History of Present Illness

A55-year-old male presented with a one and one-half week history of a sore throat, shortness of breath on exertion, ankle edema, and arthralgias that began in the ankles and subsequently spread to involve the elbows and wrists.

He had also developed a pruritic eruption involving the lower extremities, which consisted of erythematous palpable purpuric lesions and patches with superficial and central necrosis and ulceration, as well as a large 4-cm bulla of the right lateral ankle. (See Figures 1 and 2, below.) Other skin findings included petechiae of the palms and multiple ulcerations of the hard palate. Laboratory evaluation demonstrated c-ANCA antibody positivity (1:512), a proteinase 3 antibody level of greater than 100 U/ml, and a creatinine of 1.0mg/dl. TH

What is the most appropriate treatment for this condition?

1. Prednisone;
2. Azathioprine;
3. Cyclophosphamide;
4. Prednisone combined with cyclophosphamide; or
5. Vancomycin combined with rifampin

Discussion

The answer is D: Wegener’s granulomatosis (WG) is a chronic granulomatous inflammatory response of unknown etiology that usually presents with the classic triad of systemic vasculitis, necrotizing granulomatous inflammation of the upper and lower respiratory tracts, and glomerulonephritis. The generalized or classic form of WG can progress rapidly to cause irreversible organ dysfunction and death. Although the pathogenesis remains unknown, it is felt that WG may result from an exaggerated cell-mediated response to an unknown antigen.1

The average age of onset for WG is 45.2 years, with 63.5% of patients male and 91% Caucasian.2 A WG diagnosis can be very difficult, and elements of the classic triad may not all be present initially. Pulmonary infiltrates or nodules are seen via chest X-ray or CT scan in just less than half of patients as an early manifestation of WG.

Occasionally WG presents with skin lesions (13%) or oral ulcers (6%), however, 40% of patients eventually develop skin involvement consisting of painful subcutaneous nodules, papules, vesicles or bullae, petechiae, palpable purpura, and pyoderma gangrenosum-like lesions.3 Histologic evaluation of these skin lesions reveals non-specific perivascular lymphocytic inflammation, leukocytoclastic vasculitis-like changes, palisading granulomas, and granulomatous vasculitis; however, it is rare to see granulomatous vasculitis or palisading necrotizing granulomas in skin specimens.4,5

WG can also affect the eyes, heart, respiratory system, nervous system, kidneys, and joints.6 The upper respiratory tract is involved in the majority of patients, and symptoms reflecting otitis, epistaxis, rhinorrhea, or sinusitis are common and may be the first manifestation of disease. When mucosal necrotizing granulomas occur, they can result in the typical saddle nose deformity seen in patients with WG. Lower respiratory tract involvement is also common and can present with cough, dyspnea, chest pain, and hemoptysis.1

Patients with WG usually have a positive c-ANCA, however this is not specific for WG and may also indicate Churg-Strauss Syndrome and microscopic polyarteritis. The median survival of patients with untreated WG is five months, and corticosteroids used alone do not change this median survival. When corticosteroids are combined with cytotoxic agents, such as cyclophosphamide, the prognosis significantly improves in greater than 90% of patients, with a 75% remission rate, and an 87% survival of patients followed from six months to 24 years.3 TH

References

1. Hannon CW, Swerlick RA. Vasculitis. In: Bolognia JL, Jorizzo JL, Rapini RP, et al, eds. Dermatology. Vol 1. New York: Elsevier Limited; 2003: 393-395.
2. Cotch MF, Hoffman GS, Yerg DE, et al. The epidemiology of Wegener’s granulomatosis. Estimates of the five-year period prevalence, annual mortality, and geographic disease distribution from population-based data sources. Arthritis Rheum. 1996 Jan;39(1):87-92.
3. Hoffman GS, Kerr GS, Leavitt RY, et al. Wegener granulomatosis: an analysis of 158 patients. [see comments]. Ann Int Med. 1992;116:488-498.
4. Hu CH, O’Loughlin S, Winkelmann RK. Cutaneous manifestations of Wegener granulomatosis. Arch Dermatol. 1997;113(2):175-182.
5. Lie JT. Wegener’s granulomatosis: histological documentation of common and uncommon manifestations in 216 patients. Vasa. 1997;26:261-270.
6. Yi ES, Colby TV. Wegener’s granulomatosis. Semin Diagn Pathol. 2001 Feb;18(1):34-46.

History of Present Illness

A55-year-old male presented with a one and one-half week history of a sore throat, shortness of breath on exertion, ankle edema, and arthralgias that began in the ankles and subsequently spread to involve the elbows and wrists.

He had also developed a pruritic eruption involving the lower extremities, which consisted of erythematous palpable purpuric lesions and patches with superficial and central necrosis and ulceration, as well as a large 4-cm bulla of the right lateral ankle. (See Figures 1 and 2, below.) Other skin findings included petechiae of the palms and multiple ulcerations of the hard palate. Laboratory evaluation demonstrated c-ANCA antibody positivity (1:512), a proteinase 3 antibody level of greater than 100 U/ml, and a creatinine of 1.0mg/dl. TH

What is the most appropriate treatment for this condition?

1. Prednisone;
2. Azathioprine;
3. Cyclophosphamide;
4. Prednisone combined with cyclophosphamide; or
5. Vancomycin combined with rifampin

Discussion

The answer is D: Wegener’s granulomatosis (WG) is a chronic granulomatous inflammatory response of unknown etiology that usually presents with the classic triad of systemic vasculitis, necrotizing granulomatous inflammation of the upper and lower respiratory tracts, and glomerulonephritis. The generalized or classic form of WG can progress rapidly to cause irreversible organ dysfunction and death. Although the pathogenesis remains unknown, it is felt that WG may result from an exaggerated cell-mediated response to an unknown antigen.1

The average age of onset for WG is 45.2 years, with 63.5% of patients male and 91% Caucasian.2 A WG diagnosis can be very difficult, and elements of the classic triad may not all be present initially. Pulmonary infiltrates or nodules are seen via chest X-ray or CT scan in just less than half of patients as an early manifestation of WG.

Occasionally WG presents with skin lesions (13%) or oral ulcers (6%), however, 40% of patients eventually develop skin involvement consisting of painful subcutaneous nodules, papules, vesicles or bullae, petechiae, palpable purpura, and pyoderma gangrenosum-like lesions.3 Histologic evaluation of these skin lesions reveals non-specific perivascular lymphocytic inflammation, leukocytoclastic vasculitis-like changes, palisading granulomas, and granulomatous vasculitis; however, it is rare to see granulomatous vasculitis or palisading necrotizing granulomas in skin specimens.4,5

WG can also affect the eyes, heart, respiratory system, nervous system, kidneys, and joints.6 The upper respiratory tract is involved in the majority of patients, and symptoms reflecting otitis, epistaxis, rhinorrhea, or sinusitis are common and may be the first manifestation of disease. When mucosal necrotizing granulomas occur, they can result in the typical saddle nose deformity seen in patients with WG. Lower respiratory tract involvement is also common and can present with cough, dyspnea, chest pain, and hemoptysis.1

Patients with WG usually have a positive c-ANCA, however this is not specific for WG and may also indicate Churg-Strauss Syndrome and microscopic polyarteritis. The median survival of patients with untreated WG is five months, and corticosteroids used alone do not change this median survival. When corticosteroids are combined with cytotoxic agents, such as cyclophosphamide, the prognosis significantly improves in greater than 90% of patients, with a 75% remission rate, and an 87% survival of patients followed from six months to 24 years.3 TH

References

1. Hannon CW, Swerlick RA. Vasculitis. In: Bolognia JL, Jorizzo JL, Rapini RP, et al, eds. Dermatology. Vol 1. New York: Elsevier Limited; 2003: 393-395.
2. Cotch MF, Hoffman GS, Yerg DE, et al. The epidemiology of Wegener’s granulomatosis. Estimates of the five-year period prevalence, annual mortality, and geographic disease distribution from population-based data sources. Arthritis Rheum. 1996 Jan;39(1):87-92.
3. Hoffman GS, Kerr GS, Leavitt RY, et al. Wegener granulomatosis: an analysis of 158 patients. [see comments]. Ann Int Med. 1992;116:488-498.
4. Hu CH, O’Loughlin S, Winkelmann RK. Cutaneous manifestations of Wegener granulomatosis. Arch Dermatol. 1997;113(2):175-182.
5. Lie JT. Wegener’s granulomatosis: histological documentation of common and uncommon manifestations in 216 patients. Vasa. 1997;26:261-270.
6. Yi ES, Colby TV. Wegener’s granulomatosis. Semin Diagn Pathol. 2001 Feb;18(1):34-46.

History of Present Illness

A55-year-old male presented with a one and one-half week history of a sore throat, shortness of breath on exertion, ankle edema, and arthralgias that began in the ankles and subsequently spread to involve the elbows and wrists.

He had also developed a pruritic eruption involving the lower extremities, which consisted of erythematous palpable purpuric lesions and patches with superficial and central necrosis and ulceration, as well as a large 4-cm bulla of the right lateral ankle. (See Figures 1 and 2, below.) Other skin findings included petechiae of the palms and multiple ulcerations of the hard palate. Laboratory evaluation demonstrated c-ANCA antibody positivity (1:512), a proteinase 3 antibody level of greater than 100 U/ml, and a creatinine of 1.0mg/dl. TH

What is the most appropriate treatment for this condition?

1. Prednisone;
2. Azathioprine;
3. Cyclophosphamide;
4. Prednisone combined with cyclophosphamide; or
5. Vancomycin combined with rifampin

Discussion

The answer is D: Wegener’s granulomatosis (WG) is a chronic granulomatous inflammatory response of unknown etiology that usually presents with the classic triad of systemic vasculitis, necrotizing granulomatous inflammation of the upper and lower respiratory tracts, and glomerulonephritis. The generalized or classic form of WG can progress rapidly to cause irreversible organ dysfunction and death. Although the pathogenesis remains unknown, it is felt that WG may result from an exaggerated cell-mediated response to an unknown antigen.1

The average age of onset for WG is 45.2 years, with 63.5% of patients male and 91% Caucasian.2 A WG diagnosis can be very difficult, and elements of the classic triad may not all be present initially. Pulmonary infiltrates or nodules are seen via chest X-ray or CT scan in just less than half of patients as an early manifestation of WG.

Occasionally WG presents with skin lesions (13%) or oral ulcers (6%), however, 40% of patients eventually develop skin involvement consisting of painful subcutaneous nodules, papules, vesicles or bullae, petechiae, palpable purpura, and pyoderma gangrenosum-like lesions.3 Histologic evaluation of these skin lesions reveals non-specific perivascular lymphocytic inflammation, leukocytoclastic vasculitis-like changes, palisading granulomas, and granulomatous vasculitis; however, it is rare to see granulomatous vasculitis or palisading necrotizing granulomas in skin specimens.4,5

WG can also affect the eyes, heart, respiratory system, nervous system, kidneys, and joints.6 The upper respiratory tract is involved in the majority of patients, and symptoms reflecting otitis, epistaxis, rhinorrhea, or sinusitis are common and may be the first manifestation of disease. When mucosal necrotizing granulomas occur, they can result in the typical saddle nose deformity seen in patients with WG. Lower respiratory tract involvement is also common and can present with cough, dyspnea, chest pain, and hemoptysis.1

Patients with WG usually have a positive c-ANCA, however this is not specific for WG and may also indicate Churg-Strauss Syndrome and microscopic polyarteritis. The median survival of patients with untreated WG is five months, and corticosteroids used alone do not change this median survival. When corticosteroids are combined with cytotoxic agents, such as cyclophosphamide, the prognosis significantly improves in greater than 90% of patients, with a 75% remission rate, and an 87% survival of patients followed from six months to 24 years.3 TH

References

1. Hannon CW, Swerlick RA. Vasculitis. In: Bolognia JL, Jorizzo JL, Rapini RP, et al, eds. Dermatology. Vol 1. New York: Elsevier Limited; 2003: 393-395.
2. Cotch MF, Hoffman GS, Yerg DE, et al. The epidemiology of Wegener’s granulomatosis. Estimates of the five-year period prevalence, annual mortality, and geographic disease distribution from population-based data sources. Arthritis Rheum. 1996 Jan;39(1):87-92.
3. Hoffman GS, Kerr GS, Leavitt RY, et al. Wegener granulomatosis: an analysis of 158 patients. [see comments]. Ann Int Med. 1992;116:488-498.
4. Hu CH, O’Loughlin S, Winkelmann RK. Cutaneous manifestations of Wegener granulomatosis. Arch Dermatol. 1997;113(2):175-182.
5. Lie JT. Wegener’s granulomatosis: histological documentation of common and uncommon manifestations in 216 patients. Vasa. 1997;26:261-270.
6. Yi ES, Colby TV. Wegener’s granulomatosis. Semin Diagn Pathol. 2001 Feb;18(1):34-46.

In December the Journal of Hospital Medicine (JHM, the peer-reviewed sister publication of The Hospitalist) was selected for indexing and inclusion in the National Library of Medicine’s MEDLINE (Medical Literature Analysis and Retrieval System Online). MEDLINE is a bibliographic database that contains 13 million references to journal articles in medicine, nursing, dentistry, veterinary medicine, healthcare systems, and preclinical sciences. It’s the primary component of PubMed, part of the Entrez series of databases provided by the Library’s National Center for Biotechnology Information (NCBI).

“The Journal’s acceptance is a profound recognition that hospital medicine has developed its own sphere of medical knowledge and that hospitalists are making a significant impact on our modern healthcare delivery system,” says Larry Wellikson, MD, FACP, SHM CEO.

JHM, an official SHM publication, debuted in February 2006 and is the premier forum for peer-reviewed research articles and evidence-based reviews in the specialty of hospital medicine. For more information about JHM, visit www.interscience.wiley.com/journal/jhm.

