LONDON – Biologic therapies do not increase the overall risk of cancer in patients with inflammatory arthritis, according to observational data from the Danish Biologics Register, DANBIO, presented by Dr. Lene Dreyer at the annual European Congress of Rheumatology.

After an average of 9 years of follow-up, and representing almost 24,000 patient-years of treatment, the relative risk (RR) for developing any type of cancer for the first time was 1.03 (95% confidence interval [CI] 0.82-1.30) when comparing anti–tumor necrosis factor (anti-TNF) therapy with no biologic treatment.

The cancer risk was also not increased in patients with rheumatoid arthritis (RR = 1.05; 95% CI 0.82-1.34), psoriatic arthritis (RR = 1.98; 95% CI 0.24-16.18), or other arthritic diseases including ankylosing spondylitis (RR = 0.79; 95% CI 0.08-8.33).

Preliminary results suggest that the risk of nonmelanoma skin cancer (RR = 1.11; 95% CI 0.70-1.76) and non-Hodgkin’s lymphoma are also not increased (RR = 0.55; 95% CI 0.16-1.90).

While the findings add to increasing evidence that biologics may not increase cancer risk overall, more analysis is needed to determine if certain types of cancer are more likely to occur in the study population, or if certain patients are at greater risk of malignancy than others. Longer follow-up is also needed to rule out cancers that may take longer than a decade to manifest.

"There has always been concern for an increased risk of lymphoma with TNF-blockers," said Dr. Georg Schett, chair of the department of internal medicine, rheumatology, and clinical immunology at Friedrich-Alexander University Erlangen in Nuremberg, Germany.

Dr. Schett, who was not involved in the study, added that patients with more active arthritis may be more likely than those with less active disease to receive anti-TNF treatment, and so these patients may already be at increased risk for lymphoma.

Indeed, recent data from the British Society for Rheumatology Biologics Register (BSRBR) have shown that the risk of cancer is almost doubled in patients with RA compared with the general population before they are even given biologics.

"There is an increased risk of cancer in patients with rheumatoid arthritis because of the disease itself," agreed study investigator Dr. Dreyer in an interview. In particular, there was an increased risk of lung cancer in Danish patients because of smoking, said Dr. Dreyer, who is a rheumatologist at Gentofte Hospital in Copenhagen.

Dr. Merete Lund Hetland, a consultant rheumatologist from Glostrup University Hospital in Copenhagen and chair of the Danish register, added in an interview: "I think as a [physician] you would always tell your patient, ‘Well, we don’t think there is an increased risk, but there’s always a risk, so you should tell us if you experience any signs or symptoms [that might indicate cancer].’ "

Putting the cancer risk in further context, Dr. Dreyer noted that the risk of infection was higher than that of malignancy, and that of course the benefits of biologic treatment would probably outweigh the risk of malignancy in the majority of patients.

DANBIO (Dansk Reumatologisk Database) was set up in 2000 to prospectively follow all patients starting treatment with anti-TNFs for their arthritis in Denmark. Enrollment in the register is mandatory and included more than 13,500 patients with all types of inflammatory arthritis up until the data cut for the analysis of 2008. Of the enrolled patients, 5,598 had received treatment with anti-TNF agents and 8,101 had not. Two-thirds of patients had rheumatoid arthritis.

To assess cancer risk, data from DANBIO were linked to the Danish Cancer Registry, with a total of 181 first cancers occurring in patients treated with biologics and 132 in those who were not given biologics.

The risk of cancer was the same for men and women, did not increase with the cumulative duration of active treatment, and was independent of the anti-TNF agent used (primarily infliximab, etanercept, and adalimumab).

Similar to other European biologics registers, DANBIO is funded by research grants from all the major players in the biologics market in Denmark. These grants run through the Danish Rheumatism Association and the Danish Cancer Society, and the sponsors have no direct access or influence on how the registry data are collected, analyzed, or published.

"All companies are involved. They all pay the same amount, and we would monitor all drugs regardless of whether there was a sponsor or not," Dr. Hetland said.

The DANBIO team plans to examine the association between biologic treatment and malignancy further, looking at the subtypes of cancer that develop. The team also plans to investigate in more detail the different types of cancer that develop by the type of arthritis.

DANBIO is financially supported by grants from the Danish Rheumatism Association and the Danish Cancer Society. Dr. Hetland has acted as a consultant to Roche, and has received grants and research support on behalf of DANBIO from Abbott, BMS, Centocor, Roche, Schering-Plough, UCB-Nordic, and Wyeth. Dr. Dreyer had no disclosures. Dr. Schett was not involved in the study.

LONDON – Biologic therapies do not increase the overall risk of cancer in patients with inflammatory arthritis, according to observational data from the Danish Biologics Register, DANBIO, presented by Dr. Lene Dreyer at the annual European Congress of Rheumatology.

After an average of 9 years of follow-up, and representing almost 24,000 patient-years of treatment, the relative risk (RR) for developing any type of cancer for the first time was 1.03 (95% confidence interval [CI] 0.82-1.30) when comparing anti–tumor necrosis factor (anti-TNF) therapy with no biologic treatment.

