A 75-year-old man with type 2 diabetes and hypothyroidism underwent bilateral total knee replacement at our hospital.

His functional capacity had been moderately limited by knee pain, but he could easily climb one flight of stairs without symptoms. His medications at that time included levothyroxine (Synthroid) and metformin (Glucophage). He had no known cardiac or pulmonary disease. The preoperative evaluation, including laboratory tests and electrocardiography, was within normal limits.

Spinal anesthesia was used for surgery, and he was given 2 mg of midazolam (Versed) intravenously for sedation. No additional sedation was given. He was given oxygen via nasal cannula at 2 L/min.

All vital signs were stable at the start of the procedure. However, about halfway through, when the thigh tourniquet was released, his oxygen saturation dropped abruptly from 100% to 92%. All other vital signs remained stable, and he was asymptomatic, was oriented to person, time, and place, was conversing freely, and was in no distress. The oxygen flow was increased to 6 L/min, his oxygen saturation improved, and the procedure was then completed as planned.

At the conclusion of the surgery, before the patient was transported to the postanesthesia care unit (PACU) and while his oxygen flow rate was still 6 L/min, his oxygen saturation again dropped to 92%. A simple face mask was placed, and the oxygen flow rate was increased to 10 L/min. His oxygen saturation stayed low, near 90%.

Bleeding during surgery had been nominal. He had received 2 L of lactated Ringer’s solution and 500 mL of hetastarch (Hextend) during surgery. He continued to be asymptomatic in the PACU.

1. What is the most likely cause of oxygen desaturation during bilateral total knee arthroplasty?

• Fat embolism
• Intraoperative pneumonia
• Venous thromboembolism with pulmonary embolism
• Acute myocardial infarction
• Acute pulmonary edema
• Excessive sedation

The differential diagnosis of oxygen desaturation during orthopedic procedures is listed in Table 1.

Fat embolism is the most likely cause, particularly given the greater fatty embolic load that occurs with bilateral total knee arthroplasty than with unilateral total knee arthroplasty.

At what point the maximal showering of fat emboli occurs is not known. Fat may be released into the circulation with pressurization of the medullary canal during surgery or with manipulation of a fracture. The emboli may collect in the leg veins and then be released in a shower when the thigh tourniquet is released. Vasoactive mediators and methylmethacrylate cement released into the circulatory system after tourniquet deflation may also cause vasodilation, hypotension, and increased dead-space ventilation, resulting in hypoxia and a drop in end-tidal CO₂.

Pneumonia during surgery is rare without an apparent aspiration event.

Venous thromboembolism is possible but is more likely later in the postoperative period after major orthopedic surgery.

Acute myocardial infarction could present with hypoxia, particularly in a diabetic patient, who may not experience chest pain. However, intraoperative electrocardiographic changes would likely be seen. If myocardial infarction is suspected, postoperative serial electrocardiograms and measuring troponin and cardiac enzyme levels aid in the diagnosis.

Acute pulmonary edema is possible but not as highly suspected, as the patient had no history of congestive heart failure and received an appropriate amount of fluid for this type of surgery.

Excessive sedation could cause hypoventilation and, thus, oxygen desaturatation. However, this patient’s oxygen desaturatation began more than an hour after the midazolam was given. Midazolam is a short-acting benzodiazepine. It is unlikely that the patient would show signs of hypoventilation and oversedation an hour after the drug was given. Our patient also did not show any signs of excessive sedation, as he was awake and conversing during the surgery.

Fat emboli vs fat embolism syndrome

Fat embolism is the presence of fat drops within the systemic and pulmonary microcirculation, with or without clinical sequelae.¹ Fat embolism syndrome, on the other hand, is defined as injury to and dysfunction of one or more organs as a result of the embolization of fat, usually within 24 hours of injury or orthopedic surgery.²

Fat embolism syndrome is an unpredictable condition with a varied presentation. Fat droplets are thought to embolize via the venous circulation into the pulmonary arteries, occluding small blood vessels in the lung. However, they also get into the arterial circulation and occlude arteries in the brain, kidney, heart, and liver (more on this phenomenon below).

Fat embolism is reported to originate primarily from fractures of the femur, tibia, and pelvis.^2,3 As many as 90% of trauma patients have been shown to have evidence of fat embolism on autopsy.⁴ However, only a small number of patients develop the classic fat embolism syndrome,^2,3,5 Why some develop the syndrome and others do not is still unknown.

Orthopedic procedures associated with fat embolization include knee arthroplasty and hip arthroplasty, particularly if it involves intramedullary manipulation or medullary fixation.⁶ It has also been reported during spinal procedures in which pedicular screws are used.⁷ The syndrome occurs in 0.25% to 30% of patients following multiple fractures and in 0.1% to 12% of patients during or following knee or hip arthroplasty.

One study⁸ showed evidence of fat on transesophageal echocardiography in 88% of patients undergoing medullary reaming of lower-extremity fractures and hip hemiarthroplasty. Blood sampling from the right atrium confirmed that fat was responsible for the echocardiographic abnormalities. The study also showed that the severity of the embolic showering correlated with the severity of hypoxia and the decrease in end-tidal CO₂.⁸

CASE CONTINUED

On arrival at the PACU, our patient’s oxygen saturation was 94% while he was breathing oxygen via a simple face mask at a flow rate of 10 L/min. His heart rate was 60 bpm, blood pressure 110/60 mm Hg, and temperature 37.5°C (96.3°F). Chest sounds were normal on auscultation.

However, 3 hours later, his mental status rapidly deteriorated. He was oriented only to person, and he was drowsy. He had escalating respiratory distress with a rapid respiratory rate and decreasing oxygen saturation. At this point, auscultation of his chest wall revealed bilateral crackles and rales.

He was promptly intubated. Profuse fluid and secretions were noted to be coming from his lungs, filling the endotracheal tube. Arterial blood gas measurement showed a pH of 7.22, Pao₂ 64 mm Hg, and Paco₂ 56 mm Hg on 100% fraction of inspired oxygen, with no increased anion gap.

2. Which consequence of fat embolism is most likely at this time in this patient?

• Coexisting sepsis
• Fat embolism syndrome
• Acute cardioembolic stroke
• Anaphylaxis

Fat embolism syndrome should be highly suspected in this patient. As mentioned, it can affect many different organs. It is the most serious condition resulting from fat embolization after surgery or trauma.

Sepsis was unlikely in our patient, since he presented for his surgery in good health and with no preexisting signs or symptoms of infection. Acute cardioembolic stroke could have caused the neurologic signs, but this would not necessarily explain the coexisting hypoxia. An anaphylactic reaction to drugs or surgical cement would most likely present intraoperatively, shortly after exposure occurred, rather than several hours after surgery.

How common is fat embolism syndrome?

The occurrence rate of fat embolism syndrome has been reported to be 0.25% to 30% after multiple fractures and 0.1% to 12% after knee and hip joint surgery, with a mortality rate of 13% to 36%.^2,9–14 The rate of occurrence after unilateral total knee joint replacement has been reported to be 1.8% to 5%, and 4% to 12% after bilateral total knee replacement.^15–19

The syndrome is relatively more common with traumatic fractures of the lower extremities. However, it has also been reported with liposuction, total parenteral nutrition, bone marrow harvest and transplantation, burns, and acute pancreatitis, to mention a few.¹⁰

The broad range of reported incidence rates can be attributed to the fact that many studies were in patients with multiple trauma, whose concomitant injuries may have made it difficult to clearly define the contribution of fat embolism syndrome to the overall rates of morbidity and mortality. Also, different studies used different criteria to define the syndrome.

How does fat embolism syndrome occur?

Two hypotheses for how this syndrome occurs were proposed nearly a century ago.^20,21

The “mechanical” theory is that fat emboli are formed as a result of trauma and disruption of adipose tissue and other cells in the bone marrow. Increases in intramedullary pressure force the fat emboli through damaged medullary venous channels in the bone and into the circulation of the lower extremities. This embolization of fat causes an initial mechanical pulmonary obstruction. Mechanical obstruction by fat emboli in the pulmonary system leads to increased pulmonary pressures and an increase in right heart outflow pressure. The right heart becomes strained, leading to a decreased right-sided cardiac output. As a result, the left heart filling pressures diminish and hypotension ensues.²⁰

The “biochemical” theory, on the other hand, is that chylomicrons within the vascular system are modified and their stability is compromised as a result of stress. These traumatized chylomicrons then coalesce to form droplets of fat that accumulate in the pulmonary circulation and produce a mechanical obstruction. This would explain why nontraumatic, nonorthopedic insults can produce this syndrome.

Autopsy studies show that there is little correlation between the presence and quantity of intravascular fat and the severity of clinical symptoms, thus implying that the syndrome is caused by more than just mechanical obstruction. The biochemical theory postulates that fat globules within the circulatory system then cause the release of lipase from the pulmonary alveolar cells, which then hydrolyses the fat into free fatty acids. These free fatty acids cause an inflammatory reaction, complementmediated leukocyte aggregation, chemotoxin release, and subsequently endothelial damage. These vasoactive substances damage type 2 pneumocytes and lead to an increased permeability of the pulmonary capillary beds. Acute respiratory distress syndrome (ARDS) may ensue. Disseminated intravascular coagulation may occur as a result of the formation of microthrombi involving lipids, platelets, and fibrin.^21,22

Embolization of fat to the central nervous system can occur as fat globules cross into the systemic circulation via a patent foramen ovale, an atrioventricular shunt, or the pulmonary capillaries. This can then result in cerebral ischemia.²³

Although patent foramen ovale may seem the most direct route for cerebral embolization, the neurologic impairment and signs of cerebral emboli in fat embolism syndrome may occur in the absence of patent foramen ovale.^24,25 The fat globules may actually go through the lung capillaries, being flexible and forced through by increased pulmonary pressure.

But whether the cause of fat embolism syndrome is occlusion by globules, the release of biochemical mediators, or a combination of both is unknown. Both mechanisms are likely responsible. We can only suspect that the degree of fat load and intrinsic metabolic differences between individuals account for the variation in susceptibility.

FAT EMBOLI AFFECT THE LUNGS, SKIN, AND BRAIN

3. Where on the body is the rash associated with fat embolism syndrome usually seen?

• Face
• Near a site of fracture or surgery
• Chest, axilla, conjunctiva
• Distal extremities

Petechiae are part of the classic presenting triad of fat embolism syndrome, which also includes pulmonary and cerebral dysfunction.

Petechiae usually appear on the 2nd to 4th day after injury.²⁶ They are usually found across the chest, the anterior axillary folds, and the neck, as well as on the oral mucosa and the conjunctiva. The rash is caused by occlusion of dermal capillaries by fat, which increases their fragility.¹⁰

Pulmonary changes usually begin with tachypnea, dyspnea, and a drop in oxygen saturation, leading to generalized hypoxia. Respiratory symptoms are present in 100% of cases.² Respiratory symptoms can acutely develop with the sudden manipulation of a fracture, reaming of bone, or release of a limb tourniquet.²⁷

Body systems affected by fat embolism syndrome are summarized in Table 2.

4. How many hours after injury does fat embolism syndrome typically manifest?

• 1 to 2 hours
• 6 to 12 hours
• 12 to 20 hours
• 24 to 48 hours
• 72 to 84 hours

Most patients develop signs and symptoms 24 to 48 hours after injury. Patients presenting earlier than 12 hours usually have a more fulminant course.²⁹

The time between fat embolization and the development of fat embolism syndrome is thought to be related to the time required for the metabolic conversion of fat to free fatty acids.³⁰ We suspect that the early desaturation seen in our patient was the result of a heavy showering of fat intraoperatively. However, this could only be concluded after we had ruled out other causes of acute hypoxia and hypotension.

Fat embolism syndrome is a diagnosis of exclusion and is based on clinical criteria. No specific sign, symptom, or test is pathognomonic. It may often be confused with other conditions such as systemic inflammatory response syndrome or sepsis. However, the triad of respiratory and neurologic symptoms and petechiae coupled with the clinical picture of recent trauma or orthopedic surgery almost assures the diagnosis.

Fat embolism syndrome can range from subclinical to fulminating, with the more fulminating course attributable to a huge load of fat emboli, which leads to acute cor pulmonale.

Regardless of the criteria used, one must have a high index of suspicion for fat embolization syndrome in patients undergoing orthopedic procedures, particularly hip and knee surgery, and in patients with fractures, especially fractures of the femur, tibia, or pelvis and multiple, concomitant fractures.

CASE CONTINUED

Our patient was given furosemide (Lasix) empirically for diuresis and to improve oxygenation. However, his oxygen saturation remained low.

Chest radiography 4 hours after surgery showed bilateral pulmonary infiltrates. Serial electrocardiography showed no acute changes. Levels of cardiac enzymes and troponins were normal. Transthoracic echocardiography showed no left ventricular dysfunction, a normal right ventricle, and no evidence of valvular lesions. Urine and blood fat stains were negative, but the sputum stain was positive for copious extracellular fat. The patient became comatose 5 hours postoperatively. Computed tomography of the brain was normal. He was transferred to the surgical intensive care unit.

The clinical course was marked by hemodynamic instability requiring norepinephrine (Levophed) and vasopressin (Pitressin) for hypotension. Right ventricular filling pressures via central venous pressure monitoring showed no evidence of hypovolemia. The hemoglobin concentration and the hematocrit were stable, with no evidence of acute or ongoing bleeding. Blood, urine, and sputum cultures remained negative. Acute myocardial infarction was ruled out by serial electrocardiography, cardiac enzyme testing, and troponin testing.

Magnetic resonance imaging (MRI) of the brain on postoperative day 2 showed foci of acute ischemia suggestive of embolic phenomena consistent with fat embolism syndrome (Figure  1). Transthoracic echocardiography was repeated but again showed no evidence of a patent foramen ovale. Electroencephalography on postoperative day 4 showed severe, diffuse encephalopathy. There was no petechial skin rash. Other laboratory studies showed progressive thrombocytopenia with a platelet count of 53 × 199/L on postoperative day 3.

TESTS THAT AID THE CLINICAL DIAGNOSIS

Although no single laboratory test is pathognomonic for fat embolism syndrome, several tests may help raise suspicion of it, especially in the setting of fracture or an orthopedic surgical procedure.

Arterial blood gases must be measured. A Pao₂ of less than 60 mm Hg with no other obvious lung pathology in an orthopedic surgery patient is highly suspicious.¹² An alveolar-arterial gradient of greater than 100 mm Hg may further increase suspicion.

Tests for fat. The blood and urine may be examined for fat, although positive findings are not specific for fat embolism syndrome.³³ Fat in the urine indicates the occurrence of massive fat embolism, but this is not always accompanied by the syndrome.³⁴ Gurd and Wilson¹³ found fat globules larger than 8 μm circulating in the serum in all documented cases. They stated that, even though the relationship of large fat globules to the pathogenesis of the clinical picture remains obscure, the demonstration of their presence can be helpful in the diagnosis.¹³

Also, samples obtained with bronchoalveolar lavage may be examined for fat. The macrophages may be stained for fat using the oil red O stain. Again, this is a nonspecific marker, as fat-stained macrophages are seen in trauma patients,³⁵ but the finding has a very high negative predictive value.³⁶ Anemia, thrombocytopenia, hypofibrinogenemia, an elevated lipase level, and a high erythrocyte sedimentation rate may be found in fat embolism syndrome.¹³

Chest radiography may show bilateral infiltrates, as in ARDS, but this is not diagnostic for fat embolism syndrome.

Electrocardiography may show changes in ST and T waves and signs of right heart strain.

Transesophageal echocardiography may show increased right heart and pulmonary artery pressures.

Computed tomography is often negative,^37,38 but T2-weighted MRI is useful in the diagnosis of cerebral fat embolism syndrome, as it can show intracerebral microinfarcts as early as 4 hours after the onset of neurologic symptoms, and these findings correlate well with the clinical severity of brain injury.

Diffusion-weighted MRI may enhance the sensitivity and specificity of the neuroradiologic diagnosis. Diffusion-weighted MRI typically shows multiple nonconfluent areas of high-intensity signals or bright spots on a dark background, known as a “starfield pattern.” This pattern has been suggested to be pathognomonic of acute cerebral microinfarction. The abnormalities presumably reflect foci of cytotoxic edema that develops immediately, unlike vasogenic edema, seen in T2-weighted images, which may take up to several days to develop. Although these images are not necessarily specific for fat emboli, they are useful in helping make the diagnosis. Thus, diffusionweighted MRI should be done if fat embolism syndrome is suspected.^38,39

CASE CONCLUDED

The patient’s course in the intensive care unit was further complicated by gastrointestinal bleeding and renal failure. His neurologic status did not improve. Repeated MRI of the brain showed evolving bilateral watershed infarction throughout the cortices. The neurologic consult service diagnosed the patient as having severe encephalopathy with a very poor prognosis. The decision was made to withdraw care. He was placed under palliative care and died on postoperative day 22.

DRUG TREATMENT OF FAT EMBOLISM SYNDROME

5. Which of the following drugs has been proven to be effective in treating fat embolism syndrome?

• Intravenous ethanol
• Steroids
• Heparin
• Dextran
• Aspirin
• None of the above

None of the above has been proven to be effective in treating this disorder. The management is largely supportive. Thus, prevention, early diagnosis, and symptom management are vital.

Pulmonary and hemodynamic support are the cornerstones of successful treatment. Aggressive respiratory support is often needed. Management of acute lung injury and ARDS focuses on achieving acceptable gas exchange while preventing ventilator-associated lung injury. Intravascular volume must be supported. Inotropes and pulmonary vasodilators may be required to maintain hemodynamics. Exacerbation of central nervous system ischemia from hypotension or hypoxia should be avoided.

If the thrombocytopenia leads to clinical bleeding, platelet transfusions may be warranted.

Supportive care should include prophylaxis of deep venous thrombosis and of gastrointestinal bleeding, and maintenance of nutrition.⁴⁰ Patients who receive supportive care generally have a favorable outcome, with a mortality rate of less than 10%.²⁸

Drug studies have been inconclusive

Drugs suggested in the treatment of fat embolism syndrome include heparin, aspirin, dextran, hypertonic glucose, and alcohol, but the results have been inconclusive.^{3,11,23,40–43}

Heparin stimulates lipase activity, consequently decreasing the concentration of circulating fat globules. However, the increase in levels of free fatty acids may actually worsen the clinical picture. For this reason, and because of anticoagulation concerns and evidence of increased mortality rates, heparin is now contraindicated in the treatment of fat embolism syndrome.^2,41,43

Alcohol. Patients with a higher blood alcohol level at the time of injury have been reported to have a lower incidence of fat embolism syndrome. Alcohol inhibits lipase, suppressing the rise of free fatty acids. In experimental studies, the incidence of fat embolism syndrome was lower when the blood alcohol level was maintained at 20 mg/dL. However, no prospective randomized trial has been done to determine the clinical efficacy of ethanol as a treatment for this condition.^5,42

Dextran has been advocated, owing to its ability to improve small-vessel perfusion, but bleeding risk and acute renal failure associated with this drug have limited its use.⁵

N-acetylcysteine has been shown to attenuate fat-induced lung injury in a study of rats with induced fat embolism syndrome.⁴⁴

Corticosteroid treatment for this condition is controversial. Studies in patients with femoral and tibial fractures show that steroids reduce the incidence of fat embolism syndrome when given prophylactically, and those treated with steroids had a higher Pao₂ than controls. Doses of methylprednisolone in these studies ranged between 9 mg/kg to 90 mg/kg. A drawback of these studies is their small number of patients.^12,32,45,46

A meta-analysis⁴⁷ of randomized trials of corticosteroids to prevent fat embolism syndrome in patients with long-bone fractures identified 104 such studies. Only 7 of the 104 were considered adequate. In 389 patients with long-bone fractures, prophylactic corticosteroids reduced the risk of fat embolism syndrome by 78% (95% confidence interval 43%–92%) and corticosteroids also significantly reduced the risk of hypoxia with no difference in rates of infection or death. However, the overall quality of the trials was poor, and the authors of the meta-analysis concluded that more study is needed before corticosteroids could be formally recommended.⁴⁷

There is no evidence that steroids improve the overall clinical course of already established fat embolism syndrome.^12,32,45 The dosing and optimal timing of administration have also not been established. High doses pose a risk of septic complications, which may be devastating for the posttrauma or postoperative patient.

A 75-year-old man with type 2 diabetes and hypothyroidism underwent bilateral total knee replacement at our hospital.

His functional capacity had been moderately limited by knee pain, but he could easily climb one flight of stairs without symptoms. His medications at that time included levothyroxine (Synthroid) and metformin (Glucophage). He had no known cardiac or pulmonary disease. The preoperative evaluation, including laboratory tests and electrocardiography, was within normal limits.

Spinal anesthesia was used for surgery, and he was given 2 mg of midazolam (Versed) intravenously for sedation. No additional sedation was given. He was given oxygen via nasal cannula at 2 L/min.

All vital signs were stable at the start of the procedure. However, about halfway through, when the thigh tourniquet was released, his oxygen saturation dropped abruptly from 100% to 92%. All other vital signs remained stable, and he was asymptomatic, was oriented to person, time, and place, was conversing freely, and was in no distress. The oxygen flow was increased to 6 L/min, his oxygen saturation improved, and the procedure was then completed as planned.

At the conclusion of the surgery, before the patient was transported to the postanesthesia care unit (PACU) and while his oxygen flow rate was still 6 L/min, his oxygen saturation again dropped to 92%. A simple face mask was placed, and the oxygen flow rate was increased to 10 L/min. His oxygen saturation stayed low, near 90%.

Bleeding during surgery had been nominal. He had received 2 L of lactated Ringer’s solution and 500 mL of hetastarch (Hextend) during surgery. He continued to be asymptomatic in the PACU.

1. What is the most likely cause of oxygen desaturation during bilateral total knee arthroplasty?

• Fat embolism
• Intraoperative pneumonia
• Venous thromboembolism with pulmonary embolism
• Acute myocardial infarction
• Acute pulmonary edema
• Excessive sedation

The differential diagnosis of oxygen desaturation during orthopedic procedures is listed in Table 1.

Fat embolism is the most likely cause, particularly given the greater fatty embolic load that occurs with bilateral total knee arthroplasty than with unilateral total knee arthroplasty.

At what point the maximal showering of fat emboli occurs is not known. Fat may be released into the circulation with pressurization of the medullary canal during surgery or with manipulation of a fracture. The emboli may collect in the leg veins and then be released in a shower when the thigh tourniquet is released. Vasoactive mediators and methylmethacrylate cement released into the circulatory system after tourniquet deflation may also cause vasodilation, hypotension, and increased dead-space ventilation, resulting in hypoxia and a drop in end-tidal CO₂.

Pneumonia during surgery is rare without an apparent aspiration event.

Venous thromboembolism is possible but is more likely later in the postoperative period after major orthopedic surgery.

Acute myocardial infarction could present with hypoxia, particularly in a diabetic patient, who may not experience chest pain. However, intraoperative electrocardiographic changes would likely be seen. If myocardial infarction is suspected, postoperative serial electrocardiograms and measuring troponin and cardiac enzyme levels aid in the diagnosis.

Acute pulmonary edema is possible but not as highly suspected, as the patient had no history of congestive heart failure and received an appropriate amount of fluid for this type of surgery.

Excessive sedation could cause hypoventilation and, thus, oxygen desaturatation. However, this patient’s oxygen desaturatation began more than an hour after the midazolam was given. Midazolam is a short-acting benzodiazepine. It is unlikely that the patient would show signs of hypoventilation and oversedation an hour after the drug was given. Our patient also did not show any signs of excessive sedation, as he was awake and conversing during the surgery.

Fat emboli vs fat embolism syndrome

Fat embolism is the presence of fat drops within the systemic and pulmonary microcirculation, with or without clinical sequelae.¹ Fat embolism syndrome, on the other hand, is defined as injury to and dysfunction of one or more organs as a result of the embolization of fat, usually within 24 hours of injury or orthopedic surgery.²

Fat embolism syndrome is an unpredictable condition with a varied presentation. Fat droplets are thought to embolize via the venous circulation into the pulmonary arteries, occluding small blood vessels in the lung. However, they also get into the arterial circulation and occlude arteries in the brain, kidney, heart, and liver (more on this phenomenon below).

Fat embolism is reported to originate primarily from fractures of the femur, tibia, and pelvis.^2,3 As many as 90% of trauma patients have been shown to have evidence of fat embolism on autopsy.⁴ However, only a small number of patients develop the classic fat embolism syndrome,^2,3,5 Why some develop the syndrome and others do not is still unknown.

Orthopedic procedures associated with fat embolization include knee arthroplasty and hip arthroplasty, particularly if it involves intramedullary manipulation or medullary fixation.⁶ It has also been reported during spinal procedures in which pedicular screws are used.⁷ The syndrome occurs in 0.25% to 30% of patients following multiple fractures and in 0.1% to 12% of patients during or following knee or hip arthroplasty.

One study⁸ showed evidence of fat on transesophageal echocardiography in 88% of patients undergoing medullary reaming of lower-extremity fractures and hip hemiarthroplasty. Blood sampling from the right atrium confirmed that fat was responsible for the echocardiographic abnormalities. The study also showed that the severity of the embolic showering correlated with the severity of hypoxia and the decrease in end-tidal CO₂.⁸

CASE CONTINUED

On arrival at the PACU, our patient’s oxygen saturation was 94% while he was breathing oxygen via a simple face mask at a flow rate of 10 L/min. His heart rate was 60 bpm, blood pressure 110/60 mm Hg, and temperature 37.5°C (96.3°F). Chest sounds were normal on auscultation.

However, 3 hours later, his mental status rapidly deteriorated. He was oriented only to person, and he was drowsy. He had escalating respiratory distress with a rapid respiratory rate and decreasing oxygen saturation. At this point, auscultation of his chest wall revealed bilateral crackles and rales.

He was promptly intubated. Profuse fluid and secretions were noted to be coming from his lungs, filling the endotracheal tube. Arterial blood gas measurement showed a pH of 7.22, Pao₂ 64 mm Hg, and Paco₂ 56 mm Hg on 100% fraction of inspired oxygen, with no increased anion gap.

2. Which consequence of fat embolism is most likely at this time in this patient?

• Coexisting sepsis
• Fat embolism syndrome
• Acute cardioembolic stroke
• Anaphylaxis

Fat embolism syndrome should be highly suspected in this patient. As mentioned, it can affect many different organs. It is the most serious condition resulting from fat embolization after surgery or trauma.

Sepsis was unlikely in our patient, since he presented for his surgery in good health and with no preexisting signs or symptoms of infection. Acute cardioembolic stroke could have caused the neurologic signs, but this would not necessarily explain the coexisting hypoxia. An anaphylactic reaction to drugs or surgical cement would most likely present intraoperatively, shortly after exposure occurred, rather than several hours after surgery.

How common is fat embolism syndrome?

The occurrence rate of fat embolism syndrome has been reported to be 0.25% to 30% after multiple fractures and 0.1% to 12% after knee and hip joint surgery, with a mortality rate of 13% to 36%.^2,9–14 The rate of occurrence after unilateral total knee joint replacement has been reported to be 1.8% to 5%, and 4% to 12% after bilateral total knee replacement.^15–19

The syndrome is relatively more common with traumatic fractures of the lower extremities. However, it has also been reported with liposuction, total parenteral nutrition, bone marrow harvest and transplantation, burns, and acute pancreatitis, to mention a few.¹⁰

The broad range of reported incidence rates can be attributed to the fact that many studies were in patients with multiple trauma, whose concomitant injuries may have made it difficult to clearly define the contribution of fat embolism syndrome to the overall rates of morbidity and mortality. Also, different studies used different criteria to define the syndrome.

How does fat embolism syndrome occur?

Two hypotheses for how this syndrome occurs were proposed nearly a century ago.^20,21

The “mechanical” theory is that fat emboli are formed as a result of trauma and disruption of adipose tissue and other cells in the bone marrow. Increases in intramedullary pressure force the fat emboli through damaged medullary venous channels in the bone and into the circulation of the lower extremities. This embolization of fat causes an initial mechanical pulmonary obstruction. Mechanical obstruction by fat emboli in the pulmonary system leads to increased pulmonary pressures and an increase in right heart outflow pressure. The right heart becomes strained, leading to a decreased right-sided cardiac output. As a result, the left heart filling pressures diminish and hypotension ensues.²⁰

The “biochemical” theory, on the other hand, is that chylomicrons within the vascular system are modified and their stability is compromised as a result of stress. These traumatized chylomicrons then coalesce to form droplets of fat that accumulate in the pulmonary circulation and produce a mechanical obstruction. This would explain why nontraumatic, nonorthopedic insults can produce this syndrome.

