Psoriasis Collection

NEW YORK — The contemporary use of minocycline for acne and hydralazine for heart failure is expanding the spectrum of drug-induced lupus, and physicians need to be aware of this, as well as other types of drug-induced lupus.

Minocycline-induced lupus was first reported in the early 1990s, and more than 250 cases have now been reported to the World Health Organization. There is a 5:1 female-to-male predominance, and the clinical features include fever, morning stiffness, myalgias, polyarthralgias, and symmetric arthritis.

It is also characterized by large vessel vasculitis, and in more than 60% of patients, antineutrophil cytoplasmic antibodies are present and antihistone antibodies are not. This is in contrast to "classic" drug-induced lupus, in which antihistone antibodies are prominent.

Other autoantibodies also can be seen in minocycline-induced lupus, including antinuclear antibody (ANA) and anti-double-stranded DNA, according to Dr. Andrew G. Franks Jr.

"The likelihood of developing a lupuslike syndrome is elevated 8.5-fold with minocycline, so many clinicians are now moving away from using minocycline for acne and rosacea and switching to doxycycline, which really doesn't have this effect. I haven't used minocycline for 5 years," said Dr. Franks of the department of dermatology at New York University Medical Center, New York.

Hydralazine, which had fallen out of favor as an antihypertensive, has regained popularity as part of combination therapy for heart failure in African Americans following the benefits seen in the African-American Heart Failure Trial (N. Engl. J. Med. 2004;351:2049-57).

Younger physicians in particular might not be familiar with hydralazine's link to drug-induced lupus, Dr. Franks said.

Hydralazine is one of the five causes of classic drug-induced lupus, along with procainamide, isoniazid, quinidine, and phenytoin, but more than 100 drugs have been implicated, he said.

Classic drug-induced lupus is characterized by flulike symptoms and significant musculoskeletal involvement, with most patients being ANA and antihistone antibody positive. "In my opinion, patients starting hydralazine—or any drug in the big five, for that matter—should have a baseline test for ANA, although that is somewhat controversial," Dr. Franks said.

The third main type of drug-induced lupus is subacute cutaneous lupus erythematosus (SCLE), which also is associated with an ever-widening variety of agents, including the thiazide diuretics, antifungals, calcium channel blockers, and ACE inhibitors. There also have been reports involving statins, leflunomide, and tumor necrosis factor inhibitors.

Clinically, SCLE can be very difficult to sort out, according to Dr. Franks, with targetoid lesions mixed with papulosquamous or annular lesions. The presentation can also resemble erythema multiforme or toxic epidermal necrolysis, with disadhesion of the epidermal layer and sloughing of the skin, he said.

An audience member asked what happens when the offending drug is withdrawn. Dr. Franks explained that the situation is different than an allergic reaction. "It can sometimes take months for this to remit, and some patients require additional therapy, but 95% of patients ultimately do remit," he said at a rheumatology meeting sponsored by New York University.

No single unifying mechanism has been identified that can explain the variety of drugs associated with drug-induced lupus or the varied clinical and laboratory manifestations. Hypotheses include the possibility that the drugs can act as haptens or antigens that drive an immune response, or as immune system modulators that permit the development of self-directed responses (Semin. Arthritis Rheum. 2007 Dec. 31 [doi:10.1016/j.semarthrit.2007.10.001]).

Dr. Franks reported having no financial relationships to disclose. n

The likelihood of developing a lupus-like syndrome is elevated 8.5-fold with minocycline. DR. FRANKS

NEW YORK — The contemporary use of minocycline for acne and hydralazine for heart failure is expanding the spectrum of drug-induced lupus, and physicians need to be aware of this, as well as other types of drug-induced lupus.

Minocycline-induced lupus was first reported in the early 1990s, and more than 250 cases have now been reported to the World Health Organization. There is a 5:1 female-to-male predominance, and the clinical features include fever, morning stiffness, myalgias, polyarthralgias, and symmetric arthritis.

It is also characterized by large vessel vasculitis, and in more than 60% of patients, antineutrophil cytoplasmic antibodies are present and antihistone antibodies are not. This is in contrast to "classic" drug-induced lupus, in which antihistone antibodies are prominent.

Other autoantibodies also can be seen in minocycline-induced lupus, including antinuclear antibody (ANA) and anti-double-stranded DNA, according to Dr. Andrew G. Franks Jr.

"The likelihood of developing a lupuslike syndrome is elevated 8.5-fold with minocycline, so many clinicians are now moving away from using minocycline for acne and rosacea and switching to doxycycline, which really doesn't have this effect. I haven't used minocycline for 5 years," said Dr. Franks of the department of dermatology at New York University Medical Center, New York.

Hydralazine, which had fallen out of favor as an antihypertensive, has regained popularity as part of combination therapy for heart failure in African Americans following the benefits seen in the African-American Heart Failure Trial (N. Engl. J. Med. 2004;351:2049-57).

Younger physicians in particular might not be familiar with hydralazine's link to drug-induced lupus, Dr. Franks said.

Hydralazine is one of the five causes of classic drug-induced lupus, along with procainamide, isoniazid, quinidine, and phenytoin, but more than 100 drugs have been implicated, he said.

Classic drug-induced lupus is characterized by flulike symptoms and significant musculoskeletal involvement, with most patients being ANA and antihistone antibody positive. "In my opinion, patients starting hydralazine—or any drug in the big five, for that matter—should have a baseline test for ANA, although that is somewhat controversial," Dr. Franks said.

The third main type of drug-induced lupus is subacute cutaneous lupus erythematosus (SCLE), which also is associated with an ever-widening variety of agents, including the thiazide diuretics, antifungals, calcium channel blockers, and ACE inhibitors. There also have been reports involving statins, leflunomide, and tumor necrosis factor inhibitors.

Clinically, SCLE can be very difficult to sort out, according to Dr. Franks, with targetoid lesions mixed with papulosquamous or annular lesions. The presentation can also resemble erythema multiforme or toxic epidermal necrolysis, with disadhesion of the epidermal layer and sloughing of the skin, he said.

An audience member asked what happens when the offending drug is withdrawn. Dr. Franks explained that the situation is different than an allergic reaction. "It can sometimes take months for this to remit, and some patients require additional therapy, but 95% of patients ultimately do remit," he said at a rheumatology meeting sponsored by New York University.

No single unifying mechanism has been identified that can explain the variety of drugs associated with drug-induced lupus or the varied clinical and laboratory manifestations. Hypotheses include the possibility that the drugs can act as haptens or antigens that drive an immune response, or as immune system modulators that permit the development of self-directed responses (Semin. Arthritis Rheum. 2007 Dec. 31 [doi:10.1016/j.semarthrit.2007.10.001]).

Dr. Franks reported having no financial relationships to disclose. n

The likelihood of developing a lupus-like syndrome is elevated 8.5-fold with minocycline. DR. FRANKS

NEW YORK — The contemporary use of minocycline for acne and hydralazine for heart failure is expanding the spectrum of drug-induced lupus, and physicians need to be aware of this, as well as other types of drug-induced lupus.

