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.

A black man, age 65, with no known history of cardiopulmonary disease presented with acute-onset exertional dyspnea and lower extremity edema. He also reported an episode of syncope, as well as occasional dizziness and abdominal bloating. He said he experienced exertional dyspnea while doing a routine step aerobic exercise. His exercise regimen included distance walking, yoga, and aerobics four to five days per week.

The patient’s medical history was remarkable for a single episode of a bleeding ulcer in previous years, low back pain, shoulder pain, and a septic arthritic hip. His social history was negative for use of tobacco, alcohol, or illegal drugs. He was married and had two biological daughters with fairly unremarkable medical histories. The patient had earned a master’s degree, worked full-time in the insurance business, and was an avid worldwide traveler. He reported diminished quality of life as a result of his acute-onset heart failure symptoms, which reduced his ability to exercise routinely, work full-time, or travel.

The patient’s sudden experience of exertional dyspnea prompted him to visit his primary care provider, who ordered an ECG that demonstrated low voltage patterns and a first-degree atrioventricular (AV) block. Subsequent stress echocardiography showed generalized thickening of the left ventricular myocardium. Posterior wall thickness measured 1.7 cm (normal range, 0.6 to 1.1 cm), septal thickness measured 1.9 cm (normal, 0.6 to 1.1 cm), and ejection fraction was 65%. The stress echocardiogram also showed a speckling pattern (brightly scattered spots) on the myocardium.

Although stress echocardiography results were negative for ischemic disease, the patient did experience dyspnea during the exam. He underwent cardiac catheterization, which indicated normal coronary arteries.

Additional diagnostic studies included cardiac MRI with and without contrast, which showed nulling of the heart muscle and delayed patchy hyperenhancement; this suggested myocardial tissue abnormality as result of amyloid fibril deposition.¹ Both pulmonary and tricuspid aortic valves were normal, with no evidence of stenosis. No regional wall motion abnormalities were noted.

Laboratory findings during the work-up were lipid panel, unremarkable; complete blood count (CBC), mild anemia and leukopenia; and urinalysis, positive for proteinuria. Brain natriuretic peptide (BNP) was measured at 686 pg/mL (normal, 0.0 to 100 pg/mL), indicating moderate heart failure. A peripheral blood smear was negative for monoclonal plasma cells.

The patient’s physical exam was unremarkable except for 2+ pedal edema bilaterally. In consideration of normal coronary arteries on cardiac catheterization, the patient’s heart failure symptoms, and stress echocardiography abnormalities, a heart biopsy was ordered. An endomyocardial biopsy with Congo Red stain demonstrated an apple-green birefringent pattern viewed under high-definition polarized light microscope, which was consistent with amyloid deposition.²

The patient was given a diagnosis of primary amyloidosis by his local cardiologist despite negative findings on the peripheral blood smear for monoclonal plasma cells (which are typically found in primary amyloidosis).³ He presented to an institution well-known for its expertise in amyloidosis, for a second opinion. There, the diagnosis was negated, based on reevaluation of the patient’s previous heart specimen through immunohistochemical studies. These studies were positive for serum amyloid P, which is suggestive of transthyretin (TTR) or familial amyloidosis.⁴ Genetic testing revealed a familial amyloidosis DNA sequence analysis with the Val122Ile variant (ie, isoleucine for valine at position 122⁵). With the correct diagnosis confirmed, the patient was referred to another highly regarded institution to begin a work-up for cardiac transplantation. Meanwhile, he was cautiously treated with the loop diuretic furosemide to manage his shortness of breath and peripheral edema.

Fifteen months later (13 weeks after being listed for transplant), the patient underwent successful cardiac transplantation.

On pathologic review of the patient’s extricated heart, the myocardium was found to be grossly thickened (see figure, above) and weighed 540 g; the average adult heart weighs 300 to 350 g, depending on the patient’s size.⁶ Congo Red staining showed extensive amyloid deposits with infiltration throughout the myocardium.

Ninety percent of the amyloid deposits were interstitial, 5% were in the vessels, and 5% were noted in a nodular pattern. The left ventricular cavity showed dilated and thickened walls. Intramural and extramural blood vessels were infiltrated with amyloid as well.

Six months after transplantation, the patient underwent diagnostic testing to assess the function and structure of his new heart. Cardiac catheterization was negative for coronary artery disease. Thirteen months posttransplantation, endomyocardial biopsy with Congo Red stain was negative for amyloid deposition or organ rejection.

About 24 months posttransplantation, the patient was taking tacrolimus, pravastatin, pantoprazole, dapsone, propanolol, colchicine, and donepezil. Stress echocardiography demonstrated normal right and left ventricular systolic function; no wall-motion abnormalities or left ventricular hypertrophy were detected, and the right atrium was of normal size. There was abnormal structural enlargement of the left atrium at the site of anastamosis—a common finding in cardiac transplant patients. The aortic, tricuspid, and mitral valves were all normal.

At that time, it was decided not to repeat endomyocardial biopsy because of normal results on molecular expression testing (a noninvasive technique called AlloMap^®7-9), which is performed to assess for heart transplant rejection. The patient’s lipid panel remained within normal limits. CBC indicated persistent anemia and leukopenia. Urine protein and BNP test results were not available.

Since undergoing cardiac transplantation, the patient has resumed his normal routine activities, including some type of exercise five days per week. He said his diet is maintained in moderation. He denied shortness of breath, chest pain, dizziness, or edema. He has returned to full-time employment and has vacationed in Croatia, Italy, and Central America.

DISCUSSION
Familial amyloidosis is an autosomal dominant disease characterized by the production of mutated proteins, most commonly ATTR. Presence of the ATTR Val 122Ile allele has been reported in 3.9% of all black Americans, and in one study, 23% of black Americans diagnosed with cardiac amyloidosis at autopsy were heterozygous for this variant allele.^10-12 ATTR Val122Ile usually manifests in the fifth

or sixth decade of life with its characteristic presentation of infiltrative/restrictive cardiomyopathy,¹³ resulting in heart failure and sometimes peripheral neuropathy.^10,11,14

Pathophysiology
In patients with ATTR Val122Ile, cardiomyopathy results from the deposition of mutant protein fibrils in the cardiac muscle, leading to restricted heart wall motion^10,15 and stiffening of the cardiac ventricles, with subsequent disruption of the diastolic filling properties of the cardiac muscle.¹⁶ Fluid overload and heart failure follow.^3,10,17 The atrium of the heart dilates, and the walls of the ventricles become thickened and fibrous.¹⁸ Liepnieks and Benson⁶ reported that the cadaver heart of one Val122Ile patient infiltrated with amyloid protein fibrils weighed 725 g—more than double the weight of an average adult heart.

In patients with cardiac amyloidosis, ECG can detect arrhythmia, and echocardiography shows cardiac enlargement; however, as in the case patient, cardiac catheterization shows normal coronary arteries.^15,16,19,20 Thus, previously healthy patients who present with heart failure and negative results on cardiac catheterization should undergo further work-up for cardiac amyloidosis.¹⁹

Amyloidosis affects all populations globally.¹⁰ In systemic amyloidosis, amyloid releases into the plasma, infiltrating and impairing multiple organs. Poor survival has been reported in patients with heart failure symptoms resulting from amyloid deposition.^20,21

Types of Amyloidosis
Primary amyloidosis, the most common of the three amyloidosis types, can be systemic or localized.²² It occurs when protein fibrils, developed from immunoglobin light chains or monoclonal plasma cells and measuring 7 to 10 nm in diameter, adhere to the heart, kidneys, peripheral nerves, eyes, and other organs.^{5,11,20,23,24} Known for its relation to multiple myeloma,¹⁹ primary amyloidosis is associated with a poor prognosis.^3,10

Secondary amyloidosis results from a chronic inflammatory disorder, such as rheumatoid arthritis or ankylosing spondylitis—conditions that trigger the production of amyloid proteins.^3,10 This type has also been associated with substance abuse and AIDS.²³

Familial or hereditary amyloidosis, according to Benson,¹⁰ is a group of diseases, each resulting from mutation in a specific protein. In the United States, the most common type of familial amyloidosis is ATTR.¹¹ More than 100 mutant types of ATTR proteins have been identified, each involving a specific nationality or group of nationalities.^10,11,23

Mutant ATTR amyloid, when deposited in specific organs, leads to their dysfunction and ultimate failure.⁶ ATTR may affect the cardiac, gastric, renal, ophthalmic, or nervous system. Depending on the ATTR variant, the resulting clinical features are age- and time-dependent, with onset most common between the third and fifth decade of life.¹⁰

Prevalence
The prevalence of ATTR Val 122Ile amyloidosis is reportedly high in West Africa, and in the US African-American population (3.9%).^{4,11,14,25,26} In a study conducted at a county hospital in Indianapolis, 3% of black newborns were found positive for ATTR Val122Ile through DNA sampling of umbilical cord blood.²⁵ These statistics are of concern, as ATTR amyloidosis could be a significant health concern in a patient population that is already medically underserved.

Yamashita et al²⁵ estimate that 1.35 million Americans of African-American descent may be affected by ATTR Val122Ile and vulnerable to restrictive cardiomyopathy–related heart failure and death. At the very least, this disorder can impair quality of life, especially in the presence of other comorbid conditions.

Clinical Presentation
The presence of exertional syncope at presentation is ominous, as it may be a marker of severe restrictive cardiomyopathy, postural hypotension due to excessive diuresis or autonomic neuropathy, ventricular arrhythmias from localized hypoperfusion, and rarely from cardiac tamponade due to pericardial involvement.²⁷ Despite widespread involvement of the conduction system in specimens at autopsy, high-grade IV block is unusual.³

Diagnostic Studies
ECG. Both ECG and Holter monitoring can detect the arrhythmias and conduction disturbances (eg, first-degree AV block, low voltage patterns) associated with cardiac amyloidosis. Patients often experience syncopal and near-syncopal episodes as a result of conduction disturbances.²⁸ Patients with conditions such as cardiac amyloidosis who present with severe heart failure are at high risk for sudden death secondary to conduction disturbances. Many have benefited from implanted defibrillators.²⁹

Echocardiography. In patients with ATTR Val122Ile cardiac amyloidosis, echocardiography reveals thickened ventricular walls (ie, measuring ≥ 15 mm; normal, ≤ 11 mm).¹⁹ Amyloid-restrictive cardiomyopathy is associated with a marked dissociation between short- and long-axis systolic function, in cases in which left ventricular ejection fraction is normal.³⁰

Echocardiography may demonstrate the characteristic specular or granular sparkling appearance that signifies advanced disease.^15,21 Only a minority have this pattern in the myocardium, however, and changes in echocardiographic technology have made this finding less noticeable.³⁰

MRI. Among more recently used diagnostic studies, cardiac magnetic resonance (CMR) has been reported to demonstrate late gadolinium enhancement (LGE) in perhaps 80% of patients with familial amyloidosis and cardiac involvement (as determined through biopsy and Congo Red stain). LGE-CMR shows darkening of the cardiac tissue, a common occurrence in amyloidosis.³¹

LGE is associated with increased thickness of both left and right ventricles, lower ECG voltage patterns, elevated BNP, and elevated troponin T.^31,32 Globally, LGE is associated with the worst prognosis in patients with cardiac amyloidosis. Use of LGE-CMR testing can help facilitate early detection of cardiac amyloidosis in patients who may be vulnerable to cardiac damage.³¹

Cardiac catheterization. In patients with cardiac amyloidosis, cardiac catheterization usually shows normal coronary arteries.³

Diagnosis
Early diagnosis of ATTR cardiac amyloidosis is crucial to the patient’s survival; it should be ruled out in any African-American patient with unexplained heart failure and echocardiography showing increased wall thickness with a nondilated left ventricular cavity. Additional clues include significant proteinuria, hepatomegaly disproportionate to the degree of heart failure, or corresponding neuropathy. Known family history of the disease, along with variant type, allows for a prompt and correct diagnosis.¹⁰

It has been reported that most clinicians who encounter heart failure, particularly in black patients, do not consider amyloidosis in the differential diagnosis, because of the high prevalence of hypertension and congestive heart failure in this population.^10,15,19 As a result, amyloidosis often goes undiagnosed.¹⁹

Findings of enlarged and thickened cardiac walls on echocardiography but normal coronary arteries on cardiac catheterization should alert the treating clinician to further work-up for cardiac amyloidosis.¹⁹ In such a patient, according to Kristen et al,²¹ endomyocardial biopsy with Congo Red staining is the gold standard for diagnosis of amyloidosis.

In ATTR Val122Ile familial amyloidosis, it is unclear whether patients who are homozygous for the disease present with symptoms at earlier onset with more progressive illness or die sooner than those who are heterozygous^.33 Nevertheless, once the diagnosis is confirmed, it is important to determine the patient’s specific variant type by DNA testing so that appropriate treatment can be initiated and the patient’s prognosis evaluated.^5,10,13

Treatment
For familial amyloidosis in general, some researchers advocate liver transplantation to remove the source of mutant amyloid protein and stop all deposition of amyloid fibrils; this procedure can be followed later by transplantation of other affected organs (including the heart).^5,23 Maurer et al³⁴ have reported improved one-year survival rates among patients with ATTR amyloidosis who underwent both cardiac and liver transplantation: 75%, versus 23% in patients who did not receive transplanted organs.