Autopsy studies show that there is little correlation between the presence and quantity of intravascular fat and the severity of clinical symptoms, thus implying that the syndrome is caused by more than just mechanical obstruction. The biochemical theory postulates that fat globules within the circulatory system then cause the release of lipase from the pulmonary alveolar cells, which then hydrolyses the fat into free fatty acids. These free fatty acids cause an inflammatory reaction, complementmediated leukocyte aggregation, chemotoxin release, and subsequently endothelial damage. These vasoactive substances damage type 2 pneumocytes and lead to an increased permeability of the pulmonary capillary beds. Acute respiratory distress syndrome (ARDS) may ensue. Disseminated intravascular coagulation may occur as a result of the formation of microthrombi involving lipids, platelets, and fibrin.^21,22

Embolization of fat to the central nervous system can occur as fat globules cross into the systemic circulation via a patent foramen ovale, an atrioventricular shunt, or the pulmonary capillaries. This can then result in cerebral ischemia.²³

Although patent foramen ovale may seem the most direct route for cerebral embolization, the neurologic impairment and signs of cerebral emboli in fat embolism syndrome may occur in the absence of patent foramen ovale.^24,25 The fat globules may actually go through the lung capillaries, being flexible and forced through by increased pulmonary pressure.

But whether the cause of fat embolism syndrome is occlusion by globules, the release of biochemical mediators, or a combination of both is unknown. Both mechanisms are likely responsible. We can only suspect that the degree of fat load and intrinsic metabolic differences between individuals account for the variation in susceptibility.

FAT EMBOLI AFFECT THE LUNGS, SKIN, AND BRAIN

3. Where on the body is the rash associated with fat embolism syndrome usually seen?

• Face
• Near a site of fracture or surgery
• Chest, axilla, conjunctiva
• Distal extremities

Petechiae are part of the classic presenting triad of fat embolism syndrome, which also includes pulmonary and cerebral dysfunction.

Petechiae usually appear on the 2nd to 4th day after injury.²⁶ They are usually found across the chest, the anterior axillary folds, and the neck, as well as on the oral mucosa and the conjunctiva. The rash is caused by occlusion of dermal capillaries by fat, which increases their fragility.¹⁰

Pulmonary changes usually begin with tachypnea, dyspnea, and a drop in oxygen saturation, leading to generalized hypoxia. Respiratory symptoms are present in 100% of cases.² Respiratory symptoms can acutely develop with the sudden manipulation of a fracture, reaming of bone, or release of a limb tourniquet.²⁷

Body systems affected by fat embolism syndrome are summarized in Table 2.

4. How many hours after injury does fat embolism syndrome typically manifest?

• 1 to 2 hours
• 6 to 12 hours
• 12 to 20 hours
• 24 to 48 hours
• 72 to 84 hours

Most patients develop signs and symptoms 24 to 48 hours after injury. Patients presenting earlier than 12 hours usually have a more fulminant course.²⁹

The time between fat embolization and the development of fat embolism syndrome is thought to be related to the time required for the metabolic conversion of fat to free fatty acids.³⁰ We suspect that the early desaturation seen in our patient was the result of a heavy showering of fat intraoperatively. However, this could only be concluded after we had ruled out other causes of acute hypoxia and hypotension.

Fat embolism syndrome is a diagnosis of exclusion and is based on clinical criteria. No specific sign, symptom, or test is pathognomonic. It may often be confused with other conditions such as systemic inflammatory response syndrome or sepsis. However, the triad of respiratory and neurologic symptoms and petechiae coupled with the clinical picture of recent trauma or orthopedic surgery almost assures the diagnosis.

Fat embolism syndrome can range from subclinical to fulminating, with the more fulminating course attributable to a huge load of fat emboli, which leads to acute cor pulmonale.

Regardless of the criteria used, one must have a high index of suspicion for fat embolization syndrome in patients undergoing orthopedic procedures, particularly hip and knee surgery, and in patients with fractures, especially fractures of the femur, tibia, or pelvis and multiple, concomitant fractures.

CASE CONTINUED

Our patient was given furosemide (Lasix) empirically for diuresis and to improve oxygenation. However, his oxygen saturation remained low.

Chest radiography 4 hours after surgery showed bilateral pulmonary infiltrates. Serial electrocardiography showed no acute changes. Levels of cardiac enzymes and troponins were normal. Transthoracic echocardiography showed no left ventricular dysfunction, a normal right ventricle, and no evidence of valvular lesions. Urine and blood fat stains were negative, but the sputum stain was positive for copious extracellular fat. The patient became comatose 5 hours postoperatively. Computed tomography of the brain was normal. He was transferred to the surgical intensive care unit.

The clinical course was marked by hemodynamic instability requiring norepinephrine (Levophed) and vasopressin (Pitressin) for hypotension. Right ventricular filling pressures via central venous pressure monitoring showed no evidence of hypovolemia. The hemoglobin concentration and the hematocrit were stable, with no evidence of acute or ongoing bleeding. Blood, urine, and sputum cultures remained negative. Acute myocardial infarction was ruled out by serial electrocardiography, cardiac enzyme testing, and troponin testing.

Magnetic resonance imaging (MRI) of the brain on postoperative day 2 showed foci of acute ischemia suggestive of embolic phenomena consistent with fat embolism syndrome (Figure  1). Transthoracic echocardiography was repeated but again showed no evidence of a patent foramen ovale. Electroencephalography on postoperative day 4 showed severe, diffuse encephalopathy. There was no petechial skin rash. Other laboratory studies showed progressive thrombocytopenia with a platelet count of 53 × 199/L on postoperative day 3.

TESTS THAT AID THE CLINICAL DIAGNOSIS

Although no single laboratory test is pathognomonic for fat embolism syndrome, several tests may help raise suspicion of it, especially in the setting of fracture or an orthopedic surgical procedure.

Arterial blood gases must be measured. A Pao₂ of less than 60 mm Hg with no other obvious lung pathology in an orthopedic surgery patient is highly suspicious.¹² An alveolar-arterial gradient of greater than 100 mm Hg may further increase suspicion.

Tests for fat. The blood and urine may be examined for fat, although positive findings are not specific for fat embolism syndrome.³³ Fat in the urine indicates the occurrence of massive fat embolism, but this is not always accompanied by the syndrome.³⁴ Gurd and Wilson¹³ found fat globules larger than 8 μm circulating in the serum in all documented cases. They stated that, even though the relationship of large fat globules to the pathogenesis of the clinical picture remains obscure, the demonstration of their presence can be helpful in the diagnosis.¹³

Also, samples obtained with bronchoalveolar lavage may be examined for fat. The macrophages may be stained for fat using the oil red O stain. Again, this is a nonspecific marker, as fat-stained macrophages are seen in trauma patients,³⁵ but the finding has a very high negative predictive value.³⁶ Anemia, thrombocytopenia, hypofibrinogenemia, an elevated lipase level, and a high erythrocyte sedimentation rate may be found in fat embolism syndrome.¹³

Chest radiography may show bilateral infiltrates, as in ARDS, but this is not diagnostic for fat embolism syndrome.

Electrocardiography may show changes in ST and T waves and signs of right heart strain.

Transesophageal echocardiography may show increased right heart and pulmonary artery pressures.

Computed tomography is often negative,^37,38 but T2-weighted MRI is useful in the diagnosis of cerebral fat embolism syndrome, as it can show intracerebral microinfarcts as early as 4 hours after the onset of neurologic symptoms, and these findings correlate well with the clinical severity of brain injury.

Diffusion-weighted MRI may enhance the sensitivity and specificity of the neuroradiologic diagnosis. Diffusion-weighted MRI typically shows multiple nonconfluent areas of high-intensity signals or bright spots on a dark background, known as a “starfield pattern.” This pattern has been suggested to be pathognomonic of acute cerebral microinfarction. The abnormalities presumably reflect foci of cytotoxic edema that develops immediately, unlike vasogenic edema, seen in T2-weighted images, which may take up to several days to develop. Although these images are not necessarily specific for fat emboli, they are useful in helping make the diagnosis. Thus, diffusionweighted MRI should be done if fat embolism syndrome is suspected.^38,39

CASE CONCLUDED

The patient’s course in the intensive care unit was further complicated by gastrointestinal bleeding and renal failure. His neurologic status did not improve. Repeated MRI of the brain showed evolving bilateral watershed infarction throughout the cortices. The neurologic consult service diagnosed the patient as having severe encephalopathy with a very poor prognosis. The decision was made to withdraw care. He was placed under palliative care and died on postoperative day 22.

DRUG TREATMENT OF FAT EMBOLISM SYNDROME

5. Which of the following drugs has been proven to be effective in treating fat embolism syndrome?

• Intravenous ethanol
• Steroids
• Heparin
• Dextran
• Aspirin
• None of the above

None of the above has been proven to be effective in treating this disorder. The management is largely supportive. Thus, prevention, early diagnosis, and symptom management are vital.

Pulmonary and hemodynamic support are the cornerstones of successful treatment. Aggressive respiratory support is often needed. Management of acute lung injury and ARDS focuses on achieving acceptable gas exchange while preventing ventilator-associated lung injury. Intravascular volume must be supported. Inotropes and pulmonary vasodilators may be required to maintain hemodynamics. Exacerbation of central nervous system ischemia from hypotension or hypoxia should be avoided.

If the thrombocytopenia leads to clinical bleeding, platelet transfusions may be warranted.

Supportive care should include prophylaxis of deep venous thrombosis and of gastrointestinal bleeding, and maintenance of nutrition.⁴⁰ Patients who receive supportive care generally have a favorable outcome, with a mortality rate of less than 10%.²⁸

Drug studies have been inconclusive

Drugs suggested in the treatment of fat embolism syndrome include heparin, aspirin, dextran, hypertonic glucose, and alcohol, but the results have been inconclusive.^{3,11,23,40–43}

Heparin stimulates lipase activity, consequently decreasing the concentration of circulating fat globules. However, the increase in levels of free fatty acids may actually worsen the clinical picture. For this reason, and because of anticoagulation concerns and evidence of increased mortality rates, heparin is now contraindicated in the treatment of fat embolism syndrome.^2,41,43

Alcohol. Patients with a higher blood alcohol level at the time of injury have been reported to have a lower incidence of fat embolism syndrome. Alcohol inhibits lipase, suppressing the rise of free fatty acids. In experimental studies, the incidence of fat embolism syndrome was lower when the blood alcohol level was maintained at 20 mg/dL. However, no prospective randomized trial has been done to determine the clinical efficacy of ethanol as a treatment for this condition.^5,42

Dextran has been advocated, owing to its ability to improve small-vessel perfusion, but bleeding risk and acute renal failure associated with this drug have limited its use.⁵

N-acetylcysteine has been shown to attenuate fat-induced lung injury in a study of rats with induced fat embolism syndrome.⁴⁴

Corticosteroid treatment for this condition is controversial. Studies in patients with femoral and tibial fractures show that steroids reduce the incidence of fat embolism syndrome when given prophylactically, and those treated with steroids had a higher Pao₂ than controls. Doses of methylprednisolone in these studies ranged between 9 mg/kg to 90 mg/kg. A drawback of these studies is their small number of patients.^12,32,45,46

A meta-analysis⁴⁷ of randomized trials of corticosteroids to prevent fat embolism syndrome in patients with long-bone fractures identified 104 such studies. Only 7 of the 104 were considered adequate. In 389 patients with long-bone fractures, prophylactic corticosteroids reduced the risk of fat embolism syndrome by 78% (95% confidence interval 43%–92%) and corticosteroids also significantly reduced the risk of hypoxia with no difference in rates of infection or death. However, the overall quality of the trials was poor, and the authors of the meta-analysis concluded that more study is needed before corticosteroids could be formally recommended.⁴⁷

There is no evidence that steroids improve the overall clinical course of already established fat embolism syndrome.^12,32,45 The dosing and optimal timing of administration have also not been established. High doses pose a risk of septic complications, which may be devastating for the posttrauma or postoperative patient.

A 75-year-old man with type 2 diabetes and hypothyroidism underwent bilateral total knee replacement at our hospital.

His functional capacity had been moderately limited by knee pain, but he could easily climb one flight of stairs without symptoms. His medications at that time included levothyroxine (Synthroid) and metformin (Glucophage). He had no known cardiac or pulmonary disease. The preoperative evaluation, including laboratory tests and electrocardiography, was within normal limits.

Spinal anesthesia was used for surgery, and he was given 2 mg of midazolam (Versed) intravenously for sedation. No additional sedation was given. He was given oxygen via nasal cannula at 2 L/min.

All vital signs were stable at the start of the procedure. However, about halfway through, when the thigh tourniquet was released, his oxygen saturation dropped abruptly from 100% to 92%. All other vital signs remained stable, and he was asymptomatic, was oriented to person, time, and place, was conversing freely, and was in no distress. The oxygen flow was increased to 6 L/min, his oxygen saturation improved, and the procedure was then completed as planned.

At the conclusion of the surgery, before the patient was transported to the postanesthesia care unit (PACU) and while his oxygen flow rate was still 6 L/min, his oxygen saturation again dropped to 92%. A simple face mask was placed, and the oxygen flow rate was increased to 10 L/min. His oxygen saturation stayed low, near 90%.

Bleeding during surgery had been nominal. He had received 2 L of lactated Ringer’s solution and 500 mL of hetastarch (Hextend) during surgery. He continued to be asymptomatic in the PACU.

1. What is the most likely cause of oxygen desaturation during bilateral total knee arthroplasty?

• Fat embolism
• Intraoperative pneumonia
• Venous thromboembolism with pulmonary embolism
• Acute myocardial infarction
• Acute pulmonary edema
• Excessive sedation

The differential diagnosis of oxygen desaturation during orthopedic procedures is listed in Table 1.

Fat embolism is the most likely cause, particularly given the greater fatty embolic load that occurs with bilateral total knee arthroplasty than with unilateral total knee arthroplasty.

At what point the maximal showering of fat emboli occurs is not known. Fat may be released into the circulation with pressurization of the medullary canal during surgery or with manipulation of a fracture. The emboli may collect in the leg veins and then be released in a shower when the thigh tourniquet is released. Vasoactive mediators and methylmethacrylate cement released into the circulatory system after tourniquet deflation may also cause vasodilation, hypotension, and increased dead-space ventilation, resulting in hypoxia and a drop in end-tidal CO₂.

Pneumonia during surgery is rare without an apparent aspiration event.

Venous thromboembolism is possible but is more likely later in the postoperative period after major orthopedic surgery.

Acute myocardial infarction could present with hypoxia, particularly in a diabetic patient, who may not experience chest pain. However, intraoperative electrocardiographic changes would likely be seen. If myocardial infarction is suspected, postoperative serial electrocardiograms and measuring troponin and cardiac enzyme levels aid in the diagnosis.

Acute pulmonary edema is possible but not as highly suspected, as the patient had no history of congestive heart failure and received an appropriate amount of fluid for this type of surgery.

Excessive sedation could cause hypoventilation and, thus, oxygen desaturatation. However, this patient’s oxygen desaturatation began more than an hour after the midazolam was given. Midazolam is a short-acting benzodiazepine. It is unlikely that the patient would show signs of hypoventilation and oversedation an hour after the drug was given. Our patient also did not show any signs of excessive sedation, as he was awake and conversing during the surgery.

Fat emboli vs fat embolism syndrome

Fat embolism is the presence of fat drops within the systemic and pulmonary microcirculation, with or without clinical sequelae.¹ Fat embolism syndrome, on the other hand, is defined as injury to and dysfunction of one or more organs as a result of the embolization of fat, usually within 24 hours of injury or orthopedic surgery.²

Fat embolism syndrome is an unpredictable condition with a varied presentation. Fat droplets are thought to embolize via the venous circulation into the pulmonary arteries, occluding small blood vessels in the lung. However, they also get into the arterial circulation and occlude arteries in the brain, kidney, heart, and liver (more on this phenomenon below).

Fat embolism is reported to originate primarily from fractures of the femur, tibia, and pelvis.^2,3 As many as 90% of trauma patients have been shown to have evidence of fat embolism on autopsy.⁴ However, only a small number of patients develop the classic fat embolism syndrome,^2,3,5 Why some develop the syndrome and others do not is still unknown.

Orthopedic procedures associated with fat embolization include knee arthroplasty and hip arthroplasty, particularly if it involves intramedullary manipulation or medullary fixation.⁶ It has also been reported during spinal procedures in which pedicular screws are used.⁷ The syndrome occurs in 0.25% to 30% of patients following multiple fractures and in 0.1% to 12% of patients during or following knee or hip arthroplasty.

One study⁸ showed evidence of fat on transesophageal echocardiography in 88% of patients undergoing medullary reaming of lower-extremity fractures and hip hemiarthroplasty. Blood sampling from the right atrium confirmed that fat was responsible for the echocardiographic abnormalities. The study also showed that the severity of the embolic showering correlated with the severity of hypoxia and the decrease in end-tidal CO₂.⁸

CASE CONTINUED

On arrival at the PACU, our patient’s oxygen saturation was 94% while he was breathing oxygen via a simple face mask at a flow rate of 10 L/min. His heart rate was 60 bpm, blood pressure 110/60 mm Hg, and temperature 37.5°C (96.3°F). Chest sounds were normal on auscultation.

However, 3 hours later, his mental status rapidly deteriorated. He was oriented only to person, and he was drowsy. He had escalating respiratory distress with a rapid respiratory rate and decreasing oxygen saturation. At this point, auscultation of his chest wall revealed bilateral crackles and rales.

He was promptly intubated. Profuse fluid and secretions were noted to be coming from his lungs, filling the endotracheal tube. Arterial blood gas measurement showed a pH of 7.22, Pao₂ 64 mm Hg, and Paco₂ 56 mm Hg on 100% fraction of inspired oxygen, with no increased anion gap.

2. Which consequence of fat embolism is most likely at this time in this patient?

• Coexisting sepsis
• Fat embolism syndrome
• Acute cardioembolic stroke
• Anaphylaxis

Fat embolism syndrome should be highly suspected in this patient. As mentioned, it can affect many different organs. It is the most serious condition resulting from fat embolization after surgery or trauma.

Sepsis was unlikely in our patient, since he presented for his surgery in good health and with no preexisting signs or symptoms of infection. Acute cardioembolic stroke could have caused the neurologic signs, but this would not necessarily explain the coexisting hypoxia. An anaphylactic reaction to drugs or surgical cement would most likely present intraoperatively, shortly after exposure occurred, rather than several hours after surgery.

How common is fat embolism syndrome?

The occurrence rate of fat embolism syndrome has been reported to be 0.25% to 30% after multiple fractures and 0.1% to 12% after knee and hip joint surgery, with a mortality rate of 13% to 36%.^2,9–14 The rate of occurrence after unilateral total knee joint replacement has been reported to be 1.8% to 5%, and 4% to 12% after bilateral total knee replacement.^15–19

The syndrome is relatively more common with traumatic fractures of the lower extremities. However, it has also been reported with liposuction, total parenteral nutrition, bone marrow harvest and transplantation, burns, and acute pancreatitis, to mention a few.¹⁰

The broad range of reported incidence rates can be attributed to the fact that many studies were in patients with multiple trauma, whose concomitant injuries may have made it difficult to clearly define the contribution of fat embolism syndrome to the overall rates of morbidity and mortality. Also, different studies used different criteria to define the syndrome.

How does fat embolism syndrome occur?

Two hypotheses for how this syndrome occurs were proposed nearly a century ago.^20,21

The “mechanical” theory is that fat emboli are formed as a result of trauma and disruption of adipose tissue and other cells in the bone marrow. Increases in intramedullary pressure force the fat emboli through damaged medullary venous channels in the bone and into the circulation of the lower extremities. This embolization of fat causes an initial mechanical pulmonary obstruction. Mechanical obstruction by fat emboli in the pulmonary system leads to increased pulmonary pressures and an increase in right heart outflow pressure. The right heart becomes strained, leading to a decreased right-sided cardiac output. As a result, the left heart filling pressures diminish and hypotension ensues.²⁰

The “biochemical” theory, on the other hand, is that chylomicrons within the vascular system are modified and their stability is compromised as a result of stress. These traumatized chylomicrons then coalesce to form droplets of fat that accumulate in the pulmonary circulation and produce a mechanical obstruction. This would explain why nontraumatic, nonorthopedic insults can produce this syndrome.

Autopsy studies show that there is little correlation between the presence and quantity of intravascular fat and the severity of clinical symptoms, thus implying that the syndrome is caused by more than just mechanical obstruction. The biochemical theory postulates that fat globules within the circulatory system then cause the release of lipase from the pulmonary alveolar cells, which then hydrolyses the fat into free fatty acids. These free fatty acids cause an inflammatory reaction, complementmediated leukocyte aggregation, chemotoxin release, and subsequently endothelial damage. These vasoactive substances damage type 2 pneumocytes and lead to an increased permeability of the pulmonary capillary beds. Acute respiratory distress syndrome (ARDS) may ensue. Disseminated intravascular coagulation may occur as a result of the formation of microthrombi involving lipids, platelets, and fibrin.^21,22

Embolization of fat to the central nervous system can occur as fat globules cross into the systemic circulation via a patent foramen ovale, an atrioventricular shunt, or the pulmonary capillaries. This can then result in cerebral ischemia.²³

Although patent foramen ovale may seem the most direct route for cerebral embolization, the neurologic impairment and signs of cerebral emboli in fat embolism syndrome may occur in the absence of patent foramen ovale.^24,25 The fat globules may actually go through the lung capillaries, being flexible and forced through by increased pulmonary pressure.

But whether the cause of fat embolism syndrome is occlusion by globules, the release of biochemical mediators, or a combination of both is unknown. Both mechanisms are likely responsible. We can only suspect that the degree of fat load and intrinsic metabolic differences between individuals account for the variation in susceptibility.

FAT EMBOLI AFFECT THE LUNGS, SKIN, AND BRAIN

3. Where on the body is the rash associated with fat embolism syndrome usually seen?

• Face
• Near a site of fracture or surgery
• Chest, axilla, conjunctiva
• Distal extremities

Petechiae are part of the classic presenting triad of fat embolism syndrome, which also includes pulmonary and cerebral dysfunction.

Petechiae usually appear on the 2nd to 4th day after injury.²⁶ They are usually found across the chest, the anterior axillary folds, and the neck, as well as on the oral mucosa and the conjunctiva. The rash is caused by occlusion of dermal capillaries by fat, which increases their fragility.¹⁰

Pulmonary changes usually begin with tachypnea, dyspnea, and a drop in oxygen saturation, leading to generalized hypoxia. Respiratory symptoms are present in 100% of cases.² Respiratory symptoms can acutely develop with the sudden manipulation of a fracture, reaming of bone, or release of a limb tourniquet.²⁷

Body systems affected by fat embolism syndrome are summarized in Table 2.

4. How many hours after injury does fat embolism syndrome typically manifest?

• 1 to 2 hours
• 6 to 12 hours
• 12 to 20 hours
• 24 to 48 hours
• 72 to 84 hours

Most patients develop signs and symptoms 24 to 48 hours after injury. Patients presenting earlier than 12 hours usually have a more fulminant course.²⁹

The time between fat embolization and the development of fat embolism syndrome is thought to be related to the time required for the metabolic conversion of fat to free fatty acids.³⁰ We suspect that the early desaturation seen in our patient was the result of a heavy showering of fat intraoperatively. However, this could only be concluded after we had ruled out other causes of acute hypoxia and hypotension.

Fat embolism syndrome is a diagnosis of exclusion and is based on clinical criteria. No specific sign, symptom, or test is pathognomonic. It may often be confused with other conditions such as systemic inflammatory response syndrome or sepsis. However, the triad of respiratory and neurologic symptoms and petechiae coupled with the clinical picture of recent trauma or orthopedic surgery almost assures the diagnosis.

Fat embolism syndrome can range from subclinical to fulminating, with the more fulminating course attributable to a huge load of fat emboli, which leads to acute cor pulmonale.

Regardless of the criteria used, one must have a high index of suspicion for fat embolization syndrome in patients undergoing orthopedic procedures, particularly hip and knee surgery, and in patients with fractures, especially fractures of the femur, tibia, or pelvis and multiple, concomitant fractures.

CASE CONTINUED

Our patient was given furosemide (Lasix) empirically for diuresis and to improve oxygenation. However, his oxygen saturation remained low.

Chest radiography 4 hours after surgery showed bilateral pulmonary infiltrates. Serial electrocardiography showed no acute changes. Levels of cardiac enzymes and troponins were normal. Transthoracic echocardiography showed no left ventricular dysfunction, a normal right ventricle, and no evidence of valvular lesions. Urine and blood fat stains were negative, but the sputum stain was positive for copious extracellular fat. The patient became comatose 5 hours postoperatively. Computed tomography of the brain was normal. He was transferred to the surgical intensive care unit.

The clinical course was marked by hemodynamic instability requiring norepinephrine (Levophed) and vasopressin (Pitressin) for hypotension. Right ventricular filling pressures via central venous pressure monitoring showed no evidence of hypovolemia. The hemoglobin concentration and the hematocrit were stable, with no evidence of acute or ongoing bleeding. Blood, urine, and sputum cultures remained negative. Acute myocardial infarction was ruled out by serial electrocardiography, cardiac enzyme testing, and troponin testing.

Magnetic resonance imaging (MRI) of the brain on postoperative day 2 showed foci of acute ischemia suggestive of embolic phenomena consistent with fat embolism syndrome (Figure  1). Transthoracic echocardiography was repeated but again showed no evidence of a patent foramen ovale. Electroencephalography on postoperative day 4 showed severe, diffuse encephalopathy. There was no petechial skin rash. Other laboratory studies showed progressive thrombocytopenia with a platelet count of 53 × 199/L on postoperative day 3.

TESTS THAT AID THE CLINICAL DIAGNOSIS

Although no single laboratory test is pathognomonic for fat embolism syndrome, several tests may help raise suspicion of it, especially in the setting of fracture or an orthopedic surgical procedure.

Arterial blood gases must be measured. A Pao₂ of less than 60 mm Hg with no other obvious lung pathology in an orthopedic surgery patient is highly suspicious.¹² An alveolar-arterial gradient of greater than 100 mm Hg may further increase suspicion.

Tests for fat. The blood and urine may be examined for fat, although positive findings are not specific for fat embolism syndrome.³³ Fat in the urine indicates the occurrence of massive fat embolism, but this is not always accompanied by the syndrome.³⁴ Gurd and Wilson¹³ found fat globules larger than 8 μm circulating in the serum in all documented cases. They stated that, even though the relationship of large fat globules to the pathogenesis of the clinical picture remains obscure, the demonstration of their presence can be helpful in the diagnosis.¹³

Also, samples obtained with bronchoalveolar lavage may be examined for fat. The macrophages may be stained for fat using the oil red O stain. Again, this is a nonspecific marker, as fat-stained macrophages are seen in trauma patients,³⁵ but the finding has a very high negative predictive value.³⁶ Anemia, thrombocytopenia, hypofibrinogenemia, an elevated lipase level, and a high erythrocyte sedimentation rate may be found in fat embolism syndrome.¹³

Chest radiography may show bilateral infiltrates, as in ARDS, but this is not diagnostic for fat embolism syndrome.

Electrocardiography may show changes in ST and T waves and signs of right heart strain.

Transesophageal echocardiography may show increased right heart and pulmonary artery pressures.

Computed tomography is often negative,^37,38 but T2-weighted MRI is useful in the diagnosis of cerebral fat embolism syndrome, as it can show intracerebral microinfarcts as early as 4 hours after the onset of neurologic symptoms, and these findings correlate well with the clinical severity of brain injury.

Diffusion-weighted MRI may enhance the sensitivity and specificity of the neuroradiologic diagnosis. Diffusion-weighted MRI typically shows multiple nonconfluent areas of high-intensity signals or bright spots on a dark background, known as a “starfield pattern.” This pattern has been suggested to be pathognomonic of acute cerebral microinfarction. The abnormalities presumably reflect foci of cytotoxic edema that develops immediately, unlike vasogenic edema, seen in T2-weighted images, which may take up to several days to develop. Although these images are not necessarily specific for fat emboli, they are useful in helping make the diagnosis. Thus, diffusionweighted MRI should be done if fat embolism syndrome is suspected.^38,39

CASE CONCLUDED

The patient’s course in the intensive care unit was further complicated by gastrointestinal bleeding and renal failure. His neurologic status did not improve. Repeated MRI of the brain showed evolving bilateral watershed infarction throughout the cortices. The neurologic consult service diagnosed the patient as having severe encephalopathy with a very poor prognosis. The decision was made to withdraw care. He was placed under palliative care and died on postoperative day 22.

DRUG TREATMENT OF FAT EMBOLISM SYNDROME

5. Which of the following drugs has been proven to be effective in treating fat embolism syndrome?

• Intravenous ethanol
• Steroids
• Heparin
• Dextran
• Aspirin
• None of the above

None of the above has been proven to be effective in treating this disorder. The management is largely supportive. Thus, prevention, early diagnosis, and symptom management are vital.

Pulmonary and hemodynamic support are the cornerstones of successful treatment. Aggressive respiratory support is often needed. Management of acute lung injury and ARDS focuses on achieving acceptable gas exchange while preventing ventilator-associated lung injury. Intravascular volume must be supported. Inotropes and pulmonary vasodilators may be required to maintain hemodynamics. Exacerbation of central nervous system ischemia from hypotension or hypoxia should be avoided.

If the thrombocytopenia leads to clinical bleeding, platelet transfusions may be warranted.