Minocycline-induced lupus was first reported in the early 1990s, and more than 250 cases have now been reported to the World Health Organization. There is a 5:1 female-to-male predominance, and the clinical features include fever, morning stiffness, myalgias, polyarthralgias, and symmetric arthritis.

It is also characterized by large vessel vasculitis, and in more than 60% of patients, antineutrophil cytoplasmic antibodies are present and antihistone antibodies are not. This is in contrast to "classic" drug-induced lupus, in which antihistone antibodies are prominent.

Other autoantibodies also can be seen in minocycline-induced lupus, including antinuclear antibody (ANA) and anti-double-stranded DNA, according to Dr. Andrew G. Franks Jr.

"The likelihood of developing a lupuslike syndrome is elevated 8.5-fold with minocycline, so many clinicians are now moving away from using minocycline for acne and rosacea and switching to doxycycline, which really doesn't have this effect. I haven't used minocycline for 5 years," said Dr. Franks of the department of dermatology at New York University Medical Center, New York.

Hydralazine, which had fallen out of favor as an antihypertensive, has regained popularity as part of combination therapy for heart failure in African Americans following the benefits seen in the African-American Heart Failure Trial (N. Engl. J. Med. 2004;351:2049-57).

Younger physicians in particular might not be familiar with hydralazine's link to drug-induced lupus, Dr. Franks said.

Hydralazine is one of the five causes of classic drug-induced lupus, along with procainamide, isoniazid, quinidine, and phenytoin, but more than 100 drugs have been implicated, he said.

Classic drug-induced lupus is characterized by flulike symptoms and significant musculoskeletal involvement, with most patients being ANA and antihistone antibody positive. "In my opinion, patients starting hydralazine—or any drug in the big five, for that matter—should have a baseline test for ANA, although that is somewhat controversial," Dr. Franks said.

The third main type of drug-induced lupus is subacute cutaneous lupus erythematosus (SCLE), which also is associated with an ever-widening variety of agents, including the thiazide diuretics, antifungals, calcium channel blockers, and ACE inhibitors. There also have been reports involving statins, leflunomide, and tumor necrosis factor inhibitors.

Clinically, SCLE can be very difficult to sort out, according to Dr. Franks, with targetoid lesions mixed with papulosquamous or annular lesions. The presentation can also resemble erythema multiforme or toxic epidermal necrolysis, with disadhesion of the epidermal layer and sloughing of the skin, he said.

An audience member asked what happens when the offending drug is withdrawn. Dr. Franks explained that the situation is different than an allergic reaction. "It can sometimes take months for this to remit, and some patients require additional therapy, but 95% of patients ultimately do remit," he said at a rheumatology meeting sponsored by New York University.

No single unifying mechanism has been identified that can explain the variety of drugs associated with drug-induced lupus or the varied clinical and laboratory manifestations. Hypotheses include the possibility that the drugs can act as haptens or antigens that drive an immune response, or as immune system modulators that permit the development of self-directed responses (Semin. Arthritis Rheum. 2007 Dec. 31 [doi:10.1016/j.semarthrit.2007.10.001]).

Dr. Franks reported having no financial relationships to disclose. n

The likelihood of developing a lupus-like syndrome is elevated 8.5-fold with minocycline. DR. FRANKS

Manfred Kunz, MD

In recent years, DNA microarray technology has been used for the analysis of gene expression patterns in a variety of skin diseases, including malignant melanoma, psoriasis, lupus erythematosus, and systemic sclerosis. Many of the studies described herein confirmed earlier results on individual genes or functional groups of genes. However, a plethora of new candidate genes, gene patterns, and regulatory pathways have been identified. Major progresses were reached by the identification of a prognostic gene pattern in malignant melanoma, an immune signaling cluster in psoriasis, and a so-called interferon
signature in systemic lupus erythematosus. In future, interference with genes or regulatory pathways with the use of different RNA interference technologies or targeted therapy may not only underscore the functional significance of microarray data but also may open interesting therapeutic perspectives. Large-scale gene expression analyses may also help to design more individualized treatment approaches of cutaneous diseases.

*For a PDF of the full article, click on the link to the left of this introduction.

Manfred Kunz, MD

In recent years, DNA microarray technology has been used for the analysis of gene expression patterns in a variety of skin diseases, including malignant melanoma, psoriasis, lupus erythematosus, and systemic sclerosis. Many of the studies described herein confirmed earlier results on individual genes or functional groups of genes. However, a plethora of new candidate genes, gene patterns, and regulatory pathways have been identified. Major progresses were reached by the identification of a prognostic gene pattern in malignant melanoma, an immune signaling cluster in psoriasis, and a so-called interferon
signature in systemic lupus erythematosus. In future, interference with genes or regulatory pathways with the use of different RNA interference technologies or targeted therapy may not only underscore the functional significance of microarray data but also may open interesting therapeutic perspectives. Large-scale gene expression analyses may also help to design more individualized treatment approaches of cutaneous diseases.

*For a PDF of the full article, click on the link to the left of this introduction.

Manfred Kunz, MD

In recent years, DNA microarray technology has been used for the analysis of gene expression patterns in a variety of skin diseases, including malignant melanoma, psoriasis, lupus erythematosus, and systemic sclerosis. Many of the studies described herein confirmed earlier results on individual genes or functional groups of genes. However, a plethora of new candidate genes, gene patterns, and regulatory pathways have been identified. Major progresses were reached by the identification of a prognostic gene pattern in malignant melanoma, an immune signaling cluster in psoriasis, and a so-called interferon
signature in systemic lupus erythematosus. In future, interference with genes or regulatory pathways with the use of different RNA interference technologies or targeted therapy may not only underscore the functional significance of microarray data but also may open interesting therapeutic perspectives. Large-scale gene expression analyses may also help to design more individualized treatment approaches of cutaneous diseases.

*For a PDF of the full article, click on the link to the left of this introduction.

Mollie A. MacCormack, MD

Photodynamic therapy is a relatively new and rapidly evolving therapeutic option in dermatology. Photodynamic therapy is a relatively new and rapidly evolving therapeutic option in dermatology. Initially used for the treatment of actinic damage and nonmelanotic skin cancer, more recent work indicates efficacy in the treatment of a wide range of conditions, such as acne, infectious processes, cutaneous T-cell lymphoma, and photorejuvenation, among others. This article provides a comprehensive review of applications and outcomes that use topical photodynamic therapy in the treatment of dermatologic disease. Initially used for the treatment of actinic damage and nonmelanotic skin cancer, more recent work indicates efficacy in the treatment of a wide range of conditions, such as acne, infectious processes, cutaneous T-cell lymphoma, and photorejuvenation, among others. This article provides a comprehensive review of applications and outcomes that use topical photodynamic therapy in the treatment of dermatologic disease.

*For a PDF of the full article, click on the link to the left of this introduction.