Management of cardiac amyloidosis usually requires a twofold approach: treating associated congestive heart failure, and preventing further deposition of amyloid.²⁴ In the case patient (as in most patients with ATTR amyloidosis), heart transplantation was deemed the only life-sustaining treatment option.^11,19,33

Pharmacotherapeutic options are limited for patients with ATTR Val122Ile familial amyloidosis. Conventional heart failure agents (eg, ACE inhibitors, angiotensin receptor blockers, digoxin, β-blockers, calcium channel blockers) can exacerbate heart failure symptoms, leading to a potentially life-threatening arrhythmia.^{3,11,19,24,35} Amyloid fibrils bind to digitalis, increasing susceptibility to digitalis toxicity; and to nifedipine, causing hemodynamic deterioration. Verapamil should be avoided, as it may induce severe left ventricular dysfunction. ACE inhibitors often provoke profound hypotension in primary amyloidosis.^24,35

Diuretics, too (eg, furosemide, as was prescribed for the case patient), must be used with caution.³ These agents have been used to treat fluid overload and the resulting peripheral edema and shortness of breath found in ATTR Val122Ile patients who experience heart failure.³⁶ According to Dubrey et al,⁵ cautious use of diuretics is necessary for management of heart failure symptoms in these patients.

Because the risk for intracardiac thrombus is high, anticoagulation (using agents other than β-blockers or calcium channel blockers) should be implemented unless compelling risks are involved.^11,24 Amiodarone is relatively well tolerated for ventricular tachydysrhythmias and in atrial fibrillation if the goal is maintaining sinus rhythm.³⁷

Regarding heart transplantation in patients with familial amyloidosis, Jacob et al³³ hypothesize that since mutant amyloid protein is synthesized by the liver, it would take approximately 50 years for a transplanted heart to become affected by amyloid deposition. In a 59-year-old Afro-Caribbean man with familial amyloidosis who underwent cardiac transplantation, Hamour et al¹¹ reported that the donor heart remained amyloid-free three years posttransplantation, as demonstrated by serial cardiac biopsy.

On the Horizon
Clinical trials are now under way to examine pharmacotherapeutic options for patients with ATTR amyloidosis. Now being examined in clinical trials, for example, is Fx-1006A, a drug that stabilizes ATTR and prevents the misfolding of the amyloid protein fibril, in turn preventing it from binding to the target organ.³⁸ Similarly, ALN-TTR, a drug believed to prevent disease manifestation and possibly facilitate disease regression, is being investigated in early human trials.³⁹

Additionally, the use of genetic testing is recommended in at-risk individuals to identify the TTR gene. Affected patients may benefit from prophylactic medical management, which would halt amyloidogenesis of TTR—and possibly treat the condition as well.³⁵ Pharmacotherapeutic agents like diflunisal, an NSAID, antagonize the aggregation of TTR protein and hinder formation of the amyloid fibrils.⁴⁰

CONCLUSION
ATTR Val122Ile familial amyloidosis is a rare disorder that causes abnormal synthesis of amyloid protein in the liver, which then infiltrates the cardiac structure, leading to restrictive cardiomyopathy and progressive heart failure. Patients who present with symptoms of heart failure, cardiac enlargement on echocardiography, and a finding of granular speckling patterns, though not specific on echocardiography, should prompt the health care provider to refer the patient to a cardiologist familiar with cardiac amyloidosis for further work-up.

Diagnosed patients must undergo genetic testing to determine the specific variant type so that prompt treatment can be initiated. In patients with ATTR Val122Ile familial amyloidosis, the treatment of choice is cardiac transplantation. Although the mutant amyloid protein continues to be synthesized in the liver, the donor heart is unlikely to become affected by this substance for many years. Appropriately treated patients can maintain good quality of life, free of heart failure.    

REFERENCES
1. Lim RP, Srichai MB, Lee VS. Non-ischemic causes of delayed myocardial hyperenhancement on MRI. AJR Am J Roentgenol. 2007;188 (6):1675-1681.

2. Sipe JD, Benson MD, Buxbaum JN, et al. Amyloid fibril protein nomenclature: 2010 recommendations from the nomenclature committee of the International Society of Amyloidosis. Amyloid. 2010;17(3-4):101-104.

3. Kendall H. Cardiac amyloidosis. Crit Care Nurse. 2010;30(2):16-23.

4. Eriksson M, Büttener J, Todorov T, et al. Prevalence of germline mutations in the TTR gene in a consecutive series of surgical pathology specimens with AATR amyloid. Am J Surg Pathol. 2009;33(1):58-65.

5. Dubrey SW, Hawkins PN, Falk RH. Amyloid diseases of the heart: assessment, diagnosis, and referral. Heart. 2011;97(1):75-84.

6. Liepnieks JJ, Benson MD. Progression of cardiac amyloid deposition in hereditary transthyretin amyloidosis patients after liver transplantation. Amyloid. 2007;14(4):277-282.

7. XDx Expression Diagnostics. Allomap^®: molecular expression testing (2004). www.allomap.com. Accessed May 14, 2012.

8. Mandras SA, Crespo J, Patel HM. Innovative application of immunologic principles in heart transplantation. Ochsner J. 2010;10(4):231-235.

9. Yamani MH, Taylor DO, Rodriguez R, et al. Transplant vasculopathy is associated with increased AlloMap gene expression score. J Heart Lung Transplant. 2007;26(4):403-406.

10. Benson MD. The hereditary amyloidoses. Best Pract Res Clin Rheumatol. 2003;17(6):909-927.

11. Hamour IM, Lachmann HJ, Goodman HJ, et al. Heart transplantation for homozygous familial transthyretin (TTR) V122I cardiac amyloidosis. Am J Transplant. 2008;8(5):1056-1059.

12. Jacobson DR, Pastore RD, Yaghoubian R, et al. Variant-sequence transthyretin (isoleucine 122) in late-onset cardiac amyloidosis in black Americans. N Engl J Med. 1997;336(7):466-473.

13. Falk RH, Dubrey SW. Amyloid heart disease. Prog Cardiovasc Dis. 2010;52(4):347-361.

14. Askanas V, Engel WK, McFerrin J, Vattemi G. Transthyretin Val122Ile, accumulated Abeta, and inclusion-body myositis aspects in cultured muscle. Neurology. 2003;61(2):257-260.

15. Hamidi Asl K, Nakamura M, Yamashita T, Benson MD. Cardiac amyloidoses associated with the transthyretin lle122 mutation in a Caucasian family. Amyloid. 2001;8(4):263-269.

16. Mogensen J, Arbustini E. Restrictive cardiomyopathy. Curr Opin Cardiol. 2009;24(3): 214-220.

17. Nihoyannopoulos P, Dawson D. Restrictive cardiomyopathies. Eur J Echocardiogr. 2009;10 (8):iii23-iii33.

18. Bruce J. Getting to the heart of cardiomyopathies. Nursing. 2005;35(8):44-47.

19. Falk RH. The neglected entity of familial cardiac amyloidosis in African Americans. Ethn Dis. 2002;12(1):141-143.

20. Piper C, Butz T, Farr M, et al. How to diagnose cardiac amyloidosis early: impact of ECG, tissue Doppler echocardiography, and myocardial biopsy. Amyloid. 2010;17(1):1-9.

21. Kristen AV, Meyer FJ, Perz JB, et al. Risk stratification in cardiac amyloidosis: novel approaches. Transplantation. 2005;80(1 suppl):S151-S155.

22. Westermark P, Benson MD, Buxbaum JN, et al. A primer of amyloid nomenclature. Amyloid. 2007;14(3):179-183.

23. Picken MM. New insights into systemic amyloidosis: the importance of diagnosis of specific type. Curr Opin Nephrol Hypertens. 2007; 16(3):196-203.

24. Falk RH. Cardiac amyloidosis: a treatable disease, often overlooked. Circulation. 2011;124(9):1079-1085.

25. Yamashita T, Asl KH, Yazaki M, Benson MD. A prospective evaluation of the transthyretin Ile 122 allele frequency in an African-American population. Amyloid. 2005;12(2):127-130.

26. Benson MD, Yazaki M, Magy N. Laboratory assessment of transthyretin amyloidosis. Clin Chem Lab Med. 2002;40(12):1262-1265.

27. Chamarthi B, Dubrey SW, Cha K, et al. Features and prognosis of exertional syncope in light-chain associated AL cardiac amyloidosis. Am J Cardiol. 1997;80(9):1242-1245.

28. Correia MJ, Coutinho CA, Conceiçao I, et al. Role of heart rate variability in the assessment of autonomic dysfunction in type I familial amyloidotic polyneuropathy. Folia Cardiol. 2005;12(suppl C):459-462.

29. Kadish A, Mehra M. Heart failure devices: Implantable cardioverter-defibrillators and biventricular pacing therapy. Circulation. 2005; 111(24):3327-3335.

30. Rahman JE, Helou EF, Gelzer-Bell R, et al. Noninvasive diagnosis of biopsy-proven cardiac amyloidosis. J Am Coll Cardiol. 2004;43(3):410-415.

31. Syed IS, Glockner JF, Feng D, et al. Role of cardiac magnetic resonance imaging in the detection of cardiac amyloidosis. JACC Cardiovasc Imaging. 2010;3(2):155-164.

32. Fealey ME, Edwards WD, Buadi FK, et al. Echocardiographic features of cardiac amyloidosis presenting as endomyocardial disease in a 54-year-old male. J Cardiol. 2009;54(1):162-166.

33. Jacob EK, Edwards WD, Zucker M, et al. Homozygous transthyretin mutation in an African American male. J Mol Diagn. 2007; 9(1):127-131.

34. Maurer MS, Raina A, Hesdorffer C, et al. Cardiac transplantation using extended-donor criteria organs for systemic amyloidosis complicated by heart failure. Transplantation. 2007;83(5):539-545.

35. Buxbaum J, Alexander A, Koziol J, et al. Significance of the amyloidogenic transthyretin Val 122 Ile allele in African-Americans in the Arteriosclerosis Risk in Communities (ARIC) and Cardiovascular Health (CHS) Studies. Am Heart J. 2010;159(5):864-870.

36. Rose BD, Colucci WS. Use of diuretics in heart failure (2010). www.uptodate.com/con tents/use-of-diuretics-in-patients-with-heart-failure. Accessed May 14, 2012.

37. Trappe H-J. Treating critical supraventricular and ventricular arrhythmias. J Emerg Trauma Shock. 2010;3(2):143-152.

38. Sekijima Y, Kelly JW, Ikeda S. Pathogenesis of and therapeutic strategies to ameliorate the transthyretin amyloidoses. Curr Pharm Des. 2008;14(30):3219-3230.

39. Alnylam Pharmaceuticals. TTR Amyloidosis: ALN-TTR (2011). www.alnylam.com/Programs-and-Pipeline/Programs/index.php. Accessed May 14, 2012.

40. Adamski-Werner SL, Palaninathan SK, Sacchettini JC, Kelly JW. Diflunisal analogues stabilize the native state of transthyretin: potent inhibition of amyloidogenesis. J Med Chem. 2004;47(2):355-374.

A black man, age 65, with no known history of cardiopulmonary disease presented with acute-onset exertional dyspnea and lower extremity edema. He also reported an episode of syncope, as well as occasional dizziness and abdominal bloating. He said he experienced exertional dyspnea while doing a routine step aerobic exercise. His exercise regimen included distance walking, yoga, and aerobics four to five days per week.

The patient’s medical history was remarkable for a single episode of a bleeding ulcer in previous years, low back pain, shoulder pain, and a septic arthritic hip. His social history was negative for use of tobacco, alcohol, or illegal drugs. He was married and had two biological daughters with fairly unremarkable medical histories. The patient had earned a master’s degree, worked full-time in the insurance business, and was an avid worldwide traveler. He reported diminished quality of life as a result of his acute-onset heart failure symptoms, which reduced his ability to exercise routinely, work full-time, or travel.

The patient’s sudden experience of exertional dyspnea prompted him to visit his primary care provider, who ordered an ECG that demonstrated low voltage patterns and a first-degree atrioventricular (AV) block. Subsequent stress echocardiography showed generalized thickening of the left ventricular myocardium. Posterior wall thickness measured 1.7 cm (normal range, 0.6 to 1.1 cm), septal thickness measured 1.9 cm (normal, 0.6 to 1.1 cm), and ejection fraction was 65%. The stress echocardiogram also showed a speckling pattern (brightly scattered spots) on the myocardium.

Although stress echocardiography results were negative for ischemic disease, the patient did experience dyspnea during the exam. He underwent cardiac catheterization, which indicated normal coronary arteries.

Additional diagnostic studies included cardiac MRI with and without contrast, which showed nulling of the heart muscle and delayed patchy hyperenhancement; this suggested myocardial tissue abnormality as result of amyloid fibril deposition.¹ Both pulmonary and tricuspid aortic valves were normal, with no evidence of stenosis. No regional wall motion abnormalities were noted.

Laboratory findings during the work-up were lipid panel, unremarkable; complete blood count (CBC), mild anemia and leukopenia; and urinalysis, positive for proteinuria. Brain natriuretic peptide (BNP) was measured at 686 pg/mL (normal, 0.0 to 100 pg/mL), indicating moderate heart failure. A peripheral blood smear was negative for monoclonal plasma cells.

The patient’s physical exam was unremarkable except for 2+ pedal edema bilaterally. In consideration of normal coronary arteries on cardiac catheterization, the patient’s heart failure symptoms, and stress echocardiography abnormalities, a heart biopsy was ordered. An endomyocardial biopsy with Congo Red stain demonstrated an apple-green birefringent pattern viewed under high-definition polarized light microscope, which was consistent with amyloid deposition.²

The patient was given a diagnosis of primary amyloidosis by his local cardiologist despite negative findings on the peripheral blood smear for monoclonal plasma cells (which are typically found in primary amyloidosis).³ He presented to an institution well-known for its expertise in amyloidosis, for a second opinion. There, the diagnosis was negated, based on reevaluation of the patient’s previous heart specimen through immunohistochemical studies. These studies were positive for serum amyloid P, which is suggestive of transthyretin (TTR) or familial amyloidosis.⁴ Genetic testing revealed a familial amyloidosis DNA sequence analysis with the Val122Ile variant (ie, isoleucine for valine at position 122⁵). With the correct diagnosis confirmed, the patient was referred to another highly regarded institution to begin a work-up for cardiac transplantation. Meanwhile, he was cautiously treated with the loop diuretic furosemide to manage his shortness of breath and peripheral edema.

