucose < 126 mg/dL or a random blood glucose < 200 mg/dL on two occasions), 26% had known diabetes, and 12% had new hyperglycemia. Further, new hyperglycemia was associated with a higher in-hospital death rate than the other two conditions.

Failure to identify diabetes is a predictor of rehospitalization. Robbins and Webb⁴ reported that 30.6% of those who had diabetes that was missed during hospitalization were readmitted within 30 days, compared with 9.4% of patients with diabetes first diagnosed during hospitalization.

WHAT DIAGNOSTIC CRITERIA SHOULD WE USE?

Blood glucose greater than 140 mg/dL

A consensus statement from the American Association of Clinical Endocrinologists (ACE) and the American Diabetes Association (ADA)⁵ defines in-hospital hyperglycemia as a blood glucose level greater than 140 mg/dL on admission or in the hospital. If the blood glucose is higher than this, the question arises as to whether the patient has preexisting diabetes or has stress hyperglycemia.

Hemoglobin A_1c of 6.5% or higher

In view of the uncertainty as to whether a patient with an elevated blood glucose level has preexisting diabetes or stress hyperglycemia, upcoming guidelines will recommend measuring the hemoglobin A_1c level if the blood glucose level is higher than 140 mg/dL.

A patient with an elevated blood glucose level (>140 mg/dL) whose hemoglobin A_1c level is 6.5% or higher can be identified as having diabetes that preceded the hospitalization. Hemoglobin A_1c testing can also be useful to assess glycemic control before admission and in designing an optional regimen at the time of discharge. In patients with newly recognized hyperglycemia, a hemoglobin A_1c measurement can help differentiate patients with previously undiagnosed diabetes from those with stress-induced hyperglycemia.

Clinicians should keep in mind that a hemoglobin A_1c cutoff of 6.5% identifies fewer cases of undiagnosed diabetes than does a high fasting glucose concentration, and that a level less than 6.5% does not rule out the diagnosis of diabetes. Several epidemiologic studies⁶ have reported a low sensitivity (44% to 66%) but a high specificity (76% to 99%) for hemoglobin A_1c values higher than 6.5% in an outpatient population. The high specificity therefore supports the use of hemoglobin A_1c to confirm the diagnosis of diabetes in patients with hyperglycemia, but the low sensitivity indicates that this test should not be used for universal screening in the hospital.

Many factors can influence the hemoglobin A_1c level, such as anemia, iron deficiency, blood transfusions, hemolytic anemia, and renal failure.

Until now, if patients had hyperglycemia but no prior diagnosis of diabetes, the recommendation was for an oral 2-hour glucose tolerance test shortly after discharge to confirm the diagnosis of diabetes. Norhammar et al⁷ performed oral glucose tolerance tests in patients admitted with acute myocardial infarction, and Matz et al⁸ performed glucose tolerance tests in patients with acute stroke. They found that impaired glucose tolerance and undiagnosed type 2 diabetes were very common in these two groups. However, physicians rarely order oral glucose tolerance tests. We believe that hemoglobin A_1c will be a better tool than an oral glucose tolerance test to confirm diabetes in hyperglycemic patients in the hospital setting.

WHAT IS THE ASSOCIATION BETWEEN HYPERGLYCEMIA AND OUTCOMES?

In 2,471 patients admitted to the hospital with community-acquired pneumonia, McAlister et al¹⁰ found that the rates of hospital complications and of death rose with blood glucose levels.

Falguera et al¹¹ found that, in 660 episodes of community-acquired pneumonia, the rates of hospitalization, death, pleural effusion, and concomitant illnesses were all significantly higher in diabetic patients than in nondiabetic patients.

Noordzij et al¹² performed a case-control study of 108,593 patients who underwent noncardiac surgery. The odds ratio for perioperative death was 1.19 (95% confidence interval [CI] 1.1–1.3) for every 1-mmol/L increase in the glucose level.

Frisch et al,¹³ in patients undergoing noncardiac surgery, found that the 30-day rates of death and of in-hospital complications were all higher in patients with diabetes than without diabetes.

Our group³ identified hyperglycemia as an independent marker of in-hospital death in patients with undiagnosed diabetes. The rates of death were 1.7% in those with normoglycemia, 3.0% in those with known diabetes, and 16.0% (P < .01) in those with new hyperglycemia.

The ACE/ADA consensus panel¹⁴ set the following glucose targets for patients in the non-ICU setting:

• Pre-meal blood glucose < 140 mg/dL
• Random blood glucose < 180 mg/dL.

On the other hand, hypoglycemia is also associated with adverse outcomes. Therefore, to avoid hypoglycemia, the insulin regimen should be reassessed if blood glucose levels fall below 100 mg/dL. New guidelines will suggest keeping the blood glucose between 100 and 140 mg/dL.

HOW SHOULD WE MANAGE HYPERGLYCEMIA IN THE NON-ICU SETTING?

The ACE/ADA guidelines recommend subcutaneous insulin therapy for most medical-surgical patients with diabetes, reserving intravenous insulin therapy for hyperglycemic crises and uncontrolled hyperglycemia.¹⁴

Oral antidiabetic agents are not generally recommended, as we have no data to support their use in the hospital. Another argument against using noninsulin therapies in the hospital is that sulfonylureas, especially glyburide (Diabeta, Micronase) are a major cause of hypoglycemia. Metformin (Glucophage) is contraindicated in decreased renal function, in hemodynamic instability, in surgical patients, and with the use of iodinated contrast dye. Thiazolidinediones are associated with edema and congestive heart failure, and they take up to 12 weeks to lower blood glucose levels. Alpha-glucosidase inhibitors are weak glucose-lowering agents. Also, therapies directed at glucagon-like-protein 1 can cause nausea and have a greater effect on postprandial glucose.¹⁴

The two main options for managing hyperglycemia and diabetes in the non-ICU setting are short-acting insulin on a sliding scale and basal-bolus therapy, the latter with either NPH plus regular insulin or long-acting plus rapid-acting insulin analogues.

Basal-bolus vs sliding scale insulin: The RABBIT-2 trial

In the RABBIT 2 trial (Randomized Basal Bolus Versus Sliding Scale Regular Insulin in Patients With Type 2 Diabetes Mellitus),¹⁵ our group compared the efficacy and safety of a basal-bolus regimen and a sliding-scale regimen in 130 hospitalized patients with type 2 diabetes treated with diet, with oral hypoglycemic agents, or with both. Oral antidiabetic drugs were discontinued on admission, and patients were randomized to one of the treatment groups.

In the basal-bolus group, the starting total daily dose was 0.4 U/kg/day if the blood glucose level on admission was between 140 and 200 mg/dL, or 0.5 U/kg/day if the glucose level was between 201 and 400 mg/dL. Half of the total daily dose was given as insulin glargine (Lantus) once daily, and the other half was given as insulin glulisine (Apidra) before meals. These doses were adjusted if the patient’s fasting or pre-meal blood glucose levels rose above 140 mg/dL or fell below 70 mg/dL.

The sliding-scale group received regular insulin four times daily (before meals and at bedtime) for glucose levels higher than 140 mg/dL; the higher the level, the more they got.

The basal-bolus regimen was better than sliding-scale regular insulin. At admission, the mean glucose values and hemoglobin A_1c values were similar in both groups, but the mean glucose level on therapy was significantly lower in the basal-bolus group than in the sliding-scale group, 166 ± 32 mg/dL vs 193 ± 54 mg/dL, P < .001). About two-thirds of the basal-bolus group achieved a blood glucose target of less than 140 mg/dL, compared with only about one-third of the sliding-scale group. The basal-bolus group received more insulin, a mean of 42 units per day vs 12.5 units per day in the sliding-scale group. Yet the incidence of hypoglycemia was 3% in both groups.

NPH plus regular vs detemir plus aspart: The DEAN trial

Several long-acting insulin analogues are available and have a longer duration of action than NPH. Similarly, several newer rapid-acting analogues act more rapidly than regular insulin. Do these pharmacokinetic advantages matter? And do they justify the higher costs of the newer agents?

In the randomized Insulin Detemir Versus NPH Insulin in Hospitalized Patients With Diabetes (DEAN) trial,¹⁶ we compared two regimens: detemir plus aspart in a basal-bolus regimen, and NPH plus regular insulin in two divided doses, two-thirds of the total daily dose in the morning before breakfast and one-third before dinner, both doses in a ratio of two-thirds NPH and one-third regular, mixed in the same syringe. We recruited 130 patients with type 2 diabetes mellitus who were on oral hypoglycemic agents or insulin therapy.

NPH plus regular was just as good as detemir plus aspart in improving glycemic control. Blood glucose levels fell during the first day of therapy and were similar in both groups throughout the trial, as measured before breakfast, lunch, and dinner and at bedtime. The mean total daily insulin dose was not significantly different between treatment groups: 56 ± 45 units in the basal-bolus detemir-aspart group and 45 ± 32 units in the NPH-regular group. However, the basal-bolus group received significantly more short-acting insulin: 27 ± 20 units a day of aspart vs 18 ± 14 units of regular.

Somewhat fewer patients in the NPH-regular group had episodes of hypoglycemia, although the difference between groups was not statistically significant.

In a univariate analysis of the RABBIT-2 and DEAN trials,¹⁷ factors that predicted a blood glucose level less than 60 mg/dL were older age, lower body weight, higher serum creatinine level, and previous insulin therapy. Factors that were not predictive were the hemoglobin A_1c level and the enrollment blood glucose level. Based on these data, we believe that to reduce the rate of hypoglycemia, lower insulin doses are needed in elderly patients and patients with renal impairment, and that if patients have been taking insulin before they come to the hospital, the dose should be cut back by about 25% while they are hospitalized.

Does better glucose control in surgical patients affect outcomes in patients undergoing general surgery? To find out, we performed a prospective, multicenter, randomized, open-label trial in general surgery patients not in the ICU.¹⁸ We recruited and randomized 211 patients with type 2 diabetes who were on diet therapy or oral hypoglycemic agents or insulin in low doses (< 0.4 U/kg/day).

Oral drugs were discontinued on admission, and patients were randomized to receive either a basal-bolus regimen of glargine plus glulisine or regular insulin on a sliding scale. The basal-bolus group got 0.5 U/kg/day, half of it as glargine once daily and half as glulisine before meals. The total daily dose was reduced to 0.3 U/kg/day in patients age 70 and older or who had a serum creatinine level of 2.0 mg/dL or higher.

The goal was to maintain fasting and pre-meal glucose concentrations between 100 and 140 mg/dL. The total daily dose was raised by 10% (mostly in the glargine dose) if the blood glucose level was in the range of 141 to 180 mg/dL, and by 20% if the glucose level was higher than 181 mg/dL. The dose was decreased by 10% for glucose levels between 70 and 99 mg/dL, was decreased by 20% if the glucose level was between 40 and 69, and was held if the glucose level was lower than 40 mg/dL. If a patient was not able to eat, insulin glulisine was held until meals were resumed.

The sliding-scale group received regular insulin four times a day for blood glucose levels higher than 140 mg/dL.

The primary outcomes measured were the difference between groups in mean daily blood glucose concentration and a composite of hospital complications including postoperative wound infection, pneumonia, respiratory failure, acute renal failure, and bacteremia. Secondary outcomes were differences between groups in mean fasting and pre-meal blood glucose, number of hypoglycemic episodes (blood glucose < 70 mg/dL), hyperglycemic episodes (blood glucose > 200 mg/dL), length of hospital stay, need for intensive care, and rate of complications including wound infection, pneumonia, acute renal failure, and death.

Blood glucose levels were significantly lower in the basal-bolus group through the first 7 days after randomization, as measured before breakfast, lunch, and dinner, and at bedtime, and then they converged.

More patients in the sliding-scale group had hospital complications, 26 vs 9, P = .003. On the other hand, more patients in the basal-bolus group had episodes of hypoglycemia: 24 (23%) vs 5 (4.7%) had episodes of less than 70 mg/dL (P < .001), 12 (12%) vs 2 (1.9%) had episodes of less than 60 mg/dL (P = .005), and 4 (3.8%) vs 0 had episodes of less than 40 mg/dL (P = .057). The mean total daily dose of insulin was 33.4 units in the basal-bolus group and 12.3 units in the sliding-scale group.

WHAT HAVE WE LEARNED?

Don’t use a sliding-scale regimen as a single agent in patients with diabetes. Glycemic control is better with a basal-bolus regimen than with a sliding-scale regimen, and a basal-bolus insulin regimen is preferred for most patients with hyperglycemia.

The old human insulins (ie, regular and NPH) are still good and improve glycemic control as well as the new basal insulin analogues (detemir and aspart) do.

Improved control may reduce the rate of hospital complications, according to preliminary evidence. More studies are under way.

One size does not fit all. Those who are elderly or who have impaired renal function should receive lower doses of insulin, eg, 0.3 U/kg/day instead of 0.5 U/kg/day. Those who are on insulin should have their dose decreased when they are admitted to the hospital. Perhaps lean patients with type 2 diabetes should also have a lower dose.

Most hospitalized patients with diabetes and elevated blood glucose values (or hyperglycemia) should receive subcutaneous insulin treatment with a basal-bolus regimen or a multidose combination of NPH plus regular insulin. Selected patients with severe insulin resistance and persistent hyperglycemia despite subcutaneous insulin may benefit from continuous intravenous insulin infusion.

Patients treated with insulin at home should continue to receive insulin therapy in the hospital. However, the insulin dosage should be reduced by about 25% to allow for lower food intake.

QUESTIONS FOR FURTHER STUDY

Should we modify the standard basal-bolus regimen?

In a typical basal-bolus regimen, patients get 50% of their total daily insulin dose in the form of a basal injection and 50% in the form of rapid-acting boluses before meals. However, for a variety of reasons, hospitalized patients do not eat very much. Thus, a 50-50 basal-bolus regimen may not be ideal for patients with poor oral intake.

In the Basal-PLUS trial, currently under way, we are comparing the safety and efficacy of a daily dose of basal insulin (glargine) plus correction doses of a rapid-acting insulin analogue (glulisine) on a sliding scale and a standard basal-bolus regimen in medical and surgical patients.

Does one glycemic target fit all patients?

Falciglia et al¹⁹ found an association between hyperglycemia and death in patients with unstable angina, arrhythmias, stroke, pneumonia, gastrointestinal bleeding, respiratory failure, sepsis, acute renal failure, and congestive heart failure. However, they found no such association in patients with chronic obstructive pulmonary disease, liver failure, diabetic ketoacidosis, gastrointestinal neoplasm, musculoskeletal disease, peripheral vascular disease with bypass, hip fracture, amputation due to peripheral vascular disease, or prostate surgery. Should patients in this second group be treated with a less-intensive insulin regimen?

What is the best regimen after hospital discharge?

We are conducting a prospective clinical trial to assess the impact of insulin after hospital discharge. Our current practice when a patient is discharged from the hospital is as follows:

• If the admission hemoglobin A_1c level is less than 7%, we restart the previous outpatient treatment regimen of oral antidiabetic agents, or insulin, or both.
• If the admission hemoglobin A_1c is between 7% and 9%, we restart the outpatient oral agents and continue glargine once daily at 50% to 80% of the hospital dose.
• If the hemoglobin A_1c level is higher than 9%, we discharge the patient on a basal-bolus regimen at the same dosage as in the hospital. As an alternative, we could restart the oral agents and add glargine once daily at 80% of the hospital dose.

Hyperglycemia and diabetes mellitus are very common in hospitalized patients. Although more data are available on the prevalence of this problem and on how to manage it in the intensive care unit (ICU) than on regular hospital floors, the situation is changing. Information is emerging on the prevalence and impact of hyperglycemia and diabetes in the non-ICU setting, which is the focus of this paper.

HYPERGLYCEMIA IS COMMON AND PREDICTS POOR OUTCOMES

Cook et al,¹ in a survey of 126 US hospitals, found that the prevalence of hyperglycemia (blood glucose > 180 mg/dL) was 46% in the ICU and 32% in regular wards.

Kosiborod et al² reported that hyperglycemia (blood glucose > 140 mg/dL) was present in 78% of diabetic patients hospitalized with acute coronary syndrome and 26% of similar hospitalized nondiabetic patients.

Hyperglycemia is a common comorbidity in medical-surgical patients in community hospitals. Our group³ found that, in our hospital, 62% of patients were normoglycemic (ie, had a fasting blood glucose < 126 mg/dL or a random blood glucose < 200 mg/dL on two occasions), 26% had known diabetes, and 12% had new hyperglycemia. Further, new hyperglycemia was associated with a higher in-hospital death rate than the other two conditions.

Failure to identify diabetes is a predictor of rehospitalization. Robbins and Webb⁴ reported that 30.6% of those who had diabetes that was missed during hospitalization were readmitted within 30 days, compared with 9.4% of patients with diabetes first diagnosed during hospitalization.

WHAT DIAGNOSTIC CRITERIA SHOULD WE USE?

Blood glucose greater than 140 mg/dL

A consensus statement from the American Association of Clinical Endocrinologists (ACE) and the American Diabetes Association (ADA)⁵ defines in-hospital hyperglycemia as a blood glucose level greater than 140 mg/dL on admission or in the hospital. If the blood glucose is higher than this, the question arises as to whether the patient has preexisting diabetes or has stress hyperglycemia.

Hemoglobin A_1c of 6.5% or higher

In view of the uncertainty as to whether a patient with an elevated blood glucose level has preexisting diabetes or stress hyperglycemia, upcoming guidelines will recommend measuring the hemoglobin A_1c level if the blood glucose level is higher than 140 mg/dL.

A patient with an elevated blood glucose level (>140 mg/dL) whose hemoglobin A_1c level is 6.5% or higher can be identified as having diabetes that preceded the hospitalization. Hemoglobin A_1c testing can also be useful to assess glycemic control before admission and in designing an optional regimen at the time of discharge. In patients with newly recognized hyperglycemia, a hemoglobin A_1c measurement can help differentiate patients with previously undiagnosed diabetes from those with stress-induced hyperglycemia.

Clinicians should keep in mind that a hemoglobin A_1c cutoff of 6.5% identifies fewer cases of undiagnosed diabetes than does a high fasting glucose concentration, and that a level less than 6.5% does not rule out the diagnosis of diabetes. Several epidemiologic studies⁶ have reported a low sensitivity (44% to 66%) but a high specificity (76% to 99%) for hemoglobin A_1c values higher than 6.5% in an outpatient population. The high specificity therefore supports the use of hemoglobin A_1c to confirm the diagnosis of diabetes in patients with hyperglycemia, but the low sensitivity indicates that this test should not be used for universal screening in the hospital.

Many factors can influence the hemoglobin A_1c level, such as anemia, iron deficiency, blood transfusions, hemolytic anemia, and renal failure.

Until now, if patients had hyperglycemia but no prior diagnosis of diabetes, the recommendation was for an oral 2-hour glucose tolerance test shortly after discharge to confirm the diagnosis of diabetes. Norhammar et al⁷ performed oral glucose tolerance tests in patients admitted with acute myocardial infarction, and Matz et al⁸ performed glucose tolerance tests in patients with acute stroke. They found that impaired glucose tolerance and undiagnosed type 2 diabetes were very common in these two groups. However, physicians rarely order oral glucose tolerance tests. We believe that hemoglobin A_1c will be a better tool than an oral glucose tolerance test to confirm diabetes in hyperglycemic patients in the hospital setting.

WHAT IS THE ASSOCIATION BETWEEN HYPERGLYCEMIA AND OUTCOMES?

In 2,471 patients admitted to the hospital with community-acquired pneumonia, McAlister et al¹⁰ found that the rates of hospital complications and of death rose with blood glucose levels.

Falguera et al¹¹ found that, in 660 episodes of community-acquired pneumonia, the rates of hospitalization, death, pleural effusion, and concomitant illnesses were all significantly higher in diabetic patients than in nondiabetic patients.

Noordzij et al¹² performed a case-control study of 108,593 patients who underwent noncardiac surgery. The odds ratio for perioperative death was 1.19 (95% confidence interval [CI] 1.1–1.3) for every 1-mmol/L increase in the glucose level.

Frisch et al,¹³ in patients undergoing noncardiac surgery, found that the 30-day rates of death and of in-hospital complications were all higher in patients with diabetes than without diabetes.

Our group³ identified hyperglycemia as an independent marker of in-hospital death in patients with undiagnosed diabetes. The rates of death were 1.7% in those with normoglycemia, 3.0% in those with known diabetes, and 16.0% (P < .01) in those with new hyperglycemia.

The ACE/ADA consensus panel¹⁴ set the following glucose targets for patients in the non-ICU setting:

• Pre-meal blood glucose < 140 mg/dL
• Random blood glucose < 180 mg/dL.

On the other hand, hypoglycemia is also associated with adverse outcomes. Therefore, to avoid hypoglycemia, the insulin regimen should be reassessed if blood glucose levels fall below 100 mg/dL. New guidelines will suggest keeping the blood glucose between 100 and 140 mg/dL.

HOW SHOULD WE MANAGE HYPERGLYCEMIA IN THE NON-ICU SETTING?

The ACE/ADA guidelines recommend subcutaneous insulin therapy for most medical-surgical patients with diabetes, reserving intravenous insulin therapy for hyperglycemic crises and uncontrolled hyperglycemia.¹⁴

Oral antidiabetic agents are not generally recommended, as we have no data to support their use in the hospital. Another argument against using noninsulin therapies in the hospital is that sulfonylureas, especially glyburide (Diabeta, Micronase) are a major cause of hypoglycemia. Metformin (Glucophage) is contraindicated in decreased renal function, in hemodynamic instability, in surgical patients, and with the use of iodinated contrast dye. Thiazolidinediones are associated with edema and congestive heart failure, and they take up to 12 weeks to lower blood glucose levels. Alpha-glucosidase inhibitors are weak glucose-lowering agents. Also, therapies directed at glucagon-like-protein 1 can cause nausea and have a greater effect on postprandial glucose.¹⁴

The two main options for managing hyperglycemia and diabetes in the non-ICU setting are short-acting insulin on a sliding scale and basal-bolus therapy, the latter with either NPH plus regular insulin or long-acting plus rapid-acting insulin analogues.

Basal-bolus vs sliding scale insulin: The RABBIT-2 trial

In the RABBIT 2 trial (Randomized Basal Bolus Versus Sliding Scale Regular Insulin in Patients With Type 2 Diabetes Mellitus),¹⁵ our group compared the efficacy and safety of a basal-bolus regimen and a sliding-scale regimen in 130 hospitalized patients with type 2 diabetes treated with diet, with oral hypoglycemic agents, or with both. Oral antidiabetic drugs were discontinued on admission, and patients were randomized to one of the treatment groups.

In the basal-bolus group, the starting total daily dose was 0.4 U/kg/day if the blood glucose level on admission was between 140 and 200 mg/dL, or 0.5 U/kg/day if the glucose level was between 201 and 400 mg/dL. Half of the total daily dose was given as insulin glargine (Lantus) once daily, and the other half was given as insulin glulisine (Apidra) before meals. These doses were adjusted if the patient’s fasting or pre-meal blood glucose levels rose above 140 mg/dL or fell below 70 mg/dL.

The sliding-scale group received regular insulin four times daily (before meals and at bedtime) for glucose levels higher than 140 mg/dL; the higher the level, the more they got.

The basal-bolus regimen was better than sliding-scale regular insulin. At admission, the mean glucose values and hemoglobin A_1c values were similar in both groups, but the mean glucose level on therapy was significantly lower in the basal-bolus group than in the sliding-scale group, 166 ± 32 mg/dL vs 193 ± 54 mg/dL, P < .001). About two-thirds of the basal-bolus group achieved a blood glucose target of less than 140 mg/dL, compared with only about one-third of the sliding-scale group. The basal-bolus group received more insulin, a mean of 42 units per day vs 12.5 units per day in the sliding-scale group. Yet the incidence of hypoglycemia was 3% in both groups.

NPH plus regular vs detemir plus aspart: The DEAN trial

Several long-acting insulin analogues are available and have a longer duration of action than NPH. Similarly, several newer rapid-acting analogues act more rapidly than regular insulin. Do these pharmacokinetic advantages matter? And do they justify the higher costs of the newer agents?

In the randomized Insulin Detemir Versus NPH Insulin in Hospitalized Patients With Diabetes (DEAN) trial,¹⁶ we compared two regimens: detemir plus aspart in a basal-bolus regimen, and NPH plus regular insulin in two divided doses, two-thirds of the total daily dose in the morning before breakfast and one-third before dinner, both doses in a ratio of two-thirds NPH and one-third regular, mixed in the same syringe. We recruited 130 patients with type 2 diabetes mellitus who were on oral hypoglycemic agents or insulin therapy.

NPH plus regular was just as good as detemir plus aspart in improving glycemic control. Blood glucose levels fell during the first day of therapy and were similar in both groups throughout the trial, as measured before breakfast, lunch, and dinner and at bedtime. The mean total daily insulin dose was not significantly different between treatment groups: 56 ± 45 units in the basal-bolus detemir-aspart group and 45 ± 32 units in the NPH-regular group. However, the basal-bolus group received significantly more short-acting insulin: 27 ± 20 units a day of aspart vs 18 ± 14 units of regular.

