Psoriasis Collection

Systemic sclerosis and scleroderma are characterized by inflammation and fibrosis of the skin, as well as by vascular abnormalities, visceral damage, and the production of autoantibodies.

Diagnosing the chronic connective tissue disease, which can present in both limited and diffuse forms, can be complicated by the fact that it shares clinical and/or histologic features with a number of "scleroderma mimics," according to Dr. Janet E. Pope.

As with systemic sclerosis, most of these sclerodermalike conditions present with hard skin and tissue fibrosis and should be included in the differential diagnosis, noted Dr. Pope. She offered insight into ways to distinguish sclerodermalike fibrosing skin disorders from systemic sclerosis.

Skin & Allergy News: What are some of the more common "mimics" of systemic sclerosis.

Dr. Pope: Systemic sclerosis can be confused with such sclerodermalike skin disorders as eosinophilic fasciitis (EF), morphea, scleromyxedema, and nephrogenic systemic fibrosis (NSF).

SAN: How can physicians differentiate these from systemic sclerosis?

Dr. Pope: Most of these conditions lack Raynaud's phenomenon, sclerodactyly, and nailfold capillary changes.

Eosinophilic fasciitis (also called Shulman's syndrome) is a rare, localized, fibrosing disorder of subcutaneous tissues. Unlike systemic sclerosis, the overlying skin in EF is flexible enough to be pinched because the pathological disturbance is subcutaneous. This condition is often associated with venous grooving.

Generalized morphea is characterized by cutaneous sclerosis plaques caused by excessive collagen deposition, which leads to thickening of the dermis and/or subcutaneous tissues. Three or more major anatomical regions are affected by plaques in generalized morphea. Studies have shown that morphea often resolves within 2-5 years, but deeper lesions may take longer to resolve and may be accompanied by more disability and damage, depending on where they are located (J. Rheumatol. 1997;24:73-80). Additionally, many patients with morphea have antinuclear antibody and rheumatoid factor autoantibodies.

Scleromyxedema (also called papular mucinosis) is a chronic connective tissue disorder in which mucin deposits cause the skin to become red and raised, and make the movement of affected areas difficult. It tends to involve the head and neck rather than the extremities, and in most cases the sclerodermiform plaques and lichenoid papules are associated with a monoclonal gammopathy.

Finally, nephrogenic systemic fibrosis is a systemic fibrosing condition that occurs in people with kidney disease. NSF affects the skin, muscles, heart, and kidneys. It is strongly associated with exposure to gadolinium-based contrast agents.

Unlike systemic sclerosis, NSF tends to spare the skin of the face, and there is no association with autoantibodies or inflammatory cells.

The predominant histopathologic features of NSF include fibrocytelike cells, histiocytes, dermal dendritic cells, scarlike fibrosis, mucin, edema, calcification, and ossification. Diagnosing NSF requires both histopathologic and clinical findings.

SAN: Have any risk factors for the various conditions been identified?

Dr. Pope: As noted, NSF develops in patients with kidney disease and exposure to gadolinium. Renal failure is a major risk factor. With morphea, many patients who develop the condition are more likely than those without it to have an additional autoimmune disease.

SAN: How are the various conditions treated?

Dr. Pope: Corticosteroids and often methotrexate are used to treat EF, and early, aggressive treatment can minimize damage associated with the disease. Morphea is usually self-limited, and there is no proven treatment, although anecdotal evidence suggests that morphea patients who are being treated with antimalarials often develop new lesions when the treatment is stopped. IV immunoglobulin has been used in scleromyxedema treatment with mixed results.

Finally, there is no single therapeutic agent that has been proved effective for NSF. Anecdotal evidence suggests that extracorporeal photopheresis can lead to some lessening of skin thickening as well as increased mobility. Agents such as pentoxifylline, sodium, thiosulfate, and imatinib mesylate might improve skin fibrosis, but prevention through avoidance of gadolinium exposure in at-risk patients is advocated.

Dr. Pope is an associate professor of medicine in the division of rheumatology at the University of Western Ontario and a rheumatologist at St. Joseph's Health Care, both in London, Ont. She reported having no financial conflicts of interest.

Systemic sclerosis and scleroderma are characterized by inflammation and fibrosis of the skin, as well as by vascular abnormalities, visceral damage, and the production of autoantibodies.

Diagnosing the chronic connective tissue disease, which can present in both limited and diffuse forms, can be complicated by the fact that it shares clinical and/or histologic features with a number of "scleroderma mimics," according to Dr. Janet E. Pope.

As with systemic sclerosis, most of these sclerodermalike conditions present with hard skin and tissue fibrosis and should be included in the differential diagnosis, noted Dr. Pope. She offered insight into ways to distinguish sclerodermalike fibrosing skin disorders from systemic sclerosis.

Skin & Allergy News: What are some of the more common "mimics" of systemic sclerosis.

Dr. Pope: Systemic sclerosis can be confused with such sclerodermalike skin disorders as eosinophilic fasciitis (EF), morphea, scleromyxedema, and nephrogenic systemic fibrosis (NSF).

SAN: How can physicians differentiate these from systemic sclerosis?

Dr. Pope: Most of these conditions lack Raynaud's phenomenon, sclerodactyly, and nailfold capillary changes.

Eosinophilic fasciitis (also called Shulman's syndrome) is a rare, localized, fibrosing disorder of subcutaneous tissues. Unlike systemic sclerosis, the overlying skin in EF is flexible enough to be pinched because the pathological disturbance is subcutaneous. This condition is often associated with venous grooving.

Generalized morphea is characterized by cutaneous sclerosis plaques caused by excessive collagen deposition, which leads to thickening of the dermis and/or subcutaneous tissues. Three or more major anatomical regions are affected by plaques in generalized morphea. Studies have shown that morphea often resolves within 2-5 years, but deeper lesions may take longer to resolve and may be accompanied by more disability and damage, depending on where they are located (J. Rheumatol. 1997;24:73-80). Additionally, many patients with morphea have antinuclear antibody and rheumatoid factor autoantibodies.

Scleromyxedema (also called papular mucinosis) is a chronic connective tissue disorder in which mucin deposits cause the skin to become red and raised, and make the movement of affected areas difficult. It tends to involve the head and neck rather than the extremities, and in most cases the sclerodermiform plaques and lichenoid papules are associated with a monoclonal gammopathy.

Finally, nephrogenic systemic fibrosis is a systemic fibrosing condition that occurs in people with kidney disease. NSF affects the skin, muscles, heart, and kidneys. It is strongly associated with exposure to gadolinium-based contrast agents.

Unlike systemic sclerosis, NSF tends to spare the skin of the face, and there is no association with autoantibodies or inflammatory cells.

The predominant histopathologic features of NSF include fibrocytelike cells, histiocytes, dermal dendritic cells, scarlike fibrosis, mucin, edema, calcification, and ossification. Diagnosing NSF requires both histopathologic and clinical findings.

SAN: Have any risk factors for the various conditions been identified?

Dr. Pope: As noted, NSF develops in patients with kidney disease and exposure to gadolinium. Renal failure is a major risk factor. With morphea, many patients who develop the condition are more likely than those without it to have an additional autoimmune disease.

SAN: How are the various conditions treated?

Dr. Pope: Corticosteroids and often methotrexate are used to treat EF, and early, aggressive treatment can minimize damage associated with the disease. Morphea is usually self-limited, and there is no proven treatment, although anecdotal evidence suggests that morphea patients who are being treated with antimalarials often develop new lesions when the treatment is stopped. IV immunoglobulin has been used in scleromyxedema treatment with mixed results.

Finally, there is no single therapeutic agent that has been proved effective for NSF. Anecdotal evidence suggests that extracorporeal photopheresis can lead to some lessening of skin thickening as well as increased mobility. Agents such as pentoxifylline, sodium, thiosulfate, and imatinib mesylate might improve skin fibrosis, but prevention through avoidance of gadolinium exposure in at-risk patients is advocated.

Dr. Pope is an associate professor of medicine in the division of rheumatology at the University of Western Ontario and a rheumatologist at St. Joseph's Health Care, both in London, Ont. She reported having no financial conflicts of interest.

Systemic sclerosis and scleroderma are characterized by inflammation and fibrosis of the skin, as well as by vascular abnormalities, visceral damage, and the production of autoantibodies.

Diagnosing the chronic connective tissue disease, which can present in both limited and diffuse forms, can be complicated by the fact that it shares clinical and/or histologic features with a number of "scleroderma mimics," according to Dr. Janet E. Pope.

As with systemic sclerosis, most of these sclerodermalike conditions present with hard skin and tissue fibrosis and should be included in the differential diagnosis, noted Dr. Pope. She offered insight into ways to distinguish sclerodermalike fibrosing skin disorders from systemic sclerosis.

Skin & Allergy News: What are some of the more common "mimics" of systemic sclerosis.

Dr. Pope: Systemic sclerosis can be confused with such sclerodermalike skin disorders as eosinophilic fasciitis (EF), morphea, scleromyxedema, and nephrogenic systemic fibrosis (NSF).

SAN: How can physicians differentiate these from systemic sclerosis?

Dr. Pope: Most of these conditions lack Raynaud's phenomenon, sclerodactyly, and nailfold capillary changes.

Eosinophilic fasciitis (also called Shulman's syndrome) is a rare, localized, fibrosing disorder of subcutaneous tissues. Unlike systemic sclerosis, the overlying skin in EF is flexible enough to be pinched because the pathological disturbance is subcutaneous. This condition is often associated with venous grooving.

Generalized morphea is characterized by cutaneous sclerosis plaques caused by excessive collagen deposition, which leads to thickening of the dermis and/or subcutaneous tissues. Three or more major anatomical regions are affected by plaques in generalized morphea. Studies have shown that morphea often resolves within 2-5 years, but deeper lesions may take longer to resolve and may be accompanied by more disability and damage, depending on where they are located (J. Rheumatol. 1997;24:73-80). Additionally, many patients with morphea have antinuclear antibody and rheumatoid factor autoantibodies.

Scleromyxedema (also called papular mucinosis) is a chronic connective tissue disorder in which mucin deposits cause the skin to become red and raised, and make the movement of affected areas difficult. It tends to involve the head and neck rather than the extremities, and in most cases the sclerodermiform plaques and lichenoid papules are associated with a monoclonal gammopathy.

Finally, nephrogenic systemic fibrosis is a systemic fibrosing condition that occurs in people with kidney disease. NSF affects the skin, muscles, heart, and kidneys. It is strongly associated with exposure to gadolinium-based contrast agents.

Unlike systemic sclerosis, NSF tends to spare the skin of the face, and there is no association with autoantibodies or inflammatory cells.

The predominant histopathologic features of NSF include fibrocytelike cells, histiocytes, dermal dendritic cells, scarlike fibrosis, mucin, edema, calcification, and ossification. Diagnosing NSF requires both histopathologic and clinical findings.

SAN: Have any risk factors for the various conditions been identified?

Dr. Pope: As noted, NSF develops in patients with kidney disease and exposure to gadolinium. Renal failure is a major risk factor. With morphea, many patients who develop the condition are more likely than those without it to have an additional autoimmune disease.

SAN: How are the various conditions treated?

Dr. Pope: Corticosteroids and often methotrexate are used to treat EF, and early, aggressive treatment can minimize damage associated with the disease. Morphea is usually self-limited, and there is no proven treatment, although anecdotal evidence suggests that morphea patients who are being treated with antimalarials often develop new lesions when the treatment is stopped. IV immunoglobulin has been used in scleromyxedema treatment with mixed results.

Finally, there is no single therapeutic agent that has been proved effective for NSF. Anecdotal evidence suggests that extracorporeal photopheresis can lead to some lessening of skin thickening as well as increased mobility. Agents such as pentoxifylline, sodium, thiosulfate, and imatinib mesylate might improve skin fibrosis, but prevention through avoidance of gadolinium exposure in at-risk patients is advocated.

Dr. Pope is an associate professor of medicine in the division of rheumatology at the University of Western Ontario and a rheumatologist at St. Joseph's Health Care, both in London, Ont. She reported having no financial conflicts of interest.

BRIGHTON, ENGLAND – The risk of cancer is almost 50% higher in people with rheumatoid arthritis who are treated with nonbiologic agents when compared to the general population, according to data just released from the British Society for Rheumatology Biologics Register.

Although the link between rheumatoid arthritis (RA) and malignancy has been previously identified – particularly with respect to a higher risk of non-Hodgkin’s lymphoma (NHL) – these new data from the British Society for Rheumatology Biologics Register (BSRBR) are from a more-contemporary population of patients who have been treated in the era of widespread use of methotrexate (MTX) and other nonbiologic disease-modifying antirheumatic drugs (DMARDs).

Dr. Eric L. Matteson, who is a professor of medicine at the division of rheumatology at the Mayo Clinic, Rochester, Minn., noted in an interview that the registry findings seem to indicate that overall cancer risk is increased in patients with RA and that this risk is similar in patients exposed to biologics and nonbiologics, with the exception that nonmelanoma skin cancer appears to be somewhat more frequent in the biologics treated patients.

"I think the conclusions arrived at are consistent with previous studies and so not surprising regarding nonbiologics, in particular, methotrexate. A study from Australia by Dr. Rachelle Buchbinder, for example, already reported in 2008 an almost identical finding of 50% increased risk of cancer in patients with RA treated with methotrexate."

There was an estimated 50% excess risk of malignancy among RA patients exposed to MTX relative to the general population (standardized incidence ratio, 1.5; 95% confidence interval, 1.2-1.9). In that study, the risk of non-Hodgkin’s lymphoma was more than five times higher in RA patients than in the general population (SIR, 5.1; 95% CI 2.2-10.0). Other cancers for which there was evidence of increased risk were lung cancer (SIR, 2.9; 95% CI 1.6-4.8) and melanoma (SIR, 3.0; 95% CI 1.2-6.2). (Arthritis Care Res. 2008;59:794-9).

Dr. Matteson qualified his remarks by noting that he did not hear the presentation and assumes methotrexate was the comparator drug.

In reporting the findings, Dr. Louise Mercer, a clinical research fellow at the Arthritis Research UK Epidemiology Unit, University of Manchester, England, where the BRSBR is coordinated, on April 13 at the British Society for Rheumatology Annual Conference (Rheumatology 2011;50:iii37-8, abstract OP18) noted that they set a baseline for analyzing the cancer risk of biologic therapy, compared with conventional RA therapy within the BSRBR patient population – the primary reason the register was set up 10 years ago.

The analysis included 3,727 RA patients treated with nonbiologic DMARDS who were enrolled in the register between 2002 and 2008. Data from the national cancer registry for England and Wales provided information about whether or not they developed cancer. SIRs were used to compare the observed vs. the expected number of cancers and were adjusted for age and gender.

Of 148 malignancies occurring in 10,447 patient-years, 128 were solid cancers – including melanoma, and lung, breast, and colorectal cancers – and 20 were hematologic – including NHL and Hodgkin’s lymphoma. The median time from enrollment in the register to cancer diagnosis was 1.3 years, with 52% of patients dying as a result of incident cancer.

The standardized incidence ratio for all cancers was 1.48. Looking at specific types of malignancy, the highest SIR was recorded for NHL, at 3.73, although the risk of lung cancer was also substantial, with a SIR of 2.71. The SIR for colorectal cancer was 0.96.

Considering these findings, "vigilance for cancer, especially lung cancer and lymphoma should be maintained," Dr. Mercer advised.

"Our experience is that all cancers were increased by about 48%, with quite a marked increase in NHL and lung cancer, said Dr. Deborah Symmons, during a separate presentation at the meeting. An interesting finding, she noted, was that any benefit of NSAID drugs used to treat RA in lowering the risk of colorectal cancer appeared to be "wearing off."

Dr. Symmons, also of the Arthritis Research UK Epidemiology Unit in Manchester and a principle investigator for the BSRBR, explained that this adds to the evidence that, "the cancer risk in our general rheumatoid population is increased for some cancers."

These data are of interest, as they will eventually be used to compare the cancer risk of biologic vs. nonbiologic DMARDs. Such analysis is unlikely to be undertaken any time soon, however, as it is planned to occur when 20,000 years of patient follow-up have been accumulated. To date, there has been no signal that an earlier analysis is warranted.

"In the [anti-TNF] clinical trials, most of which were less than a year [in duration] there was not an increase in cancer except for [nonmelanoma skin cancer]," Dr. Symmons observed. "The cancer risk in observational studies is not increased in the short term," she added, "but we still don’t know what the long-term risk might be."

Echoing her comments were the separate findings of a Wyeth-sponsored study presented as a poster at the meeting. Dr. Peter Taylor of the Kennedy Institute of Rheumatology in London and his associates looked at the risk of malignancy associated with TNF inhibitors in registries and prospective observational studies. They reported a pooled-risk estimate of 1.11 for lymphoma, 1.45 for nonmelanoma skin cancer, and 1.79 for melanoma comparing TNF-treated patients with nonexposed RA patients.

Dr. Taylor and his team said of their findings: "This systematic review and meta-analysis provide reassurance to physicians and patients that treatment of RA patients with TNF inhibitors does not increase the risk of malignancy in general, or of lymphoma in particular, but does appear to increase the risk of skin cancer, including melanoma."

The systemic review and meta-analysis was sponsored by Wyeth. Dr. Taylor has received research grants and honoraria from Abbott, Bristol-Myers Squibb, Pfizer, Roche, Schering-Plough, and UCB. The BSRBR is funded by a grant from the British Society for Rheumatology. The BSR receives funding from Abbott Laboratories, Biovitrum/SOBI, Merck Sharp & Dohme Ltd., Pfizer, Roche, and UCB. This income finances a separate contract between the BSR and the University of Manchester that provides and run the BSRBR. All decisions concerning data analysis, interpretation and publications are made autonomously of any industrial contribution.

Dr. Mercer, Dr. Symmons, and Dr. Matteson declared that they had no personal conflicts of interest.

BRIGHTON, ENGLAND – The risk of cancer is almost 50% higher in people with rheumatoid arthritis who are treated with nonbiologic agents when compared to the general population, according to data just released from the British Society for Rheumatology Biologics Register.

Although the link between rheumatoid arthritis (RA) and malignancy has been previously identified – particularly with respect to a higher risk of non-Hodgkin’s lymphoma (NHL) – these new data from the British Society for Rheumatology Biologics Register (BSRBR) are from a more-contemporary population of patients who have been treated in the era of widespread use of methotrexate (MTX) and other nonbiologic disease-modifying antirheumatic drugs (DMARDs).

Dr. Eric L. Matteson, who is a professor of medicine at the division of rheumatology at the Mayo Clinic, Rochester, Minn., noted in an interview that the registry findings seem to indicate that overall cancer risk is increased in patients with RA and that this risk is similar in patients exposed to biologics and nonbiologics, with the exception that nonmelanoma skin cancer appears to be somewhat more frequent in the biologics treated patients.

"I think the conclusions arrived at are consistent with previous studies and so not surprising regarding nonbiologics, in particular, methotrexate. A study from Australia by Dr. Rachelle Buchbinder, for example, already reported in 2008 an almost identical finding of 50% increased risk of cancer in patients with RA treated with methotrexate."

There was an estimated 50% excess risk of malignancy among RA patients exposed to MTX relative to the general population (standardized incidence ratio, 1.5; 95% confidence interval, 1.2-1.9). In that study, the risk of non-Hodgkin’s lymphoma was more than five times higher in RA patients than in the general population (SIR, 5.1; 95% CI 2.2-10.0). Other cancers for which there was evidence of increased risk were lung cancer (SIR, 2.9; 95% CI 1.6-4.8) and melanoma (SIR, 3.0; 95% CI 1.2-6.2). (Arthritis Care Res. 2008;59:794-9).

Dr. Matteson qualified his remarks by noting that he did not hear the presentation and assumes methotrexate was the comparator drug.

In reporting the findings, Dr. Louise Mercer, a clinical research fellow at the Arthritis Research UK Epidemiology Unit, University of Manchester, England, where the BRSBR is coordinated, on April 13 at the British Society for Rheumatology Annual Conference (Rheumatology 2011;50:iii37-8, abstract OP18) noted that they set a baseline for analyzing the cancer risk of biologic therapy, compared with conventional RA therapy within the BSRBR patient population – the primary reason the register was set up 10 years ago.

The analysis included 3,727 RA patients treated with nonbiologic DMARDS who were enrolled in the register between 2002 and 2008. Data from the national cancer registry for England and Wales provided information about whether or not they developed cancer. SIRs were used to compare the observed vs. the expected number of cancers and were adjusted for age and gender.

Of 148 malignancies occurring in 10,447 patient-years, 128 were solid cancers – including melanoma, and lung, breast, and colorectal cancers – and 20 were hematologic – including NHL and Hodgkin’s lymphoma. The median time from enrollment in the register to cancer diagnosis was 1.3 years, with 52% of patients dying as a result of incident cancer.

The standardized incidence ratio for all cancers was 1.48. Looking at specific types of malignancy, the highest SIR was recorded for NHL, at 3.73, although the risk of lung cancer was also substantial, with a SIR of 2.71. The SIR for colorectal cancer was 0.96.

Considering these findings, "vigilance for cancer, especially lung cancer and lymphoma should be maintained," Dr. Mercer advised.

"Our experience is that all cancers were increased by about 48%, with quite a marked increase in NHL and lung cancer, said Dr. Deborah Symmons, during a separate presentation at the meeting. An interesting finding, she noted, was that any benefit of NSAID drugs used to treat RA in lowering the risk of colorectal cancer appeared to be "wearing off."

Dr. Symmons, also of the Arthritis Research UK Epidemiology Unit in Manchester and a principle investigator for the BSRBR, explained that this adds to the evidence that, "the cancer risk in our general rheumatoid population is increased for some cancers."

These data are of interest, as they will eventually be used to compare the cancer risk of biologic vs. nonbiologic DMARDs. Such analysis is unlikely to be undertaken any time soon, however, as it is planned to occur when 20,000 years of patient follow-up have been accumulated. To date, there has been no signal that an earlier analysis is warranted.

"In the [anti-TNF] clinical trials, most of which were less than a year [in duration] there was not an increase in cancer except for [nonmelanoma skin cancer]," Dr. Symmons observed. "The cancer risk in observational studies is not increased in the short term," she added, "but we still don’t know what the long-term risk might be."

Echoing her comments were the separate findings of a Wyeth-sponsored study presented as a poster at the meeting. Dr. Peter Taylor of the Kennedy Institute of Rheumatology in London and his associates looked at the risk of malignancy associated with TNF inhibitors in registries and prospective observational studies. They reported a pooled-risk estimate of 1.11 for lymphoma, 1.45 for nonmelanoma skin cancer, and 1.79 for melanoma comparing TNF-treated patients with nonexposed RA patients.

Dr. Taylor and his team said of their findings: "This systematic review and meta-analysis provide reassurance to physicians and patients that treatment of RA patients with TNF inhibitors does not increase the risk of malignancy in general, or of lymphoma in particular, but does appear to increase the risk of skin cancer, including melanoma."

The systemic review and meta-analysis was sponsored by Wyeth. Dr. Taylor has received research grants and honoraria from Abbott, Bristol-Myers Squibb, Pfizer, Roche, Schering-Plough, and UCB. The BSRBR is funded by a grant from the British Society for Rheumatology. The BSR receives funding from Abbott Laboratories, Biovitrum/SOBI, Merck Sharp & Dohme Ltd., Pfizer, Roche, and UCB. This income finances a separate contract between the BSR and the University of Manchester that provides and run the BSRBR. All decisions concerning data analysis, interpretation and publications are made autonomously of any industrial contribution.

Dr. Mercer, Dr. Symmons, and Dr. Matteson declared that they had no personal conflicts of interest.

BRIGHTON, ENGLAND – The risk of cancer is almost 50% higher in people with rheumatoid arthritis who are treated with nonbiologic agents when compared to the general population, according to data just released from the British Society for Rheumatology Biologics Register.

Although the link between rheumatoid arthritis (RA) and malignancy has been previously identified – particularly with respect to a higher risk of non-Hodgkin’s lymphoma (NHL) – these new data from the British Society for Rheumatology Biologics Register (BSRBR) are from a more-contemporary population of patients who have been treated in the era of widespread use of methotrexate (MTX) and other nonbiologic disease-modifying antirheumatic drugs (DMARDs).

Dr. Eric L. Matteson, who is a professor of medicine at the division of rheumatology at the Mayo Clinic, Rochester, Minn., noted in an interview that the registry findings seem to indicate that overall cancer risk is increased in patients with RA and that this risk is similar in patients exposed to biologics and nonbiologics, with the exception that nonmelanoma skin cancer appears to be somewhat more frequent in the biologics treated patients.

"I think the conclusions arrived at are consistent with previous studies and so not surprising regarding nonbiologics, in particular, methotrexate. A study from Australia by Dr. Rachelle Buchbinder, for example, already reported in 2008 an almost identical finding of 50% increased risk of cancer in patients with RA treated with methotrexate."

There was an estimated 50% excess risk of malignancy among RA patients exposed to MTX relative to the general population (standardized incidence ratio, 1.5; 95% confidence interval, 1.2-1.9). In that study, the risk of non-Hodgkin’s lymphoma was more than five times higher in RA patients than in the general population (SIR, 5.1; 95% CI 2.2-10.0). Other cancers for which there was evidence of increased risk were lung cancer (SIR, 2.9; 95% CI 1.6-4.8) and melanoma (SIR, 3.0; 95% CI 1.2-6.2). (Arthritis Care Res. 2008;59:794-9).

Dr. Matteson qualified his remarks by noting that he did not hear the presentation and assumes methotrexate was the comparator drug.

In reporting the findings, Dr. Louise Mercer, a clinical research fellow at the Arthritis Research UK Epidemiology Unit, University of Manchester, England, where the BRSBR is coordinated, on April 13 at the British Society for Rheumatology Annual Conference (Rheumatology 2011;50:iii37-8, abstract OP18) noted that they set a baseline for analyzing the cancer risk of biologic therapy, compared with conventional RA therapy within the BSRBR patient population – the primary reason the register was set up 10 years ago.

The analysis included 3,727 RA patients treated with nonbiologic DMARDS who were enrolled in the register between 2002 and 2008. Data from the national cancer registry for England and Wales provided information about whether or not they developed cancer. SIRs were used to compare the observed vs. the expected number of cancers and were adjusted for age and gender.

Of 148 malignancies occurring in 10,447 patient-years, 128 were solid cancers – including melanoma, and lung, breast, and colorectal cancers – and 20 were hematologic – including NHL and Hodgkin’s lymphoma. The median time from enrollment in the register to cancer diagnosis was 1.3 years, with 52% of patients dying as a result of incident cancer.

The standardized incidence ratio for all cancers was 1.48. Looking at specific types of malignancy, the highest SIR was recorded for NHL, at 3.73, although the risk of lung cancer was also substantial, with a SIR of 2.71. The SIR for colorectal cancer was 0.96.

Considering these findings, "vigilance for cancer, especially lung cancer and lymphoma should be maintained," Dr. Mercer advised.

"Our experience is that all cancers were increased by about 48%, with quite a marked increase in NHL and lung cancer, said Dr. Deborah Symmons, during a separate presentation at the meeting. An interesting finding, she noted, was that any benefit of NSAID drugs used to treat RA in lowering the risk of colorectal cancer appeared to be "wearing off."

Dr. Symmons, also of the Arthritis Research UK Epidemiology Unit in Manchester and a principle investigator for the BSRBR, explained that this adds to the evidence that, "the cancer risk in our general rheumatoid population is increased for some cancers."

These data are of interest, as they will eventually be used to compare the cancer risk of biologic vs. nonbiologic DMARDs. Such analysis is unlikely to be undertaken any time soon, however, as it is planned to occur when 20,000 years of patient follow-up have been accumulated. To date, there has been no signal that an earlier analysis is warranted.

"In the [anti-TNF] clinical trials, most of which were less than a year [in duration] there was not an increase in cancer except for [nonmelanoma skin cancer]," Dr. Symmons observed. "The cancer risk in observational studies is not increased in the short term," she added, "but we still don’t know what the long-term risk might be."

Echoing her comments were the separate findings of a Wyeth-sponsored study presented as a poster at the meeting. Dr. Peter Taylor of the Kennedy Institute of Rheumatology in London and his associates looked at the risk of malignancy associated with TNF inhibitors in registries and prospective observational studies. They reported a pooled-risk estimate of 1.11 for lymphoma, 1.45 for nonmelanoma skin cancer, and 1.79 for melanoma comparing TNF-treated patients with nonexposed RA patients.

Dr. Taylor and his team said of their findings: "This systematic review and meta-analysis provide reassurance to physicians and patients that treatment of RA patients with TNF inhibitors does not increase the risk of malignancy in general, or of lymphoma in particular, but does appear to increase the risk of skin cancer, including melanoma."

The systemic review and meta-analysis was sponsored by Wyeth. Dr. Taylor has received research grants and honoraria from Abbott, Bristol-Myers Squibb, Pfizer, Roche, Schering-Plough, and UCB. The BSRBR is funded by a grant from the British Society for Rheumatology. The BSR receives funding from Abbott Laboratories, Biovitrum/SOBI, Merck Sharp & Dohme Ltd., Pfizer, Roche, and UCB. This income finances a separate contract between the BSR and the University of Manchester that provides and run the BSRBR. All decisions concerning data analysis, interpretation and publications are made autonomously of any industrial contribution.

Dr. Mercer, Dr. Symmons, and Dr. Matteson declared that they had no personal conflicts of interest.

BRIGHTON, ENGLAND – Survival from scleroderma is improving, but major organ-based complications are still a significant reason for premature death, according to the results of a long-term outcomes study that were presented at the annual meeting of the British Society for Rheumatology.

The 10-year survival rates were 81% for patients with limited cutaneous systemic sclerosis (SSc) and 70% for patients with diffuse cutaneous SSc (P = .006).

Survival was significantly reduced (39%) in those who developed major heart, lung, or kidney complications, compared with 71% for those who developed no complications at 15 years' follow-up (P less than .001).

"The 10-year survival is impressive when you consider that not so long ago, we had a 5-year morality approaching 50% in the worst cases. So clearly there has been overall progress in managing the disease," commented study investigator Dr. Christopher Denton.

"Although outcomes are improving, we're still dealing with a disease that has very high case-specific mortality," added Dr. Denton, who is a professor of experimental rheumatology at University College London and a consultant rheumatologist at the Royal Free Hospital, London.

"Around 60% of patients actually die as a direct consequence of their scleroderma, and this is mostly from cardiorespiratory complications of the disease," he added.

Almost 400 patients with scleroderma – of whom 252 (63.3%) had limited cutaneous SSc and 146 (36.7%) had diffuse cutaneous SSc – were studied from their diagnosis in 1995 to 1999 (Rheumatology [Oxford] 2011;50 [suppl. 3]:iii129-iii37, abstract 223). The percentage of men with diffuse cutaneous SSc vs. limited cutaneous SSc disease was higher (17.9% vs. 9.9%; P = .037) and the mean age of onset was 50 years for limited cutaneous SSc patients and 46 years for diffuse cutaneous SSc patients (P = .003).

An important point of the study was that the frequency and timing of the major complications of scleroderma have now been defined over a 10- to 15-year period. Complications of scleroderma can be life threatening, and include pulmonary arterial hypertension (PAH), pulmonary fibrosis, renal disease, and cardiac problems.

At the 10-year follow-up, the incidences of PAH in the limited cutaneous SSc and diffuse cutaneous SSc groups were similar (15% vs. 13%), with the earliest cases seen 2 years after diagnosis. Patients who developed this complication later in the course of their disease tended to have higher 5-year survival rates than did those who had PAH earlier (49% vs. 24%), but this did not reach statistical significance.

Clinically significant pulmonary fibrosis was identified in a higher percentage of patients with diffuse than with limited disease at 10 years (45% vs. 21%; P less than .001), with almost half of patients developing lung disease within the first 3 years, and more than three-quarters within the first 5 years.

Patients with diffuse cutaneous SSc were more likely than those with limited cutaneous SSc to experience renal crisis (12% vs. 4%) at 10 years, with the higher rates occurring in the first 3 years (10% vs. 3%). Similarly, cardiac disease was more common in diffuse cutaneous SSc than in limited cutaneous SSc patients early on (7% vs. 1% at 5 years; P less than .001), but remained unchanged at 10 years.

"Whereas the limited or diffuse distinction is very relevant in the first 5 years, after the 5 years it doesn’t really matter which type of scleroderma you've got; you have an equally high frequency of complications," Dr. Denton observed in an interview.

He added that this "is a treated cohort that received standard management, so I think it's very important to start to understand the timing and frequency of the major heart, lung, and kidney complications, so that you can really identify when in the course of the disease you should be particularly vigilant."

Dr. Denton disclosed financial relationships with Actelion, Aspreva, BioVitrum, Digna, Dyax, Encysive, Genzyme, GlaxoSmithKline, Medimmune, Pfizer, and Sanofi-Aventis.

BRIGHTON, ENGLAND – Survival from scleroderma is improving, but major organ-based complications are still a significant reason for premature death, according to the results of a long-term outcomes study that were presented at the annual meeting of the British Society for Rheumatology.

The 10-year survival rates were 81% for patients with limited cutaneous systemic sclerosis (SSc) and 70% for patients with diffuse cutaneous SSc (P = .006).

Survival was significantly reduced (39%) in those who developed major heart, lung, or kidney complications, compared with 71% for those who developed no complications at 15 years' follow-up (P less than .001).

"The 10-year survival is impressive when you consider that not so long ago, we had a 5-year morality approaching 50% in the worst cases. So clearly there has been overall progress in managing the disease," commented study investigator Dr. Christopher Denton.

"Although outcomes are improving, we're still dealing with a disease that has very high case-specific mortality," added Dr. Denton, who is a professor of experimental rheumatology at University College London and a consultant rheumatologist at the Royal Free Hospital, London.

"Around 60% of patients actually die as a direct consequence of their scleroderma, and this is mostly from cardiorespiratory complications of the disease," he added.

Almost 400 patients with scleroderma – of whom 252 (63.3%) had limited cutaneous SSc and 146 (36.7%) had diffuse cutaneous SSc – were studied from their diagnosis in 1995 to 1999 (Rheumatology [Oxford] 2011;50 [suppl. 3]:iii129-iii37, abstract 223). The percentage of men with diffuse cutaneous SSc vs. limited cutaneous SSc disease was higher (17.9% vs. 9.9%; P = .037) and the mean age of onset was 50 years for limited cutaneous SSc patients and 46 years for diffuse cutaneous SSc patients (P = .003).

An important point of the study was that the frequency and timing of the major complications of scleroderma have now been defined over a 10- to 15-year period. Complications of scleroderma can be life threatening, and include pulmonary arterial hypertension (PAH), pulmonary fibrosis, renal disease, and cardiac problems.

At the 10-year follow-up, the incidences of PAH in the limited cutaneous SSc and diffuse cutaneous SSc groups were similar (15% vs. 13%), with the earliest cases seen 2 years after diagnosis. Patients who developed this complication later in the course of their disease tended to have higher 5-year survival rates than did those who had PAH earlier (49% vs. 24%), but this did not reach statistical significance.

Clinically significant pulmonary fibrosis was identified in a higher percentage of patients with diffuse than with limited disease at 10 years (45% vs. 21%; P less than .001), with almost half of patients developing lung disease within the first 3 years, and more than three-quarters within the first 5 years.

Patients with diffuse cutaneous SSc were more likely than those with limited cutaneous SSc to experience renal crisis (12% vs. 4%) at 10 years, with the higher rates occurring in the first 3 years (10% vs. 3%). Similarly, cardiac disease was more common in diffuse cutaneous SSc than in limited cutaneous SSc patients early on (7% vs. 1% at 5 years; P less than .001), but remained unchanged at 10 years.

"Whereas the limited or diffuse distinction is very relevant in the first 5 years, after the 5 years it doesn’t really matter which type of scleroderma you've got; you have an equally high frequency of complications," Dr. Denton observed in an interview.

He added that this "is a treated cohort that received standard management, so I think it's very important to start to understand the timing and frequency of the major heart, lung, and kidney complications, so that you can really identify when in the course of the disease you should be particularly vigilant."

Dr. Denton disclosed financial relationships with Actelion, Aspreva, BioVitrum, Digna, Dyax, Encysive, Genzyme, GlaxoSmithKline, Medimmune, Pfizer, and Sanofi-Aventis.

BRIGHTON, ENGLAND – Survival from scleroderma is improving, but major organ-based complications are still a significant reason for premature death, according to the results of a long-term outcomes study that were presented at the annual meeting of the British Society for Rheumatology.

The 10-year survival rates were 81% for patients with limited cutaneous systemic sclerosis (SSc) and 70% for patients with diffuse cutaneous SSc (P = .006).

Survival was significantly reduced (39%) in those who developed major heart, lung, or kidney complications, compared with 71% for those who developed no complications at 15 years' follow-up (P less than .001).

"The 10-year survival is impressive when you consider that not so long ago, we had a 5-year morality approaching 50% in the worst cases. So clearly there has been overall progress in managing the disease," commented study investigator Dr. Christopher Denton.

"Although outcomes are improving, we're still dealing with a disease that has very high case-specific mortality," added Dr. Denton, who is a professor of experimental rheumatology at University College London and a consultant rheumatologist at the Royal Free Hospital, London.

"Around 60% of patients actually die as a direct consequence of their scleroderma, and this is mostly from cardiorespiratory complications of the disease," he added.

Almost 400 patients with scleroderma – of whom 252 (63.3%) had limited cutaneous SSc and 146 (36.7%) had diffuse cutaneous SSc – were studied from their diagnosis in 1995 to 1999 (Rheumatology [Oxford] 2011;50 [suppl. 3]:iii129-iii37, abstract 223). The percentage of men with diffuse cutaneous SSc vs. limited cutaneous SSc disease was higher (17.9% vs. 9.9%; P = .037) and the mean age of onset was 50 years for limited cutaneous SSc patients and 46 years for diffuse cutaneous SSc patients (P = .003).

An important point of the study was that the frequency and timing of the major complications of scleroderma have now been defined over a 10- to 15-year period. Complications of scleroderma can be life threatening, and include pulmonary arterial hypertension (PAH), pulmonary fibrosis, renal disease, and cardiac problems.

At the 10-year follow-up, the incidences of PAH in the limited cutaneous SSc and diffuse cutaneous SSc groups were similar (15% vs. 13%), with the earliest cases seen 2 years after diagnosis. Patients who developed this complication later in the course of their disease tended to have higher 5-year survival rates than did those who had PAH earlier (49% vs. 24%), but this did not reach statistical significance.

Clinically significant pulmonary fibrosis was identified in a higher percentage of patients with diffuse than with limited disease at 10 years (45% vs. 21%; P less than .001), with almost half of patients developing lung disease within the first 3 years, and more than three-quarters within the first 5 years.

Patients with diffuse cutaneous SSc were more likely than those with limited cutaneous SSc to experience renal crisis (12% vs. 4%) at 10 years, with the higher rates occurring in the first 3 years (10% vs. 3%). Similarly, cardiac disease was more common in diffuse cutaneous SSc than in limited cutaneous SSc patients early on (7% vs. 1% at 5 years; P less than .001), but remained unchanged at 10 years.

"Whereas the limited or diffuse distinction is very relevant in the first 5 years, after the 5 years it doesn’t really matter which type of scleroderma you've got; you have an equally high frequency of complications," Dr. Denton observed in an interview.

He added that this "is a treated cohort that received standard management, so I think it's very important to start to understand the timing and frequency of the major heart, lung, and kidney complications, so that you can really identify when in the course of the disease you should be particularly vigilant."

Dr. Denton disclosed financial relationships with Actelion, Aspreva, BioVitrum, Digna, Dyax, Encysive, Genzyme, GlaxoSmithKline, Medimmune, Pfizer, and Sanofi-Aventis.

SNOWMASS, COLO. – Cardiac abnormalities were detected by magnetic resonance imaging in three-quarters of an unselected consecutive series of systemic sclerosis patients, underscoring the impressive frequency of heart involvement in this collagen vascular disease.

"The heart is something we often forget in scleroderma. The heart disease is underestimated," Dr. Fredrick M. Wigley said at the symposium sponsored by the American College of Rheumatology.

The hallmark of cardiac involvement in systemic sclerosis (SSc) is fibrosis and inflammation. Cardiac MRI is unequalled at visualizing these features, he said.

"You can see fibrosis of the myocardium, pericardium, coronary circulation, and conduction system. Arrhythmias are common. Coronary vasospasm is thought to occur, particularly with cold conduction – the so-called Raynaud's of the heart – leading to ischemic reperfusion injury and fibrosis of the heart," said Dr. Wigley, professor of medicine and director of the scleroderma center at Johns Hopkins University, Baltimore.

A resting tachycardia in patients with systemic sclerosis is a common clinical manifestation of cardiac involvement. Clinically evident heart disease carries an unfavorable prognosis, as do cardiac abnormalities detected via right heart catheterization or other invasive methods. The prognostic significance of asymptomatic abnormalities that are detected only on cardiac MRI and that are not evident at the bedside remains to be established. The noninvasive imaging technique has only recently been applied in systemic sclerosis.

Scleroderma patients at greatest risk for clinically severe cardiac involvement are those with myopathy and rapidly progressing skin disease.

Dr. Wigley highlighted a recent study by investigators at Lille 2 (France) University that effectively demonstrated the power of cardiac MRI in detecting heart involvement in SSc. The French investigators examined 52 consecutive unselected scleroderma patients with both Doppler echocardiography and cardiac MRI. One or more cardiac abnormalities were found on cardiac MRI in 75% of the patients, while Doppler detected the abnormalities in only 48% of the patients.

Moreover, only cardiac MRI permitted precise analysis of the patterns of cardiac involvement in SSc, as it was able to distinguish between the fibrotic, inflammatory, and microvascular components. Interestingly, patients with limited cutaneous SSc had cardiac MRI abnormalities that were similar to those with diffuse cutaneous disease.

Seven of the 40 patients without pulmonary arterial hypertension were found to have right ventricular dilation on cardiac MRI, underscoring the point that right ventricular dilation is not specific for this common respiratory manifestation of SSc.

Study participants had a mean 11.2-year disease history since developing Raynaud’s phenomenon. The longer a patient’s disease duration, the greater the number of cardiac segments with kinetic abnormalities and delayed contrast enhancement on MRI (Ann. Rheum. Dis. 2009;68:1878-84).

Dr. Wigley said that while to date no therapy has been shown to alter the natural course of cardiac disease in patients with scleroderma, French investigators strongly believe calcium channel blockers are cardioprotective, and they have documented increased myocardial perfusion in nifedipine-treated SSc patients.

He said that he receives consulting fees and/or research grants from Actelion, Amira, Kinemed, Medimmune, Novartis, Orion, Pfizer, and United Therapeutics.

SNOWMASS, COLO. – Cardiac abnormalities were detected by magnetic resonance imaging in three-quarters of an unselected consecutive series of systemic sclerosis patients, underscoring the impressive frequency of heart involvement in this collagen vascular disease.

"The heart is something we often forget in scleroderma. The heart disease is underestimated," Dr. Fredrick M. Wigley said at the symposium sponsored by the American College of Rheumatology.

The hallmark of cardiac involvement in systemic sclerosis (SSc) is fibrosis and inflammation. Cardiac MRI is unequalled at visualizing these features, he said.

"You can see fibrosis of the myocardium, pericardium, coronary circulation, and conduction system. Arrhythmias are common. Coronary vasospasm is thought to occur, particularly with cold conduction – the so-called Raynaud's of the heart – leading to ischemic reperfusion injury and fibrosis of the heart," said Dr. Wigley, professor of medicine and director of the scleroderma center at Johns Hopkins University, Baltimore.

A resting tachycardia in patients with systemic sclerosis is a common clinical manifestation of cardiac involvement. Clinically evident heart disease carries an unfavorable prognosis, as do cardiac abnormalities detected via right heart catheterization or other invasive methods. The prognostic significance of asymptomatic abnormalities that are detected only on cardiac MRI and that are not evident at the bedside remains to be established. The noninvasive imaging technique has only recently been applied in systemic sclerosis.

Scleroderma patients at greatest risk for clinically severe cardiac involvement are those with myopathy and rapidly progressing skin disease.

Dr. Wigley highlighted a recent study by investigators at Lille 2 (France) University that effectively demonstrated the power of cardiac MRI in detecting heart involvement in SSc. The French investigators examined 52 consecutive unselected scleroderma patients with both Doppler echocardiography and cardiac MRI. One or more cardiac abnormalities were found on cardiac MRI in 75% of the patients, while Doppler detected the abnormalities in only 48% of the patients.

Moreover, only cardiac MRI permitted precise analysis of the patterns of cardiac involvement in SSc, as it was able to distinguish between the fibrotic, inflammatory, and microvascular components. Interestingly, patients with limited cutaneous SSc had cardiac MRI abnormalities that were similar to those with diffuse cutaneous disease.

Seven of the 40 patients without pulmonary arterial hypertension were found to have right ventricular dilation on cardiac MRI, underscoring the point that right ventricular dilation is not specific for this common respiratory manifestation of SSc.

Study participants had a mean 11.2-year disease history since developing Raynaud’s phenomenon. The longer a patient’s disease duration, the greater the number of cardiac segments with kinetic abnormalities and delayed contrast enhancement on MRI (Ann. Rheum. Dis. 2009;68:1878-84).

Dr. Wigley said that while to date no therapy has been shown to alter the natural course of cardiac disease in patients with scleroderma, French investigators strongly believe calcium channel blockers are cardioprotective, and they have documented increased myocardial perfusion in nifedipine-treated SSc patients.

He said that he receives consulting fees and/or research grants from Actelion, Amira, Kinemed, Medimmune, Novartis, Orion, Pfizer, and United Therapeutics.

SNOWMASS, COLO. – Cardiac abnormalities were detected by magnetic resonance imaging in three-quarters of an unselected consecutive series of systemic sclerosis patients, underscoring the impressive frequency of heart involvement in this collagen vascular disease.

"The heart is something we often forget in scleroderma. The heart disease is underestimated," Dr. Fredrick M. Wigley said at the symposium sponsored by the American College of Rheumatology.

The hallmark of cardiac involvement in systemic sclerosis (SSc) is fibrosis and inflammation. Cardiac MRI is unequalled at visualizing these features, he said.

"You can see fibrosis of the myocardium, pericardium, coronary circulation, and conduction system. Arrhythmias are common. Coronary vasospasm is thought to occur, particularly with cold conduction – the so-called Raynaud's of the heart – leading to ischemic reperfusion injury and fibrosis of the heart," said Dr. Wigley, professor of medicine and director of the scleroderma center at Johns Hopkins University, Baltimore.

A resting tachycardia in patients with systemic sclerosis is a common clinical manifestation of cardiac involvement. Clinically evident heart disease carries an unfavorable prognosis, as do cardiac abnormalities detected via right heart catheterization or other invasive methods. The prognostic significance of asymptomatic abnormalities that are detected only on cardiac MRI and that are not evident at the bedside remains to be established. The noninvasive imaging technique has only recently been applied in systemic sclerosis.

Scleroderma patients at greatest risk for clinically severe cardiac involvement are those with myopathy and rapidly progressing skin disease.

Dr. Wigley highlighted a recent study by investigators at Lille 2 (France) University that effectively demonstrated the power of cardiac MRI in detecting heart involvement in SSc. The French investigators examined 52 consecutive unselected scleroderma patients with both Doppler echocardiography and cardiac MRI. One or more cardiac abnormalities were found on cardiac MRI in 75% of the patients, while Doppler detected the abnormalities in only 48% of the patients.

Moreover, only cardiac MRI permitted precise analysis of the patterns of cardiac involvement in SSc, as it was able to distinguish between the fibrotic, inflammatory, and microvascular components. Interestingly, patients with limited cutaneous SSc had cardiac MRI abnormalities that were similar to those with diffuse cutaneous disease.

Seven of the 40 patients without pulmonary arterial hypertension were found to have right ventricular dilation on cardiac MRI, underscoring the point that right ventricular dilation is not specific for this common respiratory manifestation of SSc.

Study participants had a mean 11.2-year disease history since developing Raynaud’s phenomenon. The longer a patient’s disease duration, the greater the number of cardiac segments with kinetic abnormalities and delayed contrast enhancement on MRI (Ann. Rheum. Dis. 2009;68:1878-84).

Dr. Wigley said that while to date no therapy has been shown to alter the natural course of cardiac disease in patients with scleroderma, French investigators strongly believe calcium channel blockers are cardioprotective, and they have documented increased myocardial perfusion in nifedipine-treated SSc patients.

He said that he receives consulting fees and/or research grants from Actelion, Amira, Kinemed, Medimmune, Novartis, Orion, Pfizer, and United Therapeutics.

NEW ORLEANS – Patients with severe psoriasis face a 6% higher 10-year risk for a cardiovascular event than do comparable people without psoriasis, according to the findings of a prospective cohort study of nearly 18,000 people.

This added cardiovascular risk can have substantial implications, as it can move psoriasis patients into a higher Framingham Risk Score category and shift the way physicians need to think about cardiovascular risk management of these patients, Dr. Nehal N. Mehta said at the annual meeting of the American College of Cardiology.

In his practice that focuses on adults with psoriasis, the average background Framingham Risk Score based on low density lipoprotein cholesterol is a 7% 10-year risk for having a cardiovascular event, a level defined as low risk. However, adding the 6% additional risk linked with their psoriasis results in many patients having a 10-year risk of 13% or higher, placing them in the intermediate risk category (generally defined as a 10%-20% risk of having a cardiovascular event).

Patients at that intermediate risk category usually have more stringent targets for lipid levels, blood pressure, and weight although, in this context, it's unclear whether patients who leap into a higher cardiovascular risk level because of their psoriasis require more aggressive medical management; cardiovascular risk management guidelines have yet to elucidate optimal management for this patient subgroup.

Dr. Mehta deals with this dilemma by implementing aggressive lifestyle interventions for these patients, and also by suggesting naturally occurring risk-reduction interventions, such as the consumption of fiber, red yeast rice, soy, phytoestrogens, fish oil, and niacin.

If, after all these interventions, a patient's low density lipoprotein cholesterol or blood pressure remains at a questionably high level, he discusses the option of starting treatment with a statin or an antihypertensive medication, making clear that these steps have not yet been endorsed by most society management guidelines.

"Ultimately, about 5% of my psoriasis patients end up on a statin," said Dr. Mehta, a cardiologist and director of the inflammatory risk clinic in preventive cardiology at the University of Pennsylvania, Philadelphia.

Dr. Mehta and his associates derived an estimate of cardiovascular disease risk attributable to psoriasis by reviewing follow-up data maintained on 3,603 patients with severe psoriasis and 14,330 control participants without psoriasis enrolled in the General Practice Research Database, a collection of records from more than 5 million people seen by U.K. general practice physicians.

The researchers identified cases of severe psoriasis based on their receiving systemic therapy or phototherapy and excluded people with a prior history of cardiovascular events. The average age of all the people in the analysis was about 50 years and, on average, people were followed for about 3 years.

In a multivariable analysis that controlled for diabetes, hypertension, hyperlipidemia, age, gender, body mass index, and smoking status, the risk for a myocardial infarction, stroke, or death from a cardiovascular cause was 53% higher among the psoriasis patients, compared with the controls, a statistically significant difference. This higher cardiovascular risk among patients with psoriasis matched the 50% increased risk proposed last year for patients with rheumatoid arthritis and other forms of inflammatory arthritis including psoriatic arthritis, according to a panel convened by the European League Against Rheumatism (Ann. Rheum. Dis. 2010;69:325-31).

To translate the 1.53 relative risk into an attributable risk, Dr. Mehta and his associates multiplied that factor against the background cardiovascular risk for someone in the general population of the study to derive an adjusted risk. They then subtracted the background risk from the adjusted risk. Over a 10-year period, this translated into an excess risk for a cardiovascular event of 6.2%.

To illustrate the potential impact of this estimate, the researchers then applied this to a consecutive sample of 103 psoriasis patients seen in Dr. Mehta's psoriasis clinic at the Penn Heart and Vascular Center, including nine patients with psoriatic arthritis.

The baseline risk for these men and women averaged 7.3%, a low-risk level, but with the additional 6.2% risk added their functional risk jumped to an average of 13.5%, or to the intermediate-risk level. For individual patients, this signaled a substantial shift in their Framingham Risk Score risk level. Dr. Mehta conceded that the risk adjustment he applied derived from patients with severe psoriasis, while only 10% of patients in his practice have severe disease. About 60% have mild psoriasis, and about 30% have moderately severe disease, he said.

"This is the best we can do" for the time being, he said. "We applied the severe psoriasis metric to everyone to get a hazard estimate. We believe this is better than just multiplying" to recalculate a person's risk, the approach suggested by the EULAR committee.

He hopes that a larger, prospective study he has begun in collaboration with Dr. Joel M. Gelfand, a dermatologist at the University of Pennsylvania and the senior investigator for this work, will eventually provide a more nuanced risk adjustment for all levels of psoriasis severity. But he said that the current estimate of the increased risk will help persuade psoriasis patients to adopt healthier lifestyles. Patients with psoriasis, at all severity levels, tend to have relatively high rates of obesity, smoking, diabetes, hypertension, and inactivity.

Dr. Mehta added that better medical control of psoriasis also might help blunt the increased cardiovascular risk.

"Psoriasis and atherosclerosis are both T-cell mediated diseases," he observed. Most likely what goes on in the skin -to form the psoriasis plaques - also is going on inside patients' blood vessels, he said.

Dr. Mehta said that he had no disclosures. 

NEW ORLEANS – Patients with severe psoriasis face a 6% higher 10-year risk for a cardiovascular event than do comparable people without psoriasis, according to the findings of a prospective cohort study of nearly 18,000 people.

This added cardiovascular risk can have substantial implications, as it can move psoriasis patients into a higher Framingham Risk Score category and shift the way physicians need to think about cardiovascular risk management of these patients, Dr. Nehal N. Mehta said at the annual meeting of the American College of Cardiology.

In his practice that focuses on adults with psoriasis, the average background Framingham Risk Score based on low density lipoprotein cholesterol is a 7% 10-year risk for having a cardiovascular event, a level defined as low risk. However, adding the 6% additional risk linked with their psoriasis results in many patients having a 10-year risk of 13% or higher, placing them in the intermediate risk category (generally defined as a 10%-20% risk of having a cardiovascular event).

Patients at that intermediate risk category usually have more stringent targets for lipid levels, blood pressure, and weight although, in this context, it's unclear whether patients who leap into a higher cardiovascular risk level because of their psoriasis require more aggressive medical management; cardiovascular risk management guidelines have yet to elucidate optimal management for this patient subgroup.

Dr. Mehta deals with this dilemma by implementing aggressive lifestyle interventions for these patients, and also by suggesting naturally occurring risk-reduction interventions, such as the consumption of fiber, red yeast rice, soy, phytoestrogens, fish oil, and niacin.

If, after all these interventions, a patient's low density lipoprotein cholesterol or blood pressure remains at a questionably high level, he discusses the option of starting treatment with a statin or an antihypertensive medication, making clear that these steps have not yet been endorsed by most society management guidelines.

"Ultimately, about 5% of my psoriasis patients end up on a statin," said Dr. Mehta, a cardiologist and director of the inflammatory risk clinic in preventive cardiology at the University of Pennsylvania, Philadelphia.

Dr. Mehta and his associates derived an estimate of cardiovascular disease risk attributable to psoriasis by reviewing follow-up data maintained on 3,603 patients with severe psoriasis and 14,330 control participants without psoriasis enrolled in the General Practice Research Database, a collection of records from more than 5 million people seen by U.K. general practice physicians.

The researchers identified cases of severe psoriasis based on their receiving systemic therapy or phototherapy and excluded people with a prior history of cardiovascular events. The average age of all the people in the analysis was about 50 years and, on average, people were followed for about 3 years.

In a multivariable analysis that controlled for diabetes, hypertension, hyperlipidemia, age, gender, body mass index, and smoking status, the risk for a myocardial infarction, stroke, or death from a cardiovascular cause was 53% higher among the psoriasis patients, compared with the controls, a statistically significant difference. This higher cardiovascular risk among patients with psoriasis matched the 50% increased risk proposed last year for patients with rheumatoid arthritis and other forms of inflammatory arthritis including psoriatic arthritis, according to a panel convened by the European League Against Rheumatism (Ann. Rheum. Dis. 2010;69:325-31).

To translate the 1.53 relative risk into an attributable risk, Dr. Mehta and his associates multiplied that factor against the background cardiovascular risk for someone in the general population of the study to derive an adjusted risk. They then subtracted the background risk from the adjusted risk. Over a 10-year period, this translated into an excess risk for a cardiovascular event of 6.2%.

To illustrate the potential impact of this estimate, the researchers then applied this to a consecutive sample of 103 psoriasis patients seen in Dr. Mehta's psoriasis clinic at the Penn Heart and Vascular Center, including nine patients with psoriatic arthritis.

The baseline risk for these men and women averaged 7.3%, a low-risk level, but with the additional 6.2% risk added their functional risk jumped to an average of 13.5%, or to the intermediate-risk level. For individual patients, this signaled a substantial shift in their Framingham Risk Score risk level. Dr. Mehta conceded that the risk adjustment he applied derived from patients with severe psoriasis, while only 10% of patients in his practice have severe disease. About 60% have mild psoriasis, and about 30% have moderately severe disease, he said.

"This is the best we can do" for the time being, he said. "We applied the severe psoriasis metric to everyone to get a hazard estimate. We believe this is better than just multiplying" to recalculate a person's risk, the approach suggested by the EULAR committee.

He hopes that a larger, prospective study he has begun in collaboration with Dr. Joel M. Gelfand, a dermatologist at the University of Pennsylvania and the senior investigator for this work, will eventually provide a more nuanced risk adjustment for all levels of psoriasis severity. But he said that the current estimate of the increased risk will help persuade psoriasis patients to adopt healthier lifestyles. Patients with psoriasis, at all severity levels, tend to have relatively high rates of obesity, smoking, diabetes, hypertension, and inactivity.

Dr. Mehta added that better medical control of psoriasis also might help blunt the increased cardiovascular risk.

"Psoriasis and atherosclerosis are both T-cell mediated diseases," he observed. Most likely what goes on in the skin -to form the psoriasis plaques - also is going on inside patients' blood vessels, he said.

Dr. Mehta said that he had no disclosures. 

NEW ORLEANS – Patients with severe psoriasis face a 6% higher 10-year risk for a cardiovascular event than do comparable people without psoriasis, according to the findings of a prospective cohort study of nearly 18,000 people.

This added cardiovascular risk can have substantial implications, as it can move psoriasis patients into a higher Framingham Risk Score category and shift the way physicians need to think about cardiovascular risk management of these patients, Dr. Nehal N. Mehta said at the annual meeting of the American College of Cardiology.

In his practice that focuses on adults with psoriasis, the average background Framingham Risk Score based on low density lipoprotein cholesterol is a 7% 10-year risk for having a cardiovascular event, a level defined as low risk. However, adding the 6% additional risk linked with their psoriasis results in many patients having a 10-year risk of 13% or higher, placing them in the intermediate risk category (generally defined as a 10%-20% risk of having a cardiovascular event).

Patients at that intermediate risk category usually have more stringent targets for lipid levels, blood pressure, and weight although, in this context, it's unclear whether patients who leap into a higher cardiovascular risk level because of their psoriasis require more aggressive medical management; cardiovascular risk management guidelines have yet to elucidate optimal management for this patient subgroup.

Dr. Mehta deals with this dilemma by implementing aggressive lifestyle interventions for these patients, and also by suggesting naturally occurring risk-reduction interventions, such as the consumption of fiber, red yeast rice, soy, phytoestrogens, fish oil, and niacin.

If, after all these interventions, a patient's low density lipoprotein cholesterol or blood pressure remains at a questionably high level, he discusses the option of starting treatment with a statin or an antihypertensive medication, making clear that these steps have not yet been endorsed by most society management guidelines.

"Ultimately, about 5% of my psoriasis patients end up on a statin," said Dr. Mehta, a cardiologist and director of the inflammatory risk clinic in preventive cardiology at the University of Pennsylvania, Philadelphia.

Dr. Mehta and his associates derived an estimate of cardiovascular disease risk attributable to psoriasis by reviewing follow-up data maintained on 3,603 patients with severe psoriasis and 14,330 control participants without psoriasis enrolled in the General Practice Research Database, a collection of records from more than 5 million people seen by U.K. general practice physicians.

The researchers identified cases of severe psoriasis based on their receiving systemic therapy or phototherapy and excluded people with a prior history of cardiovascular events. The average age of all the people in the analysis was about 50 years and, on average, people were followed for about 3 years.

In a multivariable analysis that controlled for diabetes, hypertension, hyperlipidemia, age, gender, body mass index, and smoking status, the risk for a myocardial infarction, stroke, or death from a cardiovascular cause was 53% higher among the psoriasis patients, compared with the controls, a statistically significant difference. This higher cardiovascular risk among patients with psoriasis matched the 50% increased risk proposed last year for patients with rheumatoid arthritis and other forms of inflammatory arthritis including psoriatic arthritis, according to a panel convened by the European League Against Rheumatism (Ann. Rheum. Dis. 2010;69:325-31).

To translate the 1.53 relative risk into an attributable risk, Dr. Mehta and his associates multiplied that factor against the background cardiovascular risk for someone in the general population of the study to derive an adjusted risk. They then subtracted the background risk from the adjusted risk. Over a 10-year period, this translated into an excess risk for a cardiovascular event of 6.2%.

To illustrate the potential impact of this estimate, the researchers then applied this to a consecutive sample of 103 psoriasis patients seen in Dr. Mehta's psoriasis clinic at the Penn Heart and Vascular Center, including nine patients with psoriatic arthritis.

The baseline risk for these men and women averaged 7.3%, a low-risk level, but with the additional 6.2% risk added their functional risk jumped to an average of 13.5%, or to the intermediate-risk level. For individual patients, this signaled a substantial shift in their Framingham Risk Score risk level. Dr. Mehta conceded that the risk adjustment he applied derived from patients with severe psoriasis, while only 10% of patients in his practice have severe disease. About 60% have mild psoriasis, and about 30% have moderately severe disease, he said.

"This is the best we can do" for the time being, he said. "We applied the severe psoriasis metric to everyone to get a hazard estimate. We believe this is better than just multiplying" to recalculate a person's risk, the approach suggested by the EULAR committee.

He hopes that a larger, prospective study he has begun in collaboration with Dr. Joel M. Gelfand, a dermatologist at the University of Pennsylvania and the senior investigator for this work, will eventually provide a more nuanced risk adjustment for all levels of psoriasis severity. But he said that the current estimate of the increased risk will help persuade psoriasis patients to adopt healthier lifestyles. Patients with psoriasis, at all severity levels, tend to have relatively high rates of obesity, smoking, diabetes, hypertension, and inactivity.

Dr. Mehta added that better medical control of psoriasis also might help blunt the increased cardiovascular risk.

"Psoriasis and atherosclerosis are both T-cell mediated diseases," he observed. Most likely what goes on in the skin -to form the psoriasis plaques - also is going on inside patients' blood vessels, he said.

Dr. Mehta said that he had no disclosures. 

Biologics appear to be associated with a significantly greater rate of total adverse events, withdrawals due to adverse events, and an increased risk of tuberculosis reactivation compared with control agents, based on a meta-analysis involving more than 60,000 patients.

However, there were no significant differences in the rates of serious adverse events, serious infections, lymphoma, and congestive heart failure between biologics and control agents.

"Our review included indirect comparisons of the safety of biologics and should provide some guidance to clinicians and patients until head-to-head comparisons become available," wrote Dr. Jasvinder A. Singh and his coauthors (Cochrane Database Syst. Rev. 2011 [doi: 10.1002/14651858.CD008794.pub2]).

The results come from a network meta-analysis and Cochrane overview of the adverse effects of biologic drugs that are approved for the treatment of rheumatoid arthritis and other conditions in Europe, the United Kingdom, the United States, Canada, and Australia.

The investigators included randomized controlled trials (RCTs), controlled clinical trials, and open-label extension studies that involved one of the nine biologics for use in any indication and that reported this study's prespecified adverse outcomes. The researchers did not include studies on biologics for the treatment of HIV/AIDS. The nine biologics investigated were abatacept (Orencia), adalimumab (Humira), anakinra (Kineret), certolizumab pegol (Cimzia), etanercept (Enbrel), golimumab (Simponi), infliximab (Remicade), rituximab (Rituxan/MabThera), and tocilizumab (Actemra).

They searched the Cochrane Library, Medline, and Embase (through January 2010). The investigators performed mixed-effects logistic regression using an arm-based, random-effects model within an empirical Bayes framework for the network meta-analysis.

In all, included in the analysis were 163 RCTs with 50,010 adult participants and 46 extension studies with 11,954 adult participants. The median duration was 6 months for the RCTs and 13 months for the extension studies. Given the short duration of the RCTs, all the results should be interpreted as applying to a fairly short time frame.

After the analysis was adjusted for dose, biologics as a group were associated with a significantly greater rate of total adverse events (odds ratio 1.19) and withdrawals due to adverse events (OR 1.32), as well as an increased risk of TB reactivation (OR 4.68), compared with control agents.

Notably, certolizumab pegol was associated with a significantly greater risk of serious infections than was control treatment (OR 3.51). Infliximab was associated with a significantly greater risk of withdrawals due to adverse events compared with the control (OR 2.04).

Heart failure and cancer have been of particular concern with the use of biologic drugs. There appears to be little or no difference in the number of people who experienced heart failure or cancer taking any biologic compared with people who took placebo. However, there were not many cases of congestive heart failure or cancer, so confidence in these results is low.

The researchers also were able to indirectly compare individual biologic drugs. These analyses revealed that abatacept and anakinra were associated with a significantly lower risk of serious adverse events than were most other biologics. In addition, certolizumab pegol was associated with significantly greater odds of serious infections than were etanercept, adalimumab, abatacept, anakinra, golimumab, infliximab, and rituximab. Abatacept was significantly less likely than infliximab and tocilizumab to be associated with serious infections; abatacept, adalimumab, etanercept, and golimumab were significantly less likely than infliximab to result in withdrawals due to adverse events. However, the authors noted that the overall numbers were relatively small and that these comparisons should be interpreted with caution.

The lack of long-term studies of biologics is still a concern, they added. "There is an urgent need for more research regarding the long-term safety of biologics and the comparative safety of different biologics," they concluded.

Dr. Singh and several of his coauthors reported that they have significant financial relationships with several pharmaceutical companies.

Biologics appear to be associated with a significantly greater rate of total adverse events, withdrawals due to adverse events, and an increased risk of tuberculosis reactivation compared with control agents, based on a meta-analysis involving more than 60,000 patients.

However, there were no significant differences in the rates of serious adverse events, serious infections, lymphoma, and congestive heart failure between biologics and control agents.

"Our review included indirect comparisons of the safety of biologics and should provide some guidance to clinicians and patients until head-to-head comparisons become available," wrote Dr. Jasvinder A. Singh and his coauthors (Cochrane Database Syst. Rev. 2011 [doi: 10.1002/14651858.CD008794.pub2]).

The results come from a network meta-analysis and Cochrane overview of the adverse effects of biologic drugs that are approved for the treatment of rheumatoid arthritis and other conditions in Europe, the United Kingdom, the United States, Canada, and Australia.

The investigators included randomized controlled trials (RCTs), controlled clinical trials, and open-label extension studies that involved one of the nine biologics for use in any indication and that reported this study's prespecified adverse outcomes. The researchers did not include studies on biologics for the treatment of HIV/AIDS. The nine biologics investigated were abatacept (Orencia), adalimumab (Humira), anakinra (Kineret), certolizumab pegol (Cimzia), etanercept (Enbrel), golimumab (Simponi), infliximab (Remicade), rituximab (Rituxan/MabThera), and tocilizumab (Actemra).

They searched the Cochrane Library, Medline, and Embase (through January 2010). The investigators performed mixed-effects logistic regression using an arm-based, random-effects model within an empirical Bayes framework for the network meta-analysis.

In all, included in the analysis were 163 RCTs with 50,010 adult participants and 46 extension studies with 11,954 adult participants. The median duration was 6 months for the RCTs and 13 months for the extension studies. Given the short duration of the RCTs, all the results should be interpreted as applying to a fairly short time frame.

After the analysis was adjusted for dose, biologics as a group were associated with a significantly greater rate of total adverse events (odds ratio 1.19) and withdrawals due to adverse events (OR 1.32), as well as an increased risk of TB reactivation (OR 4.68), compared with control agents.

Notably, certolizumab pegol was associated with a significantly greater risk of serious infections than was control treatment (OR 3.51). Infliximab was associated with a significantly greater risk of withdrawals due to adverse events compared with the control (OR 2.04).

Heart failure and cancer have been of particular concern with the use of biologic drugs. There appears to be little or no difference in the number of people who experienced heart failure or cancer taking any biologic compared with people who took placebo. However, there were not many cases of congestive heart failure or cancer, so confidence in these results is low.

The researchers also were able to indirectly compare individual biologic drugs. These analyses revealed that abatacept and anakinra were associated with a significantly lower risk of serious adverse events than were most other biologics. In addition, certolizumab pegol was associated with significantly greater odds of serious infections than were etanercept, adalimumab, abatacept, anakinra, golimumab, infliximab, and rituximab. Abatacept was significantly less likely than infliximab and tocilizumab to be associated with serious infections; abatacept, adalimumab, etanercept, and golimumab were significantly less likely than infliximab to result in withdrawals due to adverse events. However, the authors noted that the overall numbers were relatively small and that these comparisons should be interpreted with caution.

The lack of long-term studies of biologics is still a concern, they added. "There is an urgent need for more research regarding the long-term safety of biologics and the comparative safety of different biologics," they concluded.

Dr. Singh and several of his coauthors reported that they have significant financial relationships with several pharmaceutical companies.

Biologics appear to be associated with a significantly greater rate of total adverse events, withdrawals due to adverse events, and an increased risk of tuberculosis reactivation compared with control agents, based on a meta-analysis involving more than 60,000 patients.

However, there were no significant differences in the rates of serious adverse events, serious infections, lymphoma, and congestive heart failure between biologics and control agents.

"Our review included indirect comparisons of the safety of biologics and should provide some guidance to clinicians and patients until head-to-head comparisons become available," wrote Dr. Jasvinder A. Singh and his coauthors (Cochrane Database Syst. Rev. 2011 [doi: 10.1002/14651858.CD008794.pub2]).

The results come from a network meta-analysis and Cochrane overview of the adverse effects of biologic drugs that are approved for the treatment of rheumatoid arthritis and other conditions in Europe, the United Kingdom, the United States, Canada, and Australia.

The investigators included randomized controlled trials (RCTs), controlled clinical trials, and open-label extension studies that involved one of the nine biologics for use in any indication and that reported this study's prespecified adverse outcomes. The researchers did not include studies on biologics for the treatment of HIV/AIDS. The nine biologics investigated were abatacept (Orencia), adalimumab (Humira), anakinra (Kineret), certolizumab pegol (Cimzia), etanercept (Enbrel), golimumab (Simponi), infliximab (Remicade), rituximab (Rituxan/MabThera), and tocilizumab (Actemra).

They searched the Cochrane Library, Medline, and Embase (through January 2010). The investigators performed mixed-effects logistic regression using an arm-based, random-effects model within an empirical Bayes framework for the network meta-analysis.

In all, included in the analysis were 163 RCTs with 50,010 adult participants and 46 extension studies with 11,954 adult participants. The median duration was 6 months for the RCTs and 13 months for the extension studies. Given the short duration of the RCTs, all the results should be interpreted as applying to a fairly short time frame.

After the analysis was adjusted for dose, biologics as a group were associated with a significantly greater rate of total adverse events (odds ratio 1.19) and withdrawals due to adverse events (OR 1.32), as well as an increased risk of TB reactivation (OR 4.68), compared with control agents.

Notably, certolizumab pegol was associated with a significantly greater risk of serious infections than was control treatment (OR 3.51). Infliximab was associated with a significantly greater risk of withdrawals due to adverse events compared with the control (OR 2.04).

Heart failure and cancer have been of particular concern with the use of biologic drugs. There appears to be little or no difference in the number of people who experienced heart failure or cancer taking any biologic compared with people who took placebo. However, there were not many cases of congestive heart failure or cancer, so confidence in these results is low.

The researchers also were able to indirectly compare individual biologic drugs. These analyses revealed that abatacept and anakinra were associated with a significantly lower risk of serious adverse events than were most other biologics. In addition, certolizumab pegol was associated with significantly greater odds of serious infections than were etanercept, adalimumab, abatacept, anakinra, golimumab, infliximab, and rituximab. Abatacept was significantly less likely than infliximab and tocilizumab to be associated with serious infections; abatacept, adalimumab, etanercept, and golimumab were significantly less likely than infliximab to result in withdrawals due to adverse events. However, the authors noted that the overall numbers were relatively small and that these comparisons should be interpreted with caution.

The lack of long-term studies of biologics is still a concern, they added. "There is an urgent need for more research regarding the long-term safety of biologics and the comparative safety of different biologics," they concluded.

Dr. Singh and several of his coauthors reported that they have significant financial relationships with several pharmaceutical companies.

Studies show that severe psoriasis is associated with a 50% increased risk of mortality and up to 5 years of life lost, according to Dr. Joel M. Gelfand.

The leading causes of death in psoriasis patients are cardiovascular disease, infection, and cancer, which account for 34%, 22%, and 21% of deaths, respectively (Br. J. Dermatol. 2010;163:586-92), Dr. Gelfand said at the Hawaii Dermatology Seminar sponsored by Skin Disease Education Foundation (SDEF).

Although there are not yet enough data to confirm a causal effect between psoriasis and these leading causes of death, the findings do have implications for managing patients with psoriasis, he said. Data have consistently demonstrated an association between psoriasis and cardiovascular disease, with numerous published studies linking the two conditions.

Taken together, findings from several of these studies suggest that patients with psoriasis are at increased risk of myocardial infarction, stroke, and cardiovascular death, and that those with severe psoriasis have the greatest risks, said Dr. Gelfand of the department of dermatology at the University of Pennsylvania in Philadelphia.

The clinical significance of these findings is striking; patients with severe psoriasis, for example, are 15 times more likely to die prematurely as a result of cardiovascular disease attributable to psoriasis than they are to develop a melanoma, he said.

One study demonstrated a link between psoriasis and several cardiovascular risk factors, including smoking, obesity, dyslipidemia, hypertension, and diabetes, said Dr. Gelfand, who was one of the authors of the study (J. Am. Acad. Dermatol. 2006;55;829-35).

Furthermore, a population-based cohort study involving more than 130,000 psoriasis patients – including more than 3,800 with severe psoriasis - and up to 5 controls per patient, suggested that psoriasis confers an independent risk for myocardial infarction, particularly in young patients with severe psoriasis. The adjusted relative risk of MI in a 30-year-old patient with mild psoriasis was 1.29, and in a 30-year-old with severe psoriasis was 3.01. The adjusted relative risk of MI in a 60-year old with mild psoriasis was 1.08, and in a 60-year-old with severe psoriasis was 1.36, Dr. Gelfand and his colleagues reported (JAMA 2006;296:1735-41).

That study was conducted using the General Practice Research Database of medical records in the United Kingdom, which includes more than 9 million patients and more than 40 million person-years of follow-up data from 1987 to 2002, he said, adding that at least 12 papers have confirmed an association between psoriasis and cardiovascular disease independent of traditional risk factors for cardiovascular disease.

Although the available data on psoriasis and cardiovascular disease demonstrate the biologic credibility of an association, as well as a plausible time sequence suggesting causation, dose response has been demonstrated in only a few studies, and the strength of the study design has been variable, Dr. Gelfand said.

Although most studies have found an effect – along with a modest but clinically important strength of association similar to the association seen in heart disease, hypertension, and diabetes – data from a randomized controlled trial are needed before a causal relationship between psoriasis and cardiovascular disease can be confirmed, and before a link between aggressive treatment of psoriasis and a reduced risk of cardiovascular disease can be demonstrated, he said in an interview, adding that it currently remains unclear whether aggressive treatment will lower cardiovascular disease risk.

However, the U.S. Preventive Services Task Force, the American Diabetes Association, and the National Cholesterol Education Program recommend that severe psoriasis patients over age 21 years undergo blood pressure screening at each office visit; that those aged 45 years and older undergo fasting blood glucose testing every 3 years (unless they have diabetes risk factors, in which case they should undergo screening earlier and more often); and that those aged 20 years and older undergo cholesterol screening every 5 years.

Existing data also support recommendations for addressing concerns about infection and cancer risk in patients with psoriasis, Dr. Gelfand said.

Patients with severe psoriasis are 65% more likely to die of an infection than are those without psoriasis (Br. J. Dermatol. 2010;163:586-92). Specifically, studies have shown that streptococcal pharyngitis is a risk factor for guttate psoriasis, and that HIV is a risk factor for severe psoriasis, he said, noting that it is recommended that patients be screened for streptococcal infection with guttate flares, and that they be screened for HIV if they have severe psoriasis.

It is also important that patients with psoriasis be routinely vaccinated – prior to initiation of immunosuppressive therapy – against influenza and pneumonia. Vaccination against hepatitis B in patients at risk for infection should also be considered, as well as vaccination against zoster in patients aged 60 and older.

As for cancer, it is a concern in psoriasis patients because of the chronic use of immunosuppressive therapies, comorbid behaviors, and chronic inflammation, Dr. Gelfand said. Patients with severe psoriasis are 41% more likely to die of cancer than are those without psoriasis.

Studies have shown – although not consistently – that psoriasis may be linked with lung, liver, pancreatic, breast, colon, bladder, and kidney cancer. Lymphoma is also a particular concern, with cutaneous T-cell lymphoma having the strongest association.

As with cardiovascular disease, however, findings are not strong or consistent enough to confirm a causal effect of psoriasis on cancer risk, or to clarify whether any association is a disease effect or treatment effect.

Still, the available findings are concerning enough that biopsy should be considered in severe disease, especially if clinical features are not classic, and in those who fail to respond to treatment, because cutaneous T-cell lymphoma may progress rapidly in those on immunosuppressive therapy.

"Always consider a skin biopsy in patients with atypical features of psoriasis and those not responding to treatment," Dr. Gelfand said.

Also, encourage patients to stay up to date on age-appropriate cancer screening. According to Centers for Disease Control guidelines, women aged 21-70 years should undergo cervical cancer screening every 2-3 years, women aged 50-74 years should undergo screening for breast cancer by mammography every 2 years, and men and women aged 50-75 years should undergo screening for colon cancer by fecal occult blood testing every year, by flexible sigmoidoscopy every 5 years, and by colonoscopy every 10 years, he said.

Dr. Gelfand has been an investigator and/or consultant for Amgen, Abbott, Centocor, Pfizer, Celgene, Novartis, and Genentech. He reported having no relevant financial disclosures. SDEF and this news organization are owned by Elsevier.

Studies show that severe psoriasis is associated with a 50% increased risk of mortality and up to 5 years of life lost, according to Dr. Joel M. Gelfand.

The leading causes of death in psoriasis patients are cardiovascular disease, infection, and cancer, which account for 34%, 22%, and 21% of deaths, respectively (Br. J. Dermatol. 2010;163:586-92), Dr. Gelfand said at the Hawaii Dermatology Seminar sponsored by Skin Disease Education Foundation (SDEF).

Although there are not yet enough data to confirm a causal effect between psoriasis and these leading causes of death, the findings do have implications for managing patients with psoriasis, he said. Data have consistently demonstrated an association between psoriasis and cardiovascular disease, with numerous published studies linking the two conditions.

Taken together, findings from several of these studies suggest that patients with psoriasis are at increased risk of myocardial infarction, stroke, and cardiovascular death, and that those with severe psoriasis have the greatest risks, said Dr. Gelfand of the department of dermatology at the University of Pennsylvania in Philadelphia.

The clinical significance of these findings is striking; patients with severe psoriasis, for example, are 15 times more likely to die prematurely as a result of cardiovascular disease attributable to psoriasis than they are to develop a melanoma, he said.

One study demonstrated a link between psoriasis and several cardiovascular risk factors, including smoking, obesity, dyslipidemia, hypertension, and diabetes, said Dr. Gelfand, who was one of the authors of the study (J. Am. Acad. Dermatol. 2006;55;829-35).

Furthermore, a population-based cohort study involving more than 130,000 psoriasis patients – including more than 3,800 with severe psoriasis - and up to 5 controls per patient, suggested that psoriasis confers an independent risk for myocardial infarction, particularly in young patients with severe psoriasis. The adjusted relative risk of MI in a 30-year-old patient with mild psoriasis was 1.29, and in a 30-year-old with severe psoriasis was 3.01. The adjusted relative risk of MI in a 60-year old with mild psoriasis was 1.08, and in a 60-year-old with severe psoriasis was 1.36, Dr. Gelfand and his colleagues reported (JAMA 2006;296:1735-41).

That study was conducted using the General Practice Research Database of medical records in the United Kingdom, which includes more than 9 million patients and more than 40 million person-years of follow-up data from 1987 to 2002, he said, adding that at least 12 papers have confirmed an association between psoriasis and cardiovascular disease independent of traditional risk factors for cardiovascular disease.

Although the available data on psoriasis and cardiovascular disease demonstrate the biologic credibility of an association, as well as a plausible time sequence suggesting causation, dose response has been demonstrated in only a few studies, and the strength of the study design has been variable, Dr. Gelfand said.

Although most studies have found an effect – along with a modest but clinically important strength of association similar to the association seen in heart disease, hypertension, and diabetes – data from a randomized controlled trial are needed before a causal relationship between psoriasis and cardiovascular disease can be confirmed, and before a link between aggressive treatment of psoriasis and a reduced risk of cardiovascular disease can be demonstrated, he said in an interview, adding that it currently remains unclear whether aggressive treatment will lower cardiovascular disease risk.

However, the U.S. Preventive Services Task Force, the American Diabetes Association, and the National Cholesterol Education Program recommend that severe psoriasis patients over age 21 years undergo blood pressure screening at each office visit; that those aged 45 years and older undergo fasting blood glucose testing every 3 years (unless they have diabetes risk factors, in which case they should undergo screening earlier and more often); and that those aged 20 years and older undergo cholesterol screening every 5 years.

Existing data also support recommendations for addressing concerns about infection and cancer risk in patients with psoriasis, Dr. Gelfand said.

Patients with severe psoriasis are 65% more likely to die of an infection than are those without psoriasis (Br. J. Dermatol. 2010;163:586-92). Specifically, studies have shown that streptococcal pharyngitis is a risk factor for guttate psoriasis, and that HIV is a risk factor for severe psoriasis, he said, noting that it is recommended that patients be screened for streptococcal infection with guttate flares, and that they be screened for HIV if they have severe psoriasis.

It is also important that patients with psoriasis be routinely vaccinated – prior to initiation of immunosuppressive therapy – against influenza and pneumonia. Vaccination against hepatitis B in patients at risk for infection should also be considered, as well as vaccination against zoster in patients aged 60 and older.

As for cancer, it is a concern in psoriasis patients because of the chronic use of immunosuppressive therapies, comorbid behaviors, and chronic inflammation, Dr. Gelfand said. Patients with severe psoriasis are 41% more likely to die of cancer than are those without psoriasis.

Studies have shown – although not consistently – that psoriasis may be linked with lung, liver, pancreatic, breast, colon, bladder, and kidney cancer. Lymphoma is also a particular concern, with cutaneous T-cell lymphoma having the strongest association.

As with cardiovascular disease, however, findings are not strong or consistent enough to confirm a causal effect of psoriasis on cancer risk, or to clarify whether any association is a disease effect or treatment effect.

Still, the available findings are concerning enough that biopsy should be considered in severe disease, especially if clinical features are not classic, and in those who fail to respond to treatment, because cutaneous T-cell lymphoma may progress rapidly in those on immunosuppressive therapy.

"Always consider a skin biopsy in patients with atypical features of psoriasis and those not responding to treatment," Dr. Gelfand said.

Also, encourage patients to stay up to date on age-appropriate cancer screening. According to Centers for Disease Control guidelines, women aged 21-70 years should undergo cervical cancer screening every 2-3 years, women aged 50-74 years should undergo screening for breast cancer by mammography every 2 years, and men and women aged 50-75 years should undergo screening for colon cancer by fecal occult blood testing every year, by flexible sigmoidoscopy every 5 years, and by colonoscopy every 10 years, he said.

Dr. Gelfand has been an investigator and/or consultant for Amgen, Abbott, Centocor, Pfizer, Celgene, Novartis, and Genentech. He reported having no relevant financial disclosures. SDEF and this news organization are owned by Elsevier.

Studies show that severe psoriasis is associated with a 50% increased risk of mortality and up to 5 years of life lost, according to Dr. Joel M. Gelfand.

The leading causes of death in psoriasis patients are cardiovascular disease, infection, and cancer, which account for 34%, 22%, and 21% of deaths, respectively (Br. J. Dermatol. 2010;163:586-92), Dr. Gelfand said at the Hawaii Dermatology Seminar sponsored by Skin Disease Education Foundation (SDEF).

Although there are not yet enough data to confirm a causal effect between psoriasis and these leading causes of death, the findings do have implications for managing patients with psoriasis, he said. Data have consistently demonstrated an association between psoriasis and cardiovascular disease, with numerous published studies linking the two conditions.

Taken together, findings from several of these studies suggest that patients with psoriasis are at increased risk of myocardial infarction, stroke, and cardiovascular death, and that those with severe psoriasis have the greatest risks, said Dr. Gelfand of the department of dermatology at the University of Pennsylvania in Philadelphia.

The clinical significance of these findings is striking; patients with severe psoriasis, for example, are 15 times more likely to die prematurely as a result of cardiovascular disease attributable to psoriasis than they are to develop a melanoma, he said.

One study demonstrated a link between psoriasis and several cardiovascular risk factors, including smoking, obesity, dyslipidemia, hypertension, and diabetes, said Dr. Gelfand, who was one of the authors of the study (J. Am. Acad. Dermatol. 2006;55;829-35).

Furthermore, a population-based cohort study involving more than 130,000 psoriasis patients – including more than 3,800 with severe psoriasis - and up to 5 controls per patient, suggested that psoriasis confers an independent risk for myocardial infarction, particularly in young patients with severe psoriasis. The adjusted relative risk of MI in a 30-year-old patient with mild psoriasis was 1.29, and in a 30-year-old with severe psoriasis was 3.01. The adjusted relative risk of MI in a 60-year old with mild psoriasis was 1.08, and in a 60-year-old with severe psoriasis was 1.36, Dr. Gelfand and his colleagues reported (JAMA 2006;296:1735-41).

That study was conducted using the General Practice Research Database of medical records in the United Kingdom, which includes more than 9 million patients and more than 40 million person-years of follow-up data from 1987 to 2002, he said, adding that at least 12 papers have confirmed an association between psoriasis and cardiovascular disease independent of traditional risk factors for cardiovascular disease.

Although the available data on psoriasis and cardiovascular disease demonstrate the biologic credibility of an association, as well as a plausible time sequence suggesting causation, dose response has been demonstrated in only a few studies, and the strength of the study design has been variable, Dr. Gelfand said.

Although most studies have found an effect – along with a modest but clinically important strength of association similar to the association seen in heart disease, hypertension, and diabetes – data from a randomized controlled trial are needed before a causal relationship between psoriasis and cardiovascular disease can be confirmed, and before a link between aggressive treatment of psoriasis and a reduced risk of cardiovascular disease can be demonstrated, he said in an interview, adding that it currently remains unclear whether aggressive treatment will lower cardiovascular disease risk.

However, the U.S. Preventive Services Task Force, the American Diabetes Association, and the National Cholesterol Education Program recommend that severe psoriasis patients over age 21 years undergo blood pressure screening at each office visit; that those aged 45 years and older undergo fasting blood glucose testing every 3 years (unless they have diabetes risk factors, in which case they should undergo screening earlier and more often); and that those aged 20 years and older undergo cholesterol screening every 5 years.

Existing data also support recommendations for addressing concerns about infection and cancer risk in patients with psoriasis, Dr. Gelfand said.

Patients with severe psoriasis are 65% more likely to die of an infection than are those without psoriasis (Br. J. Dermatol. 2010;163:586-92). Specifically, studies have shown that streptococcal pharyngitis is a risk factor for guttate psoriasis, and that HIV is a risk factor for severe psoriasis, he said, noting that it is recommended that patients be screened for streptococcal infection with guttate flares, and that they be screened for HIV if they have severe psoriasis.

It is also important that patients with psoriasis be routinely vaccinated – prior to initiation of immunosuppressive therapy – against influenza and pneumonia. Vaccination against hepatitis B in patients at risk for infection should also be considered, as well as vaccination against zoster in patients aged 60 and older.

As for cancer, it is a concern in psoriasis patients because of the chronic use of immunosuppressive therapies, comorbid behaviors, and chronic inflammation, Dr. Gelfand said. Patients with severe psoriasis are 41% more likely to die of cancer than are those without psoriasis.

Studies have shown – although not consistently – that psoriasis may be linked with lung, liver, pancreatic, breast, colon, bladder, and kidney cancer. Lymphoma is also a particular concern, with cutaneous T-cell lymphoma having the strongest association.

As with cardiovascular disease, however, findings are not strong or consistent enough to confirm a causal effect of psoriasis on cancer risk, or to clarify whether any association is a disease effect or treatment effect.

Still, the available findings are concerning enough that biopsy should be considered in severe disease, especially if clinical features are not classic, and in those who fail to respond to treatment, because cutaneous T-cell lymphoma may progress rapidly in those on immunosuppressive therapy.

"Always consider a skin biopsy in patients with atypical features of psoriasis and those not responding to treatment," Dr. Gelfand said.

Also, encourage patients to stay up to date on age-appropriate cancer screening. According to Centers for Disease Control guidelines, women aged 21-70 years should undergo cervical cancer screening every 2-3 years, women aged 50-74 years should undergo screening for breast cancer by mammography every 2 years, and men and women aged 50-75 years should undergo screening for colon cancer by fecal occult blood testing every year, by flexible sigmoidoscopy every 5 years, and by colonoscopy every 10 years, he said.

Dr. Gelfand has been an investigator and/or consultant for Amgen, Abbott, Centocor, Pfizer, Celgene, Novartis, and Genentech. He reported having no relevant financial disclosures. SDEF and this news organization are owned by Elsevier.

The limitations of the drug approval process in fully characterizing a new drug's safety profile are clearly illustrated in the dermatologic therapeutics arena and clinicians should keep these limitations in mind when prescribing and counseling patients about a relatively new therapeutic agent, according to Dr. Joel M. Gelfand.

Previously unknown risks of new drugs are routinely identified after Food and Drug Administration approval, when "rare" adverse events are more likely to be detected, said Dr. Gelfand at the Hawaii Dermatology Seminar sponsored by Skin Disease Education Foundation (SDEF). Examples of rare adverse events – those that occur at a rate of less than 1 per 1,000 – include fatal arrhythmias associated with terfenadine and astemizole, lymphomas associated with biologics, and progressive multifocal leukoencephalopathy (PML) associated with efalizumab.

The clinical trials that are the basis of drug approvals evaluate short-term safety only and lack the statistical power to detect rare events, he said, pointing out that a study of 3,000 patients can only detect adverse events that occur at a rate of more than 1 per 1,000.

The types of adverse effects detected pre-approval are pharmacologic side effects, which are common and dose dependent, such as isotretinoin-induced cheilitis, said Dr. Gelfand, of the department of dermatology at the University of Pennsylvania in Philadelphia.

Adverse effects that are detected after approval fall into two categories: idiosyncratic or allergic reactions, which are rare and "occur in close proximity to exposure," he said, such as dapsone-induced agranulocytosis, and new morbidities, which are delayed and uncommon. An example of the latter is skin cancers associated with psoralen and ultraviolet A (PUVA) treatment, which was associated with melanoma in 1997, more than 2 decades after it was found to be effective for treating psoriasis.

There is a need for ongoing risk assessment throughout the life cycle of a drug, Dr. Gelfand said, which includes MedWatch, the FDA's voluntary adverse event reporting program that relies on spontaneous reporting of adverse events. MedWatch's advantages include that it is inexpensive and can identify safety signals; however, it is limited by under-reporting and MedWatch reports usually cannot be used to determine causality, he noted.

The association between efalizumab (Raptiva) and PML, an untreatable and often fatal central nervous system infection that occurs primarily in the setting of immunosuppression, is an example of "signal detection in action," Dr. Gelfand said. Efalizumab was approved in 2003 for psoriasis, based on studies of about 2,700 people, including 218 treated for more than 1 year. By 2008, after 46,000 people had been treated, including 3,000 for at least 2 years, there had been 3 confirmed cases and one suspected case of PML. All four were spontaneous reports, which "can be useful for very rare diseases such as PML," he said.

With efalizumab treatment, the overall estimated risk of PML is 1 in 15,000 patients per year and one in 1,000 patients treated for more than 2 years. These are likely underestimates because of incomplete reporting, and is a relationship that is "likely causal," he said. In the case of efalizumab, the risk was "judged unacceptable given treatment alternatives and disease indication" and the drug was withdrawn from the market in 2009.

A causal association between isotretinoin and inflammatory bowel disease (IBD) has not been established, but the drug's prescribing information includes a warning about the association.

The data on isotretinoin and IBD include a large administrative claims database of over 8,000 cases of IBD, and 21,832 controls published in 2010 (Am. J. Gastroenterol. 2010;105:1986-93). Analysis of the database found that the risk of IBD within 12 months of being treated with isotretinoin was 1.7; for ulcerative colitis, the risk was increased fourfold; for Crohn's disease the risk was slightly reduced.

In that study, which controlled for age, sex, and geographic region, the dose response was evident for ulcerative colitis only, Dr. Gelfand said.

In a review of 85 spontaneous reports of IBD in isotretinoin patients to the FDA between 1997-2002, isotretinoin was considered "highly probable" as the cause in 4 cases (5%), "probable" in 58 cases (68%), and "possible" in 23 cases (27%). These included three cases with a positive dechallenge and rechallenge.

When in comes to ulcerative colitis, the overall data available "suggest a specific association" between isotretinoin and the disease, but the data are conflicting, he said. Studies have not addressed the possibility that patients with severe acne are at an increased risk of ulcerative colitis, or of confounding variables including oral antibiotics and smoking, he said. If the risk is real, it is small, with a number needed to harm that exceeds 3,300.

With these examples in mind, Dr. Gelfand advised clinicians to "use the science of medicine in judging safety... [and] the art of medicine" when communicating the risk of therapies to their patients.

"The benefits of treatments are well-characterized relative to the long-term safety and the risk of rare but serious medical events," he said. "Sir William Osler was the first to recognize the need to be cautious when prescribing new medications advising physicians 'Do not be the first to prescribe a new drug and do not be the last to stop prescribing an old drug.' "

Dr. Gelfand disclosed that he has been an investigator and/or consultant to Amgen, Abbott, Centocor, Pfizer, Celegene, Novartis, and Genentech, and that his presentation was his work only.

SDEF and this news organization are owned by Elsevier.

The limitations of the drug approval process in fully characterizing a new drug's safety profile are clearly illustrated in the dermatologic therapeutics arena and clinicians should keep these limitations in mind when prescribing and counseling patients about a relatively new therapeutic agent, according to Dr. Joel M. Gelfand.

Previously unknown risks of new drugs are routinely identified after Food and Drug Administration approval, when "rare" adverse events are more likely to be detected, said Dr. Gelfand at the Hawaii Dermatology Seminar sponsored by Skin Disease Education Foundation (SDEF). Examples of rare adverse events – those that occur at a rate of less than 1 per 1,000 – include fatal arrhythmias associated with terfenadine and astemizole, lymphomas associated with biologics, and progressive multifocal leukoencephalopathy (PML) associated with efalizumab.

The clinical trials that are the basis of drug approvals evaluate short-term safety only and lack the statistical power to detect rare events, he said, pointing out that a study of 3,000 patients can only detect adverse events that occur at a rate of more than 1 per 1,000.

The types of adverse effects detected pre-approval are pharmacologic side effects, which are common and dose dependent, such as isotretinoin-induced cheilitis, said Dr. Gelfand, of the department of dermatology at the University of Pennsylvania in Philadelphia.

Adverse effects that are detected after approval fall into two categories: idiosyncratic or allergic reactions, which are rare and "occur in close proximity to exposure," he said, such as dapsone-induced agranulocytosis, and new morbidities, which are delayed and uncommon. An example of the latter is skin cancers associated with psoralen and ultraviolet A (PUVA) treatment, which was associated with melanoma in 1997, more than 2 decades after it was found to be effective for treating psoriasis.

There is a need for ongoing risk assessment throughout the life cycle of a drug, Dr. Gelfand said, which includes MedWatch, the FDA's voluntary adverse event reporting program that relies on spontaneous reporting of adverse events. MedWatch's advantages include that it is inexpensive and can identify safety signals; however, it is limited by under-reporting and MedWatch reports usually cannot be used to determine causality, he noted.

The association between efalizumab (Raptiva) and PML, an untreatable and often fatal central nervous system infection that occurs primarily in the setting of immunosuppression, is an example of "signal detection in action," Dr. Gelfand said. Efalizumab was approved in 2003 for psoriasis, based on studies of about 2,700 people, including 218 treated for more than 1 year. By 2008, after 46,000 people had been treated, including 3,000 for at least 2 years, there had been 3 confirmed cases and one suspected case of PML. All four were spontaneous reports, which "can be useful for very rare diseases such as PML," he said.

With efalizumab treatment, the overall estimated risk of PML is 1 in 15,000 patients per year and one in 1,000 patients treated for more than 2 years. These are likely underestimates because of incomplete reporting, and is a relationship that is "likely causal," he said. In the case of efalizumab, the risk was "judged unacceptable given treatment alternatives and disease indication" and the drug was withdrawn from the market in 2009.

A causal association between isotretinoin and inflammatory bowel disease (IBD) has not been established, but the drug's prescribing information includes a warning about the association.

The data on isotretinoin and IBD include a large administrative claims database of over 8,000 cases of IBD, and 21,832 controls published in 2010 (Am. J. Gastroenterol. 2010;105:1986-93). Analysis of the database found that the risk of IBD within 12 months of being treated with isotretinoin was 1.7; for ulcerative colitis, the risk was increased fourfold; for Crohn's disease the risk was slightly reduced.

In that study, which controlled for age, sex, and geographic region, the dose response was evident for ulcerative colitis only, Dr. Gelfand said.

In a review of 85 spontaneous reports of IBD in isotretinoin patients to the FDA between 1997-2002, isotretinoin was considered "highly probable" as the cause in 4 cases (5%), "probable" in 58 cases (68%), and "possible" in 23 cases (27%). These included three cases with a positive dechallenge and rechallenge.

When in comes to ulcerative colitis, the overall data available "suggest a specific association" between isotretinoin and the disease, but the data are conflicting, he said. Studies have not addressed the possibility that patients with severe acne are at an increased risk of ulcerative colitis, or of confounding variables including oral antibiotics and smoking, he said. If the risk is real, it is small, with a number needed to harm that exceeds 3,300.

With these examples in mind, Dr. Gelfand advised clinicians to "use the science of medicine in judging safety... [and] the art of medicine" when communicating the risk of therapies to their patients.

"The benefits of treatments are well-characterized relative to the long-term safety and the risk of rare but serious medical events," he said. "Sir William Osler was the first to recognize the need to be cautious when prescribing new medications advising physicians 'Do not be the first to prescribe a new drug and do not be the last to stop prescribing an old drug.' "

Dr. Gelfand disclosed that he has been an investigator and/or consultant to Amgen, Abbott, Centocor, Pfizer, Celegene, Novartis, and Genentech, and that his presentation was his work only.

SDEF and this news organization are owned by Elsevier.

The limitations of the drug approval process in fully characterizing a new drug's safety profile are clearly illustrated in the dermatologic therapeutics arena and clinicians should keep these limitations in mind when prescribing and counseling patients about a relatively new therapeutic agent, according to Dr. Joel M. Gelfand.

Previously unknown risks of new drugs are routinely identified after Food and Drug Administration approval, when "rare" adverse events are more likely to be detected, said Dr. Gelfand at the Hawaii Dermatology Seminar sponsored by Skin Disease Education Foundation (SDEF). Examples of rare adverse events – those that occur at a rate of less than 1 per 1,000 – include fatal arrhythmias associated with terfenadine and astemizole, lymphomas associated with biologics, and progressive multifocal leukoencephalopathy (PML) associated with efalizumab.

The clinical trials that are the basis of drug approvals evaluate short-term safety only and lack the statistical power to detect rare events, he said, pointing out that a study of 3,000 patients can only detect adverse events that occur at a rate of more than 1 per 1,000.

The types of adverse effects detected pre-approval are pharmacologic side effects, which are common and dose dependent, such as isotretinoin-induced cheilitis, said Dr. Gelfand, of the department of dermatology at the University of Pennsylvania in Philadelphia.

Adverse effects that are detected after approval fall into two categories: idiosyncratic or allergic reactions, which are rare and "occur in close proximity to exposure," he said, such as dapsone-induced agranulocytosis, and new morbidities, which are delayed and uncommon. An example of the latter is skin cancers associated with psoralen and ultraviolet A (PUVA) treatment, which was associated with melanoma in 1997, more than 2 decades after it was found to be effective for treating psoriasis.

There is a need for ongoing risk assessment throughout the life cycle of a drug, Dr. Gelfand said, which includes MedWatch, the FDA's voluntary adverse event reporting program that relies on spontaneous reporting of adverse events. MedWatch's advantages include that it is inexpensive and can identify safety signals; however, it is limited by under-reporting and MedWatch reports usually cannot be used to determine causality, he noted.

The association between efalizumab (Raptiva) and PML, an untreatable and often fatal central nervous system infection that occurs primarily in the setting of immunosuppression, is an example of "signal detection in action," Dr. Gelfand said. Efalizumab was approved in 2003 for psoriasis, based on studies of about 2,700 people, including 218 treated for more than 1 year. By 2008, after 46,000 people had been treated, including 3,000 for at least 2 years, there had been 3 confirmed cases and one suspected case of PML. All four were spontaneous reports, which "can be useful for very rare diseases such as PML," he said.

With efalizumab treatment, the overall estimated risk of PML is 1 in 15,000 patients per year and one in 1,000 patients treated for more than 2 years. These are likely underestimates because of incomplete reporting, and is a relationship that is "likely causal," he said. In the case of efalizumab, the risk was "judged unacceptable given treatment alternatives and disease indication" and the drug was withdrawn from the market in 2009.

A causal association between isotretinoin and inflammatory bowel disease (IBD) has not been established, but the drug's prescribing information includes a warning about the association.

The data on isotretinoin and IBD include a large administrative claims database of over 8,000 cases of IBD, and 21,832 controls published in 2010 (Am. J. Gastroenterol. 2010;105:1986-93). Analysis of the database found that the risk of IBD within 12 months of being treated with isotretinoin was 1.7; for ulcerative colitis, the risk was increased fourfold; for Crohn's disease the risk was slightly reduced.

In that study, which controlled for age, sex, and geographic region, the dose response was evident for ulcerative colitis only, Dr. Gelfand said.

In a review of 85 spontaneous reports of IBD in isotretinoin patients to the FDA between 1997-2002, isotretinoin was considered "highly probable" as the cause in 4 cases (5%), "probable" in 58 cases (68%), and "possible" in 23 cases (27%). These included three cases with a positive dechallenge and rechallenge.

When in comes to ulcerative colitis, the overall data available "suggest a specific association" between isotretinoin and the disease, but the data are conflicting, he said. Studies have not addressed the possibility that patients with severe acne are at an increased risk of ulcerative colitis, or of confounding variables including oral antibiotics and smoking, he said. If the risk is real, it is small, with a number needed to harm that exceeds 3,300.

With these examples in mind, Dr. Gelfand advised clinicians to "use the science of medicine in judging safety... [and] the art of medicine" when communicating the risk of therapies to their patients.

"The benefits of treatments are well-characterized relative to the long-term safety and the risk of rare but serious medical events," he said. "Sir William Osler was the first to recognize the need to be cautious when prescribing new medications advising physicians 'Do not be the first to prescribe a new drug and do not be the last to stop prescribing an old drug.' "

Dr. Gelfand disclosed that he has been an investigator and/or consultant to Amgen, Abbott, Centocor, Pfizer, Celegene, Novartis, and Genentech, and that his presentation was his work only.

SDEF and this news organization are owned by Elsevier.

The drug sildenafil reduced the frequency of attacks of Raynaud's phenomenon secondary to limited cutaneous systemic sclerosis in a small, randomized, placebo-controlled trial that was reported in Arthritis & Rheumatism.

The study enrolled 57 men and women aged 18-75 years, all of whom both had a diagnosis of Raynaud's phenomenon (RP) secondary to limited cutaneous systemic sclerosis and experienced at least 7 attacks per week. Patients were randomized to receive modified-release sildenafil (100 mg once daily for 3 days, titrated to 200 mg once daily for 25 days) or placebo, reported Dr. Ariane Herrick of the University of Manchester (England) and her associates (Arthritis Rheum. 2011;63:775-82).

Of the 57 people originally enrolled, 20 in the treatment group and 25 controls completed the 28-day study and were entered into analysis. Patients kept treatment diaries before and during the study period, recording the duration and pain intensity of each attack; serum samples were taken on days 1, 7, and 28.

The primary end point was the percent change in the number of weekly RP attacks. Secondary end points measured the severity and duration of attacks.

After 28 days, the mean number of RP attacks per week lessened from 25 at baseline to 19 in the control arm, and from 31 at baseline to 19 in the treatment arm, with a mean percent reduction of 44% in the treatment arm, compared with 18% in the control arm (P = .034). Statistically insignificant differences were noted between the groups for Raynaud’s Condition Score, duration of attacks, pain score, endothelial dysfunction, or serum biomarkers associated with RP. The most frequent adverse events reported were headache and dyspepsia.

Dr. Ulf Müller-Ladner, professor of internal medicine and rheumatology at Justus-Liebig University Giessen (Germany), said in an interview that this "is a very important study, as we do not have too many controlled clinical trials for Raynaud’s, and every controlled study showing efficacy is very helpful for daily practice." The investigators acknowledged the study’s small size and high attrition from the intention-to-treat sildenafil arm as limitations, particularly as the study was no longer powered to detect secondary end points. Also disappointing, they wrote, was that the endothelial dysfunction measures and the serum levels of biomarkers were similar between the groups.

The study's short duration was another possible limitation. The findings from an earlier, longer (5.2-month) study of sildenafil in 16 patients with systemic sclerosis – of whom 7 had limited cutaneous involvement – showed statistically significant lessening of attack pain associated with RP with the maximum tolerated dose of sildenafil (Ann. Rheum. Dis. 2010;69:1475-8).

Finally, they noted, the modified-release formulation of sildenafil may not have provided the most effective dose for the patient population studied.

Dr. Müller-Ladner agreed with the description of the study's design weaknesses: "The shortcomings of the present study are its placebo arm and its short duration. These results must be confirmed through the initiation of a large, multinational, longer-term trial."

The trial was funded by Pfizer, the drug's manufacturer. Dr. Herrick acknowledged financial relationships with Actelion, Mediquest, Pfizer, and United Therapeutics. Several of the coinvestigators also made relevant financial disclosures. Dr. Müller-Ladner had no relevant financial disclosures.

The drug sildenafil reduced the frequency of attacks of Raynaud's phenomenon secondary to limited cutaneous systemic sclerosis in a small, randomized, placebo-controlled trial that was reported in Arthritis & Rheumatism.

The study enrolled 57 men and women aged 18-75 years, all of whom both had a diagnosis of Raynaud's phenomenon (RP) secondary to limited cutaneous systemic sclerosis and experienced at least 7 attacks per week. Patients were randomized to receive modified-release sildenafil (100 mg once daily for 3 days, titrated to 200 mg once daily for 25 days) or placebo, reported Dr. Ariane Herrick of the University of Manchester (England) and her associates (Arthritis Rheum. 2011;63:775-82).

Of the 57 people originally enrolled, 20 in the treatment group and 25 controls completed the 28-day study and were entered into analysis. Patients kept treatment diaries before and during the study period, recording the duration and pain intensity of each attack; serum samples were taken on days 1, 7, and 28.

The primary end point was the percent change in the number of weekly RP attacks. Secondary end points measured the severity and duration of attacks.

After 28 days, the mean number of RP attacks per week lessened from 25 at baseline to 19 in the control arm, and from 31 at baseline to 19 in the treatment arm, with a mean percent reduction of 44% in the treatment arm, compared with 18% in the control arm (P = .034). Statistically insignificant differences were noted between the groups for Raynaud’s Condition Score, duration of attacks, pain score, endothelial dysfunction, or serum biomarkers associated with RP. The most frequent adverse events reported were headache and dyspepsia.

Dr. Ulf Müller-Ladner, professor of internal medicine and rheumatology at Justus-Liebig University Giessen (Germany), said in an interview that this "is a very important study, as we do not have too many controlled clinical trials for Raynaud’s, and every controlled study showing efficacy is very helpful for daily practice." The investigators acknowledged the study’s small size and high attrition from the intention-to-treat sildenafil arm as limitations, particularly as the study was no longer powered to detect secondary end points. Also disappointing, they wrote, was that the endothelial dysfunction measures and the serum levels of biomarkers were similar between the groups.

The study's short duration was another possible limitation. The findings from an earlier, longer (5.2-month) study of sildenafil in 16 patients with systemic sclerosis – of whom 7 had limited cutaneous involvement – showed statistically significant lessening of attack pain associated with RP with the maximum tolerated dose of sildenafil (Ann. Rheum. Dis. 2010;69:1475-8).

Finally, they noted, the modified-release formulation of sildenafil may not have provided the most effective dose for the patient population studied.

Dr. Müller-Ladner agreed with the description of the study's design weaknesses: "The shortcomings of the present study are its placebo arm and its short duration. These results must be confirmed through the initiation of a large, multinational, longer-term trial."

The trial was funded by Pfizer, the drug's manufacturer. Dr. Herrick acknowledged financial relationships with Actelion, Mediquest, Pfizer, and United Therapeutics. Several of the coinvestigators also made relevant financial disclosures. Dr. Müller-Ladner had no relevant financial disclosures.

The drug sildenafil reduced the frequency of attacks of Raynaud's phenomenon secondary to limited cutaneous systemic sclerosis in a small, randomized, placebo-controlled trial that was reported in Arthritis & Rheumatism.

The study enrolled 57 men and women aged 18-75 years, all of whom both had a diagnosis of Raynaud's phenomenon (RP) secondary to limited cutaneous systemic sclerosis and experienced at least 7 attacks per week. Patients were randomized to receive modified-release sildenafil (100 mg once daily for 3 days, titrated to 200 mg once daily for 25 days) or placebo, reported Dr. Ariane Herrick of the University of Manchester (England) and her associates (Arthritis Rheum. 2011;63:775-82).

Of the 57 people originally enrolled, 20 in the treatment group and 25 controls completed the 28-day study and were entered into analysis. Patients kept treatment diaries before and during the study period, recording the duration and pain intensity of each attack; serum samples were taken on days 1, 7, and 28.

The primary end point was the percent change in the number of weekly RP attacks. Secondary end points measured the severity and duration of attacks.

After 28 days, the mean number of RP attacks per week lessened from 25 at baseline to 19 in the control arm, and from 31 at baseline to 19 in the treatment arm, with a mean percent reduction of 44% in the treatment arm, compared with 18% in the control arm (P = .034). Statistically insignificant differences were noted between the groups for Raynaud’s Condition Score, duration of attacks, pain score, endothelial dysfunction, or serum biomarkers associated with RP. The most frequent adverse events reported were headache and dyspepsia.

Dr. Ulf Müller-Ladner, professor of internal medicine and rheumatology at Justus-Liebig University Giessen (Germany), said in an interview that this "is a very important study, as we do not have too many controlled clinical trials for Raynaud’s, and every controlled study showing efficacy is very helpful for daily practice." The investigators acknowledged the study’s small size and high attrition from the intention-to-treat sildenafil arm as limitations, particularly as the study was no longer powered to detect secondary end points. Also disappointing, they wrote, was that the endothelial dysfunction measures and the serum levels of biomarkers were similar between the groups.

The study's short duration was another possible limitation. The findings from an earlier, longer (5.2-month) study of sildenafil in 16 patients with systemic sclerosis – of whom 7 had limited cutaneous involvement – showed statistically significant lessening of attack pain associated with RP with the maximum tolerated dose of sildenafil (Ann. Rheum. Dis. 2010;69:1475-8).

Finally, they noted, the modified-release formulation of sildenafil may not have provided the most effective dose for the patient population studied.

Dr. Müller-Ladner agreed with the description of the study's design weaknesses: "The shortcomings of the present study are its placebo arm and its short duration. These results must be confirmed through the initiation of a large, multinational, longer-term trial."

The trial was funded by Pfizer, the drug's manufacturer. Dr. Herrick acknowledged financial relationships with Actelion, Mediquest, Pfizer, and United Therapeutics. Several of the coinvestigators also made relevant financial disclosures. Dr. Müller-Ladner had no relevant financial disclosures.