Fifteen months later (13 weeks after being listed for transplant), the patient underwent successful cardiac transplantation.

On pathologic review of the patient’s extricated heart, the myocardium was found to be grossly thickened (see figure, above) and weighed 540 g; the average adult heart weighs 300 to 350 g, depending on the patient’s size.⁶ Congo Red staining showed extensive amyloid deposits with infiltration throughout the myocardium.

Ninety percent of the amyloid deposits were interstitial, 5% were in the vessels, and 5% were noted in a nodular pattern. The left ventricular cavity showed dilated and thickened walls. Intramural and extramural blood vessels were infiltrated with amyloid as well.

Six months after transplantation, the patient underwent diagnostic testing to assess the function and structure of his new heart. Cardiac catheterization was negative for coronary artery disease. Thirteen months posttransplantation, endomyocardial biopsy with Congo Red stain was negative for amyloid deposition or organ rejection.

About 24 months posttransplantation, the patient was taking tacrolimus, pravastatin, pantoprazole, dapsone, propanolol, colchicine, and donepezil. Stress echocardiography demonstrated normal right and left ventricular systolic function; no wall-motion abnormalities or left ventricular hypertrophy were detected, and the right atrium was of normal size. There was abnormal structural enlargement of the left atrium at the site of anastamosis—a common finding in cardiac transplant patients. The aortic, tricuspid, and mitral valves were all normal.

At that time, it was decided not to repeat endomyocardial biopsy because of normal results on molecular expression testing (a noninvasive technique called AlloMap^®7-9), which is performed to assess for heart transplant rejection. The patient’s lipid panel remained within normal limits. CBC indicated persistent anemia and leukopenia. Urine protein and BNP test results were not available.

Since undergoing cardiac transplantation, the patient has resumed his normal routine activities, including some type of exercise five days per week. He said his diet is maintained in moderation. He denied shortness of breath, chest pain, dizziness, or edema. He has returned to full-time employment and has vacationed in Croatia, Italy, and Central America.

DISCUSSION
Familial amyloidosis is an autosomal dominant disease characterized by the production of mutated proteins, most commonly ATTR. Presence of the ATTR Val 122Ile allele has been reported in 3.9% of all black Americans, and in one study, 23% of black Americans diagnosed with cardiac amyloidosis at autopsy were heterozygous for this variant allele.^10-12 ATTR Val122Ile usually manifests in the fifth

or sixth decade of life with its characteristic presentation of infiltrative/restrictive cardiomyopathy,¹³ resulting in heart failure and sometimes peripheral neuropathy.^10,11,14

Pathophysiology
In patients with ATTR Val122Ile, cardiomyopathy results from the deposition of mutant protein fibrils in the cardiac muscle, leading to restricted heart wall motion^10,15 and stiffening of the cardiac ventricles, with subsequent disruption of the diastolic filling properties of the cardiac muscle.¹⁶ Fluid overload and heart failure follow.^3,10,17 The atrium of the heart dilates, and the walls of the ventricles become thickened and fibrous.¹⁸ Liepnieks and Benson⁶ reported that the cadaver heart of one Val122Ile patient infiltrated with amyloid protein fibrils weighed 725 g—more than double the weight of an average adult heart.

In patients with cardiac amyloidosis, ECG can detect arrhythmia, and echocardiography shows cardiac enlargement; however, as in the case patient, cardiac catheterization shows normal coronary arteries.^15,16,19,20 Thus, previously healthy patients who present with heart failure and negative results on cardiac catheterization should undergo further work-up for cardiac amyloidosis.¹⁹

Amyloidosis affects all populations globally.¹⁰ In systemic amyloidosis, amyloid releases into the plasma, infiltrating and impairing multiple organs. Poor survival has been reported in patients with heart failure symptoms resulting from amyloid deposition.^20,21

Types of Amyloidosis
Primary amyloidosis, the most common of the three amyloidosis types, can be systemic or localized.²² It occurs when protein fibrils, developed from immunoglobin light chains or monoclonal plasma cells and measuring 7 to 10 nm in diameter, adhere to the heart, kidneys, peripheral nerves, eyes, and other organs.^{5,11,20,23,24} Known for its relation to multiple myeloma,¹⁹ primary amyloidosis is associated with a poor prognosis.^3,10

Secondary amyloidosis results from a chronic inflammatory disorder, such as rheumatoid arthritis or ankylosing spondylitis—conditions that trigger the production of amyloid proteins.^3,10 This type has also been associated with substance abuse and AIDS.²³

Familial or hereditary amyloidosis, according to Benson,¹⁰ is a group of diseases, each resulting from mutation in a specific protein. In the United States, the most common type of familial amyloidosis is ATTR.¹¹ More than 100 mutant types of ATTR proteins have been identified, each involving a specific nationality or group of nationalities.^10,11,23

Mutant ATTR amyloid, when deposited in specific organs, leads to their dysfunction and ultimate failure.⁶ ATTR may affect the cardiac, gastric, renal, ophthalmic, or nervous system. Depending on the ATTR variant, the resulting clinical features are age- and time-dependent, with onset most common between the third and fifth decade of life.¹⁰

Prevalence
The prevalence of ATTR Val 122Ile amyloidosis is reportedly high in West Africa, and in the US African-American population (3.9%).^{4,11,14,25,26} In a study conducted at a county hospital in Indianapolis, 3% of black newborns were found positive for ATTR Val122Ile through DNA sampling of umbilical cord blood.²⁵ These statistics are of concern, as ATTR amyloidosis could be a significant health concern in a patient population that is already medically underserved.

Yamashita et al²⁵ estimate that 1.35 million Americans of African-American descent may be affected by ATTR Val122Ile and vulnerable to restrictive cardiomyopathy–related heart failure and death. At the very least, this disorder can impair quality of life, especially in the presence of other comorbid conditions.

Clinical Presentation
The presence of exertional syncope at presentation is ominous, as it may be a marker of severe restrictive cardiomyopathy, postural hypotension due to excessive diuresis or autonomic neuropathy, ventricular arrhythmias from localized hypoperfusion, and rarely from cardiac tamponade due to pericardial involvement.²⁷ Despite widespread involvement of the conduction system in specimens at autopsy, high-grade IV block is unusual.³

Diagnostic Studies
ECG. Both ECG and Holter monitoring can detect the arrhythmias and conduction disturbances (eg, first-degree AV block, low voltage patterns) associated with cardiac amyloidosis. Patients often experience syncopal and near-syncopal episodes as a result of conduction disturbances.²⁸ Patients with conditions such as cardiac amyloidosis who present with severe heart failure are at high risk for sudden death secondary to conduction disturbances. Many have benefited from implanted defibrillators.²⁹

Echocardiography. In patients with ATTR Val122Ile cardiac amyloidosis, echocardiography reveals thickened ventricular walls (ie, measuring ≥ 15 mm; normal, ≤ 11 mm).¹⁹ Amyloid-restrictive cardiomyopathy is associated with a marked dissociation between short- and long-axis systolic function, in cases in which left ventricular ejection fraction is normal.³⁰

Echocardiography may demonstrate the characteristic specular or granular sparkling appearance that signifies advanced disease.^15,21 Only a minority have this pattern in the myocardium, however, and changes in echocardiographic technology have made this finding less noticeable.³⁰

MRI. Among more recently used diagnostic studies, cardiac magnetic resonance (CMR) has been reported to demonstrate late gadolinium enhancement (LGE) in perhaps 80% of patients with familial amyloidosis and cardiac involvement (as determined through biopsy and Congo Red stain). LGE-CMR shows darkening of the cardiac tissue, a common occurrence in amyloidosis.³¹

LGE is associated with increased thickness of both left and right ventricles, lower ECG voltage patterns, elevated BNP, and elevated troponin T.^31,32 Globally, LGE is associated with the worst prognosis in patients with cardiac amyloidosis. Use of LGE-CMR testing can help facilitate early detection of cardiac amyloidosis in patients who may be vulnerable to cardiac damage.³¹

Cardiac catheterization. In patients with cardiac amyloidosis, cardiac catheterization usually shows normal coronary arteries.³

Diagnosis
Early diagnosis of ATTR cardiac amyloidosis is crucial to the patient’s survival; it should be ruled out in any African-American patient with unexplained heart failure and echocardiography showing increased wall thickness with a nondilated left ventricular cavity. Additional clues include significant proteinuria, hepatomegaly disproportionate to the degree of heart failure, or corresponding neuropathy. Known family history of the disease, along with variant type, allows for a prompt and correct diagnosis.¹⁰

It has been reported that most clinicians who encounter heart failure, particularly in black patients, do not consider amyloidosis in the differential diagnosis, because of the high prevalence of hypertension and congestive heart failure in this population.^10,15,19 As a result, amyloidosis often goes undiagnosed.¹⁹

Findings of enlarged and thickened cardiac walls on echocardiography but normal coronary arteries on cardiac catheterization should alert the treating clinician to further work-up for cardiac amyloidosis.¹⁹ In such a patient, according to Kristen et al,²¹ endomyocardial biopsy with Congo Red staining is the gold standard for diagnosis of amyloidosis.

In ATTR Val122Ile familial amyloidosis, it is unclear whether patients who are homozygous for the disease present with symptoms at earlier onset with more progressive illness or die sooner than those who are heterozygous^.33 Nevertheless, once the diagnosis is confirmed, it is important to determine the patient’s specific variant type by DNA testing so that appropriate treatment can be initiated and the patient’s prognosis evaluated.^5,10,13

Treatment
For familial amyloidosis in general, some researchers advocate liver transplantation to remove the source of mutant amyloid protein and stop all deposition of amyloid fibrils; this procedure can be followed later by transplantation of other affected organs (including the heart).^5,23 Maurer et al³⁴ have reported improved one-year survival rates among patients with ATTR amyloidosis who underwent both cardiac and liver transplantation: 75%, versus 23% in patients who did not receive transplanted organs.

Management of cardiac amyloidosis usually requires a twofold approach: treating associated congestive heart failure, and preventing further deposition of amyloid.²⁴ In the case patient (as in most patients with ATTR amyloidosis), heart transplantation was deemed the only life-sustaining treatment option.^11,19,33

Pharmacotherapeutic options are limited for patients with ATTR Val122Ile familial amyloidosis. Conventional heart failure agents (eg, ACE inhibitors, angiotensin receptor blockers, digoxin, β-blockers, calcium channel blockers) can exacerbate heart failure symptoms, leading to a potentially life-threatening arrhythmia.^{3,11,19,24,35} Amyloid fibrils bind to digitalis, increasing susceptibility to digitalis toxicity; and to nifedipine, causing hemodynamic deterioration. Verapamil should be avoided, as it may induce severe left ventricular dysfunction. ACE inhibitors often provoke profound hypotension in primary amyloidosis.^24,35

Diuretics, too (eg, furosemide, as was prescribed for the case patient), must be used with caution.³ These agents have been used to treat fluid overload and the resulting peripheral edema and shortness of breath found in ATTR Val122Ile patients who experience heart failure.³⁶ According to Dubrey et al,⁵ cautious use of diuretics is necessary for management of heart failure symptoms in these patients.

Because the risk for intracardiac thrombus is high, anticoagulation (using agents other than β-blockers or calcium channel blockers) should be implemented unless compelling risks are involved.^11,24 Amiodarone is relatively well tolerated for ventricular tachydysrhythmias and in atrial fibrillation if the goal is maintaining sinus rhythm.³⁷

Regarding heart transplantation in patients with familial amyloidosis, Jacob et al³³ hypothesize that since mutant amyloid protein is synthesized by the liver, it would take approximately 50 years for a transplanted heart to become affected by amyloid deposition. In a 59-year-old Afro-Caribbean man with familial amyloidosis who underwent cardiac transplantation, Hamour et al¹¹ reported that the donor heart remained amyloid-free three years posttransplantation, as demonstrated by serial cardiac biopsy.

On the Horizon
Clinical trials are now under way to examine pharmacotherapeutic options for patients with ATTR amyloidosis. Now being examined in clinical trials, for example, is Fx-1006A, a drug that stabilizes ATTR and prevents the misfolding of the amyloid protein fibril, in turn preventing it from binding to the target organ.³⁸ Similarly, ALN-TTR, a drug believed to prevent disease manifestation and possibly facilitate disease regression, is being investigated in early human trials.³⁹

Additionally, the use of genetic testing is recommended in at-risk individuals to identify the TTR gene. Affected patients may benefit from prophylactic medical management, which would halt amyloidogenesis of TTR—and possibly treat the condition as well.³⁵ Pharmacotherapeutic agents like diflunisal, an NSAID, antagonize the aggregation of TTR protein and hinder formation of the amyloid fibrils.⁴⁰

CONCLUSION
ATTR Val122Ile familial amyloidosis is a rare disorder that causes abnormal synthesis of amyloid protein in the liver, which then infiltrates the cardiac structure, leading to restrictive cardiomyopathy and progressive heart failure. Patients who present with symptoms of heart failure, cardiac enlargement on echocardiography, and a finding of granular speckling patterns, though not specific on echocardiography, should prompt the health care provider to refer the patient to a cardiologist familiar with cardiac amyloidosis for further work-up.

Diagnosed patients must undergo genetic testing to determine the specific variant type so that prompt treatment can be initiated. In patients with ATTR Val122Ile familial amyloidosis, the treatment of choice is cardiac transplantation. Although the mutant amyloid protein continues to be synthesized in the liver, the donor heart is unlikely to become affected by this substance for many years. Appropriately treated patients can maintain good quality of life, free of heart failure.    

REFERENCES
1. Lim RP, Srichai MB, Lee VS. Non-ischemic causes of delayed myocardial hyperenhancement on MRI. AJR Am J Roentgenol. 2007;188 (6):1675-1681.

2. Sipe JD, Benson MD, Buxbaum JN, et al. Amyloid fibril protein nomenclature: 2010 recommendations from the nomenclature committee of the International Society of Amyloidosis. Amyloid. 2010;17(3-4):101-104.

3. Kendall H. Cardiac amyloidosis. Crit Care Nurse. 2010;30(2):16-23.

4. Eriksson M, Büttener J, Todorov T, et al. Prevalence of germline mutations in the TTR gene in a consecutive series of surgical pathology specimens with AATR amyloid. Am J Surg Pathol. 2009;33(1):58-65.

5. Dubrey SW, Hawkins PN, Falk RH. Amyloid diseases of the heart: assessment, diagnosis, and referral. Heart. 2011;97(1):75-84.

6. Liepnieks JJ, Benson MD. Progression of cardiac amyloid deposition in hereditary transthyretin amyloidosis patients after liver transplantation. Amyloid. 2007;14(4):277-282.

7. XDx Expression Diagnostics. Allomap^®: molecular expression testing (2004). www.allomap.com. Accessed May 14, 2012.

8. Mandras SA, Crespo J, Patel HM. Innovative application of immunologic principles in heart transplantation. Ochsner J. 2010;10(4):231-235.

9. Yamani MH, Taylor DO, Rodriguez R, et al. Transplant vasculopathy is associated with increased AlloMap gene expression score. J Heart Lung Transplant. 2007;26(4):403-406.

10. Benson MD. The hereditary amyloidoses. Best Pract Res Clin Rheumatol. 2003;17(6):909-927.

11. Hamour IM, Lachmann HJ, Goodman HJ, et al. Heart transplantation for homozygous familial transthyretin (TTR) V122I cardiac amyloidosis. Am J Transplant. 2008;8(5):1056-1059.

12. Jacobson DR, Pastore RD, Yaghoubian R, et al. Variant-sequence transthyretin (isoleucine 122) in late-onset cardiac amyloidosis in black Americans. N Engl J Med. 1997;336(7):466-473.

13. Falk RH, Dubrey SW. Amyloid heart disease. Prog Cardiovasc Dis. 2010;52(4):347-361.

14. Askanas V, Engel WK, McFerrin J, Vattemi G. Transthyretin Val122Ile, accumulated Abeta, and inclusion-body myositis aspects in cultured muscle. Neurology. 2003;61(2):257-260.

15. Hamidi Asl K, Nakamura M, Yamashita T, Benson MD. Cardiac amyloidoses associated with the transthyretin lle122 mutation in a Caucasian family. Amyloid. 2001;8(4):263-269.

16. Mogensen J, Arbustini E. Restrictive cardiomyopathy. Curr Opin Cardiol. 2009;24(3): 214-220.

17. Nihoyannopoulos P, Dawson D. Restrictive cardiomyopathies. Eur J Echocardiogr. 2009;10 (8):iii23-iii33.

18. Bruce J. Getting to the heart of cardiomyopathies. Nursing. 2005;35(8):44-47.

19. Falk RH. The neglected entity of familial cardiac amyloidosis in African Americans. Ethn Dis. 2002;12(1):141-143.

20. Piper C, Butz T, Farr M, et al. How to diagnose cardiac amyloidosis early: impact of ECG, tissue Doppler echocardiography, and myocardial biopsy. Amyloid. 2010;17(1):1-9.

21. Kristen AV, Meyer FJ, Perz JB, et al. Risk stratification in cardiac amyloidosis: novel approaches. Transplantation. 2005;80(1 suppl):S151-S155.

22. Westermark P, Benson MD, Buxbaum JN, et al. A primer of amyloid nomenclature. Amyloid. 2007;14(3):179-183.

23. Picken MM. New insights into systemic amyloidosis: the importance of diagnosis of specific type. Curr Opin Nephrol Hypertens. 2007; 16(3):196-203.

24. Falk RH. Cardiac amyloidosis: a treatable disease, often overlooked. Circulation. 2011;124(9):1079-1085.

25. Yamashita T, Asl KH, Yazaki M, Benson MD. A prospective evaluation of the transthyretin Ile 122 allele frequency in an African-American population. Amyloid. 2005;12(2):127-130.

26. Benson MD, Yazaki M, Magy N. Laboratory assessment of transthyretin amyloidosis. Clin Chem Lab Med. 2002;40(12):1262-1265.

27. Chamarthi B, Dubrey SW, Cha K, et al. Features and prognosis of exertional syncope in light-chain associated AL cardiac amyloidosis. Am J Cardiol. 1997;80(9):1242-1245.

28. Correia MJ, Coutinho CA, Conceiçao I, et al. Role of heart rate variability in the assessment of autonomic dysfunction in type I familial amyloidotic polyneuropathy. Folia Cardiol. 2005;12(suppl C):459-462.

29. Kadish A, Mehra M. Heart failure devices: Implantable cardioverter-defibrillators and biventricular pacing therapy. Circulation. 2005; 111(24):3327-3335.

30. Rahman JE, Helou EF, Gelzer-Bell R, et al. Noninvasive diagnosis of biopsy-proven cardiac amyloidosis. J Am Coll Cardiol. 2004;43(3):410-415.

31. Syed IS, Glockner JF, Feng D, et al. Role of cardiac magnetic resonance imaging in the detection of cardiac amyloidosis. JACC Cardiovasc Imaging. 2010;3(2):155-164.

32. Fealey ME, Edwards WD, Buadi FK, et al. Echocardiographic features of cardiac amyloidosis presenting as endomyocardial disease in a 54-year-old male. J Cardiol. 2009;54(1):162-166.

33. Jacob EK, Edwards WD, Zucker M, et al. Homozygous transthyretin mutation in an African American male. J Mol Diagn. 2007; 9(1):127-131.

34. Maurer MS, Raina A, Hesdorffer C, et al. Cardiac transplantation using extended-donor criteria organs for systemic amyloidosis complicated by heart failure. Transplantation. 2007;83(5):539-545.

35. Buxbaum J, Alexander A, Koziol J, et al. Significance of the amyloidogenic transthyretin Val 122 Ile allele in African-Americans in the Arteriosclerosis Risk in Communities (ARIC) and Cardiovascular Health (CHS) Studies. Am Heart J. 2010;159(5):864-870.

36. Rose BD, Colucci WS. Use of diuretics in heart failure (2010). www.uptodate.com/con tents/use-of-diuretics-in-patients-with-heart-failure. Accessed May 14, 2012.

37. Trappe H-J. Treating critical supraventricular and ventricular arrhythmias. J Emerg Trauma Shock. 2010;3(2):143-152.

38. Sekijima Y, Kelly JW, Ikeda S. Pathogenesis of and therapeutic strategies to ameliorate the transthyretin amyloidoses. Curr Pharm Des. 2008;14(30):3219-3230.

39. Alnylam Pharmaceuticals. TTR Amyloidosis: ALN-TTR (2011). www.alnylam.com/Programs-and-Pipeline/Programs/index.php. Accessed May 14, 2012.

40. Adamski-Werner SL, Palaninathan SK, Sacchettini JC, Kelly JW. Diflunisal analogues stabilize the native state of transthyretin: potent inhibition of amyloidogenesis. J Med Chem. 2004;47(2):355-374.

A black man, age 65, with no known history of cardiopulmonary disease presented with acute-onset exertional dyspnea and lower extremity edema. He also reported an episode of syncope, as well as occasional dizziness and abdominal bloating. He said he experienced exertional dyspnea while doing a routine step aerobic exercise. His exercise regimen included distance walking, yoga, and aerobics four to five days per week.

The patient’s medical history was remarkable for a single episode of a bleeding ulcer in previous years, low back pain, shoulder pain, and a septic arthritic hip. His social history was negative for use of tobacco, alcohol, or illegal drugs. He was married and had two biological daughters with fairly unremarkable medical histories. The patient had earned a master’s degree, worked full-time in the insurance business, and was an avid worldwide traveler. He reported diminished quality of life as a result of his acute-onset heart failure symptoms, which reduced his ability to exercise routinely, work full-time, or travel.

The patient’s sudden experience of exertional dyspnea prompted him to visit his primary care provider, who ordered an ECG that demonstrated low voltage patterns and a first-degree atrioventricular (AV) block. Subsequent stress echocardiography showed generalized thickening of the left ventricular myocardium. Posterior wall thickness measured 1.7 cm (normal range, 0.6 to 1.1 cm), septal thickness measured 1.9 cm (normal, 0.6 to 1.1 cm), and ejection fraction was 65%. The stress echocardiogram also showed a speckling pattern (brightly scattered spots) on the myocardium.

Although stress echocardiography results were negative for ischemic disease, the patient did experience dyspnea during the exam. He underwent cardiac catheterization, which indicated normal coronary arteries.

Additional diagnostic studies included cardiac MRI with and without contrast, which showed nulling of the heart muscle and delayed patchy hyperenhancement; this suggested myocardial tissue abnormality as result of amyloid fibril deposition.¹ Both pulmonary and tricuspid aortic valves were normal, with no evidence of stenosis. No regional wall motion abnormalities were noted.

Laboratory findings during the work-up were lipid panel, unremarkable; complete blood count (CBC), mild anemia and leukopenia; and urinalysis, positive for proteinuria. Brain natriuretic peptide (BNP) was measured at 686 pg/mL (normal, 0.0 to 100 pg/mL), indicating moderate heart failure. A peripheral blood smear was negative for monoclonal plasma cells.

The patient’s physical exam was unremarkable except for 2+ pedal edema bilaterally. In consideration of normal coronary arteries on cardiac catheterization, the patient’s heart failure symptoms, and stress echocardiography abnormalities, a heart biopsy was ordered. An endomyocardial biopsy with Congo Red stain demonstrated an apple-green birefringent pattern viewed under high-definition polarized light microscope, which was consistent with amyloid deposition.²

The patient was given a diagnosis of primary amyloidosis by his local cardiologist despite negative findings on the peripheral blood smear for monoclonal plasma cells (which are typically found in primary amyloidosis).³ He presented to an institution well-known for its expertise in amyloidosis, for a second opinion. There, the diagnosis was negated, based on reevaluation of the patient’s previous heart specimen through immunohistochemical studies. These studies were positive for serum amyloid P, which is suggestive of transthyretin (TTR) or familial amyloidosis.⁴ Genetic testing revealed a familial amyloidosis DNA sequence analysis with the Val122Ile variant (ie, isoleucine for valine at position 122⁵). With the correct diagnosis confirmed, the patient was referred to another highly regarded institution to begin a work-up for cardiac transplantation. Meanwhile, he was cautiously treated with the loop diuretic furosemide to manage his shortness of breath and peripheral edema.

Fifteen months later (13 weeks after being listed for transplant), the patient underwent successful cardiac transplantation.

On pathologic review of the patient’s extricated heart, the myocardium was found to be grossly thickened (see figure, above) and weighed 540 g; the average adult heart weighs 300 to 350 g, depending on the patient’s size.⁶ Congo Red staining showed extensive amyloid deposits with infiltration throughout the myocardium.

Ninety percent of the amyloid deposits were interstitial, 5% were in the vessels, and 5% were noted in a nodular pattern. The left ventricular cavity showed dilated and thickened walls. Intramural and extramural blood vessels were infiltrated with amyloid as well.

Six months after transplantation, the patient underwent diagnostic testing to assess the function and structure of his new heart. Cardiac catheterization was negative for coronary artery disease. Thirteen months posttransplantation, endomyocardial biopsy with Congo Red stain was negative for amyloid deposition or organ rejection.

About 24 months posttransplantation, the patient was taking tacrolimus, pravastatin, pantoprazole, dapsone, propanolol, colchicine, and donepezil. Stress echocardiography demonstrated normal right and left ventricular systolic function; no wall-motion abnormalities or left ventricular hypertrophy were detected, and the right atrium was of normal size. There was abnormal structural enlargement of the left atrium at the site of anastamosis—a common finding in cardiac transplant patients. The aortic, tricuspid, and mitral valves were all normal.

At that time, it was decided not to repeat endomyocardial biopsy because of normal results on molecular expression testing (a noninvasive technique called AlloMap^®7-9), which is performed to assess for heart transplant rejection. The patient’s lipid panel remained within normal limits. CBC indicated persistent anemia and leukopenia. Urine protein and BNP test results were not available.

Since undergoing cardiac transplantation, the patient has resumed his normal routine activities, including some type of exercise five days per week. He said his diet is maintained in moderation. He denied shortness of breath, chest pain, dizziness, or edema. He has returned to full-time employment and has vacationed in Croatia, Italy, and Central America.

DISCUSSION
Familial amyloidosis is an autosomal dominant disease characterized by the production of mutated proteins, most commonly ATTR. Presence of the ATTR Val 122Ile allele has been reported in 3.9% of all black Americans, and in one study, 23% of black Americans diagnosed with cardiac amyloidosis at autopsy were heterozygous for this variant allele.^10-12 ATTR Val122Ile usually manifests in the fifth

or sixth decade of life with its characteristic presentation of infiltrative/restrictive cardiomyopathy,¹³ resulting in heart failure and sometimes peripheral neuropathy.^10,11,14

Pathophysiology
In patients with ATTR Val122Ile, cardiomyopathy results from the deposition of mutant protein fibrils in the cardiac muscle, leading to restricted heart wall motion^10,15 and stiffening of the cardiac ventricles, with subsequent disruption of the diastolic filling properties of the cardiac muscle.¹⁶ Fluid overload and heart failure follow.^3,10,17 The atrium of the heart dilates, and the walls of the ventricles become thickened and fibrous.¹⁸ Liepnieks and Benson⁶ reported that the cadaver heart of one Val122Ile patient infiltrated with amyloid protein fibrils weighed 725 g—more than double the weight of an average adult heart.