Somewhat fewer patients in the NPH-regular group had episodes of hypoglycemia, although the difference between groups was not statistically significant.

In a univariate analysis of the RABBIT-2 and DEAN trials,¹⁷ factors that predicted a blood glucose level less than 60 mg/dL were older age, lower body weight, higher serum creatinine level, and previous insulin therapy. Factors that were not predictive were the hemoglobin A_1c level and the enrollment blood glucose level. Based on these data, we believe that to reduce the rate of hypoglycemia, lower insulin doses are needed in elderly patients and patients with renal impairment, and that if patients have been taking insulin before they come to the hospital, the dose should be cut back by about 25% while they are hospitalized.

Does better glucose control in surgical patients affect outcomes in patients undergoing general surgery? To find out, we performed a prospective, multicenter, randomized, open-label trial in general surgery patients not in the ICU.¹⁸ We recruited and randomized 211 patients with type 2 diabetes who were on diet therapy or oral hypoglycemic agents or insulin in low doses (< 0.4 U/kg/day).

Oral drugs were discontinued on admission, and patients were randomized to receive either a basal-bolus regimen of glargine plus glulisine or regular insulin on a sliding scale. The basal-bolus group got 0.5 U/kg/day, half of it as glargine once daily and half as glulisine before meals. The total daily dose was reduced to 0.3 U/kg/day in patients age 70 and older or who had a serum creatinine level of 2.0 mg/dL or higher.

The goal was to maintain fasting and pre-meal glucose concentrations between 100 and 140 mg/dL. The total daily dose was raised by 10% (mostly in the glargine dose) if the blood glucose level was in the range of 141 to 180 mg/dL, and by 20% if the glucose level was higher than 181 mg/dL. The dose was decreased by 10% for glucose levels between 70 and 99 mg/dL, was decreased by 20% if the glucose level was between 40 and 69, and was held if the glucose level was lower than 40 mg/dL. If a patient was not able to eat, insulin glulisine was held until meals were resumed.

The sliding-scale group received regular insulin four times a day for blood glucose levels higher than 140 mg/dL.

The primary outcomes measured were the difference between groups in mean daily blood glucose concentration and a composite of hospital complications including postoperative wound infection, pneumonia, respiratory failure, acute renal failure, and bacteremia. Secondary outcomes were differences between groups in mean fasting and pre-meal blood glucose, number of hypoglycemic episodes (blood glucose < 70 mg/dL), hyperglycemic episodes (blood glucose > 200 mg/dL), length of hospital stay, need for intensive care, and rate of complications including wound infection, pneumonia, acute renal failure, and death.

Blood glucose levels were significantly lower in the basal-bolus group through the first 7 days after randomization, as measured before breakfast, lunch, and dinner, and at bedtime, and then they converged.

More patients in the sliding-scale group had hospital complications, 26 vs 9, P = .003. On the other hand, more patients in the basal-bolus group had episodes of hypoglycemia: 24 (23%) vs 5 (4.7%) had episodes of less than 70 mg/dL (P < .001), 12 (12%) vs 2 (1.9%) had episodes of less than 60 mg/dL (P = .005), and 4 (3.8%) vs 0 had episodes of less than 40 mg/dL (P = .057). The mean total daily dose of insulin was 33.4 units in the basal-bolus group and 12.3 units in the sliding-scale group.

WHAT HAVE WE LEARNED?

Don’t use a sliding-scale regimen as a single agent in patients with diabetes. Glycemic control is better with a basal-bolus regimen than with a sliding-scale regimen, and a basal-bolus insulin regimen is preferred for most patients with hyperglycemia.

The old human insulins (ie, regular and NPH) are still good and improve glycemic control as well as the new basal insulin analogues (detemir and aspart) do.

Improved control may reduce the rate of hospital complications, according to preliminary evidence. More studies are under way.

One size does not fit all. Those who are elderly or who have impaired renal function should receive lower doses of insulin, eg, 0.3 U/kg/day instead of 0.5 U/kg/day. Those who are on insulin should have their dose decreased when they are admitted to the hospital. Perhaps lean patients with type 2 diabetes should also have a lower dose.

Most hospitalized patients with diabetes and elevated blood glucose values (or hyperglycemia) should receive subcutaneous insulin treatment with a basal-bolus regimen or a multidose combination of NPH plus regular insulin. Selected patients with severe insulin resistance and persistent hyperglycemia despite subcutaneous insulin may benefit from continuous intravenous insulin infusion.

Patients treated with insulin at home should continue to receive insulin therapy in the hospital. However, the insulin dosage should be reduced by about 25% to allow for lower food intake.

QUESTIONS FOR FURTHER STUDY

Should we modify the standard basal-bolus regimen?

In a typical basal-bolus regimen, patients get 50% of their total daily insulin dose in the form of a basal injection and 50% in the form of rapid-acting boluses before meals. However, for a variety of reasons, hospitalized patients do not eat very much. Thus, a 50-50 basal-bolus regimen may not be ideal for patients with poor oral intake.

In the Basal-PLUS trial, currently under way, we are comparing the safety and efficacy of a daily dose of basal insulin (glargine) plus correction doses of a rapid-acting insulin analogue (glulisine) on a sliding scale and a standard basal-bolus regimen in medical and surgical patients.

Does one glycemic target fit all patients?

Falciglia et al¹⁹ found an association between hyperglycemia and death in patients with unstable angina, arrhythmias, stroke, pneumonia, gastrointestinal bleeding, respiratory failure, sepsis, acute renal failure, and congestive heart failure. However, they found no such association in patients with chronic obstructive pulmonary disease, liver failure, diabetic ketoacidosis, gastrointestinal neoplasm, musculoskeletal disease, peripheral vascular disease with bypass, hip fracture, amputation due to peripheral vascular disease, or prostate surgery. Should patients in this second group be treated with a less-intensive insulin regimen?

What is the best regimen after hospital discharge?

We are conducting a prospective clinical trial to assess the impact of insulin after hospital discharge. Our current practice when a patient is discharged from the hospital is as follows:

• If the admission hemoglobin A_1c level is less than 7%, we restart the previous outpatient treatment regimen of oral antidiabetic agents, or insulin, or both.
• If the admission hemoglobin A_1c is between 7% and 9%, we restart the outpatient oral agents and continue glargine once daily at 50% to 80% of the hospital dose.
• If the hemoglobin A_1c level is higher than 9%, we discharge the patient on a basal-bolus regimen at the same dosage as in the hospital. As an alternative, we could restart the oral agents and add glargine once daily at 80% of the hospital dose.

Hyperglycemia and diabetes mellitus are very common in hospitalized patients. Although more data are available on the prevalence of this problem and on how to manage it in the intensive care unit (ICU) than on regular hospital floors, the situation is changing. Information is emerging on the prevalence and impact of hyperglycemia and diabetes in the non-ICU setting, which is the focus of this paper.

HYPERGLYCEMIA IS COMMON AND PREDICTS POOR OUTCOMES

Cook et al,¹ in a survey of 126 US hospitals, found that the prevalence of hyperglycemia (blood glucose > 180 mg/dL) was 46% in the ICU and 32% in regular wards.

Kosiborod et al² reported that hyperglycemia (blood glucose > 140 mg/dL) was present in 78% of diabetic patients hospitalized with acute coronary syndrome and 26% of similar hospitalized nondiabetic patients.

Hyperglycemia is a common comorbidity in medical-surgical patients in community hospitals. Our group³ found that, in our hospital, 62% of patients were normoglycemic (ie, had a fasting blood glucose < 126 mg/dL or a random blood glucose < 200 mg/dL on two occasions), 26% had known diabetes, and 12% had new hyperglycemia. Further, new hyperglycemia was associated with a higher in-hospital death rate than the other two conditions.

Failure to identify diabetes is a predictor of rehospitalization. Robbins and Webb⁴ reported that 30.6% of those who had diabetes that was missed during hospitalization were readmitted within 30 days, compared with 9.4% of patients with diabetes first diagnosed during hospitalization.

WHAT DIAGNOSTIC CRITERIA SHOULD WE USE?

Blood glucose greater than 140 mg/dL

A consensus statement from the American Association of Clinical Endocrinologists (ACE) and the American Diabetes Association (ADA)⁵ defines in-hospital hyperglycemia as a blood glucose level greater than 140 mg/dL on admission or in the hospital. If the blood glucose is higher than this, the question arises as to whether the patient has preexisting diabetes or has stress hyperglycemia.

Hemoglobin A_1c of 6.5% or higher

In view of the uncertainty as to whether a patient with an elevated blood glucose level has preexisting diabetes or stress hyperglycemia, upcoming guidelines will recommend measuring the hemoglobin A_1c level if the blood glucose level is higher than 140 mg/dL.

A patient with an elevated blood glucose level (>140 mg/dL) whose hemoglobin A_1c level is 6.5% or higher can be identified as having diabetes that preceded the hospitalization. Hemoglobin A_1c testing can also be useful to assess glycemic control before admission and in designing an optional regimen at the time of discharge. In patients with newly recognized hyperglycemia, a hemoglobin A_1c measurement can help differentiate patients with previously undiagnosed diabetes from those with stress-induced hyperglycemia.

Clinicians should keep in mind that a hemoglobin A_1c cutoff of 6.5% identifies fewer cases of undiagnosed diabetes than does a high fasting glucose concentration, and that a level less than 6.5% does not rule out the diagnosis of diabetes. Several epidemiologic studies⁶ have reported a low sensitivity (44% to 66%) but a high specificity (76% to 99%) for hemoglobin A_1c values higher than 6.5% in an outpatient population. The high specificity therefore supports the use of hemoglobin A_1c to confirm the diagnosis of diabetes in patients with hyperglycemia, but the low sensitivity indicates that this test should not be used for universal screening in the hospital.

Many factors can influence the hemoglobin A_1c level, such as anemia, iron deficiency, blood transfusions, hemolytic anemia, and renal failure.

Until now, if patients had hyperglycemia but no prior diagnosis of diabetes, the recommendation was for an oral 2-hour glucose tolerance test shortly after discharge to confirm the diagnosis of diabetes. Norhammar et al⁷ performed oral glucose tolerance tests in patients admitted with acute myocardial infarction, and Matz et al⁸ performed glucose tolerance tests in patients with acute stroke. They found that impaired glucose tolerance and undiagnosed type 2 diabetes were very common in these two groups. However, physicians rarely order oral glucose tolerance tests. We believe that hemoglobin A_1c will be a better tool than an oral glucose tolerance test to confirm diabetes in hyperglycemic patients in the hospital setting.

WHAT IS THE ASSOCIATION BETWEEN HYPERGLYCEMIA AND OUTCOMES?

In 2,471 patients admitted to the hospital with community-acquired pneumonia, McAlister et al¹⁰ found that the rates of hospital complications and of death rose with blood glucose levels.

Falguera et al¹¹ found that, in 660 episodes of community-acquired pneumonia, the rates of hospitalization, death, pleural effusion, and concomitant illnesses were all significantly higher in diabetic patients than in nondiabetic patients.

Noordzij et al¹² performed a case-control study of 108,593 patients who underwent noncardiac surgery. The odds ratio for perioperative death was 1.19 (95% confidence interval [CI] 1.1–1.3) for every 1-mmol/L increase in the glucose level.

Frisch et al,¹³ in patients undergoing noncardiac surgery, found that the 30-day rates of death and of in-hospital complications were all higher in patients with diabetes than without diabetes.

Our group³ identified hyperglycemia as an independent marker of in-hospital death in patients with undiagnosed diabetes. The rates of death were 1.7% in those with normoglycemia, 3.0% in those with known diabetes, and 16.0% (P < .01) in those with new hyperglycemia.

The ACE/ADA consensus panel¹⁴ set the following glucose targets for patients in the non-ICU setting:

• Pre-meal blood glucose < 140 mg/dL
• Random blood glucose < 180 mg/dL.

On the other hand, hypoglycemia is also associated with adverse outcomes. Therefore, to avoid hypoglycemia, the insulin regimen should be reassessed if blood glucose levels fall below 100 mg/dL. New guidelines will suggest keeping the blood glucose between 100 and 140 mg/dL.

HOW SHOULD WE MANAGE HYPERGLYCEMIA IN THE NON-ICU SETTING?

The ACE/ADA guidelines recommend subcutaneous insulin therapy for most medical-surgical patients with diabetes, reserving intravenous insulin therapy for hyperglycemic crises and uncontrolled hyperglycemia.¹⁴

Oral antidiabetic agents are not generally recommended, as we have no data to support their use in the hospital. Another argument against using noninsulin therapies in the hospital is that sulfonylureas, especially glyburide (Diabeta, Micronase) are a major cause of hypoglycemia. Metformin (Glucophage) is contraindicated in decreased renal function, in hemodynamic instability, in surgical patients, and with the use of iodinated contrast dye. Thiazolidinediones are associated with edema and congestive heart failure, and they take up to 12 weeks to lower blood glucose levels. Alpha-glucosidase inhibitors are weak glucose-lowering agents. Also, therapies directed at glucagon-like-protein 1 can cause nausea and have a greater effect on postprandial glucose.¹⁴

The two main options for managing hyperglycemia and diabetes in the non-ICU setting are short-acting insulin on a sliding scale and basal-bolus therapy, the latter with either NPH plus regular insulin or long-acting plus rapid-acting insulin analogues.

Basal-bolus vs sliding scale insulin: The RABBIT-2 trial

In the RABBIT 2 trial (Randomized Basal Bolus Versus Sliding Scale Regular Insulin in Patients With Type 2 Diabetes Mellitus),¹⁵ our group compared the efficacy and safety of a basal-bolus regimen and a sliding-scale regimen in 130 hospitalized patients with type 2 diabetes treated with diet, with oral hypoglycemic agents, or with both. Oral antidiabetic drugs were discontinued on admission, and patients were randomized to one of the treatment groups.

In the basal-bolus group, the starting total daily dose was 0.4 U/kg/day if the blood glucose level on admission was between 140 and 200 mg/dL, or 0.5 U/kg/day if the glucose level was between 201 and 400 mg/dL. Half of the total daily dose was given as insulin glargine (Lantus) once daily, and the other half was given as insulin glulisine (Apidra) before meals. These doses were adjusted if the patient’s fasting or pre-meal blood glucose levels rose above 140 mg/dL or fell below 70 mg/dL.

The sliding-scale group received regular insulin four times daily (before meals and at bedtime) for glucose levels higher than 140 mg/dL; the higher the level, the more they got.

The basal-bolus regimen was better than sliding-scale regular insulin. At admission, the mean glucose values and hemoglobin A_1c values were similar in both groups, but the mean glucose level on therapy was significantly lower in the basal-bolus group than in the sliding-scale group, 166 ± 32 mg/dL vs 193 ± 54 mg/dL, P < .001). About two-thirds of the basal-bolus group achieved a blood glucose target of less than 140 mg/dL, compared with only about one-third of the sliding-scale group. The basal-bolus group received more insulin, a mean of 42 units per day vs 12.5 units per day in the sliding-scale group. Yet the incidence of hypoglycemia was 3% in both groups.

NPH plus regular vs detemir plus aspart: The DEAN trial

Several long-acting insulin analogues are available and have a longer duration of action than NPH. Similarly, several newer rapid-acting analogues act more rapidly than regular insulin. Do these pharmacokinetic advantages matter? And do they justify the higher costs of the newer agents?

In the randomized Insulin Detemir Versus NPH Insulin in Hospitalized Patients With Diabetes (DEAN) trial,¹⁶ we compared two regimens: detemir plus aspart in a basal-bolus regimen, and NPH plus regular insulin in two divided doses, two-thirds of the total daily dose in the morning before breakfast and one-third before dinner, both doses in a ratio of two-thirds NPH and one-third regular, mixed in the same syringe. We recruited 130 patients with type 2 diabetes mellitus who were on oral hypoglycemic agents or insulin therapy.

NPH plus regular was just as good as detemir plus aspart in improving glycemic control. Blood glucose levels fell during the first day of therapy and were similar in both groups throughout the trial, as measured before breakfast, lunch, and dinner and at bedtime. The mean total daily insulin dose was not significantly different between treatment groups: 56 ± 45 units in the basal-bolus detemir-aspart group and 45 ± 32 units in the NPH-regular group. However, the basal-bolus group received significantly more short-acting insulin: 27 ± 20 units a day of aspart vs 18 ± 14 units of regular.

Somewhat fewer patients in the NPH-regular group had episodes of hypoglycemia, although the difference between groups was not statistically significant.

In a univariate analysis of the RABBIT-2 and DEAN trials,¹⁷ factors that predicted a blood glucose level less than 60 mg/dL were older age, lower body weight, higher serum creatinine level, and previous insulin therapy. Factors that were not predictive were the hemoglobin A_1c level and the enrollment blood glucose level. Based on these data, we believe that to reduce the rate of hypoglycemia, lower insulin doses are needed in elderly patients and patients with renal impairment, and that if patients have been taking insulin before they come to the hospital, the dose should be cut back by about 25% while they are hospitalized.

Does better glucose control in surgical patients affect outcomes in patients undergoing general surgery? To find out, we performed a prospective, multicenter, randomized, open-label trial in general surgery patients not in the ICU.¹⁸ We recruited and randomized 211 patients with type 2 diabetes who were on diet therapy or oral hypoglycemic agents or insulin in low doses (< 0.4 U/kg/day).

Oral drugs were discontinued on admission, and patients were randomized to receive either a basal-bolus regimen of glargine plus glulisine or regular insulin on a sliding scale. The basal-bolus group got 0.5 U/kg/day, half of it as glargine once daily and half as glulisine before meals. The total daily dose was reduced to 0.3 U/kg/day in patients age 70 and older or who had a serum creatinine level of 2.0 mg/dL or higher.

The goal was to maintain fasting and pre-meal glucose concentrations between 100 and 140 mg/dL. The total daily dose was raised by 10% (mostly in the glargine dose) if the blood glucose level was in the range of 141 to 180 mg/dL, and by 20% if the glucose level was higher than 181 mg/dL. The dose was decreased by 10% for glucose levels between 70 and 99 mg/dL, was decreased by 20% if the glucose level was between 40 and 69, and was held if the glucose level was lower than 40 mg/dL. If a patient was not able to eat, insulin glulisine was held until meals were resumed.

The sliding-scale group received regular insulin four times a day for blood glucose levels higher than 140 mg/dL.

The primary outcomes measured were the difference between groups in mean daily blood glucose concentration and a composite of hospital complications including postoperative wound infection, pneumonia, respiratory failure, acute renal failure, and bacteremia. Secondary outcomes were differences between groups in mean fasting and pre-meal blood glucose, number of hypoglycemic episodes (blood glucose < 70 mg/dL), hyperglycemic episodes (blood glucose > 200 mg/dL), length of hospital stay, need for intensive care, and rate of complications including wound infection, pneumonia, acute renal failure, and death.

Blood glucose levels were significantly lower in the basal-bolus group through the first 7 days after randomization, as measured before breakfast, lunch, and dinner, and at bedtime, and then they converged.

More patients in the sliding-scale group had hospital complications, 26 vs 9, P = .003. On the other hand, more patients in the basal-bolus group had episodes of hypoglycemia: 24 (23%) vs 5 (4.7%) had episodes of less than 70 mg/dL (P < .001), 12 (12%) vs 2 (1.9%) had episodes of less than 60 mg/dL (P = .005), and 4 (3.8%) vs 0 had episodes of less than 40 mg/dL (P = .057). The mean total daily dose of insulin was 33.4 units in the basal-bolus group and 12.3 units in the sliding-scale group.

WHAT HAVE WE LEARNED?

Don’t use a sliding-scale regimen as a single agent in patients with diabetes. Glycemic control is better with a basal-bolus regimen than with a sliding-scale regimen, and a basal-bolus insulin regimen is preferred for most patients with hyperglycemia.

The old human insulins (ie, regular and NPH) are still good and improve glycemic control as well as the new basal insulin analogues (detemir and aspart) do.

Improved control may reduce the rate of hospital complications, according to preliminary evidence. More studies are under way.

One size does not fit all. Those who are elderly or who have impaired renal function should receive lower doses of insulin, eg, 0.3 U/kg/day instead of 0.5 U/kg/day. Those who are on insulin should have their dose decreased when they are admitted to the hospital. Perhaps lean patients with type 2 diabetes should also have a lower dose.

Most hospitalized patients with diabetes and elevated blood glucose values (or hyperglycemia) should receive subcutaneous insulin treatment with a basal-bolus regimen or a multidose combination of NPH plus regular insulin. Selected patients with severe insulin resistance and persistent hyperglycemia despite subcutaneous insulin may benefit from continuous intravenous insulin infusion.

Patients treated with insulin at home should continue to receive insulin therapy in the hospital. However, the insulin dosage should be reduced by about 25% to allow for lower food intake.

QUESTIONS FOR FURTHER STUDY

Should we modify the standard basal-bolus regimen?

In a typical basal-bolus regimen, patients get 50% of their total daily insulin dose in the form of a basal injection and 50% in the form of rapid-acting boluses before meals. However, for a variety of reasons, hospitalized patients do not eat very much. Thus, a 50-50 basal-bolus regimen may not be ideal for patients with poor oral intake.

In the Basal-PLUS trial, currently under way, we are comparing the safety and efficacy of a daily dose of basal insulin (glargine) plus correction doses of a rapid-acting insulin analogue (glulisine) on a sliding scale and a standard basal-bolus regimen in medical and surgical patients.

Does one glycemic target fit all patients?

Falciglia et al¹⁹ found an association between hyperglycemia and death in patients with unstable angina, arrhythmias, stroke, pneumonia, gastrointestinal bleeding, respiratory failure, sepsis, acute renal failure, and congestive heart failure. However, they found no such association in patients with chronic obstructive pulmonary disease, liver failure, diabetic ketoacidosis, gastrointestinal neoplasm, musculoskeletal disease, peripheral vascular disease with bypass, hip fracture, amputation due to peripheral vascular disease, or prostate surgery. Should patients in this second group be treated with a less-intensive insulin regimen?

What is the best regimen after hospital discharge?

We are conducting a prospective clinical trial to assess the impact of insulin after hospital discharge. Our current practice when a patient is discharged from the hospital is as follows:

• If the admission hemoglobin A_1c level is less than 7%, we restart the previous outpatient treatment regimen of oral antidiabetic agents, or insulin, or both.
• If the admission hemoglobin A_1c is between 7% and 9%, we restart the outpatient oral agents and continue glargine once daily at 50% to 80% of the hospital dose.
• If the hemoglobin A_1c level is higher than 9%, we discharge the patient on a basal-bolus regimen at the same dosage as in the hospital. As an alternative, we could restart the oral agents and add glargine once daily at 80% of the hospital dose.

A 55-year-old man presented after 3 weeks of sharp epigastric pain radiating to the right upper quadrant, fever, and generalized weakness. He had a history of significant heroin and cocaine abuse and was currently in a methadone maintenance program. He was not taking any nonsteroidal anti-inflammatory drugs.

His temperature was 38.7°C (101.7°F). He had tenderness in the right upper quadrant but no rebound tenderness.

Laboratory studies revealed an elevated white blood cell count of 14.9 × 10⁹/L (reference range 4.5–11.0) with 13% band cells, a normal lipase level, and normal liver function tests. Urine toxicology testing was positive for cocaine.

To investigate the cause of the abscess, we obtained an upper gastrointestinal radiographic series with oral contrast. This showed leaking of contrast from a perforated ulcer in the proximal duodenum (Figure 3).

TREATING PERFORATED ULCER AND ITS COMPLICATIONS

Perforated ulcers usually present with an acute abdomen and are life-threatening unless immediately recognized and treated. A more insidious presentation, as reported by Wong et al¹ and as seen in our patient, presents additional diagnostic challenges. Our patient’s presentation may have been insidious and relatively benign because the perforation was not a free perforation (ie, the bowel contents were not freely spilling into the abdominal cavity), and because the spillage and inflammation were confined to an abscess cavity. Also, he was taking methadone 60 mg per day, which may have further masked the symptoms.

Perforated duodenal ulcers are usually treated surgically. Nonoperative management—ie, fluid resuscitation, nasogastric tube aspiration, and intravenous antibiotics—has been described,² but the hemodynamic status and abdominal findings need to be continually monitored to detect any deterioration in the patient’s condition.

Initial management of the abscess with early percutaneous drainage and empiric intravenous antibiotics to cover enteric flora and anaerobes may suffice if there is no fistula.³ Also, in a series of 62 patients with subphrenic abscess managed by percutaneous drainage, Mueller et al⁴ found that this method was successful in most of the patients, noting that small-bowel perforation required the longest drainage period, generally more than 10 days.⁴

Helicobacter pylori infection and nonsteroidal anti-inflammatory drugs are responsible for the vast majority of duodenal ulcers. Serum H pylori antibody testing should be done, and if it is positive, treatment should be started. This patient did not have H pylori infection as an inpatient. He received metronidazole to cover the anaerobes and a proton pump inhibitor to treat the ulcer.

