Drug Therapy

Immune thrombocytopenia (ITP), formerly known as idiopathic thrombocytopenic purpura, is an autoimmune disorder characterized by a low platelet count and increased risk of mucocutaneous bleeding. During the last decade its management has changed, with the advent of new medications and with increased awareness of treatment side effects. This article will focus on the pathophysiology, diagnosis, and management of ITP in adults.

A SLIGHT FEMALE PREDOMINANCE UNTIL AGE 65

The estimated age-adjusted prevalence of ITP in the United States is 9.5 to 23.6 cases per 100,000.¹ In a recent study in the United Kingdom, the incidence was 4.4 per 100,000 patient-years among women and 3.4 among men.² A slight female predominance was seen until age 65; thereafter, the incidence rates in men and women were about equal.

INCREASED PLATELET DESTRUCTION AND DECREASED PRODUCTION

ITP is a complex immune process in which cellular and humoral immunity are involved in the destruction of platelets³ as well as impaired platelet production. Several theories have emerged in the last decade to explain this autoimmune process.

Autoantibodies form against platelets

The triggering event for antibody initiation in ITP is unknown.³ Autoantibodies (mostly immunoglobulin G [IgG] but sometimes IgM and IgA) are produced against the platelet membrane glycoprotein GPIIb-IIIa. The antibody-coated platelets are rapidly cleared by the reticuloendothelial system in the spleen and liver, in a process mediated by Fc-receptor expression on macrophages and dendritic cells. Autoantibodies may also affect platelet production by inhibiting megakaryocyte maturation and inducing apoptosis.^4,5

Patients with ITP also have CD4+ T cells that are autoreactive to GPIIb-IIIa and that stimulate B-cell clones to produce antiplatelet antibodies. Although autoreactive T cells are present in healthy individuals, they appear to be activated in patients with ITP by exposure to fragments of GPIIb-IIIa rather than native GPIIb-IIIa proteins.⁶ Activated macrophages internalize antibody-coated platelets and degrade GPIIb-IIIa and other glycoproteins to form “cryptic” epitopes that are expressed on the macrophage surface as novel peptides that induce further proliferation of CD4+ T-cell clones. Epitope spread thereby sustains a continuous loop that amplifies the production of GPIIb-IIIa antibodies.⁷

Defective T-regulatory cells appear to be critical to the pathogenesis of ITP by breaking self-tolerance, allowing the autoimmune process to progress.⁸ This, together with several other immune mechanisms such as molecular mimicry, abnormal cytokine profile, and B-cell abnormalities, may lead to enhanced platelet clearance.⁹

In addition to destroying platelets, antibodies may impair platelet production.¹⁰ Good evidence for platelets being underproduced in patients with ITP is that treating with thrombopoietin agonists results in increased platelet counts.

A DIAGNOSIS OF EXCLUSION

ITP is defined as isolated thrombocytopenia with no clinically apparent associated conditions or other causes of thrombocytopenia.¹¹ No diagnostic criteria currently exist, and the diagnosis is established only after excluding other causes of thrombocytopenia.

A recent report¹² from an international working group established a platelet count threshold of less than 100 × 10⁹/L for diagnosing ITP, down from the previous threshold of 150 × 10⁹/L. The panel also recommended using the term “immune” rather than “idiopathic” thrombocytopenia, emphasizing the role of underlying immune mechanisms. The term “purpura” was removed, because many patients have no or minimal signs of bleeding at the time of diagnosis.¹²

The 2011 American Society of Hematology’s evidenced-based guidelines for the treatment of ITP present the most recent authoritative diagnostic and therapeutic recommendations.¹³

ITP is considered to be primary if it occurs in isolation, and secondary if it is associated with an underlying disorder. It is further classified according to its duration since diagnosis: newly diagnosed (< 3 months), persistent (3−12 months), and chronic (> 12 months).

In adults, ITP tends to be chronic, presenting with a more indolent course than in childhood, and unlike childhood ITP, infrequently following a viral infection.

Clinical features associated with ITP are related to thrombocytopenia: petechiae (pinpoint microvascular hemorrhages that do not blanch with pressure), purpura (appearing like large bruises), epistaxis (nosebleeds), menorrhagia, gum bleeding, and other types of mucocutaneous bleeding. Other common clinical features include fatigue, impaired quality of life, and treatment-related side effects (eg, infection).¹⁴

A low platelet count may be the sole initial manifestation. The patient’s history, physical examination, blood counts, and findings on blood smear are essential to rule out other diagnoses. Few diagnostic tests are useful in the initial evaluation (Table 1). Abnormalities in the blood count or blood smear may be further investigated with bone marrow biopsy but is not required if the patient has typical features of ITP, regardless of age.

Because there are no specific criteria for diagnosing ITP, other causes of thrombocytopenia must be excluded. The differential diagnosis can be further classified as ITP due to other underlying disease (ie, secondary ITP) vs nonautoimmune causes that are frequently encountered in clinical practice.

SECONDARY ITP

The differential diagnosis of thrombocytopenia due to known underlying immune disease includes the following:

Drug-induced ITP

Recurrent episodes of acute thrombocytopenia not explained by other causes should trigger consideration of drug-induced thrombocytopenia. ¹¹ Patients should be questioned about drug use, especially of sulfonamides, antiepileptics, and quinine. Thrombocytopenia usually occurs 5 to 7 days after beginning the inciting drug for the first time and more quickly when the drug is given intermittently. Heparin is the most common cause of drug-related thrombocytopenia among hospitalized patients; the mechanism is unique and involves formation of a heparin-PF4 immune complex.

Human immunodeficiency virus infection

Approximately 40% of patients with human immunodeficiency virus (HIV) infection develop thrombocytopenia at some time.¹⁵ HIV infection can initially manifest as isolated thrombocytopenia and is sometimes clinically indistinguishable from chronic ITP, making it an important consideration in a newly diagnosed case of thrombocytopenia.

The mechanism of thrombocytopenia in early HIV is similar to that in primary ITP: as the disease progresses, low platelet counts can result from ineffective hematopoiesis due to megakaryocyte infection and marrow infiltration.¹⁶

Hepatitis C virus infection

Hepatitis C virus (HCV) infection can also cause immune thrombocytopenia. A recent study demonstrated the potential of the HCV core envelope protein 1 to induce antiplatelet antibodies (to platelet surface integrin GPIIIa49-66) by molecular mimicry.¹⁷ Other causes of thrombocytopenia in HCV infection may be related to chronic liver disease, such as portal hypertension-related hypersplenism, as well as decreased thrombopoietin production.¹⁸ Antiviral treatment with pegylated interferon may also cause mild thrombocytopenia.¹⁹

Helicobacter pylori

The association between H pylori infection and ITP remains uncertain. Eradication of infection appears to completely correct ITP in some places where the prevalence of H pylori is high (eg, Italy and Japan) but not in the United States and Canada, where the prevalence is low.²⁰ The different response may be due not only to the differences in prevalence, but to different H pylori genotypes: most H pylori strains in Japan express CagA, whereas the frequency of CagA-positive strains is much lower in western countries.²⁰

In areas where eradication therapy may be useful, the presence of H pylori infection should be determined by either a urea breath test or stool antigen testing.

Lymphoproliferative disorders

Secondary forms of ITP can occur in association with chronic lymphocytic leukemia, non-Hodgkin lymphoma, and Hodgkin lymphoma. These diagnoses should especially be considered in patients presenting with thrombocytopenia accompanied by systemic illness. ITP occurs in at least 2% of patients with chronic lymphocytic leukemia and is usually difficult to distinguish from thrombocytopenia secondary to marrow infiltration or from fludarabine (Fludora) therapy.²¹

It is especially important to determine if a lymphoproliferative disorder is present because it changes the treatment of ITP. Treatment of ITP complicating chronic lymphocytic leukemia is challenging and includes corticosteroids and steroid-sparing agents such as cyclosporine (Gengraf, Neoral, Sandimmune), rituximab (Rituxan), and intravenous immunoglobulin.²²

Systemic lupus erythematosus and other autoimmune diseases

Thrombocytopenia is a frequent clinical manifestation of systemic lupus erythematosus, occurring in 7% to 30% of patients,²³ and is an independent risk factor for death.²⁴ Lupus should be suspected in patients with ITP who have multiorgan involvement and other clinical and laboratory abnormalities. A small percentage of patients with ITP (about 2%−5%) develop lupus after several years.²¹

Thrombocytopenia can also result from other autoimmune disorders such as antiphospholipid antibody syndrome²⁵ and autoimmune thyroid diseases as well as immunodeficient states such as IgA deficiency and common variable immunodeficiency with low IgG levels.

NONAUTOIMMUNE THROMBOCYTOPENIA

Thrombocytopenia can also be caused by a number of nonautoimmune conditions.

Pseudothrombocytopenia

Pseudothrombocytopenia can occur if ex-vivo agglutination of platelets is induced by antiplatelet antibodies to EDTA, a standard blood anticoagulant. Automated counters cannot differentiate the agglutinated platelet clumps from individual cells such as red cells. This can frequently be overcome by running the counts in a citrate or ACD reagent tube. A peripheral blood smear can demonstrate whether platelet clumps are present.

Thrombotic thrombocytopenic purpura

Thrombotic thrombocytopenic purpura presents with thrombocytopenia, purpura, and anemia. Associated clinical abnormalities (fever, neurologic symptoms, and renal failure) and the presence of fragmented red cells on blood smear help to distinguish it from ITP. Plasma exchange is the treatment of choice.

Gestational thrombocytopenia

Five percent of pregnant women develop mild thrombocytopenia (platelet counts typically > 70 × 10⁹/L) near the end of gestation.²⁶ It requires no treatment and resolves after delivery. The fetus’ platelet count remains unaffected.

Gestational thrombocytopenia should be differentiated from the severe thrombocytopenia of preeclampsia and HELLP syndrome (hemolysis, elevated liver enzymes, and low platelet count), which requires immediate attention.

Myelodysplastic syndrome

Myelodysplastic syndrome is common among elderly patients and should be considered in cases of unexplained cytopenia and abnormalities in the peripheral blood smear suggestive of dysplastic cytologic features. It can be diagnosed by bone marrow biopsy. Thrombocytopenia occurs in about 40% to 65% of cases of myelodysplastic syndrome.²⁷

MANAGE ITP TO KEEP PLATELET COUNT ABOVE 30 × 10⁹/L

ITP does not necessarily require treatment, and the initial challenge is to determine whether treatment or observation is indicated. Treatment is based on two major factors: the platelet count and degree of bleeding. The goals of management are to achieve a safe platelet count to prevent serious bleeding while minimizing treatment-related toxicity.⁷

Adults with platelet counts of less than 30 × 10⁹/L are usually treated. In multiple large cohort studies, patients with platelet counts above that level have been safely observed without treatment.^11,28

Table 2 outlines a comprehensive approach to therapy.

INITIAL TREATMENT: STEROIDS AND IMMUNOGLOBULINS

Oral corticosteroids are the initial agents of choice

Oral prednisone 1 mg/kg/day in tapering doses for 4 to 6 weeks is the most common initial regimen. Other regimens, such as high-dose dexamethasone (Decadron) (40 mg daily for 4 days per month) for several cycles, have been reported to be more effective²⁹ but have not been studied in head-to-head trials with oral prednisone.

Due to their effectiveness, low cost, and convenience of use, corticosteroids have been the backbone of initial treatment in ITP. However, in most patients the platelet count decreases once the dose is tapered or stopped; remission is sustained in only 10% to 30% of cases.³⁰ Continuation of corticosteroids is limited by long-term complications such as opportunistic infections, osteoporosis, and emotional lability.³¹

Intravenous immunoglobulin and anti-D immunoglobulin are alternatives

Intravenous immunoglobulin is recommended for patients who have not responded to corticosteroids and is often used in pregnancy. It is thought to act by blocking Fc receptors in the reticuloendothelial system. Intravenous immunoglobulin rapidly increases platelet counts in 65% to 80% of patients,³² but the effect is transient and the drug requires frequent administration. It is usually well tolerated, although about 5% of patients experience headache, chills, myalgias, arthralgias, and back pain. Rare, serious complications include thrombotic events, anaphylaxis (in IgA-deficient patients), and renal failure.

Anti-D immunoglobulin, a pooled IgG product, is derived from the plasma of Rh(D)-negative donors and can be given only to patients who are Rh(D)-positive. Response rates as high as 70% have been reported, with platelet effects lasting for more than 21 days.³³ Studies have shown better results at a high dose (75 μg/kg) than with the approved dose of 50 μg/kg.³⁴

Anti-D immunoglobulin can also be given intermittently whenever the platelet count falls below a specific level (ie, 30 × 10⁹/L). This allows some patients to avoid splenectomy and may even trigger long-term remission.³²

Common side effects of anti-D immunoglobulin include fever and chills; these can be prevented by premedication with acetaminophen or corticosteroids. Rare but fatal cases of intravascular hemolysis, renal failure, and disseminated intravascular coagulation have been reported, precluding its use for ITP in some countries, including those of the European Union.

Emergency treatment: Combination therapy

Evidence-based guidelines are limited for treating patients with active bleeding or who are at high risk of bleeding. For uncontrolled bleeding, a combination of first-line therapies is recommended, using prednisone and intravenous immunoglobulin.³⁵ Other options include high-dose methylprednisolone and platelet transfusions, alone or in combination with intravenous immunoglobulin.³⁶

SECOND-LINE TREATMENTS

Splenectomy produces complete remission in most patients

Patients who relapse and have a platelet count of less than 20 × 10⁹/L are traditionally considered for splenectomy. More than two-thirds of patients respond with no need for further treatment.³⁷

Although splenectomy has the highest rate of durable platelet response, the risks associated with surgery are an important concern. Even with a laparoscopic splenectomy, complications occur in 10% of patients and death in 0.2%. Long-term risks include the rare occurrence of sepsis with an estimated mortality rate of 0.73 per 1,000 patient-years, and possible increased risk of thrombosis.^38,39

Adherence to recommended vaccination protocols and early administration of antibiotics for systemic febrile illness reduce the risk of sepsis.⁴⁰ Patients are advised to receive immunization against encapsulated bacteria with pneumococcal, Haemophilus influenzae type b, and meningococcal vaccines. These vaccines should be given at least 2 weeks before elective splenectomy.⁴¹

Treatment of patients refractory to splenectomy is challenging and requires further immunosuppressive therapy, which is associated with an increased risk of infections and infection-related deaths.⁴²

Rituximab in addition to or possibly instead of splenectomy

Rituximab (Rituxan) is a chimeric anti-CD20 monoclonal antibody that targets B cells. Although initially approved for treatment of lymphomas, rituximab has gained popularity in treating ITP due to its safety profile and ability to deplete CD20+ B cells responsible for antiplatelet antibody production by Fc-mediated cell lysis.

In the largest systematic review of published reports of rituximab use in ITP (19 studies, 313 patients), Arnold and colleagues⁴³ reported an overall platelet response (defined as platelet count > 50 × 10⁹/L) in 62.5% (95% confidence interval [CI] 52.6%−72.5%) of patients. The median duration of response was 10.5 months (range 3–20), and median follow-up was 9.5 months (range 2–25). Nearly all patients had received corticosteroid treatment and half of them had undergone splenectomy.

Rituximab has also been investigated as an alternative to splenectomy. In a prospective, single-arm, phase 2 trial, 60 patients with chronic ITP (platelet counts < 30 × 10⁹/L) for whom one or more previous treatments had failed received rituximab infusions and were followed for up to 2 years. A good response (defined as a platelet count ≥ 50 × 10⁹/L, with at least a doubling from baseline) was obtained in 24 (40%) of 60 patients (95% CI 28%–52%) at 1 year and 33.3% at 2 years. The authors concluded that rituximab could be used as a presplenectomy therapeutic option, particularly in patients with chronic ITP who are at increased surgical risk or who are reluctant to undergo surgery.⁴⁴ Based on these results, rituximab may spare some patients from splenectomy, or at least delay it. However, it has never been tested in randomized controlled trials to establish its role as a splenectomy-sparing agent in ITP.

Side effects include infusion reactions, which are usually mild but in rare cases can be severe. Recently, progressive multifocal leukoencephalopathy has been recognized as a complication of rituximab treatment in patients with lymphoproliferative and autoimmune disorders.⁴⁵ Although this complication is rare in patients with ITP, careful monitoring is required until additional long-term safety data are available.

Thrombopoietic receptor agonists require continuous treatment

In the early 1990s, recombinant thrombopoietin was tested in clinical studies. These were halted when antibodies developed to recombinant thrombopoietin that cross-reacted with endogenous thrombopoietin, resulting in severe thrombocytopenia.⁴⁶

This led to the development of nonimmunogenic thrombopoietin receptor agonists that mimic the effect of thrombopoietin and stimulate the production of platelets. In 2008, the US Food and Drug Administration approved two drugs of this class for treating ITP: romiplostim (Nplate) and eltrombopag (Promacta). They are mainly used to treat patients with chronic ITP who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy.