In December the Journal of Hospital Medicine (JHM, the peer-reviewed sister publication of The Hospitalist) was selected for indexing and inclusion in the National Library of Medicine’s MEDLINE (Medical Literature Analysis and Retrieval System Online). MEDLINE is a bibliographic database that contains 13 million references to journal articles in medicine, nursing, dentistry, veterinary medicine, healthcare systems, and preclinical sciences. It’s the primary component of PubMed, part of the Entrez series of databases provided by the Library’s National Center for Biotechnology Information (NCBI).

“The Journal’s acceptance is a profound recognition that hospital medicine has developed its own sphere of medical knowledge and that hospitalists are making a significant impact on our modern healthcare delivery system,” says Larry Wellikson, MD, FACP, SHM CEO.

JHM, an official SHM publication, debuted in February 2006 and is the premier forum for peer-reviewed research articles and evidence-based reviews in the specialty of hospital medicine. For more information about JHM, visit www.interscience.wiley.com/journal/jhm.

In December the Journal of Hospital Medicine (JHM, the peer-reviewed sister publication of The Hospitalist) was selected for indexing and inclusion in the National Library of Medicine’s MEDLINE (Medical Literature Analysis and Retrieval System Online). MEDLINE is a bibliographic database that contains 13 million references to journal articles in medicine, nursing, dentistry, veterinary medicine, healthcare systems, and preclinical sciences. It’s the primary component of PubMed, part of the Entrez series of databases provided by the Library’s National Center for Biotechnology Information (NCBI).

“The Journal’s acceptance is a profound recognition that hospital medicine has developed its own sphere of medical knowledge and that hospitalists are making a significant impact on our modern healthcare delivery system,” says Larry Wellikson, MD, FACP, SHM CEO.

JHM, an official SHM publication, debuted in February 2006 and is the premier forum for peer-reviewed research articles and evidence-based reviews in the specialty of hospital medicine. For more information about JHM, visit www.interscience.wiley.com/journal/jhm.

Productivity and compensation benchmarks can be useful when negotiating with hospital administrators for increased reimbursements and support resources, when recruiting hospitalists, and when conducting self-evaluations. For many of these processes, hospitalists—and, indeed, hospital administrators—turn to the information contained in the voluminous SHM 2005-2006 Survey, “The Authoritative Source on the State of the Hospital Medicine Movement.” (See “For More Information,” p. 32.)

With a response rate of 26%, the survey represents some 2,550 hospitalists across the nation, and its variables present a more comprehensive aerial view of hospital medicine than did previous surveys. But on the ground and in the trenches, hospital medicine groups must be careful to look at the survey’s metrics with a discerning eye.

When applying the survey metrics to one’s own practice, there can be benefits as well as pitfalls, cautions Joe Miller, SHM senior vice president and principal analyst of the survey data. He emphasizes the great variation among hospital medicine groups and warns against looking at survey medians as representing a “typical” hospital medicine practice.

“When you’ve seen one hospital medicine group, you’ve seen one hospital medicine group,” he quips. In several recent conversations, hospital medicine group leaders and SHM leaders involved in compiling the survey discussed the survey’s strengths and limitations as a benchmarking tool.

Healthy to Negotiate

According to the survey 97% of hospitalist programs receive some type of financial support. “Virtually every program in the country is challenged to defend the amount of money [they receive] or to negotiate for support dollars,” says Miller, who believes that negotiation can be a healthy dynamic. “There is a sense of equality of both sides of the table, a mutual respect between hospitalists and the hospital.” In the process of such negotiations, it will be important not to pin one’s position entirely to the survey metrics.

John Nelson, MD, medical director of the hospitalist practice at Overlake Hospital in Bellevue, Wash., a consultant for hospitalist practices with Nelson/Flores Associates, a columnist for The Hospitalist (“Practice Management”), and a co-founder and past president of SHM, believes that some hospitalists mistakenly view the survey as SHM’s position on what a hospitalist should make. “The survey is the best information we have about what hospitalists do make—there is no better source—but it’s still a survey.”

Using compensation medians as yardsticks for actual salaries and compensation packages is analogous to “learning the average weight of an American and deciding that’s what we all should weigh—and that’s a big mistake,” he says. “If you hold up the survey as the governing document, then each party will use it to their advantage.”

Because the survey is regarded as the most authoritative existing source on hospitalists’ compensation and productivity, it nevertheless ends up being used as a benchmark, says Robin L. Dauterive, assistant director of the clinical hospitalist service at Massachusetts General Hospital in Boston.

“Whenever I’m preparing billings reports or dashboard measures—anything that shows my group’s workload—sooner or later, I always have to include something in there that states, ‘This is what other people are doing,’ ” says Dauterive. “It’s something that you can’t get away from, unfortunately, in medicine.”

She realizes that the survey does not purport to set any national standards, and yet, “all administrations want comparisons.” Dr. Nelson has also noted this phenomenon with the survey. In the absence of additional guidance, hospital executives and hospitalists often find that they’re just arguing about the survey. “And that’s unfortunate,” he says. “It means they’ve lost sight of the unique attributes of a given practice that might support higher or lower incomes and higher or lower workloads.”

View in Context

Hospitalists reading the survey for the first time might first seek to analyze the metrics regarding billings and collections. Here it is especially important not to view the reported numbers in isolation, says Dr. Nelson. For instance, to learn how a hospitalist’s annual gross charges (billings) compare with others across the country (question 12 of the Individual Hospitalist questionnaire—p. 87, Appendix 2), details on pages 251 and 252 supply pertinent variables. For instance, in comparing the four regions of the country, Table 056-A shows that the median annual gross charges for physicians in the south are highest, at $354,000. Hospitalists compensated by a 100% incentive method report higher charges per year ($392,000) than those who are on a 100% salary or a mix of the two methods of payment. Turning to Table 056-B, on page 252 of the published survey, hospitalists can find annual gross charges according to practitioner type, specialty, and employment model. Hospitalists should not stop their reading there, however, as a comparison of others’ annual gross collections might give a more complete picture.

Still, the SHM Survey does not reference all possible explanatory variables. Collections can be influenced by location and payer mix. Hospitalists practicing in a large urban hospital are likely to see more indigent patients for whom the hospital is not reimbursed. A careful reading of the survey should include the questionnaire and the tables supporting chapter conclusions, and the reader must recognize the survey’s limitations.

Apples to Oranges

IPC–The Hospitalist Company participates in the SHM survey and also uses it as a recruitment tool, reports IPC Vice President of Physician Staffing Timothy Lary. “We look at the income averages, and we’re able to demonstrate how our averages are, for the most part, higher than the averages,” he explains. “We also look at the survey from an internal viewpoint, but oftentimes you are comparing apples to oranges.”

Like individual hospitalists, hospital medicine group leaders seek comparisons when they read the survey. For her part, Dr. Dauterive has found the data on starting salaries for new hospitalists useful. For example, page 259, detailed table 060-A on hospitalists’ compensation by category and total, breaks out median yearly income by years as a hospitalist, from less than a year to six or more years. (Many of the detailed “A” tables in Chapter 8 on compensation include the “years as a hospitalist” category.) Dr. Dauterive praises the wealth of data in the survey, pointing to examples of the many variables she was surprised to learn. One of those factors was that 48% of surveyed hospitalist programs were at non-teaching hospitals. (See page 7 of the survey, Executive Summary, “Teaching status of affiliated hospital.”)

Those interviewed for this article agree that productivity data are probably more telling about the day-to-day clinical realities for hospitalists. Productivity metrics figure prominently in Dr. Dauterive’s uses for the survey. Accordingly, the annual number of billable patient encounters seen by the hospitalist (Table 58-B, page 256) and the annual number of work relative value units (RVUs) worked by the hospitalist (Table 59-B, page 258) caught her interest.

Still, Dr. Dauterive found herself wanting more data to shed light on those numbers. In negotiations for resources with hospital administrators, Dr. Dauterive would like to be able to pinpoint the reasons behind reported numbers of clinical encounters seen by the hospitalist. If the median number of billable patient encounters seen by the hospitalist in a teaching service was 1,668 (based on 107 responses; page 256, Detailed Table 058-B), what were some of the influences on this number? What was the acuity level of patients? Did the hospitalist have group resources, such as physician extenders, to help with patient admissions and rounds?

“For groups that have low lengths of stay, it would be important for me to know why,” she says. “Did they have extra supports? Do their [doctors] use Palm Pilots? You don’t always know from looking at the numbers how to apply them, make the connection, and justify the resources you’re trying to achieve,” she says.

No Perfect Measure

The ideal survey for Dr. Dauterive would include specific structured models, providing links between categories so that she could compare characteristics that more closely align with her group’s situation.

“Our program is very mixed, so it would be helpful for me to know how work RVUs were being reported,” she says. Pointing to results showing higher productivity (work RVUs) in practices compensated by 100% incentive (Table 060-A, page 259 of the survey), Dr. Dauterive wonders what factors drive these results. While the 100% incentive might appear to be the most important factor, perhaps these groups also have physician extenders or are located in a geographic location that boosts their productivity.

“I’m in a nonprofit hospital, in a clinical hospitalist service, and I want to be able to approach the administration and say, ‘If you want us to see the most patients, these are the kinds of services that see the most patients,’ ”says Dr. Dauterive. “But, if you are more interested in physician retention and work/life, then these are the characteristics of those successful programs.”

This level of detail can be difficult to interpolate from the survey, agrees Dr. Nelson. Patient acuity, for instance, is not specifically queried in the survey questionnaire. “I agree, in the ideal world, this is all information that you would want to know,” he says. Answers to the following questions could help refine product metrics:

• Does your group have teaching responsibilities for residents?
• Do you take a lot of calls from home, or do you have a separate night shift?
• Do you cover more than one physical hospital on the same day?
• Does your group do more than the typical amount of committee and administrative work?

“All these factors,” notes Dr. Nelson, “would influence productivity. There is no perfect way to know the answer to any of those things.” And, he adds, the survey already comprises 292 pages, including numerous detailed tables of data. To include all pertinent variables would entail a longer questionnaire, which might affect the response rate.

Healthcare Delivery Is Local

In his consultations with hospitalist groups, Dr. Nelson always emphasizes that the survey is “a starting point” and not the goal of what hospitalists should make. He favors adjunctive methods for benchmarking practices: “I think that when you’re benchmarking your practice, it’s as important to gather as much local and regional data as you can—in addition to the SHM survey.” He tries to network with other Seattle hospitalist programs to learn about their patterns of work hours, patient loads, and the like.

Thomas Baudendistel, MD, FACP, associate program director of the Internal Medicine Residency Program at Sutter Health’s California Pacific Medical Center in San Francisco, notes that regional markets differ widely. The healthcare market in the Northern California Bay area is very different from the one in Los Angeles in terms of financial remuneration and incentivization.

“The survey,” he says, “gives a global gestalt of the regional flavor of hospital medicine” and reveals general ballpark medians that can be a good starting point for practice benchmarking. “I think what our administration [at California Pacific Medical Center] wants to see is our data compared to the people across the street and down the road, because that’s a closer comparison in terms of payer mix and insurance reimbursements.”

IPC’s Lary agrees. “When I compete, I don’t compete against people across the country; I compete with people across the street,” he says. “As large as IPC is, we realize that healthcare is delivered locally. What we try to do [with the survey] is take the information and, to the best or our ability, figure out how it applies to our individual settings and [to the] different markets that we are in.”

A Stake in the Sand

“I think the benchmarks we have in the survey are just a piece of information—[the survey] is a context, it’s a stake in the sand,” concludes Miller. “We do have variations by type of program, by size of hospital, by geographic location, by size of program. There are numbers for each one of those, and you can clue in as to what some of the more important variations are. We could list probably 25 to 50 variables that would affect hospitalists’ productivity in one way or the other—and that’s not taking into account the individual styles of hospitalists.”

For instance, some hospitalists want to work and earn as much money as possible, while others are searching for a work/life balance that will allow them time with their families.

The survey, says Lary, supplies a piece of information in a complex puzzle about a highly variable profession. “There are so many different ways this business is being conducted right now,” he says. “One medical community may be willing to subsidize a hospital medicine program, and another may not be willing.”

Hospitalists’ professional goals vary widely as well. As far as Dr. Nelson is concerned, the bottom line for hospitalists is to structure independent practices tailored to fit their goals. This means that hospitalists are connected to the economic consequences of their staffing and workload decisions. In that way, he says, rather than approaching administrators about hiring more physicians, the practice itself can decide whether it is worth the decrease in individual hospitalists’ incomes to hire another doctor.

Because their specialty is still evolving, hospitalists will find themselves educating their clients about the profession’s services and advantages. And for that process, the survey can be a helpful adjunct. Miller agrees that the use of the survey requires a certain amount of interpolation on the part of hospitalist leaders. They should be careful, he emphasizes, not to lose sight of the individuality of their own practices.

“If you hold up the survey as the governing document when you negotiate with your hospital, then each party will use it to their advantage,” says Dr. Nelson. “This can push you towards being ‘average’ when that might not be appropriate for your practice.” TH

Gretchen Henkel is a frequent contributor to The Hospitalist.

Productivity and compensation benchmarks can be useful when negotiating with hospital administrators for increased reimbursements and support resources, when recruiting hospitalists, and when conducting self-evaluations. For many of these processes, hospitalists—and, indeed, hospital administrators—turn to the information contained in the voluminous SHM 2005-2006 Survey, “The Authoritative Source on the State of the Hospital Medicine Movement.” (See “For More Information,” p. 32.)

With a response rate of 26%, the survey represents some 2,550 hospitalists across the nation, and its variables present a more comprehensive aerial view of hospital medicine than did previous surveys. But on the ground and in the trenches, hospital medicine groups must be careful to look at the survey’s metrics with a discerning eye.

When applying the survey metrics to one’s own practice, there can be benefits as well as pitfalls, cautions Joe Miller, SHM senior vice president and principal analyst of the survey data. He emphasizes the great variation among hospital medicine groups and warns against looking at survey medians as representing a “typical” hospital medicine practice.

“When you’ve seen one hospital medicine group, you’ve seen one hospital medicine group,” he quips. In several recent conversations, hospital medicine group leaders and SHM leaders involved in compiling the survey discussed the survey’s strengths and limitations as a benchmarking tool.

Healthy to Negotiate

According to the survey 97% of hospitalist programs receive some type of financial support. “Virtually every program in the country is challenged to defend the amount of money [they receive] or to negotiate for support dollars,” says Miller, who believes that negotiation can be a healthy dynamic. “There is a sense of equality of both sides of the table, a mutual respect between hospitalists and the hospital.” In the process of such negotiations, it will be important not to pin one’s position entirely to the survey metrics.

John Nelson, MD, medical director of the hospitalist practice at Overlake Hospital in Bellevue, Wash., a consultant for hospitalist practices with Nelson/Flores Associates, a columnist for The Hospitalist (“Practice Management”), and a co-founder and past president of SHM, believes that some hospitalists mistakenly view the survey as SHM’s position on what a hospitalist should make. “The survey is the best information we have about what hospitalists do make—there is no better source—but it’s still a survey.”

Using compensation medians as yardsticks for actual salaries and compensation packages is analogous to “learning the average weight of an American and deciding that’s what we all should weigh—and that’s a big mistake,” he says. “If you hold up the survey as the governing document, then each party will use it to their advantage.”

Because the survey is regarded as the most authoritative existing source on hospitalists’ compensation and productivity, it nevertheless ends up being used as a benchmark, says Robin L. Dauterive, assistant director of the clinical hospitalist service at Massachusetts General Hospital in Boston.

“Whenever I’m preparing billings reports or dashboard measures—anything that shows my group’s workload—sooner or later, I always have to include something in there that states, ‘This is what other people are doing,’ ” says Dauterive. “It’s something that you can’t get away from, unfortunately, in medicine.”

She realizes that the survey does not purport to set any national standards, and yet, “all administrations want comparisons.” Dr. Nelson has also noted this phenomenon with the survey. In the absence of additional guidance, hospital executives and hospitalists often find that they’re just arguing about the survey. “And that’s unfortunate,” he says. “It means they’ve lost sight of the unique attributes of a given practice that might support higher or lower incomes and higher or lower workloads.”

View in Context

Hospitalists reading the survey for the first time might first seek to analyze the metrics regarding billings and collections. Here it is especially important not to view the reported numbers in isolation, says Dr. Nelson. For instance, to learn how a hospitalist’s annual gross charges (billings) compare with others across the country (question 12 of the Individual Hospitalist questionnaire—p. 87, Appendix 2), details on pages 251 and 252 supply pertinent variables. For instance, in comparing the four regions of the country, Table 056-A shows that the median annual gross charges for physicians in the south are highest, at $354,000. Hospitalists compensated by a 100% incentive method report higher charges per year ($392,000) than those who are on a 100% salary or a mix of the two methods of payment. Turning to Table 056-B, on page 252 of the published survey, hospitalists can find annual gross charges according to practitioner type, specialty, and employment model. Hospitalists should not stop their reading there, however, as a comparison of others’ annual gross collections might give a more complete picture.

Still, the SHM Survey does not reference all possible explanatory variables. Collections can be influenced by location and payer mix. Hospitalists practicing in a large urban hospital are likely to see more indigent patients for whom the hospital is not reimbursed. A careful reading of the survey should include the questionnaire and the tables supporting chapter conclusions, and the reader must recognize the survey’s limitations.

Apples to Oranges

IPC–The Hospitalist Company participates in the SHM survey and also uses it as a recruitment tool, reports IPC Vice President of Physician Staffing Timothy Lary. “We look at the income averages, and we’re able to demonstrate how our averages are, for the most part, higher than the averages,” he explains. “We also look at the survey from an internal viewpoint, but oftentimes you are comparing apples to oranges.”

Like individual hospitalists, hospital medicine group leaders seek comparisons when they read the survey. For her part, Dr. Dauterive has found the data on starting salaries for new hospitalists useful. For example, page 259, detailed table 060-A on hospitalists’ compensation by category and total, breaks out median yearly income by years as a hospitalist, from less than a year to six or more years. (Many of the detailed “A” tables in Chapter 8 on compensation include the “years as a hospitalist” category.) Dr. Dauterive praises the wealth of data in the survey, pointing to examples of the many variables she was surprised to learn. One of those factors was that 48% of surveyed hospitalist programs were at non-teaching hospitals. (See page 7 of the survey, Executive Summary, “Teaching status of affiliated hospital.”)

Those interviewed for this article agree that productivity data are probably more telling about the day-to-day clinical realities for hospitalists. Productivity metrics figure prominently in Dr. Dauterive’s uses for the survey. Accordingly, the annual number of billable patient encounters seen by the hospitalist (Table 58-B, page 256) and the annual number of work relative value units (RVUs) worked by the hospitalist (Table 59-B, page 258) caught her interest.

Still, Dr. Dauterive found herself wanting more data to shed light on those numbers. In negotiations for resources with hospital administrators, Dr. Dauterive would like to be able to pinpoint the reasons behind reported numbers of clinical encounters seen by the hospitalist. If the median number of billable patient encounters seen by the hospitalist in a teaching service was 1,668 (based on 107 responses; page 256, Detailed Table 058-B), what were some of the influences on this number? What was the acuity level of patients? Did the hospitalist have group resources, such as physician extenders, to help with patient admissions and rounds?

“For groups that have low lengths of stay, it would be important for me to know why,” she says. “Did they have extra supports? Do their [doctors] use Palm Pilots? You don’t always know from looking at the numbers how to apply them, make the connection, and justify the resources you’re trying to achieve,” she says.

No Perfect Measure

The ideal survey for Dr. Dauterive would include specific structured models, providing links between categories so that she could compare characteristics that more closely align with her group’s situation.

“Our program is very mixed, so it would be helpful for me to know how work RVUs were being reported,” she says. Pointing to results showing higher productivity (work RVUs) in practices compensated by 100% incentive (Table 060-A, page 259 of the survey), Dr. Dauterive wonders what factors drive these results. While the 100% incentive might appear to be the most important factor, perhaps these groups also have physician extenders or are located in a geographic location that boosts their productivity.

“I’m in a nonprofit hospital, in a clinical hospitalist service, and I want to be able to approach the administration and say, ‘If you want us to see the most patients, these are the kinds of services that see the most patients,’ ”says Dr. Dauterive. “But, if you are more interested in physician retention and work/life, then these are the characteristics of those successful programs.”

This level of detail can be difficult to interpolate from the survey, agrees Dr. Nelson. Patient acuity, for instance, is not specifically queried in the survey questionnaire. “I agree, in the ideal world, this is all information that you would want to know,” he says. Answers to the following questions could help refine product metrics:

• Does your group have teaching responsibilities for residents?
• Do you take a lot of calls from home, or do you have a separate night shift?
• Do you cover more than one physical hospital on the same day?
• Does your group do more than the typical amount of committee and administrative work?

“All these factors,” notes Dr. Nelson, “would influence productivity. There is no perfect way to know the answer to any of those things.” And, he adds, the survey already comprises 292 pages, including numerous detailed tables of data. To include all pertinent variables would entail a longer questionnaire, which might affect the response rate.

Healthcare Delivery Is Local

In his consultations with hospitalist groups, Dr. Nelson always emphasizes that the survey is “a starting point” and not the goal of what hospitalists should make. He favors adjunctive methods for benchmarking practices: “I think that when you’re benchmarking your practice, it’s as important to gather as much local and regional data as you can—in addition to the SHM survey.” He tries to network with other Seattle hospitalist programs to learn about their patterns of work hours, patient loads, and the like.

Thomas Baudendistel, MD, FACP, associate program director of the Internal Medicine Residency Program at Sutter Health’s California Pacific Medical Center in San Francisco, notes that regional markets differ widely. The healthcare market in the Northern California Bay area is very different from the one in Los Angeles in terms of financial remuneration and incentivization.

“The survey,” he says, “gives a global gestalt of the regional flavor of hospital medicine” and reveals general ballpark medians that can be a good starting point for practice benchmarking. “I think what our administration [at California Pacific Medical Center] wants to see is our data compared to the people across the street and down the road, because that’s a closer comparison in terms of payer mix and insurance reimbursements.”

IPC’s Lary agrees. “When I compete, I don’t compete against people across the country; I compete with people across the street,” he says. “As large as IPC is, we realize that healthcare is delivered locally. What we try to do [with the survey] is take the information and, to the best or our ability, figure out how it applies to our individual settings and [to the] different markets that we are in.”

A Stake in the Sand

“I think the benchmarks we have in the survey are just a piece of information—[the survey] is a context, it’s a stake in the sand,” concludes Miller. “We do have variations by type of program, by size of hospital, by geographic location, by size of program. There are numbers for each one of those, and you can clue in as to what some of the more important variations are. We could list probably 25 to 50 variables that would affect hospitalists’ productivity in one way or the other—and that’s not taking into account the individual styles of hospitalists.”

For instance, some hospitalists want to work and earn as much money as possible, while others are searching for a work/life balance that will allow them time with their families.

The survey, says Lary, supplies a piece of information in a complex puzzle about a highly variable profession. “There are so many different ways this business is being conducted right now,” he says. “One medical community may be willing to subsidize a hospital medicine program, and another may not be willing.”

Hospitalists’ professional goals vary widely as well. As far as Dr. Nelson is concerned, the bottom line for hospitalists is to structure independent practices tailored to fit their goals. This means that hospitalists are connected to the economic consequences of their staffing and workload decisions. In that way, he says, rather than approaching administrators about hiring more physicians, the practice itself can decide whether it is worth the decrease in individual hospitalists’ incomes to hire another doctor.

Because their specialty is still evolving, hospitalists will find themselves educating their clients about the profession’s services and advantages. And for that process, the survey can be a helpful adjunct. Miller agrees that the use of the survey requires a certain amount of interpolation on the part of hospitalist leaders. They should be careful, he emphasizes, not to lose sight of the individuality of their own practices.

“If you hold up the survey as the governing document when you negotiate with your hospital, then each party will use it to their advantage,” says Dr. Nelson. “This can push you towards being ‘average’ when that might not be appropriate for your practice.” TH

Gretchen Henkel is a frequent contributor to The Hospitalist.

Productivity and compensation benchmarks can be useful when negotiating with hospital administrators for increased reimbursements and support resources, when recruiting hospitalists, and when conducting self-evaluations. For many of these processes, hospitalists—and, indeed, hospital administrators—turn to the information contained in the voluminous SHM 2005-2006 Survey, “The Authoritative Source on the State of the Hospital Medicine Movement.” (See “For More Information,” p. 32.)

With a response rate of 26%, the survey represents some 2,550 hospitalists across the nation, and its variables present a more comprehensive aerial view of hospital medicine than did previous surveys. But on the ground and in the trenches, hospital medicine groups must be careful to look at the survey’s metrics with a discerning eye.

When applying the survey metrics to one’s own practice, there can be benefits as well as pitfalls, cautions Joe Miller, SHM senior vice president and principal analyst of the survey data. He emphasizes the great variation among hospital medicine groups and warns against looking at survey medians as representing a “typical” hospital medicine practice.

“When you’ve seen one hospital medicine group, you’ve seen one hospital medicine group,” he quips. In several recent conversations, hospital medicine group leaders and SHM leaders involved in compiling the survey discussed the survey’s strengths and limitations as a benchmarking tool.

Healthy to Negotiate

According to the survey 97% of hospitalist programs receive some type of financial support. “Virtually every program in the country is challenged to defend the amount of money [they receive] or to negotiate for support dollars,” says Miller, who believes that negotiation can be a healthy dynamic. “There is a sense of equality of both sides of the table, a mutual respect between hospitalists and the hospital.” In the process of such negotiations, it will be important not to pin one’s position entirely to the survey metrics.

John Nelson, MD, medical director of the hospitalist practice at Overlake Hospital in Bellevue, Wash., a consultant for hospitalist practices with Nelson/Flores Associates, a columnist for The Hospitalist (“Practice Management”), and a co-founder and past president of SHM, believes that some hospitalists mistakenly view the survey as SHM’s position on what a hospitalist should make. “The survey is the best information we have about what hospitalists do make—there is no better source—but it’s still a survey.”

Using compensation medians as yardsticks for actual salaries and compensation packages is analogous to “learning the average weight of an American and deciding that’s what we all should weigh—and that’s a big mistake,” he says. “If you hold up the survey as the governing document, then each party will use it to their advantage.”

Because the survey is regarded as the most authoritative existing source on hospitalists’ compensation and productivity, it nevertheless ends up being used as a benchmark, says Robin L. Dauterive, assistant director of the clinical hospitalist service at Massachusetts General Hospital in Boston.

“Whenever I’m preparing billings reports or dashboard measures—anything that shows my group’s workload—sooner or later, I always have to include something in there that states, ‘This is what other people are doing,’ ” says Dauterive. “It’s something that you can’t get away from, unfortunately, in medicine.”

She realizes that the survey does not purport to set any national standards, and yet, “all administrations want comparisons.” Dr. Nelson has also noted this phenomenon with the survey. In the absence of additional guidance, hospital executives and hospitalists often find that they’re just arguing about the survey. “And that’s unfortunate,” he says. “It means they’ve lost sight of the unique attributes of a given practice that might support higher or lower incomes and higher or lower workloads.”