The cancer risk was also not increased in patients with rheumatoid arthritis (RR = 1.05; 95% CI 0.82-1.34), psoriatic arthritis (RR = 1.98; 95% CI 0.24-16.18), or other arthritic diseases including ankylosing spondylitis (RR = 0.79; 95% CI 0.08-8.33).

Preliminary results suggest that the risk of nonmelanoma skin cancer (RR = 1.11; 95% CI 0.70-1.76) and non-Hodgkin’s lymphoma are also not increased (RR = 0.55; 95% CI 0.16-1.90).

While the findings add to increasing evidence that biologics may not increase cancer risk overall, more analysis is needed to determine if certain types of cancer are more likely to occur in the study population, or if certain patients are at greater risk of malignancy than others. Longer follow-up is also needed to rule out cancers that may take longer than a decade to manifest.

"There has always been concern for an increased risk of lymphoma with TNF-blockers," said Dr. Georg Schett, chair of the department of internal medicine, rheumatology, and clinical immunology at Friedrich-Alexander University Erlangen in Nuremberg, Germany.

Dr. Schett, who was not involved in the study, added that patients with more active arthritis may be more likely than those with less active disease to receive anti-TNF treatment, and so these patients may already be at increased risk for lymphoma.

Indeed, recent data from the British Society for Rheumatology Biologics Register (BSRBR) have shown that the risk of cancer is almost doubled in patients with RA compared with the general population before they are even given biologics.

"There is an increased risk of cancer in patients with rheumatoid arthritis because of the disease itself," agreed study investigator Dr. Dreyer in an interview. In particular, there was an increased risk of lung cancer in Danish patients because of smoking, said Dr. Dreyer, who is a rheumatologist at Gentofte Hospital in Copenhagen.

Dr. Merete Lund Hetland, a consultant rheumatologist from Glostrup University Hospital in Copenhagen and chair of the Danish register, added in an interview: "I think as a [physician] you would always tell your patient, ‘Well, we don’t think there is an increased risk, but there’s always a risk, so you should tell us if you experience any signs or symptoms [that might indicate cancer].’ "

Putting the cancer risk in further context, Dr. Dreyer noted that the risk of infection was higher than that of malignancy, and that of course the benefits of biologic treatment would probably outweigh the risk of malignancy in the majority of patients.

DANBIO (Dansk Reumatologisk Database) was set up in 2000 to prospectively follow all patients starting treatment with anti-TNFs for their arthritis in Denmark. Enrollment in the register is mandatory and included more than 13,500 patients with all types of inflammatory arthritis up until the data cut for the analysis of 2008. Of the enrolled patients, 5,598 had received treatment with anti-TNF agents and 8,101 had not. Two-thirds of patients had rheumatoid arthritis.

To assess cancer risk, data from DANBIO were linked to the Danish Cancer Registry, with a total of 181 first cancers occurring in patients treated with biologics and 132 in those who were not given biologics.

The risk of cancer was the same for men and women, did not increase with the cumulative duration of active treatment, and was independent of the anti-TNF agent used (primarily infliximab, etanercept, and adalimumab).

Similar to other European biologics registers, DANBIO is funded by research grants from all the major players in the biologics market in Denmark. These grants run through the Danish Rheumatism Association and the Danish Cancer Society, and the sponsors have no direct access or influence on how the registry data are collected, analyzed, or published.

"All companies are involved. They all pay the same amount, and we would monitor all drugs regardless of whether there was a sponsor or not," Dr. Hetland said.

The DANBIO team plans to examine the association between biologic treatment and malignancy further, looking at the subtypes of cancer that develop. The team also plans to investigate in more detail the different types of cancer that develop by the type of arthritis.

DANBIO is financially supported by grants from the Danish Rheumatism Association and the Danish Cancer Society. Dr. Hetland has acted as a consultant to Roche, and has received grants and research support on behalf of DANBIO from Abbott, BMS, Centocor, Roche, Schering-Plough, UCB-Nordic, and Wyeth. Dr. Dreyer had no disclosures. Dr. Schett was not involved in the study.

LONDON – Biologic therapies do not increase the overall risk of cancer in patients with inflammatory arthritis, according to observational data from the Danish Biologics Register, DANBIO, presented by Dr. Lene Dreyer at the annual European Congress of Rheumatology.

After an average of 9 years of follow-up, and representing almost 24,000 patient-years of treatment, the relative risk (RR) for developing any type of cancer for the first time was 1.03 (95% confidence interval [CI] 0.82-1.30) when comparing anti–tumor necrosis factor (anti-TNF) therapy with no biologic treatment.

The cancer risk was also not increased in patients with rheumatoid arthritis (RR = 1.05; 95% CI 0.82-1.34), psoriatic arthritis (RR = 1.98; 95% CI 0.24-16.18), or other arthritic diseases including ankylosing spondylitis (RR = 0.79; 95% CI 0.08-8.33).

Preliminary results suggest that the risk of nonmelanoma skin cancer (RR = 1.11; 95% CI 0.70-1.76) and non-Hodgkin’s lymphoma are also not increased (RR = 0.55; 95% CI 0.16-1.90).