Although well tolerated and effective in increasing platelet counts, these agents share common drawbacks. They do not modify the course of the disease, they are used only to sustain the platelet count, they require repeated administration, and they must be given for about 7 days to achieve an adequate platelet response, so they cannot be used in emergencies. Long-term adverse effects include bone marrow fibrosis and thrombosis.

Romiplostim is a synthetic peptide capable of binding to the thrombopoietin receptor c-Mpl. It has no sequence homology with endogenous thrombopoietin,⁴⁷ so does not induce cross-reacting antibodies. It has a half-life of 120 to 160 hours and is usually given subcutaneously 1 to 10 μg/kg weekly.

Phase III clinical trials have shown the effectiveness of romiplostim in attaining a durable platelet response (platelet count > 50 × 10⁹/L) in splenectomized and nonsplenectomized populations. It is well tolerated, and only two uncommon serious adverse effects have been reported: bone marrow reticulin formation and thromboembolism.⁴⁸

A long-term open-label extension study of 142 patients treated with romiplostim for up to 156 weeks showed that 124 (87%) achieved a platelet count of more than 50 × 10⁹/L at some point, and 84% of patients were able to reduce or discontinue concurrent medications for ITP.⁴⁹

Kuter et al,⁵⁰ in a randomized controlled trial, confirmed the efficacy of romiplostim in attaining durable increased platelet counts. Patients treated with romiplostim at a mean weekly dose of 3.9 μg/kg ± 2.1 μg/kg demonstrated a higher rate of platelet response, lower incidence of treatment failure, and improved quality of life vs patients treated with standard care.

Eltrombopag is a nonpeptide thrombopoietin agonist that binds to the transmembrane domain of the thrombopoietin receptor and stimulates the proliferation and differentiation of megakaryocytes in bone marrow. It is given orally in doses of 25 to 75 mg daily.

Eltrombopag has been shown to be effective in increasing platelet counts in chronic ITP.⁵¹ In a phase III trial conducted by Cheng and colleagues, 197 patients were randomized to eltrombopag or placebo.⁵² Patients treated with eltrombopag were eight times more likely to achieve platelet counts of more than 50 × 10⁹/L during the 6-month treatment period (odds ratio 8.2, 95% CI 4.32–15.38, P < .001) vs placebo. Patients treated with eltrombopag had fewer bleeding episodes and were more likely to reduce or discontinue the dose of concurrent ITP medications. The only significant side effect seen was a rise in aminotransferases (seen in 7% of eltrombopag recipients vs 2% with placebo).⁵²

Additional thrombopoietin agonists under investigation include ARK-501, totrombopag, and LGD-4665. MDX-33, a monoclonal antibody against the Fc-receptor, is also being studied; it acts by preventing opsonization of autoantibody-coated platelets.⁵³

THIRD-LINE TREATMENTS FOR REFRACTORY CASES

Patients with ITP that is resistant to standard therapies have an increased risk of death, disease, and treatment-related complications.^28,42

Combination chemotherapy

Immunosuppressants such as azathioprine (Imuran), cyclosporine (Neoral, Sandimmune), cyclophosphamide (Cytoxan), and mycophenolate (CellCept) were used in the past in single-agent regimens with some efficacy, but their use was limited due to drug-related toxicity and a low safety profile.³ However, there is increasing evidence for a role of combination chemotherapy to treat chronic refractory ITP to achieve greater efficacy and fewer adverse effects.⁵⁴

Arnold and colleagues⁵⁵ reported that combined azathioprine, mycophenolate, and cyclosporine achieved an overall response (platelet count > 30 × 10⁹/L and doubling of the baseline) in 14 (73.7%) of 19 patients with chronic refractory ITP, lasting a median of 24 months.

Hematopoietic stem cell transplantation

Hematopoietic stem cell transplantation has provided remission in a limited number of patients. However, it is associated with fatal toxicities such as graft-vs-host disease and septicemia, and therefore it is reserved for severe refractory ITP with bleeding complications unresponsive to other therapies.^56,57

THERAPY FOR SECONDARY ITP DEPENDS ON THE CAUSE

Treatments for secondary ITP vary depending on the cause of thrombocytopenia and are often more complex than therapy for primary disease. Optimal management involves treating the underlying condition (eg, chronic lymphocytic leukemia or systemic lupus erythematosus).

Drug-induced thrombocytopenia requires prompt recognition and withdrawal of the inciting agent.

Treating ITP due to HCV infection primarily involves antiviral agents to suppress viral replication. If treating ITP is required, then intravenous immunoglobulin is preferable to glucocorticoids because of the risk of increasing viral load with the latter.⁵⁸ Eltrombopag may effectively increase platelet counts, allowing patients to receive interferon therapy for HCV.⁵⁹ However, a recent study was halted due to increased incidence of portal vein thrombosis, raising concerns about the safety of eltrombopag for patients with chronic liver disease.⁶⁰

Secondary ITP due to HIV infection should always be treated first with antivirals targeting HIV unless thrombocytopenia-related bleeding complications warrant treatment. If treatment for ITP is necessary, it should include corticosteroids, intravenous immunoglobulin, or anti-D immunoglobulin as first-line therapy.

Eradication therapy for H pylori is recommended for patients who are positive for the organism based on urea breath testing, stool antigen testing, or endoscopic biopsies.

Immune thrombocytopenia (ITP), formerly known as idiopathic thrombocytopenic purpura, is an autoimmune disorder characterized by a low platelet count and increased risk of mucocutaneous bleeding. During the last decade its management has changed, with the advent of new medications and with increased awareness of treatment side effects. This article will focus on the pathophysiology, diagnosis, and management of ITP in adults.

A SLIGHT FEMALE PREDOMINANCE UNTIL AGE 65

The estimated age-adjusted prevalence of ITP in the United States is 9.5 to 23.6 cases per 100,000.¹ In a recent study in the United Kingdom, the incidence was 4.4 per 100,000 patient-years among women and 3.4 among men.² A slight female predominance was seen until age 65; thereafter, the incidence rates in men and women were about equal.

INCREASED PLATELET DESTRUCTION AND DECREASED PRODUCTION

ITP is a complex immune process in which cellular and humoral immunity are involved in the destruction of platelets³ as well as impaired platelet production. Several theories have emerged in the last decade to explain this autoimmune process.

Autoantibodies form against platelets

The triggering event for antibody initiation in ITP is unknown.³ Autoantibodies (mostly immunoglobulin G [IgG] but sometimes IgM and IgA) are produced against the platelet membrane glycoprotein GPIIb-IIIa. The antibody-coated platelets are rapidly cleared by the reticuloendothelial system in the spleen and liver, in a process mediated by Fc-receptor expression on macrophages and dendritic cells. Autoantibodies may also affect platelet production by inhibiting megakaryocyte maturation and inducing apoptosis.^4,5

Patients with ITP also have CD4+ T cells that are autoreactive to GPIIb-IIIa and that stimulate B-cell clones to produce antiplatelet antibodies. Although autoreactive T cells are present in healthy individuals, they appear to be activated in patients with ITP by exposure to fragments of GPIIb-IIIa rather than native GPIIb-IIIa proteins.⁶ Activated macrophages internalize antibody-coated platelets and degrade GPIIb-IIIa and other glycoproteins to form “cryptic” epitopes that are expressed on the macrophage surface as novel peptides that induce further proliferation of CD4+ T-cell clones. Epitope spread thereby sustains a continuous loop that amplifies the production of GPIIb-IIIa antibodies.⁷

Defective T-regulatory cells appear to be critical to the pathogenesis of ITP by breaking self-tolerance, allowing the autoimmune process to progress.⁸ This, together with several other immune mechanisms such as molecular mimicry, abnormal cytokine profile, and B-cell abnormalities, may lead to enhanced platelet clearance.⁹

In addition to destroying platelets, antibodies may impair platelet production.¹⁰ Good evidence for platelets being underproduced in patients with ITP is that treating with thrombopoietin agonists results in increased platelet counts.

A DIAGNOSIS OF EXCLUSION

ITP is defined as isolated thrombocytopenia with no clinically apparent associated conditions or other causes of thrombocytopenia.¹¹ No diagnostic criteria currently exist, and the diagnosis is established only after excluding other causes of thrombocytopenia.

A recent report¹² from an international working group established a platelet count threshold of less than 100 × 10⁹/L for diagnosing ITP, down from the previous threshold of 150 × 10⁹/L. The panel also recommended using the term “immune” rather than “idiopathic” thrombocytopenia, emphasizing the role of underlying immune mechanisms. The term “purpura” was removed, because many patients have no or minimal signs of bleeding at the time of diagnosis.¹²

The 2011 American Society of Hematology’s evidenced-based guidelines for the treatment of ITP present the most recent authoritative diagnostic and therapeutic recommendations.¹³

ITP is considered to be primary if it occurs in isolation, and secondary if it is associated with an underlying disorder. It is further classified according to its duration since diagnosis: newly diagnosed (< 3 months), persistent (3−12 months), and chronic (> 12 months).

In adults, ITP tends to be chronic, presenting with a more indolent course than in childhood, and unlike childhood ITP, infrequently following a viral infection.

Clinical features associated with ITP are related to thrombocytopenia: petechiae (pinpoint microvascular hemorrhages that do not blanch with pressure), purpura (appearing like large bruises), epistaxis (nosebleeds), menorrhagia, gum bleeding, and other types of mucocutaneous bleeding. Other common clinical features include fatigue, impaired quality of life, and treatment-related side effects (eg, infection).¹⁴

A low platelet count may be the sole initial manifestation. The patient’s history, physical examination, blood counts, and findings on blood smear are essential to rule out other diagnoses. Few diagnostic tests are useful in the initial evaluation (Table 1). Abnormalities in the blood count or blood smear may be further investigated with bone marrow biopsy but is not required if the patient has typical features of ITP, regardless of age.

Because there are no specific criteria for diagnosing ITP, other causes of thrombocytopenia must be excluded. The differential diagnosis can be further classified as ITP due to other underlying disease (ie, secondary ITP) vs nonautoimmune causes that are frequently encountered in clinical practice.

SECONDARY ITP

The differential diagnosis of thrombocytopenia due to known underlying immune disease includes the following:

Drug-induced ITP

Recurrent episodes of acute thrombocytopenia not explained by other causes should trigger consideration of drug-induced thrombocytopenia. ¹¹ Patients should be questioned about drug use, especially of sulfonamides, antiepileptics, and quinine. Thrombocytopenia usually occurs 5 to 7 days after beginning the inciting drug for the first time and more quickly when the drug is given intermittently. Heparin is the most common cause of drug-related thrombocytopenia among hospitalized patients; the mechanism is unique and involves formation of a heparin-PF4 immune complex.

Human immunodeficiency virus infection

Approximately 40% of patients with human immunodeficiency virus (HIV) infection develop thrombocytopenia at some time.¹⁵ HIV infection can initially manifest as isolated thrombocytopenia and is sometimes clinically indistinguishable from chronic ITP, making it an important consideration in a newly diagnosed case of thrombocytopenia.

The mechanism of thrombocytopenia in early HIV is similar to that in primary ITP: as the disease progresses, low platelet counts can result from ineffective hematopoiesis due to megakaryocyte infection and marrow infiltration.¹⁶

Hepatitis C virus infection

Hepatitis C virus (HCV) infection can also cause immune thrombocytopenia. A recent study demonstrated the potential of the HCV core envelope protein 1 to induce antiplatelet antibodies (to platelet surface integrin GPIIIa49-66) by molecular mimicry.¹⁷ Other causes of thrombocytopenia in HCV infection may be related to chronic liver disease, such as portal hypertension-related hypersplenism, as well as decreased thrombopoietin production.¹⁸ Antiviral treatment with pegylated interferon may also cause mild thrombocytopenia.¹⁹

Helicobacter pylori

The association between H pylori infection and ITP remains uncertain. Eradication of infection appears to completely correct ITP in some places where the prevalence of H pylori is high (eg, Italy and Japan) but not in the United States and Canada, where the prevalence is low.²⁰ The different response may be due not only to the differences in prevalence, but to different H pylori genotypes: most H pylori strains in Japan express CagA, whereas the frequency of CagA-positive strains is much lower in western countries.²⁰

In areas where eradication therapy may be useful, the presence of H pylori infection should be determined by either a urea breath test or stool antigen testing.

Lymphoproliferative disorders

Secondary forms of ITP can occur in association with chronic lymphocytic leukemia, non-Hodgkin lymphoma, and Hodgkin lymphoma. These diagnoses should especially be considered in patients presenting with thrombocytopenia accompanied by systemic illness. ITP occurs in at least 2% of patients with chronic lymphocytic leukemia and is usually difficult to distinguish from thrombocytopenia secondary to marrow infiltration or from fludarabine (Fludora) therapy.²¹

It is especially important to determine if a lymphoproliferative disorder is present because it changes the treatment of ITP. Treatment of ITP complicating chronic lymphocytic leukemia is challenging and includes corticosteroids and steroid-sparing agents such as cyclosporine (Gengraf, Neoral, Sandimmune), rituximab (Rituxan), and intravenous immunoglobulin.²²

Systemic lupus erythematosus and other autoimmune diseases

Thrombocytopenia is a frequent clinical manifestation of systemic lupus erythematosus, occurring in 7% to 30% of patients,²³ and is an independent risk factor for death.²⁴ Lupus should be suspected in patients with ITP who have multiorgan involvement and other clinical and laboratory abnormalities. A small percentage of patients with ITP (about 2%−5%) develop lupus after several years.²¹

Thrombocytopenia can also result from other autoimmune disorders such as antiphospholipid antibody syndrome²⁵ and autoimmune thyroid diseases as well as immunodeficient states such as IgA deficiency and common variable immunodeficiency with low IgG levels.

NONAUTOIMMUNE THROMBOCYTOPENIA

Thrombocytopenia can also be caused by a number of nonautoimmune conditions.

Pseudothrombocytopenia

Pseudothrombocytopenia can occur if ex-vivo agglutination of platelets is induced by antiplatelet antibodies to EDTA, a standard blood anticoagulant. Automated counters cannot differentiate the agglutinated platelet clumps from individual cells such as red cells. This can frequently be overcome by running the counts in a citrate or ACD reagent tube. A peripheral blood smear can demonstrate whether platelet clumps are present.

Thrombotic thrombocytopenic purpura

Thrombotic thrombocytopenic purpura presents with thrombocytopenia, purpura, and anemia. Associated clinical abnormalities (fever, neurologic symptoms, and renal failure) and the presence of fragmented red cells on blood smear help to distinguish it from ITP. Plasma exchange is the treatment of choice.

Gestational thrombocytopenia

Five percent of pregnant women develop mild thrombocytopenia (platelet counts typically > 70 × 10⁹/L) near the end of gestation.²⁶ It requires no treatment and resolves after delivery. The fetus’ platelet count remains unaffected.

Gestational thrombocytopenia should be differentiated from the severe thrombocytopenia of preeclampsia and HELLP syndrome (hemolysis, elevated liver enzymes, and low platelet count), which requires immediate attention.

Myelodysplastic syndrome

Myelodysplastic syndrome is common among elderly patients and should be considered in cases of unexplained cytopenia and abnormalities in the peripheral blood smear suggestive of dysplastic cytologic features. It can be diagnosed by bone marrow biopsy. Thrombocytopenia occurs in about 40% to 65% of cases of myelodysplastic syndrome.²⁷

MANAGE ITP TO KEEP PLATELET COUNT ABOVE 30 × 10⁹/L

ITP does not necessarily require treatment, and the initial challenge is to determine whether treatment or observation is indicated. Treatment is based on two major factors: the platelet count and degree of bleeding. The goals of management are to achieve a safe platelet count to prevent serious bleeding while minimizing treatment-related toxicity.⁷

Adults with platelet counts of less than 30 × 10⁹/L are usually treated. In multiple large cohort studies, patients with platelet counts above that level have been safely observed without treatment.^11,28

Table 2 outlines a comprehensive approach to therapy.

INITIAL TREATMENT: STEROIDS AND IMMUNOGLOBULINS

Oral corticosteroids are the initial agents of choice

Oral prednisone 1 mg/kg/day in tapering doses for 4 to 6 weeks is the most common initial regimen. Other regimens, such as high-dose dexamethasone (Decadron) (40 mg daily for 4 days per month) for several cycles, have been reported to be more effective²⁹ but have not been studied in head-to-head trials with oral prednisone.