Mollie A. MacCormack, MD

Photodynamic therapy is a relatively new and rapidly evolving therapeutic option in dermatology. Photodynamic therapy is a relatively new and rapidly evolving therapeutic option in dermatology. Initially used for the treatment of actinic damage and nonmelanotic skin cancer, more recent work indicates efficacy in the treatment of a wide range of conditions, such as acne, infectious processes, cutaneous T-cell lymphoma, and photorejuvenation, among others. This article provides a comprehensive review of applications and outcomes that use topical photodynamic therapy in the treatment of dermatologic disease. Initially used for the treatment of actinic damage and nonmelanotic skin cancer, more recent work indicates efficacy in the treatment of a wide range of conditions, such as acne, infectious processes, cutaneous T-cell lymphoma, and photorejuvenation, among others. This article provides a comprehensive review of applications and outcomes that use topical photodynamic therapy in the treatment of dermatologic disease.

*For a PDF of the full article, click on the link to the left of this introduction.

Mollie A. MacCormack, MD

Photodynamic therapy is a relatively new and rapidly evolving therapeutic option in dermatology. Photodynamic therapy is a relatively new and rapidly evolving therapeutic option in dermatology. Initially used for the treatment of actinic damage and nonmelanotic skin cancer, more recent work indicates efficacy in the treatment of a wide range of conditions, such as acne, infectious processes, cutaneous T-cell lymphoma, and photorejuvenation, among others. This article provides a comprehensive review of applications and outcomes that use topical photodynamic therapy in the treatment of dermatologic disease. Initially used for the treatment of actinic damage and nonmelanotic skin cancer, more recent work indicates efficacy in the treatment of a wide range of conditions, such as acne, infectious processes, cutaneous T-cell lymphoma, and photorejuvenation, among others. This article provides a comprehensive review of applications and outcomes that use topical photodynamic therapy in the treatment of dermatologic disease.

*For a PDF of the full article, click on the link to the left of this introduction.

SAN ANTONIO — A novel oral therapy with broad anti-inflammatory activity is showing promise for the treatment of moderate to severe plaque psoriasis, according to phase II study data presented at the annual meeting of the American Academy of Dermatology.

Apremilast (CC-10004, Celgene Corp.) is a phosphodiesterase type 4 inhibitor that has potent anti-inflammatory activity believed to result in part from inhibition of tumor necrosis factor-α and other proinflammatory mediators, including interleukin-2, interferon-α, leukotrienes, and nitric oxide synthase, Dr. Kim Papp of Probity Medical Research Inc., Waterloo, Ont., explained during a poster discussion session.

A group of 260 patients was enrolled in the randomized, controlled, 12-week trial, which compared once- and twice-daily 20-mg dosages of Apremilast with placebo. The study was supported by Celgene.

At week 12 of treatment, a significantly higher proportion of patients in the twice-daily treatment group achieved Psoriasis Activity and Severity Index-75 (PASI-75) scores, compared with the other groups (24% in the twice-daily treatment group versus 10% in the once-daily treatment and placebo groups). Similarly, PASI-50 scores were achieved by 57% of those in the twice-daily treatment group, 28% in the once-daily group, and 23% in the placebo group.

PASI-90 scores were achieved by 14% of patients in the twice-daily group, by 2% in the once-daily group, and by 6% in the placebo group, Dr. Papp said.

As for Dermatology Life Quality Index scores, the mean changes from baseline were 7 points among those treated twice daily, 5 points among those treated once daily, and 3 points among given placebo, he noted.

Patients in the treatment groups continued to show improvement over time, with the greatest mean percent reduction in PASI scores demonstrated at the final assessment at 12 weeks, he said.

Adverse events in the study were generally mild and were similar in all three groups. Fifty-four percent in the twice-daily treatment group, 68% in the once-daily group, and 60% in the placebo group reported at least one adverse event. Headache and nasopharyngitis were the most common adverse events in all three groups, followed by diarrhea, pruritus, fatigue, aggravated psoriasis, and nausea.

The participants in this phase II study were at least 18 years old, had a diagnosis of moderate to severe plaque psoriasis for at least 6 months prior to enrollment (but were otherwise in good health), had PASI scores of at least 10 and body surface area involvement of at least 10%, and were candidates for photo- or systemic therapy.

The findings demonstrate a favorable risk-benefit profile for Apremilast, Dr. Papp said.

"Current therapies are limited by toxicities or by lack of efficacy," he said, noting that very few available treatments are effective across the spectrum of psoriatic disease.

"We continue to seek novel and safe therapies for chronic plaque psoriasis … and this is the first [phosphodiesterase type 4 inhibitor] that has shown itself to be well tolerated, safe, and effective," he said.

SAN ANTONIO — A novel oral therapy with broad anti-inflammatory activity is showing promise for the treatment of moderate to severe plaque psoriasis, according to phase II study data presented at the annual meeting of the American Academy of Dermatology.

Apremilast (CC-10004, Celgene Corp.) is a phosphodiesterase type 4 inhibitor that has potent anti-inflammatory activity believed to result in part from inhibition of tumor necrosis factor-α and other proinflammatory mediators, including interleukin-2, interferon-α, leukotrienes, and nitric oxide synthase, Dr. Kim Papp of Probity Medical Research Inc., Waterloo, Ont., explained during a poster discussion session.

A group of 260 patients was enrolled in the randomized, controlled, 12-week trial, which compared once- and twice-daily 20-mg dosages of Apremilast with placebo. The study was supported by Celgene.

At week 12 of treatment, a significantly higher proportion of patients in the twice-daily treatment group achieved Psoriasis Activity and Severity Index-75 (PASI-75) scores, compared with the other groups (24% in the twice-daily treatment group versus 10% in the once-daily treatment and placebo groups). Similarly, PASI-50 scores were achieved by 57% of those in the twice-daily treatment group, 28% in the once-daily group, and 23% in the placebo group.

PASI-90 scores were achieved by 14% of patients in the twice-daily group, by 2% in the once-daily group, and by 6% in the placebo group, Dr. Papp said.

As for Dermatology Life Quality Index scores, the mean changes from baseline were 7 points among those treated twice daily, 5 points among those treated once daily, and 3 points among given placebo, he noted.

Patients in the treatment groups continued to show improvement over time, with the greatest mean percent reduction in PASI scores demonstrated at the final assessment at 12 weeks, he said.

Adverse events in the study were generally mild and were similar in all three groups. Fifty-four percent in the twice-daily treatment group, 68% in the once-daily group, and 60% in the placebo group reported at least one adverse event. Headache and nasopharyngitis were the most common adverse events in all three groups, followed by diarrhea, pruritus, fatigue, aggravated psoriasis, and nausea.

The participants in this phase II study were at least 18 years old, had a diagnosis of moderate to severe plaque psoriasis for at least 6 months prior to enrollment (but were otherwise in good health), had PASI scores of at least 10 and body surface area involvement of at least 10%, and were candidates for photo- or systemic therapy.

The findings demonstrate a favorable risk-benefit profile for Apremilast, Dr. Papp said.

"Current therapies are limited by toxicities or by lack of efficacy," he said, noting that very few available treatments are effective across the spectrum of psoriatic disease.

"We continue to seek novel and safe therapies for chronic plaque psoriasis … and this is the first [phosphodiesterase type 4 inhibitor] that has shown itself to be well tolerated, safe, and effective," he said.

SAN ANTONIO — A novel oral therapy with broad anti-inflammatory activity is showing promise for the treatment of moderate to severe plaque psoriasis, according to phase II study data presented at the annual meeting of the American Academy of Dermatology.

Apremilast (CC-10004, Celgene Corp.) is a phosphodiesterase type 4 inhibitor that has potent anti-inflammatory activity believed to result in part from inhibition of tumor necrosis factor-α and other proinflammatory mediators, including interleukin-2, interferon-α, leukotrienes, and nitric oxide synthase, Dr. Kim Papp of Probity Medical Research Inc., Waterloo, Ont., explained during a poster discussion session.

A group of 260 patients was enrolled in the randomized, controlled, 12-week trial, which compared once- and twice-daily 20-mg dosages of Apremilast with placebo. The study was supported by Celgene.

At week 12 of treatment, a significantly higher proportion of patients in the twice-daily treatment group achieved Psoriasis Activity and Severity Index-75 (PASI-75) scores, compared with the other groups (24% in the twice-daily treatment group versus 10% in the once-daily treatment and placebo groups). Similarly, PASI-50 scores were achieved by 57% of those in the twice-daily treatment group, 28% in the once-daily group, and 23% in the placebo group.

PASI-90 scores were achieved by 14% of patients in the twice-daily group, by 2% in the once-daily group, and by 6% in the placebo group, Dr. Papp said.

As for Dermatology Life Quality Index scores, the mean changes from baseline were 7 points among those treated twice daily, 5 points among those treated once daily, and 3 points among given placebo, he noted.

Patients in the treatment groups continued to show improvement over time, with the greatest mean percent reduction in PASI scores demonstrated at the final assessment at 12 weeks, he said.

Adverse events in the study were generally mild and were similar in all three groups. Fifty-four percent in the twice-daily treatment group, 68% in the once-daily group, and 60% in the placebo group reported at least one adverse event. Headache and nasopharyngitis were the most common adverse events in all three groups, followed by diarrhea, pruritus, fatigue, aggravated psoriasis, and nausea.

The participants in this phase II study were at least 18 years old, had a diagnosis of moderate to severe plaque psoriasis for at least 6 months prior to enrollment (but were otherwise in good health), had PASI scores of at least 10 and body surface area involvement of at least 10%, and were candidates for photo- or systemic therapy.

The findings demonstrate a favorable risk-benefit profile for Apremilast, Dr. Papp said.

"Current therapies are limited by toxicities or by lack of efficacy," he said, noting that very few available treatments are effective across the spectrum of psoriatic disease.

"We continue to seek novel and safe therapies for chronic plaque psoriasis … and this is the first [phosphodiesterase type 4 inhibitor] that has shown itself to be well tolerated, safe, and effective," he said.

ELSEVIER GLOBAL MEDICAL NEWS

ELSEVIER GLOBAL MEDICAL NEWS

ELSEVIER GLOBAL MEDICAL NEWS

Patients taking anti-tumor necrosis factor-? medications show somewhat impaired antibody response to influenza vaccination, but there is no decrease in the proportion of patients achieving a protective titer, according to the results of a recent study.

The study, by Dr. L.B.S. Gelinck of Leiden (the Netherlands) University Medical Center and colleagues, compared immunologic responses to the influenza vaccine in 64 patients taking anti-tumor necrosis factor-? (anti-TNF-?) medications for various autoimmune diseases with 48 patients with autoimmune diseases who were not taking those drugs. There were 18 healthy controls.

All three groups achieved about an 80% rate of protection to each of the three components of the vaccine (Ann. Rheum. Dis. 2007;[doi:10.1136/ard.2007.077552]).

Guidelines issued by the Centers for Disease Control and Prevention recommend annual vaccination for patients at risk of complications of influenza, including those who are treated with anti-TNF-? agents such as infliximab, etanercept, and adalimumab. On the other hand, findings from earlier studies on the effect of influenza vaccination on these patients were conflicting.

Patients with several autoimmune diseases were represented in the study, including those with gastroenterologic disease, rheumatoid arthritis, juvenile chronic arthritis, psoriatic arthritis, spondyloarthropathy, and inflammatory bowel disease. Their mean age was 49 years (range 18-85 years). Patients in the anti-TNF group had been using the agents for an average of 24 months, with a range of 0.5-78 months.

All study participants were vaccinated in the fall or winter of 2003 with a commercially available trivalent subunit influenza vaccine. Four weeks after vaccination, patients taking an anti-TNF-? agent had significantly lower geometric mean titers to two out of the three vaccine components, compared with patients not taking an anti-TNF-? agent and with healthy controls.

Nevertheless, more than 80% of the patients in each of the three groups achieved titers high enough to protect them against infection; there were no significant differences among the groups on this measure.

When tested separately, infliximab, etanercept, and adalimumab all had similar effects on the patients' response to vaccination.

None of the patients reported major side effects, and none experienced any deterioration in an underlying condition that was attributed to the influenza vaccine. About 20% of the patients in all groups reported minor side effects following immunization, such as local pain or tenderness at the vaccine injection site, but there were no significant differences among the groups. Similarly, about 14% of all patients experienced systemic reactions such as fever, myalgia, or headache during the 4 weeks after vaccination.

Patients taking anti-tumor necrosis factor-? medications show somewhat impaired antibody response to influenza vaccination, but there is no decrease in the proportion of patients achieving a protective titer, according to the results of a recent study.

The study, by Dr. L.B.S. Gelinck of Leiden (the Netherlands) University Medical Center and colleagues, compared immunologic responses to the influenza vaccine in 64 patients taking anti-tumor necrosis factor-? (anti-TNF-?) medications for various autoimmune diseases with 48 patients with autoimmune diseases who were not taking those drugs. There were 18 healthy controls.

All three groups achieved about an 80% rate of protection to each of the three components of the vaccine (Ann. Rheum. Dis. 2007;[doi:10.1136/ard.2007.077552]).

Guidelines issued by the Centers for Disease Control and Prevention recommend annual vaccination for patients at risk of complications of influenza, including those who are treated with anti-TNF-? agents such as infliximab, etanercept, and adalimumab. On the other hand, findings from earlier studies on the effect of influenza vaccination on these patients were conflicting.

Patients with several autoimmune diseases were represented in the study, including those with gastroenterologic disease, rheumatoid arthritis, juvenile chronic arthritis, psoriatic arthritis, spondyloarthropathy, and inflammatory bowel disease. Their mean age was 49 years (range 18-85 years). Patients in the anti-TNF group had been using the agents for an average of 24 months, with a range of 0.5-78 months.

All study participants were vaccinated in the fall or winter of 2003 with a commercially available trivalent subunit influenza vaccine. Four weeks after vaccination, patients taking an anti-TNF-? agent had significantly lower geometric mean titers to two out of the three vaccine components, compared with patients not taking an anti-TNF-? agent and with healthy controls.

Nevertheless, more than 80% of the patients in each of the three groups achieved titers high enough to protect them against infection; there were no significant differences among the groups on this measure.

When tested separately, infliximab, etanercept, and adalimumab all had similar effects on the patients' response to vaccination.

None of the patients reported major side effects, and none experienced any deterioration in an underlying condition that was attributed to the influenza vaccine. About 20% of the patients in all groups reported minor side effects following immunization, such as local pain or tenderness at the vaccine injection site, but there were no significant differences among the groups. Similarly, about 14% of all patients experienced systemic reactions such as fever, myalgia, or headache during the 4 weeks after vaccination.

Patients taking anti-tumor necrosis factor-? medications show somewhat impaired antibody response to influenza vaccination, but there is no decrease in the proportion of patients achieving a protective titer, according to the results of a recent study.

The study, by Dr. L.B.S. Gelinck of Leiden (the Netherlands) University Medical Center and colleagues, compared immunologic responses to the influenza vaccine in 64 patients taking anti-tumor necrosis factor-? (anti-TNF-?) medications for various autoimmune diseases with 48 patients with autoimmune diseases who were not taking those drugs. There were 18 healthy controls.

All three groups achieved about an 80% rate of protection to each of the three components of the vaccine (Ann. Rheum. Dis. 2007;[doi:10.1136/ard.2007.077552]).

Guidelines issued by the Centers for Disease Control and Prevention recommend annual vaccination for patients at risk of complications of influenza, including those who are treated with anti-TNF-? agents such as infliximab, etanercept, and adalimumab. On the other hand, findings from earlier studies on the effect of influenza vaccination on these patients were conflicting.

Patients with several autoimmune diseases were represented in the study, including those with gastroenterologic disease, rheumatoid arthritis, juvenile chronic arthritis, psoriatic arthritis, spondyloarthropathy, and inflammatory bowel disease. Their mean age was 49 years (range 18-85 years). Patients in the anti-TNF group had been using the agents for an average of 24 months, with a range of 0.5-78 months.

All study participants were vaccinated in the fall or winter of 2003 with a commercially available trivalent subunit influenza vaccine. Four weeks after vaccination, patients taking an anti-TNF-? agent had significantly lower geometric mean titers to two out of the three vaccine components, compared with patients not taking an anti-TNF-? agent and with healthy controls.

Nevertheless, more than 80% of the patients in each of the three groups achieved titers high enough to protect them against infection; there were no significant differences among the groups on this measure.

When tested separately, infliximab, etanercept, and adalimumab all had similar effects on the patients' response to vaccination.

None of the patients reported major side effects, and none experienced any deterioration in an underlying condition that was attributed to the influenza vaccine. About 20% of the patients in all groups reported minor side effects following immunization, such as local pain or tenderness at the vaccine injection site, but there were no significant differences among the groups. Similarly, about 14% of all patients experienced systemic reactions such as fever, myalgia, or headache during the 4 weeks after vaccination.

BIRMINGHAM, ENGLAND — A direct relationship between gadodiamide—a chelate used regularly to identify renal artery stenosis in patients who are potential transplant recipients—and the activation of fibroblasts in nephrogenic systemic fibrosis has been identified, Dr. Susie Mukherjee reported at the annual meeting of the British Association of Dermatologists.

The origin of nephrogenic systemic fibrosis (NSF) has long intrigued the radiologic, renal, and dermatologic worlds because of the paucity of cases, said Dr. Mukherjee. Although NSF was initially thought to be a cutaneous condition, two recent case reports have indicated that it is in fact systemic.

Dr. Mukherjee, a dermatologist at Glasgow University, and her colleagues examined the levels of hyaluronan and collagen—both key components of the extracellular matrix—of six female patients with end-stage renal failure and biopsy proven NSF. Their median duration of dialysis was 4.8 years and the mean time to developing NSF symptoms after receiving gadodiamide was 1 month.

The investigators obtained 20 mL of blood from the patients and compared the blood with that of controls. Punch biopsies were used to establish fibroblast activity.

Serum samples from the NSF patients stimulated up to a 7-fold increase in hyaluronan synthesis and a 3.3-fold increase in collagen; both increases were statistically significant when compared with control patient samples, she said. Histology samples showed thickened collagen bundles signified by strong alcian blue staining on slides, she said.

Dr. Mukherjee also found that it only takes tiny concentrations of gadolinium to stimulate hyaluronan synthesis by fibroblasts. Both 10-mmol/L and 1-mmol/L concentrations of gadolinium caused a 2.3-fold increase in hyaluronan synthesis, "which is still quite a small level compared to what patients are exposed to," she said. "So really from these simple in vitro experiments we can suggest that NSF lesional fibroblasts synthesize excess hyaluronan and collagen, which increases after prolonged exposure to gadodiamide," explained Dr. Mukherjee. "These are the first experiments to demonstrate a direct relation between gadodiamide and activation of fibroblasts."

Evidence for a link between NSF and gadolinium was first described in a case series of 13 patients, all of whom developed NSF after being exposed to gadolinium (J. Am. Soc. Nephrol. 2006;17:2359-62).

Early symptoms of NSF include swelling, pruritus, and muscle pain of the limbs. Later changes include flexion contractures and grossly thickened indurated skin.

Further work should assess the effect of gadolinium on circulating fibrocytes and their ability to migrate into skin, according to Dr. Mukherjee.

BIRMINGHAM, ENGLAND — A direct relationship between gadodiamide—a chelate used regularly to identify renal artery stenosis in patients who are potential transplant recipients—and the activation of fibroblasts in nephrogenic systemic fibrosis has been identified, Dr. Susie Mukherjee reported at the annual meeting of the British Association of Dermatologists.

The origin of nephrogenic systemic fibrosis (NSF) has long intrigued the radiologic, renal, and dermatologic worlds because of the paucity of cases, said Dr. Mukherjee. Although NSF was initially thought to be a cutaneous condition, two recent case reports have indicated that it is in fact systemic.

Dr. Mukherjee, a dermatologist at Glasgow University, and her colleagues examined the levels of hyaluronan and collagen—both key components of the extracellular matrix—of six female patients with end-stage renal failure and biopsy proven NSF. Their median duration of dialysis was 4.8 years and the mean time to developing NSF symptoms after receiving gadodiamide was 1 month.

The investigators obtained 20 mL of blood from the patients and compared the blood with that of controls. Punch biopsies were used to establish fibroblast activity.

Serum samples from the NSF patients stimulated up to a 7-fold increase in hyaluronan synthesis and a 3.3-fold increase in collagen; both increases were statistically significant when compared with control patient samples, she said. Histology samples showed thickened collagen bundles signified by strong alcian blue staining on slides, she said.

Dr. Mukherjee also found that it only takes tiny concentrations of gadolinium to stimulate hyaluronan synthesis by fibroblasts. Both 10-mmol/L and 1-mmol/L concentrations of gadolinium caused a 2.3-fold increase in hyaluronan synthesis, "which is still quite a small level compared to what patients are exposed to," she said. "So really from these simple in vitro experiments we can suggest that NSF lesional fibroblasts synthesize excess hyaluronan and collagen, which increases after prolonged exposure to gadodiamide," explained Dr. Mukherjee. "These are the first experiments to demonstrate a direct relation between gadodiamide and activation of fibroblasts."

Evidence for a link between NSF and gadolinium was first described in a case series of 13 patients, all of whom developed NSF after being exposed to gadolinium (J. Am. Soc. Nephrol. 2006;17:2359-62).

Early symptoms of NSF include swelling, pruritus, and muscle pain of the limbs. Later changes include flexion contractures and grossly thickened indurated skin.

Further work should assess the effect of gadolinium on circulating fibrocytes and their ability to migrate into skin, according to Dr. Mukherjee.

BIRMINGHAM, ENGLAND — A direct relationship between gadodiamide—a chelate used regularly to identify renal artery stenosis in patients who are potential transplant recipients—and the activation of fibroblasts in nephrogenic systemic fibrosis has been identified, Dr. Susie Mukherjee reported at the annual meeting of the British Association of Dermatologists.

The origin of nephrogenic systemic fibrosis (NSF) has long intrigued the radiologic, renal, and dermatologic worlds because of the paucity of cases, said Dr. Mukherjee. Although NSF was initially thought to be a cutaneous condition, two recent case reports have indicated that it is in fact systemic.

Dr. Mukherjee, a dermatologist at Glasgow University, and her colleagues examined the levels of hyaluronan and collagen—both key components of the extracellular matrix—of six female patients with end-stage renal failure and biopsy proven NSF. Their median duration of dialysis was 4.8 years and the mean time to developing NSF symptoms after receiving gadodiamide was 1 month.

The investigators obtained 20 mL of blood from the patients and compared the blood with that of controls. Punch biopsies were used to establish fibroblast activity.

Serum samples from the NSF patients stimulated up to a 7-fold increase in hyaluronan synthesis and a 3.3-fold increase in collagen; both increases were statistically significant when compared with control patient samples, she said. Histology samples showed thickened collagen bundles signified by strong alcian blue staining on slides, she said.

Dr. Mukherjee also found that it only takes tiny concentrations of gadolinium to stimulate hyaluronan synthesis by fibroblasts. Both 10-mmol/L and 1-mmol/L concentrations of gadolinium caused a 2.3-fold increase in hyaluronan synthesis, "which is still quite a small level compared to what patients are exposed to," she said. "So really from these simple in vitro experiments we can suggest that NSF lesional fibroblasts synthesize excess hyaluronan and collagen, which increases after prolonged exposure to gadodiamide," explained Dr. Mukherjee. "These are the first experiments to demonstrate a direct relation between gadodiamide and activation of fibroblasts."

Evidence for a link between NSF and gadolinium was first described in a case series of 13 patients, all of whom developed NSF after being exposed to gadolinium (J. Am. Soc. Nephrol. 2006;17:2359-62).

Early symptoms of NSF include swelling, pruritus, and muscle pain of the limbs. Later changes include flexion contractures and grossly thickened indurated skin.

Further work should assess the effect of gadolinium on circulating fibrocytes and their ability to migrate into skin, according to Dr. Mukherjee.

NEW YORK — Dr. Whitney A. High is into heavy metal and skin, but if you think he's a biker with a leather vest and a Black Sabbath tattoo, you've got it wrong.

Dr. High, of the University of Colorado, Denver, is a clean-cut young dermatopathologist with a soft spot for geology and physics, and his interests in heavy metal involve titanium and vanadium, not Metallica and Megadeath.

His unique set of interests—skin disease, metals, and physics—has landed him in the center of the growing controversy around gadolinium contrast agents and their role in nephrogenic systemic fibrosis.

Dr. High is part of an elite team of investigators trying to determine whether the gadolinium agents in MRI contrast media play a causative role in this devastating, largely untreatable skin disorder. Their answer could have major medicolegal and clinical implications.

Nephrogenic systemic fibrosis (NSF) is characterized by excessive fibrosis in the skin and other soft tissues that leads to disfigurement, tissue constriction, and in some cases, respiratory failure, ocular damage, and cardiac problems. It was first reported as "scleromyxedema-like disease" in renal dialysis patients in 1997. In the last decade, hundreds of cases have emerged worldwide, primarily, if not exclusively in people with end-stage renal disease (ESRD). Other than that, there were few clues as to what caused the distinctive skin and soft tissue changes.

"For a long time, we could not figure out what was going on," Dr. High said at the American Academy of Dermatology's Summer Academy 2007. The first break came in January 2006, when Austrian researchers described nine patients with ESRD, five of whom had developed NSF, with all five having undergone imaging procedures with gadolinium contrast agents. These five patients developed signs and symptoms consistent with the disorder within about 4 weeks of exposure to gadolinium-based contrast used in magnetic angiography.

Further damning evidence emerged late last summer, when Danish investigators reported that 13 of 13 ESRD patients with NSF had received gadodiamide, a commonly used gadolinium contrast agent. There were no other shared risk factors among the 13 cases.

Is there a gadolinium smoking gun in the tissues of NSF patients? That's the question Dr. High is seeking to answer.

"I had previously reported on a granulomatous reaction to titanium alloy in a patient with ear piercings. That's how people knew I was interested in metals and skin disorders, and that's why I got called in on this gadolinium issue," he said.

There are five gadolinium contrast agents currently in use around the world. The two most common are Magnevist (gadopentetate) and Omniscan (gadodiamide). Manufacturers of the products, already reeling from the Food and Drug Administration's recent issuance of a black box warning about the potential risk of NSF, are hoping that gadolinium will be judged an innocent victim of circumstance.

Malpractice lawyers, of course, hope for the opposite.

So far, the findings seem to be favoring the lawyers. Using a technique called energy dispersive spectroscopy (EDS), investigators are able to detect metals such as titanium, vanadium, and gadolinium in human tissues, said Dr. High. He has detected gadolinium in the skin of four of seven NSF patients he has studied (J. Am. Acad. Dermatol. 2007;56:21-6).

He stressed, however, that EDS is "a semiquantitative technique, not a mass-based technique, and it should not be used as such." EDS can tell whether certain metals are present in the tissue, but it cannot be used to determine how much is present, except in a relative type of way.

That type of determination requires a technique like mass spectrometry. This method, too, showed significantly elevated levels of gadolinium in all NSF patients of Dr. High's original series.

Dr. High and his colleagues have used mass spectrometry to analyze a range of different tissues. Infant foreskin samples, predictably, show no gadolinium. Multiple sclerosis patients without renal problems who had undergone semiannual MRIs showed no gadolinium. Tissue samples from Mohs surgery for skin cancer? Also clear, as were skin samples from ESRD patients who have not had gadolinium-based scans. ESRD patients who had undergone imaging with gadolinium contrast, however, did show traces of the metal albeit at much lower levels than the patients with NSF.

Circumstantial? Unlikely. "If you have gadolinium in your tissues, you got it from somewhere. There is no regularly encountered source of gadolinium in this form in nature. So unless you happen to be a gadolinium miner, you got it from a doctor," said Dr. High.

But Dr. High seems reluctant to pin blame for NSF exclusively on gadolinium contrast agents. Bear in mind that nearly all NSF patients have ESRD, meaning that their ability to filter and eliminate toxins such as metals is sorely impaired. "Renal failure patients are a toxic soup of metals—calcium, iron, zinc, copper, aluminum—all sorts of metals," Dr. High said, adding that he believes NSF results from "a collusion of coconspirators. Gadolinium alone may not be the only prerequisite exposure, and other metals may be involved in its deposition or in disease evolution." Only time will tell.

Case in point, the prevailing model for how gadolinium ends up in the skin involves a hypothetical process called "transmetallation," in which other metals, such as iron or calcium present in the tissue, knock the gadolinium off the chelator to which it is normally bound.

"Transmetallation is just a theory at this point. It hasn't yet been irrefutably proven to occur in the body. Electron microscopy cannot detect what a metal is bound to, but a special kind of subatomic particle accelerator can."

To that end, Dr. High will soon be the first dermatopathologist to gain access to such an instrument. By the time this article is published, he will have been engaged in particle accelerator experiments designed to prove whether gadolinium in tissue is no longer bound to its chelators, as the transmetallation theory suggests. "There will likely be other information coming out to show that other metals may contribute to gadolinium deposition and perhaps to NSF itself," he said.

Even if gadolinium is not the only cause of NSF, it certainly appears a strong trigger in susceptible individuals. Estimates indicate that 3%-5% of patients with ESRD may be at risk for NSF. It appears that, in addition to ESRD, predisposition to thrombosis and inflammation may be involved. The risk is also likely proportional to the number of scans a person receives during renal failure.

For those who develop the disorder, there's little physicians can do. "I see about 10-12 patients with NSF at the University of Colorado. We've tried everything—photopheresis, plasmapheresis, renal transplant. No single treatment works uniformly well for all patients. And there are no formal studies comparing modalities."

Dr. High predicted that the current controversy about gadolinium will prompt a surge of interest in "medical geology" and the study of how elemental metals affect human health. Currently, Dr. High is working on a rapid, noninvasive screening device to detect metals such as gadolinium in human tissue.

Gadolinium conglomerations in a fibrohistiocytic cell from the skin of an NSF patient are shown above. Courtesy Dr. Whitney A. High

NEW YORK — Dr. Whitney A. High is into heavy metal and skin, but if you think he's a biker with a leather vest and a Black Sabbath tattoo, you've got it wrong.

Dr. High, of the University of Colorado, Denver, is a clean-cut young dermatopathologist with a soft spot for geology and physics, and his interests in heavy metal involve titanium and vanadium, not Metallica and Megadeath.

His unique set of interests—skin disease, metals, and physics—has landed him in the center of the growing controversy around gadolinium contrast agents and their role in nephrogenic systemic fibrosis.

Dr. High is part of an elite team of investigators trying to determine whether the gadolinium agents in MRI contrast media play a causative role in this devastating, largely untreatable skin disorder. Their answer could have major medicolegal and clinical implications.

Nephrogenic systemic fibrosis (NSF) is characterized by excessive fibrosis in the skin and other soft tissues that leads to disfigurement, tissue constriction, and in some cases, respiratory failure, ocular damage, and cardiac problems. It was first reported as "scleromyxedema-like disease" in renal dialysis patients in 1997. In the last decade, hundreds of cases have emerged worldwide, primarily, if not exclusively in people with end-stage renal disease (ESRD). Other than that, there were few clues as to what caused the distinctive skin and soft tissue changes.

"For a long time, we could not figure out what was going on," Dr. High said at the American Academy of Dermatology's Summer Academy 2007. The first break came in January 2006, when Austrian researchers described nine patients with ESRD, five of whom had developed NSF, with all five having undergone imaging procedures with gadolinium contrast agents. These five patients developed signs and symptoms consistent with the disorder within about 4 weeks of exposure to gadolinium-based contrast used in magnetic angiography.

Further damning evidence emerged late last summer, when Danish investigators reported that 13 of 13 ESRD patients with NSF had received gadodiamide, a commonly used gadolinium contrast agent. There were no other shared risk factors among the 13 cases.

Is there a gadolinium smoking gun in the tissues of NSF patients? That's the question Dr. High is seeking to answer.

"I had previously reported on a granulomatous reaction to titanium alloy in a patient with ear piercings. That's how people knew I was interested in metals and skin disorders, and that's why I got called in on this gadolinium issue," he said.

There are five gadolinium contrast agents currently in use around the world. The two most common are Magnevist (gadopentetate) and Omniscan (gadodiamide). Manufacturers of the products, already reeling from the Food and Drug Administration's recent issuance of a black box warning about the potential risk of NSF, are hoping that gadolinium will be judged an innocent victim of circumstance.

Malpractice lawyers, of course, hope for the opposite.

So far, the findings seem to be favoring the lawyers. Using a technique called energy dispersive spectroscopy (EDS), investigators are able to detect metals such as titanium, vanadium, and gadolinium in human tissues, said Dr. High. He has detected gadolinium in the skin of four of seven NSF patients he has studied (J. Am. Acad. Dermatol. 2007;56:21-6).

He stressed, however, that EDS is "a semiquantitative technique, not a mass-based technique, and it should not be used as such." EDS can tell whether certain metals are present in the tissue, but it cannot be used to determine how much is present, except in a relative type of way.

That type of determination requires a technique like mass spectrometry. This method, too, showed significantly elevated levels of gadolinium in all NSF patients of Dr. High's original series.

Dr. High and his colleagues have used mass spectrometry to analyze a range of different tissues. Infant foreskin samples, predictably, show no gadolinium. Multiple sclerosis patients without renal problems who had undergone semiannual MRIs showed no gadolinium. Tissue samples from Mohs surgery for skin cancer? Also clear, as were skin samples from ESRD patients who have not had gadolinium-based scans. ESRD patients who had undergone imaging with gadolinium contrast, however, did show traces of the metal albeit at much lower levels than the patients with NSF.

Circumstantial? Unlikely. "If you have gadolinium in your tissues, you got it from somewhere. There is no regularly encountered source of gadolinium in this form in nature. So unless you happen to be a gadolinium miner, you got it from a doctor," said Dr. High.

But Dr. High seems reluctant to pin blame for NSF exclusively on gadolinium contrast agents. Bear in mind that nearly all NSF patients have ESRD, meaning that their ability to filter and eliminate toxins such as metals is sorely impaired. "Renal failure patients are a toxic soup of metals—calcium, iron, zinc, copper, aluminum—all sorts of metals," Dr. High said, adding that he believes NSF results from "a collusion of coconspirators. Gadolinium alone may not be the only prerequisite exposure, and other metals may be involved in its deposition or in disease evolution." Only time will tell.

Case in point, the prevailing model for how gadolinium ends up in the skin involves a hypothetical process called "transmetallation," in which other metals, such as iron or calcium present in the tissue, knock the gadolinium off the chelator to which it is normally bound.

"Transmetallation is just a theory at this point. It hasn't yet been irrefutably proven to occur in the body. Electron microscopy cannot detect what a metal is bound to, but a special kind of subatomic particle accelerator can."

To that end, Dr. High will soon be the first dermatopathologist to gain access to such an instrument. By the time this article is published, he will have been engaged in particle accelerator experiments designed to prove whether gadolinium in tissue is no longer bound to its chelators, as the transmetallation theory suggests. "There will likely be other information coming out to show that other metals may contribute to gadolinium deposition and perhaps to NSF itself," he said.

Even if gadolinium is not the only cause of NSF, it certainly appears a strong trigger in susceptible individuals. Estimates indicate that 3%-5% of patients with ESRD may be at risk for NSF. It appears that, in addition to ESRD, predisposition to thrombosis and inflammation may be involved. The risk is also likely proportional to the number of scans a person receives during renal failure.

For those who develop the disorder, there's little physicians can do. "I see about 10-12 patients with NSF at the University of Colorado. We've tried everything—photopheresis, plasmapheresis, renal transplant. No single treatment works uniformly well for all patients. And there are no formal studies comparing modalities."

Dr. High predicted that the current controversy about gadolinium will prompt a surge of interest in "medical geology" and the study of how elemental metals affect human health. Currently, Dr. High is working on a rapid, noninvasive screening device to detect metals such as gadolinium in human tissue.

Gadolinium conglomerations in a fibrohistiocytic cell from the skin of an NSF patient are shown above. Courtesy Dr. Whitney A. High

NEW YORK — Dr. Whitney A. High is into heavy metal and skin, but if you think he's a biker with a leather vest and a Black Sabbath tattoo, you've got it wrong.

Dr. High, of the University of Colorado, Denver, is a clean-cut young dermatopathologist with a soft spot for geology and physics, and his interests in heavy metal involve titanium and vanadium, not Metallica and Megadeath.

His unique set of interests—skin disease, metals, and physics—has landed him in the center of the growing controversy around gadolinium contrast agents and their role in nephrogenic systemic fibrosis.

Dr. High is part of an elite team of investigators trying to determine whether the gadolinium agents in MRI contrast media play a causative role in this devastating, largely untreatable skin disorder. Their answer could have major medicolegal and clinical implications.

Nephrogenic systemic fibrosis (NSF) is characterized by excessive fibrosis in the skin and other soft tissues that leads to disfigurement, tissue constriction, and in some cases, respiratory failure, ocular damage, and cardiac problems. It was first reported as "scleromyxedema-like disease" in renal dialysis patients in 1997. In the last decade, hundreds of cases have emerged worldwide, primarily, if not exclusively in people with end-stage renal disease (ESRD). Other than that, there were few clues as to what caused the distinctive skin and soft tissue changes.

"For a long time, we could not figure out what was going on," Dr. High said at the American Academy of Dermatology's Summer Academy 2007. The first break came in January 2006, when Austrian researchers described nine patients with ESRD, five of whom had developed NSF, with all five having undergone imaging procedures with gadolinium contrast agents. These five patients developed signs and symptoms consistent with the disorder within about 4 weeks of exposure to gadolinium-based contrast used in magnetic angiography.

Further damning evidence emerged late last summer, when Danish investigators reported that 13 of 13 ESRD patients with NSF had received gadodiamide, a commonly used gadolinium contrast agent. There were no other shared risk factors among the 13 cases.

Is there a gadolinium smoking gun in the tissues of NSF patients? That's the question Dr. High is seeking to answer.

"I had previously reported on a granulomatous reaction to titanium alloy in a patient with ear piercings. That's how people knew I was interested in metals and skin disorders, and that's why I got called in on this gadolinium issue," he said.

There are five gadolinium contrast agents currently in use around the world. The two most common are Magnevist (gadopentetate) and Omniscan (gadodiamide). Manufacturers of the products, already reeling from the Food and Drug Administration's recent issuance of a black box warning about the potential risk of NSF, are hoping that gadolinium will be judged an innocent victim of circumstance.

Malpractice lawyers, of course, hope for the opposite.

So far, the findings seem to be favoring the lawyers. Using a technique called energy dispersive spectroscopy (EDS), investigators are able to detect metals such as titanium, vanadium, and gadolinium in human tissues, said Dr. High. He has detected gadolinium in the skin of four of seven NSF patients he has studied (J. Am. Acad. Dermatol. 2007;56:21-6).

He stressed, however, that EDS is "a semiquantitative technique, not a mass-based technique, and it should not be used as such." EDS can tell whether certain metals are present in the tissue, but it cannot be used to determine how much is present, except in a relative type of way.

That type of determination requires a technique like mass spectrometry. This method, too, showed significantly elevated levels of gadolinium in all NSF patients of Dr. High's original series.

Dr. High and his colleagues have used mass spectrometry to analyze a range of different tissues. Infant foreskin samples, predictably, show no gadolinium. Multiple sclerosis patients without renal problems who had undergone semiannual MRIs showed no gadolinium. Tissue samples from Mohs surgery for skin cancer? Also clear, as were skin samples from ESRD patients who have not had gadolinium-based scans. ESRD patients who had undergone imaging with gadolinium contrast, however, did show traces of the metal albeit at much lower levels than the patients with NSF.

Circumstantial? Unlikely. "If you have gadolinium in your tissues, you got it from somewhere. There is no regularly encountered source of gadolinium in this form in nature. So unless you happen to be a gadolinium miner, you got it from a doctor," said Dr. High.

But Dr. High seems reluctant to pin blame for NSF exclusively on gadolinium contrast agents. Bear in mind that nearly all NSF patients have ESRD, meaning that their ability to filter and eliminate toxins such as metals is sorely impaired. "Renal failure patients are a toxic soup of metals—calcium, iron, zinc, copper, aluminum—all sorts of metals," Dr. High said, adding that he believes NSF results from "a collusion of coconspirators. Gadolinium alone may not be the only prerequisite exposure, and other metals may be involved in its deposition or in disease evolution." Only time will tell.

Case in point, the prevailing model for how gadolinium ends up in the skin involves a hypothetical process called "transmetallation," in which other metals, such as iron or calcium present in the tissue, knock the gadolinium off the chelator to which it is normally bound.

"Transmetallation is just a theory at this point. It hasn't yet been irrefutably proven to occur in the body. Electron microscopy cannot detect what a metal is bound to, but a special kind of subatomic particle accelerator can."

To that end, Dr. High will soon be the first dermatopathologist to gain access to such an instrument. By the time this article is published, he will have been engaged in particle accelerator experiments designed to prove whether gadolinium in tissue is no longer bound to its chelators, as the transmetallation theory suggests. "There will likely be other information coming out to show that other metals may contribute to gadolinium deposition and perhaps to NSF itself," he said.

Even if gadolinium is not the only cause of NSF, it certainly appears a strong trigger in susceptible individuals. Estimates indicate that 3%-5% of patients with ESRD may be at risk for NSF. It appears that, in addition to ESRD, predisposition to thrombosis and inflammation may be involved. The risk is also likely proportional to the number of scans a person receives during renal failure.

For those who develop the disorder, there's little physicians can do. "I see about 10-12 patients with NSF at the University of Colorado. We've tried everything—photopheresis, plasmapheresis, renal transplant. No single treatment works uniformly well for all patients. And there are no formal studies comparing modalities."

Dr. High predicted that the current controversy about gadolinium will prompt a surge of interest in "medical geology" and the study of how elemental metals affect human health. Currently, Dr. High is working on a rapid, noninvasive screening device to detect metals such as gadolinium in human tissue.

Gadolinium conglomerations in a fibrohistiocytic cell from the skin of an NSF patient are shown above. Courtesy Dr. Whitney A. High