While the findings add to increasing evidence that biologics may not increase cancer risk overall, more analysis is needed to determine if certain types of cancer are more likely to occur in the study population, or if certain patients are at greater risk of malignancy than others. Longer follow-up is also needed to rule out cancers that may take longer than a decade to manifest.

"There has always been concern for an increased risk of lymphoma with TNF-blockers," said Dr. Georg Schett, chair of the department of internal medicine, rheumatology, and clinical immunology at Friedrich-Alexander University Erlangen in Nuremberg, Germany.

Dr. Schett, who was not involved in the study, added that patients with more active arthritis may be more likely than those with less active disease to receive anti-TNF treatment, and so these patients may already be at increased risk for lymphoma.

Indeed, recent data from the British Society for Rheumatology Biologics Register (BSRBR) have shown that the risk of cancer is almost doubled in patients with RA compared with the general population before they are even given biologics.

"There is an increased risk of cancer in patients with rheumatoid arthritis because of the disease itself," agreed study investigator Dr. Dreyer in an interview. In particular, there was an increased risk of lung cancer in Danish patients because of smoking, said Dr. Dreyer, who is a rheumatologist at Gentofte Hospital in Copenhagen.

Dr. Merete Lund Hetland, a consultant rheumatologist from Glostrup University Hospital in Copenhagen and chair of the Danish register, added in an interview: "I think as a [physician] you would always tell your patient, ‘Well, we don’t think there is an increased risk, but there’s always a risk, so you should tell us if you experience any signs or symptoms [that might indicate cancer].’ "

Putting the cancer risk in further context, Dr. Dreyer noted that the risk of infection was higher than that of malignancy, and that of course the benefits of biologic treatment would probably outweigh the risk of malignancy in the majority of patients.

DANBIO (Dansk Reumatologisk Database) was set up in 2000 to prospectively follow all patients starting treatment with anti-TNFs for their arthritis in Denmark. Enrollment in the register is mandatory and included more than 13,500 patients with all types of inflammatory arthritis up until the data cut for the analysis of 2008. Of the enrolled patients, 5,598 had received treatment with anti-TNF agents and 8,101 had not. Two-thirds of patients had rheumatoid arthritis.

To assess cancer risk, data from DANBIO were linked to the Danish Cancer Registry, with a total of 181 first cancers occurring in patients treated with biologics and 132 in those who were not given biologics.

The risk of cancer was the same for men and women, did not increase with the cumulative duration of active treatment, and was independent of the anti-TNF agent used (primarily infliximab, etanercept, and adalimumab).

Similar to other European biologics registers, DANBIO is funded by research grants from all the major players in the biologics market in Denmark. These grants run through the Danish Rheumatism Association and the Danish Cancer Society, and the sponsors have no direct access or influence on how the registry data are collected, analyzed, or published.

"All companies are involved. They all pay the same amount, and we would monitor all drugs regardless of whether there was a sponsor or not," Dr. Hetland said.

The DANBIO team plans to examine the association between biologic treatment and malignancy further, looking at the subtypes of cancer that develop. The team also plans to investigate in more detail the different types of cancer that develop by the type of arthritis.

DANBIO is financially supported by grants from the Danish Rheumatism Association and the Danish Cancer Society. Dr. Hetland has acted as a consultant to Roche, and has received grants and research support on behalf of DANBIO from Abbott, BMS, Centocor, Roche, Schering-Plough, UCB-Nordic, and Wyeth. Dr. Dreyer had no disclosures. Dr. Schett was not involved in the study.

CHICAGO – The list of off-label uses for biologic agents is growing, according to Dr. Eric Ruderman, who provided an update on dermatologic, ophthalmologic, and other uses at a symposium sponsored by the American College of Rheumatology.

There are scant data to support off-label uses, and these typically come from retrospective reports, small case series, or anecdotal experience, with a few exceptions, said Dr. Ruderman, a rheumatologist at Northwestern University, Chicago.

Dermatologic Uses

Infliximab is increasingly being used to treat hidradenitis suppurativa and neutrophilic dermatoses despite a lack of data from randomized controlled trials to support this practice. Findings from a small double-blind crossover trial involving 38 patients who were treated for 8 weeks, however, did suggest that infliximab improves pain, disease severity, and quality of life.

Some benefit was also shown with adalimumab in this disease in a recent case series, while benefits with etanercept were less clear in two open-label trials. Patients in the etanercept trials also had worsening of their condition after etanercept was discontinued.

As for neutrophilic dermatoses, infliximab appears to be useful for pyoderma gangrenosum and possibly for Sweet’s syndrome. In a double-blind study of 30 patients with pyoderma gangrenosum, a single dose of 5 mg/kg was associated with a 46% improvement, compared with 6% for placebo. Furthermore, nonresponders on placebo at 2 weeks were treated with infliximab with a 60% response rate, and 21% of treated patients achieved remission.

Case reports also show a benefit of infliximab in patients with Sweet's syndrome, but no controlled data are available for this condition, Dr. Ruderman said.