Although upper endoscopy was contraindicated in our patient because of his perforation, it was warranted for follow-up. Medical management with a proton pump inhibitor in high doses helped ulcer healing by reducing acid and gastric secretions. Octreotide had similar benefits, including reducing pancreatic and biliary secretion. This conservative management resulted in healing of the ulcer and early closure of the enteric fistula.

A 55-year-old man presented after 3 weeks of sharp epigastric pain radiating to the right upper quadrant, fever, and generalized weakness. He had a history of significant heroin and cocaine abuse and was currently in a methadone maintenance program. He was not taking any nonsteroidal anti-inflammatory drugs.

His temperature was 38.7°C (101.7°F). He had tenderness in the right upper quadrant but no rebound tenderness.

Laboratory studies revealed an elevated white blood cell count of 14.9 × 10⁹/L (reference range 4.5–11.0) with 13% band cells, a normal lipase level, and normal liver function tests. Urine toxicology testing was positive for cocaine.

To investigate the cause of the abscess, we obtained an upper gastrointestinal radiographic series with oral contrast. This showed leaking of contrast from a perforated ulcer in the proximal duodenum (Figure 3).

TREATING PERFORATED ULCER AND ITS COMPLICATIONS

Perforated ulcers usually present with an acute abdomen and are life-threatening unless immediately recognized and treated. A more insidious presentation, as reported by Wong et al¹ and as seen in our patient, presents additional diagnostic challenges. Our patient’s presentation may have been insidious and relatively benign because the perforation was not a free perforation (ie, the bowel contents were not freely spilling into the abdominal cavity), and because the spillage and inflammation were confined to an abscess cavity. Also, he was taking methadone 60 mg per day, which may have further masked the symptoms.

Perforated duodenal ulcers are usually treated surgically. Nonoperative management—ie, fluid resuscitation, nasogastric tube aspiration, and intravenous antibiotics—has been described,² but the hemodynamic status and abdominal findings need to be continually monitored to detect any deterioration in the patient’s condition.

Initial management of the abscess with early percutaneous drainage and empiric intravenous antibiotics to cover enteric flora and anaerobes may suffice if there is no fistula.³ Also, in a series of 62 patients with subphrenic abscess managed by percutaneous drainage, Mueller et al⁴ found that this method was successful in most of the patients, noting that small-bowel perforation required the longest drainage period, generally more than 10 days.⁴

Helicobacter pylori infection and nonsteroidal anti-inflammatory drugs are responsible for the vast majority of duodenal ulcers. Serum H pylori antibody testing should be done, and if it is positive, treatment should be started. This patient did not have H pylori infection as an inpatient. He received metronidazole to cover the anaerobes and a proton pump inhibitor to treat the ulcer.

Although upper endoscopy was contraindicated in our patient because of his perforation, it was warranted for follow-up. Medical management with a proton pump inhibitor in high doses helped ulcer healing by reducing acid and gastric secretions. Octreotide had similar benefits, including reducing pancreatic and biliary secretion. This conservative management resulted in healing of the ulcer and early closure of the enteric fistula.

A 55-year-old man presented after 3 weeks of sharp epigastric pain radiating to the right upper quadrant, fever, and generalized weakness. He had a history of significant heroin and cocaine abuse and was currently in a methadone maintenance program. He was not taking any nonsteroidal anti-inflammatory drugs.

His temperature was 38.7°C (101.7°F). He had tenderness in the right upper quadrant but no rebound tenderness.

Laboratory studies revealed an elevated white blood cell count of 14.9 × 10⁹/L (reference range 4.5–11.0) with 13% band cells, a normal lipase level, and normal liver function tests. Urine toxicology testing was positive for cocaine.

To investigate the cause of the abscess, we obtained an upper gastrointestinal radiographic series with oral contrast. This showed leaking of contrast from a perforated ulcer in the proximal duodenum (Figure 3).

TREATING PERFORATED ULCER AND ITS COMPLICATIONS

Perforated ulcers usually present with an acute abdomen and are life-threatening unless immediately recognized and treated. A more insidious presentation, as reported by Wong et al¹ and as seen in our patient, presents additional diagnostic challenges. Our patient’s presentation may have been insidious and relatively benign because the perforation was not a free perforation (ie, the bowel contents were not freely spilling into the abdominal cavity), and because the spillage and inflammation were confined to an abscess cavity. Also, he was taking methadone 60 mg per day, which may have further masked the symptoms.

Perforated duodenal ulcers are usually treated surgically. Nonoperative management—ie, fluid resuscitation, nasogastric tube aspiration, and intravenous antibiotics—has been described,² but the hemodynamic status and abdominal findings need to be continually monitored to detect any deterioration in the patient’s condition.

Initial management of the abscess with early percutaneous drainage and empiric intravenous antibiotics to cover enteric flora and anaerobes may suffice if there is no fistula.³ Also, in a series of 62 patients with subphrenic abscess managed by percutaneous drainage, Mueller et al⁴ found that this method was successful in most of the patients, noting that small-bowel perforation required the longest drainage period, generally more than 10 days.⁴

Helicobacter pylori infection and nonsteroidal anti-inflammatory drugs are responsible for the vast majority of duodenal ulcers. Serum H pylori antibody testing should be done, and if it is positive, treatment should be started. This patient did not have H pylori infection as an inpatient. He received metronidazole to cover the anaerobes and a proton pump inhibitor to treat the ulcer.

Although upper endoscopy was contraindicated in our patient because of his perforation, it was warranted for follow-up. Medical management with a proton pump inhibitor in high doses helped ulcer healing by reducing acid and gastric secretions. Octreotide had similar benefits, including reducing pancreatic and biliary secretion. This conservative management resulted in healing of the ulcer and early closure of the enteric fistula.

Once regarded as idiopathic, immune thrombocytopenia (ITP) is now understood to have a complex pathogenesis, involving the evolution of antibodies against multiple platelet antigens leading to reduced platelet survival as well as impaired platelet production. For this reason, multiple therapies with different mechanisms of action are available to treat ITP, though not all of them are effective for individual patients.

In this article, I discuss the pathogenesis, demographics, manifestations, diagnosis, and management of ITP.

THE NAME AND THE CUTOFF HAVE CHANGED

The term ITP formerly was used to refer to “idiopathic” or “immune” thrombocytopenic purpura. However, although not all aspects of the pathogenesis of ITP are understood, the disease can no longer be considered idiopathic. In addition, many patients do not have purpura at the time of diagnosis. Though the abbreviation “ITP” remains the same, it now refers to immune thrombocytopenia, which can be either primary or secondary.¹

ITP is defined as a platelet count of less than 100 × 10⁹/L (100,000/μL) with no evidence of leukopenia or anemia. This cutoff point is new: in the past, ITP was defined as a platelet count of less than 150 × 10⁹/L, which is the threshold for a normal platelet count in most laboratories.

The platelet threshold of 100 × 10⁹/L was based on a study by Stasi et al,² who followed 217 otherwise healthy people who had an incidental finding of mild thrombocytopenia (platelet count 100–150 × 10⁹/L). Within 6 months, the platelet count rose to more than 150 × 10⁹/L in 23, while three had either worsening thrombocytopenia or were diagnosed with other conditions. During long-term follow-up (median 64 months), 109 of the remaining 191 individuals remained stable, 13 developed counts greater than 150 × 10⁹/L, 12 developed ITP, 13 developed an autoimmune disorder, 18 developed other disorders, and 26 were lost to follow-up. The 10-year probability of developing ITP, defined as a platelet count persistently below 100 × 10⁹/L, was only 6.9%, indicating that the chances are small that a person with an isolated finding of mild, stable thrombocytopenia will develop ITP.

Categories of ITP

An international working group designated to standardize terminology has divided ITP into two major diagnostic categories.¹ The proportion of patients within each is not well established and varies by region and demographic characteristics.

Primary ITP accounts for the majority of cases in most studies; other conditions associated with thrombocytopenia are absent.

Secondary ITP can be due to infection with a number of agents, including hepatitis C virus (HCV), human immunodeficiency virus (HIV), and Helicobacter pylori. Other causes include underlying autoimmune and lymphoproliferative disorders such as systemic lupus erythematosus, Wiskott-Aldrich syndrome, chronic lymphocytic leukemia, antiphospholipid syndrome, and common variable immunodeficiency, as well as drugs such as quinine and trimethoprim-sulfamethoxazole.

Categories of ITP have also been established to facilitate management decisions, as follows:

Newly diagnosed ITP refers to ITP diagnosed within the preceding 3 months.

Persistent ITP refers to ITP diagnosed 3 to 12 months previously, and includes ITP in patients not reaching spontaneous remission and in those not maintaining a complete response off therapy. (When ITP spontaneously remits in adults, it usually does so within the first 12 months after the condition is diagnosed.)

Chronic ITP: Lasting for more than 12 months.

Severe ITP is defined by bleeding at presentation sufficient to mandate treatment, or new bleeding symptoms requiring additional therapeutic intervention with a different platelet-enhancing agent or an increased dosage of a current agent.

ITP IS COMMON IN OLDER ADULTS

We previously believed that ITP was a disorder that primarily affected women in their third and fourth decades. However, this was not borne out in recent epidemiologic studies, which have demonstrated that the highest age-specific incidence of ITP occurs in the elderly. This may potentially reflect the development of immune dysregulation as a consequence of aging. There is a female preponderance in the incidence of ITP throughout adulthood until around age 60, after which the overall incidence increases in both sexes, and the ratio of affected women to men is about equal.^3,4 Thus, even though thrombocytopenia in the elderly may reflect myelodysplasia in some individuals, ITP is much more common than previously appreciated.

Previous guidelines from the American Society of Hematology suggested that a bone marrow examination be strongly considered in patients over age 60 with suspected ITP. With the realization that ITP occurs more commonly in the elderly, it is apparent that bone marrow examination is not necessary in this group if there are no other cytopenias present and the physical examination and blood smear are consistent with ITP.

In children, ITP has a peak incidence between ages 5 and 6, and behaves differently from the adult syndrome. ITP in children usually follows an apparent viral infection and tends to be self-limited, with approximately 80% of cases resolving spontaneously within 6 months. In contrast, adult ITP usually develops into a chronic disease.

BLEEDING MAY NOT BE PRESENT AT DIAGNOSIS

ITP is now recognized as a diverse syndrome with a constellation of signs and symptoms.

Petechiae are pinpoint microvascular hemorrhages that do not blanch with pressure. This distinguishes them from small hemangiomas, which look similar but blanch transiently with pressure. Petechiae tend to occur on dependent areas, particularly the hands and feet, when the platelet count drops below approximately 15 × 10⁹/L.

Ecchymoses (dry purpura) appear as large bruises.

Mucosal bleeding (wet purpura) involves the oral mucosa. Particularly in children, wet purpura tends to be associated with systemic bleeding complications, involving the gastrointestinal tract for example. The incidence of intracranial hemorrhage, though very low, may also be increased in patients with wet purpura.

Other bleeding manifestations may include heavy menstrual bleeding, oral bleeding, and epistaxis.

Bleeding is generally but not entirely proportional to the platelet count. In a study of adults with newly diagnosed ITP and a platelet count of less than 50 × 10⁹/L,⁴ the presenting symptom was hemorrhage in 12% and purpura in 58%.⁴ Remarkably, 28% of cases were asymptomatic, with some patients remaining free of symptoms for years despite very low platelet counts. More than half of patients with a platelet count of 30 to 50 × 10⁹/L have no symptoms.^3,4

A PARADOXICAL RISK OF THROMBOSIS

Although ITP is primarily a bleeding disorder, it is paradoxically also associated with thrombosis. Sarpatwari et al,⁵ in a study in the United Kingdom, found that the 4-year incidence of thromboembolic events was about 1.3 times higher in patients with ITP than in matched controls.

The reason for the increased risk of thrombosis is not clear. It is possible that in some patients, antiphospholipid antibodies may contribute to the development of thrombosis, although this has not been confirmed in all studies.

A DIAGNOSIS OF EXCLUSION

The evaluation of any patient suspected of having ITP should include the following:

• Personal history, with special attention to drugs and to medical conditions that could cause thrombocytopenia.
• Family history. ITP may occasionally be mistaken for an inherited cause of thrombocytopenia. The presence of the latter can often be confirmed by review of the peripheral blood film of the patient as well as other family members with thrombocytopenia. ITP is generally not considered to be an inherited disorder, although some HLA alleles may be more prevalent in ITP patients.
• Physical examination, with special attention to lymphadenopathy or splenomegaly, which may suggest an underlying malignancy such as a lymphoproliferative disorder. In general, patients with ITP have a normal physical examination, except for signs of bleeding or bruising in some.
• Laboratory tests, including a complete blood cell count, blood smear, reticulocyte count, Rh typing, and direct antiglobulin (Coombs) test.

In ITP, the peripheral blood smear should appear normal except for the presence of thrombocytopenia, although platelets may be mildly enlarged in some individuals. Red cell and leukocyte morphology is normal. It is important to exclude the presence of schistocytes (red cell fragments) and nucleated red blood cells, which often indicate a microangiopathic hemolytic anemia caused by disorders such as thrombotic thrombocytopenic purpura.

International guidelines suggest that testing for reduced immunoglobulin levels (as seen in common variable hypogammaglobulinemia) and HIV, HCV, and H pylori infections should also be considered. Coincident HCV infection is particularly high in some regions. Other cytopenias or abnormalities in the history or physical examination may prompt bone marrow examination. Testing for antiphospholipid antibodies, antinuclear antibodies, parvovirus, and cytomegalovirus may also be indicated in specific individuals. Testing for antiplatelet antibodies is not commonly performed in the current era because of its relatively low sensitivity and specificity.

Ultimately, the diagnosis of ITP is clinical, however, and cannot be established by any specific laboratory assay. Perhaps the best diagnostic study is assessment of the patient’s response to ITP therapy.

ITP INVOLVES ACCELERATED PLATELET DESTRUCTION

In 1951, William Harrington, a fellow at Washington University, infused blood from a patient with ITP into himself and, subsequently, into normal volunteers.⁶ The majority of recipients demonstrated significant reductions in the platelet count, sometimes severe. This fascinating and bold experiment provided the first demonstration that ITP was caused by a factor that circulates in blood. What is often not emphasized, however, is that some recipients did not develop thrombocytopenia, suggesting an alternative mechanism.

Later, Luiken et al⁷ and Hirschman and Shulman⁸ demonstrated that the transmissible agent in the blood was immunoglobulin, primarily immunoglobulin G (IgG). We now understand that much of the pathogenesis of ITP is caused by antibodies against platelet glycoproteins, most commonly platelet glycoprotein IIb/IIIa, the platelet fibrinogen receptor. Most patients, especially those with chronic ITP, also have antibodies against other platelet glycoproteins, including glycoprotein Ib/IX (the receptor for von Willebrand factor), and glycoprotein Ia/IIa, a collagen receptor. It is commonly believed that ITP may begin with antibodies against a single glycoprotein, which leads to accelerated clearance of antibody-coated platelets in the spleen. Degradation of cleared platelets by splenic macrophages leads to the release and subsequent presentation of antigenic peptides from proteolyzed platelet components, including glycoproteins, on the macrophage or dendritic cell. This may lead to recruitment and activation of specific T cells that in turn interact with and stimulate B cells to produce new antibodies against the platelet-derived peptides. This phenomenon, known as epitope spreading, may be responsible for the fact that most patients with long-standing, chronic ITP develop autoantibodies against multiple platelet glycoprotein targets.⁹

Several agents used in the treatment of ITP may work by impairing clearance of antibody-coated platelets by the reticuloendothelial system. One of many potential mechanisms underlying the therapeutic efficacy of intravenous immunoglobulin (IVIG) may be its ability to interact with a specific type of Fc gamma receptor, Fc gamma RIIb. IVIG therapy stimulates increased expression of this receptor, which in turn may impair the function of other “activating” Fc gamma receptors responsible for platelet clearance.^10,11

ITP associated with infection may arise due to molecular mimicry. HCV, HIV, and H pylori contain amino acid sequences that may have structural similarity to regions within platelet glycoproteins. Thus, antibodies directed against the pathogen may cross-react with the glycoprotein, leading to thrombocytopenia.^12–15

HCV has been found in up to one-third of cases of ITP in some centers.^16–20H pylori-associated ITP is very common in some regions, particularly in Japan, and may often resolve after eradication of the infection. However, in the United States, eradication of H pylori generally does not improve the course of ITP. This may reflect antigen mimicry, in particular the fact that different cagA proteins are expressed by different strains of H pylori in certain regions of the world.

Our understanding of the immunologic basis of ITP has greatly expanded over the last decade. Although it has long been known that B cells produce autoantibodies, T cells have more recently been shown to play a critical role in regulating B-cell-mediated autoantibody production in ITP. In some situations, T cells may directly lyse platelets, or suppress megakaryopoiesis. This may explain why some patients who do not respond to standard B-cell-targeted therapy may respond to cyclosporine or other T-cell-directed agents.

ANOTHER MECHANISM OF ITP: REDUCED PLATELET PRODUCTION

In addition to accelerated platelet destruction, ITP is also associated with decreased platelet production by megakaryocytes in the bone marrow.^21–25

Increased platelet destruction and reduced platelet production are likely two ends of a spectrum of ITP, and most patients likely have some degree of both processes. This concept helps explain why different drug strategies are more effective in some patients than in others.

ARE THE RISKS OF THERAPY JUSTIFIED?

It is important to understand the natural history of ITP to determine whether the risks of therapy are justified.

A 2001 study from the Netherlands²⁶ followed 134 patients with primary ITP for 10 years: 90% had taken prednisone or had had a splenectomy. Within 2 years, 85% of these patients had platelet counts above 30 × 10⁹/L off therapy. Although this group likely experienced more bleeding and bruising than the general population, the mortality rate was not increased. Another 6% also achieved a platelet count above 30 × 10⁹/L, but required chronic maintenance therapy (usually steroids) to do so. This group led a nearly normal life but had more hospitalizations. The remaining 9% of patients had refractory ITP, with platelet counts remaining below 30 × 10⁹/L despite therapy. This group had a death rate 4.2 times that of age-matched controls. About half died of bleeding and the others died of opportunistic infections to which they were susceptible because of long-term steroid therapy.

This study was influential in the general opinion that 30 × 10⁹/L is a reasonable cutoff for treating ITP. An international consensus report states that treatment is rarely indicated in patients with platelet counts above 50 × 10⁹/L in the absence of bleeding due to platelet dysfunction or other hemostatic defect, trauma, or surgery.²⁷ Although this number is not supported by evidence-based data, it is a reasonable threshold endorsed by an international working group.²⁷ Individual factors must be weighed heavily: for example, an athlete involved in contact sports requires a higher platelet count in order to play safely.

FIRST-LINE THERAPIES

First-line therapies for ITP include corticosteroids, IVIG, and anti-Rho(D) immune globulin (WinRho).²⁷

Corticosteroids are standard therapy

Corticosteroids can be given in one of two ways:

Standard prednisone therapy, ie, 1 to 2 mg/kg per day, is given until a response is seen, and then tapered. Some maintain therapy for an additional week before tapering. There are no guidelines on how to taper: some decrease the dosage by 50% per week, although many recommend going more slowly, particularly at the lower range of dosing.

Up to 85% of patients achieve a clinical response, usually within 7 to 10 days, with platelet counts peaking in 2 to 4 weeks. Unfortunately, only about 15% of patients maintain the response over the subsequent 6 to 12 months. Restarting prednisone often initiates a vicious circle and makes patients vulnerable to steroid toxicities.

“Pulse” dexamethasone therapy consists of 40 mg per day for 4 days for one to three cycles. (Dexamethasone 1 mg is equivalent to about 10 mg of prednisone.)

Pulse dexamethasone therapy as an initial approach to ITP has been developed during the past decade and has been used primarily in research studies. This regimen evolved from studies of patients with multiple myelomas and has the potential to induce more durable remissions in some patients with newly diagnosed ITP.²⁹ However, high-dose corticosteroids may be associated with increased toxicity, at least in the short term, and should be used cautiously. A study to address the role of high-dose vs standard-dose steroid therapy has recently been opened under the guidance of the Transfusion Medicine–Hemostasis Clinical Trials Network of the National Heart, Lung, and Blood Institute.

Immunoglobulin is useful for very low platelet counts and bleeding

Another primary therapy for ITP is IVIG 0.5 to 2.0 g/kg over 2 to 5 days. Its efficacy is similar to that of prednisone: about 65% of patients achieve a platelet count above 100 × 10⁹/L, and 85% achieve 50 × 10⁹/L. However, most responses are transient, and a significant minority of cases become refractory to IVIG after repeated infusions.

IVIG is associated with numerous adverse effects, including thrombosis, renal insufficiency, headache, and anaphylaxis in IgA-deficient patients. It also converts the direct antiglobulin test to positive. IVIG is expensive, is inconvenient to administer, and may require lengthy infusions depending on the formulation.

Although IVIG is not a good long-term therapy, it can help raise the platelet count relatively quickly in patients who present with severe thrombocytopenia accompanied by bleeding. Such patients should be treated with high-dose steroids, IVIG, and platelet transfusions. IVIG may also be useful to increase platelet counts prior to interventional procedures.

Intravenous anti-Rho(D)

Anti-Rho(D) is an alternative to IVIG in patients who are Rho(D)-positive and have an intact spleen. Anti-Rho(D) binds to Rh-positive red blood cells, causing them to be cleared in the reticuloendothelial system and blocking the clearance of antibody-coated platelets. In effect, red cells are sacrificed to save platelets, but because there are many more red cells than platelets, the benefits usually outweigh the risks.

The initial dose is 50 μg/kg given intravenously over 2 to 5 minutes. Anti-Rho(D) should not be given to patients whose hemoglobin level is less than 10 g/dL or who have compromised bone marrow function. It is ineffective in Rh-negative patients or those who have undergone splenectomy.

Accelerated hemolysis is a rare but severe possible adverse event associated with this therapy, occurring in slightly more than 1 in 1,000 infusions. About 1 out of every 20,000 patients develops disseminated intravascular coagulation.³⁰ Its cause is poorly understood, and it is probably an accelerated extravascular rather than an intravascular event. The US Food and Drug Administration has recently issued a black-box warning cautioning that patients who receive anti-Rho(D) should remain in a health care setting for 8 hours after treatment, although most cases of accelerated hemolysis occur within 4 hours. Moreover, it is possible that many of these cases can be avoided by appropriate patient selection.

SECOND-LINE THERAPIES

Second-line therapies, as designated by the international working group, include azathioprine (Imuran), cyclosporine A, cyclophosphamide (Cytoxan), danazol (Danocrine), dapsone, mycophenolate mofetil (CellCept), rituximab (Rituxan), splenectomy, thrombopoietin receptor agonists, and vinca alkaloids.²⁷ Only the most commonly used therapies will be briefly discussed below.

The evidence for efficacy of the cytotoxic agents, ie, cyclophosphamide, the vinca alkaloids, and azathioprine, comes from small, nonrandomized studies.³¹ Although these agents are useful in some patients, they may be associated with significant toxicities, and they are used less commonly than in the past.

Splenectomy has a high success rate

Splenectomy probably offers the best response of any treatment for ITP. About 80% of patients with ITP respond rapidly—often within 1 week. Of those, 15% relapse within the first year, and after 10 years, two-thirds remain in remission.^32,33

Because there is no well-accepted predictor of a short- or long-term response to splenectomy, and because more medical options are currently available, the use of splenectomy has declined over the past 10 years. Nevertheless, splenectomy remains a useful option for therapy of ITP.

Whether and which second-line drugs should be tried before splenectomy is still controversial and should be determined on a case-by-case basis. Some patients are poor candidates for splenectomy because of comorbidities. If possible, splenectomy should be delayed until at least a year after diagnosis to allow an opportunity for spontaneous remission.

Splenectomy increases the risk of subsequent infection by encapsulated organisms, and patients should be immunized with pneumococcal, Haemophilus influenzae type B, and meningococcal vaccines, preferably at least 3 weeks before the spleen is removed.

Splenectomy is associated with pulmonary hypertension and thrombosis, primarily in patients who have had their spleens removed because of accelerated red cell destruction. Whether these risks are applicable to patients with ITP is unknown, but if so they are probably much lower than in patients with red cell disorders.

Rituximab

Rituximab, a humanized monoclonal antibody against the CD20 antigen on B lymphocytes, was developed for treating lymphoma. However, it has been found to have significant activity in a number of immunohematologic disorders. Although many studies of rituximab for ITP have been published,^34–38 it has never been tested in a randomized controlled study. The response rate is generally around 50%, and it is effective in patients with or without a spleen.

In one study,³⁹ 44 (32%) of 137 patients with chronic ITP who were given rituximab achieved a complete remission that was sustained 1 year. After more than 5 years, 63% of this group (ie, approximately 20% of the original group) were still in remission.

Potential drawbacks of rituximab include its expense as well as the risk of first-infusion reactions, which may be severe or, rarely, fatal. Rituxan has also been associated with rare cases of progressive multifocal leukoencephalopathy, usually in patients heavily treated with other immunosuppressive agents; however, very rare cases of progressive multifocal leukoencephalopathy have been reported in patients with ITP who received rituximab.

