Psoriasis

SANTA MONICA, Calif. – Gastroenterologists seem to be taking a page from the rheumatologists’ playbook and are starting patients with inflammatory bowel disease on a biologic agent much sooner after diagnosis than has been standard practice.

By doing so, they hope to improve the natural history of the disease, just as rheumatologists have done in rheumatoid arthritis patients, according to Dr. Russell D. Cohen, who spoke at a rheumatology seminar sponsored by Skin Disease Education Foundation (SDEF) and the University of Louisville.

Arthritis and inflammatory bowel disease (IBD) have more in common than the drugs used to treat them. Arthritis is the most common extraintestinal manifestation of IBD. Onset of joint symptoms may precede the onset of IBD, develop in parallel to it, or be unrelated, he said.

Arthritis is most likely to occur in IBD patients who have other extraintestinal manifestations such as dermatologic, ocular, or renal symptoms. The most commonly involved central joints are in the spine, where the arthritis takes the form of ankylosing spondylitis or sacroiliitis. Peripheral joints can develop arthropathies in IBD as well. About 5%-20% of IBD patients get arthritis. The cartilage and bone usually are spared from destruction. Arthritis in IBD usually involves five or more joints and lasts about 3 years.

The incidence of IBD in rheumatoid arthritis is not well defined. One of the few studies to address this question involved a review of the data sets from two large insurance companies involving 17 million people. The researchers found that the prevalence of IBD was about 0.62%-0.65% and the prevalence of RA was about 0.98%-1.08% in patients aged 47-56 years old living in the Midwest or the South. The odds ratio of having both IBD and RA was 2.1-2.7, and of having IBD and ankylosing spondylitis, about 5.8-7.8 (Inflamm. Bowel Dis. 2008;14:738-43).

The advent of biologics has changed the natural history of ulcerative colitis (UC). But before these agents became available, data from a Danish study showed that during the first year after diagnosis, 10% of UC patients lost their colon, about 23% had lost their colon after 10 years, and 31% had lost their colon 18 years out (Gut 1985;26:158-63).

In the prebiologic era, the natural history of Crohn’s disease also was grim. The disease followed an inflammatory path for the first 5 years, then became penetrating with fistula formation between years 5 and 10 in a subset of patients; stricturing could develop after year 10 (Inflamm. Bowel Dis. 2002;8:244-50).

In the past, "virtually all Crohn’s disease patients relapsed and most required one or more surgeries," said Dr. Cohen, who is codirector of the inflammatory bowel disease center at the University of Chicago. He noted that there was a 70% probability that Crohn’s would recur over a 10-year period (Gastroenterology 1985;88:1826-33).

An estimated 10% of Crohn’s patients had their colons removed surgically within 1 year of their diagnosis with IBD, and an estimated 70% of patients who had one surgery for Crohn’s would require another. The disease tended to recur at the site of anastomosis of the previous surgery and to involve as much bowel as had been removed in the previous surgery. About half of the patients needed a second surgery.

Even today, most ulcerative colitis patients are treated with steroids and many of them become steroid dependent. Findings from a study of 63 UC patients placed on steroids showed that at the end of 1 month, 34 achieved complete remission, 19 had a partial remission, and 10 had no response. Follow-up data at 1 year showed that 31 had a prolonged response, 14 were steroid dependent, and 18 needed surgery (Gastroenterology 2001;121:255-60).

These days, there is a move away from making steroids the first drug in the treatment regimen and instead starting with a biologic and adding a steroid only if necessary.

There is some overlap between the biologics used to treat rheumatologic diseases and those used to treat IBD. Recent data show that infliximab in combination with azathioprine induced a steroid-free clinical remission in 44 of 64 patients. In the same study, infliximab plus placebo induced remission in 37 of 65 patients, and azathioprine plus placebo induced remission in 21 of 75 patients. All of the patients had active IBD with a C-reactive protein level of 0.8 mg/dL or higher and lesions that were visible on endoscopy (N. Engl. J. Med. 2010;362:1383-95).

Skin Disease Education Foundation and this news organization are owned by Elsevier. Dr. Cohen disclosed financial relationships with Abbott Labs, Axcan Pharma, Elan, Centocor, Procter & Gamble, Prometheus Laboratories, Salix, Shire, UCB, and Warner Chilcott.

SANTA MONICA, Calif. – Gastroenterologists seem to be taking a page from the rheumatologists’ playbook and are starting patients with inflammatory bowel disease on a biologic agent much sooner after diagnosis than has been standard practice.

By doing so, they hope to improve the natural history of the disease, just as rheumatologists have done in rheumatoid arthritis patients, according to Dr. Russell D. Cohen, who spoke at a rheumatology seminar sponsored by Skin Disease Education Foundation (SDEF) and the University of Louisville.

Arthritis and inflammatory bowel disease (IBD) have more in common than the drugs used to treat them. Arthritis is the most common extraintestinal manifestation of IBD. Onset of joint symptoms may precede the onset of IBD, develop in parallel to it, or be unrelated, he said.

Arthritis is most likely to occur in IBD patients who have other extraintestinal manifestations such as dermatologic, ocular, or renal symptoms. The most commonly involved central joints are in the spine, where the arthritis takes the form of ankylosing spondylitis or sacroiliitis. Peripheral joints can develop arthropathies in IBD as well. About 5%-20% of IBD patients get arthritis. The cartilage and bone usually are spared from destruction. Arthritis in IBD usually involves five or more joints and lasts about 3 years.

The incidence of IBD in rheumatoid arthritis is not well defined. One of the few studies to address this question involved a review of the data sets from two large insurance companies involving 17 million people. The researchers found that the prevalence of IBD was about 0.62%-0.65% and the prevalence of RA was about 0.98%-1.08% in patients aged 47-56 years old living in the Midwest or the South. The odds ratio of having both IBD and RA was 2.1-2.7, and of having IBD and ankylosing spondylitis, about 5.8-7.8 (Inflamm. Bowel Dis. 2008;14:738-43).

The advent of biologics has changed the natural history of ulcerative colitis (UC). But before these agents became available, data from a Danish study showed that during the first year after diagnosis, 10% of UC patients lost their colon, about 23% had lost their colon after 10 years, and 31% had lost their colon 18 years out (Gut 1985;26:158-63).

In the prebiologic era, the natural history of Crohn’s disease also was grim. The disease followed an inflammatory path for the first 5 years, then became penetrating with fistula formation between years 5 and 10 in a subset of patients; stricturing could develop after year 10 (Inflamm. Bowel Dis. 2002;8:244-50).

In the past, "virtually all Crohn’s disease patients relapsed and most required one or more surgeries," said Dr. Cohen, who is codirector of the inflammatory bowel disease center at the University of Chicago. He noted that there was a 70% probability that Crohn’s would recur over a 10-year period (Gastroenterology 1985;88:1826-33).

An estimated 10% of Crohn’s patients had their colons removed surgically within 1 year of their diagnosis with IBD, and an estimated 70% of patients who had one surgery for Crohn’s would require another. The disease tended to recur at the site of anastomosis of the previous surgery and to involve as much bowel as had been removed in the previous surgery. About half of the patients needed a second surgery.

Even today, most ulcerative colitis patients are treated with steroids and many of them become steroid dependent. Findings from a study of 63 UC patients placed on steroids showed that at the end of 1 month, 34 achieved complete remission, 19 had a partial remission, and 10 had no response. Follow-up data at 1 year showed that 31 had a prolonged response, 14 were steroid dependent, and 18 needed surgery (Gastroenterology 2001;121:255-60).

These days, there is a move away from making steroids the first drug in the treatment regimen and instead starting with a biologic and adding a steroid only if necessary.

There is some overlap between the biologics used to treat rheumatologic diseases and those used to treat IBD. Recent data show that infliximab in combination with azathioprine induced a steroid-free clinical remission in 44 of 64 patients. In the same study, infliximab plus placebo induced remission in 37 of 65 patients, and azathioprine plus placebo induced remission in 21 of 75 patients. All of the patients had active IBD with a C-reactive protein level of 0.8 mg/dL or higher and lesions that were visible on endoscopy (N. Engl. J. Med. 2010;362:1383-95).

Skin Disease Education Foundation and this news organization are owned by Elsevier. Dr. Cohen disclosed financial relationships with Abbott Labs, Axcan Pharma, Elan, Centocor, Procter & Gamble, Prometheus Laboratories, Salix, Shire, UCB, and Warner Chilcott.

SANTA MONICA, Calif. – Gastroenterologists seem to be taking a page from the rheumatologists’ playbook and are starting patients with inflammatory bowel disease on a biologic agent much sooner after diagnosis than has been standard practice.

By doing so, they hope to improve the natural history of the disease, just as rheumatologists have done in rheumatoid arthritis patients, according to Dr. Russell D. Cohen, who spoke at a rheumatology seminar sponsored by Skin Disease Education Foundation (SDEF) and the University of Louisville.

Arthritis and inflammatory bowel disease (IBD) have more in common than the drugs used to treat them. Arthritis is the most common extraintestinal manifestation of IBD. Onset of joint symptoms may precede the onset of IBD, develop in parallel to it, or be unrelated, he said.

Arthritis is most likely to occur in IBD patients who have other extraintestinal manifestations such as dermatologic, ocular, or renal symptoms. The most commonly involved central joints are in the spine, where the arthritis takes the form of ankylosing spondylitis or sacroiliitis. Peripheral joints can develop arthropathies in IBD as well. About 5%-20% of IBD patients get arthritis. The cartilage and bone usually are spared from destruction. Arthritis in IBD usually involves five or more joints and lasts about 3 years.

The incidence of IBD in rheumatoid arthritis is not well defined. One of the few studies to address this question involved a review of the data sets from two large insurance companies involving 17 million people. The researchers found that the prevalence of IBD was about 0.62%-0.65% and the prevalence of RA was about 0.98%-1.08% in patients aged 47-56 years old living in the Midwest or the South. The odds ratio of having both IBD and RA was 2.1-2.7, and of having IBD and ankylosing spondylitis, about 5.8-7.8 (Inflamm. Bowel Dis. 2008;14:738-43).

The advent of biologics has changed the natural history of ulcerative colitis (UC). But before these agents became available, data from a Danish study showed that during the first year after diagnosis, 10% of UC patients lost their colon, about 23% had lost their colon after 10 years, and 31% had lost their colon 18 years out (Gut 1985;26:158-63).

In the prebiologic era, the natural history of Crohn’s disease also was grim. The disease followed an inflammatory path for the first 5 years, then became penetrating with fistula formation between years 5 and 10 in a subset of patients; stricturing could develop after year 10 (Inflamm. Bowel Dis. 2002;8:244-50).

In the past, "virtually all Crohn’s disease patients relapsed and most required one or more surgeries," said Dr. Cohen, who is codirector of the inflammatory bowel disease center at the University of Chicago. He noted that there was a 70% probability that Crohn’s would recur over a 10-year period (Gastroenterology 1985;88:1826-33).

An estimated 10% of Crohn’s patients had their colons removed surgically within 1 year of their diagnosis with IBD, and an estimated 70% of patients who had one surgery for Crohn’s would require another. The disease tended to recur at the site of anastomosis of the previous surgery and to involve as much bowel as had been removed in the previous surgery. About half of the patients needed a second surgery.

Even today, most ulcerative colitis patients are treated with steroids and many of them become steroid dependent. Findings from a study of 63 UC patients placed on steroids showed that at the end of 1 month, 34 achieved complete remission, 19 had a partial remission, and 10 had no response. Follow-up data at 1 year showed that 31 had a prolonged response, 14 were steroid dependent, and 18 needed surgery (Gastroenterology 2001;121:255-60).

These days, there is a move away from making steroids the first drug in the treatment regimen and instead starting with a biologic and adding a steroid only if necessary.

There is some overlap between the biologics used to treat rheumatologic diseases and those used to treat IBD. Recent data show that infliximab in combination with azathioprine induced a steroid-free clinical remission in 44 of 64 patients. In the same study, infliximab plus placebo induced remission in 37 of 65 patients, and azathioprine plus placebo induced remission in 21 of 75 patients. All of the patients had active IBD with a C-reactive protein level of 0.8 mg/dL or higher and lesions that were visible on endoscopy (N. Engl. J. Med. 2010;362:1383-95).

Skin Disease Education Foundation and this news organization are owned by Elsevier. Dr. Cohen disclosed financial relationships with Abbott Labs, Axcan Pharma, Elan, Centocor, Procter & Gamble, Prometheus Laboratories, Salix, Shire, UCB, and Warner Chilcott.

SILVER SPRING, MD. – The Food and Drug Administration appeared to be searching for a way to limit the clinical trial requirements for generic biologic therapies – or biosimilars – during a 2-day public hearing on implementing an approval pathway for the products.

In preparing for the hearing, the FDA hinted it might be willing to consider the possibility that a biosimilar application might not require any clinical trials.

Many presenters, including several manufacturers of approved biologic therapies, insisted that biosimilarity could not be established definitively without a clinical trial because analytical methods are not yet sophisticated enough. Others, including some generic pharmaceutical manufacturers, argued the agency should use discretion in deciding whether trials would be necessary.