Ophthalmologic Uses

Biologic therapies being used for ophthalmologic conditions include infliximab, adalimumab, and/or daclizumab for childhood uveitis and other types of uveitis, he noted.

Retrospective case series have shown benefit with infliximab, adalimumab, and daclizumab in childhood uveitis, and an open-label prospective study comparing adalimumab with infliximab demonstrated greater benefit with adalimumab (60% vs. 20% remission at 40 months), he said.

Infliximab also may have some benefit in ocular sarcoidosis, with case reports and small open-label series demonstrating some benefit. Etanercept in this disease, however, appears to be no more effective than placebo, based on findings of a randomized study of 18 patients treated for 6 months.

In Behçet's uveitis, case reports and findings from two small open trials suggest some benefit with infliximab. In the open trials, 9 of 12 patients responded to a dose of 5 mg/kg, Dr. Ruderman said, adding that treatment helped reduce steroid use, but relapse was frequent after treatment discontinuation, suggesting that ongoing therapy is necessary.

Pulmonary Uses

Other conditions in which biologics are currently being used include pulmonary and extrapulmonary sarcoidosis, asthma, and chronic obstructive pulmonary disease (COPD).

In one "nicely done" randomized, controlled, multicenter study of 138 pulmonary sarcoidosis patients, infliximab was superior to placebo for improving the percent predicted forced vital capacity at 24 weeks, and also led to improvement in extrapulmonary disease, Dr. Ruderman said.

Improvements in scores on the extrapulmonary physician organ severity tool (ePOST) were better in the treatment versus placebo group at 24 weeks, even after adjusting for the number of organs involved, he said.

Findings from an open-label study of etanercept in this disease, however, showed that only 5 of 17 patients had "success," which was defined as lack of deterioration on x-rays or pulmonary function tests.

Case reports and retrospective data – but not randomized controlled data – have also shown some benefit of infliximab for cutaneous sarcoidosis. In 54 patients who received 116 courses of therapy, resolution or near resolution of lupus pernio was achieved in 77% of patients versus 11%-29% of those treated with steroids and other therapy. Some case reports show benefit in neurosarcoidosis, as well, but no solid data are available to back those up, Dr. Ruderman said.

For asthma, there may be a role for tumor necrosis factor inhibitors, although one randomized controlled trial showed no benefit with golimumab.

The Brigham RA Sequential Study, for example, demonstrated improvement with TNF inhibitors in nine patients with both rheumatoid arthritis (RA) and asthma, and findings from a small, controlled trial of etanercept showed some benefit on several measures of response. The benefits in that study, however, were not clear-cut, and two other etanercept trials, as well as one infliximab trial, failed to show any benefit in asthma.

Similarly, golimumab showed no benefit in a 52-week randomized, controlled trial of 231 patients with severe uncontrolled asthma. Patients in that trial had no improvements over placebo in forced expiratory volume in 1 second (FEV₁) or exacerbations, and they experienced frequent severe infections, Dr. Ruderman said.

Two studies found that infliximab therapy provided no benefit in the management of COPD. The first was a 24-week study of 3 mg/kg, 5 mg/kg, and placebo in 159 patients. The findings showed no improvement in health status or FEV₁, no lessening of exacerbations with treatment vs. placebo, and an increase in the risk of pneumonia in the treated group. The second study was an observational study involving a cohort of 15,771 patients with both RA and COPD. In this study, however, treatment with etanercept was associated with a 50% reduction in the rate of COPD hospitalization.

"I don’t know entirely what to make of that," Dr. Ruderman said, adding that it might be a result of improvement in the RA and thus overall health.

It's an interesting observation, but overall the findings don't say much about the off-label use of TNF inhibitors in COPD, he said.

Dr. Ruderman reported receiving consulting fees and/or research grants from Abbott, Allos, Amgen, Biogenidec, Celgene, Centocor, Crescendo, CVS/Caremark, Pfizer, and UCB.

CHICAGO – The list of off-label uses for biologic agents is growing, according to Dr. Eric Ruderman, who provided an update on dermatologic, ophthalmologic, and other uses at a symposium sponsored by the American College of Rheumatology.

There are scant data to support off-label uses, and these typically come from retrospective reports, small case series, or anecdotal experience, with a few exceptions, said Dr. Ruderman, a rheumatologist at Northwestern University, Chicago.

Dermatologic Uses

Infliximab is increasingly being used to treat hidradenitis suppurativa and neutrophilic dermatoses despite a lack of data from randomized controlled trials to support this practice. Findings from a small double-blind crossover trial involving 38 patients who were treated for 8 weeks, however, did suggest that infliximab improves pain, disease severity, and quality of life.

Some benefit was also shown with adalimumab in this disease in a recent case series, while benefits with etanercept were less clear in two open-label trials. Patients in the etanercept trials also had worsening of their condition after etanercept was discontinued.

As for neutrophilic dermatoses, infliximab appears to be useful for pyoderma gangrenosum and possibly for Sweet’s syndrome. In a double-blind study of 30 patients with pyoderma gangrenosum, a single dose of 5 mg/kg was associated with a 46% improvement, compared with 6% for placebo. Furthermore, nonresponders on placebo at 2 weeks were treated with infliximab with a 60% response rate, and 21% of treated patients achieved remission.