Due to their effectiveness, low cost, and convenience of use, corticosteroids have been the backbone of initial treatment in ITP. However, in most patients the platelet count decreases once the dose is tapered or stopped; remission is sustained in only 10% to 30% of cases.³⁰ Continuation of corticosteroids is limited by long-term complications such as opportunistic infections, osteoporosis, and emotional lability.³¹

Intravenous immunoglobulin and anti-D immunoglobulin are alternatives

Intravenous immunoglobulin is recommended for patients who have not responded to corticosteroids and is often used in pregnancy. It is thought to act by blocking Fc receptors in the reticuloendothelial system. Intravenous immunoglobulin rapidly increases platelet counts in 65% to 80% of patients,³² but the effect is transient and the drug requires frequent administration. It is usually well tolerated, although about 5% of patients experience headache, chills, myalgias, arthralgias, and back pain. Rare, serious complications include thrombotic events, anaphylaxis (in IgA-deficient patients), and renal failure.

Anti-D immunoglobulin, a pooled IgG product, is derived from the plasma of Rh(D)-negative donors and can be given only to patients who are Rh(D)-positive. Response rates as high as 70% have been reported, with platelet effects lasting for more than 21 days.³³ Studies have shown better results at a high dose (75 μg/kg) than with the approved dose of 50 μg/kg.³⁴

Anti-D immunoglobulin can also be given intermittently whenever the platelet count falls below a specific level (ie, 30 × 10⁹/L). This allows some patients to avoid splenectomy and may even trigger long-term remission.³²

Common side effects of anti-D immunoglobulin include fever and chills; these can be prevented by premedication with acetaminophen or corticosteroids. Rare but fatal cases of intravascular hemolysis, renal failure, and disseminated intravascular coagulation have been reported, precluding its use for ITP in some countries, including those of the European Union.

Emergency treatment: Combination therapy

Evidence-based guidelines are limited for treating patients with active bleeding or who are at high risk of bleeding. For uncontrolled bleeding, a combination of first-line therapies is recommended, using prednisone and intravenous immunoglobulin.³⁵ Other options include high-dose methylprednisolone and platelet transfusions, alone or in combination with intravenous immunoglobulin.³⁶

SECOND-LINE TREATMENTS

Splenectomy produces complete remission in most patients

Patients who relapse and have a platelet count of less than 20 × 10⁹/L are traditionally considered for splenectomy. More than two-thirds of patients respond with no need for further treatment.³⁷

Although splenectomy has the highest rate of durable platelet response, the risks associated with surgery are an important concern. Even with a laparoscopic splenectomy, complications occur in 10% of patients and death in 0.2%. Long-term risks include the rare occurrence of sepsis with an estimated mortality rate of 0.73 per 1,000 patient-years, and possible increased risk of thrombosis.^38,39

Adherence to recommended vaccination protocols and early administration of antibiotics for systemic febrile illness reduce the risk of sepsis.⁴⁰ Patients are advised to receive immunization against encapsulated bacteria with pneumococcal, Haemophilus influenzae type b, and meningococcal vaccines. These vaccines should be given at least 2 weeks before elective splenectomy.⁴¹

Treatment of patients refractory to splenectomy is challenging and requires further immunosuppressive therapy, which is associated with an increased risk of infections and infection-related deaths.⁴²

Rituximab in addition to or possibly instead of splenectomy

Rituximab (Rituxan) is a chimeric anti-CD20 monoclonal antibody that targets B cells. Although initially approved for treatment of lymphomas, rituximab has gained popularity in treating ITP due to its safety profile and ability to deplete CD20+ B cells responsible for antiplatelet antibody production by Fc-mediated cell lysis.

In the largest systematic review of published reports of rituximab use in ITP (19 studies, 313 patients), Arnold and colleagues⁴³ reported an overall platelet response (defined as platelet count > 50 × 10⁹/L) in 62.5% (95% confidence interval [CI] 52.6%−72.5%) of patients. The median duration of response was 10.5 months (range 3–20), and median follow-up was 9.5 months (range 2–25). Nearly all patients had received corticosteroid treatment and half of them had undergone splenectomy.

Rituximab has also been investigated as an alternative to splenectomy. In a prospective, single-arm, phase 2 trial, 60 patients with chronic ITP (platelet counts < 30 × 10⁹/L) for whom one or more previous treatments had failed received rituximab infusions and were followed for up to 2 years. A good response (defined as a platelet count ≥ 50 × 10⁹/L, with at least a doubling from baseline) was obtained in 24 (40%) of 60 patients (95% CI 28%–52%) at 1 year and 33.3% at 2 years. The authors concluded that rituximab could be used as a presplenectomy therapeutic option, particularly in patients with chronic ITP who are at increased surgical risk or who are reluctant to undergo surgery.⁴⁴ Based on these results, rituximab may spare some patients from splenectomy, or at least delay it. However, it has never been tested in randomized controlled trials to establish its role as a splenectomy-sparing agent in ITP.

Side effects include infusion reactions, which are usually mild but in rare cases can be severe. Recently, progressive multifocal leukoencephalopathy has been recognized as a complication of rituximab treatment in patients with lymphoproliferative and autoimmune disorders.⁴⁵ Although this complication is rare in patients with ITP, careful monitoring is required until additional long-term safety data are available.

Thrombopoietic receptor agonists require continuous treatment

In the early 1990s, recombinant thrombopoietin was tested in clinical studies. These were halted when antibodies developed to recombinant thrombopoietin that cross-reacted with endogenous thrombopoietin, resulting in severe thrombocytopenia.⁴⁶

This led to the development of nonimmunogenic thrombopoietin receptor agonists that mimic the effect of thrombopoietin and stimulate the production of platelets. In 2008, the US Food and Drug Administration approved two drugs of this class for treating ITP: romiplostim (Nplate) and eltrombopag (Promacta). They are mainly used to treat patients with chronic ITP who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy.

Although well tolerated and effective in increasing platelet counts, these agents share common drawbacks. They do not modify the course of the disease, they are used only to sustain the platelet count, they require repeated administration, and they must be given for about 7 days to achieve an adequate platelet response, so they cannot be used in emergencies. Long-term adverse effects include bone marrow fibrosis and thrombosis.

Romiplostim is a synthetic peptide capable of binding to the thrombopoietin receptor c-Mpl. It has no sequence homology with endogenous thrombopoietin,⁴⁷ so does not induce cross-reacting antibodies. It has a half-life of 120 to 160 hours and is usually given subcutaneously 1 to 10 μg/kg weekly.

Phase III clinical trials have shown the effectiveness of romiplostim in attaining a durable platelet response (platelet count > 50 × 10⁹/L) in splenectomized and nonsplenectomized populations. It is well tolerated, and only two uncommon serious adverse effects have been reported: bone marrow reticulin formation and thromboembolism.⁴⁸

A long-term open-label extension study of 142 patients treated with romiplostim for up to 156 weeks showed that 124 (87%) achieved a platelet count of more than 50 × 10⁹/L at some point, and 84% of patients were able to reduce or discontinue concurrent medications for ITP.⁴⁹

Kuter et al,⁵⁰ in a randomized controlled trial, confirmed the efficacy of romiplostim in attaining durable increased platelet counts. Patients treated with romiplostim at a mean weekly dose of 3.9 μg/kg ± 2.1 μg/kg demonstrated a higher rate of platelet response, lower incidence of treatment failure, and improved quality of life vs patients treated with standard care.

Eltrombopag is a nonpeptide thrombopoietin agonist that binds to the transmembrane domain of the thrombopoietin receptor and stimulates the proliferation and differentiation of megakaryocytes in bone marrow. It is given orally in doses of 25 to 75 mg daily.

Eltrombopag has been shown to be effective in increasing platelet counts in chronic ITP.⁵¹ In a phase III trial conducted by Cheng and colleagues, 197 patients were randomized to eltrombopag or placebo.⁵² Patients treated with eltrombopag were eight times more likely to achieve platelet counts of more than 50 × 10⁹/L during the 6-month treatment period (odds ratio 8.2, 95% CI 4.32–15.38, P < .001) vs placebo. Patients treated with eltrombopag had fewer bleeding episodes and were more likely to reduce or discontinue the dose of concurrent ITP medications. The only significant side effect seen was a rise in aminotransferases (seen in 7% of eltrombopag recipients vs 2% with placebo).⁵²

Additional thrombopoietin agonists under investigation include ARK-501, totrombopag, and LGD-4665. MDX-33, a monoclonal antibody against the Fc-receptor, is also being studied; it acts by preventing opsonization of autoantibody-coated platelets.⁵³

THIRD-LINE TREATMENTS FOR REFRACTORY CASES

Patients with ITP that is resistant to standard therapies have an increased risk of death, disease, and treatment-related complications.^28,42

Combination chemotherapy

Immunosuppressants such as azathioprine (Imuran), cyclosporine (Neoral, Sandimmune), cyclophosphamide (Cytoxan), and mycophenolate (CellCept) were used in the past in single-agent regimens with some efficacy, but their use was limited due to drug-related toxicity and a low safety profile.³ However, there is increasing evidence for a role of combination chemotherapy to treat chronic refractory ITP to achieve greater efficacy and fewer adverse effects.⁵⁴

Arnold and colleagues⁵⁵ reported that combined azathioprine, mycophenolate, and cyclosporine achieved an overall response (platelet count > 30 × 10⁹/L and doubling of the baseline) in 14 (73.7%) of 19 patients with chronic refractory ITP, lasting a median of 24 months.

Hematopoietic stem cell transplantation

Hematopoietic stem cell transplantation has provided remission in a limited number of patients. However, it is associated with fatal toxicities such as graft-vs-host disease and septicemia, and therefore it is reserved for severe refractory ITP with bleeding complications unresponsive to other therapies.^56,57

THERAPY FOR SECONDARY ITP DEPENDS ON THE CAUSE

Treatments for secondary ITP vary depending on the cause of thrombocytopenia and are often more complex than therapy for primary disease. Optimal management involves treating the underlying condition (eg, chronic lymphocytic leukemia or systemic lupus erythematosus).

Drug-induced thrombocytopenia requires prompt recognition and withdrawal of the inciting agent.

Treating ITP due to HCV infection primarily involves antiviral agents to suppress viral replication. If treating ITP is required, then intravenous immunoglobulin is preferable to glucocorticoids because of the risk of increasing viral load with the latter.⁵⁸ Eltrombopag may effectively increase platelet counts, allowing patients to receive interferon therapy for HCV.⁵⁹ However, a recent study was halted due to increased incidence of portal vein thrombosis, raising concerns about the safety of eltrombopag for patients with chronic liver disease.⁶⁰

Secondary ITP due to HIV infection should always be treated first with antivirals targeting HIV unless thrombocytopenia-related bleeding complications warrant treatment. If treatment for ITP is necessary, it should include corticosteroids, intravenous immunoglobulin, or anti-D immunoglobulin as first-line therapy.

Eradication therapy for H pylori is recommended for patients who are positive for the organism based on urea breath testing, stool antigen testing, or endoscopic biopsies.

Immune thrombocytopenia (ITP), formerly known as idiopathic thrombocytopenic purpura, is an autoimmune disorder characterized by a low platelet count and increased risk of mucocutaneous bleeding. During the last decade its management has changed, with the advent of new medications and with increased awareness of treatment side effects. This article will focus on the pathophysiology, diagnosis, and management of ITP in adults.

A SLIGHT FEMALE PREDOMINANCE UNTIL AGE 65

The estimated age-adjusted prevalence of ITP in the United States is 9.5 to 23.6 cases per 100,000.¹ In a recent study in the United Kingdom, the incidence was 4.4 per 100,000 patient-years among women and 3.4 among men.² A slight female predominance was seen until age 65; thereafter, the incidence rates in men and women were about equal.

INCREASED PLATELET DESTRUCTION AND DECREASED PRODUCTION

ITP is a complex immune process in which cellular and humoral immunity are involved in the destruction of platelets³ as well as impaired platelet production. Several theories have emerged in the last decade to explain this autoimmune process.

Autoantibodies form against platelets

The triggering event for antibody initiation in ITP is unknown.³ Autoantibodies (mostly immunoglobulin G [IgG] but sometimes IgM and IgA) are produced against the platelet membrane glycoprotein GPIIb-IIIa. The antibody-coated platelets are rapidly cleared by the reticuloendothelial system in the spleen and liver, in a process mediated by Fc-receptor expression on macrophages and dendritic cells. Autoantibodies may also affect platelet production by inhibiting megakaryocyte maturation and inducing apoptosis.^4,5

Patients with ITP also have CD4+ T cells that are autoreactive to GPIIb-IIIa and that stimulate B-cell clones to produce antiplatelet antibodies. Although autoreactive T cells are present in healthy individuals, they appear to be activated in patients with ITP by exposure to fragments of GPIIb-IIIa rather than native GPIIb-IIIa proteins.⁶ Activated macrophages internalize antibody-coated platelets and degrade GPIIb-IIIa and other glycoproteins to form “cryptic” epitopes that are expressed on the macrophage surface as novel peptides that induce further proliferation of CD4+ T-cell clones. Epitope spread thereby sustains a continuous loop that amplifies the production of GPIIb-IIIa antibodies.⁷

Defective T-regulatory cells appear to be critical to the pathogenesis of ITP by breaking self-tolerance, allowing the autoimmune process to progress.⁸ This, together with several other immune mechanisms such as molecular mimicry, abnormal cytokine profile, and B-cell abnormalities, may lead to enhanced platelet clearance.⁹

In addition to destroying platelets, antibodies may impair platelet production.¹⁰ Good evidence for platelets being underproduced in patients with ITP is that treating with thrombopoietin agonists results in increased platelet counts.

A DIAGNOSIS OF EXCLUSION

ITP is defined as isolated thrombocytopenia with no clinically apparent associated conditions or other causes of thrombocytopenia.¹¹ No diagnostic criteria currently exist, and the diagnosis is established only after excluding other causes of thrombocytopenia.

A recent report¹² from an international working group established a platelet count threshold of less than 100 × 10⁹/L for diagnosing ITP, down from the previous threshold of 150 × 10⁹/L. The panel also recommended using the term “immune” rather than “idiopathic” thrombocytopenia, emphasizing the role of underlying immune mechanisms. The term “purpura” was removed, because many patients have no or minimal signs of bleeding at the time of diagnosis.¹²

The 2011 American Society of Hematology’s evidenced-based guidelines for the treatment of ITP present the most recent authoritative diagnostic and therapeutic recommendations.¹³

ITP is considered to be primary if it occurs in isolation, and secondary if it is associated with an underlying disorder. It is further classified according to its duration since diagnosis: newly diagnosed (< 3 months), persistent (3−12 months), and chronic (> 12 months).

In adults, ITP tends to be chronic, presenting with a more indolent course than in childhood, and unlike childhood ITP, infrequently following a viral infection.

Clinical features associated with ITP are related to thrombocytopenia: petechiae (pinpoint microvascular hemorrhages that do not blanch with pressure), purpura (appearing like large bruises), epistaxis (nosebleeds), menorrhagia, gum bleeding, and other types of mucocutaneous bleeding. Other common clinical features include fatigue, impaired quality of life, and treatment-related side effects (eg, infection).¹⁴

A low platelet count may be the sole initial manifestation. The patient’s history, physical examination, blood counts, and findings on blood smear are essential to rule out other diagnoses. Few diagnostic tests are useful in the initial evaluation (Table 1). Abnormalities in the blood count or blood smear may be further investigated with bone marrow biopsy but is not required if the patient has typical features of ITP, regardless of age.

Because there are no specific criteria for diagnosing ITP, other causes of thrombocytopenia must be excluded. The differential diagnosis can be further classified as ITP due to other underlying disease (ie, secondary ITP) vs nonautoimmune causes that are frequently encountered in clinical practice.

SECONDARY ITP

The differential diagnosis of thrombocytopenia due to known underlying immune disease includes the following:

Drug-induced ITP

Recurrent episodes of acute thrombocytopenia not explained by other causes should trigger consideration of drug-induced thrombocytopenia. ¹¹ Patients should be questioned about drug use, especially of sulfonamides, antiepileptics, and quinine. Thrombocytopenia usually occurs 5 to 7 days after beginning the inciting drug for the first time and more quickly when the drug is given intermittently. Heparin is the most common cause of drug-related thrombocytopenia among hospitalized patients; the mechanism is unique and involves formation of a heparin-PF4 immune complex.

Human immunodeficiency virus infection

Approximately 40% of patients with human immunodeficiency virus (HIV) infection develop thrombocytopenia at some time.¹⁵ HIV infection can initially manifest as isolated thrombocytopenia and is sometimes clinically indistinguishable from chronic ITP, making it an important consideration in a newly diagnosed case of thrombocytopenia.

The mechanism of thrombocytopenia in early HIV is similar to that in primary ITP: as the disease progresses, low platelet counts can result from ineffective hematopoiesis due to megakaryocyte infection and marrow infiltration.¹⁶

Hepatitis C virus infection

Hepatitis C virus (HCV) infection can also cause immune thrombocytopenia. A recent study demonstrated the potential of the HCV core envelope protein 1 to induce antiplatelet antibodies (to platelet surface integrin GPIIIa49-66) by molecular mimicry.¹⁷ Other causes of thrombocytopenia in HCV infection may be related to chronic liver disease, such as portal hypertension-related hypersplenism, as well as decreased thrombopoietin production.¹⁸ Antiviral treatment with pegylated interferon may also cause mild thrombocytopenia.¹⁹

Helicobacter pylori

The association between H pylori infection and ITP remains uncertain. Eradication of infection appears to completely correct ITP in some places where the prevalence of H pylori is high (eg, Italy and Japan) but not in the United States and Canada, where the prevalence is low.²⁰ The different response may be due not only to the differences in prevalence, but to different H pylori genotypes: most H pylori strains in Japan express CagA, whereas the frequency of CagA-positive strains is much lower in western countries.²⁰

In areas where eradication therapy may be useful, the presence of H pylori infection should be determined by either a urea breath test or stool antigen testing.

Lymphoproliferative disorders

Secondary forms of ITP can occur in association with chronic lymphocytic leukemia, non-Hodgkin lymphoma, and Hodgkin lymphoma. These diagnoses should especially be considered in patients presenting with thrombocytopenia accompanied by systemic illness. ITP occurs in at least 2% of patients with chronic lymphocytic leukemia and is usually difficult to distinguish from thrombocytopenia secondary to marrow infiltration or from fludarabine (Fludora) therapy.²¹

It is especially important to determine if a lymphoproliferative disorder is present because it changes the treatment of ITP. Treatment of ITP complicating chronic lymphocytic leukemia is challenging and includes corticosteroids and steroid-sparing agents such as cyclosporine (Gengraf, Neoral, Sandimmune), rituximab (Rituxan), and intravenous immunoglobulin.²²

Systemic lupus erythematosus and other autoimmune diseases

Thrombocytopenia is a frequent clinical manifestation of systemic lupus erythematosus, occurring in 7% to 30% of patients,²³ and is an independent risk factor for death.²⁴ Lupus should be suspected in patients with ITP who have multiorgan involvement and other clinical and laboratory abnormalities. A small percentage of patients with ITP (about 2%−5%) develop lupus after several years.²¹

Thrombocytopenia can also result from other autoimmune disorders such as antiphospholipid antibody syndrome²⁵ and autoimmune thyroid diseases as well as immunodeficient states such as IgA deficiency and common variable immunodeficiency with low IgG levels.

NONAUTOIMMUNE THROMBOCYTOPENIA

Thrombocytopenia can also be caused by a number of nonautoimmune conditions.

Pseudothrombocytopenia

Pseudothrombocytopenia can occur if ex-vivo agglutination of platelets is induced by antiplatelet antibodies to EDTA, a standard blood anticoagulant. Automated counters cannot differentiate the agglutinated platelet clumps from individual cells such as red cells. This can frequently be overcome by running the counts in a citrate or ACD reagent tube. A peripheral blood smear can demonstrate whether platelet clumps are present.

Thrombotic thrombocytopenic purpura

Thrombotic thrombocytopenic purpura presents with thrombocytopenia, purpura, and anemia. Associated clinical abnormalities (fever, neurologic symptoms, and renal failure) and the presence of fragmented red cells on blood smear help to distinguish it from ITP. Plasma exchange is the treatment of choice.

Gestational thrombocytopenia

Five percent of pregnant women develop mild thrombocytopenia (platelet counts typically > 70 × 10⁹/L) near the end of gestation.²⁶ It requires no treatment and resolves after delivery. The fetus’ platelet count remains unaffected.

Gestational thrombocytopenia should be differentiated from the severe thrombocytopenia of preeclampsia and HELLP syndrome (hemolysis, elevated liver enzymes, and low platelet count), which requires immediate attention.

Myelodysplastic syndrome

Myelodysplastic syndrome is common among elderly patients and should be considered in cases of unexplained cytopenia and abnormalities in the peripheral blood smear suggestive of dysplastic cytologic features. It can be diagnosed by bone marrow biopsy. Thrombocytopenia occurs in about 40% to 65% of cases of myelodysplastic syndrome.²⁷

MANAGE ITP TO KEEP PLATELET COUNT ABOVE 30 × 10⁹/L

ITP does not necessarily require treatment, and the initial challenge is to determine whether treatment or observation is indicated. Treatment is based on two major factors: the platelet count and degree of bleeding. The goals of management are to achieve a safe platelet count to prevent serious bleeding while minimizing treatment-related toxicity.⁷

Adults with platelet counts of less than 30 × 10⁹/L are usually treated. In multiple large cohort studies, patients with platelet counts above that level have been safely observed without treatment.^11,28

Table 2 outlines a comprehensive approach to therapy.

INITIAL TREATMENT: STEROIDS AND IMMUNOGLOBULINS

Oral corticosteroids are the initial agents of choice

Oral prednisone 1 mg/kg/day in tapering doses for 4 to 6 weeks is the most common initial regimen. Other regimens, such as high-dose dexamethasone (Decadron) (40 mg daily for 4 days per month) for several cycles, have been reported to be more effective²⁹ but have not been studied in head-to-head trials with oral prednisone.

Due to their effectiveness, low cost, and convenience of use, corticosteroids have been the backbone of initial treatment in ITP. However, in most patients the platelet count decreases once the dose is tapered or stopped; remission is sustained in only 10% to 30% of cases.³⁰ Continuation of corticosteroids is limited by long-term complications such as opportunistic infections, osteoporosis, and emotional lability.³¹

Intravenous immunoglobulin and anti-D immunoglobulin are alternatives

Intravenous immunoglobulin is recommended for patients who have not responded to corticosteroids and is often used in pregnancy. It is thought to act by blocking Fc receptors in the reticuloendothelial system. Intravenous immunoglobulin rapidly increases platelet counts in 65% to 80% of patients,³² but the effect is transient and the drug requires frequent administration. It is usually well tolerated, although about 5% of patients experience headache, chills, myalgias, arthralgias, and back pain. Rare, serious complications include thrombotic events, anaphylaxis (in IgA-deficient patients), and renal failure.

Anti-D immunoglobulin, a pooled IgG product, is derived from the plasma of Rh(D)-negative donors and can be given only to patients who are Rh(D)-positive. Response rates as high as 70% have been reported, with platelet effects lasting for more than 21 days.³³ Studies have shown better results at a high dose (75 μg/kg) than with the approved dose of 50 μg/kg.³⁴

Anti-D immunoglobulin can also be given intermittently whenever the platelet count falls below a specific level (ie, 30 × 10⁹/L). This allows some patients to avoid splenectomy and may even trigger long-term remission.³²

Common side effects of anti-D immunoglobulin include fever and chills; these can be prevented by premedication with acetaminophen or corticosteroids. Rare but fatal cases of intravascular hemolysis, renal failure, and disseminated intravascular coagulation have been reported, precluding its use for ITP in some countries, including those of the European Union.

Emergency treatment: Combination therapy

Evidence-based guidelines are limited for treating patients with active bleeding or who are at high risk of bleeding. For uncontrolled bleeding, a combination of first-line therapies is recommended, using prednisone and intravenous immunoglobulin.³⁵ Other options include high-dose methylprednisolone and platelet transfusions, alone or in combination with intravenous immunoglobulin.³⁶

SECOND-LINE TREATMENTS

Splenectomy produces complete remission in most patients

Patients who relapse and have a platelet count of less than 20 × 10⁹/L are traditionally considered for splenectomy. More than two-thirds of patients respond with no need for further treatment.³⁷

Although splenectomy has the highest rate of durable platelet response, the risks associated with surgery are an important concern. Even with a laparoscopic splenectomy, complications occur in 10% of patients and death in 0.2%. Long-term risks include the rare occurrence of sepsis with an estimated mortality rate of 0.73 per 1,000 patient-years, and possible increased risk of thrombosis.^38,39

Adherence to recommended vaccination protocols and early administration of antibiotics for systemic febrile illness reduce the risk of sepsis.⁴⁰ Patients are advised to receive immunization against encapsulated bacteria with pneumococcal, Haemophilus influenzae type b, and meningococcal vaccines. These vaccines should be given at least 2 weeks before elective splenectomy.⁴¹

Treatment of patients refractory to splenectomy is challenging and requires further immunosuppressive therapy, which is associated with an increased risk of infections and infection-related deaths.⁴²

Rituximab in addition to or possibly instead of splenectomy

Rituximab (Rituxan) is a chimeric anti-CD20 monoclonal antibody that targets B cells. Although initially approved for treatment of lymphomas, rituximab has gained popularity in treating ITP due to its safety profile and ability to deplete CD20+ B cells responsible for antiplatelet antibody production by Fc-mediated cell lysis.

In the largest systematic review of published reports of rituximab use in ITP (19 studies, 313 patients), Arnold and colleagues⁴³ reported an overall platelet response (defined as platelet count > 50 × 10⁹/L) in 62.5% (95% confidence interval [CI] 52.6%−72.5%) of patients. The median duration of response was 10.5 months (range 3–20), and median follow-up was 9.5 months (range 2–25). Nearly all patients had received corticosteroid treatment and half of them had undergone splenectomy.

Rituximab has also been investigated as an alternative to splenectomy. In a prospective, single-arm, phase 2 trial, 60 patients with chronic ITP (platelet counts < 30 × 10⁹/L) for whom one or more previous treatments had failed received rituximab infusions and were followed for up to 2 years. A good response (defined as a platelet count ≥ 50 × 10⁹/L, with at least a doubling from baseline) was obtained in 24 (40%) of 60 patients (95% CI 28%–52%) at 1 year and 33.3% at 2 years. The authors concluded that rituximab could be used as a presplenectomy therapeutic option, particularly in patients with chronic ITP who are at increased surgical risk or who are reluctant to undergo surgery.⁴⁴ Based on these results, rituximab may spare some patients from splenectomy, or at least delay it. However, it has never been tested in randomized controlled trials to establish its role as a splenectomy-sparing agent in ITP.

Side effects include infusion reactions, which are usually mild but in rare cases can be severe. Recently, progressive multifocal leukoencephalopathy has been recognized as a complication of rituximab treatment in patients with lymphoproliferative and autoimmune disorders.⁴⁵ Although this complication is rare in patients with ITP, careful monitoring is required until additional long-term safety data are available.

Thrombopoietic receptor agonists require continuous treatment

In the early 1990s, recombinant thrombopoietin was tested in clinical studies. These were halted when antibodies developed to recombinant thrombopoietin that cross-reacted with endogenous thrombopoietin, resulting in severe thrombocytopenia.⁴⁶

This led to the development of nonimmunogenic thrombopoietin receptor agonists that mimic the effect of thrombopoietin and stimulate the production of platelets. In 2008, the US Food and Drug Administration approved two drugs of this class for treating ITP: romiplostim (Nplate) and eltrombopag (Promacta). They are mainly used to treat patients with chronic ITP who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy.

Although well tolerated and effective in increasing platelet counts, these agents share common drawbacks. They do not modify the course of the disease, they are used only to sustain the platelet count, they require repeated administration, and they must be given for about 7 days to achieve an adequate platelet response, so they cannot be used in emergencies. Long-term adverse effects include bone marrow fibrosis and thrombosis.

Romiplostim is a synthetic peptide capable of binding to the thrombopoietin receptor c-Mpl. It has no sequence homology with endogenous thrombopoietin,⁴⁷ so does not induce cross-reacting antibodies. It has a half-life of 120 to 160 hours and is usually given subcutaneously 1 to 10 μg/kg weekly.

Phase III clinical trials have shown the effectiveness of romiplostim in attaining a durable platelet response (platelet count > 50 × 10⁹/L) in splenectomized and nonsplenectomized populations. It is well tolerated, and only two uncommon serious adverse effects have been reported: bone marrow reticulin formation and thromboembolism.⁴⁸

A long-term open-label extension study of 142 patients treated with romiplostim for up to 156 weeks showed that 124 (87%) achieved a platelet count of more than 50 × 10⁹/L at some point, and 84% of patients were able to reduce or discontinue concurrent medications for ITP.⁴⁹

Kuter et al,⁵⁰ in a randomized controlled trial, confirmed the efficacy of romiplostim in attaining durable increased platelet counts. Patients treated with romiplostim at a mean weekly dose of 3.9 μg/kg ± 2.1 μg/kg demonstrated a higher rate of platelet response, lower incidence of treatment failure, and improved quality of life vs patients treated with standard care.

Eltrombopag is a nonpeptide thrombopoietin agonist that binds to the transmembrane domain of the thrombopoietin receptor and stimulates the proliferation and differentiation of megakaryocytes in bone marrow. It is given orally in doses of 25 to 75 mg daily.

Eltrombopag has been shown to be effective in increasing platelet counts in chronic ITP.⁵¹ In a phase III trial conducted by Cheng and colleagues, 197 patients were randomized to eltrombopag or placebo.⁵² Patients treated with eltrombopag were eight times more likely to achieve platelet counts of more than 50 × 10⁹/L during the 6-month treatment period (odds ratio 8.2, 95% CI 4.32–15.38, P < .001) vs placebo. Patients treated with eltrombopag had fewer bleeding episodes and were more likely to reduce or discontinue the dose of concurrent ITP medications. The only significant side effect seen was a rise in aminotransferases (seen in 7% of eltrombopag recipients vs 2% with placebo).⁵²

Additional thrombopoietin agonists under investigation include ARK-501, totrombopag, and LGD-4665. MDX-33, a monoclonal antibody against the Fc-receptor, is also being studied; it acts by preventing opsonization of autoantibody-coated platelets.⁵³

THIRD-LINE TREATMENTS FOR REFRACTORY CASES

Patients with ITP that is resistant to standard therapies have an increased risk of death, disease, and treatment-related complications.^28,42

Combination chemotherapy

Immunosuppressants such as azathioprine (Imuran), cyclosporine (Neoral, Sandimmune), cyclophosphamide (Cytoxan), and mycophenolate (CellCept) were used in the past in single-agent regimens with some efficacy, but their use was limited due to drug-related toxicity and a low safety profile.³ However, there is increasing evidence for a role of combination chemotherapy to treat chronic refractory ITP to achieve greater efficacy and fewer adverse effects.⁵⁴

Arnold and colleagues⁵⁵ reported that combined azathioprine, mycophenolate, and cyclosporine achieved an overall response (platelet count > 30 × 10⁹/L and doubling of the baseline) in 14 (73.7%) of 19 patients with chronic refractory ITP, lasting a median of 24 months.

Hematopoietic stem cell transplantation

Hematopoietic stem cell transplantation has provided remission in a limited number of patients. However, it is associated with fatal toxicities such as graft-vs-host disease and septicemia, and therefore it is reserved for severe refractory ITP with bleeding complications unresponsive to other therapies.^56,57

THERAPY FOR SECONDARY ITP DEPENDS ON THE CAUSE

Treatments for secondary ITP vary depending on the cause of thrombocytopenia and are often more complex than therapy for primary disease. Optimal management involves treating the underlying condition (eg, chronic lymphocytic leukemia or systemic lupus erythematosus).

Drug-induced thrombocytopenia requires prompt recognition and withdrawal of the inciting agent.

Treating ITP due to HCV infection primarily involves antiviral agents to suppress viral replication. If treating ITP is required, then intravenous immunoglobulin is preferable to glucocorticoids because of the risk of increasing viral load with the latter.⁵⁸ Eltrombopag may effectively increase platelet counts, allowing patients to receive interferon therapy for HCV.⁵⁹ However, a recent study was halted due to increased incidence of portal vein thrombosis, raising concerns about the safety of eltrombopag for patients with chronic liver disease.⁶⁰

Secondary ITP due to HIV infection should always be treated first with antivirals targeting HIV unless thrombocytopenia-related bleeding complications warrant treatment. If treatment for ITP is necessary, it should include corticosteroids, intravenous immunoglobulin, or anti-D immunoglobulin as first-line therapy.

Eradication therapy for H pylori is recommended for patients who are positive for the organism based on urea breath testing, stool antigen testing, or endoscopic biopsies.

Although many developments have occurred in the last decade for managing atrial fibrillation, challenges remain. New and emerging alternatives to warfarin (Coumadin) for anticoagulation therapy prevent stroke marginally better and pose slightly less risk of hemorrhage, but they have important drawbacks.

The antiarrhythmic drug dronedarone (Multaq) has been found to offer only temporary benefit for persistent atrial fibrillation, and significant risks have emerged.

Radiofrequency ablation is gaining prominence, but repeat procedures are sometimes necessary.

An investigational device can be implanted via percutaneous catheter in the left atrial appendage to prevent embolization. It is too soon to know its eventual role in clinical practice.

This article reviews the results of clinical trials of these new treatments and discusses their role in clinical practice.

CHALLENGES OF ANTICOAGULATION

The main focus of managing atrial fibrillation is on alleviating symptoms, by either rate control or rhythm control. The other focus is on preventing stroke—a devastating outcome—with anticoagulation therapy.

For deciding whether to give warfarin to patients with atrial fibrillation, the six-point CHADS₂ score is a crude but effective way of assessing the risk of stroke based on the following risk factors: congestive heart failure, hypertension, age 75 years or older, and diabetes (1 point each); or a history of stroke or transient ischemic attack (2 points).¹ Warfarin is given if patients have a score of at least 2 points.

Warfarin has a narrow therapeutic window, with a higher risk of ischemic stroke if the international normalized ratio (INR) is less than 2.0,² and a higher risk of intracranial hemorrhage if the INR is more than 3.0.³ Keeping the INR in the therapeutic range is difficult because of variations in diet, concurrent medications, and other factors.

The percent of time that the INR is within the therapeutic range predicts the risk of adverse events. Connolly et al⁴ showed that the cumulative risk of stroke, myocardial infarction, systemic embolism, or vascular death was no better with warfarin than with clopidogrel (Plavix) plus aspirin if the INR was in the therapeutic range less than 65% of the time, but the risk was significantly less if the INR was in the therapeutic range more than 65% of the time.

Also, comparing warfarin with the combination of aspirin and clopidogrel, Verheugt⁵ found that the rates of stroke of any kind, of disabling and fatal stroke, and of stroke per major bleed were lower in patients taking warfarin. Although many physicians prefer aspirin plus clopidogrel because of concerns about bleeding with warfarin, the rates of major bleeding were about the same in the two groups.

In a trial in patients for whom warfarin was “unsuitable,”⁶ the combination of aspirin plus clopidogrel was associated with a lower rate of stroke than aspirin alone (2.4% per year vs 3.3% per year, relative risk 0.762) but a higher rate of major bleeding events (2.0% per year vs 1.3% per year, relative risk 1.57).

NEW ALTERNATIVES TO WARFARIN

Because of the problems with warfarin, alternatives have been sought for many years. Several new oral anticoagulants are available or are being developed,⁷ including the factor Xa inhibitors rivaroxaban (Xarelto) and apixaban (Eliquis) and the direct factor II (thrombin) inhibitor dabigatran (Pradaxa) (Table 1).

Dabigatran’s advantages and drawbacks

Dabigatran has been on the market for more than a year and has gained rapid acceptance. The dosage is 150 mg twice a day, or 75 mg twice a day if renal function is impaired. Cleared by the kidneys, it has a half-life of 12 to 17 hours; 75% is cleared within 24 hours. For a patient who needs surgery that poses a low risk of bleeding, the general recommendation is to stop dabigatran the night before the surgical procedure. For operations with a greater risk of bleeding, many surgeons recommend stopping the drug 3 or 4 days before.

Advantages of dabigatran include that it is not influenced by diet and that the onset of therapeutic benefit is within 1 hour. Although some drugs affect dabigatran, drug interactions are more troublesome with warfarin.

A serious concern about dabigatran and the other new agents is that if a bleeding problem arises, the effects of these drugs are not reversible by administration of fresh frozen plasma. Dabigatran is reversible by dialysis; however, if a patient is also hypotensive, dialysis is not an option, and simply waiting for the drug to clear is the only choice.

Another drawback is that therapeutic levels cannot be monitored. If a patient taking warfarin requires cardioversion, the INR is carefully monitored for several weeks beforehand to reduce the risk of stroke. With dabigatran, there is no way to know if a patient is actually taking the drug as prescribed.

In the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial,⁸ dabigatran was associated with a significantly lower incidence of intracranial hemorrhage, combined strokes, and systemic embolization than warfarin. The incidence of major bleeds was slightly lower with dabigatran. Although dabigatran performed better, the differences were small and would not require patients to change from warfarin if they are already doing well.

Apixaban and rivaroxaban are other alternatives to warfarin, with different mechanisms of action and metabolism. Although rivaroxaban’s half-life is similar to that of apixaban and dabigatran, it is being marketed as allowing once-daily dosing instead of twice-daily.

Recent randomized controlled clinical trials of the new drugs include:

• The Apixaban Versus Acetylsalicylic Acid (ASA) to Prevent Stroke in Atrial Fibrillation Patients Who Have Failed or Are Unsuitable for Vitamin K Antagonist Treatment (AVERROES) trial,⁹ which compared apixaban and aspirin
• The Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial comparing apixaban and warfarin¹⁰
• The Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF),¹¹ comparing rivaroxaban and warfarin
• RE-LY,⁸ comparing dabigatran and warfarin.

In the ARISTOTLE,¹⁰ ROCKET AF,¹¹ and RE-LY trials,⁸ the time that the warfarin patients’ INRs were in the therapeutic range varied from 55% to 68%. This seems low and is a problem when trying to compare therapies, but is probably about as high as one can expect in the real world.

In AVERROES,⁹ the combined rate of stroke and embolism was higher with aspirin than with apixaban. In the other trials, the rates were slightly better with the new drugs than with warfarin, and the rates of major hemorrhage and hemorrhagic stroke were only slightly higher with warfarin than with the new drugs. Because the differences in benefits and risks are so small, the main advantage of the newer drugs will probably be for patients who have difficulty staying in the therapeutic INR range on warfarin.

RATE CONTROL VS RESTORATION OF SINUS RHYTHM

Evidence is insufficient to determine the risk of very-long-term asymptomatic atrial fibrillation in patients on appropriate anticoagulation. Rate control is an option for asymptomatic patients but provides no change in quality of life and no definitive reduction in the risk of stroke. The main argument for restoring normal sinus rhythm in patients with mild to moderate symptoms is that it improves exercise capacity. The need for anticoagulation persists when patients are converted to sinus rhythm because the risk of recurrent atrial fibrillation remains high.

For patients with symptomatic atrial fibrillation, rate control is sometimes achieved with beta-blockers or calcium channel blockers. Rate control may be augmented with the addition of digoxin, but when used alone digoxin generally does not control the rate of atrial fibrillation. However, in many cases of atrial fibrillation, symptoms are not rate-related, and cardioversion to normal sinus rhythm should be attempted. In such cases, the symptoms may be attributable to a loss of atrial transport function.

Patients with the following risk factors should be admitted to the hospital to start antiarrhythmic drugs:

• Borderline or a long QTc interval at baseline (> 450 msec)
• Treatment with dofetilide (Tikosyn) because of its effects on the QT interval
• Heart failure or poor left-ventricular function
• Sinus node dysfunction
• Significant atrioventricular conduction disease.

Selecting an antiarrhythmic drug

Any of the antiarrhythmic drugs listed in Table 2 can be used for a patient with lone atrial fibrillation (ie, not caused by underlying heart disease). The choice of drug should be determined by whether coronary artery disease or renal failure is present as well. Liver disease or chronic obstructive pulmonary disease also may affect this decision.

Benefits of dronedarone are mixed

In a randomized trial of dronedarone vs placebo in patients with atrial fibrillation, the rate of death and the rate of first hospitalization due to a cardiovascular event at 21 months were significantly lower with dronedarone.¹² No difference was found between the two groups in the rate of death from all causes, but fewer people died of cardiovascular causes in the dronedarone group. More patients taking dronedarone developed bradycardia, QT-interval prolongation, nausea, diarrhea, rash, or a higher serum creatinine level. Gastrointestinal side effects are often a problem with dronedarone: 20% to 30% of patients cannot tolerate the drug.

Dronedarone may cause a small rise in creatinine, and although this effect should be monitored, by itself it should not be interpreted as impairment of renal function. In a study in healthy people,¹³ dronedarone caused a 10% to 15% increase in serum creatinine, but the glomerular filtration rate was unchanged, as were renal plasma flow and anion secretion.

Another trial, in patients with severe heart failure, found that patients taking dronedarone had higher rates of hospitalization and overall mortality, raising serious concern about the safety of this drug in patients with advanced heart failure.¹⁴

Singh et al¹⁵ pooled the data from two multicenter, randomized trials that compared dronedarone with placebo for maintaining sinus rhythm in patients with atrial fibrillation or flutter. The mean time to the recurrence of atrial fibrillation was 116 days with dronedarone and 53 days with placebo. Other trials also showed longer times to recurrence and lower recurrence rates with dronedarone. Although the differences were statistically significant, they may not be clinically meaningful for patients.

Dronedarone is structurally similar to amiodarone (Cordarone), but the two drugs work differently. A meta-analysis of clinical trials¹⁶ found that amiodarone recipients had a lower rate of recurrence of atrial fibrillation than did those receiving dronedarone.

Two safety warnings for dronedarone

In January 2011, the US Food and Drug Administration (FDA) issued an alert about cases of rare but severe liver injury in patients treated with dronedarone, including two cases of acute liver failure leading to liver transplantation.¹⁷

The Permanent Atrial Fibrillation Outcome Study Using Dronedarone on Top of Standard Therapy (PALLAS)¹⁸ compared dronedarone and placebo in patients with permanent atrial fibrillation. More people died or had serious cardiovascular adverse events in the dronedarone group. The study was stopped early after data monitoring showed that rates of death, stroke, and hospitalization for heart failure were two times higher in patients receiving dronedarone. This prompted the FDA to issue another safety alert in July 2011.

Interestingly, the PALLAS study did not set out to determine whether dronedarone controls atrial fibrillation, as the study patients had long-standing, persistent atrial fibrillation. The study was designed only to determine if the drug reduces the rate of adverse events; it clearly does not, and the study shows that dronedarone should not be used to control the heart rate in patients with persistent atrial fibrillation. Instead, its use is best restricted to patients with paroxysmal atrial fibrillation without significant cardiovascular disease.

ABLATION OF ATRIAL FIBRILLATION

Another way to try to restore sinus rhythm is to destroy or isolate the area that is generating the abnormal beats via a catheter-based procedure.

Radiofrequency ablation is generally tried in patients in whom one or two drugs have failed to control atrial fibrillation. Direct comparisons show that ablation is superior to drug therapy and is effective in about 75% of patients with paroxysmal atrial fibrillation vs 20% to 40% of patients on drug therapy. Ablation plus drug therapy is often more effective than either treatment alone.

Mechanisms of atrial fibrillation and ablation

In many cases, atrial fibrillation is stimulated by vagal and sympathetic inputs to the atrium that enter around the pulmonary veins and trigger electrical activations in the area, generating spiraling, reentering circuits. Focal atrial fibrillation also originates predominantly in the pulmonary veins. Ablation of tissue widely circumscribing the mouth of the pulmonary veins prevents the electrical signal from exiting into the atrium.

In about 11% to 37% of cases, atrial fibrillation originates elsewhere, eg, in the left atrium, in the superior vena cava, or in the vein of Marshall. Techniques have evolved to also ablate these regions.

Anticoagulation therapy is recommended before the procedure, and patients at low risk should continue it for a minimum of 2 months afterward. Patients with a higher CHADS₂ score should receive anticoagulation therapy for at least 1 year. The consensus statement by the Heart Rhythm Society¹⁹ recommends that patients remain on warfarin or one of the newer anticoagulants if their CHADS₂ score is 2 or higher. This is because patients have a significant risk of recurrence of atrial fibrillation after radiofrequency ablation, so if their stroke risk is high they should remain on anticoagulant therapy.

Ablation is usually effective, but it carries rare but serious risks

The efficacy of a single radiofrequency ablation procedure is in the range of 60% to 80% for paroxysmal atrial fibrillation and 40% to 60% for persistent atrial fibrillation. The Second International Ablation Registry²⁰ shows a success rate of about 75% in patients with paroxysmal atrial fibrillation and about 65% in patients with persistent and permanent atrial fibrillation. Registry data are often more favorable because reporting is optional, but these results are consistent with those from experienced medical centers. Rates of suppression of atrial fibrillation are higher in patients who also take antiarrhythmic drugs, making a “hybrid” approach useful when ablation alone fails.

According to a worldwide survey, the risk of serious complications is 4.5%. These include stroke (0.23%), tamponade (1.3%), and pulmonary vein stenosis (< 0.29%). The esophagus lies just behind the right atrium, and burning through and creating a fistula between them occurs in about 0.04% of cases and is almost uniformly fatal.²⁰

A second ablation procedure is sometimes indicated for the recurrence of atrial fibrillation, which is almost always caused by recovery of the pulmonary veins. Bhargava et al²¹ found that the success rate at Cleveland Clinic for a single procedure for paroxysmal atrial fibrillation was 77%, and that it was 92% after a repeat procedure. For persistent atrial fibrillation, success rates were 76% after the first procedure and 90% after the second. Even for long-standing persistent atrial fibrillation (ie, lasting more than 1 year), 80% success was achieved after two procedures. Patients who are less likely to have a successful ablation procedure are those with long-standing atrial fibrillation and coexisting heart disease, including severe valvular disease, although mitral regurgitation sometimes improves if sinus rhythm can be maintained.

The need for a second procedure

After ablation, patients should be closely monitored for a recurrence of atrial fibrillation. Continuous monitoring with implantable cardiac monitor loop recorders can detect unrecognized episodes of arrhythmia. Long-term follow-up is also required to track outcomes and quality of life.

According to the Heart Rhythm Society Task Force on Catheter and Surgical Ablation of Atrial Fibrillation,¹⁹ atrial fibrillation recurs after ablation in about 35% to 60% of patients in the first 3 months, with recurrence rates after 1 year ranging from 5% to 16%. The rate of success is determined by the skill of the surgeon, underlying heart disease, attention to follow-up, and how success is defined.

Freedom from recurrence early on is a good predictor that late recurrence is unlikely. Patients who only have a very early recurrence (within the first 4 weeks) are more likely to have long-term freedom from atrial fibrillation tha those who have recurrences after that time.²²

In a study of 831 patients, Hussein et al²³ found recurrence rates of 24% between months 3 to 13 following ablation and 9% after 12 months. At 55 months, 79% were free from atrial fibrillation without drugs, 11% were free of atrial fibrillation with medications, and 5% had refractory atrial fibrillation.

Recurrence—whether early or late—was more likely to occur in people with persistent vs paroxysmal atrial fibrillation. Other risk factors for late recurrence included older age and larger left atrial size (which is also a risk factor for recurrence on drug therapy). Although recurrent arrhythmia was most often atrial fibrillation, atrial flutter also occurred frequently (in 27% of patients with late recurrence). Three patients (4% of patients with late recurrence) developed atrial tachycardia.²³

In patients with early recurrence, 81% underwent repeat ablation, all of whom had recovery of one or more pulmonary veins. After the second ablation, 21% had recurrence, 65% of whom were controlled by medications.²³

Whether a patient should undergo subsequent ablation procedures depends on the severity of symptoms, the likelihood of success (based on an educated guess), and the patient’s willingness to undergo another procedure.

ATRIAL APPENDAGE OCCLUSION DEVICE UNDER INVESTIGATION

New devices are being investigated that occlude the left atrial appendage to try to prevent embolization.

The Watchman device, resembling an umbrella, is implanted via a percutaneous catheter in the left atrial appendage, closing it off to preclude a thrombus from forming in the appendage and embolizing to the body. Clinical trials showed that patients who received a device had a slightly lower risk of stroke than otherwise seen in clinical practice.²⁴ Safety and efficacy are still being determined.

The device cannot be deployed in a patient with an existing thrombus because of the danger of dislodging the thrombus, allowing it to embolize.

Although many developments have occurred in the last decade for managing atrial fibrillation, challenges remain. New and emerging alternatives to warfarin (Coumadin) for anticoagulation therapy prevent stroke marginally better and pose slightly less risk of hemorrhage, but they have important drawbacks.

The antiarrhythmic drug dronedarone (Multaq) has been found to offer only temporary benefit for persistent atrial fibrillation, and significant risks have emerged.

Radiofrequency ablation is gaining prominence, but repeat procedures are sometimes necessary.

An investigational device can be implanted via percutaneous catheter in the left atrial appendage to prevent embolization. It is too soon to know its eventual role in clinical practice.

This article reviews the results of clinical trials of these new treatments and discusses their role in clinical practice.

CHALLENGES OF ANTICOAGULATION

The main focus of managing atrial fibrillation is on alleviating symptoms, by either rate control or rhythm control. The other focus is on preventing stroke—a devastating outcome—with anticoagulation therapy.

For deciding whether to give warfarin to patients with atrial fibrillation, the six-point CHADS₂ score is a crude but effective way of assessing the risk of stroke based on the following risk factors: congestive heart failure, hypertension, age 75 years or older, and diabetes (1 point each); or a history of stroke or transient ischemic attack (2 points).¹ Warfarin is given if patients have a score of at least 2 points.

Warfarin has a narrow therapeutic window, with a higher risk of ischemic stroke if the international normalized ratio (INR) is less than 2.0,² and a higher risk of intracranial hemorrhage if the INR is more than 3.0.³ Keeping the INR in the therapeutic range is difficult because of variations in diet, concurrent medications, and other factors.

The percent of time that the INR is within the therapeutic range predicts the risk of adverse events. Connolly et al⁴ showed that the cumulative risk of stroke, myocardial infarction, systemic embolism, or vascular death was no better with warfarin than with clopidogrel (Plavix) plus aspirin if the INR was in the therapeutic range less than 65% of the time, but the risk was significantly less if the INR was in the therapeutic range more than 65% of the time.

Also, comparing warfarin with the combination of aspirin and clopidogrel, Verheugt⁵ found that the rates of stroke of any kind, of disabling and fatal stroke, and of stroke per major bleed were lower in patients taking warfarin. Although many physicians prefer aspirin plus clopidogrel because of concerns about bleeding with warfarin, the rates of major bleeding were about the same in the two groups.

In a trial in patients for whom warfarin was “unsuitable,”⁶ the combination of aspirin plus clopidogrel was associated with a lower rate of stroke than aspirin alone (2.4% per year vs 3.3% per year, relative risk 0.762) but a higher rate of major bleeding events (2.0% per year vs 1.3% per year, relative risk 1.57).

NEW ALTERNATIVES TO WARFARIN

Because of the problems with warfarin, alternatives have been sought for many years. Several new oral anticoagulants are available or are being developed,⁷ including the factor Xa inhibitors rivaroxaban (Xarelto) and apixaban (Eliquis) and the direct factor II (thrombin) inhibitor dabigatran (Pradaxa) (Table 1).

Dabigatran’s advantages and drawbacks

Dabigatran has been on the market for more than a year and has gained rapid acceptance. The dosage is 150 mg twice a day, or 75 mg twice a day if renal function is impaired. Cleared by the kidneys, it has a half-life of 12 to 17 hours; 75% is cleared within 24 hours. For a patient who needs surgery that poses a low risk of bleeding, the general recommendation is to stop dabigatran the night before the surgical procedure. For operations with a greater risk of bleeding, many surgeons recommend stopping the drug 3 or 4 days before.

Advantages of dabigatran include that it is not influenced by diet and that the onset of therapeutic benefit is within 1 hour. Although some drugs affect dabigatran, drug interactions are more troublesome with warfarin.

A serious concern about dabigatran and the other new agents is that if a bleeding problem arises, the effects of these drugs are not reversible by administration of fresh frozen plasma. Dabigatran is reversible by dialysis; however, if a patient is also hypotensive, dialysis is not an option, and simply waiting for the drug to clear is the only choice.

Another drawback is that therapeutic levels cannot be monitored. If a patient taking warfarin requires cardioversion, the INR is carefully monitored for several weeks beforehand to reduce the risk of stroke. With dabigatran, there is no way to know if a patient is actually taking the drug as prescribed.

In the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial,⁸ dabigatran was associated with a significantly lower incidence of intracranial hemorrhage, combined strokes, and systemic embolization than warfarin. The incidence of major bleeds was slightly lower with dabigatran. Although dabigatran performed better, the differences were small and would not require patients to change from warfarin if they are already doing well.

Apixaban and rivaroxaban are other alternatives to warfarin, with different mechanisms of action and metabolism. Although rivaroxaban’s half-life is similar to that of apixaban and dabigatran, it is being marketed as allowing once-daily dosing instead of twice-daily.

Recent randomized controlled clinical trials of the new drugs include:

• The Apixaban Versus Acetylsalicylic Acid (ASA) to Prevent Stroke in Atrial Fibrillation Patients Who Have Failed or Are Unsuitable for Vitamin K Antagonist Treatment (AVERROES) trial,⁹ which compared apixaban and aspirin
• The Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial comparing apixaban and warfarin¹⁰
• The Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF),¹¹ comparing rivaroxaban and warfarin
• RE-LY,⁸ comparing dabigatran and warfarin.

In the ARISTOTLE,¹⁰ ROCKET AF,¹¹ and RE-LY trials,⁸ the time that the warfarin patients’ INRs were in the therapeutic range varied from 55% to 68%. This seems low and is a problem when trying to compare therapies, but is probably about as high as one can expect in the real world.

In AVERROES,⁹ the combined rate of stroke and embolism was higher with aspirin than with apixaban. In the other trials, the rates were slightly better with the new drugs than with warfarin, and the rates of major hemorrhage and hemorrhagic stroke were only slightly higher with warfarin than with the new drugs. Because the differences in benefits and risks are so small, the main advantage of the newer drugs will probably be for patients who have difficulty staying in the therapeutic INR range on warfarin.

RATE CONTROL VS RESTORATION OF SINUS RHYTHM

Evidence is insufficient to determine the risk of very-long-term asymptomatic atrial fibrillation in patients on appropriate anticoagulation. Rate control is an option for asymptomatic patients but provides no change in quality of life and no definitive reduction in the risk of stroke. The main argument for restoring normal sinus rhythm in patients with mild to moderate symptoms is that it improves exercise capacity. The need for anticoagulation persists when patients are converted to sinus rhythm because the risk of recurrent atrial fibrillation remains high.

For patients with symptomatic atrial fibrillation, rate control is sometimes achieved with beta-blockers or calcium channel blockers. Rate control may be augmented with the addition of digoxin, but when used alone digoxin generally does not control the rate of atrial fibrillation. However, in many cases of atrial fibrillation, symptoms are not rate-related, and cardioversion to normal sinus rhythm should be attempted. In such cases, the symptoms may be attributable to a loss of atrial transport function.

Patients with the following risk factors should be admitted to the hospital to start antiarrhythmic drugs:

• Borderline or a long QTc interval at baseline (> 450 msec)
• Treatment with dofetilide (Tikosyn) because of its effects on the QT interval
• Heart failure or poor left-ventricular function
• Sinus node dysfunction
• Significant atrioventricular conduction disease.

Selecting an antiarrhythmic drug

Any of the antiarrhythmic drugs listed in Table 2 can be used for a patient with lone atrial fibrillation (ie, not caused by underlying heart disease). The choice of drug should be determined by whether coronary artery disease or renal failure is present as well. Liver disease or chronic obstructive pulmonary disease also may affect this decision.

Benefits of dronedarone are mixed

In a randomized trial of dronedarone vs placebo in patients with atrial fibrillation, the rate of death and the rate of first hospitalization due to a cardiovascular event at 21 months were significantly lower with dronedarone.¹² No difference was found between the two groups in the rate of death from all causes, but fewer people died of cardiovascular causes in the dronedarone group. More patients taking dronedarone developed bradycardia, QT-interval prolongation, nausea, diarrhea, rash, or a higher serum creatinine level. Gastrointestinal side effects are often a problem with dronedarone: 20% to 30% of patients cannot tolerate the drug.

Dronedarone may cause a small rise in creatinine, and although this effect should be monitored, by itself it should not be interpreted as impairment of renal function. In a study in healthy people,¹³ dronedarone caused a 10% to 15% increase in serum creatinine, but the glomerular filtration rate was unchanged, as were renal plasma flow and anion secretion.

Another trial, in patients with severe heart failure, found that patients taking dronedarone had higher rates of hospitalization and overall mortality, raising serious concern about the safety of this drug in patients with advanced heart failure.¹⁴

Singh et al¹⁵ pooled the data from two multicenter, randomized trials that compared dronedarone with placebo for maintaining sinus rhythm in patients with atrial fibrillation or flutter. The mean time to the recurrence of atrial fibrillation was 116 days with dronedarone and 53 days with placebo. Other trials also showed longer times to recurrence and lower recurrence rates with dronedarone. Although the differences were statistically significant, they may not be clinically meaningful for patients.

Dronedarone is structurally similar to amiodarone (Cordarone), but the two drugs work differently. A meta-analysis of clinical trials¹⁶ found that amiodarone recipients had a lower rate of recurrence of atrial fibrillation than did those receiving dronedarone.

Two safety warnings for dronedarone

In January 2011, the US Food and Drug Administration (FDA) issued an alert about cases of rare but severe liver injury in patients treated with dronedarone, including two cases of acute liver failure leading to liver transplantation.¹⁷

The Permanent Atrial Fibrillation Outcome Study Using Dronedarone on Top of Standard Therapy (PALLAS)¹⁸ compared dronedarone and placebo in patients with permanent atrial fibrillation. More people died or had serious cardiovascular adverse events in the dronedarone group. The study was stopped early after data monitoring showed that rates of death, stroke, and hospitalization for heart failure were two times higher in patients receiving dronedarone. This prompted the FDA to issue another safety alert in July 2011.

Interestingly, the PALLAS study did not set out to determine whether dronedarone controls atrial fibrillation, as the study patients had long-standing, persistent atrial fibrillation. The study was designed only to determine if the drug reduces the rate of adverse events; it clearly does not, and the study shows that dronedarone should not be used to control the heart rate in patients with persistent atrial fibrillation. Instead, its use is best restricted to patients with paroxysmal atrial fibrillation without significant cardiovascular disease.

ABLATION OF ATRIAL FIBRILLATION

Another way to try to restore sinus rhythm is to destroy or isolate the area that is generating the abnormal beats via a catheter-based procedure.

Radiofrequency ablation is generally tried in patients in whom one or two drugs have failed to control atrial fibrillation. Direct comparisons show that ablation is superior to drug therapy and is effective in about 75% of patients with paroxysmal atrial fibrillation vs 20% to 40% of patients on drug therapy. Ablation plus drug therapy is often more effective than either treatment alone.

Mechanisms of atrial fibrillation and ablation

In many cases, atrial fibrillation is stimulated by vagal and sympathetic inputs to the atrium that enter around the pulmonary veins and trigger electrical activations in the area, generating spiraling, reentering circuits. Focal atrial fibrillation also originates predominantly in the pulmonary veins. Ablation of tissue widely circumscribing the mouth of the pulmonary veins prevents the electrical signal from exiting into the atrium.

In about 11% to 37% of cases, atrial fibrillation originates elsewhere, eg, in the left atrium, in the superior vena cava, or in the vein of Marshall. Techniques have evolved to also ablate these regions.

Anticoagulation therapy is recommended before the procedure, and patients at low risk should continue it for a minimum of 2 months afterward. Patients with a higher CHADS₂ score should receive anticoagulation therapy for at least 1 year. The consensus statement by the Heart Rhythm Society¹⁹ recommends that patients remain on warfarin or one of the newer anticoagulants if their CHADS₂ score is 2 or higher. This is because patients have a significant risk of recurrence of atrial fibrillation after radiofrequency ablation, so if their stroke risk is high they should remain on anticoagulant therapy.

Ablation is usually effective, but it carries rare but serious risks

The efficacy of a single radiofrequency ablation procedure is in the range of 60% to 80% for paroxysmal atrial fibrillation and 40% to 60% for persistent atrial fibrillation. The Second International Ablation Registry²⁰ shows a success rate of about 75% in patients with paroxysmal atrial fibrillation and about 65% in patients with persistent and permanent atrial fibrillation. Registry data are often more favorable because reporting is optional, but these results are consistent with those from experienced medical centers. Rates of suppression of atrial fibrillation are higher in patients who also take antiarrhythmic drugs, making a “hybrid” approach useful when ablation alone fails.

According to a worldwide survey, the risk of serious complications is 4.5%. These include stroke (0.23%), tamponade (1.3%), and pulmonary vein stenosis (< 0.29%). The esophagus lies just behind the right atrium, and burning through and creating a fistula between them occurs in about 0.04% of cases and is almost uniformly fatal.²⁰

A second ablation procedure is sometimes indicated for the recurrence of atrial fibrillation, which is almost always caused by recovery of the pulmonary veins. Bhargava et al²¹ found that the success rate at Cleveland Clinic for a single procedure for paroxysmal atrial fibrillation was 77%, and that it was 92% after a repeat procedure. For persistent atrial fibrillation, success rates were 76% after the first procedure and 90% after the second. Even for long-standing persistent atrial fibrillation (ie, lasting more than 1 year), 80% success was achieved after two procedures. Patients who are less likely to have a successful ablation procedure are those with long-standing atrial fibrillation and coexisting heart disease, including severe valvular disease, although mitral regurgitation sometimes improves if sinus rhythm can be maintained.

The need for a second procedure

After ablation, patients should be closely monitored for a recurrence of atrial fibrillation. Continuous monitoring with implantable cardiac monitor loop recorders can detect unrecognized episodes of arrhythmia. Long-term follow-up is also required to track outcomes and quality of life.

According to the Heart Rhythm Society Task Force on Catheter and Surgical Ablation of Atrial Fibrillation,¹⁹ atrial fibrillation recurs after ablation in about 35% to 60% of patients in the first 3 months, with recurrence rates after 1 year ranging from 5% to 16%. The rate of success is determined by the skill of the surgeon, underlying heart disease, attention to follow-up, and how success is defined.

Freedom from recurrence early on is a good predictor that late recurrence is unlikely. Patients who only have a very early recurrence (within the first 4 weeks) are more likely to have long-term freedom from atrial fibrillation tha those who have recurrences after that time.²²

In a study of 831 patients, Hussein et al²³ found recurrence rates of 24% between months 3 to 13 following ablation and 9% after 12 months. At 55 months, 79% were free from atrial fibrillation without drugs, 11% were free of atrial fibrillation with medications, and 5% had refractory atrial fibrillation.

Recurrence—whether early or late—was more likely to occur in people with persistent vs paroxysmal atrial fibrillation. Other risk factors for late recurrence included older age and larger left atrial size (which is also a risk factor for recurrence on drug therapy). Although recurrent arrhythmia was most often atrial fibrillation, atrial flutter also occurred frequently (in 27% of patients with late recurrence). Three patients (4% of patients with late recurrence) developed atrial tachycardia.²³

In patients with early recurrence, 81% underwent repeat ablation, all of whom had recovery of one or more pulmonary veins. After the second ablation, 21% had recurrence, 65% of whom were controlled by medications.²³

Whether a patient should undergo subsequent ablation procedures depends on the severity of symptoms, the likelihood of success (based on an educated guess), and the patient’s willingness to undergo another procedure.

ATRIAL APPENDAGE OCCLUSION DEVICE UNDER INVESTIGATION

New devices are being investigated that occlude the left atrial appendage to try to prevent embolization.

The Watchman device, resembling an umbrella, is implanted via a percutaneous catheter in the left atrial appendage, closing it off to preclude a thrombus from forming in the appendage and embolizing to the body. Clinical trials showed that patients who received a device had a slightly lower risk of stroke than otherwise seen in clinical practice.²⁴ Safety and efficacy are still being determined.

The device cannot be deployed in a patient with an existing thrombus because of the danger of dislodging the thrombus, allowing it to embolize.

Although many developments have occurred in the last decade for managing atrial fibrillation, challenges remain. New and emerging alternatives to warfarin (Coumadin) for anticoagulation therapy prevent stroke marginally better and pose slightly less risk of hemorrhage, but they have important drawbacks.

The antiarrhythmic drug dronedarone (Multaq) has been found to offer only temporary benefit for persistent atrial fibrillation, and significant risks have emerged.

Radiofrequency ablation is gaining prominence, but repeat procedures are sometimes necessary.

An investigational device can be implanted via percutaneous catheter in the left atrial appendage to prevent embolization. It is too soon to know its eventual role in clinical practice.

This article reviews the results of clinical trials of these new treatments and discusses their role in clinical practice.

CHALLENGES OF ANTICOAGULATION

The main focus of managing atrial fibrillation is on alleviating symptoms, by either rate control or rhythm control. The other focus is on preventing stroke—a devastating outcome—with anticoagulation therapy.

For deciding whether to give warfarin to patients with atrial fibrillation, the six-point CHADS₂ score is a crude but effective way of assessing the risk of stroke based on the following risk factors: congestive heart failure, hypertension, age 75 years or older, and diabetes (1 point each); or a history of stroke or transient ischemic attack (2 points).¹ Warfarin is given if patients have a score of at least 2 points.

Warfarin has a narrow therapeutic window, with a higher risk of ischemic stroke if the international normalized ratio (INR) is less than 2.0,² and a higher risk of intracranial hemorrhage if the INR is more than 3.0.³ Keeping the INR in the therapeutic range is difficult because of variations in diet, concurrent medications, and other factors.

The percent of time that the INR is within the therapeutic range predicts the risk of adverse events. Connolly et al⁴ showed that the cumulative risk of stroke, myocardial infarction, systemic embolism, or vascular death was no better with warfarin than with clopidogrel (Plavix) plus aspirin if the INR was in the therapeutic range less than 65% of the time, but the risk was significantly less if the INR was in the therapeutic range more than 65% of the time.

Also, comparing warfarin with the combination of aspirin and clopidogrel, Verheugt⁵ found that the rates of stroke of any kind, of disabling and fatal stroke, and of stroke per major bleed were lower in patients taking warfarin. Although many physicians prefer aspirin plus clopidogrel because of concerns about bleeding with warfarin, the rates of major bleeding were about the same in the two groups.

In a trial in patients for whom warfarin was “unsuitable,”⁶ the combination of aspirin plus clopidogrel was associated with a lower rate of stroke than aspirin alone (2.4% per year vs 3.3% per year, relative risk 0.762) but a higher rate of major bleeding events (2.0% per year vs 1.3% per year, relative risk 1.57).

NEW ALTERNATIVES TO WARFARIN

Because of the problems with warfarin, alternatives have been sought for many years. Several new oral anticoagulants are available or are being developed,⁷ including the factor Xa inhibitors rivaroxaban (Xarelto) and apixaban (Eliquis) and the direct factor II (thrombin) inhibitor dabigatran (Pradaxa) (Table 1).

Dabigatran’s advantages and drawbacks

Dabigatran has been on the market for more than a year and has gained rapid acceptance. The dosage is 150 mg twice a day, or 75 mg twice a day if renal function is impaired. Cleared by the kidneys, it has a half-life of 12 to 17 hours; 75% is cleared within 24 hours. For a patient who needs surgery that poses a low risk of bleeding, the general recommendation is to stop dabigatran the night before the surgical procedure. For operations with a greater risk of bleeding, many surgeons recommend stopping the drug 3 or 4 days before.

Advantages of dabigatran include that it is not influenced by diet and that the onset of therapeutic benefit is within 1 hour. Although some drugs affect dabigatran, drug interactions are more troublesome with warfarin.

A serious concern about dabigatran and the other new agents is that if a bleeding problem arises, the effects of these drugs are not reversible by administration of fresh frozen plasma. Dabigatran is reversible by dialysis; however, if a patient is also hypotensive, dialysis is not an option, and simply waiting for the drug to clear is the only choice.

Another drawback is that therapeutic levels cannot be monitored. If a patient taking warfarin requires cardioversion, the INR is carefully monitored for several weeks beforehand to reduce the risk of stroke. With dabigatran, there is no way to know if a patient is actually taking the drug as prescribed.

In the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial,⁸ dabigatran was associated with a significantly lower incidence of intracranial hemorrhage, combined strokes, and systemic embolization than warfarin. The incidence of major bleeds was slightly lower with dabigatran. Although dabigatran performed better, the differences were small and would not require patients to change from warfarin if they are already doing well.

Apixaban and rivaroxaban are other alternatives to warfarin, with different mechanisms of action and metabolism. Although rivaroxaban’s half-life is similar to that of apixaban and dabigatran, it is being marketed as allowing once-daily dosing instead of twice-daily.

Recent randomized controlled clinical trials of the new drugs include:

• The Apixaban Versus Acetylsalicylic Acid (ASA) to Prevent Stroke in Atrial Fibrillation Patients Who Have Failed or Are Unsuitable for Vitamin K Antagonist Treatment (AVERROES) trial,⁹ which compared apixaban and aspirin
• The Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial comparing apixaban and warfarin¹⁰
• The Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF),¹¹ comparing rivaroxaban and warfarin
• RE-LY,⁸ comparing dabigatran and warfarin.

In the ARISTOTLE,¹⁰ ROCKET AF,¹¹ and RE-LY trials,⁸ the time that the warfarin patients’ INRs were in the therapeutic range varied from 55% to 68%. This seems low and is a problem when trying to compare therapies, but is probably about as high as one can expect in the real world.

In AVERROES,⁹ the combined rate of stroke and embolism was higher with aspirin than with apixaban. In the other trials, the rates were slightly better with the new drugs than with warfarin, and the rates of major hemorrhage and hemorrhagic stroke were only slightly higher with warfarin than with the new drugs. Because the differences in benefits and risks are so small, the main advantage of the newer drugs will probably be for patients who have difficulty staying in the therapeutic INR range on warfarin.

RATE CONTROL VS RESTORATION OF SINUS RHYTHM

Evidence is insufficient to determine the risk of very-long-term asymptomatic atrial fibrillation in patients on appropriate anticoagulation. Rate control is an option for asymptomatic patients but provides no change in quality of life and no definitive reduction in the risk of stroke. The main argument for restoring normal sinus rhythm in patients with mild to moderate symptoms is that it improves exercise capacity. The need for anticoagulation persists when patients are converted to sinus rhythm because the risk of recurrent atrial fibrillation remains high.

For patients with symptomatic atrial fibrillation, rate control is sometimes achieved with beta-blockers or calcium channel blockers. Rate control may be augmented with the addition of digoxin, but when used alone digoxin generally does not control the rate of atrial fibrillation. However, in many cases of atrial fibrillation, symptoms are not rate-related, and cardioversion to normal sinus rhythm should be attempted. In such cases, the symptoms may be attributable to a loss of atrial transport function.

Patients with the following risk factors should be admitted to the hospital to start antiarrhythmic drugs:

• Borderline or a long QTc interval at baseline (> 450 msec)
• Treatment with dofetilide (Tikosyn) because of its effects on the QT interval
• Heart failure or poor left-ventricular function
• Sinus node dysfunction
• Significant atrioventricular conduction disease.

Selecting an antiarrhythmic drug

Any of the antiarrhythmic drugs listed in Table 2 can be used for a patient with lone atrial fibrillation (ie, not caused by underlying heart disease). The choice of drug should be determined by whether coronary artery disease or renal failure is present as well. Liver disease or chronic obstructive pulmonary disease also may affect this decision.

Benefits of dronedarone are mixed

In a randomized trial of dronedarone vs placebo in patients with atrial fibrillation, the rate of death and the rate of first hospitalization due to a cardiovascular event at 21 months were significantly lower with dronedarone.¹² No difference was found between the two groups in the rate of death from all causes, but fewer people died of cardiovascular causes in the dronedarone group. More patients taking dronedarone developed bradycardia, QT-interval prolongation, nausea, diarrhea, rash, or a higher serum creatinine level. Gastrointestinal side effects are often a problem with dronedarone: 20% to 30% of patients cannot tolerate the drug.

Dronedarone may cause a small rise in creatinine, and although this effect should be monitored, by itself it should not be interpreted as impairment of renal function. In a study in healthy people,¹³ dronedarone caused a 10% to 15% increase in serum creatinine, but the glomerular filtration rate was unchanged, as were renal plasma flow and anion secretion.

Another trial, in patients with severe heart failure, found that patients taking dronedarone had higher rates of hospitalization and overall mortality, raising serious concern about the safety of this drug in patients with advanced heart failure.¹⁴

Singh et al¹⁵ pooled the data from two multicenter, randomized trials that compared dronedarone with placebo for maintaining sinus rhythm in patients with atrial fibrillation or flutter. The mean time to the recurrence of atrial fibrillation was 116 days with dronedarone and 53 days with placebo. Other trials also showed longer times to recurrence and lower recurrence rates with dronedarone. Although the differences were statistically significant, they may not be clinically meaningful for patients.

Dronedarone is structurally similar to amiodarone (Cordarone), but the two drugs work differently. A meta-analysis of clinical trials¹⁶ found that amiodarone recipients had a lower rate of recurrence of atrial fibrillation than did those receiving dronedarone.

Two safety warnings for dronedarone

In January 2011, the US Food and Drug Administration (FDA) issued an alert about cases of rare but severe liver injury in patients treated with dronedarone, including two cases of acute liver failure leading to liver transplantation.¹⁷

The Permanent Atrial Fibrillation Outcome Study Using Dronedarone on Top of Standard Therapy (PALLAS)¹⁸ compared dronedarone and placebo in patients with permanent atrial fibrillation. More people died or had serious cardiovascular adverse events in the dronedarone group. The study was stopped early after data monitoring showed that rates of death, stroke, and hospitalization for heart failure were two times higher in patients receiving dronedarone. This prompted the FDA to issue another safety alert in July 2011.

Interestingly, the PALLAS study did not set out to determine whether dronedarone controls atrial fibrillation, as the study patients had long-standing, persistent atrial fibrillation. The study was designed only to determine if the drug reduces the rate of adverse events; it clearly does not, and the study shows that dronedarone should not be used to control the heart rate in patients with persistent atrial fibrillation. Instead, its use is best restricted to patients with paroxysmal atrial fibrillation without significant cardiovascular disease.

ABLATION OF ATRIAL FIBRILLATION

Another way to try to restore sinus rhythm is to destroy or isolate the area that is generating the abnormal beats via a catheter-based procedure.

Radiofrequency ablation is generally tried in patients in whom one or two drugs have failed to control atrial fibrillation. Direct comparisons show that ablation is superior to drug therapy and is effective in about 75% of patients with paroxysmal atrial fibrillation vs 20% to 40% of patients on drug therapy. Ablation plus drug therapy is often more effective than either treatment alone.

Mechanisms of atrial fibrillation and ablation

In many cases, atrial fibrillation is stimulated by vagal and sympathetic inputs to the atrium that enter around the pulmonary veins and trigger electrical activations in the area, generating spiraling, reentering circuits. Focal atrial fibrillation also originates predominantly in the pulmonary veins. Ablation of tissue widely circumscribing the mouth of the pulmonary veins prevents the electrical signal from exiting into the atrium.

In about 11% to 37% of cases, atrial fibrillation originates elsewhere, eg, in the left atrium, in the superior vena cava, or in the vein of Marshall. Techniques have evolved to also ablate these regions.

Anticoagulation therapy is recommended before the procedure, and patients at low risk should continue it for a minimum of 2 months afterward. Patients with a higher CHADS₂ score should receive anticoagulation therapy for at least 1 year. The consensus statement by the Heart Rhythm Society¹⁹ recommends that patients remain on warfarin or one of the newer anticoagulants if their CHADS₂ score is 2 or higher. This is because patients have a significant risk of recurrence of atrial fibrillation after radiofrequency ablation, so if their stroke risk is high they should remain on anticoagulant therapy.

Ablation is usually effective, but it carries rare but serious risks

The efficacy of a single radiofrequency ablation procedure is in the range of 60% to 80% for paroxysmal atrial fibrillation and 40% to 60% for persistent atrial fibrillation. The Second International Ablation Registry²⁰ shows a success rate of about 75% in patients with paroxysmal atrial fibrillation and about 65% in patients with persistent and permanent atrial fibrillation. Registry data are often more favorable because reporting is optional, but these results are consistent with those from experienced medical centers. Rates of suppression of atrial fibrillation are higher in patients who also take antiarrhythmic drugs, making a “hybrid” approach useful when ablation alone fails.

According to a worldwide survey, the risk of serious complications is 4.5%. These include stroke (0.23%), tamponade (1.3%), and pulmonary vein stenosis (< 0.29%). The esophagus lies just behind the right atrium, and burning through and creating a fistula between them occurs in about 0.04% of cases and is almost uniformly fatal.²⁰

A second ablation procedure is sometimes indicated for the recurrence of atrial fibrillation, which is almost always caused by recovery of the pulmonary veins. Bhargava et al²¹ found that the success rate at Cleveland Clinic for a single procedure for paroxysmal atrial fibrillation was 77%, and that it was 92% after a repeat procedure. For persistent atrial fibrillation, success rates were 76% after the first procedure and 90% after the second. Even for long-standing persistent atrial fibrillation (ie, lasting more than 1 year), 80% success was achieved after two procedures. Patients who are less likely to have a successful ablation procedure are those with long-standing atrial fibrillation and coexisting heart disease, including severe valvular disease, although mitral regurgitation sometimes improves if sinus rhythm can be maintained.

The need for a second procedure

After ablation, patients should be closely monitored for a recurrence of atrial fibrillation. Continuous monitoring with implantable cardiac monitor loop recorders can detect unrecognized episodes of arrhythmia. Long-term follow-up is also required to track outcomes and quality of life.

According to the Heart Rhythm Society Task Force on Catheter and Surgical Ablation of Atrial Fibrillation,¹⁹ atrial fibrillation recurs after ablation in about 35% to 60% of patients in the first 3 months, with recurrence rates after 1 year ranging from 5% to 16%. The rate of success is determined by the skill of the surgeon, underlying heart disease, attention to follow-up, and how success is defined.

Freedom from recurrence early on is a good predictor that late recurrence is unlikely. Patients who only have a very early recurrence (within the first 4 weeks) are more likely to have long-term freedom from atrial fibrillation tha those who have recurrences after that time.²²

In a study of 831 patients, Hussein et al²³ found recurrence rates of 24% between months 3 to 13 following ablation and 9% after 12 months. At 55 months, 79% were free from atrial fibrillation without drugs, 11% were free of atrial fibrillation with medications, and 5% had refractory atrial fibrillation.

Recurrence—whether early or late—was more likely to occur in people with persistent vs paroxysmal atrial fibrillation. Other risk factors for late recurrence included older age and larger left atrial size (which is also a risk factor for recurrence on drug therapy). Although recurrent arrhythmia was most often atrial fibrillation, atrial flutter also occurred frequently (in 27% of patients with late recurrence). Three patients (4% of patients with late recurrence) developed atrial tachycardia.²³

In patients with early recurrence, 81% underwent repeat ablation, all of whom had recovery of one or more pulmonary veins. After the second ablation, 21% had recurrence, 65% of whom were controlled by medications.²³

Whether a patient should undergo subsequent ablation procedures depends on the severity of symptoms, the likelihood of success (based on an educated guess), and the patient’s willingness to undergo another procedure.

ATRIAL APPENDAGE OCCLUSION DEVICE UNDER INVESTIGATION

New devices are being investigated that occlude the left atrial appendage to try to prevent embolization.

The Watchman device, resembling an umbrella, is implanted via a percutaneous catheter in the left atrial appendage, closing it off to preclude a thrombus from forming in the appendage and embolizing to the body. Clinical trials showed that patients who received a device had a slightly lower risk of stroke than otherwise seen in clinical practice.²⁴ Safety and efficacy are still being determined.

The device cannot be deployed in a patient with an existing thrombus because of the danger of dislodging the thrombus, allowing it to embolize.

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.

Supplement Editors:
Nathan Pennell, MD, PhD, and Peter Mazzone, MD

Contents

Lung cancer screening: Examining the issues
Peter Mazzone

Treatment implication of the new lung cancer staging system
Cristina P. Rodriguez

Bronchoscopy and endobronchial ultrasound for diagnosis and staging of lung cancer
Francisco Aécio Almeida

Preoperative evaluation of the lung resection candidate
Peter Mazzone

Video-assisted thoracoscopic surgery for the treatment of lung cancer
Sudish Murthy

Stereotactic body radiotherapy for stage I non–small cell lung cancer
Kevin Stephans

Locally advanced non–small cell lung cancer: What is the optimal concurrent chemoradiation regimen?
Gregory M.M. Videtic

The role of surgery for locally advanced non–small cell lung cancer
David P. Mason

The role of adjuvant chemotherapy in early-stage and locally advanced non–small cell lung cancer
Marc Shapiro

Selection of chemotherapy for patients with advanced non–small cell lung cancer
Nathan A. Pennell

The emerging role of palliative medicine in the treatment of lung cancer patients
Mellar P. Davis

Personalized targeted therapy in advanced non–small cell lung cancer
Patrick C. Ma

Supplement Editors:
Nathan Pennell, MD, PhD, and Peter Mazzone, MD

Contents

Lung cancer screening: Examining the issues
Peter Mazzone

Treatment implication of the new lung cancer staging system
Cristina P. Rodriguez

Bronchoscopy and endobronchial ultrasound for diagnosis and staging of lung cancer
Francisco Aécio Almeida

Preoperative evaluation of the lung resection candidate
Peter Mazzone

Video-assisted thoracoscopic surgery for the treatment of lung cancer
Sudish Murthy

Stereotactic body radiotherapy for stage I non–small cell lung cancer
Kevin Stephans

Locally advanced non–small cell lung cancer: What is the optimal concurrent chemoradiation regimen?
Gregory M.M. Videtic

The role of surgery for locally advanced non–small cell lung cancer
David P. Mason

The role of adjuvant chemotherapy in early-stage and locally advanced non–small cell lung cancer
Marc Shapiro

Selection of chemotherapy for patients with advanced non–small cell lung cancer
Nathan A. Pennell

The emerging role of palliative medicine in the treatment of lung cancer patients
Mellar P. Davis

Personalized targeted therapy in advanced non–small cell lung cancer
Patrick C. Ma

Supplement Editors:
Nathan Pennell, MD, PhD, and Peter Mazzone, MD

Contents

Lung cancer screening: Examining the issues
Peter Mazzone

Treatment implication of the new lung cancer staging system
Cristina P. Rodriguez

Bronchoscopy and endobronchial ultrasound for diagnosis and staging of lung cancer
Francisco Aécio Almeida

Preoperative evaluation of the lung resection candidate
Peter Mazzone

Video-assisted thoracoscopic surgery for the treatment of lung cancer
Sudish Murthy

Stereotactic body radiotherapy for stage I non–small cell lung cancer
Kevin Stephans

Locally advanced non–small cell lung cancer: What is the optimal concurrent chemoradiation regimen?
Gregory M.M. Videtic

The role of surgery for locally advanced non–small cell lung cancer
David P. Mason

The role of adjuvant chemotherapy in early-stage and locally advanced non–small cell lung cancer
Marc Shapiro

Selection of chemotherapy for patients with advanced non–small cell lung cancer
Nathan A. Pennell

The emerging role of palliative medicine in the treatment of lung cancer patients
Mellar P. Davis

Personalized targeted therapy in advanced non–small cell lung cancer
Patrick C. Ma

For most patients with gastroesophageal reflux disease (GERD), a proton pump inhibitor (PPI) is the first choice for treatment.¹ But some patients have symptoms that persist despite PPI therapy, some desire surgery despite successful PPI therapy, and some have persistent extraesophageal symptoms or other complications of reflux. For these patients, surgery is an option.²

In this article, we review the management of GERD and clarify the indications for antireflux surgery based on evidence of safety and efficacy.

GERD DEFINED: SYMPTOMS OR COMPLICATIONS

Defining the role of antireflux surgery is difficult, given the variety of presentations and the absence of a gold standard for diagnosing GERD. Most adults experience several episodes of physiologic reflux daily without symptoms.³ But a broad array of symptoms have been attributed to GERD, including chest pain, cough, and sore throat, and some conditions caused by acid reflux (eg, Barrett esophagus) can be asymptomatic.^4,5

HEARTBURN ISN’T ALWAYS GERD

Typical GERD presents with the classic symptoms of pyrosis (heartburn) or acid regurgitation, or both.

Although these symptoms are often thought to be specific for GERD, other causes of esophageal injury— eg, eosinophilic esophagitis, infection (Candida, cytomegalovirus, herpes simplex virus), pill-induced esophagitis, or radiation therapy—can produce similar symptoms. Other causes, including coronary artery disease, biliary colic, foregut malignancy, or peptic ulcer disease, should also be considered in patients with supposedly typical GERD. Life-threatening mimics of GERD, such as unstable angina, should be excluded if they are likely, before proceeding with evaluating for possible GERD. Therefore, the initial history and examination should focus on appropriate diagnosis, with careful delineation of symptom quality.

Alarm features for advanced pathology^6–8 include involuntary weight loss, dysphagia, vomiting, evidence of gastrointestinal blood loss, anemia, chest pain, and an epigastric mass.⁷ Admittedly, these features are only mediocre for detecting or excluding gastric or esophageal cancer, with a sensitivity of 67% and a specificity 66%.⁹ Nevertheless, they should prompt an endoscopic examination. In patients who have alarm features but have not yet been treated for GERD, upper endoscopy can identify an abnormality in about 60% of patients.^10–12

PPIs HAVE REPLACED ANTACIDS AND HISTAMINE-2 RECEPTOR ANTAGONISTS

When the symptoms suggest GERD and no alarm features are present, an initial trial of the following lifestyle changes is reasonable:

• Avoiding acidic or refluxogenic foods (coffee, alcohol, chocolate, peppermint, fatty foods, citrus foods)
• Avoiding certain medications (anticholinergics, estrogens, calcium-channel blockers, nitroglycerine, benzodiazepines)
• Losing weight
• Quitting smoking
• Raising the head of the bed
• Staying upright for 2 to 3 hours after meals.

For someone with mild symptoms, these changes pose minimal risk. Unfortunately, they are unlikely to provide adequate symptom control for most patients.^13–17

Before PPIs were invented, drug therapy for GERD symptoms that did not resolve with lifestyle changes consisted of antacids and, later, histamine-2 receptor antagonists. When maximal therapy failed to control symptoms, fundoplication surgery was considered an appropriate next step.

PPIs substantially changed the management of GERD, suppressing acid secretion much better than histamine-2 receptor antagonists. Taken 30 minutes before breakfast, a single daily dose of a PPI normalizes esophageal acid exposure in 67% of patients.¹⁸ Adding a second dose 30 minutes before dinner raises the number to more than 90%.¹⁹

PPIs have consistently outperformed histamine-2 blockers in the healing of esophagitis and in improving heartburn symptoms and are now the first-line medical therapy for uncomplicated GERD.^6,8,20–25

WHEN PPIs WORK, SURGERY OFFERS NO ADVANTAGE

The LOTUS trial (Long-Term Usage of Esomeprazole vs Surgery for Treatment of Chronic GERD) compared long-term drug therapy with surgery to maintain remission of symptoms in GERD.²⁷ In this trial, 554 patients whose symptoms initially responded to the PPI esomeprazole (Nexium) were randomized to continue to receive esomeprazole (n = 266) or to undergo laparoscopic antireflux surgery (288 were randomly assigned, and 248 had the operation). Dose adjustment of the esomeprazole was allowed (20–40 mg/day). A total of 372 patients completed 5 years of follow-up (192 esomeprazole, 180 surgery).

Symptoms stayed in remission in 92% of the esomeprazole group and 85% of the surgery group (P = .048). However, the difference was no longer statistically significant after modeling the effects of study dropout. The rate of severe adverse events was similar in both groups: 24.1% with esomeprazole and 28.6% with surgery.

These findings indicate that if symptoms fully abate with medical therapy, surgery offers no advantage. In addition, patients who desire surgery in the hope of avoiding lifelong drug therapy should be made aware that drug therapy and reoperation are often necessary after surgery.²⁸ In most cases, antireflux surgery is unnecessary for patients whose GERD fully responds to PPI therapy.

IF PPIs FAIL, FURTHER TESTING NEEDED

But many patients who take PPIs still have symptoms, even though these drugs suppress acid secretion and heal esophagitis. In fact, symptoms completely resolve in only about one-half of patients with erosive disease and one-third of those without erosive disease.²¹

Reasons for an incomplete symptomatic response to PPIs are various. Acid reflux can persist, but this accounts for only 10% of cases.²⁹ About one-third of patients have persistent reflux that is weakly acidic, with a pH higher than 4.29. However, most patients with persistent typical GERD symptoms do not have significant, persistent reflux, or their symptoms are not related to reflux events. In these cases, an alternative cause of the refractory symptoms should be sought.

Further diagnostic testing is indicated when symptoms persist despite PPI therapy. Upper endoscopy will reveal an abnormality such as persistent erosive esophagitis, eosinophilic esophagitis, esophageal stricture, Barrett esophagus, or esophageal cancer in roughly 10% of patients in whom empiric therapy fails.¹⁰

Although patients with persistent symptoms have not been enrolled in many randomized controlled trials, a multivariate analysis showed that failure of medical therapy heralds a poor response to surgery.³⁰ Data such as these have led most experts to discourage fundoplication for such patients now, unlike in the pre-PPI era.

pH and intraluminal impedance testing

However, this recommendation against surgery is not a hard-and-fast rule.

In patients with esophageal regurgitation, most will not achieve adequate relief of symptoms with PPI therapy alone.³⁴ The therapeutic gain of PPI therapy vs placebo averaged just 17% in seven randomized, controlled trials, more than 20% less than the response rate for heartburn.³⁴ This is likely because of structural abnormalities such as reduced lower esophageal sphincter pressure, hiatal hernia, or delayed gastric emptying. Antireflux surgery can correct these structural abnormalities or prevent them from causing so much trouble; however, the presence of true regurgitation should first be confirmed by MII testing. If regurgitation is confirmed, antireflux surgery is warranted, particularly in patients with nocturnal symptoms who may be at high risk of aspiration. With careful patient selection, regurgitation symptoms improve in about 90% after surgery.²

In patients with heartburn, if esophageal acid exposure continues to be abnormal on MII-pH testing, then an escalation of therapy may improve symptoms, particularly if symptoms occur during reflux or if they partially responded to PPI therapy. Options in this scenario include alteration or intensification of acid-suppressive therapy, treatment with baclofen (Lioresal), and antireflux surgery.^18,35,36 In randomized controlled trials of patients whose symptoms partially responded to PPIs, antireflux surgery has performed similarly to PPIs in terms of improving typical GERD symptoms, particularly regurgitation.^27,37–41 Although this scenario is a reasonable indication for antireflux surgery, recommendations should be made with appropriate restraint since it is not easily reversible, some patients experience complications, and up to one-third will have no therapeutic benefit.³⁰

Nonacid reflux. In some cases, MII-pH testing during PPI therapy will reveal reflux of weakly acidic (pH > 4) or alkaline stomach contents, often called “nonacid reflux.”²⁹ Nonacid reflux is often present in patients with esophagitis that persists despite PPI therapy, indicating that even weakly acidic stomach contents can injure the mucosa.⁴² Since intensifying the acid-suppressive therapy is unlikely to improve these symptoms, antireflux surgery may have a role.

In one study,⁴³ nonacid reflux was well controlled by laparoscopic Nissen fundoplication, although 15 (48%) of 31 patients had persistent symptoms of GERD after surgery. No patient had a strong symptom correlation with postoperative reflux events, suggesting an alternative cause of the persistent symptoms. Therefore, antireflux surgery for nonacid reflux should be limited exclusively to patients with strong symptom correlation, and even then it should be considered with restraint, given the limited evidence for benefit and the potential for harm.

If testing is negative. In studies investigating the diagnostic yield of MII-pH testing, more than 50% of patients who had refractory symptoms had a negative MII-pH test.²⁹ In such situations, when the symptoms are strongly correlated with reflux events, the patient is said to have “esophageal hypersensitivity.” A few small studies have suggested that such patients may benefit from surgery, but these data have not been replicated in randomized controlled trials.³²

When the testing is negative and there is no correlation between the patient’s symptoms and reflux events, the patient is unlikely to benefit from antireflux surgery. Care of these patients is beyond the scope of this review.

SURGERY RARELY IMPROVES COUGH, ASTHMA, OR LARYNGITIS

GERD has been implicated as a cause of chronic cough, asthma, and laryngitis, although each of these has many potential causes.^44–46 Despite these associations, the evidence for therapeutic benefit from antireflux therapy is weak.

PPI therapy shows no benefit over placebo for chronic cough of uncertain etiology, but some benefit if GERD is objectively demonstrated.⁴⁷ Laryngitis resolved in just 15% of patients on esomeprazole vs 16% of patients on placebo after excluding patients with moderate to severe heartburn.⁴⁸

In a large randomized controlled trial in patients with asthma, there was no overall improvement in peak flow for the PPI group vs the placebo group, although significant improvement occurred in patients with heartburn and nocturnal respiratory symptoms.⁴⁶

Potent antisecretory therapy seems to improve extraesophageal symptoms when typical GERD symptoms are also present, but it otherwise has shown little evidence of benefit.

The evidence for a benefit from antireflux surgery in patients with extraesophageal GERD syndromes is even more limited. Although one systematic review⁴⁹ found that cough and other laryngeal symptoms improved in 60% to 100% of patients with objective evidence of GERD who underwent fundoplication, virtually all of the studies were uncontrolled case series.⁴⁹

The lone randomized controlled trial in the systematic review compared Nissen fundoplication with ranitidine (Zantac) or antacids only for patients with asthma and GERD, and found no significant difference in peak expiratory flow among the three groups after 2 years. However, asthma symptom scores improved in 75% of the surgical group, 9% of the medical group, and 4% of the control group.⁵⁰

In a study that was not included in the prior systematic review, patients with laryngopharyngeal reflux unresponsive to aggressive acid suppression who subsequently underwent fundoplication fared no better than those who did not.⁵¹

Thus, based on the available data, antireflux surgery is only rarely indicated for extraesophageal symptoms, especially in patients who have no typical GERD symptoms or in patients whose symptoms are refractory to medical therapy.

SURGERY FOR EROSIVE ESOPHAGITIS OR BARRETT ESOPHAGUS IF PPI FAILS

Lifelong antireflux therapy is indicated for patients with severe erosive esophagitis or Barrett esophagus. Erosive esophagitis recurs in more than 80% within 12 months of discontinuing antisecretory therapy.⁵² Both Barrett esophagus and esophageal adenocarcinoma are strongly associated with GERD, and nearly 10% of patients with chronic reflux have Barrett esophagus.^53,54 It is suspected that suppressing reflux reduces the rate of progression of Barrett esophagus to esophageal adenocarcinoma, but this remains to be proven.

Perhaps the strongest indication for surgery in the PPI era is for patients who have persistent symptoms and severe erosive esophagitis (Los Angeles grade C or D) despite high-dose PPI therapy. If other causes of persistent esophagitis have been ruled out, fundoplication can induce healing and improve symptoms.^55,56 In these cases, surgery is done to induce remission of the disease when maximal medical therapy has been truly unsuccessful.

Randomized controlled trials suggest that medical and surgical therapies are equally effective for preventing the recurrence of erosive esophagitis or the progression of Barrett esophagus. In a study of 225 patients, at 7 years of follow-up, esophagitis had recurred in 10.4% of patients on omeprazole vs 11.8% of those who had undergone antireflux surgery.⁴⁰ Similarly, open Nissen fundoplication was no different from drug therapy (histamine-2 receptor antagonist or PPI) for progression of Barrett esophagus over a median of 5 years.⁵⁷ A meta-analysis with nearly 5,000 person-years each in the medical and surgical groups also found no significant difference in rates of cancer progression.⁵⁸

Notably, symptoms such as dysphagia, flatulence, and the inability to burp occurred significantly more often in the surgical groups in these studies.

In view of these data, antireflux surgery has no significant advantage over medical therapy for maintaining healing of erosive esophagitis or preventing progression of Barrett esophagus. Thus, it should be reserved for patients who do not desire lifelong drug therapy, provided they understand that there is no therapeutic advantage for their esophagitis or for Barrett esophagus.

SPECIFIC INDICATIONS FOR ANTIREFLUX SURGERY

Now that we have PPIs, several situations remain in which surgery for GERD is either indicated or worth considering.

Antireflux surgery is clearly indicated for:

• Patients with erosive esophagitis that does not heal with maximal drug therapy
• Patients with volume regurgitation, particularly if it occurs at night or if there is evidence of aspiration
• Patients who require lifelong treatment for reflux but who have had a serious adverse event related to PPI therapy, such as refractory Clostridium difficile infection.

Antireflux surgery is also worth considering in patients who for personal reasons wish to avoid long-term or lifelong drug therapy.

Patients should be informed, however, that antireflux surgery has not been shown to be better than medical therapy for maintaining remission of symptoms, for preventing progression of Barrett esophagus, or for maintaining healing of erosive esophagitis. Medical therapy is still the first option for these patients.

Surgery may also be considered in patients with persistent symptoms who have a partial response to medical therapy, who show persistent acidic or weakly acidic reflux on MII-pH testing, and whose symptoms have been correlated with reflux events. Although surgery is not sure to improve their symptoms, benefit is more likely in this patient population compared with those without these characteristics.

Extraesophageal GERD

In patients suspected of having extraesophageal GERD, surgery should be considered if typical GERD symptoms are present and improve with PPI therapy, if the extraesophageal syndrome partially responds to PPI therapy, and if MII-pH testing demonstrates a correlation between symptoms and reflux. Surgery may have a stronger indication in this setting if the patient has nocturnal reflux or extraesophageal symptoms.

When is surgery not an option?

In general, surgery should not be considered in patients who do not have a partial response to PPI therapy or who do not have a strong symptom-reflux correlation on MII-pH testing. In all cases of failed medical therapy without persistent severe erosive disease, the threshold for opting for surgery should be high, given the uncertain response of these patients to surgery.

Peristaltic dysfunction is a relative but not an absolute contraindication to surgery.⁵⁹

RISKS, BENEFITS OF SURGERY FOR GERD

The patient’s preference for surgery over drug therapy should always be balanced against the risks of surgery, including both short-term and long-term adverse events, to allow the patient to make an adequately informed decision (Table 2).^2,26