In patients with cardiac amyloidosis, ECG can detect arrhythmia, and echocardiography shows cardiac enlargement; however, as in the case patient, cardiac catheterization shows normal coronary arteries.^15,16,19,20 Thus, previously healthy patients who present with heart failure and negative results on cardiac catheterization should undergo further work-up for cardiac amyloidosis.¹⁹

Amyloidosis affects all populations globally.¹⁰ In systemic amyloidosis, amyloid releases into the plasma, infiltrating and impairing multiple organs. Poor survival has been reported in patients with heart failure symptoms resulting from amyloid deposition.^20,21

Types of Amyloidosis
Primary amyloidosis, the most common of the three amyloidosis types, can be systemic or localized.²² It occurs when protein fibrils, developed from immunoglobin light chains or monoclonal plasma cells and measuring 7 to 10 nm in diameter, adhere to the heart, kidneys, peripheral nerves, eyes, and other organs.^{5,11,20,23,24} Known for its relation to multiple myeloma,¹⁹ primary amyloidosis is associated with a poor prognosis.^3,10

Secondary amyloidosis results from a chronic inflammatory disorder, such as rheumatoid arthritis or ankylosing spondylitis—conditions that trigger the production of amyloid proteins.^3,10 This type has also been associated with substance abuse and AIDS.²³

Familial or hereditary amyloidosis, according to Benson,¹⁰ is a group of diseases, each resulting from mutation in a specific protein. In the United States, the most common type of familial amyloidosis is ATTR.¹¹ More than 100 mutant types of ATTR proteins have been identified, each involving a specific nationality or group of nationalities.^10,11,23

Mutant ATTR amyloid, when deposited in specific organs, leads to their dysfunction and ultimate failure.⁶ ATTR may affect the cardiac, gastric, renal, ophthalmic, or nervous system. Depending on the ATTR variant, the resulting clinical features are age- and time-dependent, with onset most common between the third and fifth decade of life.¹⁰

Prevalence
The prevalence of ATTR Val 122Ile amyloidosis is reportedly high in West Africa, and in the US African-American population (3.9%).^{4,11,14,25,26} In a study conducted at a county hospital in Indianapolis, 3% of black newborns were found positive for ATTR Val122Ile through DNA sampling of umbilical cord blood.²⁵ These statistics are of concern, as ATTR amyloidosis could be a significant health concern in a patient population that is already medically underserved.

Yamashita et al²⁵ estimate that 1.35 million Americans of African-American descent may be affected by ATTR Val122Ile and vulnerable to restrictive cardiomyopathy–related heart failure and death. At the very least, this disorder can impair quality of life, especially in the presence of other comorbid conditions.

Clinical Presentation
The presence of exertional syncope at presentation is ominous, as it may be a marker of severe restrictive cardiomyopathy, postural hypotension due to excessive diuresis or autonomic neuropathy, ventricular arrhythmias from localized hypoperfusion, and rarely from cardiac tamponade due to pericardial involvement.²⁷ Despite widespread involvement of the conduction system in specimens at autopsy, high-grade IV block is unusual.³

Diagnostic Studies
ECG. Both ECG and Holter monitoring can detect the arrhythmias and conduction disturbances (eg, first-degree AV block, low voltage patterns) associated with cardiac amyloidosis. Patients often experience syncopal and near-syncopal episodes as a result of conduction disturbances.²⁸ Patients with conditions such as cardiac amyloidosis who present with severe heart failure are at high risk for sudden death secondary to conduction disturbances. Many have benefited from implanted defibrillators.²⁹

Echocardiography. In patients with ATTR Val122Ile cardiac amyloidosis, echocardiography reveals thickened ventricular walls (ie, measuring ≥ 15 mm; normal, ≤ 11 mm).¹⁹ Amyloid-restrictive cardiomyopathy is associated with a marked dissociation between short- and long-axis systolic function, in cases in which left ventricular ejection fraction is normal.³⁰

Echocardiography may demonstrate the characteristic specular or granular sparkling appearance that signifies advanced disease.^15,21 Only a minority have this pattern in the myocardium, however, and changes in echocardiographic technology have made this finding less noticeable.³⁰

MRI. Among more recently used diagnostic studies, cardiac magnetic resonance (CMR) has been reported to demonstrate late gadolinium enhancement (LGE) in perhaps 80% of patients with familial amyloidosis and cardiac involvement (as determined through biopsy and Congo Red stain). LGE-CMR shows darkening of the cardiac tissue, a common occurrence in amyloidosis.³¹

LGE is associated with increased thickness of both left and right ventricles, lower ECG voltage patterns, elevated BNP, and elevated troponin T.^31,32 Globally, LGE is associated with the worst prognosis in patients with cardiac amyloidosis. Use of LGE-CMR testing can help facilitate early detection of cardiac amyloidosis in patients who may be vulnerable to cardiac damage.³¹

Cardiac catheterization. In patients with cardiac amyloidosis, cardiac catheterization usually shows normal coronary arteries.³

Diagnosis
Early diagnosis of ATTR cardiac amyloidosis is crucial to the patient’s survival; it should be ruled out in any African-American patient with unexplained heart failure and echocardiography showing increased wall thickness with a nondilated left ventricular cavity. Additional clues include significant proteinuria, hepatomegaly disproportionate to the degree of heart failure, or corresponding neuropathy. Known family history of the disease, along with variant type, allows for a prompt and correct diagnosis.¹⁰

It has been reported that most clinicians who encounter heart failure, particularly in black patients, do not consider amyloidosis in the differential diagnosis, because of the high prevalence of hypertension and congestive heart failure in this population.^10,15,19 As a result, amyloidosis often goes undiagnosed.¹⁹

Findings of enlarged and thickened cardiac walls on echocardiography but normal coronary arteries on cardiac catheterization should alert the treating clinician to further work-up for cardiac amyloidosis.¹⁹ In such a patient, according to Kristen et al,²¹ endomyocardial biopsy with Congo Red staining is the gold standard for diagnosis of amyloidosis.

In ATTR Val122Ile familial amyloidosis, it is unclear whether patients who are homozygous for the disease present with symptoms at earlier onset with more progressive illness or die sooner than those who are heterozygous^.33 Nevertheless, once the diagnosis is confirmed, it is important to determine the patient’s specific variant type by DNA testing so that appropriate treatment can be initiated and the patient’s prognosis evaluated.^5,10,13

Treatment
For familial amyloidosis in general, some researchers advocate liver transplantation to remove the source of mutant amyloid protein and stop all deposition of amyloid fibrils; this procedure can be followed later by transplantation of other affected organs (including the heart).^5,23 Maurer et al³⁴ have reported improved one-year survival rates among patients with ATTR amyloidosis who underwent both cardiac and liver transplantation: 75%, versus 23% in patients who did not receive transplanted organs.

Management of cardiac amyloidosis usually requires a twofold approach: treating associated congestive heart failure, and preventing further deposition of amyloid.²⁴ In the case patient (as in most patients with ATTR amyloidosis), heart transplantation was deemed the only life-sustaining treatment option.^11,19,33

Pharmacotherapeutic options are limited for patients with ATTR Val122Ile familial amyloidosis. Conventional heart failure agents (eg, ACE inhibitors, angiotensin receptor blockers, digoxin, β-blockers, calcium channel blockers) can exacerbate heart failure symptoms, leading to a potentially life-threatening arrhythmia.^{3,11,19,24,35} Amyloid fibrils bind to digitalis, increasing susceptibility to digitalis toxicity; and to nifedipine, causing hemodynamic deterioration. Verapamil should be avoided, as it may induce severe left ventricular dysfunction. ACE inhibitors often provoke profound hypotension in primary amyloidosis.^24,35

Diuretics, too (eg, furosemide, as was prescribed for the case patient), must be used with caution.³ These agents have been used to treat fluid overload and the resulting peripheral edema and shortness of breath found in ATTR Val122Ile patients who experience heart failure.³⁶ According to Dubrey et al,⁵ cautious use of diuretics is necessary for management of heart failure symptoms in these patients.

Because the risk for intracardiac thrombus is high, anticoagulation (using agents other than β-blockers or calcium channel blockers) should be implemented unless compelling risks are involved.^11,24 Amiodarone is relatively well tolerated for ventricular tachydysrhythmias and in atrial fibrillation if the goal is maintaining sinus rhythm.³⁷

Regarding heart transplantation in patients with familial amyloidosis, Jacob et al³³ hypothesize that since mutant amyloid protein is synthesized by the liver, it would take approximately 50 years for a transplanted heart to become affected by amyloid deposition. In a 59-year-old Afro-Caribbean man with familial amyloidosis who underwent cardiac transplantation, Hamour et al¹¹ reported that the donor heart remained amyloid-free three years posttransplantation, as demonstrated by serial cardiac biopsy.

On the Horizon
Clinical trials are now under way to examine pharmacotherapeutic options for patients with ATTR amyloidosis. Now being examined in clinical trials, for example, is Fx-1006A, a drug that stabilizes ATTR and prevents the misfolding of the amyloid protein fibril, in turn preventing it from binding to the target organ.³⁸ Similarly, ALN-TTR, a drug believed to prevent disease manifestation and possibly facilitate disease regression, is being investigated in early human trials.³⁹

Additionally, the use of genetic testing is recommended in at-risk individuals to identify the TTR gene. Affected patients may benefit from prophylactic medical management, which would halt amyloidogenesis of TTR—and possibly treat the condition as well.³⁵ Pharmacotherapeutic agents like diflunisal, an NSAID, antagonize the aggregation of TTR protein and hinder formation of the amyloid fibrils.⁴⁰

CONCLUSION
ATTR Val122Ile familial amyloidosis is a rare disorder that causes abnormal synthesis of amyloid protein in the liver, which then infiltrates the cardiac structure, leading to restrictive cardiomyopathy and progressive heart failure. Patients who present with symptoms of heart failure, cardiac enlargement on echocardiography, and a finding of granular speckling patterns, though not specific on echocardiography, should prompt the health care provider to refer the patient to a cardiologist familiar with cardiac amyloidosis for further work-up.

Diagnosed patients must undergo genetic testing to determine the specific variant type so that prompt treatment can be initiated. In patients with ATTR Val122Ile familial amyloidosis, the treatment of choice is cardiac transplantation. Although the mutant amyloid protein continues to be synthesized in the liver, the donor heart is unlikely to become affected by this substance for many years. Appropriately treated patients can maintain good quality of life, free of heart failure.    

REFERENCES
1. Lim RP, Srichai MB, Lee VS. Non-ischemic causes of delayed myocardial hyperenhancement on MRI. AJR Am J Roentgenol. 2007;188 (6):1675-1681.

2. Sipe JD, Benson MD, Buxbaum JN, et al. Amyloid fibril protein nomenclature: 2010 recommendations from the nomenclature committee of the International Society of Amyloidosis. Amyloid. 2010;17(3-4):101-104.

3. Kendall H. Cardiac amyloidosis. Crit Care Nurse. 2010;30(2):16-23.

4. Eriksson M, Büttener J, Todorov T, et al. Prevalence of germline mutations in the TTR gene in a consecutive series of surgical pathology specimens with AATR amyloid. Am J Surg Pathol. 2009;33(1):58-65.

5. Dubrey SW, Hawkins PN, Falk RH. Amyloid diseases of the heart: assessment, diagnosis, and referral. Heart. 2011;97(1):75-84.

6. Liepnieks JJ, Benson MD. Progression of cardiac amyloid deposition in hereditary transthyretin amyloidosis patients after liver transplantation. Amyloid. 2007;14(4):277-282.

7. XDx Expression Diagnostics. Allomap^®: molecular expression testing (2004). www.allomap.com. Accessed May 14, 2012.

8. Mandras SA, Crespo J, Patel HM. Innovative application of immunologic principles in heart transplantation. Ochsner J. 2010;10(4):231-235.

9. Yamani MH, Taylor DO, Rodriguez R, et al. Transplant vasculopathy is associated with increased AlloMap gene expression score. J Heart Lung Transplant. 2007;26(4):403-406.

10. Benson MD. The hereditary amyloidoses. Best Pract Res Clin Rheumatol. 2003;17(6):909-927.

11. Hamour IM, Lachmann HJ, Goodman HJ, et al. Heart transplantation for homozygous familial transthyretin (TTR) V122I cardiac amyloidosis. Am J Transplant. 2008;8(5):1056-1059.

12. Jacobson DR, Pastore RD, Yaghoubian R, et al. Variant-sequence transthyretin (isoleucine 122) in late-onset cardiac amyloidosis in black Americans. N Engl J Med. 1997;336(7):466-473.

13. Falk RH, Dubrey SW. Amyloid heart disease. Prog Cardiovasc Dis. 2010;52(4):347-361.

14. Askanas V, Engel WK, McFerrin J, Vattemi G. Transthyretin Val122Ile, accumulated Abeta, and inclusion-body myositis aspects in cultured muscle. Neurology. 2003;61(2):257-260.

15. Hamidi Asl K, Nakamura M, Yamashita T, Benson MD. Cardiac amyloidoses associated with the transthyretin lle122 mutation in a Caucasian family. Amyloid. 2001;8(4):263-269.