Case reports also show a benefit of infliximab in patients with Sweet's syndrome, but no controlled data are available for this condition, Dr. Ruderman said.

Ophthalmologic Uses

Biologic therapies being used for ophthalmologic conditions include infliximab, adalimumab, and/or daclizumab for childhood uveitis and other types of uveitis, he noted.

Retrospective case series have shown benefit with infliximab, adalimumab, and daclizumab in childhood uveitis, and an open-label prospective study comparing adalimumab with infliximab demonstrated greater benefit with adalimumab (60% vs. 20% remission at 40 months), he said.

Infliximab also may have some benefit in ocular sarcoidosis, with case reports and small open-label series demonstrating some benefit. Etanercept in this disease, however, appears to be no more effective than placebo, based on findings of a randomized study of 18 patients treated for 6 months.

In Behçet's uveitis, case reports and findings from two small open trials suggest some benefit with infliximab. In the open trials, 9 of 12 patients responded to a dose of 5 mg/kg, Dr. Ruderman said, adding that treatment helped reduce steroid use, but relapse was frequent after treatment discontinuation, suggesting that ongoing therapy is necessary.

Pulmonary Uses

Other conditions in which biologics are currently being used include pulmonary and extrapulmonary sarcoidosis, asthma, and chronic obstructive pulmonary disease (COPD).

In one "nicely done" randomized, controlled, multicenter study of 138 pulmonary sarcoidosis patients, infliximab was superior to placebo for improving the percent predicted forced vital capacity at 24 weeks, and also led to improvement in extrapulmonary disease, Dr. Ruderman said.

Improvements in scores on the extrapulmonary physician organ severity tool (ePOST) were better in the treatment versus placebo group at 24 weeks, even after adjusting for the number of organs involved, he said.

Findings from an open-label study of etanercept in this disease, however, showed that only 5 of 17 patients had "success," which was defined as lack of deterioration on x-rays or pulmonary function tests.

Case reports and retrospective data – but not randomized controlled data – have also shown some benefit of infliximab for cutaneous sarcoidosis. In 54 patients who received 116 courses of therapy, resolution or near resolution of lupus pernio was achieved in 77% of patients versus 11%-29% of those treated with steroids and other therapy. Some case reports show benefit in neurosarcoidosis, as well, but no solid data are available to back those up, Dr. Ruderman said.

For asthma, there may be a role for tumor necrosis factor inhibitors, although one randomized controlled trial showed no benefit with golimumab.

The Brigham RA Sequential Study, for example, demonstrated improvement with TNF inhibitors in nine patients with both rheumatoid arthritis (RA) and asthma, and findings from a small, controlled trial of etanercept showed some benefit on several measures of response. The benefits in that study, however, were not clear-cut, and two other etanercept trials, as well as one infliximab trial, failed to show any benefit in asthma.

Similarly, golimumab showed no benefit in a 52-week randomized, controlled trial of 231 patients with severe uncontrolled asthma. Patients in that trial had no improvements over placebo in forced expiratory volume in 1 second (FEV₁) or exacerbations, and they experienced frequent severe infections, Dr. Ruderman said.

Two studies found that infliximab therapy provided no benefit in the management of COPD. The first was a 24-week study of 3 mg/kg, 5 mg/kg, and placebo in 159 patients. The findings showed no improvement in health status or FEV₁, no lessening of exacerbations with treatment vs. placebo, and an increase in the risk of pneumonia in the treated group. The second study was an observational study involving a cohort of 15,771 patients with both RA and COPD. In this study, however, treatment with etanercept was associated with a 50% reduction in the rate of COPD hospitalization.

"I don’t know entirely what to make of that," Dr. Ruderman said, adding that it might be a result of improvement in the RA and thus overall health.

It's an interesting observation, but overall the findings don't say much about the off-label use of TNF inhibitors in COPD, he said.

Dr. Ruderman reported receiving consulting fees and/or research grants from Abbott, Allos, Amgen, Biogenidec, Celgene, Centocor, Crescendo, CVS/Caremark, Pfizer, and UCB.

CHICAGO – The list of off-label uses for biologic agents is growing, according to Dr. Eric Ruderman, who provided an update on dermatologic, ophthalmologic, and other uses at a symposium sponsored by the American College of Rheumatology.

There are scant data to support off-label uses, and these typically come from retrospective reports, small case series, or anecdotal experience, with a few exceptions, said Dr. Ruderman, a rheumatologist at Northwestern University, Chicago.

Dermatologic Uses

Infliximab is increasingly being used to treat hidradenitis suppurativa and neutrophilic dermatoses despite a lack of data from randomized controlled trials to support this practice. Findings from a small double-blind crossover trial involving 38 patients who were treated for 8 weeks, however, did suggest that infliximab improves pain, disease severity, and quality of life.

Some benefit was also shown with adalimumab in this disease in a recent case series, while benefits with etanercept were less clear in two open-label trials. Patients in the etanercept trials also had worsening of their condition after etanercept was discontinued.