View in Context

Hospitalists reading the survey for the first time might first seek to analyze the metrics regarding billings and collections. Here it is especially important not to view the reported numbers in isolation, says Dr. Nelson. For instance, to learn how a hospitalist’s annual gross charges (billings) compare with others across the country (question 12 of the Individual Hospitalist questionnaire—p. 87, Appendix 2), details on pages 251 and 252 supply pertinent variables. For instance, in comparing the four regions of the country, Table 056-A shows that the median annual gross charges for physicians in the south are highest, at $354,000. Hospitalists compensated by a 100% incentive method report higher charges per year ($392,000) than those who are on a 100% salary or a mix of the two methods of payment. Turning to Table 056-B, on page 252 of the published survey, hospitalists can find annual gross charges according to practitioner type, specialty, and employment model. Hospitalists should not stop their reading there, however, as a comparison of others’ annual gross collections might give a more complete picture.

Still, the SHM Survey does not reference all possible explanatory variables. Collections can be influenced by location and payer mix. Hospitalists practicing in a large urban hospital are likely to see more indigent patients for whom the hospital is not reimbursed. A careful reading of the survey should include the questionnaire and the tables supporting chapter conclusions, and the reader must recognize the survey’s limitations.

Apples to Oranges

IPC–The Hospitalist Company participates in the SHM survey and also uses it as a recruitment tool, reports IPC Vice President of Physician Staffing Timothy Lary. “We look at the income averages, and we’re able to demonstrate how our averages are, for the most part, higher than the averages,” he explains. “We also look at the survey from an internal viewpoint, but oftentimes you are comparing apples to oranges.”

Like individual hospitalists, hospital medicine group leaders seek comparisons when they read the survey. For her part, Dr. Dauterive has found the data on starting salaries for new hospitalists useful. For example, page 259, detailed table 060-A on hospitalists’ compensation by category and total, breaks out median yearly income by years as a hospitalist, from less than a year to six or more years. (Many of the detailed “A” tables in Chapter 8 on compensation include the “years as a hospitalist” category.) Dr. Dauterive praises the wealth of data in the survey, pointing to examples of the many variables she was surprised to learn. One of those factors was that 48% of surveyed hospitalist programs were at non-teaching hospitals. (See page 7 of the survey, Executive Summary, “Teaching status of affiliated hospital.”)

Those interviewed for this article agree that productivity data are probably more telling about the day-to-day clinical realities for hospitalists. Productivity metrics figure prominently in Dr. Dauterive’s uses for the survey. Accordingly, the annual number of billable patient encounters seen by the hospitalist (Table 58-B, page 256) and the annual number of work relative value units (RVUs) worked by the hospitalist (Table 59-B, page 258) caught her interest.

Still, Dr. Dauterive found herself wanting more data to shed light on those numbers. In negotiations for resources with hospital administrators, Dr. Dauterive would like to be able to pinpoint the reasons behind reported numbers of clinical encounters seen by the hospitalist. If the median number of billable patient encounters seen by the hospitalist in a teaching service was 1,668 (based on 107 responses; page 256, Detailed Table 058-B), what were some of the influences on this number? What was the acuity level of patients? Did the hospitalist have group resources, such as physician extenders, to help with patient admissions and rounds?

“For groups that have low lengths of stay, it would be important for me to know why,” she says. “Did they have extra supports? Do their [doctors] use Palm Pilots? You don’t always know from looking at the numbers how to apply them, make the connection, and justify the resources you’re trying to achieve,” she says.

No Perfect Measure

The ideal survey for Dr. Dauterive would include specific structured models, providing links between categories so that she could compare characteristics that more closely align with her group’s situation.

“Our program is very mixed, so it would be helpful for me to know how work RVUs were being reported,” she says. Pointing to results showing higher productivity (work RVUs) in practices compensated by 100% incentive (Table 060-A, page 259 of the survey), Dr. Dauterive wonders what factors drive these results. While the 100% incentive might appear to be the most important factor, perhaps these groups also have physician extenders or are located in a geographic location that boosts their productivity.

“I’m in a nonprofit hospital, in a clinical hospitalist service, and I want to be able to approach the administration and say, ‘If you want us to see the most patients, these are the kinds of services that see the most patients,’ ”says Dr. Dauterive. “But, if you are more interested in physician retention and work/life, then these are the characteristics of those successful programs.”

This level of detail can be difficult to interpolate from the survey, agrees Dr. Nelson. Patient acuity, for instance, is not specifically queried in the survey questionnaire. “I agree, in the ideal world, this is all information that you would want to know,” he says. Answers to the following questions could help refine product metrics:

• Does your group have teaching responsibilities for residents?
• Do you take a lot of calls from home, or do you have a separate night shift?
• Do you cover more than one physical hospital on the same day?
• Does your group do more than the typical amount of committee and administrative work?

“All these factors,” notes Dr. Nelson, “would influence productivity. There is no perfect way to know the answer to any of those things.” And, he adds, the survey already comprises 292 pages, including numerous detailed tables of data. To include all pertinent variables would entail a longer questionnaire, which might affect the response rate.

Healthcare Delivery Is Local

In his consultations with hospitalist groups, Dr. Nelson always emphasizes that the survey is “a starting point” and not the goal of what hospitalists should make. He favors adjunctive methods for benchmarking practices: “I think that when you’re benchmarking your practice, it’s as important to gather as much local and regional data as you can—in addition to the SHM survey.” He tries to network with other Seattle hospitalist programs to learn about their patterns of work hours, patient loads, and the like.

Thomas Baudendistel, MD, FACP, associate program director of the Internal Medicine Residency Program at Sutter Health’s California Pacific Medical Center in San Francisco, notes that regional markets differ widely. The healthcare market in the Northern California Bay area is very different from the one in Los Angeles in terms of financial remuneration and incentivization.

“The survey,” he says, “gives a global gestalt of the regional flavor of hospital medicine” and reveals general ballpark medians that can be a good starting point for practice benchmarking. “I think what our administration [at California Pacific Medical Center] wants to see is our data compared to the people across the street and down the road, because that’s a closer comparison in terms of payer mix and insurance reimbursements.”

IPC’s Lary agrees. “When I compete, I don’t compete against people across the country; I compete with people across the street,” he says. “As large as IPC is, we realize that healthcare is delivered locally. What we try to do [with the survey] is take the information and, to the best or our ability, figure out how it applies to our individual settings and [to the] different markets that we are in.”

A Stake in the Sand

“I think the benchmarks we have in the survey are just a piece of information—[the survey] is a context, it’s a stake in the sand,” concludes Miller. “We do have variations by type of program, by size of hospital, by geographic location, by size of program. There are numbers for each one of those, and you can clue in as to what some of the more important variations are. We could list probably 25 to 50 variables that would affect hospitalists’ productivity in one way or the other—and that’s not taking into account the individual styles of hospitalists.”

For instance, some hospitalists want to work and earn as much money as possible, while others are searching for a work/life balance that will allow them time with their families.

The survey, says Lary, supplies a piece of information in a complex puzzle about a highly variable profession. “There are so many different ways this business is being conducted right now,” he says. “One medical community may be willing to subsidize a hospital medicine program, and another may not be willing.”

Hospitalists’ professional goals vary widely as well. As far as Dr. Nelson is concerned, the bottom line for hospitalists is to structure independent practices tailored to fit their goals. This means that hospitalists are connected to the economic consequences of their staffing and workload decisions. In that way, he says, rather than approaching administrators about hiring more physicians, the practice itself can decide whether it is worth the decrease in individual hospitalists’ incomes to hire another doctor.

Because their specialty is still evolving, hospitalists will find themselves educating their clients about the profession’s services and advantages. And for that process, the survey can be a helpful adjunct. Miller agrees that the use of the survey requires a certain amount of interpolation on the part of hospitalist leaders. They should be careful, he emphasizes, not to lose sight of the individuality of their own practices.

“If you hold up the survey as the governing document when you negotiate with your hospital, then each party will use it to their advantage,” says Dr. Nelson. “This can push you towards being ‘average’ when that might not be appropriate for your practice.” TH

Gretchen Henkel is a frequent contributor to The Hospitalist.

ORLANDO—A new oral anticoagulant in development, dabigatran etexilate, was shown to be as effective and safe as the low-molecular-weight enoxaparin in prophylaxis of thromboembolism in patients undergoing total knee replacement surgery.

Bengt I. Eriksson, MD, reported these results on behalf of the RE-MODEL study group during the 2006 annual meeting of the American Society of Hematology in December.

The RE-MODEL study was a large multicenter study conducted in 2010 patients undergoing elective total knee surgery in Europe, South Africa, and Australia.

Patients were randomized to receive subcutaneous injections of enoxaparin (40 mg, once daily) or to one of 2 doses of oral dabigatran etexilate (150 mg or 220 mg once daily) for 8 ± 2 days. Enoxaparin was administered 12 hours prior to surgery while dabigatran was administered 1-4 hours after the surgery.

Dabigatran etexilate met the prespecified primary endpoint of noninferiority versus enoxaparin. There was no difference in the incidence of total venous thromboembolism and all-cause mortality between the dabigatran 220 mg and 150 mg treatment arms and enoxaparin (36%, 41%, 38%, respectively).

The secondary efficacy endpoint, the incidence of proximal deep vein thrombosis and/or pulmonary embolism was similar in all treatment arms: 4%, 3%, and 4% of patients receiving dabigatran 220 mg, dabigatran 150 mg, and enoxaparin, respectively.

There was no difference among all treatment arms in bleeding rates (either major or any bleedings), and there were no signs of liver toxicity in the dabigatran arm.

Patients undergoing knee replacement surgery are at an increased risk of developing thromboembolism. Dabigatran etexilate is an oral direct thrombin inhibitor, and offers a convenient fixed oral dosing with no need for coagulation monitoring. 

ORLANDO—A new oral anticoagulant in development, dabigatran etexilate, was shown to be as effective and safe as the low-molecular-weight enoxaparin in prophylaxis of thromboembolism in patients undergoing total knee replacement surgery.

Bengt I. Eriksson, MD, reported these results on behalf of the RE-MODEL study group during the 2006 annual meeting of the American Society of Hematology in December.

The RE-MODEL study was a large multicenter study conducted in 2010 patients undergoing elective total knee surgery in Europe, South Africa, and Australia.

Patients were randomized to receive subcutaneous injections of enoxaparin (40 mg, once daily) or to one of 2 doses of oral dabigatran etexilate (150 mg or 220 mg once daily) for 8 ± 2 days. Enoxaparin was administered 12 hours prior to surgery while dabigatran was administered 1-4 hours after the surgery.

Dabigatran etexilate met the prespecified primary endpoint of noninferiority versus enoxaparin. There was no difference in the incidence of total venous thromboembolism and all-cause mortality between the dabigatran 220 mg and 150 mg treatment arms and enoxaparin (36%, 41%, 38%, respectively).

The secondary efficacy endpoint, the incidence of proximal deep vein thrombosis and/or pulmonary embolism was similar in all treatment arms: 4%, 3%, and 4% of patients receiving dabigatran 220 mg, dabigatran 150 mg, and enoxaparin, respectively.

There was no difference among all treatment arms in bleeding rates (either major or any bleedings), and there were no signs of liver toxicity in the dabigatran arm.

Patients undergoing knee replacement surgery are at an increased risk of developing thromboembolism. Dabigatran etexilate is an oral direct thrombin inhibitor, and offers a convenient fixed oral dosing with no need for coagulation monitoring. 

ORLANDO—A new oral anticoagulant in development, dabigatran etexilate, was shown to be as effective and safe as the low-molecular-weight enoxaparin in prophylaxis of thromboembolism in patients undergoing total knee replacement surgery.

Bengt I. Eriksson, MD, reported these results on behalf of the RE-MODEL study group during the 2006 annual meeting of the American Society of Hematology in December.

The RE-MODEL study was a large multicenter study conducted in 2010 patients undergoing elective total knee surgery in Europe, South Africa, and Australia.

Patients were randomized to receive subcutaneous injections of enoxaparin (40 mg, once daily) or to one of 2 doses of oral dabigatran etexilate (150 mg or 220 mg once daily) for 8 ± 2 days. Enoxaparin was administered 12 hours prior to surgery while dabigatran was administered 1-4 hours after the surgery.

Dabigatran etexilate met the prespecified primary endpoint of noninferiority versus enoxaparin. There was no difference in the incidence of total venous thromboembolism and all-cause mortality between the dabigatran 220 mg and 150 mg treatment arms and enoxaparin (36%, 41%, 38%, respectively).

The secondary efficacy endpoint, the incidence of proximal deep vein thrombosis and/or pulmonary embolism was similar in all treatment arms: 4%, 3%, and 4% of patients receiving dabigatran 220 mg, dabigatran 150 mg, and enoxaparin, respectively.

There was no difference among all treatment arms in bleeding rates (either major or any bleedings), and there were no signs of liver toxicity in the dabigatran arm.

Patients undergoing knee replacement surgery are at an increased risk of developing thromboembolism. Dabigatran etexilate is an oral direct thrombin inhibitor, and offers a convenient fixed oral dosing with no need for coagulation monitoring. 

Urticaria has been recognized since the days of Hippocrates. The name of the condition dates back to the 18th century, when the burning and edema of the skin was likened to that caused by contact with nettles (Urtica dioica). Urticaria affects 10% to 25% of the population worldwide at some point in their lives.¹ The condition is characterized by short-lived edema of the skin, mouth, and genitalia related to a transient leakage of plasma from small blood vessels into the surrounding connective tissues. Urticaria may present with superficial edema of the dermis (wheals) or deeper edema of the dermal, subcutaneous, or submucosal tissues (angioedema).² Wheals typically are itchy with a pale center, maturing into pink superficial plaques. Areas of angioedema tend to be pale and painful; last longer than wheals; and may involve the mouth and rarely the bowel.

Case Report

A 40-year-old woman in otherwise good health presented with a 5-year history of recurrent pruritic light red lesions on her chest and back. She reported that individual lesions would last up to 24 hours in one area before disappearing, while other new crops of lesions would develop in other areas of her body. She had no associated facial edema or lip or throat involvement, and she denied taking any medications. Her history failed to reveal any potential triggers for the eruptions. On physical examination, multiple elevated superficial erythematous papules and plaques were noted, with shapes varying from annular to circinate, areas of central clearing, and targetlike lesions on the trunk and extremities. The lesions blanched with pressure (Figure). The woman had no mucosal involvement, scars, or change in pigmentation. Results from the remainder of the physical examination were unremarkable.

PLEASE REFER TO THE PDF TO VIEW THE FIGURE

Because of the extent of involvement and the erythematous to violaceous aspect of certain lesions, a 3-mm punch biopsy was performed to rule out urticarial vasculitis. Histology results were consistent with urticaria with red blood extravasation but without vasculitis. Our patient initially was treated with topical clobetasol propionate ointment, 10 mg of cetirizine hydrochloride, and topical calamine lotion. At follow-up one week later, she mentioned that she had improved after 5 days of treatment but began developing new lesions 2 days prior to her second visit. Given the severity of pruritus and after a discussion of the role of corticosteroids for acute urticaria, a taper dose of prednisone was prescribed at 40 mg/d, in addition to 60 mg of fexofenadine hydrochloride twice daily. The patient was lesion- and symptom-free after 7 days of treatment, with no recurrence one month later.

Comment

Urticaria may be acute or chronic. Acute urticaria is idiopathic in more than 50% of patients but can occur as a type 1 hypersensitivity reaction to food or wasp or bee stings; an immunologic response to blood products, infection, or febrile illness; or an adverse effect of drug therapy by various mechanisms, such as penicillin or angiotensin-converting enzyme inhibitors.³ As opposed to acute urticaria, chronic urticaria is defined by recurrent episodes occurring at least twice weekly for 6 weeks.² Urticaria occurring less frequently than this, over a long period, is more accurately termed episodic because it is more likely to have an identifiable environmental trigger. All chronic urticaria implicitly go through an acute stage (<6 weeks). Although many classification systems of chronic urticaria exist, a concise clinical classification is included in the Table.² Urticarial vasculitis is a small vessel vasculitis but is included in the classification because it is clinically indistinguishable from other urticarial lesions.

PLEASE REFER TO THE PDF TO VIEW THE TABLE

Urticarial lesions in chronic urticaria typically last 4 to 36 hours and can occur in individuals of any age (though it is most common in women), usually with few systemic symptoms.⁴ Pruritus is nearly always severe, especially at night, and may prevent sleep. Fifty percent of cases resolve spontaneously by 6 months, but of those that do not, 40% still have symptoms of urticaria 10 years later.⁴ The severe effect of chronic urticaria on quality of life often is underestimated.⁵

Ordinary Urticaria

Patients previously classified as having chronic idiopathic or "ordinary" urticaria are now divided into 2 groups: 50% to 60% of these patients have chronic idiopathic urticaria (CIU), and the remainder have chronic autoimmune urticaria (CAU).⁶ Results from a study in children demonstrated that autoimmune urticaria occurs in children in as many as 30% of chronic cases.⁷ CAU is caused by an immunoglobulin (Ig) G antibody to the α subunit of the IgE receptor (35%–40% of cases) or to IgE (5%–10% of cases).⁶ The IgG subclasses that appear to be pathogenic are IgG1; IgG3; and, to a lesser degree, IgG4 (though not IgG2).⁶ Complement activation augments histamine secretion by release of C5a.⁸ CAU has been reported to be associated with antithyroid antibodies (27% of cases)^6,9; autoimmune conditions such as vitiligo, rheumatoid arthritis, and pernicious anemia; and low vitamin B₁₂ levels.¹⁰ Patients with demonstrable histamine-releasing autoantibodies have a very strong association with HLA-DR4 and its associated allele HLA-DQ8.¹¹

Histologically, the 2 groups of urticaria are indistinguishable.6 Advanced techniques show a perivascular nonnecrotizing infiltrate of CD4⁺ lymphocytes consisting of a mixture of T_H1 and T_H2 subtypes, plus monocytes, neutrophils, eosinophils, and basophils. These cells are recruited because of interactions with C5a, cell priming cytokines, chemokines, and adhesion molecules.⁶ A recent study also found inflammatory cells and mediator up-regulation in uninvolved CIU skin as a sign of prolonged and widespread "urticarial status."¹²

Physical Urticaria

Physical urticaria are classified and induced by a physical stimulus. Most physical urticaria occur within minutes of provocation and resolve within 2 hours, with the exception of delayed pressure urticaria, which may persist for 24 hours or longer.¹³ Angioedema may occur in all physical urticaria except dermographism. Overlap between groups is common, and physical urticaria often occur as an added feature of chronic urticaria.

The most common type of physical urticaria is simple immediate dermographism, presenting with linear wheals at sites of scratching or friction. It occurs in about 1.4% to 5% of the population worldwide¹⁴ and may be viewed as an exaggerated physiologic response. On average, dermographism runs a course of 2 to 3 years before usually resolving spontaneously.¹⁵

Delayed-pressure urticaria is a response to sustained pressure to the skin, presenting with deep erythematous edema after a delay of unknown cause lasting 30 minutes to 12 hours.^14,16 An increased level of interleukin 6 has been found in suction blister fluid over induced lesions.^2,15 The edema tends to be deeper, pruritic, and painful, and it may persist for days. Systemic features such as malaise, flulike symptoms, and arthralgia may occur. The prognosis is variable, but the mean duration is 6 to 9 years.¹⁷ The response to antihistamines often is poor, and oral corticosteroids may be needed for disease control.²

Cholinergic urticaria usually presents with multiple, transient, pruritic, small, red macules or papules on the neck, trunk, forearms, wrists, and thighs in response to heat, often surrounded by an obvious flare. It mainly affects young adults, with an overall prevalence of 11% in this group.¹⁸ Fifty percent of patients are atopic.¹⁵ Angioedema and systemic manifestations such as headache, palpitations, abdominal pain, wheezing, and syncope may occur. The cholinergic sympathetic innervation of sweat glands is involved because the eruption can be blocked by topical anticholinergic drugs,¹⁹ but how this leads to urticaria is unclear. The routine treatment is with low-sedation H₁-type antihistamines, with or without an anxiolytic such as oral propranolol. In severe cases, the anabolic steroid stanazolol has been used.¹⁵

Cold urticaria is a heterogeneous condition in which whealing occurs within minutes in response to cold exposure, most frequently in children and young adults. Wheals usually arise at the site of localized cooling but may be generalized following lowering of the body temperature.¹⁶ Diagnosis may be confirmed by applying an ice cube for 5 to 15 minutes to the skin, allowing an interval for skin rewarming, and observing the development of whealing that occurs on skin rewarming. Systemic symptoms such as flushing, headache, abdominal pain, and syncope can occur if large areas are affected. The cause is unknown, but a serum factor, possibly IgM or IgE, has been implicated.²⁰ A heterozygous deficiency of the protease inhibitor α1-antichymotrypsin has been demonstrated and may be etiologically important in some patients.²¹ The prognosis is good, with spontaneous improvement in an average of 2 to 3 years.¹⁵ Ninety-six percent of cases of cold urticaria are primary.²² The diagnosis of secondary acquired cold urticaria depends on being able to demonstrate cryoglobulins, cold agglutinins, or possibly cryofibrinogens.¹⁷ These findings should, in turn, lead to investigations for an underlying cause, such as hepatitis B or C infection, lymphoproliferative disease, or infectious mononucleosis.¹⁵

Other uncommon forms of physical urticaria include adrenergic urticaria, which develops during phases of stress and has been associated with an increase in the plasma concentrations of norepinephrine, epinephrine, and prolactin.²³ Aquagenic urticaria is precipitated by skin contact with water of any temperature.³ Exercise-induced anaphylaxis involves urticaria, respiratory distress, or hypotension after exercise. In localized heat urticaria, wheals occur on skin in direct contact with warm objects. Solar urticaria is a rare condition that occurs within minutes of exposure to UV light waves ranging from 280 to 760 nm¹⁴; it usually disappears in less than one hour. Vibratory urticaria occurs after a vibratory stimulus and can be a hereditary autosomaldominant disorder or an acquired sporadic disease.²⁴

Urticarial Vasculitis

Urticarial vasculitis describes a distinct entity in which the gross cutaneous lesions resemble urticaria and histologically show features of a vasculitis. The diagnosis is suggested clinically by wheals lasting more than 24 hours and residual bruising.²⁵ Although the clinical lesions may present as typical urticaria, pathophysiologically, it is a different disease caused by deposition of antigen-antibody complexes in vessel walls, a type 3 reaction causing vascular damage.¹⁷ Lesions often occur at pressure points and may resolve with residual purpura. Extracutaneous manifestations include transient and migratory arthralgia (50%); gastrointestinal symptoms (20%); and pulmonary obstructive disease (20%), particularly in smokers and patients with renal disease (5%–10%).¹⁷ Normocomplementemic urticarial vasculitis usually is idiopathic, but hypocomplementemic urticarial vasculitis may be associated with underlying systemic lupus erythematosus, Sjögren syndrome, or cryoglobulinemia.² Primary urticarial vasculitis can occasionally evolve into systemic lupus erythematosus.²⁶ Patients with urticarial vasculitis often improve on nonsteroidal anti-inflammatory drugs (NSAIDs), but some patients may need immunosuppressive therapy.

Contact Urticaria

Contact urticaria develops at the site(s) of contact of an urticant and can be divided into an allergic subgroup caused by an IgE-allergen interaction and a nonallergic subgroup that is IgE independent. The allergic form typically is seen in children with atopic dermatitis sensitized to environmental allergens such as grass, animals, food, or latex, and it may be complicated by anaphylaxis. Natural rubber latex is one of the most important causes today.²⁷ This type appears within minutes, fades within 2 hours, and is partially inhibited by antihistamines. Nonallergic contact urticaria is caused by the direct effect of the urticant on blood vessels and includes irritants such as benzoic acid and cinnamic aldehyde in cosmetics. It may take 45 minutes for lesions to appear and urticaria is partially inhibited by NSAIDs.

Angioedema Without Wheals

It is useful to classify angioedema occurring without wheals as a separate entity because its etiology may be associated with hereditary angioedema, which must be excluded. The condition usually is idiopathic or caused by a drug reaction to angiotensin-converting enzyme inhibitors, aspirin, or NSAIDs. Hereditary angioedema is a rare autosomal-dominant condition with a prevalence between 1:10,000 and 1:150,000 in the general population and is caused by a deficiency (type 1, 85%) or dysfunction (type 2, 15%) of C1 inhibitor.²⁸ A low level of C4 in the serum is a constant and diagnostic feature. A third type affecting primarily women and exacerbated by estrogens recently has been described.²⁸ Patients have lifelong episodic angioedema and may experience colicky abdominal pain. Laryngeal involvement can be life threatening. Treatment is difficult and involves fluid replacement and purified C1 inhibitor concentrate for acute attacks (not approved in the United States) and prophylactic treatment with anabolic androgens and antifibrinolytics.²⁸

Diagnosis

The diagnosis of urticaria is primarily clinical; extensive laboratory tests are very rarely needed—only when indicated by the patient history.³ Some authors argue that laboratory investigations are unnecessary for mild ordinary urticaria responding to antihistamines.²⁹ Taking a thorough patient history has been found to be almost as effective in identifying a cause as a complete diagnostic evaluation.³⁰ In acute urticaria, if the history indicates a type 1 hypersensitivity reaction, confirmation is possible by a prick test or laboratory radioallergosorbent tests.³ Many physical and contact urticaria can be confirmed by a challenge of the offending agent. An initial baseline investigation with a complete blood count and erythrocyte sedimentation rate should be taken in more severe cases to identify any internal disease or raise the possibility of urticarial vasculitis.¹⁷ Of note, a biopsy is more sensitive and specific for ruling out urticarial vasculitis than are a complete blood count and erythrocyte sedimentation rate.

A search for thyroid autoantibodies is appropriate for all chronic urticaria not responding to first-line therapies with antihistamines, especially when autoimmune urticaria is suspected.² Further investigations are guided by clinical suspicion, which may include a skin biopsy, autoimmune screening, urinalysis, serum cryoglobulins, and hepatitis B and C serology.³¹ The only available test to screen for autoantibodies against the IgE receptor is the autologous serum skin test. This test should be performed with care because infections could be transmitted, particularly if, by mistake, patients were not injected with their own serum.³¹ Measurement of C4 is indicated only in patients who present with angioedema alone and should be followed by a determination of the levels and function of C1 inhibitor, if C4 is below reference range.²⁹

Management and Treatment

Management of urticaria depends on its cause. Aggravating factors should be identified from the history, and triggering stimuli for physical urticaria should be avoided. Simple cooling lotions such as menthol 1% or 2% in an aqueous cream often are useful.³² Aspirin and NSAIDs should be avoided because they aggravate symptoms in 30% of patients.³³ Patients taking low-dose aspirin for its antithrombotic properties usually can continue regular treatment. Avoiding codeine and other opiates also is recommended because an enhanced skin test reaction may be found in chronic urticaria.³⁴ Avoiding dietary pseudoallergens, such as food coloring and natural salicylates, is controversial.^14,35 This generally has only a small role unless proven by a double-blinded placebo-controlled challenge.²

The mainstays for treatment of urticaria are oral antihistamines, as they reduce pruritus and wheal duration and numbers. Oral antihistamines have been reported to produce moderate or good response in 44% to 91% of patients with all types of urticaria.^36,37 Antihistamines can be grouped into first-generation (sedating), second generation (minimally sedating), third-generation (nonsedating), and H₂ antagonists.¹⁷ The physiologic and pathologic actions of histamine are mediated through 4 histamine receptor subtypes: H₁, H₂, H₃, and H₄.³⁸ The erythema, wheal formation, and itching associated with urticaria are mainly due to activation of H₁ receptors and the less contributory role of H₂ receptors.³⁸ Histamine H₃ receptors are located presynaptically on postganglionic sympathetic norepinephric nerves, including sympathetics innervating the heart and blood vessels. The contribution of H₃ receptors to skin responses mediated by histamine has not been fully elucidated. However, in a recent experimental study, the authors reported that the combination of H1 and H3 antagonists might be a novel approach for the treatment of urticaria.³⁸

Initially, a minimally sedating second- or third-generation antihistamine, such as loratadine,³⁹ fexofenadine hydrochloride,⁴⁰ and cetirizine hydrochloride,^41-44 should be given at a once-daily oral dosing. When one antihistamine is not helpful, it is usually worth trying a different one, and some physicians combine 2 or more antihistamines at the same time.³ It is common practice to exceed the licensed dose in severely affected patients.³¹ High doses of antihistamines have effects beyond the blockade of histamine receptors, and actions that are not due to antagonism of H₁ receptors may account for the efficacy of older antihistamines.⁴⁵ As a general rule, antihistamines are safe and have few substantial adverse effects; drug interactions are rare. If possible, it is best to avoid all antihistamines in pregnancy, though none have been proven teratogenic. If one is used, the consensus is that chlorpheniramine maleate is among the safest.⁴⁶

Addition of a sedating first-generation antihistamine such as hydroxyzine at night can be helpful, especially if nocturnal pruritus prevents sleep. The use of a sedating antihistamine as monotherapy is less desirable because of impairment of cognitive function, including driving performance and concentration. The addition of a H₂ antagonist to conventional H₁ antihistamines may be helpful in some patients.^3,47 Doxepin hydrochloride at low doses (10–50 mg) is used for its potent H1 and H2 receptor antagonist properties. Doxepin hydrochloride is highly sedative and especially suitable for patients with associated depression.⁴⁸

Oral corticosteroids given in short reducing courses may be needed for severe exacerbations not responding to full-dose antihistamines. Relatively high doses of up to 40 to 60 mg of prednisone may be needed for disease control. Alternate-day ste-roids may be used for patients with severe disease.⁶ Long-term administration should be avoided.¹

Many patients feel reassured by carrying an epinephrine pen for self-administration if they are prone to severe attacks. Leukotriene antagonists (zafirlukast and montelukast sodium) have been shown to be superior to placebo in the treatment of patients with chronic urticaria.^49,50 Nifedipine has a small effect in chronic urticaria and often is used for patients with concomitant hypertension. Thyroxine recently was reported to suppress CIU symptoms associated with antithyroid autoantibodies in some patients.⁵¹

Given the role of the immune system in a subset of patients, immunosuppressive therapy is considered for patients with a severe disabling course. Cyclosporine at 2.5 to 5 mg/kg per day is of proven value in autoantibody-positive chronic urticaria⁵² but also is effective in most cases of severe autoantibody-negative disease.¹⁵ Tacrolimus also has shown promise in a recent trial.⁵³ Other options include plasmapheresis⁵⁴ and intravenous immunoglobulin.^55,56 Optimal treatment protocols have yet to be confirmed. Treatments for CIU with only limited or anecdotal supportive evidence include sulfasalazine, methotrexate, rofecoxib, colchicine, dapsone, and cyclophosphamide.³

Future treatment may involve development of selective immunotherapy targeting the IgE receptor or vaccinations to down-regulate and induce tolerance to the IgE receptor. Other potential strategies include blocking formation of C5a and use of therapeutic antibodies such as anti-IgE, anti–tumor necrosis factor α, and anti–interleukin 5.²

Conclusion

There is no single way to manage urticaria and angioedema. Most patients are treated successfully with antihistamines. However, patients with severe antihistamine-resistant urticaria may be very disabled by their disease, and the treatment can pose a major challenge to the physician.

Urticaria has been recognized since the days of Hippocrates. The name of the condition dates back to the 18th century, when the burning and edema of the skin was likened to that caused by contact with nettles (Urtica dioica). Urticaria affects 10% to 25% of the population worldwide at some point in their lives.¹ The condition is characterized by short-lived edema of the skin, mouth, and genitalia related to a transient leakage of plasma from small blood vessels into the surrounding connective tissues. Urticaria may present with superficial edema of the dermis (wheals) or deeper edema of the dermal, subcutaneous, or submucosal tissues (angioedema).² Wheals typically are itchy with a pale center, maturing into pink superficial plaques. Areas of angioedema tend to be pale and painful; last longer than wheals; and may involve the mouth and rarely the bowel.

Case Report

A 40-year-old woman in otherwise good health presented with a 5-year history of recurrent pruritic light red lesions on her chest and back. She reported that individual lesions would last up to 24 hours in one area before disappearing, while other new crops of lesions would develop in other areas of her body. She had no associated facial edema or lip or throat involvement, and she denied taking any medications. Her history failed to reveal any potential triggers for the eruptions. On physical examination, multiple elevated superficial erythematous papules and plaques were noted, with shapes varying from annular to circinate, areas of central clearing, and targetlike lesions on the trunk and extremities. The lesions blanched with pressure (Figure). The woman had no mucosal involvement, scars, or change in pigmentation. Results from the remainder of the physical examination were unremarkable.

PLEASE REFER TO THE PDF TO VIEW THE FIGURE

Because of the extent of involvement and the erythematous to violaceous aspect of certain lesions, a 3-mm punch biopsy was performed to rule out urticarial vasculitis. Histology results were consistent with urticaria with red blood extravasation but without vasculitis. Our patient initially was treated with topical clobetasol propionate ointment, 10 mg of cetirizine hydrochloride, and topical calamine lotion. At follow-up one week later, she mentioned that she had improved after 5 days of treatment but began developing new lesions 2 days prior to her second visit. Given the severity of pruritus and after a discussion of the role of corticosteroids for acute urticaria, a taper dose of prednisone was prescribed at 40 mg/d, in addition to 60 mg of fexofenadine hydrochloride twice daily. The patient was lesion- and symptom-free after 7 days of treatment, with no recurrence one month later.

Comment

Urticaria may be acute or chronic. Acute urticaria is idiopathic in more than 50% of patients but can occur as a type 1 hypersensitivity reaction to food or wasp or bee stings; an immunologic response to blood products, infection, or febrile illness; or an adverse effect of drug therapy by various mechanisms, such as penicillin or angiotensin-converting enzyme inhibitors.³ As opposed to acute urticaria, chronic urticaria is defined by recurrent episodes occurring at least twice weekly for 6 weeks.² Urticaria occurring less frequently than this, over a long period, is more accurately termed episodic because it is more likely to have an identifiable environmental trigger. All chronic urticaria implicitly go through an acute stage (<6 weeks). Although many classification systems of chronic urticaria exist, a concise clinical classification is included in the Table.² Urticarial vasculitis is a small vessel vasculitis but is included in the classification because it is clinically indistinguishable from other urticarial lesions.

PLEASE REFER TO THE PDF TO VIEW THE TABLE

Urticarial lesions in chronic urticaria typically last 4 to 36 hours and can occur in individuals of any age (though it is most common in women), usually with few systemic symptoms.⁴ Pruritus is nearly always severe, especially at night, and may prevent sleep. Fifty percent of cases resolve spontaneously by 6 months, but of those that do not, 40% still have symptoms of urticaria 10 years later.⁴ The severe effect of chronic urticaria on quality of life often is underestimated.⁵

Ordinary Urticaria

Patients previously classified as having chronic idiopathic or "ordinary" urticaria are now divided into 2 groups: 50% to 60% of these patients have chronic idiopathic urticaria (CIU), and the remainder have chronic autoimmune urticaria (CAU).⁶ Results from a study in children demonstrated that autoimmune urticaria occurs in children in as many as 30% of chronic cases.⁷ CAU is caused by an immunoglobulin (Ig) G antibody to the α subunit of the IgE receptor (35%–40% of cases) or to IgE (5%–10% of cases).⁶ The IgG subclasses that appear to be pathogenic are IgG1; IgG3; and, to a lesser degree, IgG4 (though not IgG2).⁶ Complement activation augments histamine secretion by release of C5a.⁸ CAU has been reported to be associated with antithyroid antibodies (27% of cases)^6,9; autoimmune conditions such as vitiligo, rheumatoid arthritis, and pernicious anemia; and low vitamin B₁₂ levels.¹⁰ Patients with demonstrable histamine-releasing autoantibodies have a very strong association with HLA-DR4 and its associated allele HLA-DQ8.¹¹

Histologically, the 2 groups of urticaria are indistinguishable.6 Advanced techniques show a perivascular nonnecrotizing infiltrate of CD4⁺ lymphocytes consisting of a mixture of T_H1 and T_H2 subtypes, plus monocytes, neutrophils, eosinophils, and basophils. These cells are recruited because of interactions with C5a, cell priming cytokines, chemokines, and adhesion molecules.⁶ A recent study also found inflammatory cells and mediator up-regulation in uninvolved CIU skin as a sign of prolonged and widespread "urticarial status."¹²

Physical Urticaria

Physical urticaria are classified and induced by a physical stimulus. Most physical urticaria occur within minutes of provocation and resolve within 2 hours, with the exception of delayed pressure urticaria, which may persist for 24 hours or longer.¹³ Angioedema may occur in all physical urticaria except dermographism. Overlap between groups is common, and physical urticaria often occur as an added feature of chronic urticaria.

The most common type of physical urticaria is simple immediate dermographism, presenting with linear wheals at sites of scratching or friction. It occurs in about 1.4% to 5% of the population worldwide¹⁴ and may be viewed as an exaggerated physiologic response. On average, dermographism runs a course of 2 to 3 years before usually resolving spontaneously.¹⁵

Delayed-pressure urticaria is a response to sustained pressure to the skin, presenting with deep erythematous edema after a delay of unknown cause lasting 30 minutes to 12 hours.^14,16 An increased level of interleukin 6 has been found in suction blister fluid over induced lesions.^2,15 The edema tends to be deeper, pruritic, and painful, and it may persist for days. Systemic features such as malaise, flulike symptoms, and arthralgia may occur. The prognosis is variable, but the mean duration is 6 to 9 years.¹⁷ The response to antihistamines often is poor, and oral corticosteroids may be needed for disease control.²

Cholinergic urticaria usually presents with multiple, transient, pruritic, small, red macules or papules on the neck, trunk, forearms, wrists, and thighs in response to heat, often surrounded by an obvious flare. It mainly affects young adults, with an overall prevalence of 11% in this group.¹⁸ Fifty percent of patients are atopic.¹⁵ Angioedema and systemic manifestations such as headache, palpitations, abdominal pain, wheezing, and syncope may occur. The cholinergic sympathetic innervation of sweat glands is involved because the eruption can be blocked by topical anticholinergic drugs,¹⁹ but how this leads to urticaria is unclear. The routine treatment is with low-sedation H₁-type antihistamines, with or without an anxiolytic such as oral propranolol. In severe cases, the anabolic steroid stanazolol has been used.¹⁵

Cold urticaria is a heterogeneous condition in which whealing occurs within minutes in response to cold exposure, most frequently in children and young adults. Wheals usually arise at the site of localized cooling but may be generalized following lowering of the body temperature.¹⁶ Diagnosis may be confirmed by applying an ice cube for 5 to 15 minutes to the skin, allowing an interval for skin rewarming, and observing the development of whealing that occurs on skin rewarming. Systemic symptoms such as flushing, headache, abdominal pain, and syncope can occur if large areas are affected. The cause is unknown, but a serum factor, possibly IgM or IgE, has been implicated.²⁰ A heterozygous deficiency of the protease inhibitor α1-antichymotrypsin has been demonstrated and may be etiologically important in some patients.²¹ The prognosis is good, with spontaneous improvement in an average of 2 to 3 years.¹⁵ Ninety-six percent of cases of cold urticaria are primary.²² The diagnosis of secondary acquired cold urticaria depends on being able to demonstrate cryoglobulins, cold agglutinins, or possibly cryofibrinogens.¹⁷ These findings should, in turn, lead to investigations for an underlying cause, such as hepatitis B or C infection, lymphoproliferative disease, or infectious mononucleosis.¹⁵

Other uncommon forms of physical urticaria include adrenergic urticaria, which develops during phases of stress and has been associated with an increase in the plasma concentrations of norepinephrine, epinephrine, and prolactin.²³ Aquagenic urticaria is precipitated by skin contact with water of any temperature.³ Exercise-induced anaphylaxis involves urticaria, respiratory distress, or hypotension after exercise. In localized heat urticaria, wheals occur on skin in direct contact with warm objects. Solar urticaria is a rare condition that occurs within minutes of exposure to UV light waves ranging from 280 to 760 nm¹⁴; it usually disappears in less than one hour. Vibratory urticaria occurs after a vibratory stimulus and can be a hereditary autosomaldominant disorder or an acquired sporadic disease.²⁴

Urticarial Vasculitis

Urticarial vasculitis describes a distinct entity in which the gross cutaneous lesions resemble urticaria and histologically show features of a vasculitis. The diagnosis is suggested clinically by wheals lasting more than 24 hours and residual bruising.²⁵ Although the clinical lesions may present as typical urticaria, pathophysiologically, it is a different disease caused by deposition of antigen-antibody complexes in vessel walls, a type 3 reaction causing vascular damage.¹⁷ Lesions often occur at pressure points and may resolve with residual purpura. Extracutaneous manifestations include transient and migratory arthralgia (50%); gastrointestinal symptoms (20%); and pulmonary obstructive disease (20%), particularly in smokers and patients with renal disease (5%–10%).¹⁷ Normocomplementemic urticarial vasculitis usually is idiopathic, but hypocomplementemic urticarial vasculitis may be associated with underlying systemic lupus erythematosus, Sjögren syndrome, or cryoglobulinemia.² Primary urticarial vasculitis can occasionally evolve into systemic lupus erythematosus.²⁶ Patients with urticarial vasculitis often improve on nonsteroidal anti-inflammatory drugs (NSAIDs), but some patients may need immunosuppressive therapy.

Contact Urticaria

Contact urticaria develops at the site(s) of contact of an urticant and can be divided into an allergic subgroup caused by an IgE-allergen interaction and a nonallergic subgroup that is IgE independent. The allergic form typically is seen in children with atopic dermatitis sensitized to environmental allergens such as grass, animals, food, or latex, and it may be complicated by anaphylaxis. Natural rubber latex is one of the most important causes today.²⁷ This type appears within minutes, fades within 2 hours, and is partially inhibited by antihistamines. Nonallergic contact urticaria is caused by the direct effect of the urticant on blood vessels and includes irritants such as benzoic acid and cinnamic aldehyde in cosmetics. It may take 45 minutes for lesions to appear and urticaria is partially inhibited by NSAIDs.

Angioedema Without Wheals

It is useful to classify angioedema occurring without wheals as a separate entity because its etiology may be associated with hereditary angioedema, which must be excluded. The condition usually is idiopathic or caused by a drug reaction to angiotensin-converting enzyme inhibitors, aspirin, or NSAIDs. Hereditary angioedema is a rare autosomal-dominant condition with a prevalence between 1:10,000 and 1:150,000 in the general population and is caused by a deficiency (type 1, 85%) or dysfunction (type 2, 15%) of C1 inhibitor.²⁸ A low level of C4 in the serum is a constant and diagnostic feature. A third type affecting primarily women and exacerbated by estrogens recently has been described.²⁸ Patients have lifelong episodic angioedema and may experience colicky abdominal pain. Laryngeal involvement can be life threatening. Treatment is difficult and involves fluid replacement and purified C1 inhibitor concentrate for acute attacks (not approved in the United States) and prophylactic treatment with anabolic androgens and antifibrinolytics.²⁸

Diagnosis

The diagnosis of urticaria is primarily clinical; extensive laboratory tests are very rarely needed—only when indicated by the patient history.³ Some authors argue that laboratory investigations are unnecessary for mild ordinary urticaria responding to antihistamines.²⁹ Taking a thorough patient history has been found to be almost as effective in identifying a cause as a complete diagnostic evaluation.³⁰ In acute urticaria, if the history indicates a type 1 hypersensitivity reaction, confirmation is possible by a prick test or laboratory radioallergosorbent tests.³ Many physical and contact urticaria can be confirmed by a challenge of the offending agent. An initial baseline investigation with a complete blood count and erythrocyte sedimentation rate should be taken in more severe cases to identify any internal disease or raise the possibility of urticarial vasculitis.¹⁷ Of note, a biopsy is more sensitive and specific for ruling out urticarial vasculitis than are a complete blood count and erythrocyte sedimentation rate.

A search for thyroid autoantibodies is appropriate for all chronic urticaria not responding to first-line therapies with antihistamines, especially when autoimmune urticaria is suspected.² Further investigations are guided by clinical suspicion, which may include a skin biopsy, autoimmune screening, urinalysis, serum cryoglobulins, and hepatitis B and C serology.³¹ The only available test to screen for autoantibodies against the IgE receptor is the autologous serum skin test. This test should be performed with care because infections could be transmitted, particularly if, by mistake, patients were not injected with their own serum.³¹ Measurement of C4 is indicated only in patients who present with angioedema alone and should be followed by a determination of the levels and function of C1 inhibitor, if C4 is below reference range.²⁹

Management and Treatment

Management of urticaria depends on its cause. Aggravating factors should be identified from the history, and triggering stimuli for physical urticaria should be avoided. Simple cooling lotions such as menthol 1% or 2% in an aqueous cream often are useful.³² Aspirin and NSAIDs should be avoided because they aggravate symptoms in 30% of patients.³³ Patients taking low-dose aspirin for its antithrombotic properties usually can continue regular treatment. Avoiding codeine and other opiates also is recommended because an enhanced skin test reaction may be found in chronic urticaria.³⁴ Avoiding dietary pseudoallergens, such as food coloring and natural salicylates, is controversial.^14,35 This generally has only a small role unless proven by a double-blinded placebo-controlled challenge.²

The mainstays for treatment of urticaria are oral antihistamines, as they reduce pruritus and wheal duration and numbers. Oral antihistamines have been reported to produce moderate or good response in 44% to 91% of patients with all types of urticaria.^36,37 Antihistamines can be grouped into first-generation (sedating), second generation (minimally sedating), third-generation (nonsedating), and H₂ antagonists.¹⁷ The physiologic and pathologic actions of histamine are mediated through 4 histamine receptor subtypes: H₁, H₂, H₃, and H₄.³⁸ The erythema, wheal formation, and itching associated with urticaria are mainly due to activation of H₁ receptors and the less contributory role of H₂ receptors.³⁸ Histamine H₃ receptors are located presynaptically on postganglionic sympathetic norepinephric nerves, including sympathetics innervating the heart and blood vessels. The contribution of H₃ receptors to skin responses mediated by histamine has not been fully elucidated. However, in a recent experimental study, the authors reported that the combination of H1 and H3 antagonists might be a novel approach for the treatment of urticaria.³⁸

Initially, a minimally sedating second- or third-generation antihistamine, such as loratadine,³⁹ fexofenadine hydrochloride,⁴⁰ and cetirizine hydrochloride,^41-44 should be given at a once-daily oral dosing. When one antihistamine is not helpful, it is usually worth trying a different one, and some physicians combine 2 or more antihistamines at the same time.³ It is common practice to exceed the licensed dose in severely affected patients.³¹ High doses of antihistamines have effects beyond the blockade of histamine receptors, and actions that are not due to antagonism of H₁ receptors may account for the efficacy of older antihistamines.⁴⁵ As a general rule, antihistamines are safe and have few substantial adverse effects; drug interactions are rare. If possible, it is best to avoid all antihistamines in pregnancy, though none have been proven teratogenic. If one is used, the consensus is that chlorpheniramine maleate is among the safest.⁴⁶

Addition of a sedating first-generation antihistamine such as hydroxyzine at night can be helpful, especially if nocturnal pruritus prevents sleep. The use of a sedating antihistamine as monotherapy is less desirable because of impairment of cognitive function, including driving performance and concentration. The addition of a H₂ antagonist to conventional H₁ antihistamines may be helpful in some patients.^3,47 Doxepin hydrochloride at low doses (10–50 mg) is used for its potent H1 and H2 receptor antagonist properties. Doxepin hydrochloride is highly sedative and especially suitable for patients with associated depression.⁴⁸

Oral corticosteroids given in short reducing courses may be needed for severe exacerbations not responding to full-dose antihistamines. Relatively high doses of up to 40 to 60 mg of prednisone may be needed for disease control. Alternate-day ste-roids may be used for patients with severe disease.⁶ Long-term administration should be avoided.¹

Many patients feel reassured by carrying an epinephrine pen for self-administration if they are prone to severe attacks. Leukotriene antagonists (zafirlukast and montelukast sodium) have been shown to be superior to placebo in the treatment of patients with chronic urticaria.^49,50 Nifedipine has a small effect in chronic urticaria and often is used for patients with concomitant hypertension. Thyroxine recently was reported to suppress CIU symptoms associated with antithyroid autoantibodies in some patients.⁵¹

Given the role of the immune system in a subset of patients, immunosuppressive therapy is considered for patients with a severe disabling course. Cyclosporine at 2.5 to 5 mg/kg per day is of proven value in autoantibody-positive chronic urticaria⁵² but also is effective in most cases of severe autoantibody-negative disease.¹⁵ Tacrolimus also has shown promise in a recent trial.⁵³ Other options include plasmapheresis⁵⁴ and intravenous immunoglobulin.^55,56 Optimal treatment protocols have yet to be confirmed. Treatments for CIU with only limited or anecdotal supportive evidence include sulfasalazine, methotrexate, rofecoxib, colchicine, dapsone, and cyclophosphamide.³

Future treatment may involve development of selective immunotherapy targeting the IgE receptor or vaccinations to down-regulate and induce tolerance to the IgE receptor. Other potential strategies include blocking formation of C5a and use of therapeutic antibodies such as anti-IgE, anti–tumor necrosis factor α, and anti–interleukin 5.²

Conclusion

There is no single way to manage urticaria and angioedema. Most patients are treated successfully with antihistamines. However, patients with severe antihistamine-resistant urticaria may be very disabled by their disease, and the treatment can pose a major challenge to the physician.

Urticaria has been recognized since the days of Hippocrates. The name of the condition dates back to the 18th century, when the burning and edema of the skin was likened to that caused by contact with nettles (Urtica dioica). Urticaria affects 10% to 25% of the population worldwide at some point in their lives.¹ The condition is characterized by short-lived edema of the skin, mouth, and genitalia related to a transient leakage of plasma from small blood vessels into the surrounding connective tissues. Urticaria may present with superficial edema of the dermis (wheals) or deeper edema of the dermal, subcutaneous, or submucosal tissues (angioedema).² Wheals typically are itchy with a pale center, maturing into pink superficial plaques. Areas of angioedema tend to be pale and painful; last longer than wheals; and may involve the mouth and rarely the bowel.

Case Report

A 40-year-old woman in otherwise good health presented with a 5-year history of recurrent pruritic light red lesions on her chest and back. She reported that individual lesions would last up to 24 hours in one area before disappearing, while other new crops of lesions would develop in other areas of her body. She had no associated facial edema or lip or throat involvement, and she denied taking any medications. Her history failed to reveal any potential triggers for the eruptions. On physical examination, multiple elevated superficial erythematous papules and plaques were noted, with shapes varying from annular to circinate, areas of central clearing, and targetlike lesions on the trunk and extremities. The lesions blanched with pressure (Figure). The woman had no mucosal involvement, scars, or change in pigmentation. Results from the remainder of the physical examination were unremarkable.

PLEASE REFER TO THE PDF TO VIEW THE FIGURE

Because of the extent of involvement and the erythematous to violaceous aspect of certain lesions, a 3-mm punch biopsy was performed to rule out urticarial vasculitis. Histology results were consistent with urticaria with red blood extravasation but without vasculitis. Our patient initially was treated with topical clobetasol propionate ointment, 10 mg of cetirizine hydrochloride, and topical calamine lotion. At follow-up one week later, she mentioned that she had improved after 5 days of treatment but began developing new lesions 2 days prior to her second visit. Given the severity of pruritus and after a discussion of the role of corticosteroids for acute urticaria, a taper dose of prednisone was prescribed at 40 mg/d, in addition to 60 mg of fexofenadine hydrochloride twice daily. The patient was lesion- and symptom-free after 7 days of treatment, with no recurrence one month later.

Comment

Urticaria may be acute or chronic. Acute urticaria is idiopathic in more than 50% of patients but can occur as a type 1 hypersensitivity reaction to food or wasp or bee stings; an immunologic response to blood products, infection, or febrile illness; or an adverse effect of drug therapy by various mechanisms, such as penicillin or angiotensin-converting enzyme inhibitors.³ As opposed to acute urticaria, chronic urticaria is defined by recurrent episodes occurring at least twice weekly for 6 weeks.² Urticaria occurring less frequently than this, over a long period, is more accurately termed episodic because it is more likely to have an identifiable environmental trigger. All chronic urticaria implicitly go through an acute stage (<6 weeks). Although many classification systems of chronic urticaria exist, a concise clinical classification is included in the Table.² Urticarial vasculitis is a small vessel vasculitis but is included in the classification because it is clinically indistinguishable from other urticarial lesions.

PLEASE REFER TO THE PDF TO VIEW THE TABLE

Urticarial lesions in chronic urticaria typically last 4 to 36 hours and can occur in individuals of any age (though it is most common in women), usually with few systemic symptoms.⁴ Pruritus is nearly always severe, especially at night, and may prevent sleep. Fifty percent of cases resolve spontaneously by 6 months, but of those that do not, 40% still have symptoms of urticaria 10 years later.⁴ The severe effect of chronic urticaria on quality of life often is underestimated.⁵

Ordinary Urticaria

Patients previously classified as having chronic idiopathic or "ordinary" urticaria are now divided into 2 groups: 50% to 60% of these patients have chronic idiopathic urticaria (CIU), and the remainder have chronic autoimmune urticaria (CAU).⁶ Results from a study in children demonstrated that autoimmune urticaria occurs in children in as many as 30% of chronic cases.⁷ CAU is caused by an immunoglobulin (Ig) G antibody to the α subunit of the IgE receptor (35%–40% of cases) or to IgE (5%–10% of cases).⁶ The IgG subclasses that appear to be pathogenic are IgG1; IgG3; and, to a lesser degree, IgG4 (though not IgG2).⁶ Complement activation augments histamine secretion by release of C5a.⁸ CAU has been reported to be associated with antithyroid antibodies (27% of cases)^6,9; autoimmune conditions such as vitiligo, rheumatoid arthritis, and pernicious anemia; and low vitamin B₁₂ levels.¹⁰ Patients with demonstrable histamine-releasing autoantibodies have a very strong association with HLA-DR4 and its associated allele HLA-DQ8.¹¹

Histologically, the 2 groups of urticaria are indistinguishable.6 Advanced techniques show a perivascular nonnecrotizing infiltrate of CD4⁺ lymphocytes consisting of a mixture of T_H1 and T_H2 subtypes, plus monocytes, neutrophils, eosinophils, and basophils. These cells are recruited because of interactions with C5a, cell priming cytokines, chemokines, and adhesion molecules.⁶ A recent study also found inflammatory cells and mediator up-regulation in uninvolved CIU skin as a sign of prolonged and widespread "urticarial status."¹²

Physical Urticaria

Physical urticaria are classified and induced by a physical stimulus. Most physical urticaria occur within minutes of provocation and resolve within 2 hours, with the exception of delayed pressure urticaria, which may persist for 24 hours or longer.¹³ Angioedema may occur in all physical urticaria except dermographism. Overlap between groups is common, and physical urticaria often occur as an added feature of chronic urticaria.

The most common type of physical urticaria is simple immediate dermographism, presenting with linear wheals at sites of scratching or friction. It occurs in about 1.4% to 5% of the population worldwide¹⁴ and may be viewed as an exaggerated physiologic response. On average, dermographism runs a course of 2 to 3 years before usually resolving spontaneously.¹⁵

Delayed-pressure urticaria is a response to sustained pressure to the skin, presenting with deep erythematous edema after a delay of unknown cause lasting 30 minutes to 12 hours.^14,16 An increased level of interleukin 6 has been found in suction blister fluid over induced lesions.^2,15 The edema tends to be deeper, pruritic, and painful, and it may persist for days. Systemic features such as malaise, flulike symptoms, and arthralgia may occur. The prognosis is variable, but the mean duration is 6 to 9 years.¹⁷ The response to antihistamines often is poor, and oral corticosteroids may be needed for disease control.²

Cholinergic urticaria usually presents with multiple, transient, pruritic, small, red macules or papules on the neck, trunk, forearms, wrists, and thighs in response to heat, often surrounded by an obvious flare. It mainly affects young adults, with an overall prevalence of 11% in this group.¹⁸ Fifty percent of patients are atopic.¹⁵ Angioedema and systemic manifestations such as headache, palpitations, abdominal pain, wheezing, and syncope may occur. The cholinergic sympathetic innervation of sweat glands is involved because the eruption can be blocked by topical anticholinergic drugs,¹⁹ but how this leads to urticaria is unclear. The routine treatment is with low-sedation H₁-type antihistamines, with or without an anxiolytic such as oral propranolol. In severe cases, the anabolic steroid stanazolol has been used.¹⁵

Cold urticaria is a heterogeneous condition in which whealing occurs within minutes in response to cold exposure, most frequently in children and young adults. Wheals usually arise at the site of localized cooling but may be generalized following lowering of the body temperature.¹⁶ Diagnosis may be confirmed by applying an ice cube for 5 to 15 minutes to the skin, allowing an interval for skin rewarming, and observing the development of whealing that occurs on skin rewarming. Systemic symptoms such as flushing, headache, abdominal pain, and syncope can occur if large areas are affected. The cause is unknown, but a serum factor, possibly IgM or IgE, has been implicated.²⁰ A heterozygous deficiency of the protease inhibitor α1-antichymotrypsin has been demonstrated and may be etiologically important in some patients.²¹ The prognosis is good, with spontaneous improvement in an average of 2 to 3 years.¹⁵ Ninety-six percent of cases of cold urticaria are primary.²² The diagnosis of secondary acquired cold urticaria depends on being able to demonstrate cryoglobulins, cold agglutinins, or possibly cryofibrinogens.¹⁷ These findings should, in turn, lead to investigations for an underlying cause, such as hepatitis B or C infection, lymphoproliferative disease, or infectious mononucleosis.¹⁵

Other uncommon forms of physical urticaria include adrenergic urticaria, which develops during phases of stress and has been associated with an increase in the plasma concentrations of norepinephrine, epinephrine, and prolactin.²³ Aquagenic urticaria is precipitated by skin contact with water of any temperature.³ Exercise-induced anaphylaxis involves urticaria, respiratory distress, or hypotension after exercise. In localized heat urticaria, wheals occur on skin in direct contact with warm objects. Solar urticaria is a rare condition that occurs within minutes of exposure to UV light waves ranging from 280 to 760 nm¹⁴; it usually disappears in less than one hour. Vibratory urticaria occurs after a vibratory stimulus and can be a hereditary autosomaldominant disorder or an acquired sporadic disease.²⁴

Urticarial Vasculitis

Urticarial vasculitis describes a distinct entity in which the gross cutaneous lesions resemble urticaria and histologically show features of a vasculitis. The diagnosis is suggested clinically by wheals lasting more than 24 hours and residual bruising.²⁵ Although the clinical lesions may present as typical urticaria, pathophysiologically, it is a different disease caused by deposition of antigen-antibody complexes in vessel walls, a type 3 reaction causing vascular damage.¹⁷ Lesions often occur at pressure points and may resolve with residual purpura. Extracutaneous manifestations include transient and migratory arthralgia (50%); gastrointestinal symptoms (20%); and pulmonary obstructive disease (20%), particularly in smokers and patients with renal disease (5%–10%).¹⁷ Normocomplementemic urticarial vasculitis usually is idiopathic, but hypocomplementemic urticarial vasculitis may be associated with underlying systemic lupus erythematosus, Sjögren syndrome, or cryoglobulinemia.² Primary urticarial vasculitis can occasionally evolve into systemic lupus erythematosus.²⁶ Patients with urticarial vasculitis often improve on nonsteroidal anti-inflammatory drugs (NSAIDs), but some patients may need immunosuppressive therapy.

Contact Urticaria

Contact urticaria develops at the site(s) of contact of an urticant and can be divided into an allergic subgroup caused by an IgE-allergen interaction and a nonallergic subgroup that is IgE independent. The allergic form typically is seen in children with atopic dermatitis sensitized to environmental allergens such as grass, animals, food, or latex, and it may be complicated by anaphylaxis. Natural rubber latex is one of the most important causes today.²⁷ This type appears within minutes, fades within 2 hours, and is partially inhibited by antihistamines. Nonallergic contact urticaria is caused by the direct effect of the urticant on blood vessels and includes irritants such as benzoic acid and cinnamic aldehyde in cosmetics. It may take 45 minutes for lesions to appear and urticaria is partially inhibited by NSAIDs.

Angioedema Without Wheals

It is useful to classify angioedema occurring without wheals as a separate entity because its etiology may be associated with hereditary angioedema, which must be excluded. The condition usually is idiopathic or caused by a drug reaction to angiotensin-converting enzyme inhibitors, aspirin, or NSAIDs. Hereditary angioedema is a rare autosomal-dominant condition with a prevalence between 1:10,000 and 1:150,000 in the general population and is caused by a deficiency (type 1, 85%) or dysfunction (type 2, 15%) of C1 inhibitor.²⁸ A low level of C4 in the serum is a constant and diagnostic feature. A third type affecting primarily women and exacerbated by estrogens recently has been described.²⁸ Patients have lifelong episodic angioedema and may experience colicky abdominal pain. Laryngeal involvement can be life threatening. Treatment is difficult and involves fluid replacement and purified C1 inhibitor concentrate for acute attacks (not approved in the United States) and prophylactic treatment with anabolic androgens and antifibrinolytics.²⁸

Diagnosis

The diagnosis of urticaria is primarily clinical; extensive laboratory tests are very rarely needed—only when indicated by the patient history.³ Some authors argue that laboratory investigations are unnecessary for mild ordinary urticaria responding to antihistamines.²⁹ Taking a thorough patient history has been found to be almost as effective in identifying a cause as a complete diagnostic evaluation.³⁰ In acute urticaria, if the history indicates a type 1 hypersensitivity reaction, confirmation is possible by a prick test or laboratory radioallergosorbent tests.³ Many physical and contact urticaria can be confirmed by a challenge of the offending agent. An initial baseline investigation with a complete blood count and erythrocyte sedimentation rate should be taken in more severe cases to identify any internal disease or raise the possibility of urticarial vasculitis.¹⁷ Of note, a biopsy is more sensitive and specific for ruling out urticarial vasculitis than are a complete blood count and erythrocyte sedimentation rate.

A search for thyroid autoantibodies is appropriate for all chronic urticaria not responding to first-line therapies with antihistamines, especially when autoimmune urticaria is suspected.² Further investigations are guided by clinical suspicion, which may include a skin biopsy, autoimmune screening, urinalysis, serum cryoglobulins, and hepatitis B and C serology.³¹ The only available test to screen for autoantibodies against the IgE receptor is the autologous serum skin test. This test should be performed with care because infections could be transmitted, particularly if, by mistake, patients were not injected with their own serum.³¹ Measurement of C4 is indicated only in patients who present with angioedema alone and should be followed by a determination of the levels and function of C1 inhibitor, if C4 is below reference range.²⁹

Management and Treatment

Management of urticaria depends on its cause. Aggravating factors should be identified from the history, and triggering stimuli for physical urticaria should be avoided. Simple cooling lotions such as menthol 1% or 2% in an aqueous cream often are useful.³² Aspirin and NSAIDs should be avoided because they aggravate symptoms in 30% of patients.³³ Patients taking low-dose aspirin for its antithrombotic properties usually can continue regular treatment. Avoiding codeine and other opiates also is recommended because an enhanced skin test reaction may be found in chronic urticaria.³⁴ Avoiding dietary pseudoallergens, such as food coloring and natural salicylates, is controversial.^14,35 This generally has only a small role unless proven by a double-blinded placebo-controlled challenge.²

The mainstays for treatment of urticaria are oral antihistamines, as they reduce pruritus and wheal duration and numbers. Oral antihistamines have been reported to produce moderate or good response in 44% to 91% of patients with all types of urticaria.^36,37 Antihistamines can be grouped into first-generation (sedating), second generation (minimally sedating), third-generation (nonsedating), and H₂ antagonists.¹⁷ The physiologic and pathologic actions of histamine are mediated through 4 histamine receptor subtypes: H₁, H₂, H₃, and H₄.³⁸ The erythema, wheal formation, and itching associated with urticaria are mainly due to activation of H₁ receptors and the less contributory role of H₂ receptors.³⁸ Histamine H₃ receptors are located presynaptically on postganglionic sympathetic norepinephric nerves, including sympathetics innervating the heart and blood vessels. The contribution of H₃ receptors to skin responses mediated by histamine has not been fully elucidated. However, in a recent experimental study, the authors reported that the combination of H1 and H3 antagonists might be a novel approach for the treatment of urticaria.³⁸

Initially, a minimally sedating second- or third-generation antihistamine, such as loratadine,³⁹ fexofenadine hydrochloride,⁴⁰ and cetirizine hydrochloride,^41-44 should be given at a once-daily oral dosing. When one antihistamine is not helpful, it is usually worth trying a different one, and some physicians combine 2 or more antihistamines at the same time.³ It is common practice to exceed the licensed dose in severely affected patients.³¹ High doses of antihistamines have effects beyond the blockade of histamine receptors, and actions that are not due to antagonism of H₁ receptors may account for the efficacy of older antihistamines.⁴⁵ As a general rule, antihistamines are safe and have few substantial adverse effects; drug interactions are rare. If possible, it is best to avoid all antihistamines in pregnancy, though none have been proven teratogenic. If one is used, the consensus is that chlorpheniramine maleate is among the safest.⁴⁶

Addition of a sedating first-generation antihistamine such as hydroxyzine at night can be helpful, especially if nocturnal pruritus prevents sleep. The use of a sedating antihistamine as monotherapy is less desirable because of impairment of cognitive function, including driving performance and concentration. The addition of a H₂ antagonist to conventional H₁ antihistamines may be helpful in some patients.^3,47 Doxepin hydrochloride at low doses (10–50 mg) is used for its potent H1 and H2 receptor antagonist properties. Doxepin hydrochloride is highly sedative and especially suitable for patients with associated depression.⁴⁸

Oral corticosteroids given in short reducing courses may be needed for severe exacerbations not responding to full-dose antihistamines. Relatively high doses of up to 40 to 60 mg of prednisone may be needed for disease control. Alternate-day ste-roids may be used for patients with severe disease.⁶ Long-term administration should be avoided.¹

Many patients feel reassured by carrying an epinephrine pen for self-administration if they are prone to severe attacks. Leukotriene antagonists (zafirlukast and montelukast sodium) have been shown to be superior to placebo in the treatment of patients with chronic urticaria.^49,50 Nifedipine has a small effect in chronic urticaria and often is used for patients with concomitant hypertension. Thyroxine recently was reported to suppress CIU symptoms associated with antithyroid autoantibodies in some patients.⁵¹

Given the role of the immune system in a subset of patients, immunosuppressive therapy is considered for patients with a severe disabling course. Cyclosporine at 2.5 to 5 mg/kg per day is of proven value in autoantibody-positive chronic urticaria⁵² but also is effective in most cases of severe autoantibody-negative disease.¹⁵ Tacrolimus also has shown promise in a recent trial.⁵³ Other options include plasmapheresis⁵⁴ and intravenous immunoglobulin.^55,56 Optimal treatment protocols have yet to be confirmed. Treatments for CIU with only limited or anecdotal supportive evidence include sulfasalazine, methotrexate, rofecoxib, colchicine, dapsone, and cyclophosphamide.³

Future treatment may involve development of selective immunotherapy targeting the IgE receptor or vaccinations to down-regulate and induce tolerance to the IgE receptor. Other potential strategies include blocking formation of C5a and use of therapeutic antibodies such as anti-IgE, anti–tumor necrosis factor α, and anti–interleukin 5.²

Conclusion

There is no single way to manage urticaria and angioedema. Most patients are treated successfully with antihistamines. However, patients with severe antihistamine-resistant urticaria may be very disabled by their disease, and the treatment can pose a major challenge to the physician.