16. Mogensen J, Arbustini E. Restrictive cardiomyopathy. Curr Opin Cardiol. 2009;24(3): 214-220.

17. Nihoyannopoulos P, Dawson D. Restrictive cardiomyopathies. Eur J Echocardiogr. 2009;10 (8):iii23-iii33.

18. Bruce J. Getting to the heart of cardiomyopathies. Nursing. 2005;35(8):44-47.

19. Falk RH. The neglected entity of familial cardiac amyloidosis in African Americans. Ethn Dis. 2002;12(1):141-143.

20. Piper C, Butz T, Farr M, et al. How to diagnose cardiac amyloidosis early: impact of ECG, tissue Doppler echocardiography, and myocardial biopsy. Amyloid. 2010;17(1):1-9.

21. Kristen AV, Meyer FJ, Perz JB, et al. Risk stratification in cardiac amyloidosis: novel approaches. Transplantation. 2005;80(1 suppl):S151-S155.

22. Westermark P, Benson MD, Buxbaum JN, et al. A primer of amyloid nomenclature. Amyloid. 2007;14(3):179-183.

23. Picken MM. New insights into systemic amyloidosis: the importance of diagnosis of specific type. Curr Opin Nephrol Hypertens. 2007; 16(3):196-203.

24. Falk RH. Cardiac amyloidosis: a treatable disease, often overlooked. Circulation. 2011;124(9):1079-1085.

25. Yamashita T, Asl KH, Yazaki M, Benson MD. A prospective evaluation of the transthyretin Ile 122 allele frequency in an African-American population. Amyloid. 2005;12(2):127-130.

26. Benson MD, Yazaki M, Magy N. Laboratory assessment of transthyretin amyloidosis. Clin Chem Lab Med. 2002;40(12):1262-1265.

27. Chamarthi B, Dubrey SW, Cha K, et al. Features and prognosis of exertional syncope in light-chain associated AL cardiac amyloidosis. Am J Cardiol. 1997;80(9):1242-1245.

28. Correia MJ, Coutinho CA, Conceiçao I, et al. Role of heart rate variability in the assessment of autonomic dysfunction in type I familial amyloidotic polyneuropathy. Folia Cardiol. 2005;12(suppl C):459-462.

29. Kadish A, Mehra M. Heart failure devices: Implantable cardioverter-defibrillators and biventricular pacing therapy. Circulation. 2005; 111(24):3327-3335.

30. Rahman JE, Helou EF, Gelzer-Bell R, et al. Noninvasive diagnosis of biopsy-proven cardiac amyloidosis. J Am Coll Cardiol. 2004;43(3):410-415.

31. Syed IS, Glockner JF, Feng D, et al. Role of cardiac magnetic resonance imaging in the detection of cardiac amyloidosis. JACC Cardiovasc Imaging. 2010;3(2):155-164.

32. Fealey ME, Edwards WD, Buadi FK, et al. Echocardiographic features of cardiac amyloidosis presenting as endomyocardial disease in a 54-year-old male. J Cardiol. 2009;54(1):162-166.

33. Jacob EK, Edwards WD, Zucker M, et al. Homozygous transthyretin mutation in an African American male. J Mol Diagn. 2007; 9(1):127-131.

34. Maurer MS, Raina A, Hesdorffer C, et al. Cardiac transplantation using extended-donor criteria organs for systemic amyloidosis complicated by heart failure. Transplantation. 2007;83(5):539-545.

35. Buxbaum J, Alexander A, Koziol J, et al. Significance of the amyloidogenic transthyretin Val 122 Ile allele in African-Americans in the Arteriosclerosis Risk in Communities (ARIC) and Cardiovascular Health (CHS) Studies. Am Heart J. 2010;159(5):864-870.

36. Rose BD, Colucci WS. Use of diuretics in heart failure (2010). www.uptodate.com/con tents/use-of-diuretics-in-patients-with-heart-failure. Accessed May 14, 2012.

37. Trappe H-J. Treating critical supraventricular and ventricular arrhythmias. J Emerg Trauma Shock. 2010;3(2):143-152.

38. Sekijima Y, Kelly JW, Ikeda S. Pathogenesis of and therapeutic strategies to ameliorate the transthyretin amyloidoses. Curr Pharm Des. 2008;14(30):3219-3230.

39. Alnylam Pharmaceuticals. TTR Amyloidosis: ALN-TTR (2011). www.alnylam.com/Programs-and-Pipeline/Programs/index.php. Accessed May 14, 2012.

40. Adamski-Werner SL, Palaninathan SK, Sacchettini JC, Kelly JW. Diflunisal analogues stabilize the native state of transthyretin: potent inhibition of amyloidogenesis. J Med Chem. 2004;47(2):355-374.

CASE: Medication sensitivity

Mrs. C, age 48, is admitted to a tertiary care inpatient mood disorder unit for evaluation of severe depression characterized by depressed mood, anhedonia, and insomnia. Her initial Hamilton Rating Scale for Depression 17-Item (HRSD-17) score is 30, indicating severe depression. Her medications are fluoxetine, 10 mg/d, and diazepam, 0.5 mg/d.

Mrs. C describes a 10-month history of depression and extreme anxiety in the context of several psychosocial stressors. Her father recently died and she is having difficulty with the demands of administering her father’s estate. She is intensely obsessive and focused on nihilistic themes, her diagnosis, somatic themes, and medications side effects. Her husband confirms our observations. No history or current symptoms of typical compulsions (eg, washing hands or checking doors) are elicited. She has limited insight into her obsessive tendencies.

Mrs. C had no psychiatric history before her depressive and obsessive symptoms developed 10 months ago. However, in the past 10 months, she has been hospitalized in a psychiatric facility twice. She also received a series of 8 electroconvulsive therapy treatments, but reported minimal improvement of her depressive symptoms. Mrs. C had a few cognitive-behavioral therapy (CBT) sessions with a psychotherapist, but she said they didn’t help much.

Mrs. C has substantial difficulty adhering to medications, even at subtherapeutic doses. She states she is “extremely sensitive” to all medications. Mrs. C says she develops dizziness, increased anxiety, insomnia, nausea, and other vague reactions whenever she attempts to increase her psychotropics to therapeutic doses. She took sertraline, 10 mg/d, for 4 days, but discontinued it because of unspecified side effects. She then received escitalopram, 2.5 mg/d, for 10 days, but again stopped it because of vague side effects. She was taking paroxetine, 10 mg/d, for 2 days, but experienced vomiting and discontinued the drug. She tried venlafaxine at a low dose and also discontinued it because of vomiting. Mrs. C stayed on mirtazapine, 22.5 mg/d, for 3 months, but stopped it because of lack of efficacy and she was unwilling to increase the dose. Other unsuccessful trials include citalopram and doxepin. Mrs. C is hesitant to try another medication or increase to therapeutic doses any of the previous medications.

The authors’ observations

Before initiating another treatment, the treatment team considered Mrs. C’s pervasive medication intolerance. Her enzymatic activity may be genetically compromised, which could lead to high blood levels of medications and significant side effects when she takes very low doses. Individual variations in response to psychotropics are influenced by genetic factors.¹ Variants in the cytochrome P450 (CYP450) genes produce enzymes with increased activity, normal activity, reduced activity, or no activity, creating phenotypes of ultrarapid metabolizers, extensive metabolizers, intermediate metabolizers, and poor metabolizers, respectively. These genetic variations can affect blood levels of medications that employ these enzymes in their metabolic pathways.² Mrs. C could be a poor metabolizer of common CYP450 variant enzymes, which led to her exquisite sensitivity to psychotropics. We felt this was a reasonable hypothesis given her tumultuous 10-month course of psychiatric treatment and multiple failed medication trials.

An alternative hypothesis is that Mrs. C’s somatic obsessions about drug side effects were the primary clinical issue that led to her severe medication intolerance. Mrs. C spends hours questioning the inpatient staff about her diagnosis (eg, “Are you sure I don’t have bipolar disorder?”), medications (eg, “Are you sure this medication won’t make me sick?”), somatic themes (eg, “Are you sure I don’t have Meniere’s disease with all my dizziness?”), and nihilistic themes (eg, “What if I never get better?”). Mrs. C’s husband attested that she has spent hours researching her new medications on the Internet and reading the medication handouts from the pharmacy. She admits to mentally cycling through the DSM-IV-TR criteria for hours at a time to “figure out” if she has bipolar disorder (BD).

We initiated pharmacogenomic testing to help distinguish between these hypotheses. Mrs. C’s results are presented in Table 1. Genotype results were applied using an interpretive algorithm (Figure) in which 26 psychiatric medications were placed in categories of “use as directed” (green column), “use with caution” (yellow column), and “use with caution or more frequent monitoring” (red column). The algorithm incorporates the genetic information with the known pharmacologic profile for each of the medications in the panel. Highlights of Mrs. C’s interpretive report are shown in Table 2.

Table 1

Mrs. C’s genotype results

Figure

Genotype-phenotype integration into Mrs. C’s interpretive report

  Table 2

Mrs. C’s pharmacogenomic-based interpretive report

The authors’ observations

Mrs. C’s genotype might explain some sensitivity to medications metabolized by CYP2D6 (eg, venlafaxine, paroxetine, fluoxetine), but does not explain her acute sensitivity to all of the medications she has taken. For example, she is an extensive metabolizer for CYP2C19, which metabolizes escitalopram; therefore, it is unlikely escitalopram, 2.5 mg/d, would result in high blood levels and side effects.³ Regardless of the next step in treatment, we deemed her somatic obsessions to be the most important clinical issue. It seems unlikely that Mrs. C would adhere to any medication regimen until this underlying problem was addressed.

The focus of treatment shifted to Mrs. C’s obsessions about her medications and their side effects. Mrs. C was fixated on the content of her obsessions (eg, medications, side effects) rather than the process of her obsessional thinking. The goal was to help Mrs. C identify, label, and ultimately create distance from her obsessive thoughts associated with side effects. The treatment team employed an acceptance and commitment therapy (ACT) model of observing and defusing thoughts in the inpatient setting (Table 3).⁴ ACT is based on mindfulness and committed, values-based action.⁵ When patients are “fused” with their thoughts, they believe these thoughts are important and representative of reality. In Mrs. C’s case, she fused with the concept that her medications were making her sick and the idea that she may have BD. The treatment team thought these fused thoughts were the major problem that resulted in 10 months of protracted illness.

Conversely, in a “defused” state, patients can separate from their thoughts and observe them as disparate sounds, words, stories, or bits of language. The goal is to observe and allow the patient’s thoughts to simply be thoughts rather than trying to determine if they are “true.” Mrs. C was fused with the idea that her medications were making her ill, so this belief became the story underlying her obsessional thinking. Helping her disengage from this story became the focus of her treatment.

Table 3

6 core principles of acceptance and commitment therapy

Results guide pharmacotherapy

In addition to helping change the focus of Mrs. C’s psychotherapy, we used the pharmacogenomic results to guide medication treatment. We initially prescribed fluvoxamine, 50 mg/d, because her partially compromised CYP2D6 pathway probably would play only a minor role in metabolizing the drug.¹ Smoking induces CYP1A2, which is fluvoxamine’s primary metabolic pathway; however, Mrs. C does not smoke.⁶ When we saw Mrs. C in January 2009, the author (JGW) was unaware of any available genetic testing for CYP1A2, although now such testing is clinically available.

Mirtazapine is in the “use as directed” category for Mrs. C’s genotype (Table 2) and was the only medication she had adhered to at a therapeutic dose for more than a few days. However, she indicated that she would not adhere to this medication if we prescribed it again. Duloxetine also is in the “use as directed” category; however, given the entire clinical picture, we chose fluvoxamine because of Mrs. C’s obsessive symptomatology and because she had never reached a therapeutic dose of a selective serotonin reuptake inhibitor.

OUTCOME: Obsessions abate

Given Mrs. C’s lack of insight, we initiate a family approach to help broach the topic of obsessions as the focus of treatment. With her husband’s help, she participates in defusion techniques as an inpatient and follows up with an acceptance-based psychotherapist after discharge. After we share the pharmacogenomic information with Mrs. C, she agrees to try fluvoxamine, which is titrated to 100 mg/d. She maintains this dose at her 4-week follow-up visit. Notably, this was only the second time Mrs. C adhered to a medication trial since illness onset. Upon admission, Mrs. C had an HRSD-17 score of 30, indicating severe depression; at 4 weeks, her HRSD-17 score is 8, indicating mild depression.

The authors’ observations

In a complementary case, the author (JGW) consulted on a patient who was taking paroxetine and experiencing anorgasmia, weight gain, and loss of libido. Pharmacogenomic testing revealed that the patient was a poor metabolizer of CYP2D6. Paroxetine is substantially metabolized by CYP2D6; therefore, it was likely that high blood levels were contributing to the side effects.^3,7 The key clinical distinction is that although this patient was bothered by intrusive side effects, he was not fixated on them like Mrs. C. His pharmacogenomic test results were used to identify a metabolic issue that was causing the side effects. This is in contrast with Mrs. C, for whom the pharmacogenomic information ruled out a metabolic issue as the primary problem and helped guide the next step in treatment.

Mrs. C’s case illustrates how pharmacogenomics and ACT complemented each other to create a desirable outcome. Pharmacogenomic testing originally was developed as a safety mechanism for medication choice and dosing, but clinical applications have grown as astute clinicians utilize it to help care for their patients.⁸ ACT can be a powerful tool for patients who have difficulties creating distance from their thoughts. Both pharmacogenomic testing and ACT are noninvasive interventions that can be implemented as part of a multi-faceted treatment approach.

Related Resources

• Hayes SC, Strosahl KD, Wilson KG. Acceptance and commitment therapy: The process and practice of mindful change. 2nd ed. New York, NY: The Guilford Press; 2011.
• Mrazek DA. Psychiatric pharmacogenomics. New York, NY: Oxford University Press; 2010.