As for neutrophilic dermatoses, infliximab appears to be useful for pyoderma gangrenosum and possibly for Sweet’s syndrome. In a double-blind study of 30 patients with pyoderma gangrenosum, a single dose of 5 mg/kg was associated with a 46% improvement, compared with 6% for placebo. Furthermore, nonresponders on placebo at 2 weeks were treated with infliximab with a 60% response rate, and 21% of treated patients achieved remission.

Case reports also show a benefit of infliximab in patients with Sweet's syndrome, but no controlled data are available for this condition, Dr. Ruderman said.

Ophthalmologic Uses

Biologic therapies being used for ophthalmologic conditions include infliximab, adalimumab, and/or daclizumab for childhood uveitis and other types of uveitis, he noted.

Retrospective case series have shown benefit with infliximab, adalimumab, and daclizumab in childhood uveitis, and an open-label prospective study comparing adalimumab with infliximab demonstrated greater benefit with adalimumab (60% vs. 20% remission at 40 months), he said.

Infliximab also may have some benefit in ocular sarcoidosis, with case reports and small open-label series demonstrating some benefit. Etanercept in this disease, however, appears to be no more effective than placebo, based on findings of a randomized study of 18 patients treated for 6 months.

In Behçet's uveitis, case reports and findings from two small open trials suggest some benefit with infliximab. In the open trials, 9 of 12 patients responded to a dose of 5 mg/kg, Dr. Ruderman said, adding that treatment helped reduce steroid use, but relapse was frequent after treatment discontinuation, suggesting that ongoing therapy is necessary.

Pulmonary Uses

Other conditions in which biologics are currently being used include pulmonary and extrapulmonary sarcoidosis, asthma, and chronic obstructive pulmonary disease (COPD).

In one "nicely done" randomized, controlled, multicenter study of 138 pulmonary sarcoidosis patients, infliximab was superior to placebo for improving the percent predicted forced vital capacity at 24 weeks, and also led to improvement in extrapulmonary disease, Dr. Ruderman said.

Improvements in scores on the extrapulmonary physician organ severity tool (ePOST) were better in the treatment versus placebo group at 24 weeks, even after adjusting for the number of organs involved, he said.

Findings from an open-label study of etanercept in this disease, however, showed that only 5 of 17 patients had "success," which was defined as lack of deterioration on x-rays or pulmonary function tests.

Case reports and retrospective data – but not randomized controlled data – have also shown some benefit of infliximab for cutaneous sarcoidosis. In 54 patients who received 116 courses of therapy, resolution or near resolution of lupus pernio was achieved in 77% of patients versus 11%-29% of those treated with steroids and other therapy. Some case reports show benefit in neurosarcoidosis, as well, but no solid data are available to back those up, Dr. Ruderman said.

For asthma, there may be a role for tumor necrosis factor inhibitors, although one randomized controlled trial showed no benefit with golimumab.

The Brigham RA Sequential Study, for example, demonstrated improvement with TNF inhibitors in nine patients with both rheumatoid arthritis (RA) and asthma, and findings from a small, controlled trial of etanercept showed some benefit on several measures of response. The benefits in that study, however, were not clear-cut, and two other etanercept trials, as well as one infliximab trial, failed to show any benefit in asthma.

Similarly, golimumab showed no benefit in a 52-week randomized, controlled trial of 231 patients with severe uncontrolled asthma. Patients in that trial had no improvements over placebo in forced expiratory volume in 1 second (FEV₁) or exacerbations, and they experienced frequent severe infections, Dr. Ruderman said.

Two studies found that infliximab therapy provided no benefit in the management of COPD. The first was a 24-week study of 3 mg/kg, 5 mg/kg, and placebo in 159 patients. The findings showed no improvement in health status or FEV₁, no lessening of exacerbations with treatment vs. placebo, and an increase in the risk of pneumonia in the treated group. The second study was an observational study involving a cohort of 15,771 patients with both RA and COPD. In this study, however, treatment with etanercept was associated with a 50% reduction in the rate of COPD hospitalization.

"I don’t know entirely what to make of that," Dr. Ruderman said, adding that it might be a result of improvement in the RA and thus overall health.

It's an interesting observation, but overall the findings don't say much about the off-label use of TNF inhibitors in COPD, he said.

Dr. Ruderman reported receiving consulting fees and/or research grants from Abbott, Allos, Amgen, Biogenidec, Celgene, Centocor, Crescendo, CVS/Caremark, Pfizer, and UCB.

SEOUL, SOUTH KOREA – Results from a 4-year ustekinumab follow-up study paint a reassuring safety picture, with no evidence of cumulative toxicity, according to Dr. Kristian Reich.

Particularly welcome was the finding that a possible increased risk of major adverse cardiovascular events (MACE) noted during the initial placebo-controlled phase of the clinical trials has not been borne out at the 4-year follow-up mark.

