Cleveland Clinic Journal of Medicine

Many questions about systemic lupus erythematosus (SLE, lupus) remain unanswered. Why is this disease so difficult to diagnose even for rheumatologists? Why does lupus tend to develop in previously healthy young women? Why does the disease manifest in so many ways? Why are our current treatments suboptimal?

This article addresses these questions in a brief overview and update of SLE, with an emphasis on clinical pearls regarding prevention and treatment that are relevant to any physician who sees patients with this disease.

WOMEN AND MINORITIES ARE OVERREPRESENTED

Women have a much higher prevalence of almost all autoimmune diseases. SLE has a 12:1 female-to-male ratio during the ages of 15 to 45 years, but when disease develops in either children or the elderly, the female-to-male ratio is only 2:1.

African Americans, Asian Americans, and Hispanics have about a three to four times higher frequency of lupus than white non-Hispanics and often have more severe disease.

WHY IS SLE SO DIFFICULT TO DIAGNOSE?

SLE is frequently overlooked; patients spend an average of 4 years and see three physicians before the disease is correctly diagnosed. Part of the problem is that presentations of the disease vary so widely between patients and that signs and symptoms evolve over time. Often, physicians do not consider SLE in the differential diagnosis.

On the other hand, SLE is also often over-diagnosed. Narain et al¹ evaluated 263 patients who had a presumptive diagnosis of SLE. Only about half of the patients had a confirmed diagnosis; about 5% had a different autoimmune disease, such as scleroderma, systemic sclerosis, Sjögren syndrome, or polymyositis; 5% had fibromyalgia; 29% tested positive for ANA but did not have an autoimmune disease; and 10% had a nonrheumatic disease, such as a hematologic malignancy with rheumatic disease manifestations. For patients referred by a community rheumatologist, the diagnostic accuracy was better, about 80%.

The traditional classification criteria for SLE^2,3 are problematic. Some criteria are very specific for SLE but are not very sensitive—eg, anti-double-stranded DNA is present in about half of patients with SLE. Others tests, like ANA, are sensitive but not specific—although ANA is present in 95% of patients with SLE, the positive predictive value of the test for SLE for any given patient is only 11%.

Other criteria are highly subjective, including oral ulcers and photosensitivity. These signs may be present in normal individuals who get an occasional aphthous ulcer or who are fair-skinned and burn easily with prolonged sun exposure. It takes a trained clinician to distinguish these from the photosensitivity and oral ulcers associated with lupus.

Many diseases can mimic SLE

Fibromyalgia frequently presents in women and may include joint and muscle aches, fatigue, and occasionally a positive ANA. ANA may be seen in about 15% of healthy women.

Sjögren syndrome can also present with arthritis, fatigue, and a positive ANA; it is commonly overlooked because physicians do not often think to ask about the classic symptoms of dry eyes and dry mouth.

Dermatomyositis causes rashes that have many features in common with SLE. Even the skin biopsy is often indistinguishable from SLE.

Hematologic problems, such as idiopathic or thrombotic thrombocytopenic purpura, primary antiphospholipid syndrome, and hematologic neoplasms, can cause serologic changes, a positive ANA, and other manifestations seen in SLE.

Drug-induced lupus should always be considered in older patients presenting with SLE-like disease. Now with the use of minocycline (Minocin) and other related agents for the treatment of acne, we are seeing younger women with drug-induced lupus.

PATIENTS ASK ‘WHY ME?’

Lupus typically develops in a young woman who was previously healthy. Such patients inevitably wonder, why me?

Lupus is like a puzzle, with genetics, gender, and the environment being important pieces of the puzzle. If all the pieces come together, people develop defective immune regulation and a break in self-tolerance. Everyone generates antibodies to self, but these low-affinity, nonpathologic antibodies are inconsequential. In SLE, autoantibodies lead to the formation of immune complexes, complement activation, and tissue damage.

Genetics plays an important role

Genetics plays an important role but is clearly not the only determining factor. Clustering in families has been shown, although a patient with lupus is more likely to have a relative with another autoimmune disease, especially autoimmune thyroid disease, than with SLE. The likelihood of an identical twin of a patient with SLE having the disease is only 25% to 30%, and is only about 5% for a fraternal twin.

In the first few months of 2008, four major studies were published that shed light on the genetics of SLE.^4–7 Together, the studies evaluated more than 5,000 patients with SLE using genome-wide association scans and identified areas of the genome that are frequently different in patients with lupus than in healthy controls. Three of the four studies identified the same genetic area as important and supported the concept that B cells and complement activation play important roles in the disease pathogenesis.

Although over 95% of cases of SLE cannot be attributed to a single gene, there are rare cases of lupus that may provide important clues to mechanisms of disease. For example a homozygous deficiency of C1q (an early component of complement) is extremely rare in lupus but is associated with the highest risk (nearly 90%) of developing the disease. Deficiencies in other components of the complement cascade also carry a high risk of disease development.

Investigators discovered that C1q plays an important role in clearing away apoptotic cellular debris. If a person is deficient in C1q, clearance of this debris is impaired. In a person genetically predisposed to getting lupus, the immune system now has an opportunity to react to self-antigens exposed during apoptosis that are not being cleared away.

Even though lupus cases cannot be explained by an absence of C1q, a defect in the clearance of apoptotic cells is a common, unifying feature of the disease.

Immune response is enhanced by environmental factors

Environmental factors, especially sun exposure, are also important. Following sunburn, skin cells undergo massive cell death, and patients with lupus have a huge release of self-antigens that can be recognized by the immune system. Sunburn is like having a booster vaccine of self-antigen to stimulate autoantibody production. Not only does the skin flare, but internal organs can also flare after intense sun exposure.

LUPUS SURVIVAL HAS IMPROVED; DISEASES OF AGING NOW A FOCUS

In 1950, only 50% of patients with SLE survived 5 years after diagnosis; now, thanks to better treatment and earlier diagnosis, 80% to 90% survive at least 10 years.

Early on, patients tend to die of active disease (manifestations of vasculitis, pulmonary hemorrhage, kidney problems) or infection. Over time, cardiovascular disease and osteoporosis become more of a problem. Patients also have a higher risk of cancer throughout life.

Lupus has an unpredictable course, with flares and remissions. But underlying the reversible inflammatory changes is irreversible organ damage caused by the disease itself and, possibly, by treatment. Preventing bone disease, heart disease, and cancer now play more prominent roles in managing SLE.

Increased bone disease

Fracture rates are higher than expected in women with lupus; Ramsey-Goldman et al⁸ calculated the rate as five times higher than in the general population. The increased risk of osteoporosis is partly due to treatment with corticosteroids, but it is also likely caused by inflammation from lupus. Even controlling for steroid use, increased bone loss is still evident in patients with SLE.

African American women with lupus are not exempt. Lee et al⁹ found that, after adjusting for body mass, steroid use, thyroid disease, and menopausal status, African American women with SLE had more than five times the risk of low bone mineral density in the spine than white women with the disease.

Increased cancer risk

Patients with SLE have an increased risk of hematologic cancer and possibly lung and hepatobiliary cancers.

Bernatsky et al¹⁰ evaluated cancer risk in an international cohort of patients with SLE from 23 sites. Among patients with SLE, for all cancers combined, the standardized incidence ratio was 1.2; for hematologic cancers the ratio was 2.8; and for non-Hodgkin lymphoma it was 2.4. Surprisingly, although SLE is primarily a disease of women, reproductive cancer rates in patients with SLE did not differ from background rates. Bernatsky et al did not compare rates of cervical cancer, as many cancer registries do not record it. However, studies from the National Institutes of Health indicate that cervical dysplasia is common in patients with lupus.

Other interesting findings included an increased risk of hepatobiliary cancer, especially among men with SLE. Lung cancers were also increased, which has been observed in patients with other autoimmune diseases such as scleroderma and polymyositis. Smoking is a strong predictor for developing autoimmune conditions and may play a role in the observed increased cancer risk.

Early and advanced cardiovascular disease

Patients with SLE are at high risk of atherosclerotic cardiovascular disease. At the University of Pittsburgh Medical Center from 1980 to 1993, we compared the incidence of myocardial infarction in nearly 500 women with SLE and more than 2,000 women of similar age in the Framingham Offspring Study. At ages 15 to 24, women with lupus had a rate of 6.33 per 1,000 person-years; at age 25 to 34, the rate was 3.66 per 1,000 person-years. None of the Framingham women in those age groups had events.

Women ages 35 to 44 with lupus had a risk of heart attack 50 times higher than women in the Framingham cohort, and women in older age groups had a risk 2.5 to 4 times higher.¹¹

Subclinical cardiovascular disease is also increased in women with SLE. Asanuma et al¹² used electron-beam computed tomography to screen for coronary artery calcification in 65 patients with SLE and 69 control subjects with no history of coronary artery disease matched for age, sex, and race. Calcification was present in 31% of patients with lupus vs 9% of controls (P = .002). Roman et al¹³ performed carotid ultrasonography on 197 patients with lupus and 197 matched controls and found more plaque in patients with lupus (37%) than in controls (15%, P < .001).

Other data also suggest that women with lupus have advanced cardiovascular disease and develop it early, with most studies finding the greatest relative risk of cardiovascular disease between ages 18 and 45 years.

Traditional risk factors for cardiovascular disease cannot fully explain the increased risk. Many patients with lupus have metabolic syndrome, hypertension, and renal disease, but even after adjusting for these risk factors, patients with lupus still have about a 7 to 10 times higher risk of nonfatal coronary heart disease and a 17 times higher risk of fatal coronary heart disease.¹⁴

Many investigators are now exploring the role of immune dysfunction and inflammation in cardiovascular disease. A number of biomarkers have been proposed for predicting risk of cardiovascular disease in the general population. The list includes many inflammatory factors that rheumatologists have been studying for decades, including myeloperoxidase, autoantibodies, inflammatory cytokines, tumor necrosis factor alpha, and adhesion molecules, many of which also play a role in autoimmunity.

In our patients with SLE, we found that about 90% had three or more modifiable cardiovascular risk factors that were not being addressed appropriately (unpublished data). Lipid management was the least often addressed by rheumatologists and primary caregivers.

There is reason to believe that lupus patients are a high-risk group that merit aggressive risk-factor management, but no formal recommendations can be made without clear evidence that this approach improves outcomes.

SLE INCREASES THE RISK OF ADVERSE PREGNANCY OUTCOMES

Women with SLE more commonly miscarry and deliver low-birth-weight babies than do other women. A history of renal disease is the factor most predictive of poor pregnancy outcome, and the presence of certain autoantibodies increases the risk of neonatal lupus.