FDA officials tried to carve out a middle ground between the two camps. Dr. Steven Kozlowski, director of the Office of Biotechnology Products within the agency’s Center for Drug Evaluation and Research (CDER), and Dr. John Jenkins, director of the CDER Office of New Drugs, appeared through their questioning to indicate a strict and extensive clinical data requirement might not get many biosimilars to the market, but an overly lax standard might not uncover some safety concerns before marketing begins.

Bruce Babbitt, Ph.D., principal consultant at Parexel Consulting, said FDA’s questions and statements during the hearing seemed to indicate the agency would be willing to be flexible with requiring trials, unlike in Europe, where trials are required for all applications.

"FDA might be open to establishing comparability using [pharmacokinetic/pharmacodynamic] studies in humans head to head with a reference [product]," he said.

Dr. Babbitt argued during his formal presentation the "totality of the data" of biologic products already establishes a base for proving biosimilarity and should not be ignored.

"We consider it important to balance the value and relevance of these data against the need for clinical safety and efficacy data particularly where minor or modest differences between the biosimilar and reference products are unlikely to translate into any meaningful differences in the clinic," Dr. Babbitt said in written testimony.

Dr. Kozlowski asked if there is a way to use the totality of the data in determining what studies would be required.

"Is there a way of incorporating that totality of the data or prior knowledge to think about what the impact on clinical studies are because usually the impact is some big-step function?" he asked Dr. Babbitt.

The totality of data helps either streamline or expand the data sponsors needed for their application, Dr. Babbitt said.

Dr. Jenkins also pointed out suggestions from innovator companies that could be excessive and likely not allow for many biosimilar approvals.

"For your clinical head-to-head trials you wanted a demonstration of equivalence, and you wanted a small confidence interval, you recommend equivalence for safety and efficacy and the surrogate endpoints are not acceptable unless they’ve been clinically validated," Dr. Jenkins said to Dr. Michael Wenger, global clinical lead at Roche. "Is that really an achievable standard ... or is that essentially closing the door for a biosimilar?"

Dr. Wenger argued the drugs should be assessed on a case-by-case basis.

The issue of extrapolation – allowing a biosimilar to be used in all the indications of its reference product after being thoroughly studied in only one – generated concerns about the extent of the clinical data needed. The clinical trial program for a biosimilar would be extremely large if a sponsor was required to produce data showing similarity for each indication it wanted in an application.

Dr. Kozlowski questioned whether it was possible to extrapolate some indications using data for others.

"Say you had the two most different indications in a product that had five indications and you explore those two. Do you believe you could extrapolate the other three?" he asked.

The idea would depend on the clinical benefit achieved by the innovator drug, according to Dr. Wenger. If it was a benefit that could be achieved easily, it may be possible, he said, adding that a more complicated benefit, like overall survival in oncology, would require more work.

Dr. Kozlowski asked Vijay Tammara, Ph.D., vice president of regulatory affairs at Nuron Biotech Inc., whether requiring pharmacokinetic and pharmacodynamic studies could be sufficient premarket, saving immunogenicity testing for the postmarketing studies.

That concept came up again later, during questioning of Sara Radcliffe, executive vice president of health for the Biotechnology Industry Organization (BIO) when Dr. Kozlowski asked whether it would be useful to use pre-marketing data to establish biosimilarity and postmarketing data to test interchangeability.

Ms. Radcliffe said that idea could be possible if an interchangeability determination was not possible before marketing.

Despite the discussion that appeared to indicate a potential for flexibility at FDA, panel members did not give a definitive answer about which way they were leaning.

Dr, Kozlowski’s questions sometimes presented the case for stronger clinical trial requirements. Rasmus Rojkjaer testified on behalf of the Generic Pharmaceutical Association that data from non-U.S. referenced products should be allowed for applications to the FDA and trials should not be more extensive than those required for an innovator product.

Dr. Kozlowski said there had been cases in Europe where clinical trials were shown to be important because they uncovered information that changed the product’s development. He asked about Mr. Rojkjaer’s view of the idea.

Mr. Rojkjaer reiterated that biosimilar applications should not have over-arching rules governing their reviews.

"I think clinical trials has its role to play, but forcing the industry to fit into a one-[size]-fits-all kind of approach I think would seriously keep the development of these biogeneric compounds back," he said.

When Dr. James Roach, chief medical officer of Momenta Pharmaceuticals Inc., argued the trials should be positioned as supportive to existing data, Dr. Jenkins said the agency still has to decide how it will ensure biosimilars are actually similar enough to the reference product.

"We heard a lot of comments yesterday from patient groups and prescribers that they wanted to be very certain that the biosimilar would be highly similar to the clinical effect of the branded product," Dr. Jenkins said. "How do you reconcile those two viewpoints as far as where we should set the bar on determining the role of the clinical trials in establishing that there’s no clinically meaningful difference as the statute requires between the biosimilar and the reference product?"

Dr. Roach said he thought it was possible to provide a limited clinical data set in addition to the existing data package to gain a product approval.

"The Pink Sheet" and this news organization are both owned by Elsevier.

SILVER SPRING, MD. – The Food and Drug Administration appeared to be searching for a way to limit the clinical trial requirements for generic biologic therapies – or biosimilars – during a 2-day public hearing on implementing an approval pathway for the products.

In preparing for the hearing, the FDA hinted it might be willing to consider the possibility that a biosimilar application might not require any clinical trials.

Many presenters, including several manufacturers of approved biologic therapies, insisted that biosimilarity could not be established definitively without a clinical trial because analytical methods are not yet sophisticated enough. Others, including some generic pharmaceutical manufacturers, argued the agency should use discretion in deciding whether trials would be necessary.

FDA officials tried to carve out a middle ground between the two camps. Dr. Steven Kozlowski, director of the Office of Biotechnology Products within the agency’s Center for Drug Evaluation and Research (CDER), and Dr. John Jenkins, director of the CDER Office of New Drugs, appeared through their questioning to indicate a strict and extensive clinical data requirement might not get many biosimilars to the market, but an overly lax standard might not uncover some safety concerns before marketing begins.

Bruce Babbitt, Ph.D., principal consultant at Parexel Consulting, said FDA’s questions and statements during the hearing seemed to indicate the agency would be willing to be flexible with requiring trials, unlike in Europe, where trials are required for all applications.

"FDA might be open to establishing comparability using [pharmacokinetic/pharmacodynamic] studies in humans head to head with a reference [product]," he said.

Dr. Babbitt argued during his formal presentation the "totality of the data" of biologic products already establishes a base for proving biosimilarity and should not be ignored.

"We consider it important to balance the value and relevance of these data against the need for clinical safety and efficacy data particularly where minor or modest differences between the biosimilar and reference products are unlikely to translate into any meaningful differences in the clinic," Dr. Babbitt said in written testimony.

Dr. Kozlowski asked if there is a way to use the totality of the data in determining what studies would be required.

"Is there a way of incorporating that totality of the data or prior knowledge to think about what the impact on clinical studies are because usually the impact is some big-step function?" he asked Dr. Babbitt.

The totality of data helps either streamline or expand the data sponsors needed for their application, Dr. Babbitt said.

Dr. Jenkins also pointed out suggestions from innovator companies that could be excessive and likely not allow for many biosimilar approvals.

"For your clinical head-to-head trials you wanted a demonstration of equivalence, and you wanted a small confidence interval, you recommend equivalence for safety and efficacy and the surrogate endpoints are not acceptable unless they’ve been clinically validated," Dr. Jenkins said to Dr. Michael Wenger, global clinical lead at Roche. "Is that really an achievable standard ... or is that essentially closing the door for a biosimilar?"

Dr. Wenger argued the drugs should be assessed on a case-by-case basis.

The issue of extrapolation – allowing a biosimilar to be used in all the indications of its reference product after being thoroughly studied in only one – generated concerns about the extent of the clinical data needed. The clinical trial program for a biosimilar would be extremely large if a sponsor was required to produce data showing similarity for each indication it wanted in an application.

Dr. Kozlowski questioned whether it was possible to extrapolate some indications using data for others.

"Say you had the two most different indications in a product that had five indications and you explore those two. Do you believe you could extrapolate the other three?" he asked.

The idea would depend on the clinical benefit achieved by the innovator drug, according to Dr. Wenger. If it was a benefit that could be achieved easily, it may be possible, he said, adding that a more complicated benefit, like overall survival in oncology, would require more work.

Dr. Kozlowski asked Vijay Tammara, Ph.D., vice president of regulatory affairs at Nuron Biotech Inc., whether requiring pharmacokinetic and pharmacodynamic studies could be sufficient premarket, saving immunogenicity testing for the postmarketing studies.

That concept came up again later, during questioning of Sara Radcliffe, executive vice president of health for the Biotechnology Industry Organization (BIO) when Dr. Kozlowski asked whether it would be useful to use pre-marketing data to establish biosimilarity and postmarketing data to test interchangeability.

Ms. Radcliffe said that idea could be possible if an interchangeability determination was not possible before marketing.

Despite the discussion that appeared to indicate a potential for flexibility at FDA, panel members did not give a definitive answer about which way they were leaning.

Dr, Kozlowski’s questions sometimes presented the case for stronger clinical trial requirements. Rasmus Rojkjaer testified on behalf of the Generic Pharmaceutical Association that data from non-U.S. referenced products should be allowed for applications to the FDA and trials should not be more extensive than those required for an innovator product.

Dr. Kozlowski said there had been cases in Europe where clinical trials were shown to be important because they uncovered information that changed the product’s development. He asked about Mr. Rojkjaer’s view of the idea.

Mr. Rojkjaer reiterated that biosimilar applications should not have over-arching rules governing their reviews.

"I think clinical trials has its role to play, but forcing the industry to fit into a one-[size]-fits-all kind of approach I think would seriously keep the development of these biogeneric compounds back," he said.

When Dr. James Roach, chief medical officer of Momenta Pharmaceuticals Inc., argued the trials should be positioned as supportive to existing data, Dr. Jenkins said the agency still has to decide how it will ensure biosimilars are actually similar enough to the reference product.

"We heard a lot of comments yesterday from patient groups and prescribers that they wanted to be very certain that the biosimilar would be highly similar to the clinical effect of the branded product," Dr. Jenkins said. "How do you reconcile those two viewpoints as far as where we should set the bar on determining the role of the clinical trials in establishing that there’s no clinically meaningful difference as the statute requires between the biosimilar and the reference product?"

Dr. Roach said he thought it was possible to provide a limited clinical data set in addition to the existing data package to gain a product approval.

"The Pink Sheet" and this news organization are both owned by Elsevier.

SILVER SPRING, MD. – The Food and Drug Administration appeared to be searching for a way to limit the clinical trial requirements for generic biologic therapies – or biosimilars – during a 2-day public hearing on implementing an approval pathway for the products.

In preparing for the hearing, the FDA hinted it might be willing to consider the possibility that a biosimilar application might not require any clinical trials.

Many presenters, including several manufacturers of approved biologic therapies, insisted that biosimilarity could not be established definitively without a clinical trial because analytical methods are not yet sophisticated enough. Others, including some generic pharmaceutical manufacturers, argued the agency should use discretion in deciding whether trials would be necessary.

FDA officials tried to carve out a middle ground between the two camps. Dr. Steven Kozlowski, director of the Office of Biotechnology Products within the agency’s Center for Drug Evaluation and Research (CDER), and Dr. John Jenkins, director of the CDER Office of New Drugs, appeared through their questioning to indicate a strict and extensive clinical data requirement might not get many biosimilars to the market, but an overly lax standard might not uncover some safety concerns before marketing begins.

Bruce Babbitt, Ph.D., principal consultant at Parexel Consulting, said FDA’s questions and statements during the hearing seemed to indicate the agency would be willing to be flexible with requiring trials, unlike in Europe, where trials are required for all applications.

"FDA might be open to establishing comparability using [pharmacokinetic/pharmacodynamic] studies in humans head to head with a reference [product]," he said.

Dr. Babbitt argued during his formal presentation the "totality of the data" of biologic products already establishes a base for proving biosimilarity and should not be ignored.

"We consider it important to balance the value and relevance of these data against the need for clinical safety and efficacy data particularly where minor or modest differences between the biosimilar and reference products are unlikely to translate into any meaningful differences in the clinic," Dr. Babbitt said in written testimony.

Dr. Kozlowski asked if there is a way to use the totality of the data in determining what studies would be required.

"Is there a way of incorporating that totality of the data or prior knowledge to think about what the impact on clinical studies are because usually the impact is some big-step function?" he asked Dr. Babbitt.

The totality of data helps either streamline or expand the data sponsors needed for their application, Dr. Babbitt said.

Dr. Jenkins also pointed out suggestions from innovator companies that could be excessive and likely not allow for many biosimilar approvals.

"For your clinical head-to-head trials you wanted a demonstration of equivalence, and you wanted a small confidence interval, you recommend equivalence for safety and efficacy and the surrogate endpoints are not acceptable unless they’ve been clinically validated," Dr. Jenkins said to Dr. Michael Wenger, global clinical lead at Roche. "Is that really an achievable standard ... or is that essentially closing the door for a biosimilar?"

Dr. Wenger argued the drugs should be assessed on a case-by-case basis.