The observed combined rate of MI, stroke, and cardiovascular death in psoriasis patients on the interleukin-12/23 antagonist for at least 4 years – 0.38 events per 100 patient-years – was significantly lower than expected based upon their Framingham Risk Score or U.K. General Practice Research Database (GPRD) profile, Dr. Reich said at the World Congress of Dermatology.

This finding is consistent with the notion that reducing systemic inflammation in patients with moderate to severe psoriasis via highly effective biologic therapy may reduce their disease-related cardiovascular risk to a level similar to, and perhaps even lower than, that of the general population, observed Dr. Reich, professor of dermatology at Georg-August University in Göttingen, Germany.

He noted the ustekinumab (Stelara) safety data from the ongoing open-label extensions of major randomized clinical trials includes 1,129 psoriasis patients on the biologic agent for at least 3 years and 619 treated for 4 years or more. Total follow-up exceeds 6,700 patient-years.

"This is one of the largest long-term databases for any biologic therapy for psoriasis so far," he pointed out.

Key findings from the 4-year analysis were reported in the following areas:

• MACE. Participants in the ustekinumab clinical trials program had a substantial burden of cardiovascular risk factors: a 48% baseline prevalence of obesity, along with hypertension in 27% of patients, dyslipidemia in 20%, a past or current history of smoking in 63%, and a family history of early coronary disease in 12%. Nearly 70% were men.

The 24 MACE events observed through 4 years of ustekinumab therapy compares with an expected 47 events based upon Framingham Risk Score and 70 expected events among similar psoriasis patients not on biologic therapy in the GPRD. This translates to an adjusted 49% risk reduction in ustekinumab-treated patients compared with Framingham expectation, and a 66% relative risk reduction compared with expectation for psoriasis patients in the GPRD.

The 4-year MACE rate with ustekinumab compares favorably with rates observed with other biologic agents in psoriasis patients. For example, the combined rate of MI or stroke in 506 Canadian psoriasis patients treated with etanercept (Enbrel) for up to 4 years was 0.84 events per 100 patient-years. And in a comprehensive 4-year adalimumab (Humira) safety report Dr. Reich presented at the world congress, the MACE rate was similar to the 0.38 per 100-patient-years seen with ustekinumab.

• Serious infections. The serious infection rate in the ustekinumab analysis was 1.1 events per 100 patient-years of exposure, compared with 1.3 events per 100 patient-years in the latest adalimumab analysis, and 1.6 per 100 patient-years of exposure to etanercept in an open-label extension phase of two phase-III trials totaling 912 patients.

"There's no indication that the serious infection rate with ustekinumab is increased beyond that expected with anti–tumor necrosis factor agents. And the per-year ustekinumab analysis shows no evidence of cumulative immunosuppression that would show up in a rising serious infection rate over time; it's absolutely stable over time," he said.

• Nonmelanoma skin cancer. The cumulative rate was 0.6 cases per 100 patient-years of exposure to ustekinumab, compared with 0.7 per 100 patient-years in the adalimumab analysis. As with serious infections, there was no sign of an increased rate of nonmelanoma skin cancers year by year with ustekinumab.

• Other malignancies. The rate of 0.6 per 100 patient-years of exposure to ustekinumab translated to an observed 41 events through 4 years of follow-up, closely similar to the 39 cases to be expected in a healthy population based on extrapolation from the National Cancer Institute's Surveillance, Epidemiology, and End Results database.

Follow-up of participants in the open-label extension of the ustekinumab clinical trials in psoriasis will continue through 5 years of exposure, with additional safety data accruing from clinical trials in psoriatic arthritis, according to Dr. Reich.

Dr. Reich is a consultant to Janssen, which markets ustekinumab outside the United States.

SEOUL, SOUTH KOREA – Results from a 4-year ustekinumab follow-up study paint a reassuring safety picture, with no evidence of cumulative toxicity, according to Dr. Kristian Reich.

Particularly welcome was the finding that a possible increased risk of major adverse cardiovascular events (MACE) noted during the initial placebo-controlled phase of the clinical trials has not been borne out at the 4-year follow-up mark.

The observed combined rate of MI, stroke, and cardiovascular death in psoriasis patients on the interleukin-12/23 antagonist for at least 4 years – 0.38 events per 100 patient-years – was significantly lower than expected based upon their Framingham Risk Score or U.K. General Practice Research Database (GPRD) profile, Dr. Reich said at the World Congress of Dermatology.

This finding is consistent with the notion that reducing systemic inflammation in patients with moderate to severe psoriasis via highly effective biologic therapy may reduce their disease-related cardiovascular risk to a level similar to, and perhaps even lower than, that of the general population, observed Dr. Reich, professor of dermatology at Georg-August University in Göttingen, Germany.

He noted the ustekinumab (Stelara) safety data from the ongoing open-label extensions of major randomized clinical trials includes 1,129 psoriasis patients on the biologic agent for at least 3 years and 619 treated for 4 years or more. Total follow-up exceeds 6,700 patient-years.

"This is one of the largest long-term databases for any biologic therapy for psoriasis so far," he pointed out.