Supportive care should include prophylaxis of deep venous thrombosis and of gastrointestinal bleeding, and maintenance of nutrition.⁴⁰ Patients who receive supportive care generally have a favorable outcome, with a mortality rate of less than 10%.²⁸

Drug studies have been inconclusive

Drugs suggested in the treatment of fat embolism syndrome include heparin, aspirin, dextran, hypertonic glucose, and alcohol, but the results have been inconclusive.^{3,11,23,40–43}

Heparin stimulates lipase activity, consequently decreasing the concentration of circulating fat globules. However, the increase in levels of free fatty acids may actually worsen the clinical picture. For this reason, and because of anticoagulation concerns and evidence of increased mortality rates, heparin is now contraindicated in the treatment of fat embolism syndrome.^2,41,43

Alcohol. Patients with a higher blood alcohol level at the time of injury have been reported to have a lower incidence of fat embolism syndrome. Alcohol inhibits lipase, suppressing the rise of free fatty acids. In experimental studies, the incidence of fat embolism syndrome was lower when the blood alcohol level was maintained at 20 mg/dL. However, no prospective randomized trial has been done to determine the clinical efficacy of ethanol as a treatment for this condition.^5,42

Dextran has been advocated, owing to its ability to improve small-vessel perfusion, but bleeding risk and acute renal failure associated with this drug have limited its use.⁵

N-acetylcysteine has been shown to attenuate fat-induced lung injury in a study of rats with induced fat embolism syndrome.⁴⁴

Corticosteroid treatment for this condition is controversial. Studies in patients with femoral and tibial fractures show that steroids reduce the incidence of fat embolism syndrome when given prophylactically, and those treated with steroids had a higher Pao₂ than controls. Doses of methylprednisolone in these studies ranged between 9 mg/kg to 90 mg/kg. A drawback of these studies is their small number of patients.^12,32,45,46

A meta-analysis⁴⁷ of randomized trials of corticosteroids to prevent fat embolism syndrome in patients with long-bone fractures identified 104 such studies. Only 7 of the 104 were considered adequate. In 389 patients with long-bone fractures, prophylactic corticosteroids reduced the risk of fat embolism syndrome by 78% (95% confidence interval 43%–92%) and corticosteroids also significantly reduced the risk of hypoxia with no difference in rates of infection or death. However, the overall quality of the trials was poor, and the authors of the meta-analysis concluded that more study is needed before corticosteroids could be formally recommended.⁴⁷

There is no evidence that steroids improve the overall clinical course of already established fat embolism syndrome.^12,32,45 The dosing and optimal timing of administration have also not been established. High doses pose a risk of septic complications, which may be devastating for the posttrauma or postoperative patient.

Although the incidence and rates of morbidity and death from acute community-acquired bacterial meningitis have dramatically declined, probably as a result of vaccination and better antimicrobial and adjuvant therapy, the disease still has a high toll. From 10% to 20% of people who contract it in the United States still die of it.^1,2

In the United States, meningitis from all causes accounts for about 72,000 hospitalizations and up to $1.2 billion in hospital costs annually.³ However, the incidence of bacterial meningitis has declined from 3 to 5 per 100,000 per year a few decades ago to 1.3 to 2 per 100,000 per year currently.² In less-developed countries, rates are much higher.

In the early 1900s in the United States, the death rate from bacterial meningitis was 80% to 100%. The use of intrathecal equine meningococcal antiserum during the first decades of the 1900s dramatically reduced the rate of death from meningococcal meningitis. With the advent of antimicrobial drugs in the 1930s and 1940s, the death rate from bacterial meningitis further declined.

The organisms that cause community-acquired bacterial meningitis differ somewhat by geographic region and by age. In a recent paper based on surveillance data, in the United States, from 1998 to 2007, the most common cause of bacterial meningitis among adults was Streptococcus pneumoniae. Among young adults, Neisseria meningitidis is nearly as common as S pneumoniae. The incidence of Listeria infections increases with age in adults.²

The epidemiologic features of bacterial meningitis have changed dramatically over the past decades with the advent of the Haemophilus influenzae vaccine. In 1986, about half the cases of acute bacterial meningitis were caused by H influenzae, but a decade later the incidence of H influenzae meningitis had been reduced by 94%.⁴

Meningitis is inflammation of the pia and arachnoid (the inner two layers of the meninges). Acute community-acquired meningitis can develop within hours to days and can be viral or bacterial. Viral meningitis usually has a good prognosis, whereas bacterial meningitis is associated with significant rates of morbidity and death, so it is critical to recognize and differentiate them promptly.

PATHOGENESIS

Most cases of community-acquired bacterial meningitis begin with colonization of the nasopharyngeal mucosa. In certain individuals this leads to mucosal invasion and bacteremia. Not all organisms that cause bacteremia are capable of breaching the blood-cerebrospinal fluid barrier to enter the subarachnoid space to cause meningitis. Very few organisms have this capacity, but N meningitidis and S pneumoniae do.⁵

Some patients are at higher risk of meningitis because of an abnormal communication between the nasopharynx and the subarachnoid space due either to trauma or a congenital anatomic abnormality. The organisms in these instances can directly spread from the nasopharynx to the meninges. Patients without a spleen or with an immunoglobulin deficiency are also more prone to infections from encapsulated organisms such as pneumococci and meningococci. The opsonizing immunoglobulins coat the capsule, helping phagocytes in the spleen to remove them from the bloodstream. A patient presenting with multiple episodes of bacterial meningitis merits evaluation for these conditions.

In contrast, Listeria spp and, rarely, gramnegative bacteria enter the bloodstream through the gastrointestinal tract and then spread to the meninges.

Once in the subarachnoid space, bacteria elicit a profuse inflammatory response, which can be damaging.⁵ The inflammation in the subarachnoid space can extend along the Virchow-Robin spaces surrounding the blood vessels deep into the brain parenchyma. This perivascular inflammation can cause thrombosis in both the arterial and venous circulation.

Thus, the inflammation can lead to intracranial complications such as cerebral edema, hydrocephalus, and stroke. The complications of bacterial meningitis can be remembered by the acronym HACTIVE: hydrocephalus, abscess, cerebritis and cranial nerve lesions, thrombosis, infarct, ventriculitis and vasculopathy, and extra-axial collection.^5,6

MICROBIOLOGY: WHEN TO SUSPECT DIFFERENT ORGANISMS

S pneumoniae: The most common cause in adults

Patients without a spleen and patients with either a primary or secondary immunoglobulin deficiency, including patients with multiple myeloma or human immunodeficiency virus infection, are at a higher risk of infection with this organism.

N meningitidis: More common in young adults

N meningitidis is easily transmitted and is associated with crowding, as in school dormitories and military barracks. People with congenital deficiencies of components of terminal complement are at greater risk for both meningococcal and gonococcal infections. Patients with recurrent episodes of Neisseria infection should be evaluated for complement deficiency.

Photos courtesy of Thomas Fraser, MD.

Meningococcal infection is more commonly associated with a rash. The most common rash of meningococcal meningitis is a very transient, maculopapular rash that appears early in the course of the disease. More pathognomonic is a petechial rash (Figure 1) with thrombocytopenia, which can very rapidly progress to purpura, ecchymosis, and disseminated intravascular coagulation. The petechial rash is evident in 60% of adults and up to 90% of children,⁷ and it is most likely to appear in dependent areas (such as the back of a patient lying down) and in areas of pressure, such as under the elastic band of underwear or stockings.

Listeria

Listeria infection is usually acquired through contaminated food such as raw vegetables, unpasteurized milk and cheese, and deli meats. From the gastrointestinal tract, it spreads to the bloodstream and then to the meninges.

Listeria is an intracellular pathogen; thus, people at greater risk are those with poor cell-mediated immunity due to immunosuppressant medications such as steroids or tumor necrosis factor inhibitors.

The rate of Listeria meningitis starts to increase with age, especially after age 50, probably due to immune senescence or decreased immunity with age.

Aerobic gram-negative bacilli

Gram-negative enteric bacilli usually cause meningitis after head trauma or neurosurgery and are very uncommon causes of community-acquired meningitis. Disseminated strongyloidiasis, also known as hyperinfection syndrome, should be suspected in any patient with community-acquired meningitis caused by enteric gram-negative bacilli.

Strongyloides stercoralis is a parasitic intestinal roundworm that is found in the tropics, in the subtropics, and in certain parts of the United States and Europe. The adult worm lives in the intestines and lays eggs, which hatch in the mucosa; the larvae are excreted in the stool. A small percentage of larvae penetrate the perianal skin and gut mucosa to cause an autoinfection. People may asymptomatically harbor the parasite for decades, then develop the hyperinfection syndrome when treated with immunosuppressive drugs such as steroids. In the hyperinfection syndrome a significant proportion of the larvae penetrate the gut mucosa to enter the bloodstream and travel throughout the body, including into the brain, carrying gram-negative bacteria with them.

The mortality rate of untreated hyperinfection syndrome can sometimes reach 100%.⁸ Thus, it is important to identify and treat the hyperinfection syndrome in the context of gram-negative bacillary meningitis.

SUSPECTED MENINGITIS: CLINICAL SCENARIO

A 36-year-old man presents to the emergency department with high fever, headache, and lethargy that developed over the past 24 hours. His temperature is 104°F (40°C), pulse 120 beats/min, respiratory rate 30/min, and blood pressure 130/70 mm Hg. He is oriented only to person and has nuchal rigidity. His white blood cell count is 30 × 10⁹/L, with 20% bands.

The clinical questions that arise with such a patient are:

• Does the patient have bacterial or viral meningitis?
• Can we reliably rule out meningitis based on a history and physical examination?
• Is a lumbar puncture for cerebrospinal fluid (CSF) analysis needed? How should these studies be interpreted?
• Should computed tomography of the head be done before lumbar puncture?
• Which antimicrobial drugs should be started empirically at the outset?
• What is the role of steroids in treatment?

CLINICAL SIGNS AND SYMPTOMS

The classic triad of meningitis is fever, neck stiffness, and altered mental status. Other signs and symptoms that have been described are photophobia, headache, nausea, vomiting, focal neurologic symptoms, altered mental status, the Kernig sign (inability to allow full knee extension when the hip is flexed to a 90° angle), and the Brudzinski sign (spontaneous flexion of the hips during attempted passive flexion of the neck).

Can meningitis be ruled out if the patient does not have this classic presentation?

Unfortunately, only a few high-quality studies of the diagnostic accuracy of signs and symptoms of bacterial meningitis have been done. Fourteen retrospective studies examined this issue, but they were heterogeneous with respect to patient age, immunosuppression status, and clinical presentation, as well as to how meningitis was diagnosed (via culture or cerebrospinal fluid analysis), making the results difficult to interpret.⁹ Retrospective studies are more prone to bias, as they lack a control group, and examiner bias is more likely. Based on retrospective data, the combination of fever, neck stiffness, and altered mental status has a sensitivity of only 0.46.⁹

Two prospective studies examined symptoms and signs. Thomas et al¹⁰ evaluated 297 patients with “clinically suspected meningitis.” Unfortunately, in this study the physical examination was not standardized. In a study by Uchihara and Tsukagoshi,¹¹ the measurement was more reliable, as they used a single examiner to evaluate patients presenting with fever and headache, but only 54 patients were studied.

Based on these prospective studies, the presence of nausea and vomiting, headache, or neck stiffness does not reliably rule in meningitis (Table 1).⁹ Similarly, the absence of these does not rule it out. The 95% confidence intervals (CIs) of the positive and negative likelihood ratios include the value 1. (A simple interpretation of that would be that the likelihood of finding these features is the same in patients with meningitis when compared with those without meningitis.⁹)

For the physical examination, the presence or absence of fever, the Kernig sign, or the Brudzinski sign were also inconclusive. The CIs of the positive and negative likelihood ratios, like those of the symptoms, included the value 1. Only one test done on physical examination looked promising in having diagnostic utility to rule out meningitis: the jolt accentuation test (performed by asking a patient with a headache to quickly move his or her head twice horizontally; the result is positive if the headache worsens). If the result is negative, meningitis is unlikely (negative likelihood ratio 0.05, 95% CI 0.01–0.35).⁹ However, a positive test is not useful in making the diagnosis. A caveat is that this is based on a single study.

In summary, the history and physical examination are not sufficient to determine whether a patient has meningitis. If a patient is suspected of having meningitis, a lumbar puncture is needed.

WORKUP AND DIAGNOSTIC TESTS

Which tests are needed?

Blood cultures should be drawn before antimicrobial treatment is started.^12–14 Although positive only 19% to 70% of the time, they can help identify the pathogen.^15–17

Lumbar puncture with CSF study is essential to make the diagnosis and to identify the organism and its susceptibility to various antibiotics. If lumbar puncture can be performed immediately, it should be done before starting antibiotics, to maximize the yield of cultures. Pediatric studies show that after starting antibiotics, complete sterilization of the cerebrospinal fluid can occur within 2 hours for N meningitides and within 4 hours for S pneumoniae.¹⁴ However, starting antimicrobials should not be delayed if a lumbar puncture cannot be done expeditiously.

Is computed tomography of the brain necessary before a lumbar puncture?

The rationale behind performing CT before lumbar puncture is to determine if the patient has elevated intracranial pressure, which would increase the risk of brain herniation due to lowering of the lumbar CSF pressure during lumbar puncture. For ethical and practical reasons, it would be difficult to evaluate this in a randomized clinical trial.

Hasbun et al¹⁸ performed a study to evaluate if any features on clinical presentation can predict abnormal findings on CT of the head suggestive of elevated intracranial pressure and thus the risk of herniation. The study included 301 adults with suspected meningitis. It found that abnormal findings on CT were unlikely if all of the following features were absent at baseline:

• Immunocompromised state
• History of central nervous system disease (mass lesion, stroke, or a focal infection)
• New onset of seizure (≤ 1 week from presentation)
• Specific abnormal neurologic findings (eg, an abnormal level of consciousness, inability to answer two consecutive questions correctly or to follow two consecutive commands, gaze palsy, abnormal visual fields, facial palsy, arm drift, leg drift, abnormal language).

Absence of these baseline features made it unlikely that CT would be abnormal (negative likelihood ratio 0.1, 95% CI 0.03–0.31).

Adapted from Tunkel AR, et al. Practice guidelines for the management of bacterial meningitis. Clin Infec Dis 2004; 39:1267–1284, with permission from the Infectious Diseases Society of America.

According to the guidelines from the Infectious Diseases Society of America (IDSA),¹⁹ if none of those features is present, blood cultures and a lumbar puncture should be done immediately, followed by empiric antimicrobial therapy. If any of the features is present, blood cultures should be obtained first, then empiric antimicrobial therapy started, followed by CT of the brain to look for contraindications to a lumbar puncture (Figure 2).

What can lumbar puncture tell us?

Results of lumbar puncture studies can help determine whether meningitis is present and, if so, whether the cause is likely bacterial or viral.²⁰

The opening pressure is elevated (usually > 180 mm H₂O) in acute bacterial meningitis. The CSF white blood cell count is usually more than 1.0 × 10⁹/L, consisting predominantly of neutrophils, in acute bacterial meningitis. In viral meningitis, it is usually less than 0.1 × 10⁹/L, mostly lymphocytes.

Protein shows a mild to marked elevation in bacterial meningitis but is normal to elevated in viral meningitis.

The CSF glucose level is lower in bacterial meningitis than in viral meningitis.

The ratio of CSF glucose to blood glucose. Because the glucose levels in the CSF and the blood equilibrate, the ratio of CSF glucose to serum glucose has better diagnostic accuracy than the CSF glucose level alone. The equilibration takes place within a few hours, so the serum glucose level should be ordered at the same time lumbar puncture is done. The CSF glucose-blood glucose ratio is a better predictor of bacterial meningitis than the CSF white blood cell count. Bacterial meningitis is likely if the ratio is lower than 0.4.

Lactate levels are not usually measured, but a lactate level greater than 31.5 mg/dL (3.5 mmol/L) is predictive of meningitis, and a lower level makes the diagnosis unlikely.

The diagnostic accuracies (likelihood ratios) of the CSF tests were analyzed by Straus et al.²¹ The positive likelihood ratios for the CSF white blood cell count and for the CSF glucose-blood glucose ratio are greater than 10, but these tests have negative likelihood ratios of more than 0.1. (It is generally thought that a test with a positive likelihood ratio of more than 10 is considered good for ruling in a diagnosis, whereas one with a negative likelihood ratio of less than 0.1 is good for ruling out a diagnosis.) Thus, these tests are good to rule in bacterial meningitis, but not as good to rule it out. There are some data to show that CSF lactate and procalcitonin might be more sensitive in ruling out bacterial meningitis, but more studies are needed.²²

Gram stain of the cerebrospinal fluid can be done quickly. If no bacteria are seen, the information is not helpful in ruling out bacterial meningitis (negative likelihood ratio 0.14, 95% CI 0.08–0.27). If it is positive, it is almost 100% specific for meningitis due to the organism seen (positive likelihood ratio 735, 95% CI 230–2,295).²¹

MANAGEMENT

Empiric antimicrobial therapy must be started as soon as feasible

Most studies of the timing of antimicrobial drugs were retrospective and included a very heterogeneous population. They were thus more prone to bias and confounding.^23,24 Proulx et al,²³ in a retrospective study, found that if antibiotics were given within 6 hours of the time the patient presented to the emergency department, the case fatality rate was only 5% to 6%. If treatment started 6 to 8 hours after presentation, the death rate was 45%, and if it started from 8 to 10 hours after presentation, the death rate was 75%. Most physicians would agree that starting antimicrobials early would be beneficial.

CSF concentrations of most antimicrobial drugs are considerably less than in the serum due to poor penetration of the blood-CSF barrier. Thus, the dose for treating meningitis is usually higher than the regular dose. For example, for the treatment of pneumococcal pneumonia, ceftriaxone (Rocephin) is used at a dose of 1 g every 24 hours, but for pneumococcal meningitis the dose is 2 g every 12 hours.

Empiric treatment of community-acquired bacterial meningitis in immunocompetent adults up to 50 years of age consists of a third-generation cephalosporin such as cefotaxime (Claforan) 2 g intravenously every 4 hours or ceftriaxone 2 g intravenously every 12 hours, which covers most S pneumoniae and N meningitides strains.¹⁹ The IDSA guidelines recommend adding vancomycin (Vancocin) empirically in suspected S pneumoniae meningitis due to concerns about drug-resistant pneumococcal strains.¹⁹ For vancomycin, 45 to 60 mg/kg intravenously per day divided into every-6-hour or every-8-hour doses would achieve better CSF concentrations.²⁵

In patients over age 50 or those with a cell-mediated immunodeficiency, empiric therapy should also include ampicillin 2 g intravenously every 4 hours to cover Listeria.

It is important to tailor therapy to the results of Gram stain, culture, and susceptibility as they become available.

Role of corticosteroids

Glucocorticoids, especially dexamethasone (Decadron), have been well studied as adjunctive therapies in bacterial meningitis. The rationale behind their use is that the profuse inflammatory response to the bacterial components in the CSF by itself has deleterious effects, and steroids can reduce that.

In 2004, a Cochrane meta-analysis²⁶ of five randomized clinical trials, including 623 adults with bacterial meningitis (234 with pneumococcal meningitis and 232 with meningococcal meningitis), found a significant reduction in the death rate for patients who received steroids: the death rate was 12% in patients who received steroids vs 22% in those who did not (odds ratio 0.6; 95% CI 0.40–0.81). This led to an IDSA practice guideline recommendation that in adults with suspected or proven pneumococcal meningitis, dexamethasone would be beneficial.¹⁹

But since then, many more studies have emerged from Europe, South America, Malawi, and Vietnam, and another Cochrane metaanalysis²⁷ incorporated the new studies. Twenty-four studies involving 4,041 participants were included. Similar numbers of participants died in the corticosteroid and placebo groups (18% vs 20%; risk ratio [RR] 0.92, 95% CI 0.82–1.04, P = .18). A trend towards a lower mortality rate was noticed in adults receiving corticosteroids (RR 0.74, 95% CI 0.53–1.05, P = .09). In adults, corticosteroids were associated with lower rates of hearing loss (RR 0.74, 95% CI 0.56–0.98), and there was a trend towards fewer neurologic sequelae (RR 0.72, 95% CI 0.51–1.01). The benefits were shown in studies in adults in high-income countries, but the studies from low-income countries showed neither harm nor benefit. Based on these findings, the authors recommended the use of steroids in high-income countries, though the strength of the evidence was not optimal. The recommended steroid was dexamethasone 0.15 mg/kg intravenously every 6 hours for 4 days.

Although the incidence and rates of morbidity and death from acute community-acquired bacterial meningitis have dramatically declined, probably as a result of vaccination and better antimicrobial and adjuvant therapy, the disease still has a high toll. From 10% to 20% of people who contract it in the United States still die of it.^1,2

In the United States, meningitis from all causes accounts for about 72,000 hospitalizations and up to $1.2 billion in hospital costs annually.³ However, the incidence of bacterial meningitis has declined from 3 to 5 per 100,000 per year a few decades ago to 1.3 to 2 per 100,000 per year currently.² In less-developed countries, rates are much higher.

In the early 1900s in the United States, the death rate from bacterial meningitis was 80% to 100%. The use of intrathecal equine meningococcal antiserum during the first decades of the 1900s dramatically reduced the rate of death from meningococcal meningitis. With the advent of antimicrobial drugs in the 1930s and 1940s, the death rate from bacterial meningitis further declined.

The organisms that cause community-acquired bacterial meningitis differ somewhat by geographic region and by age. In a recent paper based on surveillance data, in the United States, from 1998 to 2007, the most common cause of bacterial meningitis among adults was Streptococcus pneumoniae. Among young adults, Neisseria meningitidis is nearly as common as S pneumoniae. The incidence of Listeria infections increases with age in adults.²

The epidemiologic features of bacterial meningitis have changed dramatically over the past decades with the advent of the Haemophilus influenzae vaccine. In 1986, about half the cases of acute bacterial meningitis were caused by H influenzae, but a decade later the incidence of H influenzae meningitis had been reduced by 94%.⁴

Meningitis is inflammation of the pia and arachnoid (the inner two layers of the meninges). Acute community-acquired meningitis can develop within hours to days and can be viral or bacterial. Viral meningitis usually has a good prognosis, whereas bacterial meningitis is associated with significant rates of morbidity and death, so it is critical to recognize and differentiate them promptly.

PATHOGENESIS

Most cases of community-acquired bacterial meningitis begin with colonization of the nasopharyngeal mucosa. In certain individuals this leads to mucosal invasion and bacteremia. Not all organisms that cause bacteremia are capable of breaching the blood-cerebrospinal fluid barrier to enter the subarachnoid space to cause meningitis. Very few organisms have this capacity, but N meningitidis and S pneumoniae do.⁵

Some patients are at higher risk of meningitis because of an abnormal communication between the nasopharynx and the subarachnoid space due either to trauma or a congenital anatomic abnormality. The organisms in these instances can directly spread from the nasopharynx to the meninges. Patients without a spleen or with an immunoglobulin deficiency are also more prone to infections from encapsulated organisms such as pneumococci and meningococci. The opsonizing immunoglobulins coat the capsule, helping phagocytes in the spleen to remove them from the bloodstream. A patient presenting with multiple episodes of bacterial meningitis merits evaluation for these conditions.

In contrast, Listeria spp and, rarely, gramnegative bacteria enter the bloodstream through the gastrointestinal tract and then spread to the meninges.

Once in the subarachnoid space, bacteria elicit a profuse inflammatory response, which can be damaging.⁵ The inflammation in the subarachnoid space can extend along the Virchow-Robin spaces surrounding the blood vessels deep into the brain parenchyma. This perivascular inflammation can cause thrombosis in both the arterial and venous circulation.

Thus, the inflammation can lead to intracranial complications such as cerebral edema, hydrocephalus, and stroke. The complications of bacterial meningitis can be remembered by the acronym HACTIVE: hydrocephalus, abscess, cerebritis and cranial nerve lesions, thrombosis, infarct, ventriculitis and vasculopathy, and extra-axial collection.^5,6

MICROBIOLOGY: WHEN TO SUSPECT DIFFERENT ORGANISMS

S pneumoniae: The most common cause in adults

Patients without a spleen and patients with either a primary or secondary immunoglobulin deficiency, including patients with multiple myeloma or human immunodeficiency virus infection, are at a higher risk of infection with this organism.

N meningitidis: More common in young adults

N meningitidis is easily transmitted and is associated with crowding, as in school dormitories and military barracks. People with congenital deficiencies of components of terminal complement are at greater risk for both meningococcal and gonococcal infections. Patients with recurrent episodes of Neisseria infection should be evaluated for complement deficiency.

Photos courtesy of Thomas Fraser, MD.

Meningococcal infection is more commonly associated with a rash. The most common rash of meningococcal meningitis is a very transient, maculopapular rash that appears early in the course of the disease. More pathognomonic is a petechial rash (Figure 1) with thrombocytopenia, which can very rapidly progress to purpura, ecchymosis, and disseminated intravascular coagulation. The petechial rash is evident in 60% of adults and up to 90% of children,⁷ and it is most likely to appear in dependent areas (such as the back of a patient lying down) and in areas of pressure, such as under the elastic band of underwear or stockings.

Listeria

Listeria infection is usually acquired through contaminated food such as raw vegetables, unpasteurized milk and cheese, and deli meats. From the gastrointestinal tract, it spreads to the bloodstream and then to the meninges.

Listeria is an intracellular pathogen; thus, people at greater risk are those with poor cell-mediated immunity due to immunosuppressant medications such as steroids or tumor necrosis factor inhibitors.

The rate of Listeria meningitis starts to increase with age, especially after age 50, probably due to immune senescence or decreased immunity with age.

Aerobic gram-negative bacilli

Gram-negative enteric bacilli usually cause meningitis after head trauma or neurosurgery and are very uncommon causes of community-acquired meningitis. Disseminated strongyloidiasis, also known as hyperinfection syndrome, should be suspected in any patient with community-acquired meningitis caused by enteric gram-negative bacilli.

Strongyloides stercoralis is a parasitic intestinal roundworm that is found in the tropics, in the subtropics, and in certain parts of the United States and Europe. The adult worm lives in the intestines and lays eggs, which hatch in the mucosa; the larvae are excreted in the stool. A small percentage of larvae penetrate the perianal skin and gut mucosa to cause an autoinfection. People may asymptomatically harbor the parasite for decades, then develop the hyperinfection syndrome when treated with immunosuppressive drugs such as steroids. In the hyperinfection syndrome a significant proportion of the larvae penetrate the gut mucosa to enter the bloodstream and travel throughout the body, including into the brain, carrying gram-negative bacteria with them.

The mortality rate of untreated hyperinfection syndrome can sometimes reach 100%.⁸ Thus, it is important to identify and treat the hyperinfection syndrome in the context of gram-negative bacillary meningitis.

SUSPECTED MENINGITIS: CLINICAL SCENARIO

A 36-year-old man presents to the emergency department with high fever, headache, and lethargy that developed over the past 24 hours. His temperature is 104°F (40°C), pulse 120 beats/min, respiratory rate 30/min, and blood pressure 130/70 mm Hg. He is oriented only to person and has nuchal rigidity. His white blood cell count is 30 × 10⁹/L, with 20% bands.

The clinical questions that arise with such a patient are:

• Does the patient have bacterial or viral meningitis?
• Can we reliably rule out meningitis based on a history and physical examination?
• Is a lumbar puncture for cerebrospinal fluid (CSF) analysis needed? How should these studies be interpreted?
• Should computed tomography of the head be done before lumbar puncture?
• Which antimicrobial drugs should be started empirically at the outset?
• What is the role of steroids in treatment?

CLINICAL SIGNS AND SYMPTOMS

The classic triad of meningitis is fever, neck stiffness, and altered mental status. Other signs and symptoms that have been described are photophobia, headache, nausea, vomiting, focal neurologic symptoms, altered mental status, the Kernig sign (inability to allow full knee extension when the hip is flexed to a 90° angle), and the Brudzinski sign (spontaneous flexion of the hips during attempted passive flexion of the neck).

Can meningitis be ruled out if the patient does not have this classic presentation?

Unfortunately, only a few high-quality studies of the diagnostic accuracy of signs and symptoms of bacterial meningitis have been done. Fourteen retrospective studies examined this issue, but they were heterogeneous with respect to patient age, immunosuppression status, and clinical presentation, as well as to how meningitis was diagnosed (via culture or cerebrospinal fluid analysis), making the results difficult to interpret.⁹ Retrospective studies are more prone to bias, as they lack a control group, and examiner bias is more likely. Based on retrospective data, the combination of fever, neck stiffness, and altered mental status has a sensitivity of only 0.46.⁹

Two prospective studies examined symptoms and signs. Thomas et al¹⁰ evaluated 297 patients with “clinically suspected meningitis.” Unfortunately, in this study the physical examination was not standardized. In a study by Uchihara and Tsukagoshi,¹¹ the measurement was more reliable, as they used a single examiner to evaluate patients presenting with fever and headache, but only 54 patients were studied.

Based on these prospective studies, the presence of nausea and vomiting, headache, or neck stiffness does not reliably rule in meningitis (Table 1).⁹ Similarly, the absence of these does not rule it out. The 95% confidence intervals (CIs) of the positive and negative likelihood ratios include the value 1. (A simple interpretation of that would be that the likelihood of finding these features is the same in patients with meningitis when compared with those without meningitis.⁹)

For the physical examination, the presence or absence of fever, the Kernig sign, or the Brudzinski sign were also inconclusive. The CIs of the positive and negative likelihood ratios, like those of the symptoms, included the value 1. Only one test done on physical examination looked promising in having diagnostic utility to rule out meningitis: the jolt accentuation test (performed by asking a patient with a headache to quickly move his or her head twice horizontally; the result is positive if the headache worsens). If the result is negative, meningitis is unlikely (negative likelihood ratio 0.05, 95% CI 0.01–0.35).⁹ However, a positive test is not useful in making the diagnosis. A caveat is that this is based on a single study.

In summary, the history and physical examination are not sufficient to determine whether a patient has meningitis. If a patient is suspected of having meningitis, a lumbar puncture is needed.

WORKUP AND DIAGNOSTIC TESTS

Which tests are needed?

Blood cultures should be drawn before antimicrobial treatment is started.^12–14 Although positive only 19% to 70% of the time, they can help identify the pathogen.^15–17

Lumbar puncture with CSF study is essential to make the diagnosis and to identify the organism and its susceptibility to various antibiotics. If lumbar puncture can be performed immediately, it should be done before starting antibiotics, to maximize the yield of cultures. Pediatric studies show that after starting antibiotics, complete sterilization of the cerebrospinal fluid can occur within 2 hours for N meningitides and within 4 hours for S pneumoniae.¹⁴ However, starting antimicrobials should not be delayed if a lumbar puncture cannot be done expeditiously.

Is computed tomography of the brain necessary before a lumbar puncture?

The rationale behind performing CT before lumbar puncture is to determine if the patient has elevated intracranial pressure, which would increase the risk of brain herniation due to lowering of the lumbar CSF pressure during lumbar puncture. For ethical and practical reasons, it would be difficult to evaluate this in a randomized clinical trial.

Hasbun et al¹⁸ performed a study to evaluate if any features on clinical presentation can predict abnormal findings on CT of the head suggestive of elevated intracranial pressure and thus the risk of herniation. The study included 301 adults with suspected meningitis. It found that abnormal findings on CT were unlikely if all of the following features were absent at baseline:

• Immunocompromised state
• History of central nervous system disease (mass lesion, stroke, or a focal infection)
• New onset of seizure (≤ 1 week from presentation)
• Specific abnormal neurologic findings (eg, an abnormal level of consciousness, inability to answer two consecutive questions correctly or to follow two consecutive commands, gaze palsy, abnormal visual fields, facial palsy, arm drift, leg drift, abnormal language).

Absence of these baseline features made it unlikely that CT would be abnormal (negative likelihood ratio 0.1, 95% CI 0.03–0.31).

Adapted from Tunkel AR, et al. Practice guidelines for the management of bacterial meningitis. Clin Infec Dis 2004; 39:1267–1284, with permission from the Infectious Diseases Society of America.

According to the guidelines from the Infectious Diseases Society of America (IDSA),¹⁹ if none of those features is present, blood cultures and a lumbar puncture should be done immediately, followed by empiric antimicrobial therapy. If any of the features is present, blood cultures should be obtained first, then empiric antimicrobial therapy started, followed by CT of the brain to look for contraindications to a lumbar puncture (Figure 2).

What can lumbar puncture tell us?

Results of lumbar puncture studies can help determine whether meningitis is present and, if so, whether the cause is likely bacterial or viral.²⁰

The opening pressure is elevated (usually > 180 mm H₂O) in acute bacterial meningitis. The CSF white blood cell count is usually more than 1.0 × 10⁹/L, consisting predominantly of neutrophils, in acute bacterial meningitis. In viral meningitis, it is usually less than 0.1 × 10⁹/L, mostly lymphocytes.

Protein shows a mild to marked elevation in bacterial meningitis but is normal to elevated in viral meningitis.

The CSF glucose level is lower in bacterial meningitis than in viral meningitis.

The ratio of CSF glucose to blood glucose. Because the glucose levels in the CSF and the blood equilibrate, the ratio of CSF glucose to serum glucose has better diagnostic accuracy than the CSF glucose level alone. The equilibration takes place within a few hours, so the serum glucose level should be ordered at the same time lumbar puncture is done. The CSF glucose-blood glucose ratio is a better predictor of bacterial meningitis than the CSF white blood cell count. Bacterial meningitis is likely if the ratio is lower than 0.4.

Lactate levels are not usually measured, but a lactate level greater than 31.5 mg/dL (3.5 mmol/L) is predictive of meningitis, and a lower level makes the diagnosis unlikely.

The diagnostic accuracies (likelihood ratios) of the CSF tests were analyzed by Straus et al.²¹ The positive likelihood ratios for the CSF white blood cell count and for the CSF glucose-blood glucose ratio are greater than 10, but these tests have negative likelihood ratios of more than 0.1. (It is generally thought that a test with a positive likelihood ratio of more than 10 is considered good for ruling in a diagnosis, whereas one with a negative likelihood ratio of less than 0.1 is good for ruling out a diagnosis.) Thus, these tests are good to rule in bacterial meningitis, but not as good to rule it out. There are some data to show that CSF lactate and procalcitonin might be more sensitive in ruling out bacterial meningitis, but more studies are needed.²²

Gram stain of the cerebrospinal fluid can be done quickly. If no bacteria are seen, the information is not helpful in ruling out bacterial meningitis (negative likelihood ratio 0.14, 95% CI 0.08–0.27). If it is positive, it is almost 100% specific for meningitis due to the organism seen (positive likelihood ratio 735, 95% CI 230–2,295).²¹

MANAGEMENT

Empiric antimicrobial therapy must be started as soon as feasible

Most studies of the timing of antimicrobial drugs were retrospective and included a very heterogeneous population. They were thus more prone to bias and confounding.^23,24 Proulx et al,²³ in a retrospective study, found that if antibiotics were given within 6 hours of the time the patient presented to the emergency department, the case fatality rate was only 5% to 6%. If treatment started 6 to 8 hours after presentation, the death rate was 45%, and if it started from 8 to 10 hours after presentation, the death rate was 75%. Most physicians would agree that starting antimicrobials early would be beneficial.

CSF concentrations of most antimicrobial drugs are considerably less than in the serum due to poor penetration of the blood-CSF barrier. Thus, the dose for treating meningitis is usually higher than the regular dose. For example, for the treatment of pneumococcal pneumonia, ceftriaxone (Rocephin) is used at a dose of 1 g every 24 hours, but for pneumococcal meningitis the dose is 2 g every 12 hours.

Empiric treatment of community-acquired bacterial meningitis in immunocompetent adults up to 50 years of age consists of a third-generation cephalosporin such as cefotaxime (Claforan) 2 g intravenously every 4 hours or ceftriaxone 2 g intravenously every 12 hours, which covers most S pneumoniae and N meningitides strains.¹⁹ The IDSA guidelines recommend adding vancomycin (Vancocin) empirically in suspected S pneumoniae meningitis due to concerns about drug-resistant pneumococcal strains.¹⁹ For vancomycin, 45 to 60 mg/kg intravenously per day divided into every-6-hour or every-8-hour doses would achieve better CSF concentrations.²⁵

In patients over age 50 or those with a cell-mediated immunodeficiency, empiric therapy should also include ampicillin 2 g intravenously every 4 hours to cover Listeria.

It is important to tailor therapy to the results of Gram stain, culture, and susceptibility as they become available.

Role of corticosteroids

Glucocorticoids, especially dexamethasone (Decadron), have been well studied as adjunctive therapies in bacterial meningitis. The rationale behind their use is that the profuse inflammatory response to the bacterial components in the CSF by itself has deleterious effects, and steroids can reduce that.

In 2004, a Cochrane meta-analysis²⁶ of five randomized clinical trials, including 623 adults with bacterial meningitis (234 with pneumococcal meningitis and 232 with meningococcal meningitis), found a significant reduction in the death rate for patients who received steroids: the death rate was 12% in patients who received steroids vs 22% in those who did not (odds ratio 0.6; 95% CI 0.40–0.81). This led to an IDSA practice guideline recommendation that in adults with suspected or proven pneumococcal meningitis, dexamethasone would be beneficial.¹⁹

But since then, many more studies have emerged from Europe, South America, Malawi, and Vietnam, and another Cochrane metaanalysis²⁷ incorporated the new studies. Twenty-four studies involving 4,041 participants were included. Similar numbers of participants died in the corticosteroid and placebo groups (18% vs 20%; risk ratio [RR] 0.92, 95% CI 0.82–1.04, P = .18). A trend towards a lower mortality rate was noticed in adults receiving corticosteroids (RR 0.74, 95% CI 0.53–1.05, P = .09). In adults, corticosteroids were associated with lower rates of hearing loss (RR 0.74, 95% CI 0.56–0.98), and there was a trend towards fewer neurologic sequelae (RR 0.72, 95% CI 0.51–1.01). The benefits were shown in studies in adults in high-income countries, but the studies from low-income countries showed neither harm nor benefit. Based on these findings, the authors recommended the use of steroids in high-income countries, though the strength of the evidence was not optimal. The recommended steroid was dexamethasone 0.15 mg/kg intravenously every 6 hours for 4 days.

Although the incidence and rates of morbidity and death from acute community-acquired bacterial meningitis have dramatically declined, probably as a result of vaccination and better antimicrobial and adjuvant therapy, the disease still has a high toll. From 10% to 20% of people who contract it in the United States still die of it.^1,2

In the United States, meningitis from all causes accounts for about 72,000 hospitalizations and up to $1.2 billion in hospital costs annually.³ However, the incidence of bacterial meningitis has declined from 3 to 5 per 100,000 per year a few decades ago to 1.3 to 2 per 100,000 per year currently.² In less-developed countries, rates are much higher.

In the early 1900s in the United States, the death rate from bacterial meningitis was 80% to 100%. The use of intrathecal equine meningococcal antiserum during the first decades of the 1900s dramatically reduced the rate of death from meningococcal meningitis. With the advent of antimicrobial drugs in the 1930s and 1940s, the death rate from bacterial meningitis further declined.

The organisms that cause community-acquired bacterial meningitis differ somewhat by geographic region and by age. In a recent paper based on surveillance data, in the United States, from 1998 to 2007, the most common cause of bacterial meningitis among adults was Streptococcus pneumoniae. Among young adults, Neisseria meningitidis is nearly as common as S pneumoniae. The incidence of Listeria infections increases with age in adults.²

The epidemiologic features of bacterial meningitis have changed dramatically over the past decades with the advent of the Haemophilus influenzae vaccine. In 1986, about half the cases of acute bacterial meningitis were caused by H influenzae, but a decade later the incidence of H influenzae meningitis had been reduced by 94%.⁴

Meningitis is inflammation of the pia and arachnoid (the inner two layers of the meninges). Acute community-acquired meningitis can develop within hours to days and can be viral or bacterial. Viral meningitis usually has a good prognosis, whereas bacterial meningitis is associated with significant rates of morbidity and death, so it is critical to recognize and differentiate them promptly.

PATHOGENESIS

Most cases of community-acquired bacterial meningitis begin with colonization of the nasopharyngeal mucosa. In certain individuals this leads to mucosal invasion and bacteremia. Not all organisms that cause bacteremia are capable of breaching the blood-cerebrospinal fluid barrier to enter the subarachnoid space to cause meningitis. Very few organisms have this capacity, but N meningitidis and S pneumoniae do.⁵

Some patients are at higher risk of meningitis because of an abnormal communication between the nasopharynx and the subarachnoid space due either to trauma or a congenital anatomic abnormality. The organisms in these instances can directly spread from the nasopharynx to the meninges. Patients without a spleen or with an immunoglobulin deficiency are also more prone to infections from encapsulated organisms such as pneumococci and meningococci. The opsonizing immunoglobulins coat the capsule, helping phagocytes in the spleen to remove them from the bloodstream. A patient presenting with multiple episodes of bacterial meningitis merits evaluation for these conditions.

In contrast, Listeria spp and, rarely, gramnegative bacteria enter the bloodstream through the gastrointestinal tract and then spread to the meninges.

Once in the subarachnoid space, bacteria elicit a profuse inflammatory response, which can be damaging.⁵ The inflammation in the subarachnoid space can extend along the Virchow-Robin spaces surrounding the blood vessels deep into the brain parenchyma. This perivascular inflammation can cause thrombosis in both the arterial and venous circulation.

Thus, the inflammation can lead to intracranial complications such as cerebral edema, hydrocephalus, and stroke. The complications of bacterial meningitis can be remembered by the acronym HACTIVE: hydrocephalus, abscess, cerebritis and cranial nerve lesions, thrombosis, infarct, ventriculitis and vasculopathy, and extra-axial collection.^5,6

MICROBIOLOGY: WHEN TO SUSPECT DIFFERENT ORGANISMS

S pneumoniae: The most common cause in adults

Patients without a spleen and patients with either a primary or secondary immunoglobulin deficiency, including patients with multiple myeloma or human immunodeficiency virus infection, are at a higher risk of infection with this organism.

N meningitidis: More common in young adults

N meningitidis is easily transmitted and is associated with crowding, as in school dormitories and military barracks. People with congenital deficiencies of components of terminal complement are at greater risk for both meningococcal and gonococcal infections. Patients with recurrent episodes of Neisseria infection should be evaluated for complement deficiency.

Photos courtesy of Thomas Fraser, MD.

Meningococcal infection is more commonly associated with a rash. The most common rash of meningococcal meningitis is a very transient, maculopapular rash that appears early in the course of the disease. More pathognomonic is a petechial rash (Figure 1) with thrombocytopenia, which can very rapidly progress to purpura, ecchymosis, and disseminated intravascular coagulation. The petechial rash is evident in 60% of adults and up to 90% of children,⁷ and it is most likely to appear in dependent areas (such as the back of a patient lying down) and in areas of pressure, such as under the elastic band of underwear or stockings.

Listeria

Listeria infection is usually acquired through contaminated food such as raw vegetables, unpasteurized milk and cheese, and deli meats. From the gastrointestinal tract, it spreads to the bloodstream and then to the meninges.

Listeria is an intracellular pathogen; thus, people at greater risk are those with poor cell-mediated immunity due to immunosuppressant medications such as steroids or tumor necrosis factor inhibitors.

The rate of Listeria meningitis starts to increase with age, especially after age 50, probably due to immune senescence or decreased immunity with age.

Aerobic gram-negative bacilli

Gram-negative enteric bacilli usually cause meningitis after head trauma or neurosurgery and are very uncommon causes of community-acquired meningitis. Disseminated strongyloidiasis, also known as hyperinfection syndrome, should be suspected in any patient with community-acquired meningitis caused by enteric gram-negative bacilli.

Strongyloides stercoralis is a parasitic intestinal roundworm that is found in the tropics, in the subtropics, and in certain parts of the United States and Europe. The adult worm lives in the intestines and lays eggs, which hatch in the mucosa; the larvae are excreted in the stool. A small percentage of larvae penetrate the perianal skin and gut mucosa to cause an autoinfection. People may asymptomatically harbor the parasite for decades, then develop the hyperinfection syndrome when treated with immunosuppressive drugs such as steroids. In the hyperinfection syndrome a significant proportion of the larvae penetrate the gut mucosa to enter the bloodstream and travel throughout the body, including into the brain, carrying gram-negative bacteria with them.

The mortality rate of untreated hyperinfection syndrome can sometimes reach 100%.⁸ Thus, it is important to identify and treat the hyperinfection syndrome in the context of gram-negative bacillary meningitis.

SUSPECTED MENINGITIS: CLINICAL SCENARIO

A 36-year-old man presents to the emergency department with high fever, headache, and lethargy that developed over the past 24 hours. His temperature is 104°F (40°C), pulse 120 beats/min, respiratory rate 30/min, and blood pressure 130/70 mm Hg. He is oriented only to person and has nuchal rigidity. His white blood cell count is 30 × 10⁹/L, with 20% bands.

The clinical questions that arise with such a patient are:

• Does the patient have bacterial or viral meningitis?
• Can we reliably rule out meningitis based on a history and physical examination?
• Is a lumbar puncture for cerebrospinal fluid (CSF) analysis needed? How should these studies be interpreted?
• Should computed tomography of the head be done before lumbar puncture?
• Which antimicrobial drugs should be started empirically at the outset?
• What is the role of steroids in treatment?

CLINICAL SIGNS AND SYMPTOMS

The classic triad of meningitis is fever, neck stiffness, and altered mental status. Other signs and symptoms that have been described are photophobia, headache, nausea, vomiting, focal neurologic symptoms, altered mental status, the Kernig sign (inability to allow full knee extension when the hip is flexed to a 90° angle), and the Brudzinski sign (spontaneous flexion of the hips during attempted passive flexion of the neck).

Can meningitis be ruled out if the patient does not have this classic presentation?

Unfortunately, only a few high-quality studies of the diagnostic accuracy of signs and symptoms of bacterial meningitis have been done. Fourteen retrospective studies examined this issue, but they were heterogeneous with respect to patient age, immunosuppression status, and clinical presentation, as well as to how meningitis was diagnosed (via culture or cerebrospinal fluid analysis), making the results difficult to interpret.⁹ Retrospective studies are more prone to bias, as they lack a control group, and examiner bias is more likely. Based on retrospective data, the combination of fever, neck stiffness, and altered mental status has a sensitivity of only 0.46.⁹

Two prospective studies examined symptoms and signs. Thomas et al¹⁰ evaluated 297 patients with “clinically suspected meningitis.” Unfortunately, in this study the physical examination was not standardized. In a study by Uchihara and Tsukagoshi,¹¹ the measurement was more reliable, as they used a single examiner to evaluate patients presenting with fever and headache, but only 54 patients were studied.

Based on these prospective studies, the presence of nausea and vomiting, headache, or neck stiffness does not reliably rule in meningitis (Table 1).⁹ Similarly, the absence of these does not rule it out. The 95% confidence intervals (CIs) of the positive and negative likelihood ratios include the value 1. (A simple interpretation of that would be that the likelihood of finding these features is the same in patients with meningitis when compared with those without meningitis.⁹)

For the physical examination, the presence or absence of fever, the Kernig sign, or the Brudzinski sign were also inconclusive. The CIs of the positive and negative likelihood ratios, like those of the symptoms, included the value 1. Only one test done on physical examination looked promising in having diagnostic utility to rule out meningitis: the jolt accentuation test (performed by asking a patient with a headache to quickly move his or her head twice horizontally; the result is positive if the headache worsens). If the result is negative, meningitis is unlikely (negative likelihood ratio 0.05, 95% CI 0.01–0.35).⁹ However, a positive test is not useful in making the diagnosis. A caveat is that this is based on a single study.

In summary, the history and physical examination are not sufficient to determine whether a patient has meningitis. If a patient is suspected of having meningitis, a lumbar puncture is needed.

WORKUP AND DIAGNOSTIC TESTS

Which tests are needed?

Blood cultures should be drawn before antimicrobial treatment is started.^12–14 Although positive only 19% to 70% of the time, they can help identify the pathogen.^15–17

Lumbar puncture with CSF study is essential to make the diagnosis and to identify the organism and its susceptibility to various antibiotics. If lumbar puncture can be performed immediately, it should be done before starting antibiotics, to maximize the yield of cultures. Pediatric studies show that after starting antibiotics, complete sterilization of the cerebrospinal fluid can occur within 2 hours for N meningitides and within 4 hours for S pneumoniae.¹⁴ However, starting antimicrobials should not be delayed if a lumbar puncture cannot be done expeditiously.

Is computed tomography of the brain necessary before a lumbar puncture?

The rationale behind performing CT before lumbar puncture is to determine if the patient has elevated intracranial pressure, which would increase the risk of brain herniation due to lowering of the lumbar CSF pressure during lumbar puncture. For ethical and practical reasons, it would be difficult to evaluate this in a randomized clinical trial.

Hasbun et al¹⁸ performed a study to evaluate if any features on clinical presentation can predict abnormal findings on CT of the head suggestive of elevated intracranial pressure and thus the risk of herniation. The study included 301 adults with suspected meningitis. It found that abnormal findings on CT were unlikely if all of the following features were absent at baseline:

• Immunocompromised state
• History of central nervous system disease (mass lesion, stroke, or a focal infection)
• New onset of seizure (≤ 1 week from presentation)
• Specific abnormal neurologic findings (eg, an abnormal level of consciousness, inability to answer two consecutive questions correctly or to follow two consecutive commands, gaze palsy, abnormal visual fields, facial palsy, arm drift, leg drift, abnormal language).

Absence of these baseline features made it unlikely that CT would be abnormal (negative likelihood ratio 0.1, 95% CI 0.03–0.31).

Adapted from Tunkel AR, et al. Practice guidelines for the management of bacterial meningitis. Clin Infec Dis 2004; 39:1267–1284, with permission from the Infectious Diseases Society of America.

According to the guidelines from the Infectious Diseases Society of America (IDSA),¹⁹ if none of those features is present, blood cultures and a lumbar puncture should be done immediately, followed by empiric antimicrobial therapy. If any of the features is present, blood cultures should be obtained first, then empiric antimicrobial therapy started, followed by CT of the brain to look for contraindications to a lumbar puncture (Figure 2).

What can lumbar puncture tell us?

Results of lumbar puncture studies can help determine whether meningitis is present and, if so, whether the cause is likely bacterial or viral.²⁰

The opening pressure is elevated (usually > 180 mm H₂O) in acute bacterial meningitis. The CSF white blood cell count is usually more than 1.0 × 10⁹/L, consisting predominantly of neutrophils, in acute bacterial meningitis. In viral meningitis, it is usually less than 0.1 × 10⁹/L, mostly lymphocytes.

Protein shows a mild to marked elevation in bacterial meningitis but is normal to elevated in viral meningitis.

The CSF glucose level is lower in bacterial meningitis than in viral meningitis.

The ratio of CSF glucose to blood glucose. Because the glucose levels in the CSF and the blood equilibrate, the ratio of CSF glucose to serum glucose has better diagnostic accuracy than the CSF glucose level alone. The equilibration takes place within a few hours, so the serum glucose level should be ordered at the same time lumbar puncture is done. The CSF glucose-blood glucose ratio is a better predictor of bacterial meningitis than the CSF white blood cell count. Bacterial meningitis is likely if the ratio is lower than 0.4.

Lactate levels are not usually measured, but a lactate level greater than 31.5 mg/dL (3.5 mmol/L) is predictive of meningitis, and a lower level makes the diagnosis unlikely.

The diagnostic accuracies (likelihood ratios) of the CSF tests were analyzed by Straus et al.²¹ The positive likelihood ratios for the CSF white blood cell count and for the CSF glucose-blood glucose ratio are greater than 10, but these tests have negative likelihood ratios of more than 0.1. (It is generally thought that a test with a positive likelihood ratio of more than 10 is considered good for ruling in a diagnosis, whereas one with a negative likelihood ratio of less than 0.1 is good for ruling out a diagnosis.) Thus, these tests are good to rule in bacterial meningitis, but not as good to rule it out. There are some data to show that CSF lactate and procalcitonin might be more sensitive in ruling out bacterial meningitis, but more studies are needed.²²

Gram stain of the cerebrospinal fluid can be done quickly. If no bacteria are seen, the information is not helpful in ruling out bacterial meningitis (negative likelihood ratio 0.14, 95% CI 0.08–0.27). If it is positive, it is almost 100% specific for meningitis due to the organism seen (positive likelihood ratio 735, 95% CI 230–2,295).²¹

MANAGEMENT

Empiric antimicrobial therapy must be started as soon as feasible

Most studies of the timing of antimicrobial drugs were retrospective and included a very heterogeneous population. They were thus more prone to bias and confounding.^23,24 Proulx et al,²³ in a retrospective study, found that if antibiotics were given within 6 hours of the time the patient presented to the emergency department, the case fatality rate was only 5% to 6%. If treatment started 6 to 8 hours after presentation, the death rate was 45%, and if it started from 8 to 10 hours after presentation, the death rate was 75%. Most physicians would agree that starting antimicrobials early would be beneficial.

CSF concentrations of most antimicrobial drugs are considerably less than in the serum due to poor penetration of the blood-CSF barrier. Thus, the dose for treating meningitis is usually higher than the regular dose. For example, for the treatment of pneumococcal pneumonia, ceftriaxone (Rocephin) is used at a dose of 1 g every 24 hours, but for pneumococcal meningitis the dose is 2 g every 12 hours.

Empiric treatment of community-acquired bacterial meningitis in immunocompetent adults up to 50 years of age consists of a third-generation cephalosporin such as cefotaxime (Claforan) 2 g intravenously every 4 hours or ceftriaxone 2 g intravenously every 12 hours, which covers most S pneumoniae and N meningitides strains.¹⁹ The IDSA guidelines recommend adding vancomycin (Vancocin) empirically in suspected S pneumoniae meningitis due to concerns about drug-resistant pneumococcal strains.¹⁹ For vancomycin, 45 to 60 mg/kg intravenously per day divided into every-6-hour or every-8-hour doses would achieve better CSF concentrations.²⁵

In patients over age 50 or those with a cell-mediated immunodeficiency, empiric therapy should also include ampicillin 2 g intravenously every 4 hours to cover Listeria.

It is important to tailor therapy to the results of Gram stain, culture, and susceptibility as they become available.

Role of corticosteroids

Glucocorticoids, especially dexamethasone (Decadron), have been well studied as adjunctive therapies in bacterial meningitis. The rationale behind their use is that the profuse inflammatory response to the bacterial components in the CSF by itself has deleterious effects, and steroids can reduce that.

In 2004, a Cochrane meta-analysis²⁶ of five randomized clinical trials, including 623 adults with bacterial meningitis (234 with pneumococcal meningitis and 232 with meningococcal meningitis), found a significant reduction in the death rate for patients who received steroids: the death rate was 12% in patients who received steroids vs 22% in those who did not (odds ratio 0.6; 95% CI 0.40–0.81). This led to an IDSA practice guideline recommendation that in adults with suspected or proven pneumococcal meningitis, dexamethasone would be beneficial.¹⁹

But since then, many more studies have emerged from Europe, South America, Malawi, and Vietnam, and another Cochrane metaanalysis²⁷ incorporated the new studies. Twenty-four studies involving 4,041 participants were included. Similar numbers of participants died in the corticosteroid and placebo groups (18% vs 20%; risk ratio [RR] 0.92, 95% CI 0.82–1.04, P = .18). A trend towards a lower mortality rate was noticed in adults receiving corticosteroids (RR 0.74, 95% CI 0.53–1.05, P = .09). In adults, corticosteroids were associated with lower rates of hearing loss (RR 0.74, 95% CI 0.56–0.98), and there was a trend towards fewer neurologic sequelae (RR 0.72, 95% CI 0.51–1.01). The benefits were shown in studies in adults in high-income countries, but the studies from low-income countries showed neither harm nor benefit. Based on these findings, the authors recommended the use of steroids in high-income countries, though the strength of the evidence was not optimal. The recommended steroid was dexamethasone 0.15 mg/kg intravenously every 6 hours for 4 days.

A 72-year-old man presented with abdominal cramping, diarrhea, intermittent flushing, asthenia, and a weight loss of 10 kg (22 lb) in the past 6 months. Physical examination revealed hepatosplenomegaly and an erythematous, maculopapular, confluent rash on the trunk (Figure 1) that displayed the Darier sign (redness, swelling, and itching in response to stroking in the involved area).

Laboratory analyses

• Hemoglobin 9.8 g/dL (normal 13–17 g/dL)
• White blood cell count 22.9 × 10⁹/L (3.8–10)
• Vitamin B₁₂ 1,730 pg/mL (220–900)
• Serum tryptase 516 μg/L (5.5–13.5)
• Beta-2 microglobulin 4.14 mg/L (1.39–2.11).

Radiologic evaluation

Radiologic evaluation showed diffuse osteosclerosis with lytic and blastic areas (Figure 2).

Q: Which is the most likely diagnosis?

• Carcinoid syndrome
• Histiocytosis
• Acute myeloblastic leukemia
• Systemic mastocytosis
• Chronic myeloblastic leukemia

A: The correct answer is systemic mastocytosis. The diagnosis was made according to the World Health Organization (WHO) diagnostic criteria for mastocytosis on the basis of the following findings in the bone marrow:

• 

  Morphologically abnormal mast cells characterized by large size, spindle shape and poorly granulated cytoplasm (Figure 3) together with criteria for refractory cytopenia and multilineage dysplasia
• Diffuse infiltration by tryptase-positive mast cells as assessed by immunohistochemical study (Figure 4)

• 

  One percent of mast cells that are immunophenotypically aberrant (CD25bright+), all of them showing an immature profile,¹ associated with features of multilineage dysplasia² as assessed by flow cytometry
• The activating D816V KIT mutation, detected by peptide nucleic acid-mediated polymerase chain reaction clamping technique.³

MASTOCYTOSIS HAS SEVEN VARIANTS

Mastocytosis is a rare heterogeneous group of disorders characterized by proliferation and accumulation of abnormal mast cells in diverse organs and tissues, such as the skin, bone marrow, gastrointestinal tract, liver, spleen, or lymph nodes.^4–6 The release of mast cell mediators causes a wide variety of symptoms, ranging from pruritus, flushing, abdominal cramping, and diarrhea to severe anaphylaxis with vascular collapse.^7,8

The WHO defines seven variants⁶:

• Cutaneous mastocytosis
• Indolent systemic mastocytosis
• Systemic mastocytosis with an associated (clonal) hematologic non-mast-cell disease (SM-AHNMD)
• Aggressive systemic mastocytosis
• Mast cell leukemia
• Mast cell sarcoma
• Extracutaneous mastocytoma.⁶

KIT mutation as a diagnostic criterion and prognostic factor

In most cases of systemic involvement, the clonal nature of the disease can be established by finding activating mutations of KIT, usually D816V, in lesions in the skin, bone marrow cells, or both.⁹ Apart from its value as a diagnostic criterion for systemic mastocytosis, KIT mutation has been reported to be strongly associated with progression of indolent systemic mastocytosis, including the development of myeloid malignancies, when the mutation is detected not only in mast cells but in all hematopoietic lineages.¹⁰

In cases of SM-AHNMD, a possible pathophysiologic relationship between the disorder in the mast cells and the disorder in other cells could be explained by a KIT mutation in early hematopoietic progenitor cells, which further evolve into phenotypically different subclones.

A rational management plan for mastocytosis must include carefully counselling the patient and care providers, avoiding factors that trigger acute release of mast cell mediators, and giving antimediator therapy such as oral cromolyn sodium (Gastrocrom), antihistamines, and leukotriene antagonists to relieve the symptoms caused by mast-cell-mediator release.¹¹ In cases of SM-AHNMD, the clinical course and long-term prognosis are usually dominated by the concomitant hematologic malignancy, which should be treated as a separate entity.

CASE CONTINUED

Our patient’s bone marrow was analyzed for the KIT mutation in highly purified bone marrow cell subpopulations sorted by fluorescence-activated cell sorting. The mutation was detected in his mast cells, CD34+ cells, eosinophils, monocytes, neutrophils, lymphocytes, and nucleated erythroid precursors. According to the WHO recommendations, he had SMAHNMD, the associated hematologic disease being a myelodysplastic syndrome.

In view of his advanced age and concomitant myelodysplastic syndrome presenting with leukocytosis, we gave him hydroxyurea (Droxia; available in Spain as Hydrea) rather than other cytoreductive drugs as the first-line therapy. Additionally, we gave him corticosteroids in low doses, sodium cromolyn, and antihistamines to treat mastocytosis-related gastrointestinal symptoms. The patient was alive with stable disease 14 months after starting therapy.

A 72-year-old man presented with abdominal cramping, diarrhea, intermittent flushing, asthenia, and a weight loss of 10 kg (22 lb) in the past 6 months. Physical examination revealed hepatosplenomegaly and an erythematous, maculopapular, confluent rash on the trunk (Figure 1) that displayed the Darier sign (redness, swelling, and itching in response to stroking in the involved area).

Laboratory analyses

• Hemoglobin 9.8 g/dL (normal 13–17 g/dL)
• White blood cell count 22.9 × 10⁹/L (3.8–10)
• Vitamin B₁₂ 1,730 pg/mL (220–900)
• Serum tryptase 516 μg/L (5.5–13.5)
• Beta-2 microglobulin 4.14 mg/L (1.39–2.11).

Radiologic evaluation

Radiologic evaluation showed diffuse osteosclerosis with lytic and blastic areas (Figure 2).

Q: Which is the most likely diagnosis?

• Carcinoid syndrome
• Histiocytosis
• Acute myeloblastic leukemia
• Systemic mastocytosis
• Chronic myeloblastic leukemia

A: The correct answer is systemic mastocytosis. The diagnosis was made according to the World Health Organization (WHO) diagnostic criteria for mastocytosis on the basis of the following findings in the bone marrow:

• 

  Morphologically abnormal mast cells characterized by large size, spindle shape and poorly granulated cytoplasm (Figure 3) together with criteria for refractory cytopenia and multilineage dysplasia
• Diffuse infiltration by tryptase-positive mast cells as assessed by immunohistochemical study (Figure 4)

• 

  One percent of mast cells that are immunophenotypically aberrant (CD25bright+), all of them showing an immature profile,¹ associated with features of multilineage dysplasia² as assessed by flow cytometry
• The activating D816V KIT mutation, detected by peptide nucleic acid-mediated polymerase chain reaction clamping technique.³

MASTOCYTOSIS HAS SEVEN VARIANTS

Mastocytosis is a rare heterogeneous group of disorders characterized by proliferation and accumulation of abnormal mast cells in diverse organs and tissues, such as the skin, bone marrow, gastrointestinal tract, liver, spleen, or lymph nodes.^4–6 The release of mast cell mediators causes a wide variety of symptoms, ranging from pruritus, flushing, abdominal cramping, and diarrhea to severe anaphylaxis with vascular collapse.^7,8

The WHO defines seven variants⁶:

• Cutaneous mastocytosis
• Indolent systemic mastocytosis
• Systemic mastocytosis with an associated (clonal) hematologic non-mast-cell disease (SM-AHNMD)
• Aggressive systemic mastocytosis
• Mast cell leukemia
• Mast cell sarcoma
• Extracutaneous mastocytoma.⁶

KIT mutation as a diagnostic criterion and prognostic factor

In most cases of systemic involvement, the clonal nature of the disease can be established by finding activating mutations of KIT, usually D816V, in lesions in the skin, bone marrow cells, or both.⁹ Apart from its value as a diagnostic criterion for systemic mastocytosis, KIT mutation has been reported to be strongly associated with progression of indolent systemic mastocytosis, including the development of myeloid malignancies, when the mutation is detected not only in mast cells but in all hematopoietic lineages.¹⁰

In cases of SM-AHNMD, a possible pathophysiologic relationship between the disorder in the mast cells and the disorder in other cells could be explained by a KIT mutation in early hematopoietic progenitor cells, which further evolve into phenotypically different subclones.

A rational management plan for mastocytosis must include carefully counselling the patient and care providers, avoiding factors that trigger acute release of mast cell mediators, and giving antimediator therapy such as oral cromolyn sodium (Gastrocrom), antihistamines, and leukotriene antagonists to relieve the symptoms caused by mast-cell-mediator release.¹¹ In cases of SM-AHNMD, the clinical course and long-term prognosis are usually dominated by the concomitant hematologic malignancy, which should be treated as a separate entity.

CASE CONTINUED

Our patient’s bone marrow was analyzed for the KIT mutation in highly purified bone marrow cell subpopulations sorted by fluorescence-activated cell sorting. The mutation was detected in his mast cells, CD34+ cells, eosinophils, monocytes, neutrophils, lymphocytes, and nucleated erythroid precursors. According to the WHO recommendations, he had SMAHNMD, the associated hematologic disease being a myelodysplastic syndrome.

In view of his advanced age and concomitant myelodysplastic syndrome presenting with leukocytosis, we gave him hydroxyurea (Droxia; available in Spain as Hydrea) rather than other cytoreductive drugs as the first-line therapy. Additionally, we gave him corticosteroids in low doses, sodium cromolyn, and antihistamines to treat mastocytosis-related gastrointestinal symptoms. The patient was alive with stable disease 14 months after starting therapy.

A 72-year-old man presented with abdominal cramping, diarrhea, intermittent flushing, asthenia, and a weight loss of 10 kg (22 lb) in the past 6 months. Physical examination revealed hepatosplenomegaly and an erythematous, maculopapular, confluent rash on the trunk (Figure 1) that displayed the Darier sign (redness, swelling, and itching in response to stroking in the involved area).

Laboratory analyses

• Hemoglobin 9.8 g/dL (normal 13–17 g/dL)
• White blood cell count 22.9 × 10⁹/L (3.8–10)
• Vitamin B₁₂ 1,730 pg/mL (220–900)
• Serum tryptase 516 μg/L (5.5–13.5)
• Beta-2 microglobulin 4.14 mg/L (1.39–2.11).

Radiologic evaluation

Radiologic evaluation showed diffuse osteosclerosis with lytic and blastic areas (Figure 2).

Q: Which is the most likely diagnosis?

• Carcinoid syndrome
• Histiocytosis
• Acute myeloblastic leukemia
• Systemic mastocytosis
• Chronic myeloblastic leukemia

A: The correct answer is systemic mastocytosis. The diagnosis was made according to the World Health Organization (WHO) diagnostic criteria for mastocytosis on the basis of the following findings in the bone marrow:

• 

  Morphologically abnormal mast cells characterized by large size, spindle shape and poorly granulated cytoplasm (Figure 3) together with criteria for refractory cytopenia and multilineage dysplasia
• Diffuse infiltration by tryptase-positive mast cells as assessed by immunohistochemical study (Figure 4)

• 

  One percent of mast cells that are immunophenotypically aberrant (CD25bright+), all of them showing an immature profile,¹ associated with features of multilineage dysplasia² as assessed by flow cytometry
• The activating D816V KIT mutation, detected by peptide nucleic acid-mediated polymerase chain reaction clamping technique.³

MASTOCYTOSIS HAS SEVEN VARIANTS

Mastocytosis is a rare heterogeneous group of disorders characterized by proliferation and accumulation of abnormal mast cells in diverse organs and tissues, such as the skin, bone marrow, gastrointestinal tract, liver, spleen, or lymph nodes.^4–6 The release of mast cell mediators causes a wide variety of symptoms, ranging from pruritus, flushing, abdominal cramping, and diarrhea to severe anaphylaxis with vascular collapse.^7,8

The WHO defines seven variants⁶:

• Cutaneous mastocytosis
• Indolent systemic mastocytosis
• Systemic mastocytosis with an associated (clonal) hematologic non-mast-cell disease (SM-AHNMD)
• Aggressive systemic mastocytosis
• Mast cell leukemia
• Mast cell sarcoma
• Extracutaneous mastocytoma.⁶

KIT mutation as a diagnostic criterion and prognostic factor

In most cases of systemic involvement, the clonal nature of the disease can be established by finding activating mutations of KIT, usually D816V, in lesions in the skin, bone marrow cells, or both.⁹ Apart from its value as a diagnostic criterion for systemic mastocytosis, KIT mutation has been reported to be strongly associated with progression of indolent systemic mastocytosis, including the development of myeloid malignancies, when the mutation is detected not only in mast cells but in all hematopoietic lineages.¹⁰

In cases of SM-AHNMD, a possible pathophysiologic relationship between the disorder in the mast cells and the disorder in other cells could be explained by a KIT mutation in early hematopoietic progenitor cells, which further evolve into phenotypically different subclones.

A rational management plan for mastocytosis must include carefully counselling the patient and care providers, avoiding factors that trigger acute release of mast cell mediators, and giving antimediator therapy such as oral cromolyn sodium (Gastrocrom), antihistamines, and leukotriene antagonists to relieve the symptoms caused by mast-cell-mediator release.¹¹ In cases of SM-AHNMD, the clinical course and long-term prognosis are usually dominated by the concomitant hematologic malignancy, which should be treated as a separate entity.

CASE CONTINUED

Our patient’s bone marrow was analyzed for the KIT mutation in highly purified bone marrow cell subpopulations sorted by fluorescence-activated cell sorting. The mutation was detected in his mast cells, CD34+ cells, eosinophils, monocytes, neutrophils, lymphocytes, and nucleated erythroid precursors. According to the WHO recommendations, he had SMAHNMD, the associated hematologic disease being a myelodysplastic syndrome.

In view of his advanced age and concomitant myelodysplastic syndrome presenting with leukocytosis, we gave him hydroxyurea (Droxia; available in Spain as Hydrea) rather than other cytoreductive drugs as the first-line therapy. Additionally, we gave him corticosteroids in low doses, sodium cromolyn, and antihistamines to treat mastocytosis-related gastrointestinal symptoms. The patient was alive with stable disease 14 months after starting therapy.

Measures of cost-effectiveness are used to compare the merits of diverse medical interventions. A novel drug for metastatic melanoma, for instance, can be compared with statin therapy for primary prevention of cardiovascular events, which in turn can be compared against a surgical procedure for pain, as all are described by a single number: dollars per life-year (or quality-adjusted life-year) gained. Presumably, this number tells practitioners and payers which interventions provide the most benefit for every dollar spent.

However, too often, studies of cost-effectiveness differ from one another. They can be based on data from different types of studies, such as randomized controlled trials, surveys of large payer databases, or single-center chart reviews. The comparison treatments may differ. And the treatments may be of unproven efficacy. In these cases, although the results are all expressed in dollars per life-year, we are comparing apples and oranges.

In the following discussion, I use three key contemporary examples to demonstrate problems central to cost-effectiveness analysis. Together, these examples show that cost-effectiveness, arguably our best tool for comparing apples and oranges, is a lot like apples and oranges itself. I conclude by proposing some solutions.

PROBLEMS WITH COST-EFFECTIVENESS: THREE EXAMPLES

Studies of three therapies highlight the dilemma of cost-effectiveness.

Example 1: Vertebroplasty

Studies of vertebroplasty, a treatment for osteoporotic vertebral fractures that involves injecting polymethylmethacrylate cement into the fractured bone, show the perils of calculating the cost-effectiveness of unproven therapies.

Vertebroplasty gained prominence during the first decade of the 2000s, but in 2009 it was found to be no better than a sham procedure.^1,2

In 2008, one study reported that vertebroplasty was cheaper than medical management at 12 months and, thus, cost-effective.³ While this finding was certainly true for the regimen of medical management the authors examined, and while it may very well be true for other protocols for medical management, the finding obscures the fact that a sham procedure would be more cost-effective than either vertebroplasty or medical therapy—an unsettling conclusion.

Example 2: Exemestane

Another dilemma occurs when we can calculate cost-effectiveness for a particular outcome only.

Studies of exemestane (Aromasin), an aromatase inhibitor given to prevent breast cancer, show the difficulty. Recently, exemestane was shown to decrease the rate of breast cancer when used as primary prevention in postmenopausal women.⁴ What is the costeffectiveness of this therapy?

While we can calculate the dollars per invasive breast cancer averted, we cannot accurately calculate the dollars per life-year gained, as the trial’s end point was not the mortality rate. We can assume that the breast cancer deaths avoided are not negated by deaths incurred through other causes, but this may or may not prove true. Fibrates, for instance, may reduce the rate of cardiovascular death but increase deaths from noncardiac causes, providing no net benefit.⁵ Such long-term effects remain unknown in the breast cancer study.

Example 3: COX-2 inhibitors

Estimates of cost-effectiveness derived from randomized trials can differ from those derived from real-world studies. Studies of cyclooxygenase 2 (COX-2) inhibitors, which were touted as causing less gastrointestinal bleeding than other nonsteroidal anti-inflammatory drugs, show that cost-effectiveness analyses performed from randomized trials may not mirror dollars spent in real-world practice.

Estimates from randomized controlled trials indicate that a COX-2 inhibitor such as celecoxib (Celebrex) costs $20,000 to prevent one gastrointestinal hemorrhage. However, when calculated using real-world data, that number rises to over $100,000.⁶

TWO PROPOSED RULES FOR COST-EFFECTIVENESS ANALYSES

How do we reconcile these and related puzzles of cost-effectiveness? First, we should agree on what type of “cost-effectiveness” we are interested in. Most often, we want to know whether the real-world use of a therapy is financially rational. Thus, we are concerned with the effectiveness of therapies and not merely their efficacy in idealized clinical trials.

Furthermore, while real-world cost-effectiveness may change over time, particularly as pricing and delivery vary, we want some assurance that the therapy is truly better than placebo. Therefore, we should only calculate the cost-effectiveness of therapies that have previously demonstrated efficacy in properly controlled, randomized studies.⁷

To correct the deficiencies noted here, I propose two rules:

• Cost-effectiveness should be calculated only for therapies that have been proven to work, and
• These calculations should be done from the best available real-world data.

When both these conditions are met—ie, a therapy has proven efficacy, and we have data from its real-world use—cost-effectiveness analysis provides useful information for payers and practitioners. Then, indeed, a novel anticancer agent costing $30,000 per life-year gained can be compared against primary prevention with statin therapy in patients at elevated cardiovascular risk costing $20,000 per life-year gained.

CAN PREVENTION BE COMPARED WITH TREATMENT?

This leaves us with the final and most difficult question. Is it right to compare such things?

Having terminal cancer is a different experience than having high cholesterol, and this is the last apple and orange of cost-effectiveness. While a strict utilitarian view of medicine might find these cases indistinguishable, most practitioners and payers are not strict utilitarians. As a society, we tend to favor paying more to treat someone who is ill than paying an equivalent amount to prevent illness. Often, such a stance is criticized as a failure to invest in prevention and primary care, but another explanation is that the bias is a fundamental one of human risk-taking.

Cost-effectiveness is, to a certain degree, a slippery concept, and it is more likely to be “off” when a therapy is given broadly (to hundreds of thousands of people as opposed to hundreds) and taken in a decentralized fashion by individual patients (as opposed to directly observed therapy in an infusion suite). Accordingly, we may favor more expensive therapies, the cost-effectiveness of which can be estimated more precisely.

A recent meta-analysis of statins for primary prevention in high-risk patients found that they were not associated with improvement in the overall rate of death.⁸ Such a finding dramatically alters our impression of their cost-effectiveness and may explain the bias against investing in such therapies in the first place.

IMPROVING COST-EFFECTIVENESS RESEARCH

Studies of cost-effectiveness are not equivalent. Currently, such studies are apples and oranges, making difficult the very comparison that cost-effectiveness should facilitate. Knowing that a therapy is efficacious should be prerequisite to cost-effectiveness calculations, as should performing calculations under real-world conditions.

Regarding efficacy, it is inappropriate to calculate cost-effectiveness from trials that use only surrogate end points, or those that are improperly controlled.

For example, adding extended-release niacin to statin therapy may raise high-density lipoprotein cholesterol levels by 25%. Such an increase is, in turn, expected to confer a certain reduction in cardiovascular events and death. Thus, the cost-effectiveness of niacin might be calculated as $20,000 per life-year saved. However, adding extended-release niacin to statin therapy does not improve hard outcomes when directly measured,⁹ and the therapy is not efficacious at all. Its true “dollars per life-year saved” approaches infinity.

Studies that use historical controls, are observational, and are performed at single centers may also mislead us regarding a therapy’s efficacy. Tight glycemic control in intensive care patients initially seemed promising^10,11 and cost-effective.¹² However, several years later it was found to increase the mortality rate.¹³

“Real world” means that the best measures of cost-effectiveness will calculate the cost per life saved that the therapy achieves in clinical practice. Adherence to COX-2 inhibitors may not be as strict in the real world as it is in the carefully selected participants in randomized controlled trials, and, thus, the true costs may be higher. A drug that prevents breast cancer may have countervailing effects that may as yet be unknown, or compliance with it may wane over years. Thus, the most accurate measures of cost-effectiveness will examine therapies as best as they can function in typical practice and likely be derived from data sets of large payers or providers.

Finally, it remains an open and contentious issue whether the cost-effectiveness of primary prevention and the cost-effectiveness of treatment are comparable at all. We must continue to ponder and debate this philosophical question.

Certainly, these are the challenges of cost-effectiveness. Equally certain is that—with renewed consideration of the goals of such research, with stricter standards for future studies, and in an economic and political climate unable to sustain the status quo—the challenges must be surmounted.

Measures of cost-effectiveness are used to compare the merits of diverse medical interventions. A novel drug for metastatic melanoma, for instance, can be compared with statin therapy for primary prevention of cardiovascular events, which in turn can be compared against a surgical procedure for pain, as all are described by a single number: dollars per life-year (or quality-adjusted life-year) gained. Presumably, this number tells practitioners and payers which interventions provide the most benefit for every dollar spent.

However, too often, studies of cost-effectiveness differ from one another. They can be based on data from different types of studies, such as randomized controlled trials, surveys of large payer databases, or single-center chart reviews. The comparison treatments may differ. And the treatments may be of unproven efficacy. In these cases, although the results are all expressed in dollars per life-year, we are comparing apples and oranges.

In the following discussion, I use three key contemporary examples to demonstrate problems central to cost-effectiveness analysis. Together, these examples show that cost-effectiveness, arguably our best tool for comparing apples and oranges, is a lot like apples and oranges itself. I conclude by proposing some solutions.

PROBLEMS WITH COST-EFFECTIVENESS: THREE EXAMPLES

Studies of three therapies highlight the dilemma of cost-effectiveness.

Example 1: Vertebroplasty

Studies of vertebroplasty, a treatment for osteoporotic vertebral fractures that involves injecting polymethylmethacrylate cement into the fractured bone, show the perils of calculating the cost-effectiveness of unproven therapies.

Vertebroplasty gained prominence during the first decade of the 2000s, but in 2009 it was found to be no better than a sham procedure.^1,2

In 2008, one study reported that vertebroplasty was cheaper than medical management at 12 months and, thus, cost-effective.³ While this finding was certainly true for the regimen of medical management the authors examined, and while it may very well be true for other protocols for medical management, the finding obscures the fact that a sham procedure would be more cost-effective than either vertebroplasty or medical therapy—an unsettling conclusion.

Example 2: Exemestane

Another dilemma occurs when we can calculate cost-effectiveness for a particular outcome only.

Studies of exemestane (Aromasin), an aromatase inhibitor given to prevent breast cancer, show the difficulty. Recently, exemestane was shown to decrease the rate of breast cancer when used as primary prevention in postmenopausal women.⁴ What is the costeffectiveness of this therapy?

While we can calculate the dollars per invasive breast cancer averted, we cannot accurately calculate the dollars per life-year gained, as the trial’s end point was not the mortality rate. We can assume that the breast cancer deaths avoided are not negated by deaths incurred through other causes, but this may or may not prove true. Fibrates, for instance, may reduce the rate of cardiovascular death but increase deaths from noncardiac causes, providing no net benefit.⁵ Such long-term effects remain unknown in the breast cancer study.

Example 3: COX-2 inhibitors

Estimates of cost-effectiveness derived from randomized trials can differ from those derived from real-world studies. Studies of cyclooxygenase 2 (COX-2) inhibitors, which were touted as causing less gastrointestinal bleeding than other nonsteroidal anti-inflammatory drugs, show that cost-effectiveness analyses performed from randomized trials may not mirror dollars spent in real-world practice.

Estimates from randomized controlled trials indicate that a COX-2 inhibitor such as celecoxib (Celebrex) costs $20,000 to prevent one gastrointestinal hemorrhage. However, when calculated using real-world data, that number rises to over $100,000.⁶

TWO PROPOSED RULES FOR COST-EFFECTIVENESS ANALYSES

How do we reconcile these and related puzzles of cost-effectiveness? First, we should agree on what type of “cost-effectiveness” we are interested in. Most often, we want to know whether the real-world use of a therapy is financially rational. Thus, we are concerned with the effectiveness of therapies and not merely their efficacy in idealized clinical trials.

Furthermore, while real-world cost-effectiveness may change over time, particularly as pricing and delivery vary, we want some assurance that the therapy is truly better than placebo. Therefore, we should only calculate the cost-effectiveness of therapies that have previously demonstrated efficacy in properly controlled, randomized studies.⁷

To correct the deficiencies noted here, I propose two rules:

• Cost-effectiveness should be calculated only for therapies that have been proven to work, and
• These calculations should be done from the best available real-world data.

When both these conditions are met—ie, a therapy has proven efficacy, and we have data from its real-world use—cost-effectiveness analysis provides useful information for payers and practitioners. Then, indeed, a novel anticancer agent costing $30,000 per life-year gained can be compared against primary prevention with statin therapy in patients at elevated cardiovascular risk costing $20,000 per life-year gained.

CAN PREVENTION BE COMPARED WITH TREATMENT?

This leaves us with the final and most difficult question. Is it right to compare such things?

Having terminal cancer is a different experience than having high cholesterol, and this is the last apple and orange of cost-effectiveness. While a strict utilitarian view of medicine might find these cases indistinguishable, most practitioners and payers are not strict utilitarians. As a society, we tend to favor paying more to treat someone who is ill than paying an equivalent amount to prevent illness. Often, such a stance is criticized as a failure to invest in prevention and primary care, but another explanation is that the bias is a fundamental one of human risk-taking.

Cost-effectiveness is, to a certain degree, a slippery concept, and it is more likely to be “off” when a therapy is given broadly (to hundreds of thousands of people as opposed to hundreds) and taken in a decentralized fashion by individual patients (as opposed to directly observed therapy in an infusion suite). Accordingly, we may favor more expensive therapies, the cost-effectiveness of which can be estimated more precisely.

A recent meta-analysis of statins for primary prevention in high-risk patients found that they were not associated with improvement in the overall rate of death.⁸ Such a finding dramatically alters our impression of their cost-effectiveness and may explain the bias against investing in such therapies in the first place.

IMPROVING COST-EFFECTIVENESS RESEARCH

Studies of cost-effectiveness are not equivalent. Currently, such studies are apples and oranges, making difficult the very comparison that cost-effectiveness should facilitate. Knowing that a therapy is efficacious should be prerequisite to cost-effectiveness calculations, as should performing calculations under real-world conditions.

Regarding efficacy, it is inappropriate to calculate cost-effectiveness from trials that use only surrogate end points, or those that are improperly controlled.

For example, adding extended-release niacin to statin therapy may raise high-density lipoprotein cholesterol levels by 25%. Such an increase is, in turn, expected to confer a certain reduction in cardiovascular events and death. Thus, the cost-effectiveness of niacin might be calculated as $20,000 per life-year saved. However, adding extended-release niacin to statin therapy does not improve hard outcomes when directly measured,⁹ and the therapy is not efficacious at all. Its true “dollars per life-year saved” approaches infinity.

Studies that use historical controls, are observational, and are performed at single centers may also mislead us regarding a therapy’s efficacy. Tight glycemic control in intensive care patients initially seemed promising^10,11 and cost-effective.¹² However, several years later it was found to increase the mortality rate.¹³

“Real world” means that the best measures of cost-effectiveness will calculate the cost per life saved that the therapy achieves in clinical practice. Adherence to COX-2 inhibitors may not be as strict in the real world as it is in the carefully selected participants in randomized controlled trials, and, thus, the true costs may be higher. A drug that prevents breast cancer may have countervailing effects that may as yet be unknown, or compliance with it may wane over years. Thus, the most accurate measures of cost-effectiveness will examine therapies as best as they can function in typical practice and likely be derived from data sets of large payers or providers.

Finally, it remains an open and contentious issue whether the cost-effectiveness of primary prevention and the cost-effectiveness of treatment are comparable at all. We must continue to ponder and debate this philosophical question.

Certainly, these are the challenges of cost-effectiveness. Equally certain is that—with renewed consideration of the goals of such research, with stricter standards for future studies, and in an economic and political climate unable to sustain the status quo—the challenges must be surmounted.

Measures of cost-effectiveness are used to compare the merits of diverse medical interventions. A novel drug for metastatic melanoma, for instance, can be compared with statin therapy for primary prevention of cardiovascular events, which in turn can be compared against a surgical procedure for pain, as all are described by a single number: dollars per life-year (or quality-adjusted life-year) gained. Presumably, this number tells practitioners and payers which interventions provide the most benefit for every dollar spent.

However, too often, studies of cost-effectiveness differ from one another. They can be based on data from different types of studies, such as randomized controlled trials, surveys of large payer databases, or single-center chart reviews. The comparison treatments may differ. And the treatments may be of unproven efficacy. In these cases, although the results are all expressed in dollars per life-year, we are comparing apples and oranges.

In the following discussion, I use three key contemporary examples to demonstrate problems central to cost-effectiveness analysis. Together, these examples show that cost-effectiveness, arguably our best tool for comparing apples and oranges, is a lot like apples and oranges itself. I conclude by proposing some solutions.

PROBLEMS WITH COST-EFFECTIVENESS: THREE EXAMPLES

Studies of three therapies highlight the dilemma of cost-effectiveness.

Example 1: Vertebroplasty

Studies of vertebroplasty, a treatment for osteoporotic vertebral fractures that involves injecting polymethylmethacrylate cement into the fractured bone, show the perils of calculating the cost-effectiveness of unproven therapies.

Vertebroplasty gained prominence during the first decade of the 2000s, but in 2009 it was found to be no better than a sham procedure.^1,2

In 2008, one study reported that vertebroplasty was cheaper than medical management at 12 months and, thus, cost-effective.³ While this finding was certainly true for the regimen of medical management the authors examined, and while it may very well be true for other protocols for medical management, the finding obscures the fact that a sham procedure would be more cost-effective than either vertebroplasty or medical therapy—an unsettling conclusion.

Example 2: Exemestane

Another dilemma occurs when we can calculate cost-effectiveness for a particular outcome only.

Studies of exemestane (Aromasin), an aromatase inhibitor given to prevent breast cancer, show the difficulty. Recently, exemestane was shown to decrease the rate of breast cancer when used as primary prevention in postmenopausal women.⁴ What is the costeffectiveness of this therapy?

While we can calculate the dollars per invasive breast cancer averted, we cannot accurately calculate the dollars per life-year gained, as the trial’s end point was not the mortality rate. We can assume that the breast cancer deaths avoided are not negated by deaths incurred through other causes, but this may or may not prove true. Fibrates, for instance, may reduce the rate of cardiovascular death but increase deaths from noncardiac causes, providing no net benefit.⁵ Such long-term effects remain unknown in the breast cancer study.

Example 3: COX-2 inhibitors

Estimates of cost-effectiveness derived from randomized trials can differ from those derived from real-world studies. Studies of cyclooxygenase 2 (COX-2) inhibitors, which were touted as causing less gastrointestinal bleeding than other nonsteroidal anti-inflammatory drugs, show that cost-effectiveness analyses performed from randomized trials may not mirror dollars spent in real-world practice.

Estimates from randomized controlled trials indicate that a COX-2 inhibitor such as celecoxib (Celebrex) costs $20,000 to prevent one gastrointestinal hemorrhage. However, when calculated using real-world data, that number rises to over $100,000.⁶

TWO PROPOSED RULES FOR COST-EFFECTIVENESS ANALYSES

How do we reconcile these and related puzzles of cost-effectiveness? First, we should agree on what type of “cost-effectiveness” we are interested in. Most often, we want to know whether the real-world use of a therapy is financially rational. Thus, we are concerned with the effectiveness of therapies and not merely their efficacy in idealized clinical trials.

Furthermore, while real-world cost-effectiveness may change over time, particularly as pricing and delivery vary, we want some assurance that the therapy is truly better than placebo. Therefore, we should only calculate the cost-effectiveness of therapies that have previously demonstrated efficacy in properly controlled, randomized studies.⁷

To correct the deficiencies noted here, I propose two rules:

• Cost-effectiveness should be calculated only for therapies that have been proven to work, and
• These calculations should be done from the best available real-world data.

When both these conditions are met—ie, a therapy has proven efficacy, and we have data from its real-world use—cost-effectiveness analysis provides useful information for payers and practitioners. Then, indeed, a novel anticancer agent costing $30,000 per life-year gained can be compared against primary prevention with statin therapy in patients at elevated cardiovascular risk costing $20,000 per life-year gained.

CAN PREVENTION BE COMPARED WITH TREATMENT?

This leaves us with the final and most difficult question. Is it right to compare such things?

Having terminal cancer is a different experience than having high cholesterol, and this is the last apple and orange of cost-effectiveness. While a strict utilitarian view of medicine might find these cases indistinguishable, most practitioners and payers are not strict utilitarians. As a society, we tend to favor paying more to treat someone who is ill than paying an equivalent amount to prevent illness. Often, such a stance is criticized as a failure to invest in prevention and primary care, but another explanation is that the bias is a fundamental one of human risk-taking.

Cost-effectiveness is, to a certain degree, a slippery concept, and it is more likely to be “off” when a therapy is given broadly (to hundreds of thousands of people as opposed to hundreds) and taken in a decentralized fashion by individual patients (as opposed to directly observed therapy in an infusion suite). Accordingly, we may favor more expensive therapies, the cost-effectiveness of which can be estimated more precisely.

A recent meta-analysis of statins for primary prevention in high-risk patients found that they were not associated with improvement in the overall rate of death.⁸ Such a finding dramatically alters our impression of their cost-effectiveness and may explain the bias against investing in such therapies in the first place.

IMPROVING COST-EFFECTIVENESS RESEARCH

Studies of cost-effectiveness are not equivalent. Currently, such studies are apples and oranges, making difficult the very comparison that cost-effectiveness should facilitate. Knowing that a therapy is efficacious should be prerequisite to cost-effectiveness calculations, as should performing calculations under real-world conditions.

Regarding efficacy, it is inappropriate to calculate cost-effectiveness from trials that use only surrogate end points, or those that are improperly controlled.

For example, adding extended-release niacin to statin therapy may raise high-density lipoprotein cholesterol levels by 25%. Such an increase is, in turn, expected to confer a certain reduction in cardiovascular events and death. Thus, the cost-effectiveness of niacin might be calculated as $20,000 per life-year saved. However, adding extended-release niacin to statin therapy does not improve hard outcomes when directly measured,⁹ and the therapy is not efficacious at all. Its true “dollars per life-year saved” approaches infinity.

Studies that use historical controls, are observational, and are performed at single centers may also mislead us regarding a therapy’s efficacy. Tight glycemic control in intensive care patients initially seemed promising^10,11 and cost-effective.¹² However, several years later it was found to increase the mortality rate.¹³

“Real world” means that the best measures of cost-effectiveness will calculate the cost per life saved that the therapy achieves in clinical practice. Adherence to COX-2 inhibitors may not be as strict in the real world as it is in the carefully selected participants in randomized controlled trials, and, thus, the true costs may be higher. A drug that prevents breast cancer may have countervailing effects that may as yet be unknown, or compliance with it may wane over years. Thus, the most accurate measures of cost-effectiveness will examine therapies as best as they can function in typical practice and likely be derived from data sets of large payers or providers.

Finally, it remains an open and contentious issue whether the cost-effectiveness of primary prevention and the cost-effectiveness of treatment are comparable at all. We must continue to ponder and debate this philosophical question.

Certainly, these are the challenges of cost-effectiveness. Equally certain is that—with renewed consideration of the goals of such research, with stricter standards for future studies, and in an economic and political climate unable to sustain the status quo—the challenges must be surmounted.

Perhaps 3% of the population has psoriasis. Thus, it is impossible to practice any aspect of internal medicine without encountering patients with this disease.

In this issue of the Journal, Dr. Jennifer Villaseñor-Park and her colleagues discuss the clinical patterns and management of psoriasis and the links between psoriasis and cardiovascular disease—links that should bind the internist and dermatologist in a shared mission of comanagement.

The connection between inflammation and atherosclerosis is now well known. Many of the same cellular and biochemical players have active roles in the inflammation of rheumatoid arthritis, systemic lupus erythematosus, psoriasis, and atherosclerosis. The observation that patients with inflammatory diseases have a higher prevalence of cardiovascular disease seems to strengthen this apparent link and supports the concept that drugs used to treat inflammation in the joints and skin might also reduce the burden of cardiovascular disease.

But addressing this risk is not so straightforward. Since the increased cardiovascular risk in rheumatoid arthritis and systemic lupus erythematosus is not completely explained by traditional risk factors, research is ongoing to identify the potential mechanisms of this risk, such as high-density lipoprotein particles modified by inflammation and high circulating levels of interferon, both of which may be atherogenic. It remains to be seen whether these and other potential nonclassic mediators of atherosclerosis can be targeted and cardiovascular events reduced.

But psoriasis is a little different. Compared with patients with rheumatoid arthritis and lupus (if they have not been affected by corticosteroid treatment), patients with psoriasis tend to be heavier and to have a higher prevalence of fatty liver disease and the metabolic syndrome. A debate continues as to whether psoriasis per se is a unique risk factor for cardiovascular disease or whether in fact these comorbidities constitute the major risk for cardiovascular events in patients with psoriasis.

The epidemiologists can continue to crunch the data in attempts to attribute the relative risks of poor outcome. But in the office, we should be vigilant and, in patients with psoriasis, should not ignore the traditional cardiovascular risk factors included in the metabolic syndrome, which is more prevalent in these patients.

Perhaps 3% of the population has psoriasis. Thus, it is impossible to practice any aspect of internal medicine without encountering patients with this disease.

In this issue of the Journal, Dr. Jennifer Villaseñor-Park and her colleagues discuss the clinical patterns and management of psoriasis and the links between psoriasis and cardiovascular disease—links that should bind the internist and dermatologist in a shared mission of comanagement.

The connection between inflammation and atherosclerosis is now well known. Many of the same cellular and biochemical players have active roles in the inflammation of rheumatoid arthritis, systemic lupus erythematosus, psoriasis, and atherosclerosis. The observation that patients with inflammatory diseases have a higher prevalence of cardiovascular disease seems to strengthen this apparent link and supports the concept that drugs used to treat inflammation in the joints and skin might also reduce the burden of cardiovascular disease.

But addressing this risk is not so straightforward. Since the increased cardiovascular risk in rheumatoid arthritis and systemic lupus erythematosus is not completely explained by traditional risk factors, research is ongoing to identify the potential mechanisms of this risk, such as high-density lipoprotein particles modified by inflammation and high circulating levels of interferon, both of which may be atherogenic. It remains to be seen whether these and other potential nonclassic mediators of atherosclerosis can be targeted and cardiovascular events reduced.

But psoriasis is a little different. Compared with patients with rheumatoid arthritis and lupus (if they have not been affected by corticosteroid treatment), patients with psoriasis tend to be heavier and to have a higher prevalence of fatty liver disease and the metabolic syndrome. A debate continues as to whether psoriasis per se is a unique risk factor for cardiovascular disease or whether in fact these comorbidities constitute the major risk for cardiovascular events in patients with psoriasis.

The epidemiologists can continue to crunch the data in attempts to attribute the relative risks of poor outcome. But in the office, we should be vigilant and, in patients with psoriasis, should not ignore the traditional cardiovascular risk factors included in the metabolic syndrome, which is more prevalent in these patients.

Perhaps 3% of the population has psoriasis. Thus, it is impossible to practice any aspect of internal medicine without encountering patients with this disease.

In this issue of the Journal, Dr. Jennifer Villaseñor-Park and her colleagues discuss the clinical patterns and management of psoriasis and the links between psoriasis and cardiovascular disease—links that should bind the internist and dermatologist in a shared mission of comanagement.

The connection between inflammation and atherosclerosis is now well known. Many of the same cellular and biochemical players have active roles in the inflammation of rheumatoid arthritis, systemic lupus erythematosus, psoriasis, and atherosclerosis. The observation that patients with inflammatory diseases have a higher prevalence of cardiovascular disease seems to strengthen this apparent link and supports the concept that drugs used to treat inflammation in the joints and skin might also reduce the burden of cardiovascular disease.

But addressing this risk is not so straightforward. Since the increased cardiovascular risk in rheumatoid arthritis and systemic lupus erythematosus is not completely explained by traditional risk factors, research is ongoing to identify the potential mechanisms of this risk, such as high-density lipoprotein particles modified by inflammation and high circulating levels of interferon, both of which may be atherogenic. It remains to be seen whether these and other potential nonclassic mediators of atherosclerosis can be targeted and cardiovascular events reduced.

But psoriasis is a little different. Compared with patients with rheumatoid arthritis and lupus (if they have not been affected by corticosteroid treatment), patients with psoriasis tend to be heavier and to have a higher prevalence of fatty liver disease and the metabolic syndrome. A debate continues as to whether psoriasis per se is a unique risk factor for cardiovascular disease or whether in fact these comorbidities constitute the major risk for cardiovascular events in patients with psoriasis.

The epidemiologists can continue to crunch the data in attempts to attribute the relative risks of poor outcome. But in the office, we should be vigilant and, in patients with psoriasis, should not ignore the traditional cardiovascular risk factors included in the metabolic syndrome, which is more prevalent in these patients.

Much has changed in our understanding of psoriasis over the past decade, which is having a major effect on its treatment.

Although topical corticosteroids and phototherapy remain mainstays of treatment, a variety of biologic agents have given new hope to those with the most severe forms of the disease. We are also beginning to understand that patients with psoriasis are at greater risk of cardiovascular disease, though the exact nature of that risk and how we should respond remains unclear. Finally, genome-wide association studies are just beginning to unravel the genetic basis of psoriasis.

In this paper, we review the epidemiology and impact of psoriasis, current views of its pathogenesis, its varied clinical forms, and its treatment.

PSORIASIS IMPOSES A GREAT BURDEN

Psoriasis is common, with a reported prevalence ranging from approximately 2%¹ to 4.7%.² It can manifest at any age, but it is most common in two age groups, ie, 20 to 30 years and 50 to 60 years.

For the patient, the burden is great, affecting physical, psychological, and occupational well-being. In fact, patients with psoriasis report quality-of-life impairment equal to or worse than that in patients with cancer or heart disease.^3,4 Notably, functional disability secondary to psoriatic arthritis has been reported in up to 19% of psoriatic arthritis patients, and this negatively affects quality of life.⁵

In 2004, the annual direct medical costs of psoriasis in the United States were estimated to exceed $1 billion. Its indirect costs, measured as missed days and loss of productivity at work, are estimated to exceed the direct costs by $15 billion annually.^6,7

Linked to cardiovascular and other diseases

Studies in the past 10 years have uncovered a link between psoriasis, metabolic syndrome, and cardiovascular disease.^8–13 Specifically, patients with severe psoriasis are at higher risk of myocardial infarction and cardiovascular death than control patients. Interestingly, the risk decreases with age; patients at greatest risk are young men with severe psoriasis.^8–10

In a large cohort study in the United Kingdom⁷ comparing patients with and without psoriasis, the hazard ratio for cardiovascular death in patients with severe psoriasis was 1.57 (95% confidence interval 1.26–1.96). This translated to 3.5 excess deaths per 1,000 patient-years. These patients were also at higher risk of death from malignancies, chronic lower respiratory disease, diabetes, dementia, infection, kidney disease, and unknown causes.

How much of the risk is due to psoriasis itself, its treatments, associated behaviors, or other factors requires more study. However, some evidence points to the dysregulation of the immune system, notably chronic elevation of pro-inflammatory cytokines.

Psoriasis and its comorbid conditions are thought to arise from chronically elevated levels of cytokines such as tumor necrosis factor alpha (TNF-alpha), interleukin 1 beta (IL-1 beta), and IL-17. These cytokines impair insulin signaling, deregulate lipid metabolism, and increase atherosclerotic changes in the coronary, cerebral, and peripheral arteries. In addition, several other diseases that involve the immune system occur more frequently with psoriasis, including Crohn disease, ulcerative colitis, lymphoma, obesity, and type 2 diabetes.^1,8,14–18

In view of the prevalence of these comorbid conditions and the risks they pose, primary care physicians should consider screening patients with severe psoriasis for metabolic disorders and cardiovascular risk factors and promptly begin preventive therapies.¹⁹ Unfortunately, to date, there are no consensus guidelines as to the appropriate screening tests or secondary cardiovascular preventive measures for patients with severe psoriasis.

A VICIOUS CIRCLE OF INFLAMMATION AND KERATINOCYTE PROLIFERATION

The hallmark of plaque psoriasis is chronic inflammation in the skin, leading to keratinocyte proliferation.

External and internal triggers that have been identified include cutaneous injury (eg, sunburn, drug rash, viral exanthems), infections (eg, streptococcal), hypocalcemia, pregnancy, psychogenic stress, drugs (eg, lithium, interferon, beta-blockers, and antimalarials), alcohol, smoking, and obesity.^20–23

As reviewed by Nestle et al,²⁴ the initiation of lesion formation is still poorly understood but is thought to occur when a trigger (physical trauma, bacterial product, cellular stress) causes DNA to be released from keratinocytes. DNA forms a complex with the antimicrobial protein LL-37 and activates plasmacytoid dendritic cells (PDCs) via toll-like receptor 9. Activated PDCs release type I interferons, which in turn activate myeloid dendritic cells. Myeloid dendritic cells release IL-20 locally, which speeds keratinocyte proliferation.

A subset of myeloid dendritic cells leaves the dermis and migrates to local lymph nodes, where they release IL-23 and activate naive T cells. T helper 1 (Th1) and Th17 cells are recruited to the lesions and begin producing numerous cytokines, including interferon gamma, IL-17, and IL-22. This cytokine milieu increases keratinocyte proliferation and causes the keratinocytes to secrete antimicrobial proteins (LL-37, beta defensins), chemokines, and S100 proteins. These soluble factors have three main functions: stimulation of dendritic cells to release more IL-23, recruitment of neutrophils to the epidermis, and activation of dermal fibroblasts.

This cycle of keratinocytes activating dendritic cells, dendritic cells activating T cells, and T cells activating keratinocytes appears to be the main force maintaining the disease.²⁴ It is unclear, however, whether this applies to all forms of psoriasis or only to plaque psoriasis.

Genetic factors discovered

In recent years, genome-wide association studies have identified at least 10 psoriasis-susceptibility loci that involve functioning of the immune system.²⁵ These genes include those of the major histocompatibility complex, cytokines, receptors, and beta-defensins.

Of specific interest, polymorphisms in the IL-12/IL-13 receptor, the p40 subunit of IL-12 and IL-23, and the p19 subunit of IL-23 strongly associate with psoriasis, supporting their critical role in the disease process and providing targets for medical therapy.²⁶

PSORIASIS HAS SEVERAL CLINICAL PHENOTYPES

Psoriasis has several clinical variants, each with a distinct clinical course and response to treatment.²⁷ Moreover, many patients present with more than one variant.

Plaque psoriasis

Plaques can persist for several months to years, even in the same location, and only about 5% of patients report complete remission for up to 5 years.

Inverse psoriasis

Photo courtesy of Joseph C. English III, MD.

Guttate psoriasis

Photo courtesy of Laura K. Ferris, MD, PhD.

Erythrodermic psoriasis

Approximately 1% to 2.25% of all patients with psoriasis develop this severe form, affecting more than 75% of the body surface area. It presents as generalized erythema, which is the most prominent feature, and it is often associated with superficial desquamation, hair loss, nail dystrophy, and systemic symptoms such as fever, chills, malaise, or high-output cardiac failure. There may be a history of preceding characteristic psoriatic plaques, recent withdrawal of treatment (usually corticosteroids), phototoxicity, or infection.

Conversely, approximately 25% of all patients with erythroderma have underlying psoriasis.²⁸

Pustular psoriasis

Photo courtesy of Joseph C. English III, MD.

There are several forms of pustular psoriasis, including generalized pustular psoriasis, annular pustular psoriasis, impetigo herpetiformis (pustular psoriasis of pregnancy), and palmoplantar pustulosis. However, there is some evidence to suggest that palmoplantar pustulosis may be distinct from psoriasis.²⁹

Several triggers have been identified, including pregnancy, rapid tapering of medications, hypocalcemia, infection, or topical irritants.

Generalized pustular psoriasis, annular pustular psoriasis, and impetigo herpetiformis often present in association with fever and other systemic symptoms and, if left untreated, can result in life-threatening complications including bacterial superinfection, sepsis, dehydration, and, in rare cases, acute respiratory distress secondary to aseptic pneumonitis.³⁰

Placental insufficiency resulting in stillbirth or neonatal death and other fetal abnormalities can occur in severe pustular psoriasis of pregnancy.³¹

Psoriatic arthritis

Psoriatic arthritis is a seronegative inflammatory spondyloarthropathy that can result in erosive arthritis in up to 57% of cases and functional disability in up to 19%.³² Although rare in the general population, it affects approximately 6% to 10% of psoriasis patients and up to 40% of patients with severe psoriasis.³³ In 70% of cases, psoriasis precedes the onset of arthritis by about 10 years, and approximately 10% to 15% of patients simultaneously present with psoriasis and arthritis or develop arthritis before skin involvement.^5,34

Patients complain of joint discomfort that is most prominent after periods of prolonged rest. Patterns of involvement are extremely variable but have been reported as an asymmetric oligoarthritis (involving four or fewer joints) or polyarthritis (involving more than four joints) in most patients. A rheumatoid arthritis-like presentation with a symmetric polyarthropathy involving the small and medium-sized joints has also been reported, making it difficult to clinically distinguish this from rheumatoid arthritis.

A distal interphalangeal-predominant pattern is reported in 5% to 10% of patients. Axial disease resembling ankylosing spondylitis occurs only in 5% of patients. Arthritis mutilans, characterized by severe, rapidly progressive joint inflammation, joint destruction, and deformity, occurs rarely. Enthesitis, ie, inflammation at the point of attachment of tendons or ligaments to bone, is present in up to 42% of patients.^5,35

Nail disease

Photo courtesy of Joseph C. English III, MD.

Disease severity also varies

Disease severity also differs among patients. An estimated 80% of patients have mild to moderate disease and 20% have moderate to severe disease, which includes disease involving more than 5% of the body surface or involvement of the face, hands, feet, or genitalia.¹

The Psoriasis Area and Severity Index (PASI) is an objective measure used in clinical trials. It incorporates the amount of redness, scaling, and induration of each psoriatic lesion over the body surface involved. A 75% improvement in the PASI score (PASI-75) is regarded as clinically significant.³⁷

PSORIASIS IS DIAGNOSED CLINICALLY

In most cases, the diagnosis of psoriasis is made clinically and is straightforward. However, in more difficult cases, biopsy may be needed. In particular:

• The plaques of psoriasis may be confused with squamous cell carcinoma in situ, dermatophyte infection, or cutaneous T-cell lymphoma, especially if they are treatment-resistant.
• Guttate psoriasis may be difficult to distinguish from pityriasis rosea.
• Erythrodermic psoriasis must be distinguished from other causes of erythroderma, including Sézary syndrome, pityriasis rubra pilaris, and drug reactions.
• Intertrigo, candidiasis, extramammary Paget disease, squamous cell carcinoma, and contact dermatitis all may mimic inverse psoriasis.
• Palmoplantar pustulosis may be difficult to differentiate from dyshidrotic eczema.
• Generalized pustular psoriasis should be distinguished from a pustular drug eruption (acute generalized exanthematous pustular drug eruption or acute generalized exanthematous pustulosis), impetigo, candidiasis, or an autoimmune blistering disorder such as pemphigus.

TREATMENT OF LIMITED DISEASE

Topical corticosteroids

A topical corticosteroid, either by itself or combined with a steroid-sparing agent, is the first-line therapy for patients with limited disease. The potency required for treatment should be based on the extent of disease and on the location, the choice of vehicle, and the patient’s preference and age.

Several double-blind studies have assessed the efficacy of various topical corticosteroids in treating psoriasis. In general, super-potent (class I) and potent (class II) topical corticosteroids are more efficacious than mild or moderate corticosteroids.³⁸ Class I and class II steroids include agents such as clobetasol propionate 0.05% (Temovate), betamethasone dipropionate 0.05% (Diprolene), fluocinonide 0.05% (Lidex), and desoximetasone 0.25% (Topicort).

Use of class I steroids should be limited to an initial treatment course of twice-daily application for 2 to 4 weeks in an effort to avoid some of the local toxicities such as skin atrophy, telangiectasia, and striae. Decreasing class I topical steroid use to 1 to 2 times per week with the gradual introduction of a steroid-sparing agent following the initial 2 to 4 weeks of treatment is advised.

Steroid-sparing agents

Steroid-sparing agents include vitamin D analogues, retinoids, and tacrolimus ointment (Protopic).

Vitamin D analogues and retinoids are thought to decrease keratinocyte proliferation and enhance keratinocyte differentiation.³⁹ The vitamin D analogues are also considered first-line topical agents and include calcipotriol (Dovonex), calcipotriene (Dovonex), and calcitriol (Vectical). To prevent hypercalcemia, use of more than 100 g of vitamin D analogues per week should be avoided.³⁹

Treatment of inverse psoriasis and scalp psoriasis may be challenging

The areas affected in inverse psoriasis, such as the genitalia and axillae, are more prone to side effects when potent topical steroids are used because of increased absorption and occlusion in these areas. Agents that minimize irritation and toxicity in sensitive areas, such as topical tacrolimus, less-potent topical steroids, or calcitriol, can be used.³⁹

For scalp psoriasis, alternative vehicles such as shampoos, gels, solutions, oils, sprays, and foams have improved patient compliance and efficacy of treatment.⁴⁰

PHOTOTHERAPY FOR SEVERE DISEASE

Narrow-band ultraviolet B

Narrow-band ultraviolet B, ie, light confined to wavelengths of 311 to 313 nm, is a first-line treatment for moderate to severe psoriasis, either as monotherapy or in combination with other treatments. It is an especially attractive option in patients who are on medications or who have comorbidities that may preclude treatment with other systemic agents.

The mechanism of action may be via immunosuppressive effects on Langerhans cells, alteration of cytokines and adhesion molecules that lead to an increase in Th2 cells, and induction of apoptosis of T lymphocytes. Additionally, ultraviolet light affects the proliferation and differentiation of keratinocytes.⁴¹

Dosing is based on skin type, and treatment usually involves two or three visits per week for a total of 15 to 20 treatments, with additional therapy for maintenance. Adding acitretin (Soriatane), with close monitoring of aspartate aminotransferase and alanine aminotransferase levels and the patient’s lipid panel, can be considered in treatment-resistant cases.⁴²

Psoralen combined with ultraviolet A

Psoralen combined with ultraviolet A is another option. It can be considered if narrow-band ultraviolet B treatment fails. It is also useful for dark-skinned patients and those with thicker plaques because ultraviolet A penetrates deeper than ultraviolet B. Oral or topical treatment with psoralen is followed by ultraviolet A treatment.

The duration of remission is much longer with psoralen plus ultraviolet A than with narrow-band ultraviolet B. However, this treatment caries a significant risk of cutaneous squamous cell carcinoma and melanoma, especially in light-skinned people and those who receive high doses of ultraviolet A (200 or more treatments) or cyclosporine.^{40,41,43–46} Long-term effects include photoaging, lentigines, and telangiectasias. As a consequence of these well-established side effects, this treatment is used less frequently.

Cautions with phototherapy

Careful screening and caution should be used in patients who have:

• Fair skin that tends to burn easily
• A history of arsenic intake or treatment with ionizing radiation
• A history of use of photosensitizing medications (fluoroquinolone antibiotics, doxycycline, hydrochlorothiazide)
• A history of melanoma or atypical nevi
• Multiple risk factors for melanoma
• A history of nonmelanoma skin cancer
• Immunosuppression due to organ transplantation.

ORAL THERAPIES FOR SEVERE PSORIASIS

Patients who have severe psoriasis—ie, affecting more than 5% of the body surface or debilitating disease affecting the palms, soles, or genitalia—are best managed with systemic medications, especially if they do not have access to phototherapy.²⁰

Methotrexate

In 1972, the US Food and Drug Administration (FDA) approved methotrexate for treating severe psoriasis.⁴² In studies of methotrexate at doses of 15 to 20 mg weekly, 36% to 68% of patients with severe plaque psoriasis achieved a PASI-75 score.^40,42,47

Dosages of methotrexate for treating severe psoriasis range from 7.5 to 25 mg once a week. Patients should also receive a folate supplement of 1 to 5 mg every day except the day they take methotrexate. The folate is to protect against gastrointestinal side effects, bone marrow suppression, and hepatic toxicity associated with methotrexate.

Other side effects of methotrexate include pulmonary fibrosis and stomatitis. Pregnancy, nursing, alcoholism, chronic liver disease, immunodeficiency syndromes, bone-marrow hypoplasia, leukopenia, thrombocytopenia, anemia, and hypersensitivity to methotrexate are all contraindications to methotrexate use.

The National Psoriasis Foundation, in its 2009 guidelines for the use of methotrexate in treating psoriasis,⁴⁸ recommends obtaining a complete blood cell count with platelets, blood urea nitrogen, creatinine, and liver function tests at baseline and at 1- to 3-month intervals thereafter.

Liver biopsies were previously recommended for patients receiving methotrexate long-term when the cumulative dose of therapy reached 1.5 g. However, given the invasive nature of the liver biopsy procedure and the low incidence of methotrexate-induced hepatotoxicity, this recommendation has been revised.

For patients with no significant risk factors for hepatic toxicity (eg, obesity, diabetes, hyperlipidemia, hepatitis, or history of or current alcohol consumption) and normal liver function tests, liver biopsy should be considered when a cumulative methotrexate dose of 3.5 to 4.0 g is reached. Alternatively, one may choose to continue to monitor the patient without liver biopsy or to switch to another medication, if possible.^42,48

Patients at high risk should be monitored more carefully, and liver biopsy should be considered soon after starting methotrexate and repeated after every 1.0 to 1.5 g.⁴⁸

No reliable noninvasive measures to evaluate for liver fibrosis are routinely available in the United States. Serial measurements of serum type III procollagen aminopeptide have been reported to correlate with the risk of developing liver fibrosis; however, this test is readily available only in Europe.⁴⁹

Cyclosporine

Cyclosporine (Gengraf, Neoral, Sandimmune) is very effective for treating psoriasis, especially erythrodermic psoriasis. It is often used only short-term or as a bridge to other maintenance therapies because it has a rapid onset and because long-term therapy (3 to 5 years) is associated with a risk of glomerulosclerosis.⁵⁰

Cyclosporine works by decreasing T-cell activation by binding cyclophilin, which leads to inhibition of transcription of calcineurin and nuclear factor of activated T cells.⁵¹ Given at doses of 2.5 to 5 mg/kg/day, cyclosporine has been shown to result in rapid improvement in up to 80% to 90% of psoriatic patients.^52,53

The initial recommended dose of cyclosporine is usually 2.5 to 3 mg/kg/day in two divided doses, which is maintained for 4 weeks and then increased by 0.5 mg/kg/day until the disease is stable.⁴²

Nephrotoxicity and hypertension are cyclosporine’s most serious side effects. Blood urea nitrogen, creatinine, and blood pressure should be monitored at baseline and then twice a month for the first 3 months and once monthly thereafter. Liver function tests, complete blood cell count, lipid profile, magnesium, uric acid, and potassium should also be checked every month.

Cyclosporine also increases the risk of cutaneous squamous cell carcinoma, especially in patients who have received psoralen plus ultraviolet A treatment.⁴²

Patients with hypersensitivity to cyclosporine, a history of chronic infection (eg, tuberculosis, hepatitis B, hepatitis C), renal insufficiency, or a history of systemic malignancy should not receive cyclosporine.

Acitretin

Acitretin, an oral retinoid, has been used for several years to treat psoriasis. Its onset is slow, typically ranging from 3 to 6 months, and its effects are dose-dependent. It is most effective as a maintenance therapy, usually after the disease has been stabilized by agents such as cyclosporine, or in combination with other treatments such as phototherapy.⁴² Acitretin has been shown to be effective in patients with pustular psoriasis.⁵⁴

Acitretin does not alter the immune system and has not been shown to have significant cumulative toxicities. Serum triglycerides are monitored closely, since acitretin can lead to hypertriglyceridemia.

All retinoids, including acitretin, are in pregnancy category X and should therefore be avoided during pregnancy. Although its half-life is only 49 hours, acitretin may be transformed to etretinate either spontaneously or as a result of alcohol ingestion. Etretinate has a half-life of 168 days and can take up to 3 years to be eliminated from the body. Therefore, acitretin is contraindicated in women who plan to become pregnant or who do not agree to use adequate contraception for 3 years after the drug is discontinued.⁴²

Biologic agents

Advances in our understanding of the pathogenesis of psoriasis have resulted in more specific, targeted therapy.

Alefacept (Amevive) is a human Fc IgG1 receptor fused to the alpha subunit of LFA3. It binds to CD2, blocks costimulatory signaling, and induces apoptosis in activated memory T cells.

Alefacept was the first biologic agent approved by the FDA for the treatment of psoriasis and one of the few biologic agents to induce long-term remission.⁵⁵ However, its use has declined because few patients achieved significant clearance of their psoriasis and its onset of action was much slower than that of other medications.⁵⁶

The currently approved biologic therapies commonly used for moderate to severe psoriasis include the TNF-alpha inhibitors and ustekinumab (Stelara).

The TNF-alpha inhibitors include infliximab (Remicade), etanercept (Enbrel), and adalimumab (Humira). They are generally well tolerated and highly effective. However, TNF-alpha inhibitors and other biologic agents are contraindicated in patients with serious infection, a personal history or a family history in a first-degree relative of demyelinating disease, or class III or IV congestive heart failure. Patients should be screened for active infection, including tuberculosis and hepatitis B, since reactivation has been reported following initiation of TNF-alpha inhibitors.¹

Adalimumab is a human monoclonal antibody against TNF-alpha. It binds to soluble and membrane-bound TNF-alpha and prevents it from binding to p55 and p75 cell-surface TNF receptors.

The dosing schedule for adalimumab is 80 mg subcutaneously for the first week, followed by 40 mg subcutaneously the next week, and then 40 mg subcutaneously every 2 weeks thereafter.¹

Etanercept is a recombinant human TNF-alpha receptor (p75) protein fused with the Fc portion of IgG1, which binds to soluble TNF-alpha.⁵⁷ Dosing for etanercept is 50 mg subcutaneously twice weekly for the first 12 weeks, followed by 50 mg weekly thereafter.

Infliximab is a chimeric antibody composed of a human IgG1 constant region fused to a mouse variable region that binds to both soluble and membrane-bound TNF-alpha.⁵⁸ Infliximab is given as an infusion at a dose of 5 mg/kg over 2 to 3 hours at weeks 0, 2, and 6, and then every 8 weeks thereafter.

Efficacy of TNF inhibitors. There are no specific guidelines for the sequence of initiation of TNF inhibitors because no studies have directly compared the efficacy of these medications. However, response to infliximab is relatively rapid compared with adalimumab and etanercept.

In a phase III clinical trial,⁵⁹ as many as 80% of patients achieved PASI-75 clearance of their psoriasis after three doses of infliximab. Interestingly, only 61% of patients maintained PASI-75 clearance by week 50. This loss of efficacy of infliximab is also reported with other TNF-alpha inhibitors and is thought to be secondary to the development of antibodies to the drugs. For infliximab, this loss of efficacy is less when infliximab is given continuously rather than on an as-needed basis. Simultaneous treatment with methotrexate is also thought to decrease the development of antibodies to infliximab.⁶⁰

Ustekinumab is an monoclonal antibody directed against the common p40 subunit of IL-12 and IL-23, which have been shown to be at increased levels in psoriatic lesions and important for the pathogenesis of psoriasis.

Between 66% and 76% of patients treated with ustekinumab achieved significant clearance of their disease after 12 weeks of treatment in two large phase III multicenter, randomized, double-blind, placebo-controlled trials.^61,62

Dosing of ustekinumab is weight-based. For those weighing less than 100 kg, ustekinumab is given at 45 mg subcutaneously at baseline, at 4 weeks, and every 12 weeks thereafter. The same dosing schedule is used for those weighing more than 100 kg, but the dose is increased to 90 mg.

Guidelines for monitoring patients while on ustekinumab are similar to those for other biologic agents. Information on long-term toxicities is still being collected. However, injection-site reactions, serious infections, malignancies, and a single case of reversible posterior leukoencephalopathy have been reported.²⁰

While biologic agents are significantly more expensive than the conventional therapies discussed above and insurance coverage for these agents varies, they have demonstrated superior efficacy and may be indicated for patients with recalcitrant moderate to severe psoriasis for whom multiple types of treatment have failed.

FOR PSORIATIC ARTHRITIS: SYSTEMIC MEDICATIONS

For patients with known or questionable psoriatic arthritis, evaluation by a rheumatologist is highly recommended.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are usually first-line in the treatment of mild psoriatic arthritis. If after 2 to 3 months of therapy with NSAIDs no benefit is achieved, treatment with methotrexate as monotherapy is a practical consideration because of its low cost. However, methotrexate as a monotherapy has not been shown to prevent radiologic progression of disease.^5,32

The TNF-alpha inhibitors have been shown to have similar efficacy when compared among each other in the treatment of psoriatic arthritis.^32,63 Based on radiologic evidence, ustekinumab has not shown to be as efficacious as the TNF-alpha inhibitors for treating psoriatic arthritis. Therefore, TNF inhibitors should be considered first-line in the treatment of psoriatic arthritis.^21,64

Few studies have been done on the efficacy or sequence of therapies that should be used in the treatment of psoriatic arthritis. The American Academy of Dermatology’s Psoriasis Guidelines of Care recommend adding a TNF-alpha inhibitor or switching to a TNF-alpha inhibitor if no significant improvement is achieved after 12 to 16 weeks of treatment with oral methotrexate.²⁰

FOR ERYTHRODERMIC PSORIASIS: MEDICATIONS THAT ACT PROMPTLY

The care of erythrodermic psoriatic patients is distinct from that of other psoriatic patients because of their associated systemic symptoms. Care should be taken to rule out sepsis, as this is a reported trigger of erythrodermic psoriasis.²⁸

Systemic medications with a quick onset, such as oral cyclosporine, are recommended. Infliximab has also been reported to be beneficial because of its rapid onset.²⁸

TREATMENT BASED ON THE TYPE AND THE SEVERITY OF PSORIASIS

The treatment of psoriasis can be as complex as the disease it itself and should be based on the type and the severity of psoriasis. Recognition of the various manifestations of psoriasis is important for effective treatment. However, in patients with moderate to severe psoriasis, atypical presentations, or recalcitrant disease, referral to a specialist is recommended.

Much has changed in our understanding of psoriasis over the past decade, which is having a major effect on its treatment.

Although topical corticosteroids and phototherapy remain mainstays of treatment, a variety of biologic agents have given new hope to those with the most severe forms of the disease. We are also beginning to understand that patients with psoriasis are at greater risk of cardiovascular disease, though the exact nature of that risk and how we should respond remains unclear. Finally, genome-wide association studies are just beginning to unravel the genetic basis of psoriasis.

In this paper, we review the epidemiology and impact of psoriasis, current views of its pathogenesis, its varied clinical forms, and its treatment.

PSORIASIS IMPOSES A GREAT BURDEN

Psoriasis is common, with a reported prevalence ranging from approximately 2%¹ to 4.7%.² It can manifest at any age, but it is most common in two age groups, ie, 20 to 30 years and 50 to 60 years.

For the patient, the burden is great, affecting physical, psychological, and occupational well-being. In fact, patients with psoriasis report quality-of-life impairment equal to or worse than that in patients with cancer or heart disease.^3,4 Notably, functional disability secondary to psoriatic arthritis has been reported in up to 19% of psoriatic arthritis patients, and this negatively affects quality of life.⁵

In 2004, the annual direct medical costs of psoriasis in the United States were estimated to exceed $1 billion. Its indirect costs, measured as missed days and loss of productivity at work, are estimated to exceed the direct costs by $15 billion annually.^6,7

Linked to cardiovascular and other diseases

Studies in the past 10 years have uncovered a link between psoriasis, metabolic syndrome, and cardiovascular disease.^8–13 Specifically, patients with severe psoriasis are at higher risk of myocardial infarction and cardiovascular death than control patients. Interestingly, the risk decreases with age; patients at greatest risk are young men with severe psoriasis.^8–10

In a large cohort study in the United Kingdom⁷ comparing patients with and without psoriasis, the hazard ratio for cardiovascular death in patients with severe psoriasis was 1.57 (95% confidence interval 1.26–1.96). This translated to 3.5 excess deaths per 1,000 patient-years. These patients were also at higher risk of death from malignancies, chronic lower respiratory disease, diabetes, dementia, infection, kidney disease, and unknown causes.

How much of the risk is due to psoriasis itself, its treatments, associated behaviors, or other factors requires more study. However, some evidence points to the dysregulation of the immune system, notably chronic elevation of pro-inflammatory cytokines.

Psoriasis and its comorbid conditions are thought to arise from chronically elevated levels of cytokines such as tumor necrosis factor alpha (TNF-alpha), interleukin 1 beta (IL-1 beta), and IL-17. These cytokines impair insulin signaling, deregulate lipid metabolism, and increase atherosclerotic changes in the coronary, cerebral, and peripheral arteries. In addition, several other diseases that involve the immune system occur more frequently with psoriasis, including Crohn disease, ulcerative colitis, lymphoma, obesity, and type 2 diabetes.^1,8,14–18

In view of the prevalence of these comorbid conditions and the risks they pose, primary care physicians should consider screening patients with severe psoriasis for metabolic disorders and cardiovascular risk factors and promptly begin preventive therapies.¹⁹ Unfortunately, to date, there are no consensus guidelines as to the appropriate screening tests or secondary cardiovascular preventive measures for patients with severe psoriasis.

A VICIOUS CIRCLE OF INFLAMMATION AND KERATINOCYTE PROLIFERATION

The hallmark of plaque psoriasis is chronic inflammation in the skin, leading to keratinocyte proliferation.

External and internal triggers that have been identified include cutaneous injury (eg, sunburn, drug rash, viral exanthems), infections (eg, streptococcal), hypocalcemia, pregnancy, psychogenic stress, drugs (eg, lithium, interferon, beta-blockers, and antimalarials), alcohol, smoking, and obesity.^20–23

As reviewed by Nestle et al,²⁴ the initiation of lesion formation is still poorly understood but is thought to occur when a trigger (physical trauma, bacterial product, cellular stress) causes DNA to be released from keratinocytes. DNA forms a complex with the antimicrobial protein LL-37 and activates plasmacytoid dendritic cells (PDCs) via toll-like receptor 9. Activated PDCs release type I interferons, which in turn activate myeloid dendritic cells. Myeloid dendritic cells release IL-20 locally, which speeds keratinocyte proliferation.

A subset of myeloid dendritic cells leaves the dermis and migrates to local lymph nodes, where they release IL-23 and activate naive T cells. T helper 1 (Th1) and Th17 cells are recruited to the lesions and begin producing numerous cytokines, including interferon gamma, IL-17, and IL-22. This cytokine milieu increases keratinocyte proliferation and causes the keratinocytes to secrete antimicrobial proteins (LL-37, beta defensins), chemokines, and S100 proteins. These soluble factors have three main functions: stimulation of dendritic cells to release more IL-23, recruitment of neutrophils to the epidermis, and activation of dermal fibroblasts.

This cycle of keratinocytes activating dendritic cells, dendritic cells activating T cells, and T cells activating keratinocytes appears to be the main force maintaining the disease.²⁴ It is unclear, however, whether this applies to all forms of psoriasis or only to plaque psoriasis.

Genetic factors discovered

In recent years, genome-wide association studies have identified at least 10 psoriasis-susceptibility loci that involve functioning of the immune system.²⁵ These genes include those of the major histocompatibility complex, cytokines, receptors, and beta-defensins.

Of specific interest, polymorphisms in the IL-12/IL-13 receptor, the p40 subunit of IL-12 and IL-23, and the p19 subunit of IL-23 strongly associate with psoriasis, supporting their critical role in the disease process and providing targets for medical therapy.²⁶

PSORIASIS HAS SEVERAL CLINICAL PHENOTYPES

Psoriasis has several clinical variants, each with a distinct clinical course and response to treatment.²⁷ Moreover, many patients present with more than one variant.

Plaque psoriasis

Plaques can persist for several months to years, even in the same location, and only about 5% of patients report complete remission for up to 5 years.

Inverse psoriasis

Photo courtesy of Joseph C. English III, MD.

Guttate psoriasis

Photo courtesy of Laura K. Ferris, MD, PhD.

Erythrodermic psoriasis

Approximately 1% to 2.25% of all patients with psoriasis develop this severe form, affecting more than 75% of the body surface area. It presents as generalized erythema, which is the most prominent feature, and it is often associated with superficial desquamation, hair loss, nail dystrophy, and systemic symptoms such as fever, chills, malaise, or high-output cardiac failure. There may be a history of preceding characteristic psoriatic plaques, recent withdrawal of treatment (usually corticosteroids), phototoxicity, or infection.

Conversely, approximately 25% of all patients with erythroderma have underlying psoriasis.²⁸

Pustular psoriasis

Photo courtesy of Joseph C. English III, MD.

There are several forms of pustular psoriasis, including generalized pustular psoriasis, annular pustular psoriasis, impetigo herpetiformis (pustular psoriasis of pregnancy), and palmoplantar pustulosis. However, there is some evidence to suggest that palmoplantar pustulosis may be distinct from psoriasis.²⁹

Several triggers have been identified, including pregnancy, rapid tapering of medications, hypocalcemia, infection, or topical irritants.

Generalized pustular psoriasis, annular pustular psoriasis, and impetigo herpetiformis often present in association with fever and other systemic symptoms and, if left untreated, can result in life-threatening complications including bacterial superinfection, sepsis, dehydration, and, in rare cases, acute respiratory distress secondary to aseptic pneumonitis.³⁰

Placental insufficiency resulting in stillbirth or neonatal death and other fetal abnormalities can occur in severe pustular psoriasis of pregnancy.³¹

Psoriatic arthritis

Psoriatic arthritis is a seronegative inflammatory spondyloarthropathy that can result in erosive arthritis in up to 57% of cases and functional disability in up to 19%.³² Although rare in the general population, it affects approximately 6% to 10% of psoriasis patients and up to 40% of patients with severe psoriasis.³³ In 70% of cases, psoriasis precedes the onset of arthritis by about 10 years, and approximately 10% to 15% of patients simultaneously present with psoriasis and arthritis or develop arthritis before skin involvement.^5,34

Patients complain of joint discomfort that is most prominent after periods of prolonged rest. Patterns of involvement are extremely variable but have been reported as an asymmetric oligoarthritis (involving four or fewer joints) or polyarthritis (involving more than four joints) in most patients. A rheumatoid arthritis-like presentation with a symmetric polyarthropathy involving the small and medium-sized joints has also been reported, making it difficult to clinically distinguish this from rheumatoid arthritis.

A distal interphalangeal-predominant pattern is reported in 5% to 10% of patients. Axial disease resembling ankylosing spondylitis occurs only in 5% of patients. Arthritis mutilans, characterized by severe, rapidly progressive joint inflammation, joint destruction, and deformity, occurs rarely. Enthesitis, ie, inflammation at the point of attachment of tendons or ligaments to bone, is present in up to 42% of patients.^5,35

Nail disease

Photo courtesy of Joseph C. English III, MD.

Disease severity also varies

Disease severity also differs among patients. An estimated 80% of patients have mild to moderate disease and 20% have moderate to severe disease, which includes disease involving more than 5% of the body surface or involvement of the face, hands, feet, or genitalia.¹

The Psoriasis Area and Severity Index (PASI) is an objective measure used in clinical trials. It incorporates the amount of redness, scaling, and induration of each psoriatic lesion over the body surface involved. A 75% improvement in the PASI score (PASI-75) is regarded as clinically significant.³⁷

PSORIASIS IS DIAGNOSED CLINICALLY

In most cases, the diagnosis of psoriasis is made clinically and is straightforward. However, in more difficult cases, biopsy may be needed. In particular:

• The plaques of psoriasis may be confused with squamous cell carcinoma in situ, dermatophyte infection, or cutaneous T-cell lymphoma, especially if they are treatment-resistant.
• Guttate psoriasis may be difficult to distinguish from pityriasis rosea.
• Erythrodermic psoriasis must be distinguished from other causes of erythroderma, including Sézary syndrome, pityriasis rubra pilaris, and drug reactions.
• Intertrigo, candidiasis, extramammary Paget disease, squamous cell carcinoma, and contact dermatitis all may mimic inverse psoriasis.
• Palmoplantar pustulosis may be difficult to differentiate from dyshidrotic eczema.
• Generalized pustular psoriasis should be distinguished from a pustular drug eruption (acute generalized exanthematous pustular drug eruption or acute generalized exanthematous pustulosis), impetigo, candidiasis, or an autoimmune blistering disorder such as pemphigus.

TREATMENT OF LIMITED DISEASE

Topical corticosteroids

A topical corticosteroid, either by itself or combined with a steroid-sparing agent, is the first-line therapy for patients with limited disease. The potency required for treatment should be based on the extent of disease and on the location, the choice of vehicle, and the patient’s preference and age.

Several double-blind studies have assessed the efficacy of various topical corticosteroids in treating psoriasis. In general, super-potent (class I) and potent (class II) topical corticosteroids are more efficacious than mild or moderate corticosteroids.³⁸ Class I and class II steroids include agents such as clobetasol propionate 0.05% (Temovate), betamethasone dipropionate 0.05% (Diprolene), fluocinonide 0.05% (Lidex), and desoximetasone 0.25% (Topicort).

Use of class I steroids should be limited to an initial treatment course of twice-daily application for 2 to 4 weeks in an effort to avoid some of the local toxicities such as skin atrophy, telangiectasia, and striae. Decreasing class I topical steroid use to 1 to 2 times per week with the gradual introduction of a steroid-sparing agent following the initial 2 to 4 weeks of treatment is advised.

Steroid-sparing agents

Steroid-sparing agents include vitamin D analogues, retinoids, and tacrolimus ointment (Protopic).

Vitamin D analogues and retinoids are thought to decrease keratinocyte proliferation and enhance keratinocyte differentiation.³⁹ The vitamin D analogues are also considered first-line topical agents and include calcipotriol (Dovonex), calcipotriene (Dovonex), and calcitriol (Vectical). To prevent hypercalcemia, use of more than 100 g of vitamin D analogues per week should be avoided.³⁹

Treatment of inverse psoriasis and scalp psoriasis may be challenging

The areas affected in inverse psoriasis, such as the genitalia and axillae, are more prone to side effects when potent topical steroids are used because of increased absorption and occlusion in these areas. Agents that minimize irritation and toxicity in sensitive areas, such as topical tacrolimus, less-potent topical steroids, or calcitriol, can be used.³⁹

For scalp psoriasis, alternative vehicles such as shampoos, gels, solutions, oils, sprays, and foams have improved patient compliance and efficacy of treatment.⁴⁰

PHOTOTHERAPY FOR SEVERE DISEASE

Narrow-band ultraviolet B

Narrow-band ultraviolet B, ie, light confined to wavelengths of 311 to 313 nm, is a first-line treatment for moderate to severe psoriasis, either as monotherapy or in combination with other treatments. It is an especially attractive option in patients who are on medications or who have comorbidities that may preclude treatment with other systemic agents.

The mechanism of action may be via immunosuppressive effects on Langerhans cells, alteration of cytokines and adhesion molecules that lead to an increase in Th2 cells, and induction of apoptosis of T lymphocytes. Additionally, ultraviolet light affects the proliferation and differentiation of keratinocytes.⁴¹

Dosing is based on skin type, and treatment usually involves two or three visits per week for a total of 15 to 20 treatments, with additional therapy for maintenance. Adding acitretin (Soriatane), with close monitoring of aspartate aminotransferase and alanine aminotransferase levels and the patient’s lipid panel, can be considered in treatment-resistant cases.⁴²

Psoralen combined with ultraviolet A

Psoralen combined with ultraviolet A is another option. It can be considered if narrow-band ultraviolet B treatment fails. It is also useful for dark-skinned patients and those with thicker plaques because ultraviolet A penetrates deeper than ultraviolet B. Oral or topical treatment with psoralen is followed by ultraviolet A treatment.

The duration of remission is much longer with psoralen plus ultraviolet A than with narrow-band ultraviolet B. However, this treatment caries a significant risk of cutaneous squamous cell carcinoma and melanoma, especially in light-skinned people and those who receive high doses of ultraviolet A (200 or more treatments) or cyclosporine.^{40,41,43–46} Long-term effects include photoaging, lentigines, and telangiectasias. As a consequence of these well-established side effects, this treatment is used less frequently.

Cautions with phototherapy

Careful screening and caution should be used in patients who have:

• Fair skin that tends to burn easily
• A history of arsenic intake or treatment with ionizing radiation
• A history of use of photosensitizing medications (fluoroquinolone antibiotics, doxycycline, hydrochlorothiazide)
• A history of melanoma or atypical nevi
• Multiple risk factors for melanoma
• A history of nonmelanoma skin cancer
• Immunosuppression due to organ transplantation.

ORAL THERAPIES FOR SEVERE PSORIASIS

Patients who have severe psoriasis—ie, affecting more than 5% of the body surface or debilitating disease affecting the palms, soles, or genitalia—are best managed with systemic medications, especially if they do not have access to phototherapy.²⁰

Methotrexate

In 1972, the US Food and Drug Administration (FDA) approved methotrexate for treating severe psoriasis.⁴² In studies of methotrexate at doses of 15 to 20 mg weekly, 36% to 68% of patients with severe plaque psoriasis achieved a PASI-75 score.^40,42,47

Dosages of methotrexate for treating severe psoriasis range from 7.5 to 25 mg once a week. Patients should also receive a folate supplement of 1 to 5 mg every day except the day they take methotrexate. The folate is to protect against gastrointestinal side effects, bone marrow suppression, and hepatic toxicity associated with methotrexate.

Other side effects of methotrexate include pulmonary fibrosis and stomatitis. Pregnancy, nursing, alcoholism, chronic liver disease, immunodeficiency syndromes, bone-marrow hypoplasia, leukopenia, thrombocytopenia, anemia, and hypersensitivity to methotrexate are all contraindications to methotrexate use.

The National Psoriasis Foundation, in its 2009 guidelines for the use of methotrexate in treating psoriasis,⁴⁸ recommends obtaining a complete blood cell count with platelets, blood urea nitrogen, creatinine, and liver function tests at baseline and at 1- to 3-month intervals thereafter.

Liver biopsies were previously recommended for patients receiving methotrexate long-term when the cumulative dose of therapy reached 1.5 g. However, given the invasive nature of the liver biopsy procedure and the low incidence of methotrexate-induced hepatotoxicity, this recommendation has been revised.

For patients with no significant risk factors for hepatic toxicity (eg, obesity, diabetes, hyperlipidemia, hepatitis, or history of or current alcohol consumption) and normal liver function tests, liver biopsy should be considered when a cumulative methotrexate dose of 3.5 to 4.0 g is reached. Alternatively, one may choose to continue to monitor the patient without liver biopsy or to switch to another medication, if possible.^42,48

Patients at high risk should be monitored more carefully, and liver biopsy should be considered soon after starting methotrexate and repeated after every 1.0 to 1.5 g.⁴⁸

No reliable noninvasive measures to evaluate for liver fibrosis are routinely available in the United States. Serial measurements of serum type III procollagen aminopeptide have been reported to correlate with the risk of developing liver fibrosis; however, this test is readily available only in Europe.⁴⁹

Cyclosporine

Cyclosporine (Gengraf, Neoral, Sandimmune) is very effective for treating psoriasis, especially erythrodermic psoriasis. It is often used only short-term or as a bridge to other maintenance therapies because it has a rapid onset and because long-term therapy (3 to 5 years) is associated with a risk of glomerulosclerosis.⁵⁰

Cyclosporine works by decreasing T-cell activation by binding cyclophilin, which leads to inhibition of transcription of calcineurin and nuclear factor of activated T cells.⁵¹ Given at doses of 2.5 to 5 mg/kg/day, cyclosporine has been shown to result in rapid improvement in up to 80% to 90% of psoriatic patients.^52,53

The initial recommended dose of cyclosporine is usually 2.5 to 3 mg/kg/day in two divided doses, which is maintained for 4 weeks and then increased by 0.5 mg/kg/day until the disease is stable.⁴²

Nephrotoxicity and hypertension are cyclosporine’s most serious side effects. Blood urea nitrogen, creatinine, and blood pressure should be monitored at baseline and then twice a month for the first 3 months and once monthly thereafter. Liver function tests, complete blood cell count, lipid profile, magnesium, uric acid, and potassium should also be checked every month.

Cyclosporine also increases the risk of cutaneous squamous cell carcinoma, especially in patients who have received psoralen plus ultraviolet A treatment.⁴²

Patients with hypersensitivity to cyclosporine, a history of chronic infection (eg, tuberculosis, hepatitis B, hepatitis C), renal insufficiency, or a history of systemic malignancy should not receive cyclosporine.

Acitretin

Acitretin, an oral retinoid, has been used for several years to treat psoriasis. Its onset is slow, typically ranging from 3 to 6 months, and its effects are dose-dependent. It is most effective as a maintenance therapy, usually after the disease has been stabilized by agents such as cyclosporine, or in combination with other treatments such as phototherapy.⁴² Acitretin has been shown to be effective in patients with pustular psoriasis.⁵⁴

Acitretin does not alter the immune system and has not been shown to have significant cumulative toxicities. Serum triglycerides are monitored closely, since acitretin can lead to hypertriglyceridemia.

All retinoids, including acitretin, are in pregnancy category X and should therefore be avoided during pregnancy. Although its half-life is only 49 hours, acitretin may be transformed to etretinate either spontaneously or as a result of alcohol ingestion. Etretinate has a half-life of 168 days and can take up to 3 years to be eliminated from the body. Therefore, acitretin is contraindicated in women who plan to become pregnant or who do not agree to use adequate contraception for 3 years after the drug is discontinued.⁴²

Biologic agents

Advances in our understanding of the pathogenesis of psoriasis have resulted in more specific, targeted therapy.

Alefacept (Amevive) is a human Fc IgG1 receptor fused to the alpha subunit of LFA3. It binds to CD2, blocks costimulatory signaling, and induces apoptosis in activated memory T cells.

Alefacept was the first biologic agent approved by the FDA for the treatment of psoriasis and one of the few biologic agents to induce long-term remission.⁵⁵ However, its use has declined because few patients achieved significant clearance of their psoriasis and its onset of action was much slower than that of other medications.⁵⁶

The currently approved biologic therapies commonly used for moderate to severe psoriasis include the TNF-alpha inhibitors and ustekinumab (Stelara).

The TNF-alpha inhibitors include infliximab (Remicade), etanercept (Enbrel), and adalimumab (Humira). They are generally well tolerated and highly effective. However, TNF-alpha inhibitors and other biologic agents are contraindicated in patients with serious infection, a personal history or a family history in a first-degree relative of demyelinating disease, or class III or IV congestive heart failure. Patients should be screened for active infection, including tuberculosis and hepatitis B, since reactivation has been reported following initiation of TNF-alpha inhibitors.¹

Adalimumab is a human monoclonal antibody against TNF-alpha. It binds to soluble and membrane-bound TNF-alpha and prevents it from binding to p55 and p75 cell-surface TNF receptors.

The dosing schedule for adalimumab is 80 mg subcutaneously for the first week, followed by 40 mg subcutaneously the next week, and then 40 mg subcutaneously every 2 weeks thereafter.¹

Etanercept is a recombinant human TNF-alpha receptor (p75) protein fused with the Fc portion of IgG1, which binds to soluble TNF-alpha.⁵⁷ Dosing for etanercept is 50 mg subcutaneously twice weekly for the first 12 weeks, followed by 50 mg weekly thereafter.

Infliximab is a chimeric antibody composed of a human IgG1 constant region fused to a mouse variable region that binds to both soluble and membrane-bound TNF-alpha.⁵⁸ Infliximab is given as an infusion at a dose of 5 mg/kg over 2 to 3 hours at weeks 0, 2, and 6, and then every 8 weeks thereafter.

Efficacy of TNF inhibitors. There are no specific guidelines for the sequence of initiation of TNF inhibitors because no studies have directly compared the efficacy of these medications. However, response to infliximab is relatively rapid compared with adalimumab and etanercept.

In a phase III clinical trial,⁵⁹ as many as 80% of patients achieved PASI-75 clearance of their psoriasis after three doses of infliximab. Interestingly, only 61% of patients maintained PASI-75 clearance by week 50. This loss of efficacy of infliximab is also reported with other TNF-alpha inhibitors and is thought to be secondary to the development of antibodies to the drugs. For infliximab, this loss of efficacy is less when infliximab is given continuously rather than on an as-needed basis. Simultaneous treatment with methotrexate is also thought to decrease the development of antibodies to infliximab.⁶⁰

Ustekinumab is an monoclonal antibody directed against the common p40 subunit of IL-12 and IL-23, which have been shown to be at increased levels in psoriatic lesions and important for the pathogenesis of psoriasis.

Between 66% and 76% of patients treated with ustekinumab achieved significant clearance of their disease after 12 weeks of treatment in two large phase III multicenter, randomized, double-blind, placebo-controlled trials.^61,62

Dosing of ustekinumab is weight-based. For those weighing less than 100 kg, ustekinumab is given at 45 mg subcutaneously at baseline, at 4 weeks, and every 12 weeks thereafter. The same dosing schedule is used for those weighing more than 100 kg, but the dose is increased to 90 mg.

Guidelines for monitoring patients while on ustekinumab are similar to those for other biologic agents. Information on long-term toxicities is still being collected. However, injection-site reactions, serious infections, malignancies, and a single case of reversible posterior leukoencephalopathy have been reported.²⁰

While biologic agents are significantly more expensive than the conventional therapies discussed above and insurance coverage for these agents varies, they have demonstrated superior efficacy and may be indicated for patients with recalcitrant moderate to severe psoriasis for whom multiple types of treatment have failed.

FOR PSORIATIC ARTHRITIS: SYSTEMIC MEDICATIONS

For patients with known or questionable psoriatic arthritis, evaluation by a rheumatologist is highly recommended.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are usually first-line in the treatment of mild psoriatic arthritis. If after 2 to 3 months of therapy with NSAIDs no benefit is achieved, treatment with methotrexate as monotherapy is a practical consideration because of its low cost. However, methotrexate as a monotherapy has not been shown to prevent radiologic progression of disease.^5,32

The TNF-alpha inhibitors have been shown to have similar efficacy when compared among each other in the treatment of psoriatic arthritis.^32,63 Based on radiologic evidence, ustekinumab has not shown to be as efficacious as the TNF-alpha inhibitors for treating psoriatic arthritis. Therefore, TNF inhibitors should be considered first-line in the treatment of psoriatic arthritis.^21,64

Few studies have been done on the efficacy or sequence of therapies that should be used in the treatment of psoriatic arthritis. The American Academy of Dermatology’s Psoriasis Guidelines of Care recommend adding a TNF-alpha inhibitor or switching to a TNF-alpha inhibitor if no significant improvement is achieved after 12 to 16 weeks of treatment with oral methotrexate.²⁰

FOR ERYTHRODERMIC PSORIASIS: MEDICATIONS THAT ACT PROMPTLY

The care of erythrodermic psoriatic patients is distinct from that of other psoriatic patients because of their associated systemic symptoms. Care should be taken to rule out sepsis, as this is a reported trigger of erythrodermic psoriasis.²⁸

Systemic medications with a quick onset, such as oral cyclosporine, are recommended. Infliximab has also been reported to be beneficial because of its rapid onset.²⁸

TREATMENT BASED ON THE TYPE AND THE SEVERITY OF PSORIASIS

The treatment of psoriasis can be as complex as the disease it itself and should be based on the type and the severity of psoriasis. Recognition of the various manifestations of psoriasis is important for effective treatment. However, in patients with moderate to severe psoriasis, atypical presentations, or recalcitrant disease, referral to a specialist is recommended.

Much has changed in our understanding of psoriasis over the past decade, which is having a major effect on its treatment.

Although topical corticosteroids and phototherapy remain mainstays of treatment, a variety of biologic agents have given new hope to those with the most severe forms of the disease. We are also beginning to understand that patients with psoriasis are at greater risk of cardiovascular disease, though the exact nature of that risk and how we should respond remains unclear. Finally, genome-wide association studies are just beginning to unravel the genetic basis of psoriasis.

In this paper, we review the epidemiology and impact of psoriasis, current views of its pathogenesis, its varied clinical forms, and its treatment.

PSORIASIS IMPOSES A GREAT BURDEN

Psoriasis is common, with a reported prevalence ranging from approximately 2%¹ to 4.7%.² It can manifest at any age, but it is most common in two age groups, ie, 20 to 30 years and 50 to 60 years.

For the patient, the burden is great, affecting physical, psychological, and occupational well-being. In fact, patients with psoriasis report quality-of-life impairment equal to or worse than that in patients with cancer or heart disease.^3,4 Notably, functional disability secondary to psoriatic arthritis has been reported in up to 19% of psoriatic arthritis patients, and this negatively affects quality of life.⁵

In 2004, the annual direct medical costs of psoriasis in the United States were estimated to exceed $1 billion. Its indirect costs, measured as missed days and loss of productivity at work, are estimated to exceed the direct costs by $15 billion annually.^6,7

Linked to cardiovascular and other diseases

Studies in the past 10 years have uncovered a link between psoriasis, metabolic syndrome, and cardiovascular disease.^8–13 Specifically, patients with severe psoriasis are at higher risk of myocardial infarction and cardiovascular death than control patients. Interestingly, the risk decreases with age; patients at greatest risk are young men with severe psoriasis.^8–10

In a large cohort study in the United Kingdom⁷ comparing patients with and without psoriasis, the hazard ratio for cardiovascular death in patients with severe psoriasis was 1.57 (95% confidence interval 1.26–1.96). This translated to 3.5 excess deaths per 1,000 patient-years. These patients were also at higher risk of death from malignancies, chronic lower respiratory disease, diabetes, dementia, infection, kidney disease, and unknown causes.

How much of the risk is due to psoriasis itself, its treatments, associated behaviors, or other factors requires more study. However, some evidence points to the dysregulation of the immune system, notably chronic elevation of pro-inflammatory cytokines.

Psoriasis and its comorbid conditions are thought to arise from chronically elevated levels of cytokines such as tumor necrosis factor alpha (TNF-alpha), interleukin 1 beta (IL-1 beta), and IL-17. These cytokines impair insulin signaling, deregulate lipid metabolism, and increase atherosclerotic changes in the coronary, cerebral, and peripheral arteries. In addition, several other diseases that involve the immune system occur more frequently with psoriasis, including Crohn disease, ulcerative colitis, lymphoma, obesity, and type 2 diabetes.^1,8,14–18

In view of the prevalence of these comorbid conditions and the risks they pose, primary care physicians should consider screening patients with severe psoriasis for metabolic disorders and cardiovascular risk factors and promptly begin preventive therapies.¹⁹ Unfortunately, to date, there are no consensus guidelines as to the appropriate screening tests or secondary cardiovascular preventive measures for patients with severe psoriasis.

A VICIOUS CIRCLE OF INFLAMMATION AND KERATINOCYTE PROLIFERATION

The hallmark of plaque psoriasis is chronic inflammation in the skin, leading to keratinocyte proliferation.

External and internal triggers that have been identified include cutaneous injury (eg, sunburn, drug rash, viral exanthems), infections (eg, streptococcal), hypocalcemia, pregnancy, psychogenic stress, drugs (eg, lithium, interferon, beta-blockers, and antimalarials), alcohol, smoking, and obesity.^20–23

As reviewed by Nestle et al,²⁴ the initiation of lesion formation is still poorly understood but is thought to occur when a trigger (physical trauma, bacterial product, cellular stress) causes DNA to be released from keratinocytes. DNA forms a complex with the antimicrobial protein LL-37 and activates plasmacytoid dendritic cells (PDCs) via toll-like receptor 9. Activated PDCs release type I interferons, which in turn activate myeloid dendritic cells. Myeloid dendritic cells release IL-20 locally, which speeds keratinocyte proliferation.

A subset of myeloid dendritic cells leaves the dermis and migrates to local lymph nodes, where they release IL-23 and activate naive T cells. T helper 1 (Th1) and Th17 cells are recruited to the lesions and begin producing numerous cytokines, including interferon gamma, IL-17, and IL-22. This cytokine milieu increases keratinocyte proliferation and causes the keratinocytes to secrete antimicrobial proteins (LL-37, beta defensins), chemokines, and S100 proteins. These soluble factors have three main functions: stimulation of dendritic cells to release more IL-23, recruitment of neutrophils to the epidermis, and activation of dermal fibroblasts.

This cycle of keratinocytes activating dendritic cells, dendritic cells activating T cells, and T cells activating keratinocytes appears to be the main force maintaining the disease.²⁴ It is unclear, however, whether this applies to all forms of psoriasis or only to plaque psoriasis.

Genetic factors discovered

In recent years, genome-wide association studies have identified at least 10 psoriasis-susceptibility loci that involve functioning of the immune system.²⁵ These genes include those of the major histocompatibility complex, cytokines, receptors, and beta-defensins.

Of specific interest, polymorphisms in the IL-12/IL-13 receptor, the p40 subunit of IL-12 and IL-23, and the p19 subunit of IL-23 strongly associate with psoriasis, supporting their critical role in the disease process and providing targets for medical therapy.²⁶

PSORIASIS HAS SEVERAL CLINICAL PHENOTYPES

Psoriasis has several clinical variants, each with a distinct clinical course and response to treatment.²⁷ Moreover, many patients present with more than one variant.

Plaque psoriasis

Plaques can persist for several months to years, even in the same location, and only about 5% of patients report complete remission for up to 5 years.

Inverse psoriasis

Photo courtesy of Joseph C. English III, MD.

Guttate psoriasis

Photo courtesy of Laura K. Ferris, MD, PhD.

Erythrodermic psoriasis

Approximately 1% to 2.25% of all patients with psoriasis develop this severe form, affecting more than 75% of the body surface area. It presents as generalized erythema, which is the most prominent feature, and it is often associated with superficial desquamation, hair loss, nail dystrophy, and systemic symptoms such as fever, chills, malaise, or high-output cardiac failure. There may be a history of preceding characteristic psoriatic plaques, recent withdrawal of treatment (usually corticosteroids), phototoxicity, or infection.

Conversely, approximately 25% of all patients with erythroderma have underlying psoriasis.²⁸

Pustular psoriasis

Photo courtesy of Joseph C. English III, MD.

There are several forms of pustular psoriasis, including generalized pustular psoriasis, annular pustular psoriasis, impetigo herpetiformis (pustular psoriasis of pregnancy), and palmoplantar pustulosis. However, there is some evidence to suggest that palmoplantar pustulosis may be distinct from psoriasis.²⁹

Several triggers have been identified, including pregnancy, rapid tapering of medications, hypocalcemia, infection, or topical irritants.

Generalized pustular psoriasis, annular pustular psoriasis, and impetigo herpetiformis often present in association with fever and other systemic symptoms and, if left untreated, can result in life-threatening complications including bacterial superinfection, sepsis, dehydration, and, in rare cases, acute respiratory distress secondary to aseptic pneumonitis.³⁰

Placental insufficiency resulting in stillbirth or neonatal death and other fetal abnormalities can occur in severe pustular psoriasis of pregnancy.³¹

Psoriatic arthritis

Psoriatic arthritis is a seronegative inflammatory spondyloarthropathy that can result in erosive arthritis in up to 57% of cases and functional disability in up to 19%.³² Although rare in the general population, it affects approximately 6% to 10% of psoriasis patients and up to 40% of patients with severe psoriasis.³³ In 70% of cases, psoriasis precedes the onset of arthritis by about 10 years, and approximately 10% to 15% of patients simultaneously present with psoriasis and arthritis or develop arthritis before skin involvement.^5,34

Patients complain of joint discomfort that is most prominent after periods of prolonged rest. Patterns of involvement are extremely variable but have been reported as an asymmetric oligoarthritis (involving four or fewer joints) or polyarthritis (involving more than four joints) in most patients. A rheumatoid arthritis-like presentation with a symmetric polyarthropathy involving the small and medium-sized joints has also been reported, making it difficult to clinically distinguish this from rheumatoid arthritis.

A distal interphalangeal-predominant pattern is reported in 5% to 10% of patients. Axial disease resembling ankylosing spondylitis occurs only in 5% of patients. Arthritis mutilans, characterized by severe, rapidly progressive joint inflammation, joint destruction, and deformity, occurs rarely. Enthesitis, ie, inflammation at the point of attachment of tendons or ligaments to bone, is present in up to 42% of patients.^5,35

Nail disease

Photo courtesy of Joseph C. English III, MD.

Disease severity also varies

Disease severity also differs among patients. An estimated 80% of patients have mild to moderate disease and 20% have moderate to severe disease, which includes disease involving more than 5% of the body surface or involvement of the face, hands, feet, or genitalia.¹

The Psoriasis Area and Severity Index (PASI) is an objective measure used in clinical trials. It incorporates the amount of redness, scaling, and induration of each psoriatic lesion over the body surface involved. A 75% improvement in the PASI score (PASI-75) is regarded as clinically significant.³⁷

PSORIASIS IS DIAGNOSED CLINICALLY

In most cases, the diagnosis of psoriasis is made clinically and is straightforward. However, in more difficult cases, biopsy may be needed. In particular:

• The plaques of psoriasis may be confused with squamous cell carcinoma in situ, dermatophyte infection, or cutaneous T-cell lymphoma, especially if they are treatment-resistant.
• Guttate psoriasis may be difficult to distinguish from pityriasis rosea.
• Erythrodermic psoriasis must be distinguished from other causes of erythroderma, including Sézary syndrome, pityriasis rubra pilaris, and drug reactions.
• Intertrigo, candidiasis, extramammary Paget disease, squamous cell carcinoma, and contact dermatitis all may mimic inverse psoriasis.
• Palmoplantar pustulosis may be difficult to differentiate from dyshidrotic eczema.
• Generalized pustular psoriasis should be distinguished from a pustular drug eruption (acute generalized exanthematous pustular drug eruption or acute generalized exanthematous pustulosis), impetigo, candidiasis, or an autoimmune blistering disorder such as pemphigus.

TREATMENT OF LIMITED DISEASE

Topical corticosteroids

A topical corticosteroid, either by itself or combined with a steroid-sparing agent, is the first-line therapy for patients with limited disease. The potency required for treatment should be based on the extent of disease and on the location, the choice of vehicle, and the patient’s preference and age.

Several double-blind studies have assessed the efficacy of various topical corticosteroids in treating psoriasis. In general, super-potent (class I) and potent (class II) topical corticosteroids are more efficacious than mild or moderate corticosteroids.³⁸ Class I and class II steroids include agents such as clobetasol propionate 0.05% (Temovate), betamethasone dipropionate 0.05% (Diprolene), fluocinonide 0.05% (Lidex), and desoximetasone 0.25% (Topicort).

Use of class I steroids should be limited to an initial treatment course of twice-daily application for 2 to 4 weeks in an effort to avoid some of the local toxicities such as skin atrophy, telangiectasia, and striae. Decreasing class I topical steroid use to 1 to 2 times per week with the gradual introduction of a steroid-sparing agent following the initial 2 to 4 weeks of treatment is advised.

Steroid-sparing agents

Steroid-sparing agents include vitamin D analogues, retinoids, and tacrolimus ointment (Protopic).

Vitamin D analogues and retinoids are thought to decrease keratinocyte proliferation and enhance keratinocyte differentiation.³⁹ The vitamin D analogues are also considered first-line topical agents and include calcipotriol (Dovonex), calcipotriene (Dovonex), and calcitriol (Vectical). To prevent hypercalcemia, use of more than 100 g of vitamin D analogues per week should be avoided.³⁹

Treatment of inverse psoriasis and scalp psoriasis may be challenging

The areas affected in inverse psoriasis, such as the genitalia and axillae, are more prone to side effects when potent topical steroids are used because of increased absorption and occlusion in these areas. Agents that minimize irritation and toxicity in sensitive areas, such as topical tacrolimus, less-potent topical steroids, or calcitriol, can be used.³⁹

For scalp psoriasis, alternative vehicles such as shampoos, gels, solutions, oils, sprays, and foams have improved patient compliance and efficacy of treatment.⁴⁰

PHOTOTHERAPY FOR SEVERE DISEASE

Narrow-band ultraviolet B

Narrow-band ultraviolet B, ie, light confined to wavelengths of 311 to 313 nm, is a first-line treatment for moderate to severe psoriasis, either as monotherapy or in combination with other treatments. It is an especially attractive option in patients who are on medications or who have comorbidities that may preclude treatment with other systemic agents.

The mechanism of action may be via immunosuppressive effects on Langerhans cells, alteration of cytokines and adhesion molecules that lead to an increase in Th2 cells, and induction of apoptosis of T lymphocytes. Additionally, ultraviolet light affects the proliferation and differentiation of keratinocytes.⁴¹

Dosing is based on skin type, and treatment usually involves two or three visits per week for a total of 15 to 20 treatments, with additional therapy for maintenance. Adding acitretin (Soriatane), with close monitoring of aspartate aminotransferase and alanine aminotransferase levels and the patient’s lipid panel, can be considered in treatment-resistant cases.⁴²

Psoralen combined with ultraviolet A

Psoralen combined with ultraviolet A is another option. It can be considered if narrow-band ultraviolet B treatment fails. It is also useful for dark-skinned patients and those with thicker plaques because ultraviolet A penetrates deeper than ultraviolet B. Oral or topical treatment with psoralen is followed by ultraviolet A treatment.

The duration of remission is much longer with psoralen plus ultraviolet A than with narrow-band ultraviolet B. However, this treatment caries a significant risk of cutaneous squamous cell carcinoma and melanoma, especially in light-skinned people and those who receive high doses of ultraviolet A (200 or more treatments) or cyclosporine.^{40,41,43–46} Long-term effects include photoaging, lentigines, and telangiectasias. As a consequence of these well-established side effects, this treatment is used less frequently.

Cautions with phototherapy

Careful screening and caution should be used in patients who have:

• Fair skin that tends to burn easily
• A history of arsenic intake or treatment with ionizing radiation
• A history of use of photosensitizing medications (fluoroquinolone antibiotics, doxycycline, hydrochlorothiazide)
• A history of melanoma or atypical nevi
• Multiple risk factors for melanoma
• A history of nonmelanoma skin cancer
• Immunosuppression due to organ transplantation.

ORAL THERAPIES FOR SEVERE PSORIASIS

Patients who have severe psoriasis—ie, affecting more than 5% of the body surface or debilitating disease affecting the palms, soles, or genitalia—are best managed with systemic medications, especially if they do not have access to phototherapy.²⁰

Methotrexate

In 1972, the US Food and Drug Administration (FDA) approved methotrexate for treating severe psoriasis.⁴² In studies of methotrexate at doses of 15 to 20 mg weekly, 36% to 68% of patients with severe plaque psoriasis achieved a PASI-75 score.^40,42,47

Dosages of methotrexate for treating severe psoriasis range from 7.5 to 25 mg once a week. Patients should also receive a folate supplement of 1 to 5 mg every day except the day they take methotrexate. The folate is to protect against gastrointestinal side effects, bone marrow suppression, and hepatic toxicity associated with methotrexate.

Other side effects of methotrexate include pulmonary fibrosis and stomatitis. Pregnancy, nursing, alcoholism, chronic liver disease, immunodeficiency syndromes, bone-marrow hypoplasia, leukopenia, thrombocytopenia, anemia, and hypersensitivity to methotrexate are all contraindications to methotrexate use.

The National Psoriasis Foundation, in its 2009 guidelines for the use of methotrexate in treating psoriasis,⁴⁸ recommends obtaining a complete blood cell count with platelets, blood urea nitrogen, creatinine, and liver function tests at baseline and at 1- to 3-month intervals thereafter.

Liver biopsies were previously recommended for patients receiving methotrexate long-term when the cumulative dose of therapy reached 1.5 g. However, given the invasive nature of the liver biopsy procedure and the low incidence of methotrexate-induced hepatotoxicity, this recommendation has been revised.

For patients with no significant risk factors for hepatic toxicity (eg, obesity, diabetes, hyperlipidemia, hepatitis, or history of or current alcohol consumption) and normal liver function tests, liver biopsy should be considered when a cumulative methotrexate dose of 3.5 to 4.0 g is reached. Alternatively, one may choose to continue to monitor the patient without liver biopsy or to switch to another medication, if possible.^42,48

Patients at high risk should be monitored more carefully, and liver biopsy should be considered soon after starting methotrexate and repeated after every 1.0 to 1.5 g.⁴⁸

No reliable noninvasive measures to evaluate for liver fibrosis are routinely available in the United States. Serial measurements of serum type III procollagen aminopeptide have been reported to correlate with the risk of developing liver fibrosis; however, this test is readily available only in Europe.⁴⁹

Cyclosporine

Cyclosporine (Gengraf, Neoral, Sandimmune) is very effective for treating psoriasis, especially erythrodermic psoriasis. It is often used only short-term or as a bridge to other maintenance therapies because it has a rapid onset and because long-term therapy (3 to 5 years) is associated with a risk of glomerulosclerosis.⁵⁰

Cyclosporine works by decreasing T-cell activation by binding cyclophilin, which leads to inhibition of transcription of calcineurin and nuclear factor of activated T cells.⁵¹ Given at doses of 2.5 to 5 mg/kg/day, cyclosporine has been shown to result in rapid improvement in up to 80% to 90% of psoriatic patients.^52,53

The initial recommended dose of cyclosporine is usually 2.5 to 3 mg/kg/day in two divided doses, which is maintained for 4 weeks and then increased by 0.5 mg/kg/day until the disease is stable.⁴²

Nephrotoxicity and hypertension are cyclosporine’s most serious side effects. Blood urea nitrogen, creatinine, and blood pressure should be monitored at baseline and then twice a month for the first 3 months and once monthly thereafter. Liver function tests, complete blood cell count, lipid profile, magnesium, uric acid, and potassium should also be checked every month.

Cyclosporine also increases the risk of cutaneous squamous cell carcinoma, especially in patients who have received psoralen plus ultraviolet A treatment.⁴²

Patients with hypersensitivity to cyclosporine, a history of chronic infection (eg, tuberculosis, hepatitis B, hepatitis C), renal insufficiency, or a history of systemic malignancy should not receive cyclosporine.

Acitretin

Acitretin, an oral retinoid, has been used for several years to treat psoriasis. Its onset is slow, typically ranging from 3 to 6 months, and its effects are dose-dependent. It is most effective as a maintenance therapy, usually after the disease has been stabilized by agents such as cyclosporine, or in combination with other treatments such as phototherapy.⁴² Acitretin has been shown to be effective in patients with pustular psoriasis.⁵⁴

Acitretin does not alter the immune system and has not been shown to have significant cumulative toxicities. Serum triglycerides are monitored closely, since acitretin can lead to hypertriglyceridemia.

All retinoids, including acitretin, are in pregnancy category X and should therefore be avoided during pregnancy. Although its half-life is only 49 hours, acitretin may be transformed to etretinate either spontaneously or as a result of alcohol ingestion. Etretinate has a half-life of 168 days and can take up to 3 years to be eliminated from the body. Therefore, acitretin is contraindicated in women who plan to become pregnant or who do not agree to use adequate contraception for 3 years after the drug is discontinued.⁴²

Biologic agents

Advances in our understanding of the pathogenesis of psoriasis have resulted in more specific, targeted therapy.

Alefacept (Amevive) is a human Fc IgG1 receptor fused to the alpha subunit of LFA3. It binds to CD2, blocks costimulatory signaling, and induces apoptosis in activated memory T cells.

Alefacept was the first biologic agent approved by the FDA for the treatment of psoriasis and one of the few biologic agents to induce long-term remission.⁵⁵ However, its use has declined because few patients achieved significant clearance of their psoriasis and its onset of action was much slower than that of other medications.⁵⁶

The currently approved biologic therapies commonly used for moderate to severe psoriasis include the TNF-alpha inhibitors and ustekinumab (Stelara).

The TNF-alpha inhibitors include infliximab (Remicade), etanercept (Enbrel), and adalimumab (Humira). They are generally well tolerated and highly effective. However, TNF-alpha inhibitors and other biologic agents are contraindicated in patients with serious infection, a personal history or a family history in a first-degree relative of demyelinating disease, or class III or IV congestive heart failure. Patients should be screened for active infection, including tuberculosis and hepatitis B, since reactivation has been reported following initiation of TNF-alpha inhibitors.¹

Adalimumab is a human monoclonal antibody against TNF-alpha. It binds to soluble and membrane-bound TNF-alpha and prevents it from binding to p55 and p75 cell-surface TNF receptors.

The dosing schedule for adalimumab is 80 mg subcutaneously for the first week, followed by 40 mg subcutaneously the next week, and then 40 mg subcutaneously every 2 weeks thereafter.¹

Etanercept is a recombinant human TNF-alpha receptor (p75) protein fused with the Fc portion of IgG1, which binds to soluble TNF-alpha.⁵⁷ Dosing for etanercept is 50 mg subcutaneously twice weekly for the first 12 weeks, followed by 50 mg weekly thereafter.

Infliximab is a chimeric antibody composed of a human IgG1 constant region fused to a mouse variable region that binds to both soluble and membrane-bound TNF-alpha.⁵⁸ Infliximab is given as an infusion at a dose of 5 mg/kg over 2 to 3 hours at weeks 0, 2, and 6, and then every 8 weeks thereafter.

Efficacy of TNF inhibitors. There are no specific guidelines for the sequence of initiation of TNF inhibitors because no studies have directly compared the efficacy of these medications. However, response to infliximab is relatively rapid compared with adalimumab and etanercept.

In a phase III clinical trial,⁵⁹ as many as 80% of patients achieved PASI-75 clearance of their psoriasis after three doses of infliximab. Interestingly, only 61% of patients maintained PASI-75 clearance by week 50. This loss of efficacy of infliximab is also reported with other TNF-alpha inhibitors and is thought to be secondary to the development of antibodies to the drugs. For infliximab, this loss of efficacy is less when infliximab is given continuously rather than on an as-needed basis. Simultaneous treatment with methotrexate is also thought to decrease the development of antibodies to infliximab.⁶⁰

Ustekinumab is an monoclonal antibody directed against the common p40 subunit of IL-12 and IL-23, which have been shown to be at increased levels in psoriatic lesions and important for the pathogenesis of psoriasis.

Between 66% and 76% of patients treated with ustekinumab achieved significant clearance of their disease after 12 weeks of treatment in two large phase III multicenter, randomized, double-blind, placebo-controlled trials.^61,62

Dosing of ustekinumab is weight-based. For those weighing less than 100 kg, ustekinumab is given at 45 mg subcutaneously at baseline, at 4 weeks, and every 12 weeks thereafter. The same dosing schedule is used for those weighing more than 100 kg, but the dose is increased to 90 mg.

Guidelines for monitoring patients while on ustekinumab are similar to those for other biologic agents. Information on long-term toxicities is still being collected. However, injection-site reactions, serious infections, malignancies, and a single case of reversible posterior leukoencephalopathy have been reported.²⁰

While biologic agents are significantly more expensive than the conventional therapies discussed above and insurance coverage for these agents varies, they have demonstrated superior efficacy and may be indicated for patients with recalcitrant moderate to severe psoriasis for whom multiple types of treatment have failed.

FOR PSORIATIC ARTHRITIS: SYSTEMIC MEDICATIONS

For patients with known or questionable psoriatic arthritis, evaluation by a rheumatologist is highly recommended.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are usually first-line in the treatment of mild psoriatic arthritis. If after 2 to 3 months of therapy with NSAIDs no benefit is achieved, treatment with methotrexate as monotherapy is a practical consideration because of its low cost. However, methotrexate as a monotherapy has not been shown to prevent radiologic progression of disease.^5,32

The TNF-alpha inhibitors have been shown to have similar efficacy when compared among each other in the treatment of psoriatic arthritis.^32,63 Based on radiologic evidence, ustekinumab has not shown to be as efficacious as the TNF-alpha inhibitors for treating psoriatic arthritis. Therefore, TNF inhibitors should be considered first-line in the treatment of psoriatic arthritis.^21,64

Few studies have been done on the efficacy or sequence of therapies that should be used in the treatment of psoriatic arthritis. The American Academy of Dermatology’s Psoriasis Guidelines of Care recommend adding a TNF-alpha inhibitor or switching to a TNF-alpha inhibitor if no significant improvement is achieved after 12 to 16 weeks of treatment with oral methotrexate.²⁰

FOR ERYTHRODERMIC PSORIASIS: MEDICATIONS THAT ACT PROMPTLY

The care of erythrodermic psoriatic patients is distinct from that of other psoriatic patients because of their associated systemic symptoms. Care should be taken to rule out sepsis, as this is a reported trigger of erythrodermic psoriasis.²⁸

Systemic medications with a quick onset, such as oral cyclosporine, are recommended. Infliximab has also been reported to be beneficial because of its rapid onset.²⁸

TREATMENT BASED ON THE TYPE AND THE SEVERITY OF PSORIASIS

The treatment of psoriasis can be as complex as the disease it itself and should be based on the type and the severity of psoriasis. Recognition of the various manifestations of psoriasis is important for effective treatment. However, in patients with moderate to severe psoriasis, atypical presentations, or recalcitrant disease, referral to a specialist is recommended.