Drug Brand Names

• Amitriptyline • Elavil
• Aripiprazole • Abilify
• Bupropion • Wellbutrin, Zyban
• Citalopram • Celexa
• Clomipramine • Anafranil
• Clozapine • Clozaril
• Desipramine • Norpramin
• Diazepam • Valium
• Doxepin • Adapin, Silenor
• Duloxetine • Cymbalta
• Escitalopram • Lexapro
• Fluoxetine • Prozac
• Fluvoxamine • Luvox
• Haloperidol • Haldol
• Imipramine • Tofranil
• Lithium • Eskalith, Lithobid
• Mirtazapine • Remeron
• Olanzapine • Zyprexa
• Nortriptyline • Pamelor
• Paroxetine • Paxil
• Perphenazine • Trilafon
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Sertraline • Zoloft
• Trazodone • Desyrel, Oleptro
• Venlafaxine • Effexor
• Ziprasidone • Geodon

Disclosure

The authors are employed by AssureRx Health, Inc., the provider of the pharmacogenomic testing used in this article.

CASE: Medication sensitivity

Mrs. C, age 48, is admitted to a tertiary care inpatient mood disorder unit for evaluation of severe depression characterized by depressed mood, anhedonia, and insomnia. Her initial Hamilton Rating Scale for Depression 17-Item (HRSD-17) score is 30, indicating severe depression. Her medications are fluoxetine, 10 mg/d, and diazepam, 0.5 mg/d.

Mrs. C describes a 10-month history of depression and extreme anxiety in the context of several psychosocial stressors. Her father recently died and she is having difficulty with the demands of administering her father’s estate. She is intensely obsessive and focused on nihilistic themes, her diagnosis, somatic themes, and medications side effects. Her husband confirms our observations. No history or current symptoms of typical compulsions (eg, washing hands or checking doors) are elicited. She has limited insight into her obsessive tendencies.

Mrs. C had no psychiatric history before her depressive and obsessive symptoms developed 10 months ago. However, in the past 10 months, she has been hospitalized in a psychiatric facility twice. She also received a series of 8 electroconvulsive therapy treatments, but reported minimal improvement of her depressive symptoms. Mrs. C had a few cognitive-behavioral therapy (CBT) sessions with a psychotherapist, but she said they didn’t help much.

Mrs. C has substantial difficulty adhering to medications, even at subtherapeutic doses. She states she is “extremely sensitive” to all medications. Mrs. C says she develops dizziness, increased anxiety, insomnia, nausea, and other vague reactions whenever she attempts to increase her psychotropics to therapeutic doses. She took sertraline, 10 mg/d, for 4 days, but discontinued it because of unspecified side effects. She then received escitalopram, 2.5 mg/d, for 10 days, but again stopped it because of vague side effects. She was taking paroxetine, 10 mg/d, for 2 days, but experienced vomiting and discontinued the drug. She tried venlafaxine at a low dose and also discontinued it because of vomiting. Mrs. C stayed on mirtazapine, 22.5 mg/d, for 3 months, but stopped it because of lack of efficacy and she was unwilling to increase the dose. Other unsuccessful trials include citalopram and doxepin. Mrs. C is hesitant to try another medication or increase to therapeutic doses any of the previous medications.

The authors’ observations

Before initiating another treatment, the treatment team considered Mrs. C’s pervasive medication intolerance. Her enzymatic activity may be genetically compromised, which could lead to high blood levels of medications and significant side effects when she takes very low doses. Individual variations in response to psychotropics are influenced by genetic factors.¹ Variants in the cytochrome P450 (CYP450) genes produce enzymes with increased activity, normal activity, reduced activity, or no activity, creating phenotypes of ultrarapid metabolizers, extensive metabolizers, intermediate metabolizers, and poor metabolizers, respectively. These genetic variations can affect blood levels of medications that employ these enzymes in their metabolic pathways.² Mrs. C could be a poor metabolizer of common CYP450 variant enzymes, which led to her exquisite sensitivity to psychotropics. We felt this was a reasonable hypothesis given her tumultuous 10-month course of psychiatric treatment and multiple failed medication trials.

An alternative hypothesis is that Mrs. C’s somatic obsessions about drug side effects were the primary clinical issue that led to her severe medication intolerance. Mrs. C spends hours questioning the inpatient staff about her diagnosis (eg, “Are you sure I don’t have bipolar disorder?”), medications (eg, “Are you sure this medication won’t make me sick?”), somatic themes (eg, “Are you sure I don’t have Meniere’s disease with all my dizziness?”), and nihilistic themes (eg, “What if I never get better?”). Mrs. C’s husband attested that she has spent hours researching her new medications on the Internet and reading the medication handouts from the pharmacy. She admits to mentally cycling through the DSM-IV-TR criteria for hours at a time to “figure out” if she has bipolar disorder (BD).

We initiated pharmacogenomic testing to help distinguish between these hypotheses. Mrs. C’s results are presented in Table 1. Genotype results were applied using an interpretive algorithm (Figure) in which 26 psychiatric medications were placed in categories of “use as directed” (green column), “use with caution” (yellow column), and “use with caution or more frequent monitoring” (red column). The algorithm incorporates the genetic information with the known pharmacologic profile for each of the medications in the panel. Highlights of Mrs. C’s interpretive report are shown in Table 2.

Table 1

Mrs. C’s genotype results

Figure

Genotype-phenotype integration into Mrs. C’s interpretive report

  Table 2

Mrs. C’s pharmacogenomic-based interpretive report

The authors’ observations

Mrs. C’s genotype might explain some sensitivity to medications metabolized by CYP2D6 (eg, venlafaxine, paroxetine, fluoxetine), but does not explain her acute sensitivity to all of the medications she has taken. For example, she is an extensive metabolizer for CYP2C19, which metabolizes escitalopram; therefore, it is unlikely escitalopram, 2.5 mg/d, would result in high blood levels and side effects.³ Regardless of the next step in treatment, we deemed her somatic obsessions to be the most important clinical issue. It seems unlikely that Mrs. C would adhere to any medication regimen until this underlying problem was addressed.

The focus of treatment shifted to Mrs. C’s obsessions about her medications and their side effects. Mrs. C was fixated on the content of her obsessions (eg, medications, side effects) rather than the process of her obsessional thinking. The goal was to help Mrs. C identify, label, and ultimately create distance from her obsessive thoughts associated with side effects. The treatment team employed an acceptance and commitment therapy (ACT) model of observing and defusing thoughts in the inpatient setting (Table 3).⁴ ACT is based on mindfulness and committed, values-based action.⁵ When patients are “fused” with their thoughts, they believe these thoughts are important and representative of reality. In Mrs. C’s case, she fused with the concept that her medications were making her sick and the idea that she may have BD. The treatment team thought these fused thoughts were the major problem that resulted in 10 months of protracted illness.

Conversely, in a “defused” state, patients can separate from their thoughts and observe them as disparate sounds, words, stories, or bits of language. The goal is to observe and allow the patient’s thoughts to simply be thoughts rather than trying to determine if they are “true.” Mrs. C was fused with the idea that her medications were making her ill, so this belief became the story underlying her obsessional thinking. Helping her disengage from this story became the focus of her treatment.

Table 3

6 core principles of acceptance and commitment therapy

Results guide pharmacotherapy

In addition to helping change the focus of Mrs. C’s psychotherapy, we used the pharmacogenomic results to guide medication treatment. We initially prescribed fluvoxamine, 50 mg/d, because her partially compromised CYP2D6 pathway probably would play only a minor role in metabolizing the drug.¹ Smoking induces CYP1A2, which is fluvoxamine’s primary metabolic pathway; however, Mrs. C does not smoke.⁶ When we saw Mrs. C in January 2009, the author (JGW) was unaware of any available genetic testing for CYP1A2, although now such testing is clinically available.

Mirtazapine is in the “use as directed” category for Mrs. C’s genotype (Table 2) and was the only medication she had adhered to at a therapeutic dose for more than a few days. However, she indicated that she would not adhere to this medication if we prescribed it again. Duloxetine also is in the “use as directed” category; however, given the entire clinical picture, we chose fluvoxamine because of Mrs. C’s obsessive symptomatology and because she had never reached a therapeutic dose of a selective serotonin reuptake inhibitor.

OUTCOME: Obsessions abate

Given Mrs. C’s lack of insight, we initiate a family approach to help broach the topic of obsessions as the focus of treatment. With her husband’s help, she participates in defusion techniques as an inpatient and follows up with an acceptance-based psychotherapist after discharge. After we share the pharmacogenomic information with Mrs. C, she agrees to try fluvoxamine, which is titrated to 100 mg/d. She maintains this dose at her 4-week follow-up visit. Notably, this was only the second time Mrs. C adhered to a medication trial since illness onset. Upon admission, Mrs. C had an HRSD-17 score of 30, indicating severe depression; at 4 weeks, her HRSD-17 score is 8, indicating mild depression.

The authors’ observations

In a complementary case, the author (JGW) consulted on a patient who was taking paroxetine and experiencing anorgasmia, weight gain, and loss of libido. Pharmacogenomic testing revealed that the patient was a poor metabolizer of CYP2D6. Paroxetine is substantially metabolized by CYP2D6; therefore, it was likely that high blood levels were contributing to the side effects.^3,7 The key clinical distinction is that although this patient was bothered by intrusive side effects, he was not fixated on them like Mrs. C. His pharmacogenomic test results were used to identify a metabolic issue that was causing the side effects. This is in contrast with Mrs. C, for whom the pharmacogenomic information ruled out a metabolic issue as the primary problem and helped guide the next step in treatment.

Mrs. C’s case illustrates how pharmacogenomics and ACT complemented each other to create a desirable outcome. Pharmacogenomic testing originally was developed as a safety mechanism for medication choice and dosing, but clinical applications have grown as astute clinicians utilize it to help care for their patients.⁸ ACT can be a powerful tool for patients who have difficulties creating distance from their thoughts. Both pharmacogenomic testing and ACT are noninvasive interventions that can be implemented as part of a multi-faceted treatment approach.

Related Resources

• Hayes SC, Strosahl KD, Wilson KG. Acceptance and commitment therapy: The process and practice of mindful change. 2nd ed. New York, NY: The Guilford Press; 2011.
• Mrazek DA. Psychiatric pharmacogenomics. New York, NY: Oxford University Press; 2010.

Drug Brand Names

• Amitriptyline • Elavil
• Aripiprazole • Abilify
• Bupropion • Wellbutrin, Zyban
• Citalopram • Celexa
• Clomipramine • Anafranil
• Clozapine • Clozaril
• Desipramine • Norpramin
• Diazepam • Valium
• Doxepin • Adapin, Silenor
• Duloxetine • Cymbalta
• Escitalopram • Lexapro
• Fluoxetine • Prozac
• Fluvoxamine • Luvox
• Haloperidol • Haldol
• Imipramine • Tofranil
• Lithium • Eskalith, Lithobid
• Mirtazapine • Remeron
• Olanzapine • Zyprexa
• Nortriptyline • Pamelor
• Paroxetine • Paxil
• Perphenazine • Trilafon
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Sertraline • Zoloft
• Trazodone • Desyrel, Oleptro
• Venlafaxine • Effexor
• Ziprasidone • Geodon

Disclosure

The authors are employed by AssureRx Health, Inc., the provider of the pharmacogenomic testing used in this article.

CASE: Medication sensitivity

Mrs. C, age 48, is admitted to a tertiary care inpatient mood disorder unit for evaluation of severe depression characterized by depressed mood, anhedonia, and insomnia. Her initial Hamilton Rating Scale for Depression 17-Item (HRSD-17) score is 30, indicating severe depression. Her medications are fluoxetine, 10 mg/d, and diazepam, 0.5 mg/d.

Mrs. C describes a 10-month history of depression and extreme anxiety in the context of several psychosocial stressors. Her father recently died and she is having difficulty with the demands of administering her father’s estate. She is intensely obsessive and focused on nihilistic themes, her diagnosis, somatic themes, and medications side effects. Her husband confirms our observations. No history or current symptoms of typical compulsions (eg, washing hands or checking doors) are elicited. She has limited insight into her obsessive tendencies.

Mrs. C had no psychiatric history before her depressive and obsessive symptoms developed 10 months ago. However, in the past 10 months, she has been hospitalized in a psychiatric facility twice. She also received a series of 8 electroconvulsive therapy treatments, but reported minimal improvement of her depressive symptoms. Mrs. C had a few cognitive-behavioral therapy (CBT) sessions with a psychotherapist, but she said they didn’t help much.

Mrs. C has substantial difficulty adhering to medications, even at subtherapeutic doses. She states she is “extremely sensitive” to all medications. Mrs. C says she develops dizziness, increased anxiety, insomnia, nausea, and other vague reactions whenever she attempts to increase her psychotropics to therapeutic doses. She took sertraline, 10 mg/d, for 4 days, but discontinued it because of unspecified side effects. She then received escitalopram, 2.5 mg/d, for 10 days, but again stopped it because of vague side effects. She was taking paroxetine, 10 mg/d, for 2 days, but experienced vomiting and discontinued the drug. She tried venlafaxine at a low dose and also discontinued it because of vomiting. Mrs. C stayed on mirtazapine, 22.5 mg/d, for 3 months, but stopped it because of lack of efficacy and she was unwilling to increase the dose. Other unsuccessful trials include citalopram and doxepin. Mrs. C is hesitant to try another medication or increase to therapeutic doses any of the previous medications.

The authors’ observations

Before initiating another treatment, the treatment team considered Mrs. C’s pervasive medication intolerance. Her enzymatic activity may be genetically compromised, which could lead to high blood levels of medications and significant side effects when she takes very low doses. Individual variations in response to psychotropics are influenced by genetic factors.¹ Variants in the cytochrome P450 (CYP450) genes produce enzymes with increased activity, normal activity, reduced activity, or no activity, creating phenotypes of ultrarapid metabolizers, extensive metabolizers, intermediate metabolizers, and poor metabolizers, respectively. These genetic variations can affect blood levels of medications that employ these enzymes in their metabolic pathways.² Mrs. C could be a poor metabolizer of common CYP450 variant enzymes, which led to her exquisite sensitivity to psychotropics. We felt this was a reasonable hypothesis given her tumultuous 10-month course of psychiatric treatment and multiple failed medication trials.

An alternative hypothesis is that Mrs. C’s somatic obsessions about drug side effects were the primary clinical issue that led to her severe medication intolerance. Mrs. C spends hours questioning the inpatient staff about her diagnosis (eg, “Are you sure I don’t have bipolar disorder?”), medications (eg, “Are you sure this medication won’t make me sick?”), somatic themes (eg, “Are you sure I don’t have Meniere’s disease with all my dizziness?”), and nihilistic themes (eg, “What if I never get better?”). Mrs. C’s husband attested that she has spent hours researching her new medications on the Internet and reading the medication handouts from the pharmacy. She admits to mentally cycling through the DSM-IV-TR criteria for hours at a time to “figure out” if she has bipolar disorder (BD).

We initiated pharmacogenomic testing to help distinguish between these hypotheses. Mrs. C’s results are presented in Table 1. Genotype results were applied using an interpretive algorithm (Figure) in which 26 psychiatric medications were placed in categories of “use as directed” (green column), “use with caution” (yellow column), and “use with caution or more frequent monitoring” (red column). The algorithm incorporates the genetic information with the known pharmacologic profile for each of the medications in the panel. Highlights of Mrs. C’s interpretive report are shown in Table 2.

Table 1

Mrs. C’s genotype results

Figure

Genotype-phenotype integration into Mrs. C’s interpretive report

  Table 2

Mrs. C’s pharmacogenomic-based interpretive report

The authors’ observations

Mrs. C’s genotype might explain some sensitivity to medications metabolized by CYP2D6 (eg, venlafaxine, paroxetine, fluoxetine), but does not explain her acute sensitivity to all of the medications she has taken. For example, she is an extensive metabolizer for CYP2C19, which metabolizes escitalopram; therefore, it is unlikely escitalopram, 2.5 mg/d, would result in high blood levels and side effects.³ Regardless of the next step in treatment, we deemed her somatic obsessions to be the most important clinical issue. It seems unlikely that Mrs. C would adhere to any medication regimen until this underlying problem was addressed.

The focus of treatment shifted to Mrs. C’s obsessions about her medications and their side effects. Mrs. C was fixated on the content of her obsessions (eg, medications, side effects) rather than the process of her obsessional thinking. The goal was to help Mrs. C identify, label, and ultimately create distance from her obsessive thoughts associated with side effects. The treatment team employed an acceptance and commitment therapy (ACT) model of observing and defusing thoughts in the inpatient setting (Table 3).⁴ ACT is based on mindfulness and committed, values-based action.⁵ When patients are “fused” with their thoughts, they believe these thoughts are important and representative of reality. In Mrs. C’s case, she fused with the concept that her medications were making her sick and the idea that she may have BD. The treatment team thought these fused thoughts were the major problem that resulted in 10 months of protracted illness.

Conversely, in a “defused” state, patients can separate from their thoughts and observe them as disparate sounds, words, stories, or bits of language. The goal is to observe and allow the patient’s thoughts to simply be thoughts rather than trying to determine if they are “true.” Mrs. C was fused with the idea that her medications were making her ill, so this belief became the story underlying her obsessional thinking. Helping her disengage from this story became the focus of her treatment.

Table 3

6 core principles of acceptance and commitment therapy

Results guide pharmacotherapy

In addition to helping change the focus of Mrs. C’s psychotherapy, we used the pharmacogenomic results to guide medication treatment. We initially prescribed fluvoxamine, 50 mg/d, because her partially compromised CYP2D6 pathway probably would play only a minor role in metabolizing the drug.¹ Smoking induces CYP1A2, which is fluvoxamine’s primary metabolic pathway; however, Mrs. C does not smoke.⁶ When we saw Mrs. C in January 2009, the author (JGW) was unaware of any available genetic testing for CYP1A2, although now such testing is clinically available.

Mirtazapine is in the “use as directed” category for Mrs. C’s genotype (Table 2) and was the only medication she had adhered to at a therapeutic dose for more than a few days. However, she indicated that she would not adhere to this medication if we prescribed it again. Duloxetine also is in the “use as directed” category; however, given the entire clinical picture, we chose fluvoxamine because of Mrs. C’s obsessive symptomatology and because she had never reached a therapeutic dose of a selective serotonin reuptake inhibitor.

OUTCOME: Obsessions abate

Given Mrs. C’s lack of insight, we initiate a family approach to help broach the topic of obsessions as the focus of treatment. With her husband’s help, she participates in defusion techniques as an inpatient and follows up with an acceptance-based psychotherapist after discharge. After we share the pharmacogenomic information with Mrs. C, she agrees to try fluvoxamine, which is titrated to 100 mg/d. She maintains this dose at her 4-week follow-up visit. Notably, this was only the second time Mrs. C adhered to a medication trial since illness onset. Upon admission, Mrs. C had an HRSD-17 score of 30, indicating severe depression; at 4 weeks, her HRSD-17 score is 8, indicating mild depression.

The authors’ observations

In a complementary case, the author (JGW) consulted on a patient who was taking paroxetine and experiencing anorgasmia, weight gain, and loss of libido. Pharmacogenomic testing revealed that the patient was a poor metabolizer of CYP2D6. Paroxetine is substantially metabolized by CYP2D6; therefore, it was likely that high blood levels were contributing to the side effects.^3,7 The key clinical distinction is that although this patient was bothered by intrusive side effects, he was not fixated on them like Mrs. C. His pharmacogenomic test results were used to identify a metabolic issue that was causing the side effects. This is in contrast with Mrs. C, for whom the pharmacogenomic information ruled out a metabolic issue as the primary problem and helped guide the next step in treatment.

Mrs. C’s case illustrates how pharmacogenomics and ACT complemented each other to create a desirable outcome. Pharmacogenomic testing originally was developed as a safety mechanism for medication choice and dosing, but clinical applications have grown as astute clinicians utilize it to help care for their patients.⁸ ACT can be a powerful tool for patients who have difficulties creating distance from their thoughts. Both pharmacogenomic testing and ACT are noninvasive interventions that can be implemented as part of a multi-faceted treatment approach.

Related Resources

• Hayes SC, Strosahl KD, Wilson KG. Acceptance and commitment therapy: The process and practice of mindful change. 2nd ed. New York, NY: The Guilford Press; 2011.
• Mrazek DA. Psychiatric pharmacogenomics. New York, NY: Oxford University Press; 2010.

Drug Brand Names

• Amitriptyline • Elavil
• Aripiprazole • Abilify
• Bupropion • Wellbutrin, Zyban
• Citalopram • Celexa
• Clomipramine • Anafranil
• Clozapine • Clozaril
• Desipramine • Norpramin
• Diazepam • Valium
• Doxepin • Adapin, Silenor
• Duloxetine • Cymbalta
• Escitalopram • Lexapro
• Fluoxetine • Prozac
• Fluvoxamine • Luvox
• Haloperidol • Haldol
• Imipramine • Tofranil
• Lithium • Eskalith, Lithobid
• Mirtazapine • Remeron
• Olanzapine • Zyprexa
• Nortriptyline • Pamelor
• Paroxetine • Paxil
• Perphenazine • Trilafon
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Sertraline • Zoloft
• Trazodone • Desyrel, Oleptro
• Venlafaxine • Effexor
• Ziprasidone • Geodon

Disclosure

The authors are employed by AssureRx Health, Inc., the provider of the pharmacogenomic testing used in this article.

A 64-year-old woman came into our emergency department (ED) complaining of constipation and worsening rectal pain. In an attempt to promote her overall health, the patient had recently begun experimenting with healthy alternatives to her regular diet. Three days before her visit, she had ceased having stools and was experiencing intermittent abdominal cramping. She self-administered 2 bisacodyl suppositories, 2 sodium biphosphate enemas, one 10-ounce bottle of magnesium citrate, and 15 senna-containing laxative tablets without improvement.

She sought care at an urgent care clinic where she received 2 additional enemas and a trial of manual disimpaction—without results. She was sent home to rest and asked to return the next morning for another trial of disimpaction. When the patient’s efforts to manually disimpact herself at home were unsuccessful, she contacted her primary care physician, who arranged a house call. When his own protracted disimpaction procedure was unsuccessful, he referred her to our ED.

On presentation, the patient had lower abdominal and rectal discomfort. Her vital signs were normal except for a temperature of 38.8° C. Her abdomen was soft and nontender. Inspection of her perianal area revealed erythema and excoriations. On digital rectal exam (which was poorly tolerated because of pain), we noted a moderate amount of soft, clay-like feces in the rectal vault, with overflow liquid stool expulsion.

Computed tomography (CT) imaging of the abdomen was obtained to rule out rectal injury or colonic perforation (FIGURE 1).

FIGURE 1
CT scan reveals a speckled intraluminal mass

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

Diagnosis: Fecal impaction caused by a proctophytobezoar

CT imaging revealed a proctophytobezoar. On follow-up questioning, the patient recalled consuming approximately 10 ounces of cooked quinoa, a nutritious, gluten-free, high-protein seed, just prior to the onset of her constipation.

Constipation disproportionately affects the elderly and the young.¹ Fecal impaction is a sequelae of constipation. Most commonly defined as hard, compacted feces in the rectum, fecal impaction can also include more proximal impactions due to fecal loading or retention.²

Causes of constipation and fecal impaction are similar and include low intake of dietary fiber, dehydration, immobility, alcohol ingestion, laxative abuse, medication adverse effects, depression, dementia, spinal cord dysfunction, diabetes, metabolic imbalances, and hypothyroidism.^2,3 Insufficient hydration with consumption of a high-fiber food, as in this case, or with a bulk-forming laxative such as psyllium seed can result in fecal impaction.³

The many causes of a bezoar
A bezoar is a mass of poorly digested material that forms within the gastrointestinal tract—usually in the stomach—and less commonly in the small or large intestine.⁴ Trichobezoars (hair), lactobezoars (milk curd), phytobezoars (plant fiber), medication bezoars, and lithobezoars (small stones, pebbles, or gravel) are named after their contents. In keeping with this naming tradition, a gummi bear bezoar⁵ has also been described. Fecal impaction due to phytobezoars primarily composed of seeds has been associated with prickly pears, watermelons, sunflowers, pumpkins, pomegranates,^6,7 and sesame seeds.⁴ Our patient’s experience adds quinoa seeds to this list.

Patients will complain of nausea and rectal urgency
Patients with fecal impaction may complain of nausea, rectal urgency, and rectalgia. A ball-valve effect of the fecal mass may allow paradoxical fecal incontinence and diarrhea.³ Digital rectal exam may demonstrate stool of any consistency, from rock hard pellets to soft clay-like stool.³ Absence of stool in the rectal vault does not rule out fecal impaction, and more proximal impactions may be revealed on plain abdominal radiography as bubbly, speckled masses of stool with associated signs of obstruction, such as colonic dilatation.

Fever, increased leukocyte count, and abdominal tenderness may indicate colonic perforation or ulceration. Signs of generalized peritonitis and free air on abdominal radiography warrant an immediate surgical consult.³

Complications from fecal impaction include bowel obstruction, sigmoid volvulus, and rectal prolapse.² Stercoral ulceration and perforation due to pressure necrosis from a hard, inspissated fecal mass is an uncommon but life-threatening complication requiring resection of the affected colonic segment.⁸

What to look for on the CT. When the diagnosis is unclear or signs of complications are present, an abdominal CT is indicated. Concerning CT findings include ulceration, bowel wall enhancement and thickening (FIGURE 2), discontinuity of the bowel wall, presence of fecal material either protruding through the colonic wall or lying free within the intra-abdominal cavity, and extraluminal air.⁸

FIGURE 2
CT scan shows bowel wall thickening

Treatment begins with a pharmacologic approach

By the time a patient with a fecal impaction gets to your office, it’s likely that he or she will have already tried over-the-counter laxatives, stool softeners, and perhaps an enema.

When such pharmacologic management has failed, you’ll need to perform a manual fragmentation and extraction of the fecal mass. Apply topical 2% lidocaine jelly for analgesia and lubrication, and then gently and progressively dilate the anal sphincter with one and then 2 fingers. A scissoring action will fragment the impaction.³

Once fragmentation and partial expulsion has been achieved, you may want to try a lubricating mineral oil enema, bisacodyl suppository, or rectal lavage. If the impaction extends beyond the reach of the fingers, sigmoidoscopic visualization and lavage are indicated.

Adding water-soluble contrast material (Gastrografin) in 20% to 50% solutions directed by fluoroscopy draws water into the lumen, thus lubricating the fecal mass^3,9 and helping it to pass spontaneously.

Our patient’s case resolved with a trip to the OR
Since conservative and comprehensive management to improve our patient’s condition failed, she was taken to the operating room for a proctosigmoidoscopic disimpaction. A beveled metal proctoscope was used to disimpact the distal-most 10 cm and then a rigid sigmoidoscope was used to clear the colon of quinoa-laden fecal material to a total distance of 18 cm. Bowel walls were ecchymotic, yet viable and without laceration. She made an uneventful recovery and was discharged on hospital Day 3.

CORRESPONDENCE George L. Higgins, III, MD, Maine Medical Center, Department of Emergency Medicine, 47 Bramhall Street, Portland, ME 04102; [email protected]