We recommend that women with lupus have inactive disease for at least 6 months before becoming pregnant.

ORAL CONTRACEPTIVES AND HORMONE REPLACEMENT

Hormone replacement therapy and oral contraceptives do not increase the risk of significant disease activity flares in lupus. However, women with lupus have an increased risk of cardiovascular disease and thrombosis.

Buyon et al¹⁵ randomly assigned 351 menopausal women with inactive or stable active SLE to receive either hormone replacement therapy or placebo for 12 months. No significant increase in severe flares of the disease was observed, although the treatment group had a mild increase in minor flares.

Petri et al¹⁶ randomly assigned 183 women with inactive or stable active SLE to receive either combined oral contraceptives or placebo for 12 months and found similar rates of disease activity between the two groups.

A weakness of these trials is that women with antiphospholipid antibodies in high titers or who had previous thrombotic events were excluded.

TREATMENTS ON THE HORIZON?

In the past 50 years, only three drug treatments have been approved for lupus: corticosteroids, hydroxychloroquine, and aspirin. Fortunately, research in autoimmune diseases has rapidly expanded, and new drugs are on the horizon.

Mycophenolate mofetil (CellCept) may be a reasonable alternative to cyclophosphamide (Cytoxan) for lupus nephritis and may be appropriate as maintenance therapy after induction with cyclophosphamide.

Ginzler et al,¹⁷ in a randomized, open-label trial in 140 patients with active lupus nephritis, gave either oral mycophenolate mofetil (initial dosage 1,000 mg/day, increased to 3,000 mg/day) or monthly intravenous cyclophosphamide (0.5 g/m², increased to 1.0 g/m²). Mycophenolate mofetil was more effective in inducing remission than cyclophosphamide and had a better safety profile.

The Aspreva Lupus Management Study was designed to assess the efficacy of oral mycophenolate mofetil compared with intravenous cyclophosphamide in the initial treatment of patients with active class III–V lupus nephritis and to assess the long-term efficacy of mycophenolate mofetil compared with azathioprine in maintaining remission and renal function. It was the largest study of mycophenolate mofetil in lupus nephritis to date. There were 370 patients with SLE enrolled. In the 24-week induction phase, patients were randomized to receive open-label mycophenolate mofetil with a target dose of 3 g/day or intravenous cyclophosphamide 0.5 to 1.0 g/m² in monthly pulses. Both groups received prednisone. Response to treatment was defined as a decrease in proteinuria (as measured by the urinary protein-creatinine ratio) and improvement or stabilization in serum creatinine.

The results (presented at the American College of Rheumatology Meeting, November 6–11, 2007, in Boston, MA) showed that 104 (56%) of the 185 patients treated with mycophenolate mofetil responded, compared with 98 (53%) of the 185 patients treated with intravenous cyclophosphamide (P = .575). The study therefore did not meet its primary objective of showing a superior response rate with mycophenolate mofetil compared with cyclophosphamide. There was no difference in adverse events. It is this author’s opinion that having an agent that is at least as good as cyclphosphamide in treating lupus nephritis is a major step forward.

Mycophenolate mofetil can cause fetal harm and should not be used during pregnancy. It is recommended that the drug be stopped for 3 to 6 months before a woman tries to conceive.

New drugs target B cells

Many new drugs for lupus target B cells.

Rituximab (Rituxan) is a monoclonal antibody that depletes B cells by targeting the B-cell-specific antigen CD20. It has been studied for treating lupus in several open-label studies that altogether have included more than 400 patients.^18–21 Regimens included either those used in oncology for treatment of lymphoma or those used in rheumatoid arthritis, coupled with high-dose corticosteroids and cyclophosphamide. In early studies, nearly 80% of treated patients entered at least partial remission, and 25% to 50% are still in remission more than 12 months later.

The first randomized controlled trial of rituximab vs placebo was recently completed and presented at the American College of Rheumatology meeting, October 24–28, 2008, in Boston, MA. The EXPLORER trial (sponsored by Genentech) included 257 patients with moderate to severe disease activity. The results showed that there was no difference in major or partial clinical response (based on a change in the British Isles Lupus Assessment Group index) in those on rituximab (28.4%) vs placebo (29.6%) at 12 months (P = .97). Overall, adverse events were balanced between the groups. It is this author’s opinion that the bar for “response” was set very high in this study, considering that all patients who entered were fairly sick and received significant doses of corticosteroids that were tapered over the course of the trial.

B-cell toleragens, which render B cells incapable of presenting specific antigens, are also of interest.

Other experimental drugs target the soluble cytokine BLyS, which normally binds to a B-cell receptor and prolongs B-cell survival. It may also be possible to inhibit costimulatory pathways (which are normally important for inducing activation, proliferation, and class-switching of B cells) with the use of cytotoxic T-lymphocyte-associated antigen 4 immunoglobulin inhibitor (CTLA4Ig) and anti-CD40 ligand.

The results of a 12-month exploratory, phase II trial of abatacept (Bristol-Myers Squibb) in patients with SLE and active polyarthritis, serositis, or discoid lesions were presented at the American College of Rheumatology meeting in 2008. The primary and secondary end points (based on an adjudicated British Isles Lupus Assessment Group index) were not met. There were no differences in adverse events. Post hoc analyses of other clinical end points and biomarkers suggested that abatacept may have benefit in lupus. Further studies are under way.

Downstream blockade may also be useful, with drugs that inhibit inflammatory cytokines, particularly interferon alfa. This is now being tested in clinical trials.

Many questions about systemic lupus erythematosus (SLE, lupus) remain unanswered. Why is this disease so difficult to diagnose even for rheumatologists? Why does lupus tend to develop in previously healthy young women? Why does the disease manifest in so many ways? Why are our current treatments suboptimal?

This article addresses these questions in a brief overview and update of SLE, with an emphasis on clinical pearls regarding prevention and treatment that are relevant to any physician who sees patients with this disease.

WOMEN AND MINORITIES ARE OVERREPRESENTED

Women have a much higher prevalence of almost all autoimmune diseases. SLE has a 12:1 female-to-male ratio during the ages of 15 to 45 years, but when disease develops in either children or the elderly, the female-to-male ratio is only 2:1.

African Americans, Asian Americans, and Hispanics have about a three to four times higher frequency of lupus than white non-Hispanics and often have more severe disease.

WHY IS SLE SO DIFFICULT TO DIAGNOSE?

SLE is frequently overlooked; patients spend an average of 4 years and see three physicians before the disease is correctly diagnosed. Part of the problem is that presentations of the disease vary so widely between patients and that signs and symptoms evolve over time. Often, physicians do not consider SLE in the differential diagnosis.

On the other hand, SLE is also often over-diagnosed. Narain et al¹ evaluated 263 patients who had a presumptive diagnosis of SLE. Only about half of the patients had a confirmed diagnosis; about 5% had a different autoimmune disease, such as scleroderma, systemic sclerosis, Sjögren syndrome, or polymyositis; 5% had fibromyalgia; 29% tested positive for ANA but did not have an autoimmune disease; and 10% had a nonrheumatic disease, such as a hematologic malignancy with rheumatic disease manifestations. For patients referred by a community rheumatologist, the diagnostic accuracy was better, about 80%.

The traditional classification criteria for SLE^2,3 are problematic. Some criteria are very specific for SLE but are not very sensitive—eg, anti-double-stranded DNA is present in about half of patients with SLE. Others tests, like ANA, are sensitive but not specific—although ANA is present in 95% of patients with SLE, the positive predictive value of the test for SLE for any given patient is only 11%.

Other criteria are highly subjective, including oral ulcers and photosensitivity. These signs may be present in normal individuals who get an occasional aphthous ulcer or who are fair-skinned and burn easily with prolonged sun exposure. It takes a trained clinician to distinguish these from the photosensitivity and oral ulcers associated with lupus.

Many diseases can mimic SLE

Fibromyalgia frequently presents in women and may include joint and muscle aches, fatigue, and occasionally a positive ANA. ANA may be seen in about 15% of healthy women.

Sjögren syndrome can also present with arthritis, fatigue, and a positive ANA; it is commonly overlooked because physicians do not often think to ask about the classic symptoms of dry eyes and dry mouth.

Dermatomyositis causes rashes that have many features in common with SLE. Even the skin biopsy is often indistinguishable from SLE.

Hematologic problems, such as idiopathic or thrombotic thrombocytopenic purpura, primary antiphospholipid syndrome, and hematologic neoplasms, can cause serologic changes, a positive ANA, and other manifestations seen in SLE.

Drug-induced lupus should always be considered in older patients presenting with SLE-like disease. Now with the use of minocycline (Minocin) and other related agents for the treatment of acne, we are seeing younger women with drug-induced lupus.

PATIENTS ASK ‘WHY ME?’

Lupus typically develops in a young woman who was previously healthy. Such patients inevitably wonder, why me?

Lupus is like a puzzle, with genetics, gender, and the environment being important pieces of the puzzle. If all the pieces come together, people develop defective immune regulation and a break in self-tolerance. Everyone generates antibodies to self, but these low-affinity, nonpathologic antibodies are inconsequential. In SLE, autoantibodies lead to the formation of immune complexes, complement activation, and tissue damage.

Genetics plays an important role

Genetics plays an important role but is clearly not the only determining factor. Clustering in families has been shown, although a patient with lupus is more likely to have a relative with another autoimmune disease, especially autoimmune thyroid disease, than with SLE. The likelihood of an identical twin of a patient with SLE having the disease is only 25% to 30%, and is only about 5% for a fraternal twin.

In the first few months of 2008, four major studies were published that shed light on the genetics of SLE.^4–7 Together, the studies evaluated more than 5,000 patients with SLE using genome-wide association scans and identified areas of the genome that are frequently different in patients with lupus than in healthy controls. Three of the four studies identified the same genetic area as important and supported the concept that B cells and complement activation play important roles in the disease pathogenesis.

Although over 95% of cases of SLE cannot be attributed to a single gene, there are rare cases of lupus that may provide important clues to mechanisms of disease. For example a homozygous deficiency of C1q (an early component of complement) is extremely rare in lupus but is associated with the highest risk (nearly 90%) of developing the disease. Deficiencies in other components of the complement cascade also carry a high risk of disease development.

Investigators discovered that C1q plays an important role in clearing away apoptotic cellular debris. If a person is deficient in C1q, clearance of this debris is impaired. In a person genetically predisposed to getting lupus, the immune system now has an opportunity to react to self-antigens exposed during apoptosis that are not being cleared away.

Even though lupus cases cannot be explained by an absence of C1q, a defect in the clearance of apoptotic cells is a common, unifying feature of the disease.

Immune response is enhanced by environmental factors

Environmental factors, especially sun exposure, are also important. Following sunburn, skin cells undergo massive cell death, and patients with lupus have a huge release of self-antigens that can be recognized by the immune system. Sunburn is like having a booster vaccine of self-antigen to stimulate autoantibody production. Not only does the skin flare, but internal organs can also flare after intense sun exposure.

LUPUS SURVIVAL HAS IMPROVED; DISEASES OF AGING NOW A FOCUS

In 1950, only 50% of patients with SLE survived 5 years after diagnosis; now, thanks to better treatment and earlier diagnosis, 80% to 90% survive at least 10 years.

Early on, patients tend to die of active disease (manifestations of vasculitis, pulmonary hemorrhage, kidney problems) or infection. Over time, cardiovascular disease and osteoporosis become more of a problem. Patients also have a higher risk of cancer throughout life.

Lupus has an unpredictable course, with flares and remissions. But underlying the reversible inflammatory changes is irreversible organ damage caused by the disease itself and, possibly, by treatment. Preventing bone disease, heart disease, and cancer now play more prominent roles in managing SLE.

Increased bone disease

Fracture rates are higher than expected in women with lupus; Ramsey-Goldman et al⁸ calculated the rate as five times higher than in the general population. The increased risk of osteoporosis is partly due to treatment with corticosteroids, but it is also likely caused by inflammation from lupus. Even controlling for steroid use, increased bone loss is still evident in patients with SLE.

African American women with lupus are not exempt. Lee et al⁹ found that, after adjusting for body mass, steroid use, thyroid disease, and menopausal status, African American women with SLE had more than five times the risk of low bone mineral density in the spine than white women with the disease.

Increased cancer risk

Patients with SLE have an increased risk of hematologic cancer and possibly lung and hepatobiliary cancers.

Bernatsky et al¹⁰ evaluated cancer risk in an international cohort of patients with SLE from 23 sites. Among patients with SLE, for all cancers combined, the standardized incidence ratio was 1.2; for hematologic cancers the ratio was 2.8; and for non-Hodgkin lymphoma it was 2.4. Surprisingly, although SLE is primarily a disease of women, reproductive cancer rates in patients with SLE did not differ from background rates. Bernatsky et al did not compare rates of cervical cancer, as many cancer registries do not record it. However, studies from the National Institutes of Health indicate that cervical dysplasia is common in patients with lupus.

Other interesting findings included an increased risk of hepatobiliary cancer, especially among men with SLE. Lung cancers were also increased, which has been observed in patients with other autoimmune diseases such as scleroderma and polymyositis. Smoking is a strong predictor for developing autoimmune conditions and may play a role in the observed increased cancer risk.

Early and advanced cardiovascular disease

Patients with SLE are at high risk of atherosclerotic cardiovascular disease. At the University of Pittsburgh Medical Center from 1980 to 1993, we compared the incidence of myocardial infarction in nearly 500 women with SLE and more than 2,000 women of similar age in the Framingham Offspring Study. At ages 15 to 24, women with lupus had a rate of 6.33 per 1,000 person-years; at age 25 to 34, the rate was 3.66 per 1,000 person-years. None of the Framingham women in those age groups had events.

Women ages 35 to 44 with lupus had a risk of heart attack 50 times higher than women in the Framingham cohort, and women in older age groups had a risk 2.5 to 4 times higher.¹¹

Subclinical cardiovascular disease is also increased in women with SLE. Asanuma et al¹² used electron-beam computed tomography to screen for coronary artery calcification in 65 patients with SLE and 69 control subjects with no history of coronary artery disease matched for age, sex, and race. Calcification was present in 31% of patients with lupus vs 9% of controls (P = .002). Roman et al¹³ performed carotid ultrasonography on 197 patients with lupus and 197 matched controls and found more plaque in patients with lupus (37%) than in controls (15%, P < .001).

Other data also suggest that women with lupus have advanced cardiovascular disease and develop it early, with most studies finding the greatest relative risk of cardiovascular disease between ages 18 and 45 years.

Traditional risk factors for cardiovascular disease cannot fully explain the increased risk. Many patients with lupus have metabolic syndrome, hypertension, and renal disease, but even after adjusting for these risk factors, patients with lupus still have about a 7 to 10 times higher risk of nonfatal coronary heart disease and a 17 times higher risk of fatal coronary heart disease.¹⁴

Many investigators are now exploring the role of immune dysfunction and inflammation in cardiovascular disease. A number of biomarkers have been proposed for predicting risk of cardiovascular disease in the general population. The list includes many inflammatory factors that rheumatologists have been studying for decades, including myeloperoxidase, autoantibodies, inflammatory cytokines, tumor necrosis factor alpha, and adhesion molecules, many of which also play a role in autoimmunity.

In our patients with SLE, we found that about 90% had three or more modifiable cardiovascular risk factors that were not being addressed appropriately (unpublished data). Lipid management was the least often addressed by rheumatologists and primary caregivers.

There is reason to believe that lupus patients are a high-risk group that merit aggressive risk-factor management, but no formal recommendations can be made without clear evidence that this approach improves outcomes.

SLE INCREASES THE RISK OF ADVERSE PREGNANCY OUTCOMES

Women with SLE more commonly miscarry and deliver low-birth-weight babies than do other women. A history of renal disease is the factor most predictive of poor pregnancy outcome, and the presence of certain autoantibodies increases the risk of neonatal lupus.

We recommend that women with lupus have inactive disease for at least 6 months before becoming pregnant.

ORAL CONTRACEPTIVES AND HORMONE REPLACEMENT

Hormone replacement therapy and oral contraceptives do not increase the risk of significant disease activity flares in lupus. However, women with lupus have an increased risk of cardiovascular disease and thrombosis.

Buyon et al¹⁵ randomly assigned 351 menopausal women with inactive or stable active SLE to receive either hormone replacement therapy or placebo for 12 months. No significant increase in severe flares of the disease was observed, although the treatment group had a mild increase in minor flares.

Petri et al¹⁶ randomly assigned 183 women with inactive or stable active SLE to receive either combined oral contraceptives or placebo for 12 months and found similar rates of disease activity between the two groups.

A weakness of these trials is that women with antiphospholipid antibodies in high titers or who had previous thrombotic events were excluded.

TREATMENTS ON THE HORIZON?

In the past 50 years, only three drug treatments have been approved for lupus: corticosteroids, hydroxychloroquine, and aspirin. Fortunately, research in autoimmune diseases has rapidly expanded, and new drugs are on the horizon.

Mycophenolate mofetil (CellCept) may be a reasonable alternative to cyclophosphamide (Cytoxan) for lupus nephritis and may be appropriate as maintenance therapy after induction with cyclophosphamide.

Ginzler et al,¹⁷ in a randomized, open-label trial in 140 patients with active lupus nephritis, gave either oral mycophenolate mofetil (initial dosage 1,000 mg/day, increased to 3,000 mg/day) or monthly intravenous cyclophosphamide (0.5 g/m², increased to 1.0 g/m²). Mycophenolate mofetil was more effective in inducing remission than cyclophosphamide and had a better safety profile.

The Aspreva Lupus Management Study was designed to assess the efficacy of oral mycophenolate mofetil compared with intravenous cyclophosphamide in the initial treatment of patients with active class III–V lupus nephritis and to assess the long-term efficacy of mycophenolate mofetil compared with azathioprine in maintaining remission and renal function. It was the largest study of mycophenolate mofetil in lupus nephritis to date. There were 370 patients with SLE enrolled. In the 24-week induction phase, patients were randomized to receive open-label mycophenolate mofetil with a target dose of 3 g/day or intravenous cyclophosphamide 0.5 to 1.0 g/m² in monthly pulses. Both groups received prednisone. Response to treatment was defined as a decrease in proteinuria (as measured by the urinary protein-creatinine ratio) and improvement or stabilization in serum creatinine.

The results (presented at the American College of Rheumatology Meeting, November 6–11, 2007, in Boston, MA) showed that 104 (56%) of the 185 patients treated with mycophenolate mofetil responded, compared with 98 (53%) of the 185 patients treated with intravenous cyclophosphamide (P = .575). The study therefore did not meet its primary objective of showing a superior response rate with mycophenolate mofetil compared with cyclophosphamide. There was no difference in adverse events. It is this author’s opinion that having an agent that is at least as good as cyclphosphamide in treating lupus nephritis is a major step forward.

Mycophenolate mofetil can cause fetal harm and should not be used during pregnancy. It is recommended that the drug be stopped for 3 to 6 months before a woman tries to conceive.

New drugs target B cells

Many new drugs for lupus target B cells.

Rituximab (Rituxan) is a monoclonal antibody that depletes B cells by targeting the B-cell-specific antigen CD20. It has been studied for treating lupus in several open-label studies that altogether have included more than 400 patients.^18–21 Regimens included either those used in oncology for treatment of lymphoma or those used in rheumatoid arthritis, coupled with high-dose corticosteroids and cyclophosphamide. In early studies, nearly 80% of treated patients entered at least partial remission, and 25% to 50% are still in remission more than 12 months later.

The first randomized controlled trial of rituximab vs placebo was recently completed and presented at the American College of Rheumatology meeting, October 24–28, 2008, in Boston, MA. The EXPLORER trial (sponsored by Genentech) included 257 patients with moderate to severe disease activity. The results showed that there was no difference in major or partial clinical response (based on a change in the British Isles Lupus Assessment Group index) in those on rituximab (28.4%) vs placebo (29.6%) at 12 months (P = .97). Overall, adverse events were balanced between the groups. It is this author’s opinion that the bar for “response” was set very high in this study, considering that all patients who entered were fairly sick and received significant doses of corticosteroids that were tapered over the course of the trial.

B-cell toleragens, which render B cells incapable of presenting specific antigens, are also of interest.

Other experimental drugs target the soluble cytokine BLyS, which normally binds to a B-cell receptor and prolongs B-cell survival. It may also be possible to inhibit costimulatory pathways (which are normally important for inducing activation, proliferation, and class-switching of B cells) with the use of cytotoxic T-lymphocyte-associated antigen 4 immunoglobulin inhibitor (CTLA4Ig) and anti-CD40 ligand.

The results of a 12-month exploratory, phase II trial of abatacept (Bristol-Myers Squibb) in patients with SLE and active polyarthritis, serositis, or discoid lesions were presented at the American College of Rheumatology meeting in 2008. The primary and secondary end points (based on an adjudicated British Isles Lupus Assessment Group index) were not met. There were no differences in adverse events. Post hoc analyses of other clinical end points and biomarkers suggested that abatacept may have benefit in lupus. Further studies are under way.

Downstream blockade may also be useful, with drugs that inhibit inflammatory cytokines, particularly interferon alfa. This is now being tested in clinical trials.

Many questions about systemic lupus erythematosus (SLE, lupus) remain unanswered. Why is this disease so difficult to diagnose even for rheumatologists? Why does lupus tend to develop in previously healthy young women? Why does the disease manifest in so many ways? Why are our current treatments suboptimal?

This article addresses these questions in a brief overview and update of SLE, with an emphasis on clinical pearls regarding prevention and treatment that are relevant to any physician who sees patients with this disease.

WOMEN AND MINORITIES ARE OVERREPRESENTED

Women have a much higher prevalence of almost all autoimmune diseases. SLE has a 12:1 female-to-male ratio during the ages of 15 to 45 years, but when disease develops in either children or the elderly, the female-to-male ratio is only 2:1.

African Americans, Asian Americans, and Hispanics have about a three to four times higher frequency of lupus than white non-Hispanics and often have more severe disease.

WHY IS SLE SO DIFFICULT TO DIAGNOSE?

SLE is frequently overlooked; patients spend an average of 4 years and see three physicians before the disease is correctly diagnosed. Part of the problem is that presentations of the disease vary so widely between patients and that signs and symptoms evolve over time. Often, physicians do not consider SLE in the differential diagnosis.

On the other hand, SLE is also often over-diagnosed. Narain et al¹ evaluated 263 patients who had a presumptive diagnosis of SLE. Only about half of the patients had a confirmed diagnosis; about 5% had a different autoimmune disease, such as scleroderma, systemic sclerosis, Sjögren syndrome, or polymyositis; 5% had fibromyalgia; 29% tested positive for ANA but did not have an autoimmune disease; and 10% had a nonrheumatic disease, such as a hematologic malignancy with rheumatic disease manifestations. For patients referred by a community rheumatologist, the diagnostic accuracy was better, about 80%.

The traditional classification criteria for SLE^2,3 are problematic. Some criteria are very specific for SLE but are not very sensitive—eg, anti-double-stranded DNA is present in about half of patients with SLE. Others tests, like ANA, are sensitive but not specific—although ANA is present in 95% of patients with SLE, the positive predictive value of the test for SLE for any given patient is only 11%.

Other criteria are highly subjective, including oral ulcers and photosensitivity. These signs may be present in normal individuals who get an occasional aphthous ulcer or who are fair-skinned and burn easily with prolonged sun exposure. It takes a trained clinician to distinguish these from the photosensitivity and oral ulcers associated with lupus.

Many diseases can mimic SLE

Fibromyalgia frequently presents in women and may include joint and muscle aches, fatigue, and occasionally a positive ANA. ANA may be seen in about 15% of healthy women.

Sjögren syndrome can also present with arthritis, fatigue, and a positive ANA; it is commonly overlooked because physicians do not often think to ask about the classic symptoms of dry eyes and dry mouth.

Dermatomyositis causes rashes that have many features in common with SLE. Even the skin biopsy is often indistinguishable from SLE.

Hematologic problems, such as idiopathic or thrombotic thrombocytopenic purpura, primary antiphospholipid syndrome, and hematologic neoplasms, can cause serologic changes, a positive ANA, and other manifestations seen in SLE.

Drug-induced lupus should always be considered in older patients presenting with SLE-like disease. Now with the use of minocycline (Minocin) and other related agents for the treatment of acne, we are seeing younger women with drug-induced lupus.

PATIENTS ASK ‘WHY ME?’

Lupus typically develops in a young woman who was previously healthy. Such patients inevitably wonder, why me?

Lupus is like a puzzle, with genetics, gender, and the environment being important pieces of the puzzle. If all the pieces come together, people develop defective immune regulation and a break in self-tolerance. Everyone generates antibodies to self, but these low-affinity, nonpathologic antibodies are inconsequential. In SLE, autoantibodies lead to the formation of immune complexes, complement activation, and tissue damage.

Genetics plays an important role

Genetics plays an important role but is clearly not the only determining factor. Clustering in families has been shown, although a patient with lupus is more likely to have a relative with another autoimmune disease, especially autoimmune thyroid disease, than with SLE. The likelihood of an identical twin of a patient with SLE having the disease is only 25% to 30%, and is only about 5% for a fraternal twin.

In the first few months of 2008, four major studies were published that shed light on the genetics of SLE.^4–7 Together, the studies evaluated more than 5,000 patients with SLE using genome-wide association scans and identified areas of the genome that are frequently different in patients with lupus than in healthy controls. Three of the four studies identified the same genetic area as important and supported the concept that B cells and complement activation play important roles in the disease pathogenesis.

Although over 95% of cases of SLE cannot be attributed to a single gene, there are rare cases of lupus that may provide important clues to mechanisms of disease. For example a homozygous deficiency of C1q (an early component of complement) is extremely rare in lupus but is associated with the highest risk (nearly 90%) of developing the disease. Deficiencies in other components of the complement cascade also carry a high risk of disease development.

Investigators discovered that C1q plays an important role in clearing away apoptotic cellular debris. If a person is deficient in C1q, clearance of this debris is impaired. In a person genetically predisposed to getting lupus, the immune system now has an opportunity to react to self-antigens exposed during apoptosis that are not being cleared away.

Even though lupus cases cannot be explained by an absence of C1q, a defect in the clearance of apoptotic cells is a common, unifying feature of the disease.

Immune response is enhanced by environmental factors

Environmental factors, especially sun exposure, are also important. Following sunburn, skin cells undergo massive cell death, and patients with lupus have a huge release of self-antigens that can be recognized by the immune system. Sunburn is like having a booster vaccine of self-antigen to stimulate autoantibody production. Not only does the skin flare, but internal organs can also flare after intense sun exposure.

LUPUS SURVIVAL HAS IMPROVED; DISEASES OF AGING NOW A FOCUS

In 1950, only 50% of patients with SLE survived 5 years after diagnosis; now, thanks to better treatment and earlier diagnosis, 80% to 90% survive at least 10 years.

Early on, patients tend to die of active disease (manifestations of vasculitis, pulmonary hemorrhage, kidney problems) or infection. Over time, cardiovascular disease and osteoporosis become more of a problem. Patients also have a higher risk of cancer throughout life.

Lupus has an unpredictable course, with flares and remissions. But underlying the reversible inflammatory changes is irreversible organ damage caused by the disease itself and, possibly, by treatment. Preventing bone disease, heart disease, and cancer now play more prominent roles in managing SLE.

Increased bone disease

Fracture rates are higher than expected in women with lupus; Ramsey-Goldman et al⁸ calculated the rate as five times higher than in the general population. The increased risk of osteoporosis is partly due to treatment with corticosteroids, but it is also likely caused by inflammation from lupus. Even controlling for steroid use, increased bone loss is still evident in patients with SLE.

African American women with lupus are not exempt. Lee et al⁹ found that, after adjusting for body mass, steroid use, thyroid disease, and menopausal status, African American women with SLE had more than five times the risk of low bone mineral density in the spine than white women with the disease.

Increased cancer risk

Patients with SLE have an increased risk of hematologic cancer and possibly lung and hepatobiliary cancers.

Bernatsky et al¹⁰ evaluated cancer risk in an international cohort of patients with SLE from 23 sites. Among patients with SLE, for all cancers combined, the standardized incidence ratio was 1.2; for hematologic cancers the ratio was 2.8; and for non-Hodgkin lymphoma it was 2.4. Surprisingly, although SLE is primarily a disease of women, reproductive cancer rates in patients with SLE did not differ from background rates. Bernatsky et al did not compare rates of cervical cancer, as many cancer registries do not record it. However, studies from the National Institutes of Health indicate that cervical dysplasia is common in patients with lupus.

Other interesting findings included an increased risk of hepatobiliary cancer, especially among men with SLE. Lung cancers were also increased, which has been observed in patients with other autoimmune diseases such as scleroderma and polymyositis. Smoking is a strong predictor for developing autoimmune conditions and may play a role in the observed increased cancer risk.

Early and advanced cardiovascular disease

Patients with SLE are at high risk of atherosclerotic cardiovascular disease. At the University of Pittsburgh Medical Center from 1980 to 1993, we compared the incidence of myocardial infarction in nearly 500 women with SLE and more than 2,000 women of similar age in the Framingham Offspring Study. At ages 15 to 24, women with lupus had a rate of 6.33 per 1,000 person-years; at age 25 to 34, the rate was 3.66 per 1,000 person-years. None of the Framingham women in those age groups had events.

Women ages 35 to 44 with lupus had a risk of heart attack 50 times higher than women in the Framingham cohort, and women in older age groups had a risk 2.5 to 4 times higher.¹¹

Subclinical cardiovascular disease is also increased in women with SLE. Asanuma et al¹² used electron-beam computed tomography to screen for coronary artery calcification in 65 patients with SLE and 69 control subjects with no history of coronary artery disease matched for age, sex, and race. Calcification was present in 31% of patients with lupus vs 9% of controls (P = .002). Roman et al¹³ performed carotid ultrasonography on 197 patients with lupus and 197 matched controls and found more plaque in patients with lupus (37%) than in controls (15%, P < .001).

Other data also suggest that women with lupus have advanced cardiovascular disease and develop it early, with most studies finding the greatest relative risk of cardiovascular disease between ages 18 and 45 years.

Traditional risk factors for cardiovascular disease cannot fully explain the increased risk. Many patients with lupus have metabolic syndrome, hypertension, and renal disease, but even after adjusting for these risk factors, patients with lupus still have about a 7 to 10 times higher risk of nonfatal coronary heart disease and a 17 times higher risk of fatal coronary heart disease.¹⁴

Many investigators are now exploring the role of immune dysfunction and inflammation in cardiovascular disease. A number of biomarkers have been proposed for predicting risk of cardiovascular disease in the general population. The list includes many inflammatory factors that rheumatologists have been studying for decades, including myeloperoxidase, autoantibodies, inflammatory cytokines, tumor necrosis factor alpha, and adhesion molecules, many of which also play a role in autoimmunity.

In our patients with SLE, we found that about 90% had three or more modifiable cardiovascular risk factors that were not being addressed appropriately (unpublished data). Lipid management was the least often addressed by rheumatologists and primary caregivers.

There is reason to believe that lupus patients are a high-risk group that merit aggressive risk-factor management, but no formal recommendations can be made without clear evidence that this approach improves outcomes.

SLE INCREASES THE RISK OF ADVERSE PREGNANCY OUTCOMES

Women with SLE more commonly miscarry and deliver low-birth-weight babies than do other women. A history of renal disease is the factor most predictive of poor pregnancy outcome, and the presence of certain autoantibodies increases the risk of neonatal lupus.

We recommend that women with lupus have inactive disease for at least 6 months before becoming pregnant.

ORAL CONTRACEPTIVES AND HORMONE REPLACEMENT

Hormone replacement therapy and oral contraceptives do not increase the risk of significant disease activity flares in lupus. However, women with lupus have an increased risk of cardiovascular disease and thrombosis.

Buyon et al¹⁵ randomly assigned 351 menopausal women with inactive or stable active SLE to receive either hormone replacement therapy or placebo for 12 months. No significant increase in severe flares of the disease was observed, although the treatment group had a mild increase in minor flares.

Petri et al¹⁶ randomly assigned 183 women with inactive or stable active SLE to receive either combined oral contraceptives or placebo for 12 months and found similar rates of disease activity between the two groups.

A weakness of these trials is that women with antiphospholipid antibodies in high titers or who had previous thrombotic events were excluded.

TREATMENTS ON THE HORIZON?

In the past 50 years, only three drug treatments have been approved for lupus: corticosteroids, hydroxychloroquine, and aspirin. Fortunately, research in autoimmune diseases has rapidly expanded, and new drugs are on the horizon.

Mycophenolate mofetil (CellCept) may be a reasonable alternative to cyclophosphamide (Cytoxan) for lupus nephritis and may be appropriate as maintenance therapy after induction with cyclophosphamide.

Ginzler et al,¹⁷ in a randomized, open-label trial in 140 patients with active lupus nephritis, gave either oral mycophenolate mofetil (initial dosage 1,000 mg/day, increased to 3,000 mg/day) or monthly intravenous cyclophosphamide (0.5 g/m², increased to 1.0 g/m²). Mycophenolate mofetil was more effective in inducing remission than cyclophosphamide and had a better safety profile.

The Aspreva Lupus Management Study was designed to assess the efficacy of oral mycophenolate mofetil compared with intravenous cyclophosphamide in the initial treatment of patients with active class III–V lupus nephritis and to assess the long-term efficacy of mycophenolate mofetil compared with azathioprine in maintaining remission and renal function. It was the largest study of mycophenolate mofetil in lupus nephritis to date. There were 370 patients with SLE enrolled. In the 24-week induction phase, patients were randomized to receive open-label mycophenolate mofetil with a target dose of 3 g/day or intravenous cyclophosphamide 0.5 to 1.0 g/m² in monthly pulses. Both groups received prednisone. Response to treatment was defined as a decrease in proteinuria (as measured by the urinary protein-creatinine ratio) and improvement or stabilization in serum creatinine.

The results (presented at the American College of Rheumatology Meeting, November 6–11, 2007, in Boston, MA) showed that 104 (56%) of the 185 patients treated with mycophenolate mofetil responded, compared with 98 (53%) of the 185 patients treated with intravenous cyclophosphamide (P = .575). The study therefore did not meet its primary objective of showing a superior response rate with mycophenolate mofetil compared with cyclophosphamide. There was no difference in adverse events. It is this author’s opinion that having an agent that is at least as good as cyclphosphamide in treating lupus nephritis is a major step forward.

Mycophenolate mofetil can cause fetal harm and should not be used during pregnancy. It is recommended that the drug be stopped for 3 to 6 months before a woman tries to conceive.

New drugs target B cells

Many new drugs for lupus target B cells.

Rituximab (Rituxan) is a monoclonal antibody that depletes B cells by targeting the B-cell-specific antigen CD20. It has been studied for treating lupus in several open-label studies that altogether have included more than 400 patients.^18–21 Regimens included either those used in oncology for treatment of lymphoma or those used in rheumatoid arthritis, coupled with high-dose corticosteroids and cyclophosphamide. In early studies, nearly 80% of treated patients entered at least partial remission, and 25% to 50% are still in remission more than 12 months later.

The first randomized controlled trial of rituximab vs placebo was recently completed and presented at the American College of Rheumatology meeting, October 24–28, 2008, in Boston, MA. The EXPLORER trial (sponsored by Genentech) included 257 patients with moderate to severe disease activity. The results showed that there was no difference in major or partial clinical response (based on a change in the British Isles Lupus Assessment Group index) in those on rituximab (28.4%) vs placebo (29.6%) at 12 months (P = .97). Overall, adverse events were balanced between the groups. It is this author’s opinion that the bar for “response” was set very high in this study, considering that all patients who entered were fairly sick and received significant doses of corticosteroids that were tapered over the course of the trial.

B-cell toleragens, which render B cells incapable of presenting specific antigens, are also of interest.

Other experimental drugs target the soluble cytokine BLyS, which normally binds to a B-cell receptor and prolongs B-cell survival. It may also be possible to inhibit costimulatory pathways (which are normally important for inducing activation, proliferation, and class-switching of B cells) with the use of cytotoxic T-lymphocyte-associated antigen 4 immunoglobulin inhibitor (CTLA4Ig) and anti-CD40 ligand.

The results of a 12-month exploratory, phase II trial of abatacept (Bristol-Myers Squibb) in patients with SLE and active polyarthritis, serositis, or discoid lesions were presented at the American College of Rheumatology meeting in 2008. The primary and secondary end points (based on an adjudicated British Isles Lupus Assessment Group index) were not met. There were no differences in adverse events. Post hoc analyses of other clinical end points and biomarkers suggested that abatacept may have benefit in lupus. Further studies are under way.

Downstream blockade may also be useful, with drugs that inhibit inflammatory cytokines, particularly interferon alfa. This is now being tested in clinical trials.

A 55-year-old woman presents with an intermittent sensation of food getting stuck in her mid to lower chest. The symptoms have occurred several times per year over the last 2 or 3 years and appear to be slowly worsening. She says she has no trouble swallowing liquids. She has a history of gastroesophageal reflux disease, for which she takes a proton pump inhibitor once a day. She says she has had no odynophagia, cough, regurgitation, or weight loss.

How should her symptoms best be evaluated?

DYSPHAGIA CAN BE OROPHARYNGEAL OR ESOPHAGEAL

Dysphagia is the subjective sensation of difficulty swallowing solids, liquids, or both. Symptoms can range from the inability to initiate a swallow to the sensation of esophageal obstruction. Other symptoms of esophageal disease may also be present, such as chest pain, heartburn, and regurgitation. There may also be nonesophageal symptoms related to the disease process causing the dysphagia.

Dysphagia can be separated into oropharyngeal and esophageal types.

Interestingly, many patients with symptoms of oropharyngeal dysphagia in fact have referred symptoms from primary esophageal dysphagia²; many patients with a distal mucosal ring describe a sense of something sticking in the cervical esophagus.

Esophageal dysphagia arises in the mid to distal esophagus or gastric cardia, and as a result, the symptoms are typically retrosternal.¹ It can be caused by structural problems such as strictures, rings, webs, extrinsic compression, or a primary esophageal or gastroesophageal neoplasm, or by a primary motility abnormality such as achalasia (Table 1). Eosinophilic esophagitis is now a frequent cause of esophageal dysphagia, especially in white men.³

ESOPHAGOGRAPHY VS ENDOSCOPY IN EVALUATING DYSPHAGIA

Many gastroenterologists recommend endoscopy rather than barium esophagography as the initial examination in patients with dysphagia.^4–8 Each test has certain advantages.

Advantages of endoscopy. Endoscopy is superior to esophagography in detecting milder grades of esophagitis. Further, interventions can be performed endoscopically (eg, dilation, biopsy, attachment of a wireless pH testing probe) that cannot be done during a radiographic procedure, and endoscopy does not expose the patient to radiation.

Advantages of esophagography. Endoscopy cannot detect evidence of gastroesophageal reflux disease unless mucosal injury is present. In dysphagia, the radiologic findings correlate well with endoscopic findings, including the detection of esophageal malignancy and moderate to severe esophagitis. Further, motility disorders can be detected with barium esophagography but not with endoscopy.^9,10

Subtle abnormalities, especially rings and strictures, may be missed by narrow-diameter (9.8–10 mm) modern upper-endoscopic equipment. Further, esophagography is noninvasive, costs less, and may be more convenient (it does not require sedation and a chaperone for the patient after sedation). This examination also provides dynamic evaluation of the complex process of swallowing. Causes of dysphagia external to the esophagus can also be determined.

In view of the respective advantages and disadvantages of the two methods, we believe that in most instances barium esophagography should be the initial examination,^1,9,11–15 and at our institution most patients presenting with dysphagia undergo barium esophagography before they undergo other examinations.¹⁴

OBTAIN A HISTORY BEFORE ORDERING ESOPHAGOGRAPHY

Before a barium examination of the esophagus is done, a focused medical history should be obtained, as it can guide the further workup as well as the esophageal study itself.

An attempt should be made to determine whether the dysphagia is oropharyngeal or if it is esophageal, as the former is generally best initially evaluated by a speech and language pathologist. Generally, the physician who orders the test judges whether the patient has oropharyngeal or esophageal dysphagia. Often, both an oropharyngeal examination, performed by a speech and language pathologist, and an esophageal examination, performed by a radiologist, are ordered.

Rapidly progressive symptoms, especially if accompanied by weight loss, should make one suspect cancer. Chronic symptoms usually point to gastroesophageal reflux disease or a motility disorder such as achalasia. Liquid dysphagia almost always means the patient has a motility disorder such as achalasia.

In view of the possibility of eosinophilic esophagitis, one should ask about food or seasonal allergies, especially in young patients with intermittent difficulty swallowing solids.³

BARIUM ESOPHAGOGRAPHY HAS EIGHT SEPARATE PHASES

Barium esophagography is tailored to the patient with dysphagia on the basis of his or her history. The standard examination is divided into eight separate phases (see below).¹⁴ Each phase addresses a specific question or questions concerning the structure and function of the esophagus.

At our institution, the first phase of the examination is determined by the presenting symptoms. If the patient has liquid dysphagia, we start with a timed barium swallow to assess esophageal emptying. If the patient does not have liquid dysphagia, we start with an air-contrast mucosal examination.

The patient must be cooperative and mobile to complete all phases of the examination.

Timed barium swallow to measure esophageal emptying

The timed barium swallow is an objective measure of esophageal emptying.^16–18 This technique is essential in the initial evaluation of a patient with liquid dysphagia, a symptom common in patients with severe dysmotility, usually achalasia.

We use this examination in our patients with suspected or confirmed achalasia and to follow up patients who have been treated with pneumatic dilatation, botulinum toxin injection, and Heller myotomy.^17,18 In addition, this timed test is an objective measure of emptying in patients who have undergone intervention but whose symptoms have not subjectively improved, and can suggest that further intervention may be required.

Air-contrast or mucosal phase

Although this phase is not as sensitive as endoscopy, it can detect masses, mucosal erosions, ulcers, and—most importantly in our experience—fixed hernias. Patients with a fixed hernia have a foreshortened esophagus, which is important to know about before repairing the hernia. Many esophageal surgeons believe that a foreshortened esophagus precludes a standard Nissen fundoplication and necessitates an esophageal lengthening procedure (ie, Collis gastroplasty with a Nissen fundoplication).¹⁴

Motility phase

The third phase examines esophageal motility. With the patient in a semiprone position, low-density barium is given in single swallows, separated by 25 to 30 seconds. The images are recorded on digital media to allow one to review them frame by frame.

The findings on this phase correlate well with those of manometry.¹⁹ This portion of the examination also uses impedance monitoring to assess bolus transfer, an aspect not evaluated by manometry.^20,21 Impedance monitoring detects changes in resistance to current flow and correlates well with esophagraphic findings regarding bolus transfer.

While many patients with dysphagia also undergo esophageal manometry, the findings from this phase of the esophagographic examination may be the first indication of an esophageal motility disorder. In fact, this portion of the examination shows the distinct advantage of esophagography over endoscopy as the initial test in patients with dysphagia, as endoscopy may not identify patients with achalasia, especially early on.⁴

Single-contrast (full-column) phase to detect strictures, rings

The fourth phase of the esophagographic evaluation is the distended, single-contrast examination (Figure 2B). This is performed in the semiprone position with the patient rapidly drinking thin barium. It is done to detect esophageal strictures, rings, and contour abnormalities caused by extrinsic processes. Subtle abnormalities shown by this technique, including benign strictures and rings, are often not visualized with endoscopy.

Mucosal relief phase

The fifth phase is performed with a collapsed esophagus immediately after the distended, single-contrast phase, where spot films are taken of the barium-coated, collapsed esophagus (Figure 2C). This phase is used to evaluate thickened mucosal folds, a common finding in moderate to severe reflux esophagitis.

Reflux evaluation

Provocative maneuvers are used in the sixth phase to elicit gastroesophageal reflux (Figure 2D). With the patient supine, he or she is asked to roll side to side, do a Valsalva maneuver, and do a straight-leg raise. The patient then sips water in the supine position to assess for reflux (the water siphon test). If reflux is seen, the cause, the height of the reflux, and the duration of reflux retention are recorded.

Solid-bolus phase to assess strictures

In the seventh phase, the patient swallows a 13-mm barium tablet (Figure 2E). This allows one to assess the significance of a ring or stricture and to assess if dysphagia symptoms recur as a result of tablet obstruction. Subtle strictures that were not detected during the prior phases can also be detected using a tablet. If obstruction or impaired passage occurs, the site of obstruction and the presence or absence of symptoms are recorded.

The final or eighth phase of barium esophagography is called “modified barium esophagography” or the modified barium swallow. However, it may be the first phase of the examination performed or the only portion of the examination performed, or it may not be performed at all.

Modified barium esophagography is used to define the anatomy of the oropharynx and to assess its function in swallowing.¹² It may also guide rehabilitation strategies aimed at eliminating a patient’s swallowing symptoms.

Most patients referred for this test have sustained damage to the central nervous system or structures of the oropharynx, such as stroke or radiation therapy for laryngeal cancer. Many have difficulty in starting to swallow, aspirate when they try to swallow, or both.

The final esophagographic report should document the findings of each phase of the examination (Table 2).

WHAT HAPPENED TO OUR PATIENT?

Our patient underwent barium esophagography (Figure 2). A distal mucosal ring that transiently obstructed a 13-mm tablet was found. The patient underwent endoscopy and the ring was dilated. No biopsies were necessary.

A 55-year-old woman presents with an intermittent sensation of food getting stuck in her mid to lower chest. The symptoms have occurred several times per year over the last 2 or 3 years and appear to be slowly worsening. She says she has no trouble swallowing liquids. She has a history of gastroesophageal reflux disease, for which she takes a proton pump inhibitor once a day. She says she has had no odynophagia, cough, regurgitation, or weight loss.

How should her symptoms best be evaluated?

DYSPHAGIA CAN BE OROPHARYNGEAL OR ESOPHAGEAL

Dysphagia is the subjective sensation of difficulty swallowing solids, liquids, or both. Symptoms can range from the inability to initiate a swallow to the sensation of esophageal obstruction. Other symptoms of esophageal disease may also be present, such as chest pain, heartburn, and regurgitation. There may also be nonesophageal symptoms related to the disease process causing the dysphagia.

Dysphagia can be separated into oropharyngeal and esophageal types.

Interestingly, many patients with symptoms of oropharyngeal dysphagia in fact have referred symptoms from primary esophageal dysphagia²; many patients with a distal mucosal ring describe a sense of something sticking in the cervical esophagus.

Esophageal dysphagia arises in the mid to distal esophagus or gastric cardia, and as a result, the symptoms are typically retrosternal.¹ It can be caused by structural problems such as strictures, rings, webs, extrinsic compression, or a primary esophageal or gastroesophageal neoplasm, or by a primary motility abnormality such as achalasia (Table 1). Eosinophilic esophagitis is now a frequent cause of esophageal dysphagia, especially in white men.³

ESOPHAGOGRAPHY VS ENDOSCOPY IN EVALUATING DYSPHAGIA

Many gastroenterologists recommend endoscopy rather than barium esophagography as the initial examination in patients with dysphagia.^4–8 Each test has certain advantages.

Advantages of endoscopy. Endoscopy is superior to esophagography in detecting milder grades of esophagitis. Further, interventions can be performed endoscopically (eg, dilation, biopsy, attachment of a wireless pH testing probe) that cannot be done during a radiographic procedure, and endoscopy does not expose the patient to radiation.

Advantages of esophagography. Endoscopy cannot detect evidence of gastroesophageal reflux disease unless mucosal injury is present. In dysphagia, the radiologic findings correlate well with endoscopic findings, including the detection of esophageal malignancy and moderate to severe esophagitis. Further, motility disorders can be detected with barium esophagography but not with endoscopy.^9,10

Subtle abnormalities, especially rings and strictures, may be missed by narrow-diameter (9.8–10 mm) modern upper-endoscopic equipment. Further, esophagography is noninvasive, costs less, and may be more convenient (it does not require sedation and a chaperone for the patient after sedation). This examination also provides dynamic evaluation of the complex process of swallowing. Causes of dysphagia external to the esophagus can also be determined.

In view of the respective advantages and disadvantages of the two methods, we believe that in most instances barium esophagography should be the initial examination,^1,9,11–15 and at our institution most patients presenting with dysphagia undergo barium esophagography before they undergo other examinations.¹⁴

OBTAIN A HISTORY BEFORE ORDERING ESOPHAGOGRAPHY

Before a barium examination of the esophagus is done, a focused medical history should be obtained, as it can guide the further workup as well as the esophageal study itself.

An attempt should be made to determine whether the dysphagia is oropharyngeal or if it is esophageal, as the former is generally best initially evaluated by a speech and language pathologist. Generally, the physician who orders the test judges whether the patient has oropharyngeal or esophageal dysphagia. Often, both an oropharyngeal examination, performed by a speech and language pathologist, and an esophageal examination, performed by a radiologist, are ordered.

Rapidly progressive symptoms, especially if accompanied by weight loss, should make one suspect cancer. Chronic symptoms usually point to gastroesophageal reflux disease or a motility disorder such as achalasia. Liquid dysphagia almost always means the patient has a motility disorder such as achalasia.

In view of the possibility of eosinophilic esophagitis, one should ask about food or seasonal allergies, especially in young patients with intermittent difficulty swallowing solids.³

BARIUM ESOPHAGOGRAPHY HAS EIGHT SEPARATE PHASES

Barium esophagography is tailored to the patient with dysphagia on the basis of his or her history. The standard examination is divided into eight separate phases (see below).¹⁴ Each phase addresses a specific question or questions concerning the structure and function of the esophagus.

At our institution, the first phase of the examination is determined by the presenting symptoms. If the patient has liquid dysphagia, we start with a timed barium swallow to assess esophageal emptying. If the patient does not have liquid dysphagia, we start with an air-contrast mucosal examination.

The patient must be cooperative and mobile to complete all phases of the examination.

Timed barium swallow to measure esophageal emptying

The timed barium swallow is an objective measure of esophageal emptying.^16–18 This technique is essential in the initial evaluation of a patient with liquid dysphagia, a symptom common in patients with severe dysmotility, usually achalasia.

We use this examination in our patients with suspected or confirmed achalasia and to follow up patients who have been treated with pneumatic dilatation, botulinum toxin injection, and Heller myotomy.^17,18 In addition, this timed test is an objective measure of emptying in patients who have undergone intervention but whose symptoms have not subjectively improved, and can suggest that further intervention may be required.

Air-contrast or mucosal phase

Although this phase is not as sensitive as endoscopy, it can detect masses, mucosal erosions, ulcers, and—most importantly in our experience—fixed hernias. Patients with a fixed hernia have a foreshortened esophagus, which is important to know about before repairing the hernia. Many esophageal surgeons believe that a foreshortened esophagus precludes a standard Nissen fundoplication and necessitates an esophageal lengthening procedure (ie, Collis gastroplasty with a Nissen fundoplication).¹⁴

Motility phase

The third phase examines esophageal motility. With the patient in a semiprone position, low-density barium is given in single swallows, separated by 25 to 30 seconds. The images are recorded on digital media to allow one to review them frame by frame.

The findings on this phase correlate well with those of manometry.¹⁹ This portion of the examination also uses impedance monitoring to assess bolus transfer, an aspect not evaluated by manometry.^20,21 Impedance monitoring detects changes in resistance to current flow and correlates well with esophagraphic findings regarding bolus transfer.

While many patients with dysphagia also undergo esophageal manometry, the findings from this phase of the esophagographic examination may be the first indication of an esophageal motility disorder. In fact, this portion of the examination shows the distinct advantage of esophagography over endoscopy as the initial test in patients with dysphagia, as endoscopy may not identify patients with achalasia, especially early on.⁴

Single-contrast (full-column) phase to detect strictures, rings

The fourth phase of the esophagographic evaluation is the distended, single-contrast examination (Figure 2B). This is performed in the semiprone position with the patient rapidly drinking thin barium. It is done to detect esophageal strictures, rings, and contour abnormalities caused by extrinsic processes. Subtle abnormalities shown by this technique, including benign strictures and rings, are often not visualized with endoscopy.

Mucosal relief phase

The fifth phase is performed with a collapsed esophagus immediately after the distended, single-contrast phase, where spot films are taken of the barium-coated, collapsed esophagus (Figure 2C). This phase is used to evaluate thickened mucosal folds, a common finding in moderate to severe reflux esophagitis.

Reflux evaluation

Provocative maneuvers are used in the sixth phase to elicit gastroesophageal reflux (Figure 2D). With the patient supine, he or she is asked to roll side to side, do a Valsalva maneuver, and do a straight-leg raise. The patient then sips water in the supine position to assess for reflux (the water siphon test). If reflux is seen, the cause, the height of the reflux, and the duration of reflux retention are recorded.

Solid-bolus phase to assess strictures

In the seventh phase, the patient swallows a 13-mm barium tablet (Figure 2E). This allows one to assess the significance of a ring or stricture and to assess if dysphagia symptoms recur as a result of tablet obstruction. Subtle strictures that were not detected during the prior phases can also be detected using a tablet. If obstruction or impaired passage occurs, the site of obstruction and the presence or absence of symptoms are recorded.

The final or eighth phase of barium esophagography is called “modified barium esophagography” or the modified barium swallow. However, it may be the first phase of the examination performed or the only portion of the examination performed, or it may not be performed at all.

Modified barium esophagography is used to define the anatomy of the oropharynx and to assess its function in swallowing.¹² It may also guide rehabilitation strategies aimed at eliminating a patient’s swallowing symptoms.

Most patients referred for this test have sustained damage to the central nervous system or structures of the oropharynx, such as stroke or radiation therapy for laryngeal cancer. Many have difficulty in starting to swallow, aspirate when they try to swallow, or both.

The final esophagographic report should document the findings of each phase of the examination (Table 2).

WHAT HAPPENED TO OUR PATIENT?

Our patient underwent barium esophagography (Figure 2). A distal mucosal ring that transiently obstructed a 13-mm tablet was found. The patient underwent endoscopy and the ring was dilated. No biopsies were necessary.

A 55-year-old woman presents with an intermittent sensation of food getting stuck in her mid to lower chest. The symptoms have occurred several times per year over the last 2 or 3 years and appear to be slowly worsening. She says she has no trouble swallowing liquids. She has a history of gastroesophageal reflux disease, for which she takes a proton pump inhibitor once a day. She says she has had no odynophagia, cough, regurgitation, or weight loss.

How should her symptoms best be evaluated?

DYSPHAGIA CAN BE OROPHARYNGEAL OR ESOPHAGEAL

Dysphagia is the subjective sensation of difficulty swallowing solids, liquids, or both. Symptoms can range from the inability to initiate a swallow to the sensation of esophageal obstruction. Other symptoms of esophageal disease may also be present, such as chest pain, heartburn, and regurgitation. There may also be nonesophageal symptoms related to the disease process causing the dysphagia.

Dysphagia can be separated into oropharyngeal and esophageal types.

Interestingly, many patients with symptoms of oropharyngeal dysphagia in fact have referred symptoms from primary esophageal dysphagia²; many patients with a distal mucosal ring describe a sense of something sticking in the cervical esophagus.

Esophageal dysphagia arises in the mid to distal esophagus or gastric cardia, and as a result, the symptoms are typically retrosternal.¹ It can be caused by structural problems such as strictures, rings, webs, extrinsic compression, or a primary esophageal or gastroesophageal neoplasm, or by a primary motility abnormality such as achalasia (Table 1). Eosinophilic esophagitis is now a frequent cause of esophageal dysphagia, especially in white men.³

ESOPHAGOGRAPHY VS ENDOSCOPY IN EVALUATING DYSPHAGIA

Many gastroenterologists recommend endoscopy rather than barium esophagography as the initial examination in patients with dysphagia.^4–8 Each test has certain advantages.

Advantages of endoscopy. Endoscopy is superior to esophagography in detecting milder grades of esophagitis. Further, interventions can be performed endoscopically (eg, dilation, biopsy, attachment of a wireless pH testing probe) that cannot be done during a radiographic procedure, and endoscopy does not expose the patient to radiation.

Advantages of esophagography. Endoscopy cannot detect evidence of gastroesophageal reflux disease unless mucosal injury is present. In dysphagia, the radiologic findings correlate well with endoscopic findings, including the detection of esophageal malignancy and moderate to severe esophagitis. Further, motility disorders can be detected with barium esophagography but not with endoscopy.^9,10

Subtle abnormalities, especially rings and strictures, may be missed by narrow-diameter (9.8–10 mm) modern upper-endoscopic equipment. Further, esophagography is noninvasive, costs less, and may be more convenient (it does not require sedation and a chaperone for the patient after sedation). This examination also provides dynamic evaluation of the complex process of swallowing. Causes of dysphagia external to the esophagus can also be determined.

In view of the respective advantages and disadvantages of the two methods, we believe that in most instances barium esophagography should be the initial examination,^1,9,11–15 and at our institution most patients presenting with dysphagia undergo barium esophagography before they undergo other examinations.¹⁴

OBTAIN A HISTORY BEFORE ORDERING ESOPHAGOGRAPHY

Before a barium examination of the esophagus is done, a focused medical history should be obtained, as it can guide the further workup as well as the esophageal study itself.

An attempt should be made to determine whether the dysphagia is oropharyngeal or if it is esophageal, as the former is generally best initially evaluated by a speech and language pathologist. Generally, the physician who orders the test judges whether the patient has oropharyngeal or esophageal dysphagia. Often, both an oropharyngeal examination, performed by a speech and language pathologist, and an esophageal examination, performed by a radiologist, are ordered.

Rapidly progressive symptoms, especially if accompanied by weight loss, should make one suspect cancer. Chronic symptoms usually point to gastroesophageal reflux disease or a motility disorder such as achalasia. Liquid dysphagia almost always means the patient has a motility disorder such as achalasia.

In view of the possibility of eosinophilic esophagitis, one should ask about food or seasonal allergies, especially in young patients with intermittent difficulty swallowing solids.³

BARIUM ESOPHAGOGRAPHY HAS EIGHT SEPARATE PHASES

Barium esophagography is tailored to the patient with dysphagia on the basis of his or her history. The standard examination is divided into eight separate phases (see below).¹⁴ Each phase addresses a specific question or questions concerning the structure and function of the esophagus.

At our institution, the first phase of the examination is determined by the presenting symptoms. If the patient has liquid dysphagia, we start with a timed barium swallow to assess esophageal emptying. If the patient does not have liquid dysphagia, we start with an air-contrast mucosal examination.

The patient must be cooperative and mobile to complete all phases of the examination.

Timed barium swallow to measure esophageal emptying

The timed barium swallow is an objective measure of esophageal emptying.^16–18 This technique is essential in the initial evaluation of a patient with liquid dysphagia, a symptom common in patients with severe dysmotility, usually achalasia.

We use this examination in our patients with suspected or confirmed achalasia and to follow up patients who have been treated with pneumatic dilatation, botulinum toxin injection, and Heller myotomy.^17,18 In addition, this timed test is an objective measure of emptying in patients who have undergone intervention but whose symptoms have not subjectively improved, and can suggest that further intervention may be required.

Air-contrast or mucosal phase

Although this phase is not as sensitive as endoscopy, it can detect masses, mucosal erosions, ulcers, and—most importantly in our experience—fixed hernias. Patients with a fixed hernia have a foreshortened esophagus, which is important to know about before repairing the hernia. Many esophageal surgeons believe that a foreshortened esophagus precludes a standard Nissen fundoplication and necessitates an esophageal lengthening procedure (ie, Collis gastroplasty with a Nissen fundoplication).¹⁴

Motility phase

The third phase examines esophageal motility. With the patient in a semiprone position, low-density barium is given in single swallows, separated by 25 to 30 seconds. The images are recorded on digital media to allow one to review them frame by frame.

The findings on this phase correlate well with those of manometry.¹⁹ This portion of the examination also uses impedance monitoring to assess bolus transfer, an aspect not evaluated by manometry.^20,21 Impedance monitoring detects changes in resistance to current flow and correlates well with esophagraphic findings regarding bolus transfer.

While many patients with dysphagia also undergo esophageal manometry, the findings from this phase of the esophagographic examination may be the first indication of an esophageal motility disorder. In fact, this portion of the examination shows the distinct advantage of esophagography over endoscopy as the initial test in patients with dysphagia, as endoscopy may not identify patients with achalasia, especially early on.⁴

Single-contrast (full-column) phase to detect strictures, rings

The fourth phase of the esophagographic evaluation is the distended, single-contrast examination (Figure 2B). This is performed in the semiprone position with the patient rapidly drinking thin barium. It is done to detect esophageal strictures, rings, and contour abnormalities caused by extrinsic processes. Subtle abnormalities shown by this technique, including benign strictures and rings, are often not visualized with endoscopy.

Mucosal relief phase

The fifth phase is performed with a collapsed esophagus immediately after the distended, single-contrast phase, where spot films are taken of the barium-coated, collapsed esophagus (Figure 2C). This phase is used to evaluate thickened mucosal folds, a common finding in moderate to severe reflux esophagitis.

Reflux evaluation

Provocative maneuvers are used in the sixth phase to elicit gastroesophageal reflux (Figure 2D). With the patient supine, he or she is asked to roll side to side, do a Valsalva maneuver, and do a straight-leg raise. The patient then sips water in the supine position to assess for reflux (the water siphon test). If reflux is seen, the cause, the height of the reflux, and the duration of reflux retention are recorded.

Solid-bolus phase to assess strictures

In the seventh phase, the patient swallows a 13-mm barium tablet (Figure 2E). This allows one to assess the significance of a ring or stricture and to assess if dysphagia symptoms recur as a result of tablet obstruction. Subtle strictures that were not detected during the prior phases can also be detected using a tablet. If obstruction or impaired passage occurs, the site of obstruction and the presence or absence of symptoms are recorded.