Key findings from the 4-year analysis were reported in the following areas:

• MACE. Participants in the ustekinumab clinical trials program had a substantial burden of cardiovascular risk factors: a 48% baseline prevalence of obesity, along with hypertension in 27% of patients, dyslipidemia in 20%, a past or current history of smoking in 63%, and a family history of early coronary disease in 12%. Nearly 70% were men.

The 24 MACE events observed through 4 years of ustekinumab therapy compares with an expected 47 events based upon Framingham Risk Score and 70 expected events among similar psoriasis patients not on biologic therapy in the GPRD. This translates to an adjusted 49% risk reduction in ustekinumab-treated patients compared with Framingham expectation, and a 66% relative risk reduction compared with expectation for psoriasis patients in the GPRD.

The 4-year MACE rate with ustekinumab compares favorably with rates observed with other biologic agents in psoriasis patients. For example, the combined rate of MI or stroke in 506 Canadian psoriasis patients treated with etanercept (Enbrel) for up to 4 years was 0.84 events per 100 patient-years. And in a comprehensive 4-year adalimumab (Humira) safety report Dr. Reich presented at the world congress, the MACE rate was similar to the 0.38 per 100-patient-years seen with ustekinumab.

• Serious infections. The serious infection rate in the ustekinumab analysis was 1.1 events per 100 patient-years of exposure, compared with 1.3 events per 100 patient-years in the latest adalimumab analysis, and 1.6 per 100 patient-years of exposure to etanercept in an open-label extension phase of two phase-III trials totaling 912 patients.

"There's no indication that the serious infection rate with ustekinumab is increased beyond that expected with anti–tumor necrosis factor agents. And the per-year ustekinumab analysis shows no evidence of cumulative immunosuppression that would show up in a rising serious infection rate over time; it's absolutely stable over time," he said.

• Nonmelanoma skin cancer. The cumulative rate was 0.6 cases per 100 patient-years of exposure to ustekinumab, compared with 0.7 per 100 patient-years in the adalimumab analysis. As with serious infections, there was no sign of an increased rate of nonmelanoma skin cancers year by year with ustekinumab.

• Other malignancies. The rate of 0.6 per 100 patient-years of exposure to ustekinumab translated to an observed 41 events through 4 years of follow-up, closely similar to the 39 cases to be expected in a healthy population based on extrapolation from the National Cancer Institute's Surveillance, Epidemiology, and End Results database.

Follow-up of participants in the open-label extension of the ustekinumab clinical trials in psoriasis will continue through 5 years of exposure, with additional safety data accruing from clinical trials in psoriatic arthritis, according to Dr. Reich.

Dr. Reich is a consultant to Janssen, which markets ustekinumab outside the United States.

SEOUL, SOUTH KOREA – Results from a 4-year ustekinumab follow-up study paint a reassuring safety picture, with no evidence of cumulative toxicity, according to Dr. Kristian Reich.

Particularly welcome was the finding that a possible increased risk of major adverse cardiovascular events (MACE) noted during the initial placebo-controlled phase of the clinical trials has not been borne out at the 4-year follow-up mark.

The observed combined rate of MI, stroke, and cardiovascular death in psoriasis patients on the interleukin-12/23 antagonist for at least 4 years – 0.38 events per 100 patient-years – was significantly lower than expected based upon their Framingham Risk Score or U.K. General Practice Research Database (GPRD) profile, Dr. Reich said at the World Congress of Dermatology.

This finding is consistent with the notion that reducing systemic inflammation in patients with moderate to severe psoriasis via highly effective biologic therapy may reduce their disease-related cardiovascular risk to a level similar to, and perhaps even lower than, that of the general population, observed Dr. Reich, professor of dermatology at Georg-August University in Göttingen, Germany.

He noted the ustekinumab (Stelara) safety data from the ongoing open-label extensions of major randomized clinical trials includes 1,129 psoriasis patients on the biologic agent for at least 3 years and 619 treated for 4 years or more. Total follow-up exceeds 6,700 patient-years.

"This is one of the largest long-term databases for any biologic therapy for psoriasis so far," he pointed out.

Key findings from the 4-year analysis were reported in the following areas:

• MACE. Participants in the ustekinumab clinical trials program had a substantial burden of cardiovascular risk factors: a 48% baseline prevalence of obesity, along with hypertension in 27% of patients, dyslipidemia in 20%, a past or current history of smoking in 63%, and a family history of early coronary disease in 12%. Nearly 70% were men.

The 24 MACE events observed through 4 years of ustekinumab therapy compares with an expected 47 events based upon Framingham Risk Score and 70 expected events among similar psoriasis patients not on biologic therapy in the GPRD. This translates to an adjusted 49% risk reduction in ustekinumab-treated patients compared with Framingham expectation, and a 66% relative risk reduction compared with expectation for psoriasis patients in the GPRD.

The 4-year MACE rate with ustekinumab compares favorably with rates observed with other biologic agents in psoriasis patients. For example, the combined rate of MI or stroke in 506 Canadian psoriasis patients treated with etanercept (Enbrel) for up to 4 years was 0.84 events per 100 patient-years. And in a comprehensive 4-year adalimumab (Humira) safety report Dr. Reich presented at the world congress, the MACE rate was similