Rheumatoid Arthritis

SAN FRANCISCO — Clinical disease activity lessened rapidly and persistently for 12 weeks in the first study of a spleen tyrosine kinase inhibitor in rheumatoid arthritis, based on findings from a phase II trial reported by Dr. Michael E. Weinblatt of the center for arthritis and joint disease at Brigham and Women's Hospital, Boston.

The double-blind, placebo-controlled study was a pivotal test of whether the novel oral molecule can inhibit inflammation by blocking activation signals in the complex kinase pathway, which serves as a facilitator of cellular activity involving neutrophils, B cells, mast cells, and microphages, he said at the annual meeting of the American College of Rheumatology.

Inhibition of the spleen tyrosine kinase (Syk) pathway is being studied in a variety of immune and inflammatory diseases, including asthma, lymphoma, and autoimmune thrombocytopenia.

In all, 189 patients who had long-standing, active RA and were on background methotrexate therapy, were randomized to receive the drug R788 at twice-daily dosages of 150 mg, 100 mg, 50 mg, or placebo at study sites in the United States and Mexico. An “adaptive” dosing regimen mandated dose reduction at any point that laboratory testing showed a decline in white blood cell count or a decline in liver function.

At 12 weeks, 84% of patients had completed the trial (122 patients who had received R788 and 36 in the placebo group). Any patient who withdrew from the study was treated as a “nonresponder” for the sake of data analysis, said Dr. Weinblatt, who is also professor of medicine at Harvard Medical School, Boston.

By week 1, significantly more patients on morning and evening 100-mg and 150-mg dosages showed an ACR 20 response versus those on a lower dose or placebo. A similar separation could be seen at week 1 and throughout the trial in interleukin-6 and metalloproteinase-3 levels, which were evaluated as surrogate biomarkers for inflammation and bone destruction. By week 12, the primary end point of an ACR 20 response rate was achieved by 72% of patients in the 150-mg group. (See box.) A higher bar, an ACR 70 response, was achieved in 40% of patients in the 150-mg cohort, 33% in the 100-mg group, and just 2% of the 50-mg group, versus 4% of the placebo group.

Remission, as defined by Disease Activity Score, occurred in 22 of 47 (47%) patients receiving the highest dosage, 17 of 49 (35%) patients in the 100-mg group, and 9 of 46 (20%) receiving the 50-mg, twice-daily dosage.

Diarrhea was experienced by 40% of patients receiving the highest dosage, causing one patient to withdraw from the trial. Dizziness, neutropenia, an increase in blood pressure, and a twofold increase in liver transaminases were also seen in patients receiving 150 mg twice daily, he said. Overall a “clear dose-response curve” pointed to an efficacious and safe dose of 100 mg twice daily, as opposed to relative ineffectiveness at 50 mg twice daily and unacceptable toxicity at 150 mg twice a day.

A future phase II study is planned to compare a 100-mg twice-daily dosage with a dosage of 150 mg once daily and placebo, he said.

The researchers disclosed research support from Rigel Pharmaceuticals Inc., the sponsor of the study.

ELSEVIER GLOBAL MEDICAL NEWS

SAN FRANCISCO — Clinical disease activity lessened rapidly and persistently for 12 weeks in the first study of a spleen tyrosine kinase inhibitor in rheumatoid arthritis, based on findings from a phase II trial reported by Dr. Michael E. Weinblatt of the center for arthritis and joint disease at Brigham and Women's Hospital, Boston.

The double-blind, placebo-controlled study was a pivotal test of whether the novel oral molecule can inhibit inflammation by blocking activation signals in the complex kinase pathway, which serves as a facilitator of cellular activity involving neutrophils, B cells, mast cells, and microphages, he said at the annual meeting of the American College of Rheumatology.

Inhibition of the spleen tyrosine kinase (Syk) pathway is being studied in a variety of immune and inflammatory diseases, including asthma, lymphoma, and autoimmune thrombocytopenia.

In all, 189 patients who had long-standing, active RA and were on background methotrexate therapy, were randomized to receive the drug R788 at twice-daily dosages of 150 mg, 100 mg, 50 mg, or placebo at study sites in the United States and Mexico. An “adaptive” dosing regimen mandated dose reduction at any point that laboratory testing showed a decline in white blood cell count or a decline in liver function.

At 12 weeks, 84% of patients had completed the trial (122 patients who had received R788 and 36 in the placebo group). Any patient who withdrew from the study was treated as a “nonresponder” for the sake of data analysis, said Dr. Weinblatt, who is also professor of medicine at Harvard Medical School, Boston.

By week 1, significantly more patients on morning and evening 100-mg and 150-mg dosages showed an ACR 20 response versus those on a lower dose or placebo. A similar separation could be seen at week 1 and throughout the trial in interleukin-6 and metalloproteinase-3 levels, which were evaluated as surrogate biomarkers for inflammation and bone destruction. By week 12, the primary end point of an ACR 20 response rate was achieved by 72% of patients in the 150-mg group. (See box.) A higher bar, an ACR 70 response, was achieved in 40% of patients in the 150-mg cohort, 33% in the 100-mg group, and just 2% of the 50-mg group, versus 4% of the placebo group.

Remission, as defined by Disease Activity Score, occurred in 22 of 47 (47%) patients receiving the highest dosage, 17 of 49 (35%) patients in the 100-mg group, and 9 of 46 (20%) receiving the 50-mg, twice-daily dosage.

Diarrhea was experienced by 40% of patients receiving the highest dosage, causing one patient to withdraw from the trial. Dizziness, neutropenia, an increase in blood pressure, and a twofold increase in liver transaminases were also seen in patients receiving 150 mg twice daily, he said. Overall a “clear dose-response curve” pointed to an efficacious and safe dose of 100 mg twice daily, as opposed to relative ineffectiveness at 50 mg twice daily and unacceptable toxicity at 150 mg twice a day.

A future phase II study is planned to compare a 100-mg twice-daily dosage with a dosage of 150 mg once daily and placebo, he said.

The researchers disclosed research support from Rigel Pharmaceuticals Inc., the sponsor of the study.

ELSEVIER GLOBAL MEDICAL NEWS

SAN FRANCISCO — Clinical disease activity lessened rapidly and persistently for 12 weeks in the first study of a spleen tyrosine kinase inhibitor in rheumatoid arthritis, based on findings from a phase II trial reported by Dr. Michael E. Weinblatt of the center for arthritis and joint disease at Brigham and Women's Hospital, Boston.

The double-blind, placebo-controlled study was a pivotal test of whether the novel oral molecule can inhibit inflammation by blocking activation signals in the complex kinase pathway, which serves as a facilitator of cellular activity involving neutrophils, B cells, mast cells, and microphages, he said at the annual meeting of the American College of Rheumatology.

Inhibition of the spleen tyrosine kinase (Syk) pathway is being studied in a variety of immune and inflammatory diseases, including asthma, lymphoma, and autoimmune thrombocytopenia.

In all, 189 patients who had long-standing, active RA and were on background methotrexate therapy, were randomized to receive the drug R788 at twice-daily dosages of 150 mg, 100 mg, 50 mg, or placebo at study sites in the United States and Mexico. An “adaptive” dosing regimen mandated dose reduction at any point that laboratory testing showed a decline in white blood cell count or a decline in liver function.

At 12 weeks, 84% of patients had completed the trial (122 patients who had received R788 and 36 in the placebo group). Any patient who withdrew from the study was treated as a “nonresponder” for the sake of data analysis, said Dr. Weinblatt, who is also professor of medicine at Harvard Medical School, Boston.

By week 1, significantly more patients on morning and evening 100-mg and 150-mg dosages showed an ACR 20 response versus those on a lower dose or placebo. A similar separation could be seen at week 1 and throughout the trial in interleukin-6 and metalloproteinase-3 levels, which were evaluated as surrogate biomarkers for inflammation and bone destruction. By week 12, the primary end point of an ACR 20 response rate was achieved by 72% of patients in the 150-mg group. (See box.) A higher bar, an ACR 70 response, was achieved in 40% of patients in the 150-mg cohort, 33% in the 100-mg group, and just 2% of the 50-mg group, versus 4% of the placebo group.

Remission, as defined by Disease Activity Score, occurred in 22 of 47 (47%) patients receiving the highest dosage, 17 of 49 (35%) patients in the 100-mg group, and 9 of 46 (20%) receiving the 50-mg, twice-daily dosage.

Diarrhea was experienced by 40% of patients receiving the highest dosage, causing one patient to withdraw from the trial. Dizziness, neutropenia, an increase in blood pressure, and a twofold increase in liver transaminases were also seen in patients receiving 150 mg twice daily, he said. Overall a “clear dose-response curve” pointed to an efficacious and safe dose of 100 mg twice daily, as opposed to relative ineffectiveness at 50 mg twice daily and unacceptable toxicity at 150 mg twice a day.

A future phase II study is planned to compare a 100-mg twice-daily dosage with a dosage of 150 mg once daily and placebo, he said.

The researchers disclosed research support from Rigel Pharmaceuticals Inc., the sponsor of the study.

ELSEVIER GLOBAL MEDICAL NEWS

FORT LAUDERDALE, FLA. — Despite greater understanding of genetic influences and phenotypic manifestations, and the availability of multiple immunomodulatory medications, inflammatory bowel disease continues to pose significant clinical challenges.

Why is IBD of particular interest to rheumatologists? According to Dr. Sunanda Kane, there appear to be several shared mechanisms for inflammation, and there are certainly patients with “overlap” syndromes who have significant rheumatologic abnormalities along with intestinal inflammation.

Trying to understand the common threads—rather than focusing on the differences—of both conditions will ultimately help more patients, she said.

There is mounting evidence of a genetic link between rheumatoid arthritis and inflammatory bowel disease. The STAT4 polymorphism has been found to be associated with increased susceptibility to IBD and rheumatoid arthritis (Arthritis Rheum. 2008;58;9:2598–602).

Further research suggests a link between Th17 cells and interleukin-23. Th17 cells have been implicated in the pathogenesis of rheumatoid arthritis. These cells are found in high numbers in joints with RA-induced inflammatory destruction. Their production is dependent on growth factor IL-23. Findings from animal models show that IL-23 also plays a role in gut inflammation, and loss of IL-23 was associated with a loss of inflammation. Although it remains to be seen whether gut inflammation is totally dependent on Th17, it seems clear that IL-23 plays a significant role there (Ann. Rheum. Diseases 2008;67[suppl. 3]:iii26–9)

“Classically, in inflammatory bowel disease we talk about ulcerative colitis and Crohn's disease, but sometimes there is so much overlap it's hard to tell the difference,” said Dr. Kane of the Mayo Clinic, Rochester, Minn. “We don't fully understand what causes Crohn's and colitis, but we do know that the normal gut is always mildly inflamed. It has to be, because this is what 'tastes' the environment and determines what's friend and what's foe,” she said at a meeting sponsored by RHEUMATOLOGY NEWS and Skin Disease Education Foundation.

Genetic studies revealed genes that predispose to an inability to downregulate gut inflammation, such as the NOD2/CARD15 gene, located at chromosome 16q12.

This gene's product is similar to disease-resistance proteins in plants, and is related to immune response to bacteria. Mutations in this gene are associated with Crohn's disease through abnormal activation of downstream inflammatory cell signaling, she explained.

Diet, smoking, and stress all can contribute to worsening of disease, as can the use of antibiotics—particularly penicillin and the other “-illins”—and non-steroidal anti-inflammatory drugs, she said.

“There is a 30% increased risk of disease flare with regular NSAID use in IBD, so when patients have extraintestinal manifestations or concomitant rheumatologic conditions, we gastroenterologists really have to partner with the rheumatologists to make sure they use drugs other than NSAIDs,” she said.

Treatment also remains challenging, despite the availability of immunomodulating drugs. Infliximab, adalimumab, and certolizumab have been used successfully, but etanercept and onercept have not been superior to placebo, and ulcerative colitis has worsened in patients treated with rituximab for other conditions.

Dr. Kane is a consultant for and receives research support from Elan Pharmaceuticals Inc., Procter & Gamble Co., Shire Pharmaceuticals Group, and UCB Pharma Inc. SDEF and this news organization are owned by Elsevier.

FORT LAUDERDALE, FLA. — Despite greater understanding of genetic influences and phenotypic manifestations, and the availability of multiple immunomodulatory medications, inflammatory bowel disease continues to pose significant clinical challenges.

Why is IBD of particular interest to rheumatologists? According to Dr. Sunanda Kane, there appear to be several shared mechanisms for inflammation, and there are certainly patients with “overlap” syndromes who have significant rheumatologic abnormalities along with intestinal inflammation.

Trying to understand the common threads—rather than focusing on the differences—of both conditions will ultimately help more patients, she said.

There is mounting evidence of a genetic link between rheumatoid arthritis and inflammatory bowel disease. The STAT4 polymorphism has been found to be associated with increased susceptibility to IBD and rheumatoid arthritis (Arthritis Rheum. 2008;58;9:2598–602).

Further research suggests a link between Th17 cells and interleukin-23. Th17 cells have been implicated in the pathogenesis of rheumatoid arthritis. These cells are found in high numbers in joints with RA-induced inflammatory destruction. Their production is dependent on growth factor IL-23. Findings from animal models show that IL-23 also plays a role in gut inflammation, and loss of IL-23 was associated with a loss of inflammation. Although it remains to be seen whether gut inflammation is totally dependent on Th17, it seems clear that IL-23 plays a significant role there (Ann. Rheum. Diseases 2008;67[suppl. 3]:iii26–9)

“Classically, in inflammatory bowel disease we talk about ulcerative colitis and Crohn's disease, but sometimes there is so much overlap it's hard to tell the difference,” said Dr. Kane of the Mayo Clinic, Rochester, Minn. “We don't fully understand what causes Crohn's and colitis, but we do know that the normal gut is always mildly inflamed. It has to be, because this is what 'tastes' the environment and determines what's friend and what's foe,” she said at a meeting sponsored by RHEUMATOLOGY NEWS and Skin Disease Education Foundation.

Genetic studies revealed genes that predispose to an inability to downregulate gut inflammation, such as the NOD2/CARD15 gene, located at chromosome 16q12.

This gene's product is similar to disease-resistance proteins in plants, and is related to immune response to bacteria. Mutations in this gene are associated with Crohn's disease through abnormal activation of downstream inflammatory cell signaling, she explained.

Diet, smoking, and stress all can contribute to worsening of disease, as can the use of antibiotics—particularly penicillin and the other “-illins”—and non-steroidal anti-inflammatory drugs, she said.

“There is a 30% increased risk of disease flare with regular NSAID use in IBD, so when patients have extraintestinal manifestations or concomitant rheumatologic conditions, we gastroenterologists really have to partner with the rheumatologists to make sure they use drugs other than NSAIDs,” she said.

Treatment also remains challenging, despite the availability of immunomodulating drugs. Infliximab, adalimumab, and certolizumab have been used successfully, but etanercept and onercept have not been superior to placebo, and ulcerative colitis has worsened in patients treated with rituximab for other conditions.

Dr. Kane is a consultant for and receives research support from Elan Pharmaceuticals Inc., Procter & Gamble Co., Shire Pharmaceuticals Group, and UCB Pharma Inc. SDEF and this news organization are owned by Elsevier.

FORT LAUDERDALE, FLA. — Despite greater understanding of genetic influences and phenotypic manifestations, and the availability of multiple immunomodulatory medications, inflammatory bowel disease continues to pose significant clinical challenges.

Why is IBD of particular interest to rheumatologists? According to Dr. Sunanda Kane, there appear to be several shared mechanisms for inflammation, and there are certainly patients with “overlap” syndromes who have significant rheumatologic abnormalities along with intestinal inflammation.

Trying to understand the common threads—rather than focusing on the differences—of both conditions will ultimately help more patients, she said.

There is mounting evidence of a genetic link between rheumatoid arthritis and inflammatory bowel disease. The STAT4 polymorphism has been found to be associated with increased susceptibility to IBD and rheumatoid arthritis (Arthritis Rheum. 2008;58;9:2598–602).

Further research suggests a link between Th17 cells and interleukin-23. Th17 cells have been implicated in the pathogenesis of rheumatoid arthritis. These cells are found in high numbers in joints with RA-induced inflammatory destruction. Their production is dependent on growth factor IL-23. Findings from animal models show that IL-23 also plays a role in gut inflammation, and loss of IL-23 was associated with a loss of inflammation. Although it remains to be seen whether gut inflammation is totally dependent on Th17, it seems clear that IL-23 plays a significant role there (Ann. Rheum. Diseases 2008;67[suppl. 3]:iii26–9)

“Classically, in inflammatory bowel disease we talk about ulcerative colitis and Crohn's disease, but sometimes there is so much overlap it's hard to tell the difference,” said Dr. Kane of the Mayo Clinic, Rochester, Minn. “We don't fully understand what causes Crohn's and colitis, but we do know that the normal gut is always mildly inflamed. It has to be, because this is what 'tastes' the environment and determines what's friend and what's foe,” she said at a meeting sponsored by RHEUMATOLOGY NEWS and Skin Disease Education Foundation.

Genetic studies revealed genes that predispose to an inability to downregulate gut inflammation, such as the NOD2/CARD15 gene, located at chromosome 16q12.

This gene's product is similar to disease-resistance proteins in plants, and is related to immune response to bacteria. Mutations in this gene are associated with Crohn's disease through abnormal activation of downstream inflammatory cell signaling, she explained.

Diet, smoking, and stress all can contribute to worsening of disease, as can the use of antibiotics—particularly penicillin and the other “-illins”—and non-steroidal anti-inflammatory drugs, she said.

“There is a 30% increased risk of disease flare with regular NSAID use in IBD, so when patients have extraintestinal manifestations or concomitant rheumatologic conditions, we gastroenterologists really have to partner with the rheumatologists to make sure they use drugs other than NSAIDs,” she said.

Treatment also remains challenging, despite the availability of immunomodulating drugs. Infliximab, adalimumab, and certolizumab have been used successfully, but etanercept and onercept have not been superior to placebo, and ulcerative colitis has worsened in patients treated with rituximab for other conditions.

Dr. Kane is a consultant for and receives research support from Elan Pharmaceuticals Inc., Procter & Gamble Co., Shire Pharmaceuticals Group, and UCB Pharma Inc. SDEF and this news organization are owned by Elsevier.

FORT LAUDERDALE, FLA. — A group of rheumatologists and dermatologists has published new recommendations for treatment of the heterogeneous manifestations of psoriatic arthritis, despite a paucity of randomized trial data.

The Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) performed a formal literature review for the symptoms of peripheral arthritis, skin and nail disease, axial disease, dactylitis, and enthesitis.

Significant challenges exist in the management of PsA, said lead author Dr. Christopher T. Ritchlin. There have been few double-blind, randomized trials that have examined the efficacy of traditional agents such as sulfasalazine and cyclosporine. There is also no evidence that these agents slow radiographic progression or are effective for axial disease, dactylitis, or enthesopathy, said Dr. Ritchlin, professor of medicine and director of clinical immunology, University of Rochester (New York) Medical Center.

“But it's not that we know these drugs don't work—the studies simply haven't been done,” he said at a meeting sponsored by RHEUMATOLOGY NEWS and Skin Disease Education Foundation.

Particularly problematic is the lack of data for methotrexate, with only one older double-blind randomized clinical trial which failed to show efficacy (Arthritis Rheum. 1984;27:376–81).

Improvements in trial design in the intervening years favor newer biologics over older disease-modifying antirheumatic drugs (DMARDs). But while there have been three double-blind trials of tumor necrosis factor (TNF) inhibitors, there have been no head-to-head trials of methotrexate versus a TNF inhibitor.

The recommendations include:

▸ For mild peripheral arthritis, initial treatment can include nonsteroidal anti-inflammatory drugs (NSAIDs) and intra-articular glucocorticoid injections, and for moderate or severe arthritis, DMARDs or TNF inhibitors (Ann. Rheum. Dis. Oct. 24; [Epub doi:10.1136/ard.2008.094946

While TNF inhibitors are recommended for patients who have failed at least one DMARD, patients with poor prognoses can be considered for a TNF agent without DMARD failure. Prognosis is worse in patients with polyarticular disease, an elevated erythrocyte sedimentation rate, previous medication failure, or the presence of joint damage, loss of joint function, or diminished quality of life. Systemic corticosteroids are typically not used in PsA because of the possibility of psoriasis flare upon withdrawal.

▸ For skin disease, first-line therapies include phototherapy, methotrexate, fumaric acid esters, TNF inhibitors, efalizumab, and cyclosporine; second-line therapies include acitretin and alefacept; and third-line therapies include sulfasalazine and hydroxyurea. Nail disease can be managed with retinoids, oral psoralen plus ultraviolet A, cyclosporine, or TNF inhibitors.

▸ For mild to moderate axial disease, treatment includes NSAIDs, physiotherapy, analgesia, and injection of the sacroiliac joint. Moderate to severe involvement of the spine can be treated with TNF inhibitors.

▸ Mild dactylitis typically can be managed with NSAIDs and injected corticosteroids, but if symptoms are resistant DMARDs or infliximab can be tried.

▸ For mild enthesitis, typically of the Achilles' tendon area, NSAIDs, physical therapy, and corticosteroids can be used. Moderate disease can be treated with DMARDs. Severe enthesitis may respond to a TNF inhibitor.

Dr. Ritchlin disclosed grant research support from Centocor Inc. He is a consultant to Abbott Laboratories, Amgen Inc., and Wyeth. SDEF and RHEUMATOLOGY NEWS are owned by Elsevier.

Particularly problematic is a lack of data for methotrexate, with only one older double-blind RCT. DR. RITCHLIN

FORT LAUDERDALE, FLA. — A group of rheumatologists and dermatologists has published new recommendations for treatment of the heterogeneous manifestations of psoriatic arthritis, despite a paucity of randomized trial data.

The Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) performed a formal literature review for the symptoms of peripheral arthritis, skin and nail disease, axial disease, dactylitis, and enthesitis.

Significant challenges exist in the management of PsA, said lead author Dr. Christopher T. Ritchlin. There have been few double-blind, randomized trials that have examined the efficacy of traditional agents such as sulfasalazine and cyclosporine. There is also no evidence that these agents slow radiographic progression or are effective for axial disease, dactylitis, or enthesopathy, said Dr. Ritchlin, professor of medicine and director of clinical immunology, University of Rochester (New York) Medical Center.

“But it's not that we know these drugs don't work—the studies simply haven't been done,” he said at a meeting sponsored by RHEUMATOLOGY NEWS and Skin Disease Education Foundation.

Particularly problematic is the lack of data for methotrexate, with only one older double-blind randomized clinical trial which failed to show efficacy (Arthritis Rheum. 1984;27:376–81).

Improvements in trial design in the intervening years favor newer biologics over older disease-modifying antirheumatic drugs (DMARDs). But while there have been three double-blind trials of tumor necrosis factor (TNF) inhibitors, there have been no head-to-head trials of methotrexate versus a TNF inhibitor.

The recommendations include:

▸ For mild peripheral arthritis, initial treatment can include nonsteroidal anti-inflammatory drugs (NSAIDs) and intra-articular glucocorticoid injections, and for moderate or severe arthritis, DMARDs or TNF inhibitors (Ann. Rheum. Dis. Oct. 24; [Epub doi:10.1136/ard.2008.094946

While TNF inhibitors are recommended for patients who have failed at least one DMARD, patients with poor prognoses can be considered for a TNF agent without DMARD failure. Prognosis is worse in patients with polyarticular disease, an elevated erythrocyte sedimentation rate, previous medication failure, or the presence of joint damage, loss of joint function, or diminished quality of life. Systemic corticosteroids are typically not used in PsA because of the possibility of psoriasis flare upon withdrawal.

▸ For skin disease, first-line therapies include phototherapy, methotrexate, fumaric acid esters, TNF inhibitors, efalizumab, and cyclosporine; second-line therapies include acitretin and alefacept; and third-line therapies include sulfasalazine and hydroxyurea. Nail disease can be managed with retinoids, oral psoralen plus ultraviolet A, cyclosporine, or TNF inhibitors.

▸ For mild to moderate axial disease, treatment includes NSAIDs, physiotherapy, analgesia, and injection of the sacroiliac joint. Moderate to severe involvement of the spine can be treated with TNF inhibitors.

▸ Mild dactylitis typically can be managed with NSAIDs and injected corticosteroids, but if symptoms are resistant DMARDs or infliximab can be tried.

▸ For mild enthesitis, typically of the Achilles' tendon area, NSAIDs, physical therapy, and corticosteroids can be used. Moderate disease can be treated with DMARDs. Severe enthesitis may respond to a TNF inhibitor.

Dr. Ritchlin disclosed grant research support from Centocor Inc. He is a consultant to Abbott Laboratories, Amgen Inc., and Wyeth. SDEF and RHEUMATOLOGY NEWS are owned by Elsevier.

Particularly problematic is a lack of data for methotrexate, with only one older double-blind RCT. DR. RITCHLIN

FORT LAUDERDALE, FLA. — A group of rheumatologists and dermatologists has published new recommendations for treatment of the heterogeneous manifestations of psoriatic arthritis, despite a paucity of randomized trial data.

The Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) performed a formal literature review for the symptoms of peripheral arthritis, skin and nail disease, axial disease, dactylitis, and enthesitis.

Significant challenges exist in the management of PsA, said lead author Dr. Christopher T. Ritchlin. There have been few double-blind, randomized trials that have examined the efficacy of traditional agents such as sulfasalazine and cyclosporine. There is also no evidence that these agents slow radiographic progression or are effective for axial disease, dactylitis, or enthesopathy, said Dr. Ritchlin, professor of medicine and director of clinical immunology, University of Rochester (New York) Medical Center.

“But it's not that we know these drugs don't work—the studies simply haven't been done,” he said at a meeting sponsored by RHEUMATOLOGY NEWS and Skin Disease Education Foundation.

Particularly problematic is the lack of data for methotrexate, with only one older double-blind randomized clinical trial which failed to show efficacy (Arthritis Rheum. 1984;27:376–81).

Improvements in trial design in the intervening years favor newer biologics over older disease-modifying antirheumatic drugs (DMARDs). But while there have been three double-blind trials of tumor necrosis factor (TNF) inhibitors, there have been no head-to-head trials of methotrexate versus a TNF inhibitor.

The recommendations include:

▸ For mild peripheral arthritis, initial treatment can include nonsteroidal anti-inflammatory drugs (NSAIDs) and intra-articular glucocorticoid injections, and for moderate or severe arthritis, DMARDs or TNF inhibitors (Ann. Rheum. Dis. Oct. 24; [Epub doi:10.1136/ard.2008.094946

While TNF inhibitors are recommended for patients who have failed at least one DMARD, patients with poor prognoses can be considered for a TNF agent without DMARD failure. Prognosis is worse in patients with polyarticular disease, an elevated erythrocyte sedimentation rate, previous medication failure, or the presence of joint damage, loss of joint function, or diminished quality of life. Systemic corticosteroids are typically not used in PsA because of the possibility of psoriasis flare upon withdrawal.

▸ For skin disease, first-line therapies include phototherapy, methotrexate, fumaric acid esters, TNF inhibitors, efalizumab, and cyclosporine; second-line therapies include acitretin and alefacept; and third-line therapies include sulfasalazine and hydroxyurea. Nail disease can be managed with retinoids, oral psoralen plus ultraviolet A, cyclosporine, or TNF inhibitors.

▸ For mild to moderate axial disease, treatment includes NSAIDs, physiotherapy, analgesia, and injection of the sacroiliac joint. Moderate to severe involvement of the spine can be treated with TNF inhibitors.

▸ Mild dactylitis typically can be managed with NSAIDs and injected corticosteroids, but if symptoms are resistant DMARDs or infliximab can be tried.

▸ For mild enthesitis, typically of the Achilles' tendon area, NSAIDs, physical therapy, and corticosteroids can be used. Moderate disease can be treated with DMARDs. Severe enthesitis may respond to a TNF inhibitor.

Dr. Ritchlin disclosed grant research support from Centocor Inc. He is a consultant to Abbott Laboratories, Amgen Inc., and Wyeth. SDEF and RHEUMATOLOGY NEWS are owned by Elsevier.

Particularly problematic is a lack of data for methotrexate, with only one older double-blind RCT. DR. RITCHLIN

Data from a Food and Drug Administration registry suggesting an increase in birth defects among women treated with etanercept and infliximab have rekindled controversy over use of tumor necrosis factor blockers in pregnancy.

However, conflicting preliminary data from an ongoing study by the Organization of Teratology Information Specialists (OTIS) argue that anti-tumor necrosis factor agents are safe for this population.

Dr. Christina Chambers, a coinvestigator on the OTIS study, said it was alarmist to recommend avoiding anti-TNF agents in pregnancy, and said that reviews of the FDA adverse events database are “inherently biased.” Based on her group's results, she said, “We're not able to draw any conclusions that suggest that we are seeing any specific pattern of defects, whether major or minor, based on the children that have been evaluated so far.”

Dr. John J. Cush, who is not involved with either of these studies, said in an interview that “the FDA database serves an important role.” However, he agreed that the database has incomplete and biased data.

“There is no reason or convincing data to emphatically deny effective anti-TNF therapy to patients who need it to control their disease, either before or during pregnancy,” he said.

Neither the American College of Rheumatology nor the European League Against Rheumatism have any guidelines concerning treatment during pregnancy, added Dr. Cush, director of the clinical rheumatology program at Baylor Research Institute in Dallas.

The review of the FDA adverse events database, led by Dr. John D. Carter, involved more than 120,000 adverse events for all entries between 1999 and 2005. A total of 41 children with 61 congenital anomalies born to 40 different mothers who were taking a TNF antagonist during pregnancy were recorded (J. Rheumatol. 2008 Dec. 15 [doi:10.3899/jrheum.080545

Overall, 22 of these mothers took etanercept at some point in pregnancy; 19 took infliximab. “In all 41 cases, the TNF-α antagonist was considered the 'primary suspect' as the cause of the birth defect,” wrote Dr. Carter of the division of rheumatology at the University of South Florida, Tampa.

A total of 34 different types of birth defects were seen, 19 of which were part of the VACTERL spectrum (vertebral abnormalities, anal atresia, cardiac defect, tracheoesophageal, renal, and limb abnormalities). “Since congenital anomalies are present in 3%-5% of all live births, and VACTERL occurs in 1.6/10,000 live births, you would expect to see [about] 1.6 cases of VACTERL association in every 300–500 children born with congenital anomalies,” wrote the authors. “We have now seen 2/42 (4.8%) cases of VACTERL” (including 1 case outside of the study period).

In an interview, Dr. Chambers took issue with the VACTERL findings, noting that to include a case as part of the VACTERL spectrum they must exhibit at least three of the seven defects in the spectrum—not just one. And though the authors emphasize that 24 of 41 children (59%) “had one or more congenital anomalies that are part of VACTERL,” only 1 was diagnosed with the pattern of associated birth defects within the original study period, said Dr. Chambers.

Dr. Cush pointed out that there are currently no studies that address the potential effects of stopping anti-TNF therapy before pregnancy, though it could be hazardous. Furthermore, the lack of alternative therapies that approximate the effect of anti-TNFs on disease means that clinicians may have to lean on palliative agents such as prednisone and NSAIDs, “both of which also pose potential harms to mother and child.”

Dr. Carter did not declare any conflicts of interest. Dr. Chambers said she did not have any personal conflicts, but OTIS receives grant funding from nine drug companies, two of which make anti-TNFs. Dr. Cush has served as a consultant or adviser to, or received grant money from, multiple drug companies, including the makers of anti-TNFs.

Data from a Food and Drug Administration registry suggesting an increase in birth defects among women treated with etanercept and infliximab have rekindled controversy over use of tumor necrosis factor blockers in pregnancy.

However, conflicting preliminary data from an ongoing study by the Organization of Teratology Information Specialists (OTIS) argue that anti-tumor necrosis factor agents are safe for this population.

Dr. Christina Chambers, a coinvestigator on the OTIS study, said it was alarmist to recommend avoiding anti-TNF agents in pregnancy, and said that reviews of the FDA adverse events database are “inherently biased.” Based on her group's results, she said, “We're not able to draw any conclusions that suggest that we are seeing any specific pattern of defects, whether major or minor, based on the children that have been evaluated so far.”

Dr. John J. Cush, who is not involved with either of these studies, said in an interview that “the FDA database serves an important role.” However, he agreed that the database has incomplete and biased data.

“There is no reason or convincing data to emphatically deny effective anti-TNF therapy to patients who need it to control their disease, either before or during pregnancy,” he said.

Neither the American College of Rheumatology nor the European League Against Rheumatism have any guidelines concerning treatment during pregnancy, added Dr. Cush, director of the clinical rheumatology program at Baylor Research Institute in Dallas.

The review of the FDA adverse events database, led by Dr. John D. Carter, involved more than 120,000 adverse events for all entries between 1999 and 2005. A total of 41 children with 61 congenital anomalies born to 40 different mothers who were taking a TNF antagonist during pregnancy were recorded (J. Rheumatol. 2008 Dec. 15 [doi:10.3899/jrheum.080545

Overall, 22 of these mothers took etanercept at some point in pregnancy; 19 took infliximab. “In all 41 cases, the TNF-α antagonist was considered the 'primary suspect' as the cause of the birth defect,” wrote Dr. Carter of the division of rheumatology at the University of South Florida, Tampa.

A total of 34 different types of birth defects were seen, 19 of which were part of the VACTERL spectrum (vertebral abnormalities, anal atresia, cardiac defect, tracheoesophageal, renal, and limb abnormalities). “Since congenital anomalies are present in 3%-5% of all live births, and VACTERL occurs in 1.6/10,000 live births, you would expect to see [about] 1.6 cases of VACTERL association in every 300–500 children born with congenital anomalies,” wrote the authors. “We have now seen 2/42 (4.8%) cases of VACTERL” (including 1 case outside of the study period).

In an interview, Dr. Chambers took issue with the VACTERL findings, noting that to include a case as part of the VACTERL spectrum they must exhibit at least three of the seven defects in the spectrum—not just one. And though the authors emphasize that 24 of 41 children (59%) “had one or more congenital anomalies that are part of VACTERL,” only 1 was diagnosed with the pattern of associated birth defects within the original study period, said Dr. Chambers.

Dr. Cush pointed out that there are currently no studies that address the potential effects of stopping anti-TNF therapy before pregnancy, though it could be hazardous. Furthermore, the lack of alternative therapies that approximate the effect of anti-TNFs on disease means that clinicians may have to lean on palliative agents such as prednisone and NSAIDs, “both of which also pose potential harms to mother and child.”

Dr. Carter did not declare any conflicts of interest. Dr. Chambers said she did not have any personal conflicts, but OTIS receives grant funding from nine drug companies, two of which make anti-TNFs. Dr. Cush has served as a consultant or adviser to, or received grant money from, multiple drug companies, including the makers of anti-TNFs.

Data from a Food and Drug Administration registry suggesting an increase in birth defects among women treated with etanercept and infliximab have rekindled controversy over use of tumor necrosis factor blockers in pregnancy.

However, conflicting preliminary data from an ongoing study by the Organization of Teratology Information Specialists (OTIS) argue that anti-tumor necrosis factor agents are safe for this population.

Dr. Christina Chambers, a coinvestigator on the OTIS study, said it was alarmist to recommend avoiding anti-TNF agents in pregnancy, and said that reviews of the FDA adverse events database are “inherently biased.” Based on her group's results, she said, “We're not able to draw any conclusions that suggest that we are seeing any specific pattern of defects, whether major or minor, based on the children that have been evaluated so far.”

Dr. John J. Cush, who is not involved with either of these studies, said in an interview that “the FDA database serves an important role.” However, he agreed that the database has incomplete and biased data.

“There is no reason or convincing data to emphatically deny effective anti-TNF therapy to patients who need it to control their disease, either before or during pregnancy,” he said.

Neither the American College of Rheumatology nor the European League Against Rheumatism have any guidelines concerning treatment during pregnancy, added Dr. Cush, director of the clinical rheumatology program at Baylor Research Institute in Dallas.

The review of the FDA adverse events database, led by Dr. John D. Carter, involved more than 120,000 adverse events for all entries between 1999 and 2005. A total of 41 children with 61 congenital anomalies born to 40 different mothers who were taking a TNF antagonist during pregnancy were recorded (J. Rheumatol. 2008 Dec. 15 [doi:10.3899/jrheum.080545

Overall, 22 of these mothers took etanercept at some point in pregnancy; 19 took infliximab. “In all 41 cases, the TNF-α antagonist was considered the 'primary suspect' as the cause of the birth defect,” wrote Dr. Carter of the division of rheumatology at the University of South Florida, Tampa.

A total of 34 different types of birth defects were seen, 19 of which were part of the VACTERL spectrum (vertebral abnormalities, anal atresia, cardiac defect, tracheoesophageal, renal, and limb abnormalities). “Since congenital anomalies are present in 3%-5% of all live births, and VACTERL occurs in 1.6/10,000 live births, you would expect to see [about] 1.6 cases of VACTERL association in every 300–500 children born with congenital anomalies,” wrote the authors. “We have now seen 2/42 (4.8%) cases of VACTERL” (including 1 case outside of the study period).

In an interview, Dr. Chambers took issue with the VACTERL findings, noting that to include a case as part of the VACTERL spectrum they must exhibit at least three of the seven defects in the spectrum—not just one. And though the authors emphasize that 24 of 41 children (59%) “had one or more congenital anomalies that are part of VACTERL,” only 1 was diagnosed with the pattern of associated birth defects within the original study period, said Dr. Chambers.

Dr. Cush pointed out that there are currently no studies that address the potential effects of stopping anti-TNF therapy before pregnancy, though it could be hazardous. Furthermore, the lack of alternative therapies that approximate the effect of anti-TNFs on disease means that clinicians may have to lean on palliative agents such as prednisone and NSAIDs, “both of which also pose potential harms to mother and child.”

Dr. Carter did not declare any conflicts of interest. Dr. Chambers said she did not have any personal conflicts, but OTIS receives grant funding from nine drug companies, two of which make anti-TNFs. Dr. Cush has served as a consultant or adviser to, or received grant money from, multiple drug companies, including the makers of anti-TNFs.

SAN FRANCISCO — An observational study of 395 patients with suspected early arthritis identified two factors that predicted a diagnosis of rheumatoid arthritis within a year's time.

Patients with swelling in a small joint of the hands and/or feet were six times more likely to be diagnosed with RA within a year than were patients whose swollen joints did not include those sites. A diagnosis was 39 times more likely in patients whose laboratory tests at baseline showed the presence of anti-cyclic citrullinated peptide antibodies, versus anti-CCP-negative patients, Dr. Maria D. Mjaavatten said at the annual meeting of the American College of Rheumatology.

The same factors also predicted (to a lesser degree) persistent arthritis and of subsequent use of disease-modifying antirheumatic drugs within a year, added Dr. Mjaavatten of the rheumatology department at Diakonhjemmet Hospital, Oslo.

Patients with small-joint arthritis were twice as likely to develop persistent arthritis and four times as likely to start a DMARD within a year compared with patients without small-joint involvement. Patients with anti-CCP positivity were five times more likely to develop persistent arthritis and nine times more likely to start a DMARD compared with anti-CCP-negative patients.

The results will help inform an ongoing effort by a joint European-American task force to define new diagnostic criteria for early rheumatoid arthritis, Dr. Mjaavatten said. Classification criteria from the ACR were developed in 1997 for established disease and are not as useful in early arthritis. The ACR and the European League Against Rheumatism convened the current task force.

The study enrolled adult patients with at least a 16-week history of one or more clinically swollen joints diagnosed as arthritis by rheumatologists at one of five Norwegian centers, and followed patients for at least a year. Although physicians were aware of the ACR diagnostic criteria for rheumatoid arthritis, diagnoses were not limited to patients who met those criteria, Dr. Mjaavatten noted.

The cohort represented approximately 70% of all patients enrolled. The other 30% were lost to follow-up before completing at least two follow-up assessments and were presumed to have nonpersistent arthritis. The study defined persistent arthritis as the presence of joint swelling on at least two out of three follow-up assessments during the first year.

The cohort was younger (mean age, 46) and included fewer women (57%) than a “typical” RA cohort, she noted. The mean arthritis duration at baseline was very short (30 days), with a duration of 10 days or less in a quarter of the patients.

During the year of follow-up, 18% of patients were diagnosed with rheumatoid arthritis and 26% had persistent arthritis. Among 301 patients whose charts had information on DMARDs, 36% started a DMARD during the year. Methotrexate was the dominant drug, used by 59% of patients on a DMARD. Another 9% used sulfasalazine, 28% took a combination of DMARDs or more than one DMARD during the year (including 13 patients who received biologics), and 4% used other DMARDs.

Some patients had more than one of the three main outcomes: an RA diagnosis, persistent arthritis, or DMARD use.

DMARDs were not started in about 5% of patients diagnosed with RA and about 15% of patients with persistent arthritis, Dr. Mjaavatten said. Around 16% of DMARD users had neither a diagnosis of RA nor persistent arthritis. At presentation, 38% of patients had single-joint arthritis, 33% had two to four swollen joints, and 29% had polyarthritis.

Dr. Mjaavatten reported no conflicts of interest relevant to this study.

SAN FRANCISCO — An observational study of 395 patients with suspected early arthritis identified two factors that predicted a diagnosis of rheumatoid arthritis within a year's time.

Patients with swelling in a small joint of the hands and/or feet were six times more likely to be diagnosed with RA within a year than were patients whose swollen joints did not include those sites. A diagnosis was 39 times more likely in patients whose laboratory tests at baseline showed the presence of anti-cyclic citrullinated peptide antibodies, versus anti-CCP-negative patients, Dr. Maria D. Mjaavatten said at the annual meeting of the American College of Rheumatology.

The same factors also predicted (to a lesser degree) persistent arthritis and of subsequent use of disease-modifying antirheumatic drugs within a year, added Dr. Mjaavatten of the rheumatology department at Diakonhjemmet Hospital, Oslo.

Patients with small-joint arthritis were twice as likely to develop persistent arthritis and four times as likely to start a DMARD within a year compared with patients without small-joint involvement. Patients with anti-CCP positivity were five times more likely to develop persistent arthritis and nine times more likely to start a DMARD compared with anti-CCP-negative patients.

The results will help inform an ongoing effort by a joint European-American task force to define new diagnostic criteria for early rheumatoid arthritis, Dr. Mjaavatten said. Classification criteria from the ACR were developed in 1997 for established disease and are not as useful in early arthritis. The ACR and the European League Against Rheumatism convened the current task force.

The study enrolled adult patients with at least a 16-week history of one or more clinically swollen joints diagnosed as arthritis by rheumatologists at one of five Norwegian centers, and followed patients for at least a year. Although physicians were aware of the ACR diagnostic criteria for rheumatoid arthritis, diagnoses were not limited to patients who met those criteria, Dr. Mjaavatten noted.

The cohort represented approximately 70% of all patients enrolled. The other 30% were lost to follow-up before completing at least two follow-up assessments and were presumed to have nonpersistent arthritis. The study defined persistent arthritis as the presence of joint swelling on at least two out of three follow-up assessments during the first year.

The cohort was younger (mean age, 46) and included fewer women (57%) than a “typical” RA cohort, she noted. The mean arthritis duration at baseline was very short (30 days), with a duration of 10 days or less in a quarter of the patients.

During the year of follow-up, 18% of patients were diagnosed with rheumatoid arthritis and 26% had persistent arthritis. Among 301 patients whose charts had information on DMARDs, 36% started a DMARD during the year. Methotrexate was the dominant drug, used by 59% of patients on a DMARD. Another 9% used sulfasalazine, 28% took a combination of DMARDs or more than one DMARD during the year (including 13 patients who received biologics), and 4% used other DMARDs.

Some patients had more than one of the three main outcomes: an RA diagnosis, persistent arthritis, or DMARD use.

DMARDs were not started in about 5% of patients diagnosed with RA and about 15% of patients with persistent arthritis, Dr. Mjaavatten said. Around 16% of DMARD users had neither a diagnosis of RA nor persistent arthritis. At presentation, 38% of patients had single-joint arthritis, 33% had two to four swollen joints, and 29% had polyarthritis.

Dr. Mjaavatten reported no conflicts of interest relevant to this study.

SAN FRANCISCO — An observational study of 395 patients with suspected early arthritis identified two factors that predicted a diagnosis of rheumatoid arthritis within a year's time.

Patients with swelling in a small joint of the hands and/or feet were six times more likely to be diagnosed with RA within a year than were patients whose swollen joints did not include those sites. A diagnosis was 39 times more likely in patients whose laboratory tests at baseline showed the presence of anti-cyclic citrullinated peptide antibodies, versus anti-CCP-negative patients, Dr. Maria D. Mjaavatten said at the annual meeting of the American College of Rheumatology.

The same factors also predicted (to a lesser degree) persistent arthritis and of subsequent use of disease-modifying antirheumatic drugs within a year, added Dr. Mjaavatten of the rheumatology department at Diakonhjemmet Hospital, Oslo.

Patients with small-joint arthritis were twice as likely to develop persistent arthritis and four times as likely to start a DMARD within a year compared with patients without small-joint involvement. Patients with anti-CCP positivity were five times more likely to develop persistent arthritis and nine times more likely to start a DMARD compared with anti-CCP-negative patients.

The results will help inform an ongoing effort by a joint European-American task force to define new diagnostic criteria for early rheumatoid arthritis, Dr. Mjaavatten said. Classification criteria from the ACR were developed in 1997 for established disease and are not as useful in early arthritis. The ACR and the European League Against Rheumatism convened the current task force.

The study enrolled adult patients with at least a 16-week history of one or more clinically swollen joints diagnosed as arthritis by rheumatologists at one of five Norwegian centers, and followed patients for at least a year. Although physicians were aware of the ACR diagnostic criteria for rheumatoid arthritis, diagnoses were not limited to patients who met those criteria, Dr. Mjaavatten noted.

The cohort represented approximately 70% of all patients enrolled. The other 30% were lost to follow-up before completing at least two follow-up assessments and were presumed to have nonpersistent arthritis. The study defined persistent arthritis as the presence of joint swelling on at least two out of three follow-up assessments during the first year.

The cohort was younger (mean age, 46) and included fewer women (57%) than a “typical” RA cohort, she noted. The mean arthritis duration at baseline was very short (30 days), with a duration of 10 days or less in a quarter of the patients.

During the year of follow-up, 18% of patients were diagnosed with rheumatoid arthritis and 26% had persistent arthritis. Among 301 patients whose charts had information on DMARDs, 36% started a DMARD during the year. Methotrexate was the dominant drug, used by 59% of patients on a DMARD. Another 9% used sulfasalazine, 28% took a combination of DMARDs or more than one DMARD during the year (including 13 patients who received biologics), and 4% used other DMARDs.

Some patients had more than one of the three main outcomes: an RA diagnosis, persistent arthritis, or DMARD use.

DMARDs were not started in about 5% of patients diagnosed with RA and about 15% of patients with persistent arthritis, Dr. Mjaavatten said. Around 16% of DMARD users had neither a diagnosis of RA nor persistent arthritis. At presentation, 38% of patients had single-joint arthritis, 33% had two to four swollen joints, and 29% had polyarthritis.

Dr. Mjaavatten reported no conflicts of interest relevant to this study.

SAN FRANCISCO — Clinicians detected underlying rheumatic disease in 17 of 28 patients referred to a multidisciplinary clinic for interstitial lung disease.

The evaluations changed the diagnosis in 11 of the 28 patients, including 4 of 15 patients who had been referred for idiopathic interstitial lung disease and 7 of 13 who had been referred for rheumatic disease related to interstitial lung disease.

As a result, clinicians changed therapy for 14 (50%) of the patients, Dr. Flavia V. Castelino and her associates reported at the annual meeting of the American College of Rheumatology.

The results emphasize that all patients with interstitial lung disease should be evaluated by a rheumatologist, concluded Dr. Castelino of Massachusetts General Hospital, Boston.

Distinguishing between interstitial lung disease that is idiopathic versus related to rheumatic disease is important because the former carries a worse prognosis, and the response to treatment may differ, she said.

A separate retrospective study of 362 cases of interstitial lung disease found 5-year survival rates of approximately 40% with idiopathic disease and approximately 70% with cases that were associated with rheumatic disease (Am. J. Resp. Crit. Care Med. 2007;175:705–11).

The difference in prognosis is thought to be related to the major lung histopathology, previously published studies suggest.

For example, nonspecific interstitial pneumonia was present in 4 (9%) of 47 patients with idiopathic interstitial lung disease and in 23 (83%) of 28 patients with undifferentiated connective tissue disease and interstitial lung disease in one study (Am. J. Resp. Crit. Care Med. 2007;176:691–7).

A separate, recently published study of 39 cases of interstitial lung disease found that community physicians were more likely to diagnose the condition as idiopathic disease, compared with retrospective diagnoses from a multidisciplinary academic team review conducted by a group of pulmonologists, radiologists, and pathologists (Am. J. Resp. Crit. Care Med. 2007;175:1054–60).

In the current prospective study of patients referred by pulmonologists over an 8-month period to a new multidisciplinary clinic at Brigham and Women's Hospital, Boston, all patients were evaluated by a pulmonologist and a rheumatologist, who took a complete history and physical examination (including capillary microscopy) and reviewed laboratory and serologic data.

The physicians also reviewed available imaging and pathologic specimens in consultation with a dedicated radiologist and a pathologist experienced in interstitial lung disease.

Additional serologic tests, imaging, or biopsies were performed at the discretion of the clinic physicians.

They initiated or changed therapy in collaboration with the referring physician.

Evaluations by a rheumatologist significantly affected diagnoses because of additional serologic testing (such as a myositis panel) and because the rheumatologist was able to elicit subtle clues suggestive of a rheumatologic diagnosis.

Recognition of “mechanic's hands,” periungual erythema, abnormal capillary microscopy and inflammatory arthritis led to new diagnoses including antisynthetase syndrome, systemic sclerosis, rheumatoid arthritis-associated interstitial lung disease, mixed connective tissue disease, dermatomyositis, and also undifferentiated connective tissue disease.

The patient cohort was half female, with a median age of 63 years and a history of smoking in 23 (82%) of patients.

The multidisciplinary interstitial lung disease clinic now meets weekly and has evaluated an additional 28 patients.

In this group, diagnoses were changed in eight patients, including five patients referred for idiopathic disease who were ultimately found to have rheumatic disease-related interstitial lung disease, Dr. Castelino commented.

The investigators reported having no potential conflicts of interest related to this study.

Rheumatologists' recognition of rheumatic lung disease changed therapy in 50% of cases. DR. CASTELINO

SAN FRANCISCO — Clinicians detected underlying rheumatic disease in 17 of 28 patients referred to a multidisciplinary clinic for interstitial lung disease.

The evaluations changed the diagnosis in 11 of the 28 patients, including 4 of 15 patients who had been referred for idiopathic interstitial lung disease and 7 of 13 who had been referred for rheumatic disease related to interstitial lung disease.

As a result, clinicians changed therapy for 14 (50%) of the patients, Dr. Flavia V. Castelino and her associates reported at the annual meeting of the American College of Rheumatology.

The results emphasize that all patients with interstitial lung disease should be evaluated by a rheumatologist, concluded Dr. Castelino of Massachusetts General Hospital, Boston.

Distinguishing between interstitial lung disease that is idiopathic versus related to rheumatic disease is important because the former carries a worse prognosis, and the response to treatment may differ, she said.

A separate retrospective study of 362 cases of interstitial lung disease found 5-year survival rates of approximately 40% with idiopathic disease and approximately 70% with cases that were associated with rheumatic disease (Am. J. Resp. Crit. Care Med. 2007;175:705–11).

The difference in prognosis is thought to be related to the major lung histopathology, previously published studies suggest.

For example, nonspecific interstitial pneumonia was present in 4 (9%) of 47 patients with idiopathic interstitial lung disease and in 23 (83%) of 28 patients with undifferentiated connective tissue disease and interstitial lung disease in one study (Am. J. Resp. Crit. Care Med. 2007;176:691–7).

A separate, recently published study of 39 cases of interstitial lung disease found that community physicians were more likely to diagnose the condition as idiopathic disease, compared with retrospective diagnoses from a multidisciplinary academic team review conducted by a group of pulmonologists, radiologists, and pathologists (Am. J. Resp. Crit. Care Med. 2007;175:1054–60).

In the current prospective study of patients referred by pulmonologists over an 8-month period to a new multidisciplinary clinic at Brigham and Women's Hospital, Boston, all patients were evaluated by a pulmonologist and a rheumatologist, who took a complete history and physical examination (including capillary microscopy) and reviewed laboratory and serologic data.

The physicians also reviewed available imaging and pathologic specimens in consultation with a dedicated radiologist and a pathologist experienced in interstitial lung disease.

Additional serologic tests, imaging, or biopsies were performed at the discretion of the clinic physicians.

They initiated or changed therapy in collaboration with the referring physician.

Evaluations by a rheumatologist significantly affected diagnoses because of additional serologic testing (such as a myositis panel) and because the rheumatologist was able to elicit subtle clues suggestive of a rheumatologic diagnosis.

Recognition of “mechanic's hands,” periungual erythema, abnormal capillary microscopy and inflammatory arthritis led to new diagnoses including antisynthetase syndrome, systemic sclerosis, rheumatoid arthritis-associated interstitial lung disease, mixed connective tissue disease, dermatomyositis, and also undifferentiated connective tissue disease.

The patient cohort was half female, with a median age of 63 years and a history of smoking in 23 (82%) of patients.

The multidisciplinary interstitial lung disease clinic now meets weekly and has evaluated an additional 28 patients.

In this group, diagnoses were changed in eight patients, including five patients referred for idiopathic disease who were ultimately found to have rheumatic disease-related interstitial lung disease, Dr. Castelino commented.

The investigators reported having no potential conflicts of interest related to this study.

Rheumatologists' recognition of rheumatic lung disease changed therapy in 50% of cases. DR. CASTELINO

SAN FRANCISCO — Clinicians detected underlying rheumatic disease in 17 of 28 patients referred to a multidisciplinary clinic for interstitial lung disease.

The evaluations changed the diagnosis in 11 of the 28 patients, including 4 of 15 patients who had been referred for idiopathic interstitial lung disease and 7 of 13 who had been referred for rheumatic disease related to interstitial lung disease.

As a result, clinicians changed therapy for 14 (50%) of the patients, Dr. Flavia V. Castelino and her associates reported at the annual meeting of the American College of Rheumatology.

The results emphasize that all patients with interstitial lung disease should be evaluated by a rheumatologist, concluded Dr. Castelino of Massachusetts General Hospital, Boston.

Distinguishing between interstitial lung disease that is idiopathic versus related to rheumatic disease is important because the former carries a worse prognosis, and the response to treatment may differ, she said.

A separate retrospective study of 362 cases of interstitial lung disease found 5-year survival rates of approximately 40% with idiopathic disease and approximately 70% with cases that were associated with rheumatic disease (Am. J. Resp. Crit. Care Med. 2007;175:705–11).

The difference in prognosis is thought to be related to the major lung histopathology, previously published studies suggest.

For example, nonspecific interstitial pneumonia was present in 4 (9%) of 47 patients with idiopathic interstitial lung disease and in 23 (83%) of 28 patients with undifferentiated connective tissue disease and interstitial lung disease in one study (Am. J. Resp. Crit. Care Med. 2007;176:691–7).

A separate, recently published study of 39 cases of interstitial lung disease found that community physicians were more likely to diagnose the condition as idiopathic disease, compared with retrospective diagnoses from a multidisciplinary academic team review conducted by a group of pulmonologists, radiologists, and pathologists (Am. J. Resp. Crit. Care Med. 2007;175:1054–60).

In the current prospective study of patients referred by pulmonologists over an 8-month period to a new multidisciplinary clinic at Brigham and Women's Hospital, Boston, all patients were evaluated by a pulmonologist and a rheumatologist, who took a complete history and physical examination (including capillary microscopy) and reviewed laboratory and serologic data.

The physicians also reviewed available imaging and pathologic specimens in consultation with a dedicated radiologist and a pathologist experienced in interstitial lung disease.

Additional serologic tests, imaging, or biopsies were performed at the discretion of the clinic physicians.

They initiated or changed therapy in collaboration with the referring physician.

Evaluations by a rheumatologist significantly affected diagnoses because of additional serologic testing (such as a myositis panel) and because the rheumatologist was able to elicit subtle clues suggestive of a rheumatologic diagnosis.

Recognition of “mechanic's hands,” periungual erythema, abnormal capillary microscopy and inflammatory arthritis led to new diagnoses including antisynthetase syndrome, systemic sclerosis, rheumatoid arthritis-associated interstitial lung disease, mixed connective tissue disease, dermatomyositis, and also undifferentiated connective tissue disease.

The patient cohort was half female, with a median age of 63 years and a history of smoking in 23 (82%) of patients.

The multidisciplinary interstitial lung disease clinic now meets weekly and has evaluated an additional 28 patients.

In this group, diagnoses were changed in eight patients, including five patients referred for idiopathic disease who were ultimately found to have rheumatic disease-related interstitial lung disease, Dr. Castelino commented.

The investigators reported having no potential conflicts of interest related to this study.

Rheumatologists' recognition of rheumatic lung disease changed therapy in 50% of cases. DR. CASTELINO

SAN FRANCISCO — Patients with rheumatoid arthritis have a “markedly” lower mean left ventricular mass than do age-matched controls, a finding that provides what may be a significant clue to elevated cardiovascular mortality in this population, according to a group of Maryland researchers.

The specific mechanisms underlying cardiovascular risk are only now being fully explored in this population, in part because RA patients often fail to present with the classic early signs and symptoms of cardiac disease, commented Dr. Jon Giles, who is a rheumatologist at the Johns Hopkins Division of Rheumatology in Baltimore, in a presentation given at the recent annual meeting of the American College of Rheumatology.

For example, Dr. Giles cited heart failure rates that are “nearly doubled” in RA patients.

Yet, “little is known about the myocardial changes that precede clinical heart failure in these patients,” he said.

Dr. Giles and his associates turned to cardiac MRI, a highly sensitive tool for assessing left ventricular structure and function, to hunt for preclinical risk factors for heart failure.

Rheumatoid arthritis patients with moderate disease (average 7 years' duration) who enrolled in the ESCAPE RA trial (n = 75) were compared with 775 participants in the Multi-Ethnic Study of Atherosclerosis who did not have RA. None of the members of either group had a history of cardiovascular events or procedures.

The rheumatoid arthritis cohort was younger than was the control group (mean age 59, compared with 63), and was also less likely to have a diagnosis of diabetes (4% versus 14%) or hypertension (32% versus 49%).

However, the patients' mean unadjusted left ventricular mass was 18% lower (120 g/m

The difference was particularly pronounced for male patients with RA, whose mean adjusted left ventricular mass was found to be fully 19% lower than that of men who did not have a rheumatoid arthritis diagnosis.

Female rheumatoid arthritis patients had a 9% lower left ventricular mass than did women without the inflammatory disease.

In both the RA and control groups, mean left ventricular mass decreased with age.

However, it was lower in rheumatoid arthritis patients than in controls in every age group, including the youngest patients in the study.

“In fact, the mean left ventricular mass was lower in 45-year-old RA patients than mean left ventricular mass in 80-year-old control patients, regardless of gender,” Dr. Giles commented during his podium presentation.

Left ventricular stroke volume was marginally lower in RA patients than in controls, significantly so in men.

“Small but significant” reductions in adjusted mean ejection fraction were seen as well, Dr. Giles said.

No differences were seen in RA patients and controls with regard to adjusted mean end diastolic volume.

The Johns Hopkins team also explored potentially significant associations between cardiovascular risk markers and RA disease characteristics such as disease severity, activity, treatment, and systemic inflammation.

They found only two factors that were independently associated with left ventricular mass, stroke volume, and end diastolic volume in rheumatoid arthritis patients.

One factor was increased anti-cyclic citrullinated peptide antibodies.

The other was the use of biological disease-modifying drugs (predominantly tumor necrosis factor-α inhibitors).

No characteristics were associated with ejection fraction.

The study findings raise intriguing questions about whether rheumatoid arthritis and its treatment heighten patients' cardiovascular risk through different mechanisms than in the general, non-RA population, said Dr. Giles.

For example, markedly lower left ventricular mass may reflect the “aftereffects” of subclinical myocarditis.

On the other hand, lower left ventricular mass measurements “may support the concept that RA is a disorder of accelerated aging,” he said.

Dr. Giles and his associates reported having no financial conflicts of interest with regard to this study.

ELSEVIER GLOBAL MEDICAL NEWS

SAN FRANCISCO — Patients with rheumatoid arthritis have a “markedly” lower mean left ventricular mass than do age-matched controls, a finding that provides what may be a significant clue to elevated cardiovascular mortality in this population, according to a group of Maryland researchers.

The specific mechanisms underlying cardiovascular risk are only now being fully explored in this population, in part because RA patients often fail to present with the classic early signs and symptoms of cardiac disease, commented Dr. Jon Giles, who is a rheumatologist at the Johns Hopkins Division of Rheumatology in Baltimore, in a presentation given at the recent annual meeting of the American College of Rheumatology.

For example, Dr. Giles cited heart failure rates that are “nearly doubled” in RA patients.

Yet, “little is known about the myocardial changes that precede clinical heart failure in these patients,” he said.

Dr. Giles and his associates turned to cardiac MRI, a highly sensitive tool for assessing left ventricular structure and function, to hunt for preclinical risk factors for heart failure.

Rheumatoid arthritis patients with moderate disease (average 7 years' duration) who enrolled in the ESCAPE RA trial (n = 75) were compared with 775 participants in the Multi-Ethnic Study of Atherosclerosis who did not have RA. None of the members of either group had a history of cardiovascular events or procedures.

The rheumatoid arthritis cohort was younger than was the control group (mean age 59, compared with 63), and was also less likely to have a diagnosis of diabetes (4% versus 14%) or hypertension (32% versus 49%).

However, the patients' mean unadjusted left ventricular mass was 18% lower (120 g/m

The difference was particularly pronounced for male patients with RA, whose mean adjusted left ventricular mass was found to be fully 19% lower than that of men who did not have a rheumatoid arthritis diagnosis.

Female rheumatoid arthritis patients had a 9% lower left ventricular mass than did women without the inflammatory disease.

In both the RA and control groups, mean left ventricular mass decreased with age.

However, it was lower in rheumatoid arthritis patients than in controls in every age group, including the youngest patients in the study.

“In fact, the mean left ventricular mass was lower in 45-year-old RA patients than mean left ventricular mass in 80-year-old control patients, regardless of gender,” Dr. Giles commented during his podium presentation.

Left ventricular stroke volume was marginally lower in RA patients than in controls, significantly so in men.

“Small but significant” reductions in adjusted mean ejection fraction were seen as well, Dr. Giles said.

No differences were seen in RA patients and controls with regard to adjusted mean end diastolic volume.

The Johns Hopkins team also explored potentially significant associations between cardiovascular risk markers and RA disease characteristics such as disease severity, activity, treatment, and systemic inflammation.

They found only two factors that were independently associated with left ventricular mass, stroke volume, and end diastolic volume in rheumatoid arthritis patients.

One factor was increased anti-cyclic citrullinated peptide antibodies.

The other was the use of biological disease-modifying drugs (predominantly tumor necrosis factor-α inhibitors).

No characteristics were associated with ejection fraction.

The study findings raise intriguing questions about whether rheumatoid arthritis and its treatment heighten patients' cardiovascular risk through different mechanisms than in the general, non-RA population, said Dr. Giles.

For example, markedly lower left ventricular mass may reflect the “aftereffects” of subclinical myocarditis.

On the other hand, lower left ventricular mass measurements “may support the concept that RA is a disorder of accelerated aging,” he said.

Dr. Giles and his associates reported having no financial conflicts of interest with regard to this study.

ELSEVIER GLOBAL MEDICAL NEWS

SAN FRANCISCO — Patients with rheumatoid arthritis have a “markedly” lower mean left ventricular mass than do age-matched controls, a finding that provides what may be a significant clue to elevated cardiovascular mortality in this population, according to a group of Maryland researchers.

The specific mechanisms underlying cardiovascular risk are only now being fully explored in this population, in part because RA patients often fail to present with the classic early signs and symptoms of cardiac disease, commented Dr. Jon Giles, who is a rheumatologist at the Johns Hopkins Division of Rheumatology in Baltimore, in a presentation given at the recent annual meeting of the American College of Rheumatology.

For example, Dr. Giles cited heart failure rates that are “nearly doubled” in RA patients.

Yet, “little is known about the myocardial changes that precede clinical heart failure in these patients,” he said.

Dr. Giles and his associates turned to cardiac MRI, a highly sensitive tool for assessing left ventricular structure and function, to hunt for preclinical risk factors for heart failure.

Rheumatoid arthritis patients with moderate disease (average 7 years' duration) who enrolled in the ESCAPE RA trial (n = 75) were compared with 775 participants in the Multi-Ethnic Study of Atherosclerosis who did not have RA. None of the members of either group had a history of cardiovascular events or procedures.

The rheumatoid arthritis cohort was younger than was the control group (mean age 59, compared with 63), and was also less likely to have a diagnosis of diabetes (4% versus 14%) or hypertension (32% versus 49%).

However, the patients' mean unadjusted left ventricular mass was 18% lower (120 g/m

The difference was particularly pronounced for male patients with RA, whose mean adjusted left ventricular mass was found to be fully 19% lower than that of men who did not have a rheumatoid arthritis diagnosis.

Female rheumatoid arthritis patients had a 9% lower left ventricular mass than did women without the inflammatory disease.

In both the RA and control groups, mean left ventricular mass decreased with age.

However, it was lower in rheumatoid arthritis patients than in controls in every age group, including the youngest patients in the study.

“In fact, the mean left ventricular mass was lower in 45-year-old RA patients than mean left ventricular mass in 80-year-old control patients, regardless of gender,” Dr. Giles commented during his podium presentation.

Left ventricular stroke volume was marginally lower in RA patients than in controls, significantly so in men.

“Small but significant” reductions in adjusted mean ejection fraction were seen as well, Dr. Giles said.

No differences were seen in RA patients and controls with regard to adjusted mean end diastolic volume.

The Johns Hopkins team also explored potentially significant associations between cardiovascular risk markers and RA disease characteristics such as disease severity, activity, treatment, and systemic inflammation.

They found only two factors that were independently associated with left ventricular mass, stroke volume, and end diastolic volume in rheumatoid arthritis patients.

One factor was increased anti-cyclic citrullinated peptide antibodies.

The other was the use of biological disease-modifying drugs (predominantly tumor necrosis factor-α inhibitors).

No characteristics were associated with ejection fraction.

The study findings raise intriguing questions about whether rheumatoid arthritis and its treatment heighten patients' cardiovascular risk through different mechanisms than in the general, non-RA population, said Dr. Giles.

For example, markedly lower left ventricular mass may reflect the “aftereffects” of subclinical myocarditis.

On the other hand, lower left ventricular mass measurements “may support the concept that RA is a disorder of accelerated aging,” he said.

Dr. Giles and his associates reported having no financial conflicts of interest with regard to this study.

ELSEVIER GLOBAL MEDICAL NEWS

SAN FRANCISCO — The investigational drug pegloticase significantly reduced serum urate levels compared with placebo in two randomized, double-blind studies of 212 patients with gout who had previously failed treatment with allopurinol.

Patients received intravenous infusions of placebo or 8 mg pegloticase (Puricase) every 2 or 4 weeks in the 24-week Gout Outcome and Urate Therapy studies (GOUT1 and GOUT2), the results of which were presented by Dr. John S. Sundy at the annual meeting of the American College of Rheumatology.

At baseline, all patients had a serum urate level that was higher than 8 mg/dL (an average of 10 mg/dL) and severe, symptomatic gout, with three or more gout flares in the previous 18 months (an average of 10 flares), one or more tophi (present in 73% of patients), or chronic gouty arthropathy (present in 58% of patients in the studies).

The patient cohort had had gout for a mean of 15 years.

Allopurinol treatment was contraindicated or had failed to reduce serum urate to below 6 mg/dL in these patients.

Treatment in the study was considered successful if a patient's uric acid readings were within the normal range (less than 6 mg/dL) at least 80% of the time in months 3 and 6 of the studies.

None of the patients in the placebo groups of either the 104-patient GOUT1 study or the 108-patient GOUT2 study achieved this goal in the intent-to-treat analysis, according to Dr. Sundy.

However, on a regimen of pegloticase every 2 weeks, 47% of the patients in GOUT1 and 38% of patients in GOUT2 were treated successfully.

On a treatment regimen of pegloticase every 4 weeks, 20% of GOUT1 patients and 48% of GOUT2 patients achieved successful improvements, reported Dr. Sundy, who is a rheumatologist at Duke University, Durham, N.C., and his associates.

The serum urate improvements that were seen with both of the pegloticase regimens were significant compared with placebo, he commented.

Dr. Sundy disclosed that the company that makes pegloticase, Savient Pharmaceuticals, both funded the study and has given research funds or other payments to Dr. Sundy and many of the other investigators on this study, some of whom are Savient employees.

Additionally, Duke University and one of its employees who was not involved in the study hold patents on pegloticase.

A total of eight serious cardiovascular events occurred in patients getting pegloticase: two cardiac arrests, two exacerbations of heart failure leading to death in one patient, two dysrhythmias, one myocardial infection, and one case of angina.

Among other side effects, infusion reactions led to discontinuation of treatment in 11%–13% of patients on pegloticase and none on placebo.

Dr. Sundy said the cardiovascular events “may reflect underlying comorbidity.”

A physician in the audience challenged this assumption, saying the events should occur in the placebo group, too, if that were the case.

A current, ongoing 12-month open-label extension of the study might soon shed some light on this, Dr. Sundy said.

Secondary measures of efficacy in the double-blinded studies found clinically and statistically significant improvements in the pegloticase groups compared with placebo.

Among patients with at least one tophus who were evaluated by computer-assisted photographic analysis, a tophus resolved completely in 21 (40%) of 52 patients getting pegloticase every 2 weeks and 11 (21%) of 52 patients getting pegloticase every 4 weeks, compared with 1 (4%) of 27 patients on placebo.

The number of tender joints decreased by seven in the 2-week pegloticase group and by six in the 4-week group compared with an average decrease of one tender joint on placebo. The number of swollen joints did not differ significantly between groups.

Both pegloticase groups, but not the placebo group, showed significant improvements in the Short Form-36 Health Survey physical component summary score and the physical functioning subscale of the Health Assessment Questionnaire-Disability Index.

The study cohort was 82% male, with a mean age of 55 years and a high degree of comorbidity.

Hypertension was present in 72% of patients, chronic kidney disease in 30%, diabetes in 22%, hypercholesterolemia in 21%, and coronary artery disease in 11% of the patients.

Pegloticase is a recombinant mammalian urate oxidase modified with polyethylene glycol that converts urate to allantoin.

SAN FRANCISCO — The investigational drug pegloticase significantly reduced serum urate levels compared with placebo in two randomized, double-blind studies of 212 patients with gout who had previously failed treatment with allopurinol.

Patients received intravenous infusions of placebo or 8 mg pegloticase (Puricase) every 2 or 4 weeks in the 24-week Gout Outcome and Urate Therapy studies (GOUT1 and GOUT2), the results of which were presented by Dr. John S. Sundy at the annual meeting of the American College of Rheumatology.

At baseline, all patients had a serum urate level that was higher than 8 mg/dL (an average of 10 mg/dL) and severe, symptomatic gout, with three or more gout flares in the previous 18 months (an average of 10 flares), one or more tophi (present in 73% of patients), or chronic gouty arthropathy (present in 58% of patients in the studies).

The patient cohort had had gout for a mean of 15 years.

Allopurinol treatment was contraindicated or had failed to reduce serum urate to below 6 mg/dL in these patients.

Treatment in the study was considered successful if a patient's uric acid readings were within the normal range (less than 6 mg/dL) at least 80% of the time in months 3 and 6 of the studies.

None of the patients in the placebo groups of either the 104-patient GOUT1 study or the 108-patient GOUT2 study achieved this goal in the intent-to-treat analysis, according to Dr. Sundy.

However, on a regimen of pegloticase every 2 weeks, 47% of the patients in GOUT1 and 38% of patients in GOUT2 were treated successfully.

On a treatment regimen of pegloticase every 4 weeks, 20% of GOUT1 patients and 48% of GOUT2 patients achieved successful improvements, reported Dr. Sundy, who is a rheumatologist at Duke University, Durham, N.C., and his associates.

The serum urate improvements that were seen with both of the pegloticase regimens were significant compared with placebo, he commented.

Dr. Sundy disclosed that the company that makes pegloticase, Savient Pharmaceuticals, both funded the study and has given research funds or other payments to Dr. Sundy and many of the other investigators on this study, some of whom are Savient employees.

Additionally, Duke University and one of its employees who was not involved in the study hold patents on pegloticase.

A total of eight serious cardiovascular events occurred in patients getting pegloticase: two cardiac arrests, two exacerbations of heart failure leading to death in one patient, two dysrhythmias, one myocardial infection, and one case of angina.

Among other side effects, infusion reactions led to discontinuation of treatment in 11%–13% of patients on pegloticase and none on placebo.

Dr. Sundy said the cardiovascular events “may reflect underlying comorbidity.”

A physician in the audience challenged this assumption, saying the events should occur in the placebo group, too, if that were the case.

A current, ongoing 12-month open-label extension of the study might soon shed some light on this, Dr. Sundy said.

Secondary measures of efficacy in the double-blinded studies found clinically and statistically significant improvements in the pegloticase groups compared with placebo.

Among patients with at least one tophus who were evaluated by computer-assisted photographic analysis, a tophus resolved completely in 21 (40%) of 52 patients getting pegloticase every 2 weeks and 11 (21%) of 52 patients getting pegloticase every 4 weeks, compared with 1 (4%) of 27 patients on placebo.

The number of tender joints decreased by seven in the 2-week pegloticase group and by six in the 4-week group compared with an average decrease of one tender joint on placebo. The number of swollen joints did not differ significantly between groups.

Both pegloticase groups, but not the placebo group, showed significant improvements in the Short Form-36 Health Survey physical component summary score and the physical functioning subscale of the Health Assessment Questionnaire-Disability Index.

The study cohort was 82% male, with a mean age of 55 years and a high degree of comorbidity.

Hypertension was present in 72% of patients, chronic kidney disease in 30%, diabetes in 22%, hypercholesterolemia in 21%, and coronary artery disease in 11% of the patients.

Pegloticase is a recombinant mammalian urate oxidase modified with polyethylene glycol that converts urate to allantoin.

SAN FRANCISCO — The investigational drug pegloticase significantly reduced serum urate levels compared with placebo in two randomized, double-blind studies of 212 patients with gout who had previously failed treatment with allopurinol.

Patients received intravenous infusions of placebo or 8 mg pegloticase (Puricase) every 2 or 4 weeks in the 24-week Gout Outcome and Urate Therapy studies (GOUT1 and GOUT2), the results of which were presented by Dr. John S. Sundy at the annual meeting of the American College of Rheumatology.

At baseline, all patients had a serum urate level that was higher than 8 mg/dL (an average of 10 mg/dL) and severe, symptomatic gout, with three or more gout flares in the previous 18 months (an average of 10 flares), one or more tophi (present in 73% of patients), or chronic gouty arthropathy (present in 58% of patients in the studies).

The patient cohort had had gout for a mean of 15 years.

Allopurinol treatment was contraindicated or had failed to reduce serum urate to below 6 mg/dL in these patients.

Treatment in the study was considered successful if a patient's uric acid readings were within the normal range (less than 6 mg/dL) at least 80% of the time in months 3 and 6 of the studies.

None of the patients in the placebo groups of either the 104-patient GOUT1 study or the 108-patient GOUT2 study achieved this goal in the intent-to-treat analysis, according to Dr. Sundy.

However, on a regimen of pegloticase every 2 weeks, 47% of the patients in GOUT1 and 38% of patients in GOUT2 were treated successfully.

On a treatment regimen of pegloticase every 4 weeks, 20% of GOUT1 patients and 48% of GOUT2 patients achieved successful improvements, reported Dr. Sundy, who is a rheumatologist at Duke University, Durham, N.C., and his associates.

The serum urate improvements that were seen with both of the pegloticase regimens were significant compared with placebo, he commented.

Dr. Sundy disclosed that the company that makes pegloticase, Savient Pharmaceuticals, both funded the study and has given research funds or other payments to Dr. Sundy and many of the other investigators on this study, some of whom are Savient employees.

Additionally, Duke University and one of its employees who was not involved in the study hold patents on pegloticase.

A total of eight serious cardiovascular events occurred in patients getting pegloticase: two cardiac arrests, two exacerbations of heart failure leading to death in one patient, two dysrhythmias, one myocardial infection, and one case of angina.

Among other side effects, infusion reactions led to discontinuation of treatment in 11%–13% of patients on pegloticase and none on placebo.

Dr. Sundy said the cardiovascular events “may reflect underlying comorbidity.”

A physician in the audience challenged this assumption, saying the events should occur in the placebo group, too, if that were the case.

A current, ongoing 12-month open-label extension of the study might soon shed some light on this, Dr. Sundy said.

Secondary measures of efficacy in the double-blinded studies found clinically and statistically significant improvements in the pegloticase groups compared with placebo.

Among patients with at least one tophus who were evaluated by computer-assisted photographic analysis, a tophus resolved completely in 21 (40%) of 52 patients getting pegloticase every 2 weeks and 11 (21%) of 52 patients getting pegloticase every 4 weeks, compared with 1 (4%) of 27 patients on placebo.

The number of tender joints decreased by seven in the 2-week pegloticase group and by six in the 4-week group compared with an average decrease of one tender joint on placebo. The number of swollen joints did not differ significantly between groups.

Both pegloticase groups, but not the placebo group, showed significant improvements in the Short Form-36 Health Survey physical component summary score and the physical functioning subscale of the Health Assessment Questionnaire-Disability Index.

The study cohort was 82% male, with a mean age of 55 years and a high degree of comorbidity.

Hypertension was present in 72% of patients, chronic kidney disease in 30%, diabetes in 22%, hypercholesterolemia in 21%, and coronary artery disease in 11% of the patients.

Pegloticase is a recombinant mammalian urate oxidase modified with polyethylene glycol that converts urate to allantoin.

SAN FRANCISCO — Dual-energy computed tomography scans showed red-colored uric acid deposits in 20 consecutive patients with clinically obvious tophaceous gout but not in 10 controls with other nongout joint conditions.

The 100% sensitivity and specificity of dual-energy computed tomography (DECT) to identify uric acid deposits could provide a needed imaging tool to aid in gout diagnosis and treatment, Dr. Abdullatif M. Alarfaj said at the annual meeting of the American College of Rheumatology.

DECT assesses chemical composition and provides specific color-coded displays to differentiate between uric acid (which shows red), calcium (blue), and other renal calculi, previous investigators have shown.

The current proof-of-concept study, in addition to assessing the accuracy of DECT in gout patients, also measured the uric acid burden in peripheral joints and performed a computerized quantification of tophus volume. The volume of uric acid in each anatomic area was measured by automated volume estimation software. The sum of tophus volume in the hands, wrists, elbows, feet, ankles, and knees comprised the total uric acid volume of peripheral joints.

DECT scans identified 440 areas of urate deposition, compared with 111 areas identified on clinical examination, reported Dr. Alarfaj of the University of British Columbia, Vancouver, and his associates. The investigators have no conflicts of interest related to this study.

DECT could be used to detect subclinical tophus deposits and the extent of intra- and extra-articular gout, he said, adding it could be used to measure individual tophus volume and total burden.

The relatively new technology also may be used in evaluating nodular lesions, diagnosing concurrent gout in patients with other arthropathies, and identifying urate deposits in body areas atypical for gout. An individual DECT scan can cost about one-sixth of the amount for an MRI, Dr. Alarfaj's senior investigator, Dr. Hyon Choi, said. The DECT hardware equipment is very expensive but is used for a variety of purposes, such as imaging coronary artery calcifications and renal calculi. The technology provides dramatic color displays and can be used to create impressive three-dimensional images of uric acid deposits that could aid clinicians in communicating about the disease to patients with gout, he added. The patients in the gout group had an average 12-year history of gout and nine painful joints in the previous year. Mean serum uric acid level was 492 micromol/L; mean age was 63; 75% were male; and 12 were white. Comorbidities were present in 17 patients.

SAN FRANCISCO — Dual-energy computed tomography scans showed red-colored uric acid deposits in 20 consecutive patients with clinically obvious tophaceous gout but not in 10 controls with other nongout joint conditions.

The 100% sensitivity and specificity of dual-energy computed tomography (DECT) to identify uric acid deposits could provide a needed imaging tool to aid in gout diagnosis and treatment, Dr. Abdullatif M. Alarfaj said at the annual meeting of the American College of Rheumatology.

DECT assesses chemical composition and provides specific color-coded displays to differentiate between uric acid (which shows red), calcium (blue), and other renal calculi, previous investigators have shown.

The current proof-of-concept study, in addition to assessing the accuracy of DECT in gout patients, also measured the uric acid burden in peripheral joints and performed a computerized quantification of tophus volume. The volume of uric acid in each anatomic area was measured by automated volume estimation software. The sum of tophus volume in the hands, wrists, elbows, feet, ankles, and knees comprised the total uric acid volume of peripheral joints.

DECT scans identified 440 areas of urate deposition, compared with 111 areas identified on clinical examination, reported Dr. Alarfaj of the University of British Columbia, Vancouver, and his associates. The investigators have no conflicts of interest related to this study.

DECT could be used to detect subclinical tophus deposits and the extent of intra- and extra-articular gout, he said, adding it could be used to measure individual tophus volume and total burden.

The relatively new technology also may be used in evaluating nodular lesions, diagnosing concurrent gout in patients with other arthropathies, and identifying urate deposits in body areas atypical for gout. An individual DECT scan can cost about one-sixth of the amount for an MRI, Dr. Alarfaj's senior investigator, Dr. Hyon Choi, said. The DECT hardware equipment is very expensive but is used for a variety of purposes, such as imaging coronary artery calcifications and renal calculi. The technology provides dramatic color displays and can be used to create impressive three-dimensional images of uric acid deposits that could aid clinicians in communicating about the disease to patients with gout, he added. The patients in the gout group had an average 12-year history of gout and nine painful joints in the previous year. Mean serum uric acid level was 492 micromol/L; mean age was 63; 75% were male; and 12 were white. Comorbidities were present in 17 patients.

SAN FRANCISCO — Dual-energy computed tomography scans showed red-colored uric acid deposits in 20 consecutive patients with clinically obvious tophaceous gout but not in 10 controls with other nongout joint conditions.

The 100% sensitivity and specificity of dual-energy computed tomography (DECT) to identify uric acid deposits could provide a needed imaging tool to aid in gout diagnosis and treatment, Dr. Abdullatif M. Alarfaj said at the annual meeting of the American College of Rheumatology.

DECT assesses chemical composition and provides specific color-coded displays to differentiate between uric acid (which shows red), calcium (blue), and other renal calculi, previous investigators have shown.

The current proof-of-concept study, in addition to assessing the accuracy of DECT in gout patients, also measured the uric acid burden in peripheral joints and performed a computerized quantification of tophus volume. The volume of uric acid in each anatomic area was measured by automated volume estimation software. The sum of tophus volume in the hands, wrists, elbows, feet, ankles, and knees comprised the total uric acid volume of peripheral joints.

DECT scans identified 440 areas of urate deposition, compared with 111 areas identified on clinical examination, reported Dr. Alarfaj of the University of British Columbia, Vancouver, and his associates. The investigators have no conflicts of interest related to this study.

DECT could be used to detect subclinical tophus deposits and the extent of intra- and extra-articular gout, he said, adding it could be used to measure individual tophus volume and total burden.

The relatively new technology also may be used in evaluating nodular lesions, diagnosing concurrent gout in patients with other arthropathies, and identifying urate deposits in body areas atypical for gout. An individual DECT scan can cost about one-sixth of the amount for an MRI, Dr. Alarfaj's senior investigator, Dr. Hyon Choi, said. The DECT hardware equipment is very expensive but is used for a variety of purposes, such as imaging coronary artery calcifications and renal calculi. The technology provides dramatic color displays and can be used to create impressive three-dimensional images of uric acid deposits that could aid clinicians in communicating about the disease to patients with gout, he added. The patients in the gout group had an average 12-year history of gout and nine painful joints in the previous year. Mean serum uric acid level was 492 micromol/L; mean age was 63; 75% were male; and 12 were white. Comorbidities were present in 17 patients.

SAN FRANCISCO — The increased risk for cardiovascular disease associated with the diagnosis of rheumatoid arthritis was offset by the protective effects of disease-modifying antirheumatic drugs but heightened by prednisolone therapy in a large community-based study.

The study used data on individuals registered in the United Kingdom General Practice Research Database who were treated for rheumatoid arthritis between 1987 and 2002. This period predates the widespread use of anti-tumor necrosis factor (TNF) agents, so the findings offer no information on whether these agents are protective against cardiovascular disease, Dr. Christopher J. Edwards said at the annual meeting of the American College of Rheumatology.

The research involved about 35,000 individuals diagnosed with RA and compared their rates of myocardial infarction (as a surrogate marker for cardiovascular disease) with those of 100,000 matched healthy controls.

The incidence of MI in patients with RA was 6.49/1,000 person-years vs. 2.96/1,000 person-years for controls.

The incident rate ratio was increased for MI by an RA diagnosis (2.23), according to a Poisson regression analysis.

The increased risk persisted even after a multifactor regression analysis controlled for traditional cardiovascular disease risk factors, including age, BMI, sex, smoking, serum lipid levels, hypercholesterolemia, and hypertension.

Of the 966 patients with RA who had an MI during the study period, 705 (73%) received treatment with either a disease-modifying antirheumatic drug (DMARD) or prednisolone during that time.

Of these 705, a total of 538 took either DMARDs or prednisolone within the 2 months that immediately preceded their MI.

The incident rate ratio for MI among patients on either a DMARD or prednisolone, compared with those not on these agents, was 0.94. Further analysis of DMARDs showed that the individual incident rate ratio for hydroxycholoroquine, methotrexate, and sulfasalazine vs. no drug were 0.42, 0.67, and 0.69, respectively. In contrast, use of prednisolone vs. no drug was associated with an incident rate ratio of 1.49. The effect sizes remained similar after controlling for traditional cardiovascular disease risks but were no longer significant.

The strong anti-inflammatory effects of DMARDs are the likely explanation of their protective effect against MI, Dr. Edwards said in an interview. Data from a number of trials have shown that these agents lower C-reactive protein (CRP) levels. It is reasonable but still pure conjecture to conclude that lowering CRP levels in RA patients lowers the risk of cardiovascular disease, said Dr. Edwards, consultant rheumatologist and senior lecturer at Southampton University Hospital (England).

While prednisolone has similarly strong anti-inflammatory effects in RA, these effects do not translate into protection against cardiovascular disease. Prednisolone use is associated with increased blood pressure and serum lipids levels and weight gain, which offset any anti-inflammatory benefits for the cardiovascular system, he continued in the interview.

In contrast to data presented by Dr. Edwards, findings from the recent QUEST-RA (Quantitative Patient Questionnaires in Standard Monitoring of Patients with Rheumatoid Arthritis) study show that prednisolone was protective against cardiovascular disease in RA (Ann. Rheum. Dis. 2007;66:1491–6). As an explanation for the conflicting findings, Dr. Edwards suggested that the difference may be that the patients in the British cohort had earlier RA and were more susceptible to the adverse effects of prednisolone than were the cohort patients in QUEST-RA, all of whom were referred to the study from tertiary care centers with advanced RA.

Dr. Edwards reported he has no conflict of interest concerning this research.

SAN FRANCISCO — The increased risk for cardiovascular disease associated with the diagnosis of rheumatoid arthritis was offset by the protective effects of disease-modifying antirheumatic drugs but heightened by prednisolone therapy in a large community-based study.

The study used data on individuals registered in the United Kingdom General Practice Research Database who were treated for rheumatoid arthritis between 1987 and 2002. This period predates the widespread use of anti-tumor necrosis factor (TNF) agents, so the findings offer no information on whether these agents are protective against cardiovascular disease, Dr. Christopher J. Edwards said at the annual meeting of the American College of Rheumatology.

The research involved about 35,000 individuals diagnosed with RA and compared their rates of myocardial infarction (as a surrogate marker for cardiovascular disease) with those of 100,000 matched healthy controls.

The incidence of MI in patients with RA was 6.49/1,000 person-years vs. 2.96/1,000 person-years for controls.

The incident rate ratio was increased for MI by an RA diagnosis (2.23), according to a Poisson regression analysis.

The increased risk persisted even after a multifactor regression analysis controlled for traditional cardiovascular disease risk factors, including age, BMI, sex, smoking, serum lipid levels, hypercholesterolemia, and hypertension.

Of the 966 patients with RA who had an MI during the study period, 705 (73%) received treatment with either a disease-modifying antirheumatic drug (DMARD) or prednisolone during that time.

Of these 705, a total of 538 took either DMARDs or prednisolone within the 2 months that immediately preceded their MI.

The incident rate ratio for MI among patients on either a DMARD or prednisolone, compared with those not on these agents, was 0.94. Further analysis of DMARDs showed that the individual incident rate ratio for hydroxycholoroquine, methotrexate, and sulfasalazine vs. no drug were 0.42, 0.67, and 0.69, respectively. In contrast, use of prednisolone vs. no drug was associated with an incident rate ratio of 1.49. The effect sizes remained similar after controlling for traditional cardiovascular disease risks but were no longer significant.

The strong anti-inflammatory effects of DMARDs are the likely explanation of their protective effect against MI, Dr. Edwards said in an interview. Data from a number of trials have shown that these agents lower C-reactive protein (CRP) levels. It is reasonable but still pure conjecture to conclude that lowering CRP levels in RA patients lowers the risk of cardiovascular disease, said Dr. Edwards, consultant rheumatologist and senior lecturer at Southampton University Hospital (England).

While prednisolone has similarly strong anti-inflammatory effects in RA, these effects do not translate into protection against cardiovascular disease. Prednisolone use is associated with increased blood pressure and serum lipids levels and weight gain, which offset any anti-inflammatory benefits for the cardiovascular system, he continued in the interview.

In contrast to data presented by Dr. Edwards, findings from the recent QUEST-RA (Quantitative Patient Questionnaires in Standard Monitoring of Patients with Rheumatoid Arthritis) study show that prednisolone was protective against cardiovascular disease in RA (Ann. Rheum. Dis. 2007;66:1491–6). As an explanation for the conflicting findings, Dr. Edwards suggested that the difference may be that the patients in the British cohort had earlier RA and were more susceptible to the adverse effects of prednisolone than were the cohort patients in QUEST-RA, all of whom were referred to the study from tertiary care centers with advanced RA.

Dr. Edwards reported he has no conflict of interest concerning this research.

SAN FRANCISCO — The increased risk for cardiovascular disease associated with the diagnosis of rheumatoid arthritis was offset by the protective effects of disease-modifying antirheumatic drugs but heightened by prednisolone therapy in a large community-based study.

The study used data on individuals registered in the United Kingdom General Practice Research Database who were treated for rheumatoid arthritis between 1987 and 2002. This period predates the widespread use of anti-tumor necrosis factor (TNF) agents, so the findings offer no information on whether these agents are protective against cardiovascular disease, Dr. Christopher J. Edwards said at the annual meeting of the American College of Rheumatology.

The research involved about 35,000 individuals diagnosed with RA and compared their rates of myocardial infarction (as a surrogate marker for cardiovascular disease) with those of 100,000 matched healthy controls.

The incidence of MI in patients with RA was 6.49/1,000 person-years vs. 2.96/1,000 person-years for controls.

The incident rate ratio was increased for MI by an RA diagnosis (2.23), according to a Poisson regression analysis.

The increased risk persisted even after a multifactor regression analysis controlled for traditional cardiovascular disease risk factors, including age, BMI, sex, smoking, serum lipid levels, hypercholesterolemia, and hypertension.

Of the 966 patients with RA who had an MI during the study period, 705 (73%) received treatment with either a disease-modifying antirheumatic drug (DMARD) or prednisolone during that time.

Of these 705, a total of 538 took either DMARDs or prednisolone within the 2 months that immediately preceded their MI.

The incident rate ratio for MI among patients on either a DMARD or prednisolone, compared with those not on these agents, was 0.94. Further analysis of DMARDs showed that the individual incident rate ratio for hydroxycholoroquine, methotrexate, and sulfasalazine vs. no drug were 0.42, 0.67, and 0.69, respectively. In contrast, use of prednisolone vs. no drug was associated with an incident rate ratio of 1.49. The effect sizes remained similar after controlling for traditional cardiovascular disease risks but were no longer significant.

The strong anti-inflammatory effects of DMARDs are the likely explanation of their protective effect against MI, Dr. Edwards said in an interview. Data from a number of trials have shown that these agents lower C-reactive protein (CRP) levels. It is reasonable but still pure conjecture to conclude that lowering CRP levels in RA patients lowers the risk of cardiovascular disease, said Dr. Edwards, consultant rheumatologist and senior lecturer at Southampton University Hospital (England).

While prednisolone has similarly strong anti-inflammatory effects in RA, these effects do not translate into protection against cardiovascular disease. Prednisolone use is associated with increased blood pressure and serum lipids levels and weight gain, which offset any anti-inflammatory benefits for the cardiovascular system, he continued in the interview.

In contrast to data presented by Dr. Edwards, findings from the recent QUEST-RA (Quantitative Patient Questionnaires in Standard Monitoring of Patients with Rheumatoid Arthritis) study show that prednisolone was protective against cardiovascular disease in RA (Ann. Rheum. Dis. 2007;66:1491–6). As an explanation for the conflicting findings, Dr. Edwards suggested that the difference may be that the patients in the British cohort had earlier RA and were more susceptible to the adverse effects of prednisolone than were the cohort patients in QUEST-RA, all of whom were referred to the study from tertiary care centers with advanced RA.

Dr. Edwards reported he has no conflict of interest concerning this research.