The issue of extrapolation – allowing a biosimilar to be used in all the indications of its reference product after being thoroughly studied in only one – generated concerns about the extent of the clinical data needed. The clinical trial program for a biosimilar would be extremely large if a sponsor was required to produce data showing similarity for each indication it wanted in an application.

Dr. Kozlowski questioned whether it was possible to extrapolate some indications using data for others.

"Say you had the two most different indications in a product that had five indications and you explore those two. Do you believe you could extrapolate the other three?" he asked.

The idea would depend on the clinical benefit achieved by the innovator drug, according to Dr. Wenger. If it was a benefit that could be achieved easily, it may be possible, he said, adding that a more complicated benefit, like overall survival in oncology, would require more work.

Dr. Kozlowski asked Vijay Tammara, Ph.D., vice president of regulatory affairs at Nuron Biotech Inc., whether requiring pharmacokinetic and pharmacodynamic studies could be sufficient premarket, saving immunogenicity testing for the postmarketing studies.

That concept came up again later, during questioning of Sara Radcliffe, executive vice president of health for the Biotechnology Industry Organization (BIO) when Dr. Kozlowski asked whether it would be useful to use pre-marketing data to establish biosimilarity and postmarketing data to test interchangeability.

Ms. Radcliffe said that idea could be possible if an interchangeability determination was not possible before marketing.

Despite the discussion that appeared to indicate a potential for flexibility at FDA, panel members did not give a definitive answer about which way they were leaning.

Dr, Kozlowski’s questions sometimes presented the case for stronger clinical trial requirements. Rasmus Rojkjaer testified on behalf of the Generic Pharmaceutical Association that data from non-U.S. referenced products should be allowed for applications to the FDA and trials should not be more extensive than those required for an innovator product.

Dr. Kozlowski said there had been cases in Europe where clinical trials were shown to be important because they uncovered information that changed the product’s development. He asked about Mr. Rojkjaer’s view of the idea.

Mr. Rojkjaer reiterated that biosimilar applications should not have over-arching rules governing their reviews.

"I think clinical trials has its role to play, but forcing the industry to fit into a one-[size]-fits-all kind of approach I think would seriously keep the development of these biogeneric compounds back," he said.

When Dr. James Roach, chief medical officer of Momenta Pharmaceuticals Inc., argued the trials should be positioned as supportive to existing data, Dr. Jenkins said the agency still has to decide how it will ensure biosimilars are actually similar enough to the reference product.

"We heard a lot of comments yesterday from patient groups and prescribers that they wanted to be very certain that the biosimilar would be highly similar to the clinical effect of the branded product," Dr. Jenkins said. "How do you reconcile those two viewpoints as far as where we should set the bar on determining the role of the clinical trials in establishing that there’s no clinically meaningful difference as the statute requires between the biosimilar and the reference product?"

Dr. Roach said he thought it was possible to provide a limited clinical data set in addition to the existing data package to gain a product approval.

"The Pink Sheet" and this news organization are both owned by Elsevier.

GOTHENBURG, SWEDEN – Long-term risks of malignancies, serious infections, and cardiovascular events in ustekinumab-treated psoriasis patients was found to be what is expected in the general U.S. population, according to a 3-year safety analysis of the major randomized clinical trials of the biologic agent.

Placebo-treated control groups were utilized during the first 12 weeks of the phase III PHOENIX I and II trials and not at all in the phase III Active Comparator Psoriasis Trial (ACCEPT). For the safety analysis based on 3 years of follow-up – for purposes of comparison – risk estimates for the general U.S. population were derived from the National Institute of Health’s Surveillance, Epidemiology and End Results (SEER) database and MarketScan Research Data, Dr. Kenneth B. Gordon explained at the annual congress of the European Academy of Dermatology and Venereology.

The 3-year safety analysis included 3,117 psoriasis patients treated with ustekinumab (Stelara) at 45 mg or 90 mg per dose based on body weight, in accordance with the product labeling. Among this group were 1,247 patients who received the interleukin-12 and -23 inhibitor for at least 2 years, noted Dr. Gordon, a dermatologist at the University of Chicago.

The cumulative incidence of nonmelanoma skin cancer through year 3 in the 3,117 psoriasis patients was 0.64 cases per 100 patient-years in patients on ustekinumab 45 mg and 0.77 per 100 patient-years in those on ustekinumab 90 mg. During the 12-week controlled period of the studies, the incidence in placebo-treated patients was 1.13 cases per 100 patient-years.

Rates of other malignancies, including melanoma and lymphoma, through 3 years were 0.69 and 0.46 cases per 100 patient-years in patients on ustekinumab 45 and 90 mg, respectively. These rates were consistent with those expected in the U.S. general population based upon SEER data. Rates of malignancies other than nonmelanoma skin cancer were also comparable to those reported in a large population of psoriasis patients treated with systemic agents in the U.K. General Practice Research Database, where the incidence was 0.58 cases per 100 patient-years (J. Invest. Dermatol. 2009;129:2604-12).

The rate of serious infections through 3 years was 0.82 per 100 patient-years in psoriasis patients on ustekinumab 45 mg and 1.5 per 100 patient-years in those on the higher dose, for a combined event rate of 1.19 per 100 patient-years. This compared favorably to the expected rate of 1.51 per 100 patient-years in psoriasis patients with nonbiologic systemic agents derived from the MarketScan database, Dr. Gordon said.

The combined rate of cardiovascular death, MI, or stroke through 3 years in ustekinumab-treated psoriasis patients was 0.41 per 100 patient-years in those on the lower dose and 0.35 per 100 patient-years in those receiving 90 mg. These rates were lower, albeit not significantly so, than rates expected in the general population using data from the Framingham Heart Study and in psoriasis patients using the U.K. General Practice Research Database.

Rates of malignancies, serious infections, and cardiovascular events in ustekinumab-treated patients remained stable over time without any indication of cumulative toxicity. Another safety analysis is planned when participants in the phase III trials reach the 5-year follow-up mark.

The study was funded by Centocor. Dr. Gordon disclosed that he serves as a consultant to the company.

GOTHENBURG, SWEDEN – Long-term risks of malignancies, serious infections, and cardiovascular events in ustekinumab-treated psoriasis patients was found to be what is expected in the general U.S. population, according to a 3-year safety analysis of the major randomized clinical trials of the biologic agent.

Placebo-treated control groups were utilized during the first 12 weeks of the phase III PHOENIX I and II trials and not at all in the phase III Active Comparator Psoriasis Trial (ACCEPT). For the safety analysis based on 3 years of follow-up – for purposes of comparison – risk estimates for the general U.S. population were derived from the National Institute of Health’s Surveillance, Epidemiology and End Results (SEER) database and MarketScan Research Data, Dr. Kenneth B. Gordon explained at the annual congress of the European Academy of Dermatology and Venereology.

The 3-year safety analysis included 3,117 psoriasis patients treated with ustekinumab (Stelara) at 45 mg or 90 mg per dose based on body weight, in accordance with the product labeling. Among this group were 1,247 patients who received the interleukin-12 and -23 inhibitor for at least 2 years, noted Dr. Gordon, a dermatologist at the University of Chicago.

The cumulative incidence of nonmelanoma skin cancer through year 3 in the 3,117 psoriasis patients was 0.64 cases per 100 patient-years in patients on ustekinumab 45 mg and 0.77 per 100 patient-years in those on ustekinumab 90 mg. During the 12-week controlled period of the studies, the incidence in placebo-treated patients was 1.13 cases per 100 patient-years.

Rates of other malignancies, including melanoma and lymphoma, through 3 years were 0.69 and 0.46 cases per 100 patient-years in patients on ustekinumab 45 and 90 mg, respectively. These rates were consistent with those expected in the U.S. general population based upon SEER data. Rates of malignancies other than nonmelanoma skin cancer were also comparable to those reported in a large population of psoriasis patients treated with systemic agents in the U.K. General Practice Research Database, where the incidence was 0.58 cases per 100 patient-years (J. Invest. Dermatol. 2009;129:2604-12).

The rate of serious infections through 3 years was 0.82 per 100 patient-years in psoriasis patients on ustekinumab 45 mg and 1.5 per 100 patient-years in those on the higher dose, for a combined event rate of 1.19 per 100 patient-years. This compared favorably to the expected rate of 1.51 per 100 patient-years in psoriasis patients with nonbiologic systemic agents derived from the MarketScan database, Dr. Gordon said.

The combined rate of cardiovascular death, MI, or stroke through 3 years in ustekinumab-treated psoriasis patients was 0.41 per 100 patient-years in those on the lower dose and 0.35 per 100 patient-years in those receiving 90 mg. These rates were lower, albeit not significantly so, than rates expected in the general population using data from the Framingham Heart Study and in psoriasis patients using the U.K. General Practice Research Database.

Rates of malignancies, serious infections, and cardiovascular events in ustekinumab-treated patients remained stable over time without any indication of cumulative toxicity. Another safety analysis is planned when participants in the phase III trials reach the 5-year follow-up mark.

The study was funded by Centocor. Dr. Gordon disclosed that he serves as a consultant to the company.

GOTHENBURG, SWEDEN – Long-term risks of malignancies, serious infections, and cardiovascular events in ustekinumab-treated psoriasis patients was found to be what is expected in the general U.S. population, according to a 3-year safety analysis of the major randomized clinical trials of the biologic agent.

Placebo-treated control groups were utilized during the first 12 weeks of the phase III PHOENIX I and II trials and not at all in the phase III Active Comparator Psoriasis Trial (ACCEPT). For the safety analysis based on 3 years of follow-up – for purposes of comparison – risk estimates for the general U.S. population were derived from the National Institute of Health’s Surveillance, Epidemiology and End Results (SEER) database and MarketScan Research Data, Dr. Kenneth B. Gordon explained at the annual congress of the European Academy of Dermatology and Venereology.

The 3-year safety analysis included 3,117 psoriasis patients treated with ustekinumab (Stelara) at 45 mg or 90 mg per dose based on body weight, in accordance with the product labeling. Among this group were 1,247 patients who received the interleukin-12 and -23 inhibitor for at least 2 years, noted Dr. Gordon, a dermatologist at the University of Chicago.

The cumulative incidence of nonmelanoma skin cancer through year 3 in the 3,117 psoriasis patients was 0.64 cases per 100 patient-years in patients on ustekinumab 45 mg and 0.77 per 100 patient-years in those on ustekinumab 90 mg. During the 12-week controlled period of the studies, the incidence in placebo-treated patients was 1.13 cases per 100 patient-years.

Rates of other malignancies, including melanoma and lymphoma, through 3 years were 0.69 and 0.46 cases per 100 patient-years in patients on ustekinumab 45 and 90 mg, respectively. These rates were consistent with those expected in the U.S. general population based upon SEER data. Rates of malignancies other than nonmelanoma skin cancer were also comparable to those reported in a large population of psoriasis patients treated with systemic agents in the U.K. General Practice Research Database, where the incidence was 0.58 cases per 100 patient-years (J. Invest. Dermatol. 2009;129:2604-12).

The rate of serious infections through 3 years was 0.82 per 100 patient-years in psoriasis patients on ustekinumab 45 mg and 1.5 per 100 patient-years in those on the higher dose, for a combined event rate of 1.19 per 100 patient-years. This compared favorably to the expected rate of 1.51 per 100 patient-years in psoriasis patients with nonbiologic systemic agents derived from the MarketScan database, Dr. Gordon said.

The combined rate of cardiovascular death, MI, or stroke through 3 years in ustekinumab-treated psoriasis patients was 0.41 per 100 patient-years in those on the lower dose and 0.35 per 100 patient-years in those receiving 90 mg. These rates were lower, albeit not significantly so, than rates expected in the general population using data from the Framingham Heart Study and in psoriasis patients using the U.K. General Practice Research Database.

Rates of malignancies, serious infections, and cardiovascular events in ustekinumab-treated patients remained stable over time without any indication of cumulative toxicity. Another safety analysis is planned when participants in the phase III trials reach the 5-year follow-up mark.

The study was funded by Centocor. Dr. Gordon disclosed that he serves as a consultant to the company.

WASHINGTON – Breakthroughs in human genetics combined with funding from the Affordable Care Act have poised the National Institutes of Health to make real progress in the areas of orphan human diseases, according to NIH Director Francis S. Collins.

Speaking with enthusiasm to those he addressed as his "peeps" at the annual meeting of the American Society of Human Genetics, Dr. Collins shared his excitement at the state of human genetics in the post-genomic world, in large part driven by technology that has significantly lowered the cost of DNA sequencing, in turn speeding genetic research tremendously.

This, combined with new ACA funding, has enabled NIH to fund and pursue translational research, moving laboratory results toward and into clinical trials, something that is a new way of thinking for the agency, Dr. Collins said.

Rather than relying on pharmaceutical and biotechnology companies to take charge of the translational research, Dr. Collins encouraged academic researchers to consider partnering with NIH, at least for those orphan disease conditions in which the federal government would not be seen as being in competition with private enterprise.

"There is a serious crisis underway in the way in which this pipeline for drug discovery has been floundering. ... Pharma has been investing a larger and larger amount of money – between $40 and $50 billion dollars a year – and yet in spite of that, FDA approvals of new molecular entities, that is genuinely new drug therapeutics, not ‘me-toos,’ have been dropping steadily over the last 15 years," Dr. Collins said.

The reasons for this are complex, he said, but a big part of the problem involves coming up with appropriate targets and targeting compounds. He said this is an area in which NIH is and can be very much involved.

NIH now encourages academic researchers to take their targets to the assay stage and beyond, providing high-throughput screening (HTS) assistance from the NIH Chemical Genomics Center. Subsequent medicinal chemistry assistance is also available to help to modify HTS hits to enable compounds to become more drug-like and to match current ADME (absorption, distribution, metabolism, and excretion) criteria.

With NIH assistance, more than 150 lead compounds have reached this stage over the last 4-5 years, more than half of which are "poised to go to the next step" of preclinical trials in animals, or the "Valley of Death," according to Dr. Collins, "because this is where projects often go to die."

NIH is now able to assist in this high-risk area through the Therapeutics for Rare and Neglected Diseases (TRND) program in its Office of Rare Diseases Research. The TRND was funded at $24 million in fiscal year 2009.

NIH also is positioned to assist researchers in early phase human trials of orphan diseases through its 240-bed Clinical Center, Dr. Collins said.

"And we have 50 and soon we will have 60 Clinical and Translational Science Awards scattered all across the country which will also be set up to conduct these sorts of trials for new molecular entities," he added.

This new direction in research funding has involved unprecedented cooperation with the Food and Drug Administration, Dr. Collins said, with an NIH-FDA leadership council formed to ensure that new drug candidates are most safely and efficiently moved into the clinical trials framework in ways that would best enable FDA analysis and validation, particularly for rare diseases.

Dr. Collins was particularly excited about five instances in which NIH is using this new model of helping "de-risk" the drug development process for orphan or neglected diseases through TRND. These include four rare diseases (Niemann-Pick Disease Type C, hereditary inclusion body myopathy, sickle cell disease, and chronic lymphocytic leukemia) and one neglected disease (schistosomiasis).

If and when these compounds and those for other rare diseases become ready for marketing and production, NIH would then work with private companies to achieve licensing agreement to enable their manufacture and sale, according to Dr. Collins.

Dr. Collins reported having no financial conflicts of interest with regard to his presentation.

WASHINGTON – Breakthroughs in human genetics combined with funding from the Affordable Care Act have poised the National Institutes of Health to make real progress in the areas of orphan human diseases, according to NIH Director Francis S. Collins.

Speaking with enthusiasm to those he addressed as his "peeps" at the annual meeting of the American Society of Human Genetics, Dr. Collins shared his excitement at the state of human genetics in the post-genomic world, in large part driven by technology that has significantly lowered the cost of DNA sequencing, in turn speeding genetic research tremendously.

This, combined with new ACA funding, has enabled NIH to fund and pursue translational research, moving laboratory results toward and into clinical trials, something that is a new way of thinking for the agency, Dr. Collins said.

Rather than relying on pharmaceutical and biotechnology companies to take charge of the translational research, Dr. Collins encouraged academic researchers to consider partnering with NIH, at least for those orphan disease conditions in which the federal government would not be seen as being in competition with private enterprise.

"There is a serious crisis underway in the way in which this pipeline for drug discovery has been floundering. ... Pharma has been investing a larger and larger amount of money – between $40 and $50 billion dollars a year – and yet in spite of that, FDA approvals of new molecular entities, that is genuinely new drug therapeutics, not ‘me-toos,’ have been dropping steadily over the last 15 years," Dr. Collins said.

The reasons for this are complex, he said, but a big part of the problem involves coming up with appropriate targets and targeting compounds. He said this is an area in which NIH is and can be very much involved.

NIH now encourages academic researchers to take their targets to the assay stage and beyond, providing high-throughput screening (HTS) assistance from the NIH Chemical Genomics Center. Subsequent medicinal chemistry assistance is also available to help to modify HTS hits to enable compounds to become more drug-like and to match current ADME (absorption, distribution, metabolism, and excretion) criteria.

With NIH assistance, more than 150 lead compounds have reached this stage over the last 4-5 years, more than half of which are "poised to go to the next step" of preclinical trials in animals, or the "Valley of Death," according to Dr. Collins, "because this is where projects often go to die."

NIH is now able to assist in this high-risk area through the Therapeutics for Rare and Neglected Diseases (TRND) program in its Office of Rare Diseases Research. The TRND was funded at $24 million in fiscal year 2009.

NIH also is positioned to assist researchers in early phase human trials of orphan diseases through its 240-bed Clinical Center, Dr. Collins said.

"And we have 50 and soon we will have 60 Clinical and Translational Science Awards scattered all across the country which will also be set up to conduct these sorts of trials for new molecular entities," he added.

This new direction in research funding has involved unprecedented cooperation with the Food and Drug Administration, Dr. Collins said, with an NIH-FDA leadership council formed to ensure that new drug candidates are most safely and efficiently moved into the clinical trials framework in ways that would best enable FDA analysis and validation, particularly for rare diseases.

Dr. Collins was particularly excited about five instances in which NIH is using this new model of helping "de-risk" the drug development process for orphan or neglected diseases through TRND. These include four rare diseases (Niemann-Pick Disease Type C, hereditary inclusion body myopathy, sickle cell disease, and chronic lymphocytic leukemia) and one neglected disease (schistosomiasis).

If and when these compounds and those for other rare diseases become ready for marketing and production, NIH would then work with private companies to achieve licensing agreement to enable their manufacture and sale, according to Dr. Collins.

Dr. Collins reported having no financial conflicts of interest with regard to his presentation.

WASHINGTON – Breakthroughs in human genetics combined with funding from the Affordable Care Act have poised the National Institutes of Health to make real progress in the areas of orphan human diseases, according to NIH Director Francis S. Collins.

Speaking with enthusiasm to those he addressed as his "peeps" at the annual meeting of the American Society of Human Genetics, Dr. Collins shared his excitement at the state of human genetics in the post-genomic world, in large part driven by technology that has significantly lowered the cost of DNA sequencing, in turn speeding genetic research tremendously.

This, combined with new ACA funding, has enabled NIH to fund and pursue translational research, moving laboratory results toward and into clinical trials, something that is a new way of thinking for the agency, Dr. Collins said.

Rather than relying on pharmaceutical and biotechnology companies to take charge of the translational research, Dr. Collins encouraged academic researchers to consider partnering with NIH, at least for those orphan disease conditions in which the federal government would not be seen as being in competition with private enterprise.

"There is a serious crisis underway in the way in which this pipeline for drug discovery has been floundering. ... Pharma has been investing a larger and larger amount of money – between $40 and $50 billion dollars a year – and yet in spite of that, FDA approvals of new molecular entities, that is genuinely new drug therapeutics, not ‘me-toos,’ have been dropping steadily over the last 15 years," Dr. Collins said.

The reasons for this are complex, he said, but a big part of the problem involves coming up with appropriate targets and targeting compounds. He said this is an area in which NIH is and can be very much involved.

NIH now encourages academic researchers to take their targets to the assay stage and beyond, providing high-throughput screening (HTS) assistance from the NIH Chemical Genomics Center. Subsequent medicinal chemistry assistance is also available to help to modify HTS hits to enable compounds to become more drug-like and to match current ADME (absorption, distribution, metabolism, and excretion) criteria.

With NIH assistance, more than 150 lead compounds have reached this stage over the last 4-5 years, more than half of which are "poised to go to the next step" of preclinical trials in animals, or the "Valley of Death," according to Dr. Collins, "because this is where projects often go to die."

NIH is now able to assist in this high-risk area through the Therapeutics for Rare and Neglected Diseases (TRND) program in its Office of Rare Diseases Research. The TRND was funded at $24 million in fiscal year 2009.

NIH also is positioned to assist researchers in early phase human trials of orphan diseases through its 240-bed Clinical Center, Dr. Collins said.

"And we have 50 and soon we will have 60 Clinical and Translational Science Awards scattered all across the country which will also be set up to conduct these sorts of trials for new molecular entities," he added.

This new direction in research funding has involved unprecedented cooperation with the Food and Drug Administration, Dr. Collins said, with an NIH-FDA leadership council formed to ensure that new drug candidates are most safely and efficiently moved into the clinical trials framework in ways that would best enable FDA analysis and validation, particularly for rare diseases.

Dr. Collins was particularly excited about five instances in which NIH is using this new model of helping "de-risk" the drug development process for orphan or neglected diseases through TRND. These include four rare diseases (Niemann-Pick Disease Type C, hereditary inclusion body myopathy, sickle cell disease, and chronic lymphocytic leukemia) and one neglected disease (schistosomiasis).

If and when these compounds and those for other rare diseases become ready for marketing and production, NIH would then work with private companies to achieve licensing agreement to enable their manufacture and sale, according to Dr. Collins.

Dr. Collins reported having no financial conflicts of interest with regard to his presentation.

Azathioprine was more effective than was mycophenolate mofetil for the prevention of relapse in antineutrophil cytoplasmic antibody–associated vasculitis.

"Although mycophenolate mofetil may be considered in refractory cases, it should not be considered the first-line remission maintenance therapy in AAV," wrote Dr. Thomas F. Hiemstra and colleagues in an article published online Nov. 8 in JAMA (doi:10.1001/jama.2010.1658).

Dr. Hiemstra of the University of Cambridge, England, looked at 156 patients in an open-label, multicenter, randomized controlled trial known as IMPROVE (International Mycophenolate Mofetil Protocol to Reduce Outbreaks of Vasculitides).

Patients were aged at least 18 years with a new diagnosis of either Wegener granulomatosis or microscopic polyangiitis, recruited between April, 2002 and January, 2009. All patients had a positive indirect immunofluorescence or enzyme-linked immunosorbent assay test result for antineutrophil cytoplasmic antibodies, or ANCAs.

Initially, all study participants received cyclophosphamide and glucocorticoids for induction of remission. Once remission was established, patients were divided into two groups, to receive either azathioprine or mycophenolate mofetil.

A total of 80 patients in the azathioprine group were given 2 mg/kg per day of azathioprine, up to 200 mg. The dose was titrated to 1.5 mg/kg per day after 12 months of treatment, down to 1 mg/kg per day after 18 months, and discontinued after 42 months.

The remaining 76 patients received mycophenolate mofetil at 2,000 mg/day. The dose was reduced to 1,500 mg/day after 12 months, to 1,000 mg/day after 18 months and withdrawn after 42 months.

The median follow-up for both groups was 39 months. All participants were counted in an intent-to-treat analysis.

Dr. Hiemstra recorded 42 relapses in the mycophenolate mofetil group, out of 76 patients (55%), compared with the azathioprine group, which had 30 relapses out of 80 patients (38%).

That amounted to an unadjusted hazard ratio for relapse of 1.69 among mycophenolate mofetil users (95% confidence interval, 1.06-2.70; P = .03).

"After adjustment for the prespecified factors of age, sex, diagnostic subtype, route of cyclophosphamide administration [during initial treatment], and baseline creatinine level, the HR for relapses associated with mycophenolate mofetil use was 1.80 (95% CI, 1.10-2.93; P = .02)," added the researchers.

There were no significant adverse event rate differences between the groups. According to Dr. Hiemstra, there were 22 severe adverse events in 13 patients in the azathioprine group, and 8 events in 8 patients in the mycophenolate mofetil group.

These included severe infection (8 in the azathioprine group and 3 in the mycophenolate mofetil group); leukopenia (11 episodes in the azathioprine group and 5 in the mycophenolate mofetil group); and malignancies (2 bladder cancers and 3 skin cancers in the azathioprine group, versus 1 skin malignancy among mycophenolate mofetil users).

Intolerance led to discontinuation of therapy among six azathioprine and two mycophenolate mofetil users.

"Although mycophenolate mofetil is frequently regarded as a potent alternative to azathioprine, we found no evidence to support its use as the initial remission maintenance therapy for patients with AAV," they investigators said.

Moreover, "we found no significant advantages to the use of mycophenolate mofetil in terms of safety or tolerability," they added.

Dr. Hiemstra reported receiving honoraria from Amgen, and several coinvestigators disclosed financial relationships with other drug makers. The study was partially funded by Hoffmann-La Roche Ltd., which markets mycophenolate mofetil as CellCept.

Azathioprine was more effective than was mycophenolate mofetil for the prevention of relapse in antineutrophil cytoplasmic antibody–associated vasculitis.

"Although mycophenolate mofetil may be considered in refractory cases, it should not be considered the first-line remission maintenance therapy in AAV," wrote Dr. Thomas F. Hiemstra and colleagues in an article published online Nov. 8 in JAMA (doi:10.1001/jama.2010.1658).

Dr. Hiemstra of the University of Cambridge, England, looked at 156 patients in an open-label, multicenter, randomized controlled trial known as IMPROVE (International Mycophenolate Mofetil Protocol to Reduce Outbreaks of Vasculitides).

Patients were aged at least 18 years with a new diagnosis of either Wegener granulomatosis or microscopic polyangiitis, recruited between April, 2002 and January, 2009. All patients had a positive indirect immunofluorescence or enzyme-linked immunosorbent assay test result for antineutrophil cytoplasmic antibodies, or ANCAs.

Initially, all study participants received cyclophosphamide and glucocorticoids for induction of remission. Once remission was established, patients were divided into two groups, to receive either azathioprine or mycophenolate mofetil.

A total of 80 patients in the azathioprine group were given 2 mg/kg per day of azathioprine, up to 200 mg. The dose was titrated to 1.5 mg/kg per day after 12 months of treatment, down to 1 mg/kg per day after 18 months, and discontinued after 42 months.

The remaining 76 patients received mycophenolate mofetil at 2,000 mg/day. The dose was reduced to 1,500 mg/day after 12 months, to 1,000 mg/day after 18 months and withdrawn after 42 months.

The median follow-up for both groups was 39 months. All participants were counted in an intent-to-treat analysis.

Dr. Hiemstra recorded 42 relapses in the mycophenolate mofetil group, out of 76 patients (55%), compared with the azathioprine group, which had 30 relapses out of 80 patients (38%).

That amounted to an unadjusted hazard ratio for relapse of 1.69 among mycophenolate mofetil users (95% confidence interval, 1.06-2.70; P = .03).

"After adjustment for the prespecified factors of age, sex, diagnostic subtype, route of cyclophosphamide administration [during initial treatment], and baseline creatinine level, the HR for relapses associated with mycophenolate mofetil use was 1.80 (95% CI, 1.10-2.93; P = .02)," added the researchers.

There were no significant adverse event rate differences between the groups. According to Dr. Hiemstra, there were 22 severe adverse events in 13 patients in the azathioprine group, and 8 events in 8 patients in the mycophenolate mofetil group.

These included severe infection (8 in the azathioprine group and 3 in the mycophenolate mofetil group); leukopenia (11 episodes in the azathioprine group and 5 in the mycophenolate mofetil group); and malignancies (2 bladder cancers and 3 skin cancers in the azathioprine group, versus 1 skin malignancy among mycophenolate mofetil users).

Intolerance led to discontinuation of therapy among six azathioprine and two mycophenolate mofetil users.

"Although mycophenolate mofetil is frequently regarded as a potent alternative to azathioprine, we found no evidence to support its use as the initial remission maintenance therapy for patients with AAV," they investigators said.

Moreover, "we found no significant advantages to the use of mycophenolate mofetil in terms of safety or tolerability," they added.

Dr. Hiemstra reported receiving honoraria from Amgen, and several coinvestigators disclosed financial relationships with other drug makers. The study was partially funded by Hoffmann-La Roche Ltd., which markets mycophenolate mofetil as CellCept.

Azathioprine was more effective than was mycophenolate mofetil for the prevention of relapse in antineutrophil cytoplasmic antibody–associated vasculitis.

"Although mycophenolate mofetil may be considered in refractory cases, it should not be considered the first-line remission maintenance therapy in AAV," wrote Dr. Thomas F. Hiemstra and colleagues in an article published online Nov. 8 in JAMA (doi:10.1001/jama.2010.1658).

Dr. Hiemstra of the University of Cambridge, England, looked at 156 patients in an open-label, multicenter, randomized controlled trial known as IMPROVE (International Mycophenolate Mofetil Protocol to Reduce Outbreaks of Vasculitides).

Patients were aged at least 18 years with a new diagnosis of either Wegener granulomatosis or microscopic polyangiitis, recruited between April, 2002 and January, 2009. All patients had a positive indirect immunofluorescence or enzyme-linked immunosorbent assay test result for antineutrophil cytoplasmic antibodies, or ANCAs.

Initially, all study participants received cyclophosphamide and glucocorticoids for induction of remission. Once remission was established, patients were divided into two groups, to receive either azathioprine or mycophenolate mofetil.

A total of 80 patients in the azathioprine group were given 2 mg/kg per day of azathioprine, up to 200 mg. The dose was titrated to 1.5 mg/kg per day after 12 months of treatment, down to 1 mg/kg per day after 18 months, and discontinued after 42 months.

The remaining 76 patients received mycophenolate mofetil at 2,000 mg/day. The dose was reduced to 1,500 mg/day after 12 months, to 1,000 mg/day after 18 months and withdrawn after 42 months.

The median follow-up for both groups was 39 months. All participants were counted in an intent-to-treat analysis.

Dr. Hiemstra recorded 42 relapses in the mycophenolate mofetil group, out of 76 patients (55%), compared with the azathioprine group, which had 30 relapses out of 80 patients (38%).

That amounted to an unadjusted hazard ratio for relapse of 1.69 among mycophenolate mofetil users (95% confidence interval, 1.06-2.70; P = .03).

"After adjustment for the prespecified factors of age, sex, diagnostic subtype, route of cyclophosphamide administration [during initial treatment], and baseline creatinine level, the HR for relapses associated with mycophenolate mofetil use was 1.80 (95% CI, 1.10-2.93; P = .02)," added the researchers.

There were no significant adverse event rate differences between the groups. According to Dr. Hiemstra, there were 22 severe adverse events in 13 patients in the azathioprine group, and 8 events in 8 patients in the mycophenolate mofetil group.

These included severe infection (8 in the azathioprine group and 3 in the mycophenolate mofetil group); leukopenia (11 episodes in the azathioprine group and 5 in the mycophenolate mofetil group); and malignancies (2 bladder cancers and 3 skin cancers in the azathioprine group, versus 1 skin malignancy among mycophenolate mofetil users).

Intolerance led to discontinuation of therapy among six azathioprine and two mycophenolate mofetil users.

"Although mycophenolate mofetil is frequently regarded as a potent alternative to azathioprine, we found no evidence to support its use as the initial remission maintenance therapy for patients with AAV," they investigators said.

Moreover, "we found no significant advantages to the use of mycophenolate mofetil in terms of safety or tolerability," they added.

Dr. Hiemstra reported receiving honoraria from Amgen, and several coinvestigators disclosed financial relationships with other drug makers. The study was partially funded by Hoffmann-La Roche Ltd., which markets mycophenolate mofetil as CellCept.

GOTHENBURG, SWEDEN - New evidence identifying the optimal dosing regimen for methotrexate in psoriasis comes from a just-completed year-long randomized clinical trial.

"There's a huge long-standing discussion about which is the best dosing regimen for methotrexate. I think we will be able to give you an answer today," promised Dr. Kristian Reich.

That he did, highlighting the oral methotrexate arm of a new phase-III randomized trial of briakinumab, an investigational, fully human monoclonal antibody–targeting interleukin-12 and interleukin-23, in which the biologic agent was compared to oral methotrexate used in a dosing regimen designed to minimize potential toxicities.

The take-home messages regarding methotrexate from the M10-255 study:

• Nearly 60% of psoriasis patients who are started on methotrexate will discontinue the drug during the first year due to lack of efficacy.

• A starting dose of 15 mg once weekly is well tolerated and effective; in only a small percentage of patients is up-titration beneficial.

• Patients who show a good response to methotrexate 15 mg/week by week 6-8 have a high probability of having a full PASI 75 response after 52 weeks.

• Methotrexate’s safety profile in psoriasis patients is better than it’s often painted, based upon the favorable results of the briakinumab study and phase-III trials of two other biologic agents featuring methotrexate arms.

• The peak response to methotrexate is seen by week 16-20 and thereafter declines steadily.

"I think that for many dermatologists there was a perception that the longer we give methotrexate, the better this drug is going to be. Wrong!" declared Dr. Reich, professor of dermatology at the University of Göttingen, Germany.

Confirmation on this score comes from the methotrexate arm of the phase-III Raptiva (efalizumab) Evaluation of Safety and Treatment Optimization (RESTORE) study. The highest PASI 75 response rate to methotrexate in RESTORE was seen at week 16, when patients were on 15 or 20 mg/week. This was followed by a nearly 12% absolute decline in PASI 75 responders between weeks 16 and 26, he added at the satellite symposium supported by Abbott.

"I think these studies may change the way we view methotrexate," Dr. Reich observed.

The M10-255 trial involved 317 psoriasis patients with a mean baseline PASI score of 18 and a 19-year history of the disease. They were randomized to briakinumab or to oral methotrexate with folic acid on the following schedule: 5 mg of methotrexate on week 1, 10 mg during week 2, 15 mg/week for weeks 3-9, and then an increase to 20 mg/week if a PASI 75 wasn’t achieved on week 10. If a PASI 75 was not reached by week 16, the weekly dose could be further increased to 25 mg.

Of the patients in the methotrexate arm, 72% had discontinued the drug by week 52, with lack of efficacy the reason for 80% of dropouts. Only 6% of subjects discontinued methotrexate due to adverse events.

A PASI 75 efficacy end point was achieved in 40% of patients in the methotrexate arm at 24 weeks and in 24% at week 52.

"In only a low percentage of patients was the week-10 increase to 20 mg/week necessary and helpful to make them achieve a PASI 75 response. And there is no evidence that the further increase to 25 mg is doing any good to the patient," Dr. Reich reported.

This 40% PASI 75 response at week 24 is quite similar to what was seen earlier in the methotrexate arms of the RESTORE and Comparative Study of Humira vs. Methotrexate vs. Placebo in Psoriasis Patients (CHAMPION) trials, which recorded week-16 PASI 75s of 36% and 42%, respectively.

"These three trials used three different methotrexate dosing regimens. Let's get this straight: The methotrexate efficacy was independent of the dosing regimens. No matter if you started with a low dose of 5 mg or with 15 mg straight away, the efficacy was the same. The safety profile of methotrexate was also very similar across these trials," the dermatologist continued.

Dr. Reich said these three trials have changed the way he approaches methotrexate therapy in psoriasis.

"I will no longer use the Weinstein regimen or start with a 5-mg test dose. I think it's fair to say, based on these data, that we can start with 15 mg right away. However, it is now for me absolutely clear that methotrexate is going to produce a good response in 35%-40% of patients, and that's it. And it's not true that the longer we give methotrexate the higher the clinical response will be. We are going to see a decrease, as with every psoriasis drug, beyond week 16-20," according to Dr. Reich.

He disclosed that he has served as a consultant and speaker for and/or participated in clinical trials sponsored by Abbott, which funded the M10-255 trial, as well as Biogen Idec, Bristol-Myers-Squibb, Centocor, Merck Serono, Schering-Plough, UCB Pharma, and Wyeth.

GOTHENBURG, SWEDEN - New evidence identifying the optimal dosing regimen for methotrexate in psoriasis comes from a just-completed year-long randomized clinical trial.

"There's a huge long-standing discussion about which is the best dosing regimen for methotrexate. I think we will be able to give you an answer today," promised Dr. Kristian Reich.

That he did, highlighting the oral methotrexate arm of a new phase-III randomized trial of briakinumab, an investigational, fully human monoclonal antibody–targeting interleukin-12 and interleukin-23, in which the biologic agent was compared to oral methotrexate used in a dosing regimen designed to minimize potential toxicities.

The take-home messages regarding methotrexate from the M10-255 study:

• Nearly 60% of psoriasis patients who are started on methotrexate will discontinue the drug during the first year due to lack of efficacy.

• A starting dose of 15 mg once weekly is well tolerated and effective; in only a small percentage of patients is up-titration beneficial.

• Patients who show a good response to methotrexate 15 mg/week by week 6-8 have a high probability of having a full PASI 75 response after 52 weeks.

• Methotrexate’s safety profile in psoriasis patients is better than it’s often painted, based upon the favorable results of the briakinumab study and phase-III trials of two other biologic agents featuring methotrexate arms.

• The peak response to methotrexate is seen by week 16-20 and thereafter declines steadily.

"I think that for many dermatologists there was a perception that the longer we give methotrexate, the better this drug is going to be. Wrong!" declared Dr. Reich, professor of dermatology at the University of Göttingen, Germany.

Confirmation on this score comes from the methotrexate arm of the phase-III Raptiva (efalizumab) Evaluation of Safety and Treatment Optimization (RESTORE) study. The highest PASI 75 response rate to methotrexate in RESTORE was seen at week 16, when patients were on 15 or 20 mg/week. This was followed by a nearly 12% absolute decline in PASI 75 responders between weeks 16 and 26, he added at the satellite symposium supported by Abbott.

"I think these studies may change the way we view methotrexate," Dr. Reich observed.

The M10-255 trial involved 317 psoriasis patients with a mean baseline PASI score of 18 and a 19-year history of the disease. They were randomized to briakinumab or to oral methotrexate with folic acid on the following schedule: 5 mg of methotrexate on week 1, 10 mg during week 2, 15 mg/week for weeks 3-9, and then an increase to 20 mg/week if a PASI 75 wasn’t achieved on week 10. If a PASI 75 was not reached by week 16, the weekly dose could be further increased to 25 mg.

Of the patients in the methotrexate arm, 72% had discontinued the drug by week 52, with lack of efficacy the reason for 80% of dropouts. Only 6% of subjects discontinued methotrexate due to adverse events.

A PASI 75 efficacy end point was achieved in 40% of patients in the methotrexate arm at 24 weeks and in 24% at week 52.

"In only a low percentage of patients was the week-10 increase to 20 mg/week necessary and helpful to make them achieve a PASI 75 response. And there is no evidence that the further increase to 25 mg is doing any good to the patient," Dr. Reich reported.

This 40% PASI 75 response at week 24 is quite similar to what was seen earlier in the methotrexate arms of the RESTORE and Comparative Study of Humira vs. Methotrexate vs. Placebo in Psoriasis Patients (CHAMPION) trials, which recorded week-16 PASI 75s of 36% and 42%, respectively.

"These three trials used three different methotrexate dosing regimens. Let's get this straight: The methotrexate efficacy was independent of the dosing regimens. No matter if you started with a low dose of 5 mg or with 15 mg straight away, the efficacy was the same. The safety profile of methotrexate was also very similar across these trials," the dermatologist continued.

Dr. Reich said these three trials have changed the way he approaches methotrexate therapy in psoriasis.

"I will no longer use the Weinstein regimen or start with a 5-mg test dose. I think it's fair to say, based on these data, that we can start with 15 mg right away. However, it is now for me absolutely clear that methotrexate is going to produce a good response in 35%-40% of patients, and that's it. And it's not true that the longer we give methotrexate the higher the clinical response will be. We are going to see a decrease, as with every psoriasis drug, beyond week 16-20," according to Dr. Reich.

He disclosed that he has served as a consultant and speaker for and/or participated in clinical trials sponsored by Abbott, which funded the M10-255 trial, as well as Biogen Idec, Bristol-Myers-Squibb, Centocor, Merck Serono, Schering-Plough, UCB Pharma, and Wyeth.

GOTHENBURG, SWEDEN - New evidence identifying the optimal dosing regimen for methotrexate in psoriasis comes from a just-completed year-long randomized clinical trial.

"There's a huge long-standing discussion about which is the best dosing regimen for methotrexate. I think we will be able to give you an answer today," promised Dr. Kristian Reich.

That he did, highlighting the oral methotrexate arm of a new phase-III randomized trial of briakinumab, an investigational, fully human monoclonal antibody–targeting interleukin-12 and interleukin-23, in which the biologic agent was compared to oral methotrexate used in a dosing regimen designed to minimize potential toxicities.

The take-home messages regarding methotrexate from the M10-255 study:

• Nearly 60% of psoriasis patients who are started on methotrexate will discontinue the drug during the first year due to lack of efficacy.

• A starting dose of 15 mg once weekly is well tolerated and effective; in only a small percentage of patients is up-titration beneficial.

• Patients who show a good response to methotrexate 15 mg/week by week 6-8 have a high probability of having a full PASI 75 response after 52 weeks.

• Methotrexate’s safety profile in psoriasis patients is better than it’s often painted, based upon the favorable results of the briakinumab study and phase-III trials of two other biologic agents featuring methotrexate arms.

• The peak response to methotrexate is seen by week 16-20 and thereafter declines steadily.

"I think that for many dermatologists there was a perception that the longer we give methotrexate, the better this drug is going to be. Wrong!" declared Dr. Reich, professor of dermatology at the University of Göttingen, Germany.

Confirmation on this score comes from the methotrexate arm of the phase-III Raptiva (efalizumab) Evaluation of Safety and Treatment Optimization (RESTORE) study. The highest PASI 75 response rate to methotrexate in RESTORE was seen at week 16, when patients were on 15 or 20 mg/week. This was followed by a nearly 12% absolute decline in PASI 75 responders between weeks 16 and 26, he added at the satellite symposium supported by Abbott.

"I think these studies may change the way we view methotrexate," Dr. Reich observed.

The M10-255 trial involved 317 psoriasis patients with a mean baseline PASI score of 18 and a 19-year history of the disease. They were randomized to briakinumab or to oral methotrexate with folic acid on the following schedule: 5 mg of methotrexate on week 1, 10 mg during week 2, 15 mg/week for weeks 3-9, and then an increase to 20 mg/week if a PASI 75 wasn’t achieved on week 10. If a PASI 75 was not reached by week 16, the weekly dose could be further increased to 25 mg.

Of the patients in the methotrexate arm, 72% had discontinued the drug by week 52, with lack of efficacy the reason for 80% of dropouts. Only 6% of subjects discontinued methotrexate due to adverse events.

A PASI 75 efficacy end point was achieved in 40% of patients in the methotrexate arm at 24 weeks and in 24% at week 52.

"In only a low percentage of patients was the week-10 increase to 20 mg/week necessary and helpful to make them achieve a PASI 75 response. And there is no evidence that the further increase to 25 mg is doing any good to the patient," Dr. Reich reported.

This 40% PASI 75 response at week 24 is quite similar to what was seen earlier in the methotrexate arms of the RESTORE and Comparative Study of Humira vs. Methotrexate vs. Placebo in Psoriasis Patients (CHAMPION) trials, which recorded week-16 PASI 75s of 36% and 42%, respectively.

"These three trials used three different methotrexate dosing regimens. Let's get this straight: The methotrexate efficacy was independent of the dosing regimens. No matter if you started with a low dose of 5 mg or with 15 mg straight away, the efficacy was the same. The safety profile of methotrexate was also very similar across these trials," the dermatologist continued.

Dr. Reich said these three trials have changed the way he approaches methotrexate therapy in psoriasis.

"I will no longer use the Weinstein regimen or start with a 5-mg test dose. I think it's fair to say, based on these data, that we can start with 15 mg right away. However, it is now for me absolutely clear that methotrexate is going to produce a good response in 35%-40% of patients, and that's it. And it's not true that the longer we give methotrexate the higher the clinical response will be. We are going to see a decrease, as with every psoriasis drug, beyond week 16-20," according to Dr. Reich.

He disclosed that he has served as a consultant and speaker for and/or participated in clinical trials sponsored by Abbott, which funded the M10-255 trial, as well as Biogen Idec, Bristol-Myers-Squibb, Centocor, Merck Serono, Schering-Plough, UCB Pharma, and Wyeth.

Methotrexate and cyclosporine are proven effective treatments for psoriasis, but each presents unique clinical challenges, according to Dr. Bruce Strober.

"Both drugs are effective and safe if used correctly," said Dr. Strober of the New York University. Despite being relatively "old" medications, they remain important tools for the dermatologist, because not every patient is a good candidate for the newer biologics. Additionally, Dr. Strober noted at the Las Vegas Dermatology Seminar sponsored by Skin Disease Education Foundation (SDEF), "Biologics may fail as monotherapy, but succeed in combination with these traditional systemic medications." They can also be useful rescue therapies in tough clinical scenarios.

Methotrexate is especially attractive because of its moderate efficacy, simplicity of dosing, and low cost. Dr. Strober maintained that methotrexate should be considered as a first-line agent for many patients, whether they have Medicare, private insurance, or no insurance.

The downside of methotrexate can be its GI side effects; it also can exert some stress on the liver. Folic acid can help with both of those problems. "Folate supplementation reduces the incidence of hepatotoxicity and gastrointestinal intolerance without impairing the efficacy of methotrexate," Dr. Strober said. Folic acid and folinic acid are both equally effective, although folic acid is less expensive, and folinic acid must be dosed more than 6 hours from the dose of methotrexate.

Methotrexate must never be administered to women who are trying to conceive, are pregnant or breastfeeding, he added. There are also some relative contraindications, including high alcohol intake; renal or liver disease, including fatty liver; hematologic abnormalities; active infectious disease; and latent infections with hepatitis B and C.

Although the risk of liver damage is low for cumulative doses of less than 3 g of methotrexate, higher doses and long-term therapy can raise the chance of hepatotoxicity as much as 25%. A liver biopsy should be considered in patients who surpass this cumulative level. But the liver biopsy should be viewed as an imperfect test with poor sensitivity, specificity, and procedural risks, he said.

Patients taking methotrexate should always undergo a complete blood count, liver function tests, a blood urea nitrogen and creatinine level check, and hepatitis serologies at baseline; blood counts and liver function tests should be monitored periodically throughout the treatment period.

Although rare, patients may experience idiopathic pulmonary disease due to methotrexate; therefore, unexplained cough and shortness of breath should be evaluated immediately.

Cyclosporine is more suited for patients with severe disease that requires rapid clearing. Also, cyclosporine is safe for pregnant patients and can be used for those who fail other treatments. At lower doses, it can be combined with biologics, noted Dr. Strober.

It is associated with more potential adverse effects than is methotrexate, however. Nephrotoxicity, hypertension, and an increased risk of some cancers are the primary risks, he reported. The drug can also cause electrolyte imbalances (including hypomagnesemia), increase lipid levels, and can cause headache or nausea, hypertrichosis, gingival hyperplasia, and paresthesias. "Cyclosporine has predictable toxicities, and, therefore, its use needs to be short in duration," said Dr. Strober.

Cyclosporine is relatively contraindicated in hypertensive patients, those with a history of nonmelanoma skin cancer, and patients with kidney problems, significant cardiovascular disease, or infections.

Baseline monitoring should include a complete blood count, a metabolic profile, serum magnesium, tuberculosis skin testing, and blood pressure. "Stress the risk of drug interactions to the patient, because cyclosporine is associated with many."

Dr. Strober is a consultant and on the advisory boards of Abbott, Amgen, Centocor Ortho Biotech, Pfizer, and Celgene. He has received honoraria from Abbott, Amgen, Centocor, and Pfizer. SDEF and this news organization are owned by Elsevier.

Methotrexate and cyclosporine are proven effective treatments for psoriasis, but each presents unique clinical challenges, according to Dr. Bruce Strober.

"Both drugs are effective and safe if used correctly," said Dr. Strober of the New York University. Despite being relatively "old" medications, they remain important tools for the dermatologist, because not every patient is a good candidate for the newer biologics. Additionally, Dr. Strober noted at the Las Vegas Dermatology Seminar sponsored by Skin Disease Education Foundation (SDEF), "Biologics may fail as monotherapy, but succeed in combination with these traditional systemic medications." They can also be useful rescue therapies in tough clinical scenarios.

Methotrexate is especially attractive because of its moderate efficacy, simplicity of dosing, and low cost. Dr. Strober maintained that methotrexate should be considered as a first-line agent for many patients, whether they have Medicare, private insurance, or no insurance.

The downside of methotrexate can be its GI side effects; it also can exert some stress on the liver. Folic acid can help with both of those problems. "Folate supplementation reduces the incidence of hepatotoxicity and gastrointestinal intolerance without impairing the efficacy of methotrexate," Dr. Strober said. Folic acid and folinic acid are both equally effective, although folic acid is less expensive, and folinic acid must be dosed more than 6 hours from the dose of methotrexate.

Methotrexate must never be administered to women who are trying to conceive, are pregnant or breastfeeding, he added. There are also some relative contraindications, including high alcohol intake; renal or liver disease, including fatty liver; hematologic abnormalities; active infectious disease; and latent infections with hepatitis B and C.

Although the risk of liver damage is low for cumulative doses of less than 3 g of methotrexate, higher doses and long-term therapy can raise the chance of hepatotoxicity as much as 25%. A liver biopsy should be considered in patients who surpass this cumulative level. But the liver biopsy should be viewed as an imperfect test with poor sensitivity, specificity, and procedural risks, he said.

Patients taking methotrexate should always undergo a complete blood count, liver function tests, a blood urea nitrogen and creatinine level check, and hepatitis serologies at baseline; blood counts and liver function tests should be monitored periodically throughout the treatment period.

Although rare, patients may experience idiopathic pulmonary disease due to methotrexate; therefore, unexplained cough and shortness of breath should be evaluated immediately.

Cyclosporine is more suited for patients with severe disease that requires rapid clearing. Also, cyclosporine is safe for pregnant patients and can be used for those who fail other treatments. At lower doses, it can be combined with biologics, noted Dr. Strober.

It is associated with more potential adverse effects than is methotrexate, however. Nephrotoxicity, hypertension, and an increased risk of some cancers are the primary risks, he reported. The drug can also cause electrolyte imbalances (including hypomagnesemia), increase lipid levels, and can cause headache or nausea, hypertrichosis, gingival hyperplasia, and paresthesias. "Cyclosporine has predictable toxicities, and, therefore, its use needs to be short in duration," said Dr. Strober.

Cyclosporine is relatively contraindicated in hypertensive patients, those with a history of nonmelanoma skin cancer, and patients with kidney problems, significant cardiovascular disease, or infections.

Baseline monitoring should include a complete blood count, a metabolic profile, serum magnesium, tuberculosis skin testing, and blood pressure. "Stress the risk of drug interactions to the patient, because cyclosporine is associated with many."

Dr. Strober is a consultant and on the advisory boards of Abbott, Amgen, Centocor Ortho Biotech, Pfizer, and Celgene. He has received honoraria from Abbott, Amgen, Centocor, and Pfizer. SDEF and this news organization are owned by Elsevier.

Methotrexate and cyclosporine are proven effective treatments for psoriasis, but each presents unique clinical challenges, according to Dr. Bruce Strober.

"Both drugs are effective and safe if used correctly," said Dr. Strober of the New York University. Despite being relatively "old" medications, they remain important tools for the dermatologist, because not every patient is a good candidate for the newer biologics. Additionally, Dr. Strober noted at the Las Vegas Dermatology Seminar sponsored by Skin Disease Education Foundation (SDEF), "Biologics may fail as monotherapy, but succeed in combination with these traditional systemic medications." They can also be useful rescue therapies in tough clinical scenarios.

Methotrexate is especially attractive because of its moderate efficacy, simplicity of dosing, and low cost. Dr. Strober maintained that methotrexate should be considered as a first-line agent for many patients, whether they have Medicare, private insurance, or no insurance.

The downside of methotrexate can be its GI side effects; it also can exert some stress on the liver. Folic acid can help with both of those problems. "Folate supplementation reduces the incidence of hepatotoxicity and gastrointestinal intolerance without impairing the efficacy of methotrexate," Dr. Strober said. Folic acid and folinic acid are both equally effective, although folic acid is less expensive, and folinic acid must be dosed more than 6 hours from the dose of methotrexate.

Methotrexate must never be administered to women who are trying to conceive, are pregnant or breastfeeding, he added. There are also some relative contraindications, including high alcohol intake; renal or liver disease, including fatty liver; hematologic abnormalities; active infectious disease; and latent infections with hepatitis B and C.

Although the risk of liver damage is low for cumulative doses of less than 3 g of methotrexate, higher doses and long-term therapy can raise the chance of hepatotoxicity as much as 25%. A liver biopsy should be considered in patients who surpass this cumulative level. But the liver biopsy should be viewed as an imperfect test with poor sensitivity, specificity, and procedural risks, he said.

Patients taking methotrexate should always undergo a complete blood count, liver function tests, a blood urea nitrogen and creatinine level check, and hepatitis serologies at baseline; blood counts and liver function tests should be monitored periodically throughout the treatment period.

Although rare, patients may experience idiopathic pulmonary disease due to methotrexate; therefore, unexplained cough and shortness of breath should be evaluated immediately.

Cyclosporine is more suited for patients with severe disease that requires rapid clearing. Also, cyclosporine is safe for pregnant patients and can be used for those who fail other treatments. At lower doses, it can be combined with biologics, noted Dr. Strober.

It is associated with more potential adverse effects than is methotrexate, however. Nephrotoxicity, hypertension, and an increased risk of some cancers are the primary risks, he reported. The drug can also cause electrolyte imbalances (including hypomagnesemia), increase lipid levels, and can cause headache or nausea, hypertrichosis, gingival hyperplasia, and paresthesias. "Cyclosporine has predictable toxicities, and, therefore, its use needs to be short in duration," said Dr. Strober.

Cyclosporine is relatively contraindicated in hypertensive patients, those with a history of nonmelanoma skin cancer, and patients with kidney problems, significant cardiovascular disease, or infections.

Baseline monitoring should include a complete blood count, a metabolic profile, serum magnesium, tuberculosis skin testing, and blood pressure. "Stress the risk of drug interactions to the patient, because cyclosporine is associated with many."

Dr. Strober is a consultant and on the advisory boards of Abbott, Amgen, Centocor Ortho Biotech, Pfizer, and Celgene. He has received honoraria from Abbott, Amgen, Centocor, and Pfizer. SDEF and this news organization are owned by Elsevier.

GOTHENBURG, SWEDEN – Swedes with systemic lupus erythematosus tend to die early and at a substantially higher rate than does the general population.

During 13 years of prospective follow-up, 20% of 208 Swedish SLE patients died at a mean age of 60 years. That translates into an age-adjusted 3.3-fold increased rate of all-cause mortality, Dr. Elisabet Svenungsson reported at the annual congress of the European Academy of Dermatology and Venereology.

Cardiovascular disease accounted for 52% of the deaths, a proportion similar to what's seen in the general population. The difference is that cardiovascular death in the SLE cohort occurred predominantly in women at a substantially younger age than is common in women without SLE, observed Dr. Svenungsson, a rheumatologist at Karolinska University Hospital in Stockholm.

In addition to cardiovascular disease, patients with SLE have a number of other comorbidities, including osteoporosis, Sjögren's syndrome, and autoimmune thyroid disease, she reported.

Vascular disease is one of the most common of the many comorbidities associated with SLE, she noted. In a cross-sectional study of 597 patients in the Swedish SLE Network, 11% had ischemic heart disease, 10% had ischemic cerebrovascular disease, and 16% had a history of venous thromboembolism.

The conventional Framingham risk factors don't explain the accelerated atherosclerosis present in patients with SLE. In a prospective cohort study involving 182 SLE patients with a mean age of 44 years, all of whom were free of known cardiovascular disease at baseline, Dr. Svenungsson and coworkers found that the incidence of a first cardiovascular event was 13% during a mean 8.3 years of follow-up. In an age-adjusted, Cox multivariate regression analysis, the only conventional risk factors independently associated with a first cardiovascular event were smoking and age. Smokers with SLE were 2.6-fold more likely to experience an event than were nonsmokers. The risk rose 2.4-fold per 10 years of age.

The other independent predictors of a first cardiovascular event were the presence of any positive antiphospholipid antibody test, which conferred a 4.2-fold increased risk; an elevated von Willebrand factor level, associated with a 2.0-fold risk; and the presence of thrombocytopenia, which was a protective factor associated with a 65% reduction in the risk of a cardiovascular event, Dr. Svenungsson said in her keynote lecture at the meeting of the European Society of Cutaneous Lupus Erythematosus, which was held in conjunction with the EADV congress.

Multiple studies have established that one or more antiphospholipid antibodies are present in 30%-50% of SLE patients. Among a cohort of 320 SLE patients who were being followed by Dr. Svenungsson and her associates, 18% fulfilled strict 2006 criteria for antiphospholipid syndrome. SLE patients with antiphospholipid syndrome have a high rate of thrombotic events that don't track with SLE disease activity.

"They just hit here and there; you never really know when," she said.

Turning to osteoporosis and SLE, Dr. Svenungsson cited a new cross-sectional study by physicians at the University of Gothenburg, who obtained x-rays of the thoracic and lumbar spine in 150 women with SLE who had a median age of 47 years and disease duration of 11 years. Although 29% of the SLE patients had at least one radiologic vertebral compression fracture, only 4% had been diagnosed with a compression fracture.

"You have here a lot of women with a subclinical history of vertebral fractures. That we don't detect most of these fractures may be one reason why patients with SLE often complain about pain," according to Dr. Svenungsson.

In the Gothenburg study, advanced age was an independent risk factor for one or more vertebral fractures at any site, whereas low bone mineral density in the total hip was associated with vertebral fracture in the lumbar spine. Interestingly, cumulative glucocorticoid dose wasn't predictive of vertebral fracture risk (Arthritis Res. Ther. 2010 Aug. 2 [doi:10.1186/ar3104]).

A number of autoimmune diseases commonly overlap with SLE. Among them is autoimmune thyroid disease, which was present in 17% of 331 SLE patients being followed by Dr. Svenungsson and her associates at Karolinska, compared with 8% of matched controls. Hypothyroidism was far more common than hyperthyroid disease in the Karolinska cohort, as has been reported in other SLE studies.

Another autoimmune disease commonly overlapping with SLE is Sj?gren’s syndrome. In the Karolinska cohort, 25% of SLE patients met strict diagnostic criteria for Sjögren's syndrome. Dry mouth was reported by 40% of patients, compared with 7% of matched controls. Dry eyes were reported by 32% of SLE patients vs. 7% of controls.

In addition to cardiovascular disease, osteoporosis, Sjögren's syndrome, antiphospholipid syndrome, and autoimmune thyroid disease, other conditions that occur at an increased rate in patients with SLE include malignancies, rheumatoid arthritis, systemic sclerosis, myositis, vasculitis, autoimmune hepatitis, and infections.

"Lupus is an imitator. It's difficult to say what is comorbidity and what is really a manifestation of lupus," Dr. Svenungsson concluded.

She reported having no relevant financial interests.

GOTHENBURG, SWEDEN – Swedes with systemic lupus erythematosus tend to die early and at a substantially higher rate than does the general population.

During 13 years of prospective follow-up, 20% of 208 Swedish SLE patients died at a mean age of 60 years. That translates into an age-adjusted 3.3-fold increased rate of all-cause mortality, Dr. Elisabet Svenungsson reported at the annual congress of the European Academy of Dermatology and Venereology.

Cardiovascular disease accounted for 52% of the deaths, a proportion similar to what's seen in the general population. The difference is that cardiovascular death in the SLE cohort occurred predominantly in women at a substantially younger age than is common in women without SLE, observed Dr. Svenungsson, a rheumatologist at Karolinska University Hospital in Stockholm.

In addition to cardiovascular disease, patients with SLE have a number of other comorbidities, including osteoporosis, Sjögren's syndrome, and autoimmune thyroid disease, she reported.

Vascular disease is one of the most common of the many comorbidities associated with SLE, she noted. In a cross-sectional study of 597 patients in the Swedish SLE Network, 11% had ischemic heart disease, 10% had ischemic cerebrovascular disease, and 16% had a history of venous thromboembolism.

The conventional Framingham risk factors don't explain the accelerated atherosclerosis present in patients with SLE. In a prospective cohort study involving 182 SLE patients with a mean age of 44 years, all of whom were free of known cardiovascular disease at baseline, Dr. Svenungsson and coworkers found that the incidence of a first cardiovascular event was 13% during a mean 8.3 years of follow-up. In an age-adjusted, Cox multivariate regression analysis, the only conventional risk factors independently associated with a first cardiovascular event were smoking and age. Smokers with SLE were 2.6-fold more likely to experience an event than were nonsmokers. The risk rose 2.4-fold per 10 years of age.

The other independent predictors of a first cardiovascular event were the presence of any positive antiphospholipid antibody test, which conferred a 4.2-fold increased risk; an elevated von Willebrand factor level, associated with a 2.0-fold risk; and the presence of thrombocytopenia, which was a protective factor associated with a 65% reduction in the risk of a cardiovascular event, Dr. Svenungsson said in her keynote lecture at the meeting of the European Society of Cutaneous Lupus Erythematosus, which was held in conjunction with the EADV congress.

Multiple studies have established that one or more antiphospholipid antibodies are present in 30%-50% of SLE patients. Among a cohort of 320 SLE patients who were being followed by Dr. Svenungsson and her associates, 18% fulfilled strict 2006 criteria for antiphospholipid syndrome. SLE patients with antiphospholipid syndrome have a high rate of thrombotic events that don't track with SLE disease activity.

"They just hit here and there; you never really know when," she said.

Turning to osteoporosis and SLE, Dr. Svenungsson cited a new cross-sectional study by physicians at the University of Gothenburg, who obtained x-rays of the thoracic and lumbar spine in 150 women with SLE who had a median age of 47 years and disease duration of 11 years. Although 29% of the SLE patients had at least one radiologic vertebral compression fracture, only 4% had been diagnosed with a compression fracture.

"You have here a lot of women with a subclinical history of vertebral fractures. That we don't detect most of these fractures may be one reason why patients with SLE often complain about pain," according to Dr. Svenungsson.

In the Gothenburg study, advanced age was an independent risk factor for one or more vertebral fractures at any site, whereas low bone mineral density in the total hip was associated with vertebral fracture in the lumbar spine. Interestingly, cumulative glucocorticoid dose wasn't predictive of vertebral fracture risk (Arthritis Res. Ther. 2010 Aug. 2 [doi:10.1186/ar3104]).

A number of autoimmune diseases commonly overlap with SLE. Among them is autoimmune thyroid disease, which was present in 17% of 331 SLE patients being followed by Dr. Svenungsson and her associates at Karolinska, compared with 8% of matched controls. Hypothyroidism was far more common than hyperthyroid disease in the Karolinska cohort, as has been reported in other SLE studies.

Another autoimmune disease commonly overlapping with SLE is Sj?gren’s syndrome. In the Karolinska cohort, 25% of SLE patients met strict diagnostic criteria for Sjögren's syndrome. Dry mouth was reported by 40% of patients, compared with 7% of matched controls. Dry eyes were reported by 32% of SLE patients vs. 7% of controls.

In addition to cardiovascular disease, osteoporosis, Sjögren's syndrome, antiphospholipid syndrome, and autoimmune thyroid disease, other conditions that occur at an increased rate in patients with SLE include malignancies, rheumatoid arthritis, systemic sclerosis, myositis, vasculitis, autoimmune hepatitis, and infections.

"Lupus is an imitator. It's difficult to say what is comorbidity and what is really a manifestation of lupus," Dr. Svenungsson concluded.

She reported having no relevant financial interests.

GOTHENBURG, SWEDEN – Swedes with systemic lupus erythematosus tend to die early and at a substantially higher rate than does the general population.

During 13 years of prospective follow-up, 20% of 208 Swedish SLE patients died at a mean age of 60 years. That translates into an age-adjusted 3.3-fold increased rate of all-cause mortality, Dr. Elisabet Svenungsson reported at the annual congress of the European Academy of Dermatology and Venereology.

Cardiovascular disease accounted for 52% of the deaths, a proportion similar to what's seen in the general population. The difference is that cardiovascular death in the SLE cohort occurred predominantly in women at a substantially younger age than is common in women without SLE, observed Dr. Svenungsson, a rheumatologist at Karolinska University Hospital in Stockholm.

In addition to cardiovascular disease, patients with SLE have a number of other comorbidities, including osteoporosis, Sjögren's syndrome, and autoimmune thyroid disease, she reported.

Vascular disease is one of the most common of the many comorbidities associated with SLE, she noted. In a cross-sectional study of 597 patients in the Swedish SLE Network, 11% had ischemic heart disease, 10% had ischemic cerebrovascular disease, and 16% had a history of venous thromboembolism.

The conventional Framingham risk factors don't explain the accelerated atherosclerosis present in patients with SLE. In a prospective cohort study involving 182 SLE patients with a mean age of 44 years, all of whom were free of known cardiovascular disease at baseline, Dr. Svenungsson and coworkers found that the incidence of a first cardiovascular event was 13% during a mean 8.3 years of follow-up. In an age-adjusted, Cox multivariate regression analysis, the only conventional risk factors independently associated with a first cardiovascular event were smoking and age. Smokers with SLE were 2.6-fold more likely to experience an event than were nonsmokers. The risk rose 2.4-fold per 10 years of age.

The other independent predictors of a first cardiovascular event were the presence of any positive antiphospholipid antibody test, which conferred a 4.2-fold increased risk; an elevated von Willebrand factor level, associated with a 2.0-fold risk; and the presence of thrombocytopenia, which was a protective factor associated with a 65% reduction in the risk of a cardiovascular event, Dr. Svenungsson said in her keynote lecture at the meeting of the European Society of Cutaneous Lupus Erythematosus, which was held in conjunction with the EADV congress.

Multiple studies have established that one or more antiphospholipid antibodies are present in 30%-50% of SLE patients. Among a cohort of 320 SLE patients who were being followed by Dr. Svenungsson and her associates, 18% fulfilled strict 2006 criteria for antiphospholipid syndrome. SLE patients with antiphospholipid syndrome have a high rate of thrombotic events that don't track with SLE disease activity.

"They just hit here and there; you never really know when," she said.

Turning to osteoporosis and SLE, Dr. Svenungsson cited a new cross-sectional study by physicians at the University of Gothenburg, who obtained x-rays of the thoracic and lumbar spine in 150 women with SLE who had a median age of 47 years and disease duration of 11 years. Although 29% of the SLE patients had at least one radiologic vertebral compression fracture, only 4% had been diagnosed with a compression fracture.

"You have here a lot of women with a subclinical history of vertebral fractures. That we don't detect most of these fractures may be one reason why patients with SLE often complain about pain," according to Dr. Svenungsson.

In the Gothenburg study, advanced age was an independent risk factor for one or more vertebral fractures at any site, whereas low bone mineral density in the total hip was associated with vertebral fracture in the lumbar spine. Interestingly, cumulative glucocorticoid dose wasn't predictive of vertebral fracture risk (Arthritis Res. Ther. 2010 Aug. 2 [doi:10.1186/ar3104]).

A number of autoimmune diseases commonly overlap with SLE. Among them is autoimmune thyroid disease, which was present in 17% of 331 SLE patients being followed by Dr. Svenungsson and her associates at Karolinska, compared with 8% of matched controls. Hypothyroidism was far more common than hyperthyroid disease in the Karolinska cohort, as has been reported in other SLE studies.

Another autoimmune disease commonly overlapping with SLE is Sj?gren’s syndrome. In the Karolinska cohort, 25% of SLE patients met strict diagnostic criteria for Sjögren's syndrome. Dry mouth was reported by 40% of patients, compared with 7% of matched controls. Dry eyes were reported by 32% of SLE patients vs. 7% of controls.

In addition to cardiovascular disease, osteoporosis, Sjögren's syndrome, antiphospholipid syndrome, and autoimmune thyroid disease, other conditions that occur at an increased rate in patients with SLE include malignancies, rheumatoid arthritis, systemic sclerosis, myositis, vasculitis, autoimmune hepatitis, and infections.

"Lupus is an imitator. It's difficult to say what is comorbidity and what is really a manifestation of lupus," Dr. Svenungsson concluded.

She reported having no relevant financial interests.

GOTHENBURG, SWEDEN - Tonsillectomy has beneficial clinical and immunologic effects on chronic plaque psoriasis in patients who get exacerbations associated with streptococcal throat infections, according to a small, prospective, randomized trial.

The proposed mechanism of benefit from the surgery is that it removes an important source of circulating pathogenic T-cells generated in the palatine tonsils. The T-cells respond to antigenic short peptides common to streptococcal M-protein and skin keratins, Dr. Ragna Hlin Thorleifsdottir explained at the annual congress of the European Academy of Dermatology and Venereology.

Photo credit: strfireblue/flickr (Creative Commons)

"Streptococcal M-protein contains a number of amino acid sequences also found in keratins that are upregulated in psoriatic lesions. It’s possible that T-cells that recognize such M-protein sequences in the tonsils also recognize corresponding sequences in the skin. We have identified such cross-reactive T-cells in the blood of psoriasis patients," said Dr. Thorleifsdottir of Landspitali University Hospital, Reykjavik, Iceland.

She reported on 29 patients with chronic plaque psoriasis and a history of exacerbations linked to strep throat randomized to tonsillectomy or a nonsurgical control group. Participants were followed prospectively for 2 years by blinded observers who assessed them every 6 months by Psoriasis Area and Severity Index (PASI) scores and quality of life instruments. Patients remained on their pre-enrollment psoriasis therapies.

Thirteen of 15 tonsillectomy patients showed significant improvement, with reductions of 30%-90% in PASI scores during 2 years of follow-up. The reduction in PASI scores peaked a mean of 18 months post-surgery, at which point 9 of 15 patients (60%) reached PASI 50 (50% improvement), compared with baseline. At 24 months, the tonsillectomy group still had a mean 32% reduction in PASI scores. In contrast, PASI scores did not change significantly over time in the control group.

The improvement in PASI scores in the tonsillectomy group was strongly correlated with a reduction in circulating, cross-reactive, skin-homing CLA+ CD8+ T-cells responsive to 16 homologous M-protein and skin keratin peptides. Skin-homing CLA+ CD4+ T-cells also declined with decreasing PASI scores in the tonsillectomy patients, although this association, while significant, was not as strong as for CD8+ T-cells.

Other investigators have anecdotally reported in uncontrolled series that tonsillectomy appears to have a beneficial effect on psoriasis, said Dr. Thorleifsdottir. What distinguishes the Iceland study is that it was randomized, prospective, and blinded, and it evaluated a specific proposed mechanism involving cross-reactive T-cells. Whether the observed clinical improvement will be maintained beyond 2 years remains to be seen.

Dr. Thorleifsdottir said she had no financial conflicts regarding the tonsillectomy study, which was funded by the University of Iceland Research Fund.

GOTHENBURG, SWEDEN - Tonsillectomy has beneficial clinical and immunologic effects on chronic plaque psoriasis in patients who get exacerbations associated with streptococcal throat infections, according to a small, prospective, randomized trial.

The proposed mechanism of benefit from the surgery is that it removes an important source of circulating pathogenic T-cells generated in the palatine tonsils. The T-cells respond to antigenic short peptides common to streptococcal M-protein and skin keratins, Dr. Ragna Hlin Thorleifsdottir explained at the annual congress of the European Academy of Dermatology and Venereology.

Photo credit: strfireblue/flickr (Creative Commons)

"Streptococcal M-protein contains a number of amino acid sequences also found in keratins that are upregulated in psoriatic lesions. It’s possible that T-cells that recognize such M-protein sequences in the tonsils also recognize corresponding sequences in the skin. We have identified such cross-reactive T-cells in the blood of psoriasis patients," said Dr. Thorleifsdottir of Landspitali University Hospital, Reykjavik, Iceland.

She reported on 29 patients with chronic plaque psoriasis and a history of exacerbations linked to strep throat randomized to tonsillectomy or a nonsurgical control group. Participants were followed prospectively for 2 years by blinded observers who assessed them every 6 months by Psoriasis Area and Severity Index (PASI) scores and quality of life instruments. Patients remained on their pre-enrollment psoriasis therapies.

Thirteen of 15 tonsillectomy patients showed significant improvement, with reductions of 30%-90% in PASI scores during 2 years of follow-up. The reduction in PASI scores peaked a mean of 18 months post-surgery, at which point 9 of 15 patients (60%) reached PASI 50 (50% improvement), compared with baseline. At 24 months, the tonsillectomy group still had a mean 32% reduction in PASI scores. In contrast, PASI scores did not change significantly over time in the control group.

The improvement in PASI scores in the tonsillectomy group was strongly correlated with a reduction in circulating, cross-reactive, skin-homing CLA+ CD8+ T-cells responsive to 16 homologous M-protein and skin keratin peptides. Skin-homing CLA+ CD4+ T-cells also declined with decreasing PASI scores in the tonsillectomy patients, although this association, while significant, was not as strong as for CD8+ T-cells.

Other investigators have anecdotally reported in uncontrolled series that tonsillectomy appears to have a beneficial effect on psoriasis, said Dr. Thorleifsdottir. What distinguishes the Iceland study is that it was randomized, prospective, and blinded, and it evaluated a specific proposed mechanism involving cross-reactive T-cells. Whether the observed clinical improvement will be maintained beyond 2 years remains to be seen.

Dr. Thorleifsdottir said she had no financial conflicts regarding the tonsillectomy study, which was funded by the University of Iceland Research Fund.

GOTHENBURG, SWEDEN - Tonsillectomy has beneficial clinical and immunologic effects on chronic plaque psoriasis in patients who get exacerbations associated with streptococcal throat infections, according to a small, prospective, randomized trial.

The proposed mechanism of benefit from the surgery is that it removes an important source of circulating pathogenic T-cells generated in the palatine tonsils. The T-cells respond to antigenic short peptides common to streptococcal M-protein and skin keratins, Dr. Ragna Hlin Thorleifsdottir explained at the annual congress of the European Academy of Dermatology and Venereology.

Photo credit: strfireblue/flickr (Creative Commons)

"Streptococcal M-protein contains a number of amino acid sequences also found in keratins that are upregulated in psoriatic lesions. It’s possible that T-cells that recognize such M-protein sequences in the tonsils also recognize corresponding sequences in the skin. We have identified such cross-reactive T-cells in the blood of psoriasis patients," said Dr. Thorleifsdottir of Landspitali University Hospital, Reykjavik, Iceland.

She reported on 29 patients with chronic plaque psoriasis and a history of exacerbations linked to strep throat randomized to tonsillectomy or a nonsurgical control group. Participants were followed prospectively for 2 years by blinded observers who assessed them every 6 months by Psoriasis Area and Severity Index (PASI) scores and quality of life instruments. Patients remained on their pre-enrollment psoriasis therapies.

Thirteen of 15 tonsillectomy patients showed significant improvement, with reductions of 30%-90% in PASI scores during 2 years of follow-up. The reduction in PASI scores peaked a mean of 18 months post-surgery, at which point 9 of 15 patients (60%) reached PASI 50 (50% improvement), compared with baseline. At 24 months, the tonsillectomy group still had a mean 32% reduction in PASI scores. In contrast, PASI scores did not change significantly over time in the control group.

The improvement in PASI scores in the tonsillectomy group was strongly correlated with a reduction in circulating, cross-reactive, skin-homing CLA+ CD8+ T-cells responsive to 16 homologous M-protein and skin keratin peptides. Skin-homing CLA+ CD4+ T-cells also declined with decreasing PASI scores in the tonsillectomy patients, although this association, while significant, was not as strong as for CD8+ T-cells.

Other investigators have anecdotally reported in uncontrolled series that tonsillectomy appears to have a beneficial effect on psoriasis, said Dr. Thorleifsdottir. What distinguishes the Iceland study is that it was randomized, prospective, and blinded, and it evaluated a specific proposed mechanism involving cross-reactive T-cells. Whether the observed clinical improvement will be maintained beyond 2 years remains to be seen.

Dr. Thorleifsdottir said she had no financial conflicts regarding the tonsillectomy study, which was funded by the University of Iceland Research Fund.

Sandoz Inc. has voluntarily recalled all lots of Methotrexate Injection, after small glass flakes were found in four lots.

The glass flakes were found by Sandoz quality control, and are a result of delamination of the glass that is used to manufacture the vials, according to a statement released by Sandoz.

The manufacturer noted that lodging of the particles could lead to serious adverse events that could result in disability or death.

More information, including lot numbers, label type, and expiration date can be found on the Sandoz and Food and Drug Administration websites.

Patients should discontinue use of the product immediately.

Sandoz Inc. has voluntarily recalled all lots of Methotrexate Injection, after small glass flakes were found in four lots.

The glass flakes were found by Sandoz quality control, and are a result of delamination of the glass that is used to manufacture the vials, according to a statement released by Sandoz.

The manufacturer noted that lodging of the particles could lead to serious adverse events that could result in disability or death.

More information, including lot numbers, label type, and expiration date can be found on the Sandoz and Food and Drug Administration websites.

Patients should discontinue use of the product immediately.

Sandoz Inc. has voluntarily recalled all lots of Methotrexate Injection, after small glass flakes were found in four lots.

The glass flakes were found by Sandoz quality control, and are a result of delamination of the glass that is used to manufacture the vials, according to a statement released by Sandoz.

The manufacturer noted that lodging of the particles could lead to serious adverse events that could result in disability or death.

More information, including lot numbers, label type, and expiration date can be found on the Sandoz and Food and Drug Administration websites.

Patients should discontinue use of the product immediately.