Thrombopoietin receptor agonists increase platelet production

Thrombopoietin receptor agonists are approved for patients with chronic ITP who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy. Rather than inhibit platelet destruction, as do all the other ITP therapies, they enhance platelet production.

Diseases involving bone marrow failure that also involve a low platelet count tend to be associated with very high levels of serum thrombopoietin, which is produced constitutively by the liver. In ITP, thrombopoeitin levels tend to be close to normal and not significantly elevated, most likely because of accelerated thrombopoietin clearance when bound to antibody-coated platelets.⁴⁰ This provides a rationale for the use of thrombopoietic agents in the treatment of ITP.

Earlier-generation thrombopoietic drugs had significant amino acid homology with natural thrombopoietin, and some patients who were treated with these drugs developed antibodies against them that cross-reacted with endogenous thrombopoietin. In some cases, this led to severe, refractory thrombocytopenia. Because the newer thrombopoietic agents have no sequence homology to natural thrombopoietin, antibody production has not been a significant problem.

Two drugs in this class are currently available for treating ITP:

Romiplostim (Nplate) is a peptibody (comprising an IgG Fc region and four peptidometic regions that interact with the thrombopoietin receptor, c-mpl) that is given subcutaneously once a week.

Romiplostim performed well in several phase I clinical trials.⁴¹ In a 24-week phase III trial that compared romiplostim against placebo in patients with ITP that had been refractory to other primary treatments, 79% of splenectomized patients and 88% of nonsplenectomized patients had an overall response (defined as a platelet count > 50 × 10⁹/L for 4 weeks during the study period), and 38% of splenectomized patients and 61% of nonsplenectomized patients had a durable response (platelet count > 50 × 10⁹/L for 6 of the last 8 weeks of the study).⁴²

In an ongoing long-term extension study of romiplostim that allows dose adjustments to maintain a platelet count between 50 and 200 × 10⁹/L, romiplostim dosage and efficacy have remained stable over 5 years.^42,43

Eltrombopag (Promacta) is a nonpeptide small-molecule c-mpl agonist that is taken orally once daily. A recent randomized, placebo-controlled study in patients with ITP refractory to other primary treatments found that eltrombopag was highly effective in raising platelet counts over the 6 months of the study.⁴⁴ Like romiplostim, it was effective in both splenectomized and nonsplenectomized patients.

Although eltrombopag has not been studied for as long as romiplostim, data over 3 years indicate that increased platelet counts are maintained without the emergence of drug resistance or cumulative toxicity.⁴⁵

Several other drugs in this class are currently in development.

Adverse effects of thrombopoietic agents

Thrombopoietic agents have several associated toxicities:

Rebound thrombocytopenia occurs in up to 10% of patients following treatment with either romiplostim or eltrombopag. Rebound thrombocytopenia is defined as a fall in the platelet count that occurs following discontinuation of a thrombopoietic agent that may result in more severe thrombocytopenia, transiently, than before the drug was initiated. Thus, the platelet count must be closely monitored after treatment with these drugs is discontinued.

Bone marrow fibrosis, which consists primarily of increased marrow reticulin content, occurs in less than 10% of treated patients, and all patients on therapy must be monitored for this potential complication by close examination of the peripheral blood film on a frequent basis. Appearance of abnormalities such as teardrop cells or nucleated red blood cells in the peripheral blood smear should prompt at least temporary discontinuation of the drug and consideration of bone marrow examination. There have been no cases of actual irreversible myelofibrosis in which thrombopoietic agents have been clearly implicated in causation. Interestingly, some reports suggest that increased reticulin is a common finding in marrow from ITP patients who have not been treated with thrombopoietic agents.⁴⁶

Thrombosis must be considered a risk of treatment with thrombopoietic agents, which increase the platelet count in a disease that may already be thrombogenic. However, in the placebo-controlled studies, a significantly increased incidence of thrombosis was not observed in the treatment arms vs placebo. Moreover, even in treated patients who developed thrombosis, there was no clear association with the degree of elevation in the platelet count. Nevertheless, thrombopoietic agents should be used according to the manufacturer’s recommendations, to increase the platelet count to a range of 50 to 200 × 10⁹/L, but not to exceed that.

Progression of hematologic malignancies. Thrombopoietin receptor agonists act not only on megakaryocytes but also on stem cells and other hematopoieic precursors. Although trials for treating patients with hematologic malignancies and bone marrow failure with thrombopoietic agents are ongoing, there is concern that they could worsen certain hematologic malignancies, though there are no controlled data to either support or refute this concern at present. At this time, these drugs are approved only for ITP and should not be used for other conditions.

Hepatotoxicity has been seen with eltrombopag, but it is usually reversible and may resolve with continued therapy. Nevertheless, close monitoring for this potential complication is indicated.

Once regarded as idiopathic, immune thrombocytopenia (ITP) is now understood to have a complex pathogenesis, involving the evolution of antibodies against multiple platelet antigens leading to reduced platelet survival as well as impaired platelet production. For this reason, multiple therapies with different mechanisms of action are available to treat ITP, though not all of them are effective for individual patients.

In this article, I discuss the pathogenesis, demographics, manifestations, diagnosis, and management of ITP.

THE NAME AND THE CUTOFF HAVE CHANGED

The term ITP formerly was used to refer to “idiopathic” or “immune” thrombocytopenic purpura. However, although not all aspects of the pathogenesis of ITP are understood, the disease can no longer be considered idiopathic. In addition, many patients do not have purpura at the time of diagnosis. Though the abbreviation “ITP” remains the same, it now refers to immune thrombocytopenia, which can be either primary or secondary.¹

ITP is defined as a platelet count of less than 100 × 10⁹/L (100,000/μL) with no evidence of leukopenia or anemia. This cutoff point is new: in the past, ITP was defined as a platelet count of less than 150 × 10⁹/L, which is the threshold for a normal platelet count in most laboratories.

The platelet threshold of 100 × 10⁹/L was based on a study by Stasi et al,² who followed 217 otherwise healthy people who had an incidental finding of mild thrombocytopenia (platelet count 100–150 × 10⁹/L). Within 6 months, the platelet count rose to more than 150 × 10⁹/L in 23, while three had either worsening thrombocytopenia or were diagnosed with other conditions. During long-term follow-up (median 64 months), 109 of the remaining 191 individuals remained stable, 13 developed counts greater than 150 × 10⁹/L, 12 developed ITP, 13 developed an autoimmune disorder, 18 developed other disorders, and 26 were lost to follow-up. The 10-year probability of developing ITP, defined as a platelet count persistently below 100 × 10⁹/L, was only 6.9%, indicating that the chances are small that a person with an isolated finding of mild, stable thrombocytopenia will develop ITP.

Categories of ITP

An international working group designated to standardize terminology has divided ITP into two major diagnostic categories.¹ The proportion of patients within each is not well established and varies by region and demographic characteristics.

Primary ITP accounts for the majority of cases in most studies; other conditions associated with thrombocytopenia are absent.

Secondary ITP can be due to infection with a number of agents, including hepatitis C virus (HCV), human immunodeficiency virus (HIV), and Helicobacter pylori. Other causes include underlying autoimmune and lymphoproliferative disorders such as systemic lupus erythematosus, Wiskott-Aldrich syndrome, chronic lymphocytic leukemia, antiphospholipid syndrome, and common variable immunodeficiency, as well as drugs such as quinine and trimethoprim-sulfamethoxazole.

Categories of ITP have also been established to facilitate management decisions, as follows:

Newly diagnosed ITP refers to ITP diagnosed within the preceding 3 months.

Persistent ITP refers to ITP diagnosed 3 to 12 months previously, and includes ITP in patients not reaching spontaneous remission and in those not maintaining a complete response off therapy. (When ITP spontaneously remits in adults, it usually does so within the first 12 months after the condition is diagnosed.)

Chronic ITP: Lasting for more than 12 months.

Severe ITP is defined by bleeding at presentation sufficient to mandate treatment, or new bleeding symptoms requiring additional therapeutic intervention with a different platelet-enhancing agent or an increased dosage of a current agent.

ITP IS COMMON IN OLDER ADULTS

We previously believed that ITP was a disorder that primarily affected women in their third and fourth decades. However, this was not borne out in recent epidemiologic studies, which have demonstrated that the highest age-specific incidence of ITP occurs in the elderly. This may potentially reflect the development of immune dysregulation as a consequence of aging. There is a female preponderance in the incidence of ITP throughout adulthood until around age 60, after which the overall incidence increases in both sexes, and the ratio of affected women to men is about equal.^3,4 Thus, even though thrombocytopenia in the elderly may reflect myelodysplasia in some individuals, ITP is much more common than previously appreciated.

Previous guidelines from the American Society of Hematology suggested that a bone marrow examination be strongly considered in patients over age 60 with suspected ITP. With the realization that ITP occurs more commonly in the elderly, it is apparent that bone marrow examination is not necessary in this group if there are no other cytopenias present and the physical examination and blood smear are consistent with ITP.

In children, ITP has a peak incidence between ages 5 and 6, and behaves differently from the adult syndrome. ITP in children usually follows an apparent viral infection and tends to be self-limited, with approximately 80% of cases resolving spontaneously within 6 months. In contrast, adult ITP usually develops into a chronic disease.

BLEEDING MAY NOT BE PRESENT AT DIAGNOSIS

ITP is now recognized as a diverse syndrome with a constellation of signs and symptoms.

Petechiae are pinpoint microvascular hemorrhages that do not blanch with pressure. This distinguishes them from small hemangiomas, which look similar but blanch transiently with pressure. Petechiae tend to occur on dependent areas, particularly the hands and feet, when the platelet count drops below approximately 15 × 10⁹/L.

Ecchymoses (dry purpura) appear as large bruises.

Mucosal bleeding (wet purpura) involves the oral mucosa. Particularly in children, wet purpura tends to be associated with systemic bleeding complications, involving the gastrointestinal tract for example. The incidence of intracranial hemorrhage, though very low, may also be increased in patients with wet purpura.

Other bleeding manifestations may include heavy menstrual bleeding, oral bleeding, and epistaxis.

Bleeding is generally but not entirely proportional to the platelet count. In a study of adults with newly diagnosed ITP and a platelet count of less than 50 × 10⁹/L,⁴ the presenting symptom was hemorrhage in 12% and purpura in 58%.⁴ Remarkably, 28% of cases were asymptomatic, with some patients remaining free of symptoms for years despite very low platelet counts. More than half of patients with a platelet count of 30 to 50 × 10⁹/L have no symptoms.^3,4

A PARADOXICAL RISK OF THROMBOSIS

Although ITP is primarily a bleeding disorder, it is paradoxically also associated with thrombosis. Sarpatwari et al,⁵ in a study in the United Kingdom, found that the 4-year incidence of thromboembolic events was about 1.3 times higher in patients with ITP than in matched controls.

The reason for the increased risk of thrombosis is not clear. It is possible that in some patients, antiphospholipid antibodies may contribute to the development of thrombosis, although this has not been confirmed in all studies.

A DIAGNOSIS OF EXCLUSION

The evaluation of any patient suspected of having ITP should include the following:

• Personal history, with special attention to drugs and to medical conditions that could cause thrombocytopenia.
• Family history. ITP may occasionally be mistaken for an inherited cause of thrombocytopenia. The presence of the latter can often be confirmed by review of the peripheral blood film of the patient as well as other family members with thrombocytopenia. ITP is generally not considered to be an inherited disorder, although some HLA alleles may be more prevalent in ITP patients.
• Physical examination, with special attention to lymphadenopathy or splenomegaly, which may suggest an underlying malignancy such as a lymphoproliferative disorder. In general, patients with ITP have a normal physical examination, except for signs of bleeding or bruising in some.
• Laboratory tests, including a complete blood cell count, blood smear, reticulocyte count, Rh typing, and direct antiglobulin (Coombs) test.

In ITP, the peripheral blood smear should appear normal except for the presence of thrombocytopenia, although platelets may be mildly enlarged in some individuals. Red cell and leukocyte morphology is normal. It is important to exclude the presence of schistocytes (red cell fragments) and nucleated red blood cells, which often indicate a microangiopathic hemolytic anemia caused by disorders such as thrombotic thrombocytopenic purpura.

International guidelines suggest that testing for reduced immunoglobulin levels (as seen in common variable hypogammaglobulinemia) and HIV, HCV, and H pylori infections should also be considered. Coincident HCV infection is particularly high in some regions. Other cytopenias or abnormalities in the history or physical examination may prompt bone marrow examination. Testing for antiphospholipid antibodies, antinuclear antibodies, parvovirus, and cytomegalovirus may also be indicated in specific individuals. Testing for antiplatelet antibodies is not commonly performed in the current era because of its relatively low sensitivity and specificity.

Ultimately, the diagnosis of ITP is clinical, however, and cannot be established by any specific laboratory assay. Perhaps the best diagnostic study is assessment of the patient’s response to ITP therapy.

ITP INVOLVES ACCELERATED PLATELET DESTRUCTION

In 1951, William Harrington, a fellow at Washington University, infused blood from a patient with ITP into himself and, subsequently, into normal volunteers.⁶ The majority of recipients demonstrated significant reductions in the platelet count, sometimes severe. This fascinating and bold experiment provided the first demonstration that ITP was caused by a factor that circulates in blood. What is often not emphasized, however, is that some recipients did not develop thrombocytopenia, suggesting an alternative mechanism.

Later, Luiken et al⁷ and Hirschman and Shulman⁸ demonstrated that the transmissible agent in the blood was immunoglobulin, primarily immunoglobulin G (IgG). We now understand that much of the pathogenesis of ITP is caused by antibodies against platelet glycoproteins, most commonly platelet glycoprotein IIb/IIIa, the platelet fibrinogen receptor. Most patients, especially those with chronic ITP, also have antibodies against other platelet glycoproteins, including glycoprotein Ib/IX (the receptor for von Willebrand factor), and glycoprotein Ia/IIa, a collagen receptor. It is commonly believed that ITP may begin with antibodies against a single glycoprotein, which leads to accelerated clearance of antibody-coated platelets in the spleen. Degradation of cleared platelets by splenic macrophages leads to the release and subsequent presentation of antigenic peptides from proteolyzed platelet components, including glycoproteins, on the macrophage or dendritic cell. This may lead to recruitment and activation of specific T cells that in turn interact with and stimulate B cells to produce new antibodies against the platelet-derived peptides. This phenomenon, known as epitope spreading, may be responsible for the fact that most patients with long-standing, chronic ITP develop autoantibodies against multiple platelet glycoprotein targets.⁹

Several agents used in the treatment of ITP may work by impairing clearance of antibody-coated platelets by the reticuloendothelial system. One of many potential mechanisms underlying the therapeutic efficacy of intravenous immunoglobulin (IVIG) may be its ability to interact with a specific type of Fc gamma receptor, Fc gamma RIIb. IVIG therapy stimulates increased expression of this receptor, which in turn may impair the function of other “activating” Fc gamma receptors responsible for platelet clearance.^10,11

ITP associated with infection may arise due to molecular mimicry. HCV, HIV, and H pylori contain amino acid sequences that may have structural similarity to regions within platelet glycoproteins. Thus, antibodies directed against the pathogen may cross-react with the glycoprotein, leading to thrombocytopenia.^12–15

HCV has been found in up to one-third of cases of ITP in some centers.^16–20H pylori-associated ITP is very common in some regions, particularly in Japan, and may often resolve after eradication of the infection. However, in the United States, eradication of H pylori generally does not improve the course of ITP. This may reflect antigen mimicry, in particular the fact that different cagA proteins are expressed by different strains of H pylori in certain regions of the world.

Our understanding of the immunologic basis of ITP has greatly expanded over the last decade. Although it has long been known that B cells produce autoantibodies, T cells have more recently been shown to play a critical role in regulating B-cell-mediated autoantibody production in ITP. In some situations, T cells may directly lyse platelets, or suppress megakaryopoiesis. This may explain why some patients who do not respond to standard B-cell-targeted therapy may respond to cyclosporine or other T-cell-directed agents.

ANOTHER MECHANISM OF ITP: REDUCED PLATELET PRODUCTION

In addition to accelerated platelet destruction, ITP is also associated with decreased platelet production by megakaryocytes in the bone marrow.^21–25

Increased platelet destruction and reduced platelet production are likely two ends of a spectrum of ITP, and most patients likely have some degree of both processes. This concept helps explain why different drug strategies are more effective in some patients than in others.

ARE THE RISKS OF THERAPY JUSTIFIED?

It is important to understand the natural history of ITP to determine whether the risks of therapy are justified.

A 2001 study from the Netherlands²⁶ followed 134 patients with primary ITP for 10 years: 90% had taken prednisone or had had a splenectomy. Within 2 years, 85% of these patients had platelet counts above 30 × 10⁹/L off therapy. Although this group likely experienced more bleeding and bruising than the general population, the mortality rate was not increased. Another 6% also achieved a platelet count above 30 × 10⁹/L, but required chronic maintenance therapy (usually steroids) to do so. This group led a nearly normal life but had more hospitalizations. The remaining 9% of patients had refractory ITP, with platelet counts remaining below 30 × 10⁹/L despite therapy. This group had a death rate 4.2 times that of age-matched controls. About half died of bleeding and the others died of opportunistic infections to which they were susceptible because of long-term steroid therapy.

This study was influential in the general opinion that 30 × 10⁹/L is a reasonable cutoff for treating ITP. An international consensus report states that treatment is rarely indicated in patients with platelet counts above 50 × 10⁹/L in the absence of bleeding due to platelet dysfunction or other hemostatic defect, trauma, or surgery.²⁷ Although this number is not supported by evidence-based data, it is a reasonable threshold endorsed by an international working group.²⁷ Individual factors must be weighed heavily: for example, an athlete involved in contact sports requires a higher platelet count in order to play safely.

FIRST-LINE THERAPIES

First-line therapies for ITP include corticosteroids, IVIG, and anti-Rho(D) immune globulin (WinRho).²⁷

Corticosteroids are standard therapy

Corticosteroids can be given in one of two ways:

Standard prednisone therapy, ie, 1 to 2 mg/kg per day, is given until a response is seen, and then tapered. Some maintain therapy for an additional week before tapering. There are no guidelines on how to taper: some decrease the dosage by 50% per week, although many recommend going more slowly, particularly at the lower range of dosing.

Up to 85% of patients achieve a clinical response, usually within 7 to 10 days, with platelet counts peaking in 2 to 4 weeks. Unfortunately, only about 15% of patients maintain the response over the subsequent 6 to 12 months. Restarting prednisone often initiates a vicious circle and makes patients vulnerable to steroid toxicities.

“Pulse” dexamethasone therapy consists of 40 mg per day for 4 days for one to three cycles. (Dexamethasone 1 mg is equivalent to about 10 mg of prednisone.)

Pulse dexamethasone therapy as an initial approach to ITP has been developed during the past decade and has been used primarily in research studies. This regimen evolved from studies of patients with multiple myelomas and has the potential to induce more durable remissions in some patients with newly diagnosed ITP.²⁹ However, high-dose corticosteroids may be associated with increased toxicity, at least in the short term, and should be used cautiously. A study to address the role of high-dose vs standard-dose steroid therapy has recently been opened under the guidance of the Transfusion Medicine–Hemostasis Clinical Trials Network of the National Heart, Lung, and Blood Institute.

Immunoglobulin is useful for very low platelet counts and bleeding

Another primary therapy for ITP is IVIG 0.5 to 2.0 g/kg over 2 to 5 days. Its efficacy is similar to that of prednisone: about 65% of patients achieve a platelet count above 100 × 10⁹/L, and 85% achieve 50 × 10⁹/L. However, most responses are transient, and a significant minority of cases become refractory to IVIG after repeated infusions.

IVIG is associated with numerous adverse effects, including thrombosis, renal insufficiency, headache, and anaphylaxis in IgA-deficient patients. It also converts the direct antiglobulin test to positive. IVIG is expensive, is inconvenient to administer, and may require lengthy infusions depending on the formulation.

Although IVIG is not a good long-term therapy, it can help raise the platelet count relatively quickly in patients who present with severe thrombocytopenia accompanied by bleeding. Such patients should be treated with high-dose steroids, IVIG, and platelet transfusions. IVIG may also be useful to increase platelet counts prior to interventional procedures.

Intravenous anti-Rho(D)

Anti-Rho(D) is an alternative to IVIG in patients who are Rho(D)-positive and have an intact spleen. Anti-Rho(D) binds to Rh-positive red blood cells, causing them to be cleared in the reticuloendothelial system and blocking the clearance of antibody-coated platelets. In effect, red cells are sacrificed to save platelets, but because there are many more red cells than platelets, the benefits usually outweigh the risks.

The initial dose is 50 μg/kg given intravenously over 2 to 5 minutes. Anti-Rho(D) should not be given to patients whose hemoglobin level is less than 10 g/dL or who have compromised bone marrow function. It is ineffective in Rh-negative patients or those who have undergone splenectomy.

Accelerated hemolysis is a rare but severe possible adverse event associated with this therapy, occurring in slightly more than 1 in 1,000 infusions. About 1 out of every 20,000 patients develops disseminated intravascular coagulation.³⁰ Its cause is poorly understood, and it is probably an accelerated extravascular rather than an intravascular event. The US Food and Drug Administration has recently issued a black-box warning cautioning that patients who receive anti-Rho(D) should remain in a health care setting for 8 hours after treatment, although most cases of accelerated hemolysis occur within 4 hours. Moreover, it is possible that many of these cases can be avoided by appropriate patient selection.

SECOND-LINE THERAPIES

Second-line therapies, as designated by the international working group, include azathioprine (Imuran), cyclosporine A, cyclophosphamide (Cytoxan), danazol (Danocrine), dapsone, mycophenolate mofetil (CellCept), rituximab (Rituxan), splenectomy, thrombopoietin receptor agonists, and vinca alkaloids.²⁷ Only the most commonly used therapies will be briefly discussed below.

The evidence for efficacy of the cytotoxic agents, ie, cyclophosphamide, the vinca alkaloids, and azathioprine, comes from small, nonrandomized studies.³¹ Although these agents are useful in some patients, they may be associated with significant toxicities, and they are used less commonly than in the past.

Splenectomy has a high success rate

Splenectomy probably offers the best response of any treatment for ITP. About 80% of patients with ITP respond rapidly—often within 1 week. Of those, 15% relapse within the first year, and after 10 years, two-thirds remain in remission.^32,33

Because there is no well-accepted predictor of a short- or long-term response to splenectomy, and because more medical options are currently available, the use of splenectomy has declined over the past 10 years. Nevertheless, splenectomy remains a useful option for therapy of ITP.

Whether and which second-line drugs should be tried before splenectomy is still controversial and should be determined on a case-by-case basis. Some patients are poor candidates for splenectomy because of comorbidities. If possible, splenectomy should be delayed until at least a year after diagnosis to allow an opportunity for spontaneous remission.

Splenectomy increases the risk of subsequent infection by encapsulated organisms, and patients should be immunized with pneumococcal, Haemophilus influenzae type B, and meningococcal vaccines, preferably at least 3 weeks before the spleen is removed.

Splenectomy is associated with pulmonary hypertension and thrombosis, primarily in patients who have had their spleens removed because of accelerated red cell destruction. Whether these risks are applicable to patients with ITP is unknown, but if so they are probably much lower than in patients with red cell disorders.

Rituximab

Rituximab, a humanized monoclonal antibody against the CD20 antigen on B lymphocytes, was developed for treating lymphoma. However, it has been found to have significant activity in a number of immunohematologic disorders. Although many studies of rituximab for ITP have been published,^34–38 it has never been tested in a randomized controlled study. The response rate is generally around 50%, and it is effective in patients with or without a spleen.

In one study,³⁹ 44 (32%) of 137 patients with chronic ITP who were given rituximab achieved a complete remission that was sustained 1 year. After more than 5 years, 63% of this group (ie, approximately 20% of the original group) were still in remission.

Potential drawbacks of rituximab include its expense as well as the risk of first-infusion reactions, which may be severe or, rarely, fatal. Rituxan has also been associated with rare cases of progressive multifocal leukoencephalopathy, usually in patients heavily treated with other immunosuppressive agents; however, very rare cases of progressive multifocal leukoencephalopathy have been reported in patients with ITP who received rituximab.

Thrombopoietin receptor agonists increase platelet production

Thrombopoietin receptor agonists are approved for patients with chronic ITP who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy. Rather than inhibit platelet destruction, as do all the other ITP therapies, they enhance platelet production.

Diseases involving bone marrow failure that also involve a low platelet count tend to be associated with very high levels of serum thrombopoietin, which is produced constitutively by the liver. In ITP, thrombopoeitin levels tend to be close to normal and not significantly elevated, most likely because of accelerated thrombopoietin clearance when bound to antibody-coated platelets.⁴⁰ This provides a rationale for the use of thrombopoietic agents in the treatment of ITP.

Earlier-generation thrombopoietic drugs had significant amino acid homology with natural thrombopoietin, and some patients who were treated with these drugs developed antibodies against them that cross-reacted with endogenous thrombopoietin. In some cases, this led to severe, refractory thrombocytopenia. Because the newer thrombopoietic agents have no sequence homology to natural thrombopoietin, antibody production has not been a significant problem.

Two drugs in this class are currently available for treating ITP:

Romiplostim (Nplate) is a peptibody (comprising an IgG Fc region and four peptidometic regions that interact with the thrombopoietin receptor, c-mpl) that is given subcutaneously once a week.

Romiplostim performed well in several phase I clinical trials.⁴¹ In a 24-week phase III trial that compared romiplostim against placebo in patients with ITP that had been refractory to other primary treatments, 79% of splenectomized patients and 88% of nonsplenectomized patients had an overall response (defined as a platelet count > 50 × 10⁹/L for 4 weeks during the study period), and 38% of splenectomized patients and 61% of nonsplenectomized patients had a durable response (platelet count > 50 × 10⁹/L for 6 of the last 8 weeks of the study).⁴²

In an ongoing long-term extension study of romiplostim that allows dose adjustments to maintain a platelet count between 50 and 200 × 10⁹/L, romiplostim dosage and efficacy have remained stable over 5 years.^42,43

Eltrombopag (Promacta) is a nonpeptide small-molecule c-mpl agonist that is taken orally once daily. A recent randomized, placebo-controlled study in patients with ITP refractory to other primary treatments found that eltrombopag was highly effective in raising platelet counts over the 6 months of the study.⁴⁴ Like romiplostim, it was effective in both splenectomized and nonsplenectomized patients.

Although eltrombopag has not been studied for as long as romiplostim, data over 3 years indicate that increased platelet counts are maintained without the emergence of drug resistance or cumulative toxicity.⁴⁵

Several other drugs in this class are currently in development.

Adverse effects of thrombopoietic agents

Thrombopoietic agents have several associated toxicities:

Rebound thrombocytopenia occurs in up to 10% of patients following treatment with either romiplostim or eltrombopag. Rebound thrombocytopenia is defined as a fall in the platelet count that occurs following discontinuation of a thrombopoietic agent that may result in more severe thrombocytopenia, transiently, than before the drug was initiated. Thus, the platelet count must be closely monitored after treatment with these drugs is discontinued.

Bone marrow fibrosis, which consists primarily of increased marrow reticulin content, occurs in less than 10% of treated patients, and all patients on therapy must be monitored for this potential complication by close examination of the peripheral blood film on a frequent basis. Appearance of abnormalities such as teardrop cells or nucleated red blood cells in the peripheral blood smear should prompt at least temporary discontinuation of the drug and consideration of bone marrow examination. There have been no cases of actual irreversible myelofibrosis in which thrombopoietic agents have been clearly implicated in causation. Interestingly, some reports suggest that increased reticulin is a common finding in marrow from ITP patients who have not been treated with thrombopoietic agents.⁴⁶

Thrombosis must be considered a risk of treatment with thrombopoietic agents, which increase the platelet count in a disease that may already be thrombogenic. However, in the placebo-controlled studies, a significantly increased incidence of thrombosis was not observed in the treatment arms vs placebo. Moreover, even in treated patients who developed thrombosis, there was no clear association with the degree of elevation in the platelet count. Nevertheless, thrombopoietic agents should be used according to the manufacturer’s recommendations, to increase the platelet count to a range of 50 to 200 × 10⁹/L, but not to exceed that.

Progression of hematologic malignancies. Thrombopoietin receptor agonists act not only on megakaryocytes but also on stem cells and other hematopoieic precursors. Although trials for treating patients with hematologic malignancies and bone marrow failure with thrombopoietic agents are ongoing, there is concern that they could worsen certain hematologic malignancies, though there are no controlled data to either support or refute this concern at present. At this time, these drugs are approved only for ITP and should not be used for other conditions.

Hepatotoxicity has been seen with eltrombopag, but it is usually reversible and may resolve with continued therapy. Nevertheless, close monitoring for this potential complication is indicated.

Once regarded as idiopathic, immune thrombocytopenia (ITP) is now understood to have a complex pathogenesis, involving the evolution of antibodies against multiple platelet antigens leading to reduced platelet survival as well as impaired platelet production. For this reason, multiple therapies with different mechanisms of action are available to treat ITP, though not all of them are effective for individual patients.

In this article, I discuss the pathogenesis, demographics, manifestations, diagnosis, and management of ITP.

THE NAME AND THE CUTOFF HAVE CHANGED

The term ITP formerly was used to refer to “idiopathic” or “immune” thrombocytopenic purpura. However, although not all aspects of the pathogenesis of ITP are understood, the disease can no longer be considered idiopathic. In addition, many patients do not have purpura at the time of diagnosis. Though the abbreviation “ITP” remains the same, it now refers to immune thrombocytopenia, which can be either primary or secondary.¹

ITP is defined as a platelet count of less than 100 × 10⁹/L (100,000/μL) with no evidence of leukopenia or anemia. This cutoff point is new: in the past, ITP was defined as a platelet count of less than 150 × 10⁹/L, which is the threshold for a normal platelet count in most laboratories.

The platelet threshold of 100 × 10⁹/L was based on a study by Stasi et al,² who followed 217 otherwise healthy people who had an incidental finding of mild thrombocytopenia (platelet count 100–150 × 10⁹/L). Within 6 months, the platelet count rose to more than 150 × 10⁹/L in 23, while three had either worsening thrombocytopenia or were diagnosed with other conditions. During long-term follow-up (median 64 months), 109 of the remaining 191 individuals remained stable, 13 developed counts greater than 150 × 10⁹/L, 12 developed ITP, 13 developed an autoimmune disorder, 18 developed other disorders, and 26 were lost to follow-up. The 10-year probability of developing ITP, defined as a platelet count persistently below 100 × 10⁹/L, was only 6.9%, indicating that the chances are small that a person with an isolated finding of mild, stable thrombocytopenia will develop ITP.

Categories of ITP

An international working group designated to standardize terminology has divided ITP into two major diagnostic categories.¹ The proportion of patients within each is not well established and varies by region and demographic characteristics.

Primary ITP accounts for the majority of cases in most studies; other conditions associated with thrombocytopenia are absent.

Secondary ITP can be due to infection with a number of agents, including hepatitis C virus (HCV), human immunodeficiency virus (HIV), and Helicobacter pylori. Other causes include underlying autoimmune and lymphoproliferative disorders such as systemic lupus erythematosus, Wiskott-Aldrich syndrome, chronic lymphocytic leukemia, antiphospholipid syndrome, and common variable immunodeficiency, as well as drugs such as quinine and trimethoprim-sulfamethoxazole.

Categories of ITP have also been established to facilitate management decisions, as follows:

Newly diagnosed ITP refers to ITP diagnosed within the preceding 3 months.

Persistent ITP refers to ITP diagnosed 3 to 12 months previously, and includes ITP in patients not reaching spontaneous remission and in those not maintaining a complete response off therapy. (When ITP spontaneously remits in adults, it usually does so within the first 12 months after the condition is diagnosed.)

Chronic ITP: Lasting for more than 12 months.

Severe ITP is defined by bleeding at presentation sufficient to mandate treatment, or new bleeding symptoms requiring additional therapeutic intervention with a different platelet-enhancing agent or an increased dosage of a current agent.

ITP IS COMMON IN OLDER ADULTS

We previously believed that ITP was a disorder that primarily affected women in their third and fourth decades. However, this was not borne out in recent epidemiologic studies, which have demonstrated that the highest age-specific incidence of ITP occurs in the elderly. This may potentially reflect the development of immune dysregulation as a consequence of aging. There is a female preponderance in the incidence of ITP throughout adulthood until around age 60, after which the overall incidence increases in both sexes, and the ratio of affected women to men is about equal.^3,4 Thus, even though thrombocytopenia in the elderly may reflect myelodysplasia in some individuals, ITP is much more common than previously appreciated.

Previous guidelines from the American Society of Hematology suggested that a bone marrow examination be strongly considered in patients over age 60 with suspected ITP. With the realization that ITP occurs more commonly in the elderly, it is apparent that bone marrow examination is not necessary in this group if there are no other cytopenias present and the physical examination and blood smear are consistent with ITP.

In children, ITP has a peak incidence between ages 5 and 6, and behaves differently from the adult syndrome. ITP in children usually follows an apparent viral infection and tends to be self-limited, with approximately 80% of cases resolving spontaneously within 6 months. In contrast, adult ITP usually develops into a chronic disease.

BLEEDING MAY NOT BE PRESENT AT DIAGNOSIS

ITP is now recognized as a diverse syndrome with a constellation of signs and symptoms.

Petechiae are pinpoint microvascular hemorrhages that do not blanch with pressure. This distinguishes them from small hemangiomas, which look similar but blanch transiently with pressure. Petechiae tend to occur on dependent areas, particularly the hands and feet, when the platelet count drops below approximately 15 × 10⁹/L.

Ecchymoses (dry purpura) appear as large bruises.

Mucosal bleeding (wet purpura) involves the oral mucosa. Particularly in children, wet purpura tends to be associated with systemic bleeding complications, involving the gastrointestinal tract for example. The incidence of intracranial hemorrhage, though very low, may also be increased in patients with wet purpura.

Other bleeding manifestations may include heavy menstrual bleeding, oral bleeding, and epistaxis.

Bleeding is generally but not entirely proportional to the platelet count. In a study of adults with newly diagnosed ITP and a platelet count of less than 50 × 10⁹/L,⁴ the presenting symptom was hemorrhage in 12% and purpura in 58%.⁴ Remarkably, 28% of cases were asymptomatic, with some patients remaining free of symptoms for years despite very low platelet counts. More than half of patients with a platelet count of 30 to 50 × 10⁹/L have no symptoms.^3,4

A PARADOXICAL RISK OF THROMBOSIS

Although ITP is primarily a bleeding disorder, it is paradoxically also associated with thrombosis. Sarpatwari et al,⁵ in a study in the United Kingdom, found that the 4-year incidence of thromboembolic events was about 1.3 times higher in patients with ITP than in matched controls.

The reason for the increased risk of thrombosis is not clear. It is possible that in some patients, antiphospholipid antibodies may contribute to the development of thrombosis, although this has not been confirmed in all studies.

A DIAGNOSIS OF EXCLUSION

The evaluation of any patient suspected of having ITP should include the following:

• Personal history, with special attention to drugs and to medical conditions that could cause thrombocytopenia.
• Family history. ITP may occasionally be mistaken for an inherited cause of thrombocytopenia. The presence of the latter can often be confirmed by review of the peripheral blood film of the patient as well as other family members with thrombocytopenia. ITP is generally not considered to be an inherited disorder, although some HLA alleles may be more prevalent in ITP patients.
• Physical examination, with special attention to lymphadenopathy or splenomegaly, which may suggest an underlying malignancy such as a lymphoproliferative disorder. In general, patients with ITP have a normal physical examination, except for signs of bleeding or bruising in some.
• Laboratory tests, including a complete blood cell count, blood smear, reticulocyte count, Rh typing, and direct antiglobulin (Coombs) test.

In ITP, the peripheral blood smear should appear normal except for the presence of thrombocytopenia, although platelets may be mildly enlarged in some individuals. Red cell and leukocyte morphology is normal. It is important to exclude the presence of schistocytes (red cell fragments) and nucleated red blood cells, which often indicate a microangiopathic hemolytic anemia caused by disorders such as thrombotic thrombocytopenic purpura.

International guidelines suggest that testing for reduced immunoglobulin levels (as seen in common variable hypogammaglobulinemia) and HIV, HCV, and H pylori infections should also be considered. Coincident HCV infection is particularly high in some regions. Other cytopenias or abnormalities in the history or physical examination may prompt bone marrow examination. Testing for antiphospholipid antibodies, antinuclear antibodies, parvovirus, and cytomegalovirus may also be indicated in specific individuals. Testing for antiplatelet antibodies is not commonly performed in the current era because of its relatively low sensitivity and specificity.

Ultimately, the diagnosis of ITP is clinical, however, and cannot be established by any specific laboratory assay. Perhaps the best diagnostic study is assessment of the patient’s response to ITP therapy.

ITP INVOLVES ACCELERATED PLATELET DESTRUCTION

In 1951, William Harrington, a fellow at Washington University, infused blood from a patient with ITP into himself and, subsequently, into normal volunteers.⁶ The majority of recipients demonstrated significant reductions in the platelet count, sometimes severe. This fascinating and bold experiment provided the first demonstration that ITP was caused by a factor that circulates in blood. What is often not emphasized, however, is that some recipients did not develop thrombocytopenia, suggesting an alternative mechanism.

Later, Luiken et al⁷ and Hirschman and Shulman⁸ demonstrated that the transmissible agent in the blood was immunoglobulin, primarily immunoglobulin G (IgG). We now understand that much of the pathogenesis of ITP is caused by antibodies against platelet glycoproteins, most commonly platelet glycoprotein IIb/IIIa, the platelet fibrinogen receptor. Most patients, especially those with chronic ITP, also have antibodies against other platelet glycoproteins, including glycoprotein Ib/IX (the receptor for von Willebrand factor), and glycoprotein Ia/IIa, a collagen receptor. It is commonly believed that ITP may begin with antibodies against a single glycoprotein, which leads to accelerated clearance of antibody-coated platelets in the spleen. Degradation of cleared platelets by splenic macrophages leads to the release and subsequent presentation of antigenic peptides from proteolyzed platelet components, including glycoproteins, on the macrophage or dendritic cell. This may lead to recruitment and activation of specific T cells that in turn interact with and stimulate B cells to produce new antibodies against the platelet-derived peptides. This phenomenon, known as epitope spreading, may be responsible for the fact that most patients with long-standing, chronic ITP develop autoantibodies against multiple platelet glycoprotein targets.⁹

Several agents used in the treatment of ITP may work by impairing clearance of antibody-coated platelets by the reticuloendothelial system. One of many potential mechanisms underlying the therapeutic efficacy of intravenous immunoglobulin (IVIG) may be its ability to interact with a specific type of Fc gamma receptor, Fc gamma RIIb. IVIG therapy stimulates increased expression of this receptor, which in turn may impair the function of other “activating” Fc gamma receptors responsible for platelet clearance.^10,11

ITP associated with infection may arise due to molecular mimicry. HCV, HIV, and H pylori contain amino acid sequences that may have structural similarity to regions within platelet glycoproteins. Thus, antibodies directed against the pathogen may cross-react with the glycoprotein, leading to thrombocytopenia.^12–15

HCV has been found in up to one-third of cases of ITP in some centers.^16–20H pylori-associated ITP is very common in some regions, particularly in Japan, and may often resolve after eradication of the infection. However, in the United States, eradication of H pylori generally does not improve the course of ITP. This may reflect antigen mimicry, in particular the fact that different cagA proteins are expressed by different strains of H pylori in certain regions of the world.

Our understanding of the immunologic basis of ITP has greatly expanded over the last decade. Although it has long been known that B cells produce autoantibodies, T cells have more recently been shown to play a critical role in regulating B-cell-mediated autoantibody production in ITP. In some situations, T cells may directly lyse platelets, or suppress megakaryopoiesis. This may explain why some patients who do not respond to standard B-cell-targeted therapy may respond to cyclosporine or other T-cell-directed agents.

ANOTHER MECHANISM OF ITP: REDUCED PLATELET PRODUCTION

In addition to accelerated platelet destruction, ITP is also associated with decreased platelet production by megakaryocytes in the bone marrow.^21–25

Increased platelet destruction and reduced platelet production are likely two ends of a spectrum of ITP, and most patients likely have some degree of both processes. This concept helps explain why different drug strategies are more effective in some patients than in others.

ARE THE RISKS OF THERAPY JUSTIFIED?

It is important to understand the natural history of ITP to determine whether the risks of therapy are justified.

A 2001 study from the Netherlands²⁶ followed 134 patients with primary ITP for 10 years: 90% had taken prednisone or had had a splenectomy. Within 2 years, 85% of these patients had platelet counts above 30 × 10⁹/L off therapy. Although this group likely experienced more bleeding and bruising than the general population, the mortality rate was not increased. Another 6% also achieved a platelet count above 30 × 10⁹/L, but required chronic maintenance therapy (usually steroids) to do so. This group led a nearly normal life but had more hospitalizations. The remaining 9% of patients had refractory ITP, with platelet counts remaining below 30 × 10⁹/L despite therapy. This group had a death rate 4.2 times that of age-matched controls. About half died of bleeding and the others died of opportunistic infections to which they were susceptible because of long-term steroid therapy.

This study was influential in the general opinion that 30 × 10⁹/L is a reasonable cutoff for treating ITP. An international consensus report states that treatment is rarely indicated in patients with platelet counts above 50 × 10⁹/L in the absence of bleeding due to platelet dysfunction or other hemostatic defect, trauma, or surgery.²⁷ Although this number is not supported by evidence-based data, it is a reasonable threshold endorsed by an international working group.²⁷ Individual factors must be weighed heavily: for example, an athlete involved in contact sports requires a higher platelet count in order to play safely.

FIRST-LINE THERAPIES

First-line therapies for ITP include corticosteroids, IVIG, and anti-Rho(D) immune globulin (WinRho).²⁷

Corticosteroids are standard therapy

Corticosteroids can be given in one of two ways:

Standard prednisone therapy, ie, 1 to 2 mg/kg per day, is given until a response is seen, and then tapered. Some maintain therapy for an additional week before tapering. There are no guidelines on how to taper: some decrease the dosage by 50% per week, although many recommend going more slowly, particularly at the lower range of dosing.

Up to 85% of patients achieve a clinical response, usually within 7 to 10 days, with platelet counts peaking in 2 to 4 weeks. Unfortunately, only about 15% of patients maintain the response over the subsequent 6 to 12 months. Restarting prednisone often initiates a vicious circle and makes patients vulnerable to steroid toxicities.

“Pulse” dexamethasone therapy consists of 40 mg per day for 4 days for one to three cycles. (Dexamethasone 1 mg is equivalent to about 10 mg of prednisone.)

Pulse dexamethasone therapy as an initial approach to ITP has been developed during the past decade and has been used primarily in research studies. This regimen evolved from studies of patients with multiple myelomas and has the potential to induce more durable remissions in some patients with newly diagnosed ITP.²⁹ However, high-dose corticosteroids may be associated with increased toxicity, at least in the short term, and should be used cautiously. A study to address the role of high-dose vs standard-dose steroid therapy has recently been opened under the guidance of the Transfusion Medicine–Hemostasis Clinical Trials Network of the National Heart, Lung, and Blood Institute.

Immunoglobulin is useful for very low platelet counts and bleeding

Another primary therapy for ITP is IVIG 0.5 to 2.0 g/kg over 2 to 5 days. Its efficacy is similar to that of prednisone: about 65% of patients achieve a platelet count above 100 × 10⁹/L, and 85% achieve 50 × 10⁹/L. However, most responses are transient, and a significant minority of cases become refractory to IVIG after repeated infusions.

IVIG is associated with numerous adverse effects, including thrombosis, renal insufficiency, headache, and anaphylaxis in IgA-deficient patients. It also converts the direct antiglobulin test to positive. IVIG is expensive, is inconvenient to administer, and may require lengthy infusions depending on the formulation.

Although IVIG is not a good long-term therapy, it can help raise the platelet count relatively quickly in patients who present with severe thrombocytopenia accompanied by bleeding. Such patients should be treated with high-dose steroids, IVIG, and platelet transfusions. IVIG may also be useful to increase platelet counts prior to interventional procedures.

Intravenous anti-Rho(D)

Anti-Rho(D) is an alternative to IVIG in patients who are Rho(D)-positive and have an intact spleen. Anti-Rho(D) binds to Rh-positive red blood cells, causing them to be cleared in the reticuloendothelial system and blocking the clearance of antibody-coated platelets. In effect, red cells are sacrificed to save platelets, but because there are many more red cells than platelets, the benefits usually outweigh the risks.

The initial dose is 50 μg/kg given intravenously over 2 to 5 minutes. Anti-Rho(D) should not be given to patients whose hemoglobin level is less than 10 g/dL or who have compromised bone marrow function. It is ineffective in Rh-negative patients or those who have undergone splenectomy.

Accelerated hemolysis is a rare but severe possible adverse event associated with this therapy, occurring in slightly more than 1 in 1,000 infusions. About 1 out of every 20,000 patients develops disseminated intravascular coagulation.³⁰ Its cause is poorly understood, and it is probably an accelerated extravascular rather than an intravascular event. The US Food and Drug Administration has recently issued a black-box warning cautioning that patients who receive anti-Rho(D) should remain in a health care setting for 8 hours after treatment, although most cases of accelerated hemolysis occur within 4 hours. Moreover, it is possible that many of these cases can be avoided by appropriate patient selection.

SECOND-LINE THERAPIES

Second-line therapies, as designated by the international working group, include azathioprine (Imuran), cyclosporine A, cyclophosphamide (Cytoxan), danazol (Danocrine), dapsone, mycophenolate mofetil (CellCept), rituximab (Rituxan), splenectomy, thrombopoietin receptor agonists, and vinca alkaloids.²⁷ Only the most commonly used therapies will be briefly discussed below.

The evidence for efficacy of the cytotoxic agents, ie, cyclophosphamide, the vinca alkaloids, and azathioprine, comes from small, nonrandomized studies.³¹ Although these agents are useful in some patients, they may be associated with significant toxicities, and they are used less commonly than in the past.

Splenectomy has a high success rate

Splenectomy probably offers the best response of any treatment for ITP. About 80% of patients with ITP respond rapidly—often within 1 week. Of those, 15% relapse within the first year, and after 10 years, two-thirds remain in remission.^32,33

Because there is no well-accepted predictor of a short- or long-term response to splenectomy, and because more medical options are currently available, the use of splenectomy has declined over the past 10 years. Nevertheless, splenectomy remains a useful option for therapy of ITP.

Whether and which second-line drugs should be tried before splenectomy is still controversial and should be determined on a case-by-case basis. Some patients are poor candidates for splenectomy because of comorbidities. If possible, splenectomy should be delayed until at least a year after diagnosis to allow an opportunity for spontaneous remission.

Splenectomy increases the risk of subsequent infection by encapsulated organisms, and patients should be immunized with pneumococcal, Haemophilus influenzae type B, and meningococcal vaccines, preferably at least 3 weeks before the spleen is removed.

Splenectomy is associated with pulmonary hypertension and thrombosis, primarily in patients who have had their spleens removed because of accelerated red cell destruction. Whether these risks are applicable to patients with ITP is unknown, but if so they are probably much lower than in patients with red cell disorders.

Rituximab

Rituximab, a humanized monoclonal antibody against the CD20 antigen on B lymphocytes, was developed for treating lymphoma. However, it has been found to have significant activity in a number of immunohematologic disorders. Although many studies of rituximab for ITP have been published,^34–38 it has never been tested in a randomized controlled study. The response rate is generally around 50%, and it is effective in patients with or without a spleen.

In one study,³⁹ 44 (32%) of 137 patients with chronic ITP who were given rituximab achieved a complete remission that was sustained 1 year. After more than 5 years, 63% of this group (ie, approximately 20% of the original group) were still in remission.

Potential drawbacks of rituximab include its expense as well as the risk of first-infusion reactions, which may be severe or, rarely, fatal. Rituxan has also been associated with rare cases of progressive multifocal leukoencephalopathy, usually in patients heavily treated with other immunosuppressive agents; however, very rare cases of progressive multifocal leukoencephalopathy have been reported in patients with ITP who received rituximab.

Thrombopoietin receptor agonists increase platelet production

Thrombopoietin receptor agonists are approved for patients with chronic ITP who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy. Rather than inhibit platelet destruction, as do all the other ITP therapies, they enhance platelet production.

Diseases involving bone marrow failure that also involve a low platelet count tend to be associated with very high levels of serum thrombopoietin, which is produced constitutively by the liver. In ITP, thrombopoeitin levels tend to be close to normal and not significantly elevated, most likely because of accelerated thrombopoietin clearance when bound to antibody-coated platelets.⁴⁰ This provides a rationale for the use of thrombopoietic agents in the treatment of ITP.

Earlier-generation thrombopoietic drugs had significant amino acid homology with natural thrombopoietin, and some patients who were treated with these drugs developed antibodies against them that cross-reacted with endogenous thrombopoietin. In some cases, this led to severe, refractory thrombocytopenia. Because the newer thrombopoietic agents have no sequence homology to natural thrombopoietin, antibody production has not been a significant problem.

Two drugs in this class are currently available for treating ITP:

Romiplostim (Nplate) is a peptibody (comprising an IgG Fc region and four peptidometic regions that interact with the thrombopoietin receptor, c-mpl) that is given subcutaneously once a week.

Romiplostim performed well in several phase I clinical trials.⁴¹ In a 24-week phase III trial that compared romiplostim against placebo in patients with ITP that had been refractory to other primary treatments, 79% of splenectomized patients and 88% of nonsplenectomized patients had an overall response (defined as a platelet count > 50 × 10⁹/L for 4 weeks during the study period), and 38% of splenectomized patients and 61% of nonsplenectomized patients had a durable response (platelet count > 50 × 10⁹/L for 6 of the last 8 weeks of the study).⁴²

In an ongoing long-term extension study of romiplostim that allows dose adjustments to maintain a platelet count between 50 and 200 × 10⁹/L, romiplostim dosage and efficacy have remained stable over 5 years.^42,43

Eltrombopag (Promacta) is a nonpeptide small-molecule c-mpl agonist that is taken orally once daily. A recent randomized, placebo-controlled study in patients with ITP refractory to other primary treatments found that eltrombopag was highly effective in raising platelet counts over the 6 months of the study.⁴⁴ Like romiplostim, it was effective in both splenectomized and nonsplenectomized patients.

Although eltrombopag has not been studied for as long as romiplostim, data over 3 years indicate that increased platelet counts are maintained without the emergence of drug resistance or cumulative toxicity.⁴⁵

Several other drugs in this class are currently in development.

Adverse effects of thrombopoietic agents

Thrombopoietic agents have several associated toxicities:

Rebound thrombocytopenia occurs in up to 10% of patients following treatment with either romiplostim or eltrombopag. Rebound thrombocytopenia is defined as a fall in the platelet count that occurs following discontinuation of a thrombopoietic agent that may result in more severe thrombocytopenia, transiently, than before the drug was initiated. Thus, the platelet count must be closely monitored after treatment with these drugs is discontinued.

Bone marrow fibrosis, which consists primarily of increased marrow reticulin content, occurs in less than 10% of treated patients, and all patients on therapy must be monitored for this potential complication by close examination of the peripheral blood film on a frequent basis. Appearance of abnormalities such as teardrop cells or nucleated red blood cells in the peripheral blood smear should prompt at least temporary discontinuation of the drug and consideration of bone marrow examination. There have been no cases of actual irreversible myelofibrosis in which thrombopoietic agents have been clearly implicated in causation. Interestingly, some reports suggest that increased reticulin is a common finding in marrow from ITP patients who have not been treated with thrombopoietic agents.⁴⁶

Thrombosis must be considered a risk of treatment with thrombopoietic agents, which increase the platelet count in a disease that may already be thrombogenic. However, in the placebo-controlled studies, a significantly increased incidence of thrombosis was not observed in the treatment arms vs placebo. Moreover, even in treated patients who developed thrombosis, there was no clear association with the degree of elevation in the platelet count. Nevertheless, thrombopoietic agents should be used according to the manufacturer’s recommendations, to increase the platelet count to a range of 50 to 200 × 10⁹/L, but not to exceed that.

Progression of hematologic malignancies. Thrombopoietin receptor agonists act not only on megakaryocytes but also on stem cells and other hematopoieic precursors. Although trials for treating patients with hematologic malignancies and bone marrow failure with thrombopoietic agents are ongoing, there is concern that they could worsen certain hematologic malignancies, though there are no controlled data to either support or refute this concern at present. At this time, these drugs are approved only for ITP and should not be used for other conditions.

Hepatotoxicity has been seen with eltrombopag, but it is usually reversible and may resolve with continued therapy. Nevertheless, close monitoring for this potential complication is indicated.

Given the perception that statin myopathy is common, the incidence of significant myalgias in clinical trials is surprisingly low and similar to that with placebo (generally less than 5%), and that of myositis or rhabdomyolysis is much rarer.

In this issue of the Journal, Dr. Genaro Fernandez and colleagues discuss possible reasons for the discrepancy between the prevalence of statin-associated myalgias in clinical trials vs real practice. They suggest that patients more likely to develop myalgias are weeded out in the screening phase of clinical trials and that the trials may be too small and too short to capture this information. Yet in practice, many patients develop muscle pain shortly after starting statin therapy. I suggest another explanation—ie, that volunteers in clinical trials want to take the medication, while in the clinic my patients are reluctant to take one more medication and have trepidations about starting one that they “know” causes muscle pain.

But I don’t think all statin myopathy is due to the power of suggestion. Some patients clearly have drug-elicited elevations in creatine kinase (CK), and others (including me) experience significant myalgias with one statin but can tolerate another.

A challenge in my rheumatology clinic is distinguishing statin myopathy from other underlying problems in patients referred for evaluation of pain, weakness, or elevated CK. I first establish a temporal relationship between the drug initiation and the start of symptoms, and I look for other drugs or possible drug interactions that could be causing the problem, such as colchicine vacuolar myopathy in the setting of newly initiated statin therapy. I look for an alternative explanation for the pain syndrome, such as upper-arm pain and physical findings that suggest rotator cuff disease, or lateral hip-area pain due to bursitis. In some patients, statins may pose a metabolic challenge that unmasks (or brings to the physician’s attention) an underlying biochemical disorder of the muscle, such as myotonic dystrophy or even polymyositis.

Dr. Fernandez et al offer sound advice, as they suggest keeping an open diagnostic mind when evaluating patients with apparent statin myopathy. In particular, with these authors, I urge you to perform a careful personal and family history and a focused examination, ask about vigorous physical exercise, check the CK, and withhold and then rechallenge with the statin before ordering a slew of serologic and metabolic tests.

Given the perception that statin myopathy is common, the incidence of significant myalgias in clinical trials is surprisingly low and similar to that with placebo (generally less than 5%), and that of myositis or rhabdomyolysis is much rarer.

In this issue of the Journal, Dr. Genaro Fernandez and colleagues discuss possible reasons for the discrepancy between the prevalence of statin-associated myalgias in clinical trials vs real practice. They suggest that patients more likely to develop myalgias are weeded out in the screening phase of clinical trials and that the trials may be too small and too short to capture this information. Yet in practice, many patients develop muscle pain shortly after starting statin therapy. I suggest another explanation—ie, that volunteers in clinical trials want to take the medication, while in the clinic my patients are reluctant to take one more medication and have trepidations about starting one that they “know” causes muscle pain.

But I don’t think all statin myopathy is due to the power of suggestion. Some patients clearly have drug-elicited elevations in creatine kinase (CK), and others (including me) experience significant myalgias with one statin but can tolerate another.

A challenge in my rheumatology clinic is distinguishing statin myopathy from other underlying problems in patients referred for evaluation of pain, weakness, or elevated CK. I first establish a temporal relationship between the drug initiation and the start of symptoms, and I look for other drugs or possible drug interactions that could be causing the problem, such as colchicine vacuolar myopathy in the setting of newly initiated statin therapy. I look for an alternative explanation for the pain syndrome, such as upper-arm pain and physical findings that suggest rotator cuff disease, or lateral hip-area pain due to bursitis. In some patients, statins may pose a metabolic challenge that unmasks (or brings to the physician’s attention) an underlying biochemical disorder of the muscle, such as myotonic dystrophy or even polymyositis.

Dr. Fernandez et al offer sound advice, as they suggest keeping an open diagnostic mind when evaluating patients with apparent statin myopathy. In particular, with these authors, I urge you to perform a careful personal and family history and a focused examination, ask about vigorous physical exercise, check the CK, and withhold and then rechallenge with the statin before ordering a slew of serologic and metabolic tests.

Given the perception that statin myopathy is common, the incidence of significant myalgias in clinical trials is surprisingly low and similar to that with placebo (generally less than 5%), and that of myositis or rhabdomyolysis is much rarer.

In this issue of the Journal, Dr. Genaro Fernandez and colleagues discuss possible reasons for the discrepancy between the prevalence of statin-associated myalgias in clinical trials vs real practice. They suggest that patients more likely to develop myalgias are weeded out in the screening phase of clinical trials and that the trials may be too small and too short to capture this information. Yet in practice, many patients develop muscle pain shortly after starting statin therapy. I suggest another explanation—ie, that volunteers in clinical trials want to take the medication, while in the clinic my patients are reluctant to take one more medication and have trepidations about starting one that they “know” causes muscle pain.

But I don’t think all statin myopathy is due to the power of suggestion. Some patients clearly have drug-elicited elevations in creatine kinase (CK), and others (including me) experience significant myalgias with one statin but can tolerate another.

A challenge in my rheumatology clinic is distinguishing statin myopathy from other underlying problems in patients referred for evaluation of pain, weakness, or elevated CK. I first establish a temporal relationship between the drug initiation and the start of symptoms, and I look for other drugs or possible drug interactions that could be causing the problem, such as colchicine vacuolar myopathy in the setting of newly initiated statin therapy. I look for an alternative explanation for the pain syndrome, such as upper-arm pain and physical findings that suggest rotator cuff disease, or lateral hip-area pain due to bursitis. In some patients, statins may pose a metabolic challenge that unmasks (or brings to the physician’s attention) an underlying biochemical disorder of the muscle, such as myotonic dystrophy or even polymyositis.

Dr. Fernandez et al offer sound advice, as they suggest keeping an open diagnostic mind when evaluating patients with apparent statin myopathy. In particular, with these authors, I urge you to perform a careful personal and family history and a focused examination, ask about vigorous physical exercise, check the CK, and withhold and then rechallenge with the statin before ordering a slew of serologic and metabolic tests.

When a patient taking a statin complains of muscle aches, is he or she experiencing statin-induced myopathy or some other problem? Should statin therapy be discontinued?

Statins have proven efficacy in preventing heart attacks and death,¹ and they are the most widely prescribed drugs worldwide. Nevertheless, they remain underused, with only 50% of those who would benefit from being on a statin receiving one.^2,3 In addition, at least 25% of adults who start taking statins stop taking them by 6 months, and up to 60% stop by 2 years.⁴

Patient and physician fears about myopathy remain a key reason for stopping. Myopathy, a known side effect of statins, is rare in randomized controlled trials, but less so in observational studies and clinical experience. This discrepancy between clinical trials and clinical experience reduces confidence in lipid-lowering therapy and contributes to its underuse.

This review emphasizes clinical aspects of statin myopathy that are important to the practicing physician. We will define myopathy, review its purported mechanisms, and describe a clinical approach to patients with possible toxicity, including risk factors, physical findings, and consideration of alternate diagnoses. Since there is no single test to diagnose statin-induced myopathy, we offer a framework to aid clinicians in stratifying patients based on the likelihood that their symptoms are due to statin toxicity weighed against the likelihood that they will benefit from statin therapy.

DEFINITIONS DIFFER

Little consensus exists on how to define the adverse muscle effects of statins,⁵ which may contribute to the underdiagnosis of this complication. The magnitude of creatine kinase (CK) elevation required to define rhabdomyolysis has increased from 500 IU/L in 1982,⁶ to 1,000 IU/L in 1988,⁷ to 50 times the upper limit of normal in one current definition.⁸ The American Heart Association, the American College of Cardiology, the National Heart Lung and Blood Institute,⁹ the National Lipid Association,⁸ and the US Food and Drug Administration¹⁰ all differ in their definitions.

Our definitions

For the purpose of this article, we offer the following definitions:

Myalgia—muscle weakness, soreness, tenderness, stiffness, cramping, or aching, either at rest or with exertion, without any elevation in CK.

Myositis—elevated CK with or without muscle symptoms. The “-itis” suffix is unfortunate since myositis does not correspond to inflammation on biopsy.

Rhabdomyolysis—muscle symptoms with a CK level 10 times the upper limit of normal or higher. Evidence of renal dysfunction is not required for the diagnosis, as preexisting renal disease and hydration status are more closely related to kidney damage than the degree of muscle injury.¹¹

STATIN MYOPATHY IS MORE COMMON IN THE REAL WORLD THAN IN TRIALS

The incidence of statin-induced myopathy is significantly lower in randomized controlled trials of statin efficacy than in observational studies of real-world patients. In randomized clinical trials, myalgia was reported in 1% to 5% of patients in the statin groups and placebo groups alike,^9,12 whereas clinical practice would suggest it is more common.

Why is statin-induced myopathy so uncommon in clinical trials?

A reason may be that patients in clinical trials are carefully screened. To minimize toxicity, the clinical trials of statins excluded patients with renal insufficiency, hepatic insufficiency, a history of muscular complaints, and poorly controlled diabetes, as well as patients taking drugs with possible interactions. Large efficacy trials have excluded up to 30% of the participants in active prerandomization phases.^13,14

Another reason is that these trials were designed to assess the efficacy of statins and were not sensitive to adverse effects like muscle pain. When they looked at myopathy, they focused on rhabdomyolysis—the most severe form—rather than on myalgia, fatigue, or other minor muscle complaints.¹⁵ Additionally, most trials enrolled too few patients and did not have long enough follow-up to reveal infrequent toxicities.

Despite the strict criteria, a significant number of trial patients discontinued statin therapy during the study period. In the Treat to New Targets (TNT) trial, 5% of patients in both the high- and low-dose atorvastatin (Lipitor) groups experienced muscle toxicity, even though 35% of eligible patients had been excluded during the open-label run-in phase.¹⁴

Also, physicians may overlook and patients may fail to report symptoms such as fatigue, malaise, or dyspnea that are not commonly accepted as signs of statin toxicity.¹⁶

Findings from observational studies

Observational studies in nonselected outpatients show a higher frequency of muscle complaints in the statin groups than in the control groups. These studies suggest the frequency of statin myopathy is 9% to 20%.^17–19

The Prediction of Muscular Risk in Observational Conditions (PRIMO) study²⁰ was one of the largest and best-defined observational studies of muscular symptoms in an unselected population. It included 7,924 French outpatients with hypercholesterolemia, ages 18 to 75 years, on high-dose statins for 3 or more months before the study. Daily statin regimens included atorvastatin 40 to 80 mg, fluvastatin (Lescol) 80 mg, pravastatin (Pravachol) 40 mg, and simvastatin (Zocor) 40 to 80 mg. In this study, 10.5% of patients reported muscle-related symptoms.

Buettner et al,²¹ in another cross-sectional study, interviewed and examined 3,580 adults over age 40. Of those taking statins, 22% reported having had musculoskeletal pain in at least one anatomic region in the last 30 days, compared with 16.7% of those not taking a statin.

In the United States, where an estimated 33 million adults use statins, musculoskeletal pain can be expected to occur in 7 million people, likely induced by statin therapy in 25% of cases.²²

WHAT CAUSES STATIN MYOPATHY?

The causes of statin-induced myopathy are poorly understood.

Historically, statin-induced toxicity was thought to be caused by inhibition of the synthesis of mevalonate, leading to depletion of its metabolites, such as cholesterol, isoprenoids, and ubiquinone (coenzyme Q10). Depletion of intracellular cholesterol may lead to abnormal membrane behaviors; depletion of isoprenoids may affect intracellular signaling; depletion of coenzyme Q10 may in turn reduce mitochondrial respiratory function. Genetic factors may also play a role, contributing to pharmacokinetics and predisposing metabolic muscle disorders.^23,24

Statin-induced myopathy seems to be different in randomized efficacy trials than in the clinical setting. In randomized trials, the mechanism appears to involve abnormal pharmacokinetics. The participants are carefully selected to have a low risk of muscle toxicity, but some develop toxicity when statin levels are elevated because of reduced drug breakdown and metabolism. However, in clinical practice, where a much larger group of unselected patients are exposed to statins, toxicity appears to be more related to a metabolic predisposition.^25–27

Multiple minor metabolic abnormalities have been described in the muscles of patients with statin-induced muscle toxicity, suggesting that some patients have a predisposition for muscle complaints.²³ About 25% of patients with recurrent rhabdomyolysis irrespective of lipid-lowering therapy have an underlying metabolic muscle disorder.²⁸ In these vulnerable patients, minor metabolic defects are exacerbated by any agent that reduces the delivery of fat substrate to muscle, leading to muscle starvation.

This concept explains why patients may develop the same muscle complaint on different lipid-lowering agents.^29,30 It also may explain why rhabdomyolysis can occur after apheresis of lipids, when no drugs have been given.³¹ In vulnerable patients, muscle toxicity may result from any agent that lessens the lipid substrate available to muscle rather than from the reduction of products downstream from mevalonate by statins.

SOME STATINS MAY BE LESS TOXIC

In the PRIMO study, muscle-related symptoms occurred with the various regimens as follows:

• Fluvastatin XL 40 mg—5.1%
• Pravastatin 40 mg—10.9%
• Atorvastatin 40 to 80 mg—14.9%
• Simvastatin 40 to 80 mg—18.2%.

Others have also shown that fluvastatin contributed to the smallest number of reported cases of rhabdomyolysis among statins: 55 (1.6%) of 3,339 cases.³⁴

More recent studies indicate that rosuvastatin (Crestor), the most hydrophilic statin, may be well tolerated in those who do not tolerate other statins,^35–37 though no head-to-head trial has been done.

RISK FACTORS FOR STATIN-INDUCED MYOPATHY

APPROACH TO SUSPECTED STATIN-INDUCED MYOPATHY

The recommendations that follow are based on observations from our statin myopathy clinic in more than 650 patients, of whom more than 60 have suffered rhabdomyolysis. This experience is largely anecdotal, since such patients have not been well studied in controlled trials.

Are the symptoms due to the statin?

In our experience, most patients who develop significant weakness and pain on statin therapy have normal CK levels.⁴⁰

Since there is as yet no test to confirm or reject the diagnosis of statin toxicity, the first objective is to determine the likelihood that the muscle complaint is being caused by statin therapy. Factors that make statin toxicity more likely must be weighed against any features that are atypical or that favor an alternate diagnosis.

The final decision about future statin treatment depends on the balance between the expected benefit of statin therapy for each individual and the likelihood that the symptoms are due to statin therapy. Below, we provide an algorithmic approach based on history, physical examination, and laboratory findings.

Findings from the history that implicate statins

Many muscle symptoms resolve within 2 weeks of starting statin therapy. Therefore, if patients have a normal CK level and can tolerate the symptoms, we ask them to continue therapy and see if their symptoms resolve with continued use.

Symptoms that persist beyond the first 2 weeks of therapy are likely due to the statin. These include symmetric burning or pain in the large muscles during exercise that was not present before lipid-lowering therapy. Any symptom that reproducibly recurs with statin rechallenge and disappears within 2 weeks of discontinuing therapy is more likely to be caused by the statin.

Findings of the PRIMO study are representative of typical statin-induced symptoms that we see in our clinic.²⁰

• Most patients did not identify a trigger, but the 40% who did had engaged in unusual physical exertion or had received a new drug in addition to the statin.
• Heaviness, stiffness, or cramps predominated in 70%, with only a quarter noting weakness and another quarter suffering myalgias during exercise. Pain was diffuse in 60% and more common in the lower extremities than the upper extremities.
• Physically active patients were more likely to suffer muscle symptoms than sedentary patients, echoing the observation by Sinzinger and O’Grady that athletes are especially intolerant of lipid-lowering therapy.⁴¹
• Patients who have had muscle complaints with other drug therapies such as bisphosphonates, ⁴² raloxifene (Evista),⁴³ or diuretics may be having the same provocation of an underlying muscle predisposition by the statin.
• A personal or family history of muscle complaints predisposed patients to statin-induced myopathy.²⁰

Finally, we have repeatedly found that when dyspnea and fatigue are associated with the muscle complaint, they are more likely to be caused by statins.⁴⁴

Atypical complaints require us to search for an alternate diagnosis before dismissing them as not statin-induced.

Previous episodes of myoglobinuria (dark urine after exertion) would raise the possibility of a metabolic myopathy. Frequent muscle cramps raise the possibility of a metabolic myopathy or motor neuron disease.

Asymmetric pain or pain involving joints and ligaments is less likely to be statin-related but in our experience occasionally occurs.

Some patients with underlying degenerative arthritis or tendinitis repeatedly develop worsening symptoms each time they take statins, perhaps because muscle weakness exacerbates the arthropathy or tendinopathy.⁴⁵

Although statin-related muscle complaints are almost always symmetric, many patients with underlying peripheral vascular disease have asymmetric pain in the limb with poor vascular supply; the pain is reproducible by statin rechallenge.

In our experience, many patients whose chronic low back pain is due to a lumbar radiculopathy experience exacerbations of that pain whenever they start statins.

Weakness preceding the use of the statins or a family history of neuromuscular disorders may indicate a neurodegenerative disorder and warrants consideration of early neurological consultation.

Although these rules are not absolute, they are helpful in the initial evaluation, which must exclude alternative diagnoses.

Is the patient a vegetarian? A drinker? Taking supplements?

Taking a careful history of diet and supplement use is important to find exposures that may increase the risk of statin-related muscle complaints. Vegetarians may develop carnitine or vitamin B₁₂ deficiencies. Alcohol and vitamin E and other supplements are occasional causes of muscle symptoms falsely attributed to statin therapy. It is also important to remember that red yeast rice contains lovastatin, which can exacerbate myopathy, especially when taken in conjunction with another statin.

Physical examination

The examination of patients with possible statin-induced myopathy begins with a general assessment for signs of hypothyroidism or excess alcohol consumption.

Ankle-brachial indices are used to exclude significant peripheral vascular disease.

The musculoskeletal examination focuses on muscle atrophy, tone, and strength but also excludes tendinopathies, arthropathies, and myofascial pain syndromes, which are often confused with muscle pain.

We conduct quantitative dynamometry, measuring handgrip with a Jamar dynamometer and hip abduction with a Nicholas Manual Muscle Tester. Precise dynamometric measurements are tracked at subsequent visits and are helpful in following recovery from myopathy as well as in tracking strength during subsequent statin rechallenges.

We routinely look for hyperreflexia, fasciculations, extensor-plantar responses, and decreased heel-to-shin movement, which would suggest myelopathy. Reflexes and a sensory examination including vibration and temperature sensation help exclude radiculopathy and peripheral neuropathy.

Laboratory evaluation

In every patient with possibly statin myopathy, the primary care physician should measure:

• The serum CK level (preferably more than 72 hours after exercise)
• The 25-hydroxy vitamin level
• The thyroid-stimulating hormone level.

Further laboratory evaluation depends on the findings and will often be directed by subspecialists. For example, we assess the sedimentation rate, anti-Ro and anti-La antibodies, and the myositis panel in patients with elevated CK whose other findings suggest an autoimmune or inflammatory process. We test serum carnitine levels (free, total, and esterified), fasting serum lactate levels, and serum cortisol in those with findings suggestive of metabolic myopathy. We order electromyography and nerve conduction studies in patients with possible myelopathy, peripheral neuropathy, or inflammatory myopathy.

Ultimately, a muscle biopsy may be necessary to exclude inflammatory or necrotizing myopathies in patients whose CK remains elevated despite withdrawal of statins. It may also be helpful when other findings suggest a metabolic myopathy. When a biopsy is needed, magnetic resonance imaging of the affected limb may identify an affected muscle for biopsy.

MANAGEMENT

Reassess the lipid goal

If the source of a complaint remains unclear after challenge and rechallenge with alternate statins, we generally recommend restarting therapy and trying to achieve the LDL-C goal. If the workup suggests a neurologic or rheumatolic etiology, a referral to a specialist is indicated. However, if the evaluation leads to a diagnosis of statin-induced myopathy, the next task is to reassess the lipid treatment goals.

The Adult Treatment Panel (ATP) III guidelines should be used to assess the patient’s risk of having major coronary heart disease in the next 10 years, and to determine appropriate LDL-C goals.⁴⁶ Some patients with suspected toxicity may have been treated to more aggressive LDL-C levels than recommended by these guidelines. The first step in these patients is to reduce or discontinue the unnecessary statin, even if there is no clear evidence of toxicity.

For the rest of patients with suspected toxicity, the decision to discontinue statin therapy must be weighed against the estimated reduction in risk associated with taking a statin medication.

In patients whose evaluation suggests statin myopathy, we stop all lipid-lowering therapy for 6 weeks and see if symptoms resolve and if grip and hip strength increase by dynamometry.

We often give these patient supplements of 600 mg daily of a bioavailable source of coenzyme Q10 and fish oil during this statin holiday. The data supporting the use of these supplements are mixed but the risks are minimal.⁵ In patients whose evaluation suggests a primary disorder in fatty acid oxidation, we add a trial of l-carnitine supplementation if symptoms do not resolve after a 6-week course of the coenzyme Q10 and fish oil.

If symptoms persist or if resolution is unclear at 6 weeks, we extend the holiday for an additional 6 weeks, except in patients with recent unstable coronary disease: for these patients, unless there is evidence of rhabdomyolysis, we believe that the benefits of continued statin therapy exceed the risks.

If the initial evaluation is consistent with statin myopathy and the neuromuscular symptoms (myalgias and weakness) do not respond within a few months of statin withdrawal, neurologic consultation is indicated to evaluate for an underlying neurologic disorder that has become symptomatic during statin therapy but whose existence is independent of the statin therapy. In some cases, the preexisting neurologic disorder may become symptomatic because of the statin therapy and remain symptomatic despite discontinuation of the statin therapy.

Restarting lipid-lowering therapy

Once the myopathy symptoms have abated or are controlled, a rechallenge of statin therapy is in order for those whose risk profile suggests greater benefit from statin therapy.

We consider the complete statin exposure history and any concomitant therapy that may have been competing with cytochrome P450 (CYP) metabolism of statins in designing an alternate lipid-lowering plan.

For patients with known coronary or vascular disease, in whom the survival benefit of statins is greatest, we generally try to find a statin regimen that is tolerable. Long-acting fluvastatin or a statin with less CYP dependence, such as pravastatin, is often successful.⁵⁹ For patients whose myopathy has recurred with multiple statin rechallenges or whose lipid-lowering goal requires a more potent therapy, rosuvastatin in alternate-day or once- or twice-a-week schedules is efficacious and well tolerated in many patients.^36,37,60 Of note, however, although such alternate-day therapies may produce excellent reductions in cholesterol levels, these regimens have not been proven to reduce cardiovascular end points.

Alternative lipid-lowering therapy. Occasionally, a patient cannot tolerate even intermittent rosuvastatin. In these cases, we prescribe resin therapy, which is well tolerated in those with recurrent statin myopathy.⁶¹

Although some believe that ezetimibe (Zetia) is an option for these patients, we do not agree, since it often causes similar muscle complaints in the most sensitive statin myopathy patients.³⁰ Furthermore, ezetimibe has not been shown to improve cardiac end points.

Red yeast rice is also not a safe alternative in these patients, in whom muscle complaints and CK elevations frequently develop anew on this unregulated supplement despite its low lovastatin equivalence, 6 mg a day.⁶² A recent study showed that there is wide variability in the amount of lovastatin in over-the-counter red yeast rice; the median dose was 6 mg, and the maximum dose was 14.5 mg.⁶³

The ultimate lipid-lowering plan for most of these patients will require a compromise between the ideal LDL-C goal and the LDL-C level that is achievable with these alternate attempts at lipid lowering.

While combination therapy may be attractive in patients with combined lipid disorders and no muscle complaints, fibrates are more likely to cause muscle toxicity per dose prescribed than statins, and the addition of fibrates to statin therapy increases the risks of muscle reactions.^64,65 The evidence that fibrates reduce cardiovascular end points is much less robust than that for statins, which further reduces enthusiasm for combination therapy in patients with statin muscle toxicity.^66,67

When a patient taking a statin complains of muscle aches, is he or she experiencing statin-induced myopathy or some other problem? Should statin therapy be discontinued?

Statins have proven efficacy in preventing heart attacks and death,¹ and they are the most widely prescribed drugs worldwide. Nevertheless, they remain underused, with only 50% of those who would benefit from being on a statin receiving one.^2,3 In addition, at least 25% of adults who start taking statins stop taking them by 6 months, and up to 60% stop by 2 years.⁴

Patient and physician fears about myopathy remain a key reason for stopping. Myopathy, a known side effect of statins, is rare in randomized controlled trials, but less so in observational studies and clinical experience. This discrepancy between clinical trials and clinical experience reduces confidence in lipid-lowering therapy and contributes to its underuse.

This review emphasizes clinical aspects of statin myopathy that are important to the practicing physician. We will define myopathy, review its purported mechanisms, and describe a clinical approach to patients with possible toxicity, including risk factors, physical findings, and consideration of alternate diagnoses. Since there is no single test to diagnose statin-induced myopathy, we offer a framework to aid clinicians in stratifying patients based on the likelihood that their symptoms are due to statin toxicity weighed against the likelihood that they will benefit from statin therapy.

DEFINITIONS DIFFER

Little consensus exists on how to define the adverse muscle effects of statins,⁵ which may contribute to the underdiagnosis of this complication. The magnitude of creatine kinase (CK) elevation required to define rhabdomyolysis has increased from 500 IU/L in 1982,⁶ to 1,000 IU/L in 1988,⁷ to 50 times the upper limit of normal in one current definition.⁸ The American Heart Association, the American College of Cardiology, the National Heart Lung and Blood Institute,⁹ the National Lipid Association,⁸ and the US Food and Drug Administration¹⁰ all differ in their definitions.

Our definitions

For the purpose of this article, we offer the following definitions:

Myalgia—muscle weakness, soreness, tenderness, stiffness, cramping, or aching, either at rest or with exertion, without any elevation in CK.

Myositis—elevated CK with or without muscle symptoms. The “-itis” suffix is unfortunate since myositis does not correspond to inflammation on biopsy.

Rhabdomyolysis—muscle symptoms with a CK level 10 times the upper limit of normal or higher. Evidence of renal dysfunction is not required for the diagnosis, as preexisting renal disease and hydration status are more closely related to kidney damage than the degree of muscle injury.¹¹

STATIN MYOPATHY IS MORE COMMON IN THE REAL WORLD THAN IN TRIALS

The incidence of statin-induced myopathy is significantly lower in randomized controlled trials of statin efficacy than in observational studies of real-world patients. In randomized clinical trials, myalgia was reported in 1% to 5% of patients in the statin groups and placebo groups alike,^9,12 whereas clinical practice would suggest it is more common.

Why is statin-induced myopathy so uncommon in clinical trials?

A reason may be that patients in clinical trials are carefully screened. To minimize toxicity, the clinical trials of statins excluded patients with renal insufficiency, hepatic insufficiency, a history of muscular complaints, and poorly controlled diabetes, as well as patients taking drugs with possible interactions. Large efficacy trials have excluded up to 30% of the participants in active prerandomization phases.^13,14

Another reason is that these trials were designed to assess the efficacy of statins and were not sensitive to adverse effects like muscle pain. When they looked at myopathy, they focused on rhabdomyolysis—the most severe form—rather than on myalgia, fatigue, or other minor muscle complaints.¹⁵ Additionally, most trials enrolled too few patients and did not have long enough follow-up to reveal infrequent toxicities.

Despite the strict criteria, a significant number of trial patients discontinued statin therapy during the study period. In the Treat to New Targets (TNT) trial, 5% of patients in both the high- and low-dose atorvastatin (Lipitor) groups experienced muscle toxicity, even though 35% of eligible patients had been excluded during the open-label run-in phase.¹⁴

Also, physicians may overlook and patients may fail to report symptoms such as fatigue, malaise, or dyspnea that are not commonly accepted as signs of statin toxicity.¹⁶

Findings from observational studies

Observational studies in nonselected outpatients show a higher frequency of muscle complaints in the statin groups than in the control groups. These studies suggest the frequency of statin myopathy is 9% to 20%.^17–19

The Prediction of Muscular Risk in Observational Conditions (PRIMO) study²⁰ was one of the largest and best-defined observational studies of muscular symptoms in an unselected population. It included 7,924 French outpatients with hypercholesterolemia, ages 18 to 75 years, on high-dose statins for 3 or more months before the study. Daily statin regimens included atorvastatin 40 to 80 mg, fluvastatin (Lescol) 80 mg, pravastatin (Pravachol) 40 mg, and simvastatin (Zocor) 40 to 80 mg. In this study, 10.5% of patients reported muscle-related symptoms.

Buettner et al,²¹ in another cross-sectional study, interviewed and examined 3,580 adults over age 40. Of those taking statins, 22% reported having had musculoskeletal pain in at least one anatomic region in the last 30 days, compared with 16.7% of those not taking a statin.

In the United States, where an estimated 33 million adults use statins, musculoskeletal pain can be expected to occur in 7 million people, likely induced by statin therapy in 25% of cases.²²

WHAT CAUSES STATIN MYOPATHY?

The causes of statin-induced myopathy are poorly understood.

Historically, statin-induced toxicity was thought to be caused by inhibition of the synthesis of mevalonate, leading to depletion of its metabolites, such as cholesterol, isoprenoids, and ubiquinone (coenzyme Q10). Depletion of intracellular cholesterol may lead to abnormal membrane behaviors; depletion of isoprenoids may affect intracellular signaling; depletion of coenzyme Q10 may in turn reduce mitochondrial respiratory function. Genetic factors may also play a role, contributing to pharmacokinetics and predisposing metabolic muscle disorders.^23,24

Statin-induced myopathy seems to be different in randomized efficacy trials than in the clinical setting. In randomized trials, the mechanism appears to involve abnormal pharmacokinetics. The participants are carefully selected to have a low risk of muscle toxicity, but some develop toxicity when statin levels are elevated because of reduced drug breakdown and metabolism. However, in clinical practice, where a much larger group of unselected patients are exposed to statins, toxicity appears to be more related to a metabolic predisposition.^25–27

Multiple minor metabolic abnormalities have been described in the muscles of patients with statin-induced muscle toxicity, suggesting that some patients have a predisposition for muscle complaints.²³ About 25% of patients with recurrent rhabdomyolysis irrespective of lipid-lowering therapy have an underlying metabolic muscle disorder.²⁸ In these vulnerable patients, minor metabolic defects are exacerbated by any agent that reduces the delivery of fat substrate to muscle, leading to muscle starvation.

This concept explains why patients may develop the same muscle complaint on different lipid-lowering agents.^29,30 It also may explain why rhabdomyolysis can occur after apheresis of lipids, when no drugs have been given.³¹ In vulnerable patients, muscle toxicity may result from any agent that lessens the lipid substrate available to muscle rather than from the reduction of products downstream from mevalonate by statins.

SOME STATINS MAY BE LESS TOXIC

In the PRIMO study, muscle-related symptoms occurred with the various regimens as follows:

• Fluvastatin XL 40 mg—5.1%
• Pravastatin 40 mg—10.9%
• Atorvastatin 40 to 80 mg—14.9%
• Simvastatin 40 to 80 mg—18.2%.

Others have also shown that fluvastatin contributed to the smallest number of reported cases of rhabdomyolysis among statins: 55 (1.6%) of 3,339 cases.³⁴

More recent studies indicate that rosuvastatin (Crestor), the most hydrophilic statin, may be well tolerated in those who do not tolerate other statins,^35–37 though no head-to-head trial has been done.

RISK FACTORS FOR STATIN-INDUCED MYOPATHY

APPROACH TO SUSPECTED STATIN-INDUCED MYOPATHY

The recommendations that follow are based on observations from our statin myopathy clinic in more than 650 patients, of whom more than 60 have suffered rhabdomyolysis. This experience is largely anecdotal, since such patients have not been well studied in controlled trials.

Are the symptoms due to the statin?

In our experience, most patients who develop significant weakness and pain on statin therapy have normal CK levels.⁴⁰

Since there is as yet no test to confirm or reject the diagnosis of statin toxicity, the first objective is to determine the likelihood that the muscle complaint is being caused by statin therapy. Factors that make statin toxicity more likely must be weighed against any features that are atypical or that favor an alternate diagnosis.

The final decision about future statin treatment depends on the balance between the expected benefit of statin therapy for each individual and the likelihood that the symptoms are due to statin therapy. Below, we provide an algorithmic approach based on history, physical examination, and laboratory findings.

Findings from the history that implicate statins

Many muscle symptoms resolve within 2 weeks of starting statin therapy. Therefore, if patients have a normal CK level and can tolerate the symptoms, we ask them to continue therapy and see if their symptoms resolve with continued use.

Symptoms that persist beyond the first 2 weeks of therapy are likely due to the statin. These include symmetric burning or pain in the large muscles during exercise that was not present before lipid-lowering therapy. Any symptom that reproducibly recurs with statin rechallenge and disappears within 2 weeks of discontinuing therapy is more likely to be caused by the statin.

Findings of the PRIMO study are representative of typical statin-induced symptoms that we see in our clinic.²⁰

• Most patients did not identify a trigger, but the 40% who did had engaged in unusual physical exertion or had received a new drug in addition to the statin.
• Heaviness, stiffness, or cramps predominated in 70%, with only a quarter noting weakness and another quarter suffering myalgias during exercise. Pain was diffuse in 60% and more common in the lower extremities than the upper extremities.
• Physically active patients were more likely to suffer muscle symptoms than sedentary patients, echoing the observation by Sinzinger and O’Grady that athletes are especially intolerant of lipid-lowering therapy.⁴¹
• Patients who have had muscle complaints with other drug therapies such as bisphosphonates, ⁴² raloxifene (Evista),⁴³ or diuretics may be having the same provocation of an underlying muscle predisposition by the statin.
• A personal or family history of muscle complaints predisposed patients to statin-induced myopathy.²⁰

Finally, we have repeatedly found that when dyspnea and fatigue are associated with the muscle complaint, they are more likely to be caused by statins.⁴⁴

Atypical complaints require us to search for an alternate diagnosis before dismissing them as not statin-induced.

Previous episodes of myoglobinuria (dark urine after exertion) would raise the possibility of a metabolic myopathy. Frequent muscle cramps raise the possibility of a metabolic myopathy or motor neuron disease.

Asymmetric pain or pain involving joints and ligaments is less likely to be statin-related but in our experience occasionally occurs.

Some patients with underlying degenerative arthritis or tendinitis repeatedly develop worsening symptoms each time they take statins, perhaps because muscle weakness exacerbates the arthropathy or tendinopathy.⁴⁵

Although statin-related muscle complaints are almost always symmetric, many patients with underlying peripheral vascular disease have asymmetric pain in the limb with poor vascular supply; the pain is reproducible by statin rechallenge.

In our experience, many patients whose chronic low back pain is due to a lumbar radiculopathy experience exacerbations of that pain whenever they start statins.

Weakness preceding the use of the statins or a family history of neuromuscular disorders may indicate a neurodegenerative disorder and warrants consideration of early neurological consultation.

Although these rules are not absolute, they are helpful in the initial evaluation, which must exclude alternative diagnoses.

Is the patient a vegetarian? A drinker? Taking supplements?

Taking a careful history of diet and supplement use is important to find exposures that may increase the risk of statin-related muscle complaints. Vegetarians may develop carnitine or vitamin B₁₂ deficiencies. Alcohol and vitamin E and other supplements are occasional causes of muscle symptoms falsely attributed to statin therapy. It is also important to remember that red yeast rice contains lovastatin, which can exacerbate myopathy, especially when taken in conjunction with another statin.

Physical examination

The examination of patients with possible statin-induced myopathy begins with a general assessment for signs of hypothyroidism or excess alcohol consumption.

Ankle-brachial indices are used to exclude significant peripheral vascular disease.

The musculoskeletal examination focuses on muscle atrophy, tone, and strength but also excludes tendinopathies, arthropathies, and myofascial pain syndromes, which are often confused with muscle pain.

We conduct quantitative dynamometry, measuring handgrip with a Jamar dynamometer and hip abduction with a Nicholas Manual Muscle Tester. Precise dynamometric measurements are tracked at subsequent visits and are helpful in following recovery from myopathy as well as in tracking strength during subsequent statin rechallenges.

We routinely look for hyperreflexia, fasciculations, extensor-plantar responses, and decreased heel-to-shin movement, which would suggest myelopathy. Reflexes and a sensory examination including vibration and temperature sensation help exclude radiculopathy and peripheral neuropathy.

Laboratory evaluation

In every patient with possibly statin myopathy, the primary care physician should measure:

• The serum CK level (preferably more than 72 hours after exercise)
• The 25-hydroxy vitamin level
• The thyroid-stimulating hormone level.

Further laboratory evaluation depends on the findings and will often be directed by subspecialists. For example, we assess the sedimentation rate, anti-Ro and anti-La antibodies, and the myositis panel in patients with elevated CK whose other findings suggest an autoimmune or inflammatory process. We test serum carnitine levels (free, total, and esterified), fasting serum lactate levels, and serum cortisol in those with findings suggestive of metabolic myopathy. We order electromyography and nerve conduction studies in patients with possible myelopathy, peripheral neuropathy, or inflammatory myopathy.

Ultimately, a muscle biopsy may be necessary to exclude inflammatory or necrotizing myopathies in patients whose CK remains elevated despite withdrawal of statins. It may also be helpful when other findings suggest a metabolic myopathy. When a biopsy is needed, magnetic resonance imaging of the affected limb may identify an affected muscle for biopsy.

MANAGEMENT

Reassess the lipid goal

If the source of a complaint remains unclear after challenge and rechallenge with alternate statins, we generally recommend restarting therapy and trying to achieve the LDL-C goal. If the workup suggests a neurologic or rheumatolic etiology, a referral to a specialist is indicated. However, if the evaluation leads to a diagnosis of statin-induced myopathy, the next task is to reassess the lipid treatment goals.

The Adult Treatment Panel (ATP) III guidelines should be used to assess the patient’s risk of having major coronary heart disease in the next 10 years, and to determine appropriate LDL-C goals.⁴⁶ Some patients with suspected toxicity may have been treated to more aggressive LDL-C levels than recommended by these guidelines. The first step in these patients is to reduce or discontinue the unnecessary statin, even if there is no clear evidence of toxicity.

For the rest of patients with suspected toxicity, the decision to discontinue statin therapy must be weighed against the estimated reduction in risk associated with taking a statin medication.

In patients whose evaluation suggests statin myopathy, we stop all lipid-lowering therapy for 6 weeks and see if symptoms resolve and if grip and hip strength increase by dynamometry.

We often give these patient supplements of 600 mg daily of a bioavailable source of coenzyme Q10 and fish oil during this statin holiday. The data supporting the use of these supplements are mixed but the risks are minimal.⁵ In patients whose evaluation suggests a primary disorder in fatty acid oxidation, we add a trial of l-carnitine supplementation if symptoms do not resolve after a 6-week course of the coenzyme Q10 and fish oil.

If symptoms persist or if resolution is unclear at 6 weeks, we extend the holiday for an additional 6 weeks, except in patients with recent unstable coronary disease: for these patients, unless there is evidence of rhabdomyolysis, we believe that the benefits of continued statin therapy exceed the risks.

If the initial evaluation is consistent with statin myopathy and the neuromuscular symptoms (myalgias and weakness) do not respond within a few months of statin withdrawal, neurologic consultation is indicated to evaluate for an underlying neurologic disorder that has become symptomatic during statin therapy but whose existence is independent of the statin therapy. In some cases, the preexisting neurologic disorder may become symptomatic because of the statin therapy and remain symptomatic despite discontinuation of the statin therapy.

Restarting lipid-lowering therapy

Once the myopathy symptoms have abated or are controlled, a rechallenge of statin therapy is in order for those whose risk profile suggests greater benefit from statin therapy.

We consider the complete statin exposure history and any concomitant therapy that may have been competing with cytochrome P450 (CYP) metabolism of statins in designing an alternate lipid-lowering plan.

For patients with known coronary or vascular disease, in whom the survival benefit of statins is greatest, we generally try to find a statin regimen that is tolerable. Long-acting fluvastatin or a statin with less CYP dependence, such as pravastatin, is often successful.⁵⁹ For patients whose myopathy has recurred with multiple statin rechallenges or whose lipid-lowering goal requires a more potent therapy, rosuvastatin in alternate-day or once- or twice-a-week schedules is efficacious and well tolerated in many patients.^36,37,60 Of note, however, although such alternate-day therapies may produce excellent reductions in cholesterol levels, these regimens have not been proven to reduce cardiovascular end points.

Alternative lipid-lowering therapy. Occasionally, a patient cannot tolerate even intermittent rosuvastatin. In these cases, we prescribe resin therapy, which is well tolerated in those with recurrent statin myopathy.⁶¹

Although some believe that ezetimibe (Zetia) is an option for these patients, we do not agree, since it often causes similar muscle complaints in the most sensitive statin myopathy patients.³⁰ Furthermore, ezetimibe has not been shown to improve cardiac end points.

Red yeast rice is also not a safe alternative in these patients, in whom muscle complaints and CK elevations frequently develop anew on this unregulated supplement despite its low lovastatin equivalence, 6 mg a day.⁶² A recent study showed that there is wide variability in the amount of lovastatin in over-the-counter red yeast rice; the median dose was 6 mg, and the maximum dose was 14.5 mg.⁶³

The ultimate lipid-lowering plan for most of these patients will require a compromise between the ideal LDL-C goal and the LDL-C level that is achievable with these alternate attempts at lipid lowering.

While combination therapy may be attractive in patients with combined lipid disorders and no muscle complaints, fibrates are more likely to cause muscle toxicity per dose prescribed than statins, and the addition of fibrates to statin therapy increases the risks of muscle reactions.^64,65 The evidence that fibrates reduce cardiovascular end points is much less robust than that for statins, which further reduces enthusiasm for combination therapy in patients with statin muscle toxicity.^66,67

When a patient taking a statin complains of muscle aches, is he or she experiencing statin-induced myopathy or some other problem? Should statin therapy be discontinued?

Statins have proven efficacy in preventing heart attacks and death,¹ and they are the most widely prescribed drugs worldwide. Nevertheless, they remain underused, with only 50% of those who would benefit from being on a statin receiving one.^2,3 In addition, at least 25% of adults who start taking statins stop taking them by 6 months, and up to 60% stop by 2 years.⁴

Patient and physician fears about myopathy remain a key reason for stopping. Myopathy, a known side effect of statins, is rare in randomized controlled trials, but less so in observational studies and clinical experience. This discrepancy between clinical trials and clinical experience reduces confidence in lipid-lowering therapy and contributes to its underuse.

This review emphasizes clinical aspects of statin myopathy that are important to the practicing physician. We will define myopathy, review its purported mechanisms, and describe a clinical approach to patients with possible toxicity, including risk factors, physical findings, and consideration of alternate diagnoses. Since there is no single test to diagnose statin-induced myopathy, we offer a framework to aid clinicians in stratifying patients based on the likelihood that their symptoms are due to statin toxicity weighed against the likelihood that they will benefit from statin therapy.

DEFINITIONS DIFFER

Little consensus exists on how to define the adverse muscle effects of statins,⁵ which may contribute to the underdiagnosis of this complication. The magnitude of creatine kinase (CK) elevation required to define rhabdomyolysis has increased from 500 IU/L in 1982,⁶ to 1,000 IU/L in 1988,⁷ to 50 times the upper limit of normal in one current definition.⁸ The American Heart Association, the American College of Cardiology, the National Heart Lung and Blood Institute,⁹ the National Lipid Association,⁸ and the US Food and Drug Administration¹⁰ all differ in their definitions.

Our definitions

For the purpose of this article, we offer the following definitions:

Myalgia—muscle weakness, soreness, tenderness, stiffness, cramping, or aching, either at rest or with exertion, without any elevation in CK.

Myositis—elevated CK with or without muscle symptoms. The “-itis” suffix is unfortunate since myositis does not correspond to inflammation on biopsy.

Rhabdomyolysis—muscle symptoms with a CK level 10 times the upper limit of normal or higher. Evidence of renal dysfunction is not required for the diagnosis, as preexisting renal disease and hydration status are more closely related to kidney damage than the degree of muscle injury.¹¹

STATIN MYOPATHY IS MORE COMMON IN THE REAL WORLD THAN IN TRIALS

The incidence of statin-induced myopathy is significantly lower in randomized controlled trials of statin efficacy than in observational studies of real-world patients. In randomized clinical trials, myalgia was reported in 1% to 5% of patients in the statin groups and placebo groups alike,^9,12 whereas clinical practice would suggest it is more common.

Why is statin-induced myopathy so uncommon in clinical trials?

A reason may be that patients in clinical trials are carefully screened. To minimize toxicity, the clinical trials of statins excluded patients with renal insufficiency, hepatic insufficiency, a history of muscular complaints, and poorly controlled diabetes, as well as patients taking drugs with possible interactions. Large efficacy trials have excluded up to 30% of the participants in active prerandomization phases.^13,14

Another reason is that these trials were designed to assess the efficacy of statins and were not sensitive to adverse effects like muscle pain. When they looked at myopathy, they focused on rhabdomyolysis—the most severe form—rather than on myalgia, fatigue, or other minor muscle complaints.¹⁵ Additionally, most trials enrolled too few patients and did not have long enough follow-up to reveal infrequent toxicities.

Despite the strict criteria, a significant number of trial patients discontinued statin therapy during the study period. In the Treat to New Targets (TNT) trial, 5% of patients in both the high- and low-dose atorvastatin (Lipitor) groups experienced muscle toxicity, even though 35% of eligible patients had been excluded during the open-label run-in phase.¹⁴

Also, physicians may overlook and patients may fail to report symptoms such as fatigue, malaise, or dyspnea that are not commonly accepted as signs of statin toxicity.¹⁶

Findings from observational studies

Observational studies in nonselected outpatients show a higher frequency of muscle complaints in the statin groups than in the control groups. These studies suggest the frequency of statin myopathy is 9% to 20%.^17–19

The Prediction of Muscular Risk in Observational Conditions (PRIMO) study²⁰ was one of the largest and best-defined observational studies of muscular symptoms in an unselected population. It included 7,924 French outpatients with hypercholesterolemia, ages 18 to 75 years, on high-dose statins for 3 or more months before the study. Daily statin regimens included atorvastatin 40 to 80 mg, fluvastatin (Lescol) 80 mg, pravastatin (Pravachol) 40 mg, and simvastatin (Zocor) 40 to 80 mg. In this study, 10.5% of patients reported muscle-related symptoms.

Buettner et al,²¹ in another cross-sectional study, interviewed and examined 3,580 adults over age 40. Of those taking statins, 22% reported having had musculoskeletal pain in at least one anatomic region in the last 30 days, compared with 16.7% of those not taking a statin.

In the United States, where an estimated 33 million adults use statins, musculoskeletal pain can be expected to occur in 7 million people, likely induced by statin therapy in 25% of cases.²²

WHAT CAUSES STATIN MYOPATHY?

The causes of statin-induced myopathy are poorly understood.

Historically, statin-induced toxicity was thought to be caused by inhibition of the synthesis of mevalonate, leading to depletion of its metabolites, such as cholesterol, isoprenoids, and ubiquinone (coenzyme Q10). Depletion of intracellular cholesterol may lead to abnormal membrane behaviors; depletion of isoprenoids may affect intracellular signaling; depletion of coenzyme Q10 may in turn reduce mitochondrial respiratory function. Genetic factors may also play a role, contributing to pharmacokinetics and predisposing metabolic muscle disorders.^23,24

Statin-induced myopathy seems to be different in randomized efficacy trials than in the clinical setting. In randomized trials, the mechanism appears to involve abnormal pharmacokinetics. The participants are carefully selected to have a low risk of muscle toxicity, but some develop toxicity when statin levels are elevated because of reduced drug breakdown and metabolism. However, in clinical practice, where a much larger group of unselected patients are exposed to statins, toxicity appears to be more related to a metabolic predisposition.^25–27

Multiple minor metabolic abnormalities have been described in the muscles of patients with statin-induced muscle toxicity, suggesting that some patients have a predisposition for muscle complaints.²³ About 25% of patients with recurrent rhabdomyolysis irrespective of lipid-lowering therapy have an underlying metabolic muscle disorder.²⁸ In these vulnerable patients, minor metabolic defects are exacerbated by any agent that reduces the delivery of fat substrate to muscle, leading to muscle starvation.

This concept explains why patients may develop the same muscle complaint on different lipid-lowering agents.^29,30 It also may explain why rhabdomyolysis can occur after apheresis of lipids, when no drugs have been given.³¹ In vulnerable patients, muscle toxicity may result from any agent that lessens the lipid substrate available to muscle rather than from the reduction of products downstream from mevalonate by statins.

SOME STATINS MAY BE LESS TOXIC

In the PRIMO study, muscle-related symptoms occurred with the various regimens as follows:

• Fluvastatin XL 40 mg—5.1%
• Pravastatin 40 mg—10.9%
• Atorvastatin 40 to 80 mg—14.9%
• Simvastatin 40 to 80 mg—18.2%.

Others have also shown that fluvastatin contributed to the smallest number of reported cases of rhabdomyolysis among statins: 55 (1.6%) of 3,339 cases.³⁴

More recent studies indicate that rosuvastatin (Crestor), the most hydrophilic statin, may be well tolerated in those who do not tolerate other statins,^35–37 though no head-to-head trial has been done.

RISK FACTORS FOR STATIN-INDUCED MYOPATHY

APPROACH TO SUSPECTED STATIN-INDUCED MYOPATHY

The recommendations that follow are based on observations from our statin myopathy clinic in more than 650 patients, of whom more than 60 have suffered rhabdomyolysis. This experience is largely anecdotal, since such patients have not been well studied in controlled trials.

Are the symptoms due to the statin?

In our experience, most patients who develop significant weakness and pain on statin therapy have normal CK levels.⁴⁰

Since there is as yet no test to confirm or reject the diagnosis of statin toxicity, the first objective is to determine the likelihood that the muscle complaint is being caused by statin therapy. Factors that make statin toxicity more likely must be weighed against any features that are atypical or that favor an alternate diagnosis.

The final decision about future statin treatment depends on the balance between the expected benefit of statin therapy for each individual and the likelihood that the symptoms are due to statin therapy. Below, we provide an algorithmic approach based on history, physical examination, and laboratory findings.

Findings from the history that implicate statins

Many muscle symptoms resolve within 2 weeks of starting statin therapy. Therefore, if patients have a normal CK level and can tolerate the symptoms, we ask them to continue therapy and see if their symptoms resolve with continued use.

Symptoms that persist beyond the first 2 weeks of therapy are likely due to the statin. These include symmetric burning or pain in the large muscles during exercise that was not present before lipid-lowering therapy. Any symptom that reproducibly recurs with statin rechallenge and disappears within 2 weeks of discontinuing therapy is more likely to be caused by the statin.

Findings of the PRIMO study are representative of typical statin-induced symptoms that we see in our clinic.²⁰

• Most patients did not identify a trigger, but the 40% who did had engaged in unusual physical exertion or had received a new drug in addition to the statin.
• Heaviness, stiffness, or cramps predominated in 70%, with only a quarter noting weakness and another quarter suffering myalgias during exercise. Pain was diffuse in 60% and more common in the lower extremities than the upper extremities.
• Physically active patients were more likely to suffer muscle symptoms than sedentary patients, echoing the observation by Sinzinger and O’Grady that athletes are especially intolerant of lipid-lowering therapy.⁴¹
• Patients who have had muscle complaints with other drug therapies such as bisphosphonates, ⁴² raloxifene (Evista),⁴³ or diuretics may be having the same provocation of an underlying muscle predisposition by the statin.
• A personal or family history of muscle complaints predisposed patients to statin-induced myopathy.²⁰

Finally, we have repeatedly found that when dyspnea and fatigue are associated with the muscle complaint, they are more likely to be caused by statins.⁴⁴

Atypical complaints require us to search for an alternate diagnosis before dismissing them as not statin-induced.

Previous episodes of myoglobinuria (dark urine after exertion) would raise the possibility of a metabolic myopathy. Frequent muscle cramps raise the possibility of a metabolic myopathy or motor neuron disease.

Asymmetric pain or pain involving joints and ligaments is less likely to be statin-related but in our experience occasionally occurs.

Some patients with underlying degenerative arthritis or tendinitis repeatedly develop worsening symptoms each time they take statins, perhaps because muscle weakness exacerbates the arthropathy or tendinopathy.⁴⁵

Although statin-related muscle complaints are almost always symmetric, many patients with underlying peripheral vascular disease have asymmetric pain in the limb with poor vascular supply; the pain is reproducible by statin rechallenge.

In our experience, many patients whose chronic low back pain is due to a lumbar radiculopathy experience exacerbations of that pain whenever they start statins.

Weakness preceding the use of the statins or a family history of neuromuscular disorders may indicate a neurodegenerative disorder and warrants consideration of early neurological consultation.

Although these rules are not absolute, they are helpful in the initial evaluation, which must exclude alternative diagnoses.

Is the patient a vegetarian? A drinker? Taking supplements?

Taking a careful history of diet and supplement use is important to find exposures that may increase the risk of statin-related muscle complaints. Vegetarians may develop carnitine or vitamin B₁₂ deficiencies. Alcohol and vitamin E and other supplements are occasional causes of muscle symptoms falsely attributed to statin therapy. It is also important to remember that red yeast rice contains lovastatin, which can exacerbate myopathy, especially when taken in conjunction with another statin.

Physical examination

The examination of patients with possible statin-induced myopathy begins with a general assessment for signs of hypothyroidism or excess alcohol consumption.

Ankle-brachial indices are used to exclude significant peripheral vascular disease.

The musculoskeletal examination focuses on muscle atrophy, tone, and strength but also excludes tendinopathies, arthropathies, and myofascial pain syndromes, which are often confused with muscle pain.

We conduct quantitative dynamometry, measuring handgrip with a Jamar dynamometer and hip abduction with a Nicholas Manual Muscle Tester. Precise dynamometric measurements are tracked at subsequent visits and are helpful in following recovery from myopathy as well as in tracking strength during subsequent statin rechallenges.

We routinely look for hyperreflexia, fasciculations, extensor-plantar responses, and decreased heel-to-shin movement, which would suggest myelopathy. Reflexes and a sensory examination including vibration and temperature sensation help exclude radiculopathy and peripheral neuropathy.

Laboratory evaluation

In every patient with possibly statin myopathy, the primary care physician should measure:

• The serum CK level (preferably more than 72 hours after exercise)
• The 25-hydroxy vitamin level
• The thyroid-stimulating hormone level.

Further laboratory evaluation depends on the findings and will often be directed by subspecialists. For example, we assess the sedimentation rate, anti-Ro and anti-La antibodies, and the myositis panel in patients with elevated CK whose other findings suggest an autoimmune or inflammatory process. We test serum carnitine levels (free, total, and esterified), fasting serum lactate levels, and serum cortisol in those with findings suggestive of metabolic myopathy. We order electromyography and nerve conduction studies in patients with possible myelopathy, peripheral neuropathy, or inflammatory myopathy.

Ultimately, a muscle biopsy may be necessary to exclude inflammatory or necrotizing myopathies in patients whose CK remains elevated despite withdrawal of statins. It may also be helpful when other findings suggest a metabolic myopathy. When a biopsy is needed, magnetic resonance imaging of the affected limb may identify an affected muscle for biopsy.

MANAGEMENT

Reassess the lipid goal

If the source of a complaint remains unclear after challenge and rechallenge with alternate statins, we generally recommend restarting therapy and trying to achieve the LDL-C goal. If the workup suggests a neurologic or rheumatolic etiology, a referral to a specialist is indicated. However, if the evaluation leads to a diagnosis of statin-induced myopathy, the next task is to reassess the lipid treatment goals.

The Adult Treatment Panel (ATP) III guidelines should be used to assess the patient’s risk of having major coronary heart disease in the next 10 years, and to determine appropriate LDL-C goals.⁴⁶ Some patients with suspected toxicity may have been treated to more aggressive LDL-C levels than recommended by these guidelines. The first step in these patients is to reduce or discontinue the unnecessary statin, even if there is no clear evidence of toxicity.

For the rest of patients with suspected toxicity, the decision to discontinue statin therapy must be weighed against the estimated reduction in risk associated with taking a statin medication.

In patients whose evaluation suggests statin myopathy, we stop all lipid-lowering therapy for 6 weeks and see if symptoms resolve and if grip and hip strength increase by dynamometry.

We often give these patient supplements of 600 mg daily of a bioavailable source of coenzyme Q10 and fish oil during this statin holiday. The data supporting the use of these supplements are mixed but the risks are minimal.⁵ In patients whose evaluation suggests a primary disorder in fatty acid oxidation, we add a trial of l-carnitine supplementation if symptoms do not resolve after a 6-week course of the coenzyme Q10 and fish oil.

If symptoms persist or if resolution is unclear at 6 weeks, we extend the holiday for an additional 6 weeks, except in patients with recent unstable coronary disease: for these patients, unless there is evidence of rhabdomyolysis, we believe that the benefits of continued statin therapy exceed the risks.

If the initial evaluation is consistent with statin myopathy and the neuromuscular symptoms (myalgias and weakness) do not respond within a few months of statin withdrawal, neurologic consultation is indicated to evaluate for an underlying neurologic disorder that has become symptomatic during statin therapy but whose existence is independent of the statin therapy. In some cases, the preexisting neurologic disorder may become symptomatic because of the statin therapy and remain symptomatic despite discontinuation of the statin therapy.

Restarting lipid-lowering therapy

Once the myopathy symptoms have abated or are controlled, a rechallenge of statin therapy is in order for those whose risk profile suggests greater benefit from statin therapy.

We consider the complete statin exposure history and any concomitant therapy that may have been competing with cytochrome P450 (CYP) metabolism of statins in designing an alternate lipid-lowering plan.

For patients with known coronary or vascular disease, in whom the survival benefit of statins is greatest, we generally try to find a statin regimen that is tolerable. Long-acting fluvastatin or a statin with less CYP dependence, such as pravastatin, is often successful.⁵⁹ For patients whose myopathy has recurred with multiple statin rechallenges or whose lipid-lowering goal requires a more potent therapy, rosuvastatin in alternate-day or once- or twice-a-week schedules is efficacious and well tolerated in many patients.^36,37,60 Of note, however, although such alternate-day therapies may produce excellent reductions in cholesterol levels, these regimens have not been proven to reduce cardiovascular end points.

Alternative lipid-lowering therapy. Occasionally, a patient cannot tolerate even intermittent rosuvastatin. In these cases, we prescribe resin therapy, which is well tolerated in those with recurrent statin myopathy.⁶¹

Although some believe that ezetimibe (Zetia) is an option for these patients, we do not agree, since it often causes similar muscle complaints in the most sensitive statin myopathy patients.³⁰ Furthermore, ezetimibe has not been shown to improve cardiac end points.

Red yeast rice is also not a safe alternative in these patients, in whom muscle complaints and CK elevations frequently develop anew on this unregulated supplement despite its low lovastatin equivalence, 6 mg a day.⁶² A recent study showed that there is wide variability in the amount of lovastatin in over-the-counter red yeast rice; the median dose was 6 mg, and the maximum dose was 14.5 mg.⁶³

The ultimate lipid-lowering plan for most of these patients will require a compromise between the ideal LDL-C goal and the LDL-C level that is achievable with these alternate attempts at lipid lowering.

While combination therapy may be attractive in patients with combined lipid disorders and no muscle complaints, fibrates are more likely to cause muscle toxicity per dose prescribed than statins, and the addition of fibrates to statin therapy increases the risks of muscle reactions.^64,65 The evidence that fibrates reduce cardiovascular end points is much less robust than that for statins, which further reduces enthusiasm for combination therapy in patients with statin muscle toxicity.^66,67

There was an error in the caption for Figure 2 in: Villa-Forte A. Giant cell arteritis: Suspect it, treat it promptly. Cleve Clin J Med 2011; 78:265–270. The image was of digital subtraction angiography, not magnetic resonance angiography. The caption has been corrected in the online version of the article.

There was an error in the caption for Figure 2 in: Villa-Forte A. Giant cell arteritis: Suspect it, treat it promptly. Cleve Clin J Med 2011; 78:265–270. The image was of digital subtraction angiography, not magnetic resonance angiography. The caption has been corrected in the online version of the article.

There was an error in the caption for Figure 2 in: Villa-Forte A. Giant cell arteritis: Suspect it, treat it promptly. Cleve Clin J Med 2011; 78:265–270. The image was of digital subtraction angiography, not magnetic resonance angiography. The caption has been corrected in the online version of the article.

A 52-year-old woman is referred to our dermatology clinic by her primary care physician for swelling and redness of seven old scars. The swelling began 3 months ago.

She is on no regular medications. She has never smoked. She underwent liposuction 7 years ago and appendectomy at age 15.

Laboratory testing shows mild leukopenia, with a white blood cell count of 3.0 × 10⁹/L (reference range 4.2–9.0). Other routine laboratory values are normal, including antinuclear antibody, extractable nuclear antibody, anti-double-stranded DNA, rheumatoid factor, urinalysis, erythrocyte sedimentation rate, C-reactive protein, serum calcium concentration, and liver and renal function tests.

Chest radiography reveals bilateral hilar lymphadenopathy.

Q: What is the next most appropriate diagnostic procedure?

• Skin biopsy
• High-resolution computed tomography (CT) of the chest
• QuantiFERON-TB Gold test
• Ventilatory function tests
• Serum angiotensin-converting enzyme (ACE) level

A: All are appropriate at this point. In this case, skin biopsy and high-resolution CT were performed. Histopathologic examination of one of the scars showed multiple well-demarcated, large, noncaseating epitheloid granulomas with histiocytes and multinucleated giant cells. High-resolution CT confirmed bilateral hilar and mediastinal lymphadenopathy and revealed micronodular densities with a bronchovascular and subpleural distribution.

An interferon-gamma-release assay for tuberculosis—QuantiFERON-TB Gold (Cellestis, Carnegie, Australia)—was negative. Ventilatory function tests showed a normal pattern, while the serum ACE level, electrocardiography, and an eye examination revealed no pathologic findings.

Q: What is the diagnosis?

• Keloids
• Scar sarcoidosis
• Paraneoplastic sign
• Dermatofibrosarcoma protuberans
• Tubercolosis

A: Based on the data outlined above, we made the diagnosis of scar sarcoidosis with involvement of hilar and mediastinal lymph nodes. The patient began systemic treatment with oral prednisone 1 mg/kg/day for 6 weeks, which was then gradually withdrawn, until the skin and hilar lesions resolved completely.

SCAR SARCOIDOSIS

Sarcoidosis is a multisystem disorder of unknown cause characterized by the formation of noncaseating granulomas in the affected organs. Patients may present with symptoms related to the specific organ affected, but they may have no symptoms or only general symptoms such as fever or general malaise.

The skin is involved in 25% of cases and presents so many polymorphous manifestations that sarcoidosis has become known as one of the “great imitators” in dermatology.^1,2

Although sarcoidosis on liposuction scars has not been reported previously, the reactivation of old scars is well known on sites of previous injections, tattoos, herpes zoster, and burns.^2,3

The finding of granuloma is not specific for sarcoidosis (Figure 2). The histologic differential diagnosis of sarcoidosis includes tuberculosis, atypical mycobacteriosis, fungal infection, reaction to a foreign body, rheumatoid nodules, leishmaniasis, Crohn disease, and necrobiosis lipoidica diabeticorum.

The diagnosis of scar sarcoidosis is confirmed only by excluding other conditions via a comprehensive evaluation of clinical manifestations, histology, history, and radiologic and laboratory findings.

It has been suggested that the most satisfying therapy for the patient and physician in sarcoidosis is no treatment at all,⁴ and in fact sarcoidosis often remits spontaneously. Currently, the choice of treatment depends on the degree of systemic involvement, and the oral corticosteroid prednisone remains the first-line treatment. If the condition does not respond, the use of other systemic agents has been reported, but their effectiveness has not been evaluated in controlled clinical trials.

Recurrence is common after the suspension of treatment; therefore, treatment may need to be continued for several years, with frequent checkups.

Skin lesions are a visible clue to the diagnosis. Reactivation of old scars may be the single manifestation of cutaneous sarcoidosis, but it may also precede or accompany systemic involvement, often representing the main sign of an exacerbation or a relapse of systemic sarcoidosis, as in our patient.⁵

A 52-year-old woman is referred to our dermatology clinic by her primary care physician for swelling and redness of seven old scars. The swelling began 3 months ago.

She is on no regular medications. She has never smoked. She underwent liposuction 7 years ago and appendectomy at age 15.

Laboratory testing shows mild leukopenia, with a white blood cell count of 3.0 × 10⁹/L (reference range 4.2–9.0). Other routine laboratory values are normal, including antinuclear antibody, extractable nuclear antibody, anti-double-stranded DNA, rheumatoid factor, urinalysis, erythrocyte sedimentation rate, C-reactive protein, serum calcium concentration, and liver and renal function tests.

Chest radiography reveals bilateral hilar lymphadenopathy.

Q: What is the next most appropriate diagnostic procedure?

• Skin biopsy
• High-resolution computed tomography (CT) of the chest
• QuantiFERON-TB Gold test
• Ventilatory function tests
• Serum angiotensin-converting enzyme (ACE) level

A: All are appropriate at this point. In this case, skin biopsy and high-resolution CT were performed. Histopathologic examination of one of the scars showed multiple well-demarcated, large, noncaseating epitheloid granulomas with histiocytes and multinucleated giant cells. High-resolution CT confirmed bilateral hilar and mediastinal lymphadenopathy and revealed micronodular densities with a bronchovascular and subpleural distribution.

An interferon-gamma-release assay for tuberculosis—QuantiFERON-TB Gold (Cellestis, Carnegie, Australia)—was negative. Ventilatory function tests showed a normal pattern, while the serum ACE level, electrocardiography, and an eye examination revealed no pathologic findings.

Q: What is the diagnosis?

• Keloids
• Scar sarcoidosis
• Paraneoplastic sign
• Dermatofibrosarcoma protuberans
• Tubercolosis

A: Based on the data outlined above, we made the diagnosis of scar sarcoidosis with involvement of hilar and mediastinal lymph nodes. The patient began systemic treatment with oral prednisone 1 mg/kg/day for 6 weeks, which was then gradually withdrawn, until the skin and hilar lesions resolved completely.

SCAR SARCOIDOSIS

Sarcoidosis is a multisystem disorder of unknown cause characterized by the formation of noncaseating granulomas in the affected organs. Patients may present with symptoms related to the specific organ affected, but they may have no symptoms or only general symptoms such as fever or general malaise.

The skin is involved in 25% of cases and presents so many polymorphous manifestations that sarcoidosis has become known as one of the “great imitators” in dermatology.^1,2

Although sarcoidosis on liposuction scars has not been reported previously, the reactivation of old scars is well known on sites of previous injections, tattoos, herpes zoster, and burns.^2,3

The finding of granuloma is not specific for sarcoidosis (Figure 2). The histologic differential diagnosis of sarcoidosis includes tuberculosis, atypical mycobacteriosis, fungal infection, reaction to a foreign body, rheumatoid nodules, leishmaniasis, Crohn disease, and necrobiosis lipoidica diabeticorum.

The diagnosis of scar sarcoidosis is confirmed only by excluding other conditions via a comprehensive evaluation of clinical manifestations, histology, history, and radiologic and laboratory findings.

It has been suggested that the most satisfying therapy for the patient and physician in sarcoidosis is no treatment at all,⁴ and in fact sarcoidosis often remits spontaneously. Currently, the choice of treatment depends on the degree of systemic involvement, and the oral corticosteroid prednisone remains the first-line treatment. If the condition does not respond, the use of other systemic agents has been reported, but their effectiveness has not been evaluated in controlled clinical trials.

Recurrence is common after the suspension of treatment; therefore, treatment may need to be continued for several years, with frequent checkups.

Skin lesions are a visible clue to the diagnosis. Reactivation of old scars may be the single manifestation of cutaneous sarcoidosis, but it may also precede or accompany systemic involvement, often representing the main sign of an exacerbation or a relapse of systemic sarcoidosis, as in our patient.⁵

A 52-year-old woman is referred to our dermatology clinic by her primary care physician for swelling and redness of seven old scars. The swelling began 3 months ago.

She is on no regular medications. She has never smoked. She underwent liposuction 7 years ago and appendectomy at age 15.

Laboratory testing shows mild leukopenia, with a white blood cell count of 3.0 × 10⁹/L (reference range 4.2–9.0). Other routine laboratory values are normal, including antinuclear antibody, extractable nuclear antibody, anti-double-stranded DNA, rheumatoid factor, urinalysis, erythrocyte sedimentation rate, C-reactive protein, serum calcium concentration, and liver and renal function tests.

Chest radiography reveals bilateral hilar lymphadenopathy.

Q: What is the next most appropriate diagnostic procedure?

• Skin biopsy
• High-resolution computed tomography (CT) of the chest
• QuantiFERON-TB Gold test
• Ventilatory function tests
• Serum angiotensin-converting enzyme (ACE) level

A: All are appropriate at this point. In this case, skin biopsy and high-resolution CT were performed. Histopathologic examination of one of the scars showed multiple well-demarcated, large, noncaseating epitheloid granulomas with histiocytes and multinucleated giant cells. High-resolution CT confirmed bilateral hilar and mediastinal lymphadenopathy and revealed micronodular densities with a bronchovascular and subpleural distribution.

An interferon-gamma-release assay for tuberculosis—QuantiFERON-TB Gold (Cellestis, Carnegie, Australia)—was negative. Ventilatory function tests showed a normal pattern, while the serum ACE level, electrocardiography, and an eye examination revealed no pathologic findings.

Q: What is the diagnosis?

• Keloids
• Scar sarcoidosis
• Paraneoplastic sign
• Dermatofibrosarcoma protuberans
• Tubercolosis

A: Based on the data outlined above, we made the diagnosis of scar sarcoidosis with involvement of hilar and mediastinal lymph nodes. The patient began systemic treatment with oral prednisone 1 mg/kg/day for 6 weeks, which was then gradually withdrawn, until the skin and hilar lesions resolved completely.

SCAR SARCOIDOSIS

Sarcoidosis is a multisystem disorder of unknown cause characterized by the formation of noncaseating granulomas in the affected organs. Patients may present with symptoms related to the specific organ affected, but they may have no symptoms or only general symptoms such as fever or general malaise.

The skin is involved in 25% of cases and presents so many polymorphous manifestations that sarcoidosis has become known as one of the “great imitators” in dermatology.^1,2

Although sarcoidosis on liposuction scars has not been reported previously, the reactivation of old scars is well known on sites of previous injections, tattoos, herpes zoster, and burns.^2,3

The finding of granuloma is not specific for sarcoidosis (Figure 2). The histologic differential diagnosis of sarcoidosis includes tuberculosis, atypical mycobacteriosis, fungal infection, reaction to a foreign body, rheumatoid nodules, leishmaniasis, Crohn disease, and necrobiosis lipoidica diabeticorum.

The diagnosis of scar sarcoidosis is confirmed only by excluding other conditions via a comprehensive evaluation of clinical manifestations, histology, history, and radiologic and laboratory findings.

It has been suggested that the most satisfying therapy for the patient and physician in sarcoidosis is no treatment at all,⁴ and in fact sarcoidosis often remits spontaneously. Currently, the choice of treatment depends on the degree of systemic involvement, and the oral corticosteroid prednisone remains the first-line treatment. If the condition does not respond, the use of other systemic agents has been reported, but their effectiveness has not been evaluated in controlled clinical trials.

Recurrence is common after the suspension of treatment; therefore, treatment may need to be continued for several years, with frequent checkups.

Skin lesions are a visible clue to the diagnosis. Reactivation of old scars may be the single manifestation of cutaneous sarcoidosis, but it may also precede or accompany systemic involvement, often representing the main sign of an exacerbation or a relapse of systemic sarcoidosis, as in our patient.⁵