The final or eighth phase of barium esophagography is called “modified barium esophagography” or the modified barium swallow. However, it may be the first phase of the examination performed or the only portion of the examination performed, or it may not be performed at all.

Modified barium esophagography is used to define the anatomy of the oropharynx and to assess its function in swallowing.¹² It may also guide rehabilitation strategies aimed at eliminating a patient’s swallowing symptoms.

Most patients referred for this test have sustained damage to the central nervous system or structures of the oropharynx, such as stroke or radiation therapy for laryngeal cancer. Many have difficulty in starting to swallow, aspirate when they try to swallow, or both.

The final esophagographic report should document the findings of each phase of the examination (Table 2).

WHAT HAPPENED TO OUR PATIENT?

Our patient underwent barium esophagography (Figure 2). A distal mucosal ring that transiently obstructed a 13-mm tablet was found. The patient underwent endoscopy and the ring was dilated. No biopsies were necessary.

A 25-year-old married white woman presented to a clinic because of pelvic pain. A computed tomographic scan of her abdomen and pelvis without intravenous contrast showed two definite cysts in the right kidney (the larger measuring 2.5 cm) and a 1.5-cm cyst in the left kidney. It also showed several smaller (< 1 cm) areas of low density in both kidneys that suggested cysts. Renal ultrasonography also showed two cysts in the left kidney and one in the right kidney. The kidneys were normal-sized—the right one measured 12.5 cm and the left one 12.7 cm.

She had no family history of autosomal dominant polycystic kidney disease (ADPKD), and renal ultrasonography of her parents showed no cystic disease. She had no history of headache or heart murmur, and her blood pressure was normal. Her kidneys were barely palpable, her liver was not enlarged, and she had no cardiac murmur or click. She was not taking any medications. Her serum creatinine level was 0.7 mg/dL, hemoglobin 14.0 g/dL, and urinalysis normal.

Does this patient have ADPKD? Based on the studies done so far, would genetic testing be useful? If the genetic analysis does show a mutation, what additional information can be derived from the location of that mutation? Can she do anything to improve her prognosis?

ADPKD ACCOUNTS FOR ABOUT 3% OF END-STAGE RENAL DISEASE

ADPKD is the most common of all inherited renal diseases, with 600,000 to 700,000 cases in the United States and about 12.5 million cases worldwide. About 5,000 to 6,000 new cases are diagnosed yearly in the United States, about 40% of them by age 45. Typically, patients with ADPKD have a family history of the disease, but about 5% to 10% do not. In about 50% of cases, ADPKD progresses to end-stage renal disease by age 60, and it accounts for about 3% of cases of end-stage renal disease in the United States.¹

CYSTS IN KIDNEYS AND OTHER ORGANS, AND NONCYSTIC FEATURES

In ADPKD, cysts in the kidneys increase in number and size over time, ultimately destroying normal renal tissue. However, renal function remains steady over many years until the kidneys have approximately quadrupled in volume to 1,500 cm³ (normal combined kidney volume is about 250 to 400 cm³), which defines a tipping point beyond which renal function can rapidly decline.^2,3 Ultimately, the patient will need renal replacement therapy, ie, dialysis or renal transplantation.

The cysts (kidney and liver) cause discomfort and pain by putting pressure on the abdominal wall, flanks, and back, by impinging on neighboring organs, by bleeding into the cysts, and by the development of kidney stones or infected cysts (which are uncommon, though urinary tract infections themselves are more frequent). Kidney stones occur in about 20% of patients with ADPKD, and uric acid stones are almost as common as calcium oxalate stones. Compression of the iliac vein and inferior vena cava with possible thrombus formation and pulmonary embolism can be caused by enormous enlargement of the cystic kidneys, particularly the right.⁴ Interestingly, the patients at greatest risk of pulmonary embolism after renal transplantation are those with ADPKD.⁵

Cysts can also develop in other organs. Liver cysts develop in about 80% of patients. Usually, the cysts do not affect liver function, but because they are substantially estrogen-dependent they can be more of a clinical problem in women. About 10% of patients have cysts in the pancreas, but these are functionally insignificant. Other locations of cysts include the spleen, arachnoid membranes, and seminal vesicles in men.

Intracranial aneurysms are a key noncystic feature, and these are strongly influenced by family history. A patient with ADPKD who has a family member with ADPKD as well as an intracranial aneurysm or subarachnoid hemorrhage has about a 20% chance of having an intracranial aneurysm. A key clinical warning is a “sentinel” or “thunderclap” headache, which patients typically rate as at least a 10 on a scale of 10 in severity. In a patient with ADPKD, this type of headache can signal a leaking aneurysm causing irritation and edema of the surrounding brain tissue that temporarily tamponades the bleeding before the aneurysm actually ruptures. This is a critical period when a patient should immediately obtain emergency care.

Cardiac valve abnormalities occur in about one-third of patients. Most common is mitral valve prolapse, which is usually mild. Abnormalities can also occur in the aortic valve and the left ventricular outflow tract.

Hernias are the third general noncystic feature of ADPKD. Patients with ADPKD have an increased prevalence of umbilical, hiatal, and inguinal hernias, as well as diverticulae of the colon.

DOES THIS PATIENT HAVE ADPKD?

The Ravine ultrasonographic criteria for the diagnosis of ADPKD are based on the patient’s age, family history, and number of cysts (Table 1).^6,7 Alternatively, Torres (Vincent E. Torres, personal communication, March 2008) recommends that, in the absence of a family history of ADPKD or other findings to suggest other cystic disease, the diagnosis of ADPKD can be made if the patient has a total of at least 20 renal cysts.

Our patient had only three definite cysts, was 25 years old, and had no family history of ADPKD and so did not technically meet the Ravine criteria of five cysts at this age, or the Torres criteria, for having ADPKD. Nevertheless, because she was concerned about overt disease possibly developing later and about passing on a genetic defect to her future offspring, she decided to undergo genetic testing.

CLINICAL GENETICS OF ADPKD: TWO MAJOR TYPES

There are two major genetic forms of ADPKD, caused by mutations in the genes PKD1 and PKD2.

PKD1 has been mapped to the short arm of the 16th chromosome. Its gene product is polycystin 1. Mutations in PKD1 account for about 85% of all cases of polycystic kidney disease. The cysts appear when patients are in their 20s, and the disease progresses relatively rapidly, so that most patients enter end-stage renal disease when they are in their 50s.

PKD2 has been mapped to the long arm of the fourth chromosome. Its product is polycystin 2. PKD2 mutations account for about 15% of all cases of ADPKD, and the disease progresses more slowly, usually with end-stage disease developing when the patients usually are in their 70s.

Screening for mutations by direct DNA sequencing in ADPKD

Genetic testing for PKD1 and PKD2 mutations is available (www.athenadiagnostics.com).⁸ The Human Gene Mutation Database lists at least 270 different PKD1 mutations and 70 different PKD2 mutations.⁸ Most are unique to a single family.

Our patient was tested for mutations of the PKD1 and PKD2 genes by polymerase chain reaction amplification and direct DNA sequencing. She was found to possess a DNA sequence variant at a nucleotide position in the PKD1 gene previously reported as a disease-associated mutation. She is therefore likely to be affected with or predisposed to developing ADPKD.

Furthermore, the position of her mutation means she has a worse prognosis. Rossetti et al,⁹ in a study of 324 PKD1 patients, found that only 19% of those who had mutations in the 5′ region of the gene (ie, at positions below 7,812) still had adequate renal function at 60 years of age, compared with 40% of those with mutations in the 3′ region (P = .025).

Other risk factors for more rapid kidney failure in ADPKD include male sex, onset of hypertension before age 35, gross hematuria before age 30 in men, and, in women, having had three or more pregnancies.

THE ‘TWO-HIT’ HYPOTHESIS

The time of onset and the rate of progression of ADPKD can vary from patient to patient, even in the same family. Besides the factors mentioned above, another reason may be that second mutations (“second hits”) have to occur before the cysts develop.

The first mutation exists in all the kidney tubular cells and is the germline mutation in the PKD gene inherited from the affected parent. This is necessary but not sufficient for cyst formation.

The second hit is a somatic mutation in an individual tubular cell that inactivates to varying degrees the unaffected gene from the normal parent. It is these second hits that allow abnormal focal (monoclonal) proliferation of renal tubular cells and cyst formation (reviewed by Arnaout¹⁰ and by Pei¹¹). There is no way to predict these second hits, and their identity is unknown.

Other genetic variations may occur, such as transheterozygous mutations, in which a person may have a mutation of PKD1 as well as PKD2.

Germline mutations of PKD1 or PKD2 combined with somatic mutations of the normal paired chromosome depress levels of their normal gene products (polycystin 1 and polycystin 2) to the point that cysts develop.

The timing and frequency of these second hits blur the distinction between the time course for the progression of PKD1 and PKD2 disease, and can accelerate the course of both.

BASIC RESEARCH POINTS THE WAY TO TREATMENTS FOR ADPKD

Polycystin 1 and polycystin 2 are the normal gene products of the genes which, when mutated, are responsible for PKD1 and PKD2, respectively. Research into the structure and function of the polycystin 1 and polycystin 2 proteins—and what goes wrong when they are not produced in sufficient quantity or accurately—is pointing the way to possible treatments for ADPKD.

When the polycystins are not functioning, as in ADPKD, these proliferative pathways are unopposed. However, proliferation can be countered in other ways. One of the prime movers of cell proliferation, acting through adenylyl cyclase and cAMP, is vasopressin. In genetically produced polycystic animals, two antagonists of the vasopressin V2 receptor (VPV2R), OPC31260 and OPC41061 (tolvaptan), decreased cAMP and ERK, prevented or reduced renal cysts, and preserved renal function.^15,16 Not surprisingly, simply increasing water intake decreases vasopressin production and the development of polycystic kidney disease in rats.¹⁷ Definitive proof of the role of vasopressin in causing cyst formation was achieved by crossing PCK rats (genetically destined to develop polycystic kidneys) with Brattleboro rats (totally lacking vasopressin) in order to generate rats with polycystic kidneys and varying amounts of vasopressin.¹⁸ PCK animals with no vasopressin had virtually no cAMP or renal cysts, whereas PCK animals with increasing amounts of vasopressin had progressively larger kidneys with more numerous cysts. Administration of synthetic vasopressin to PCK rats that totally lacked vasopressin re-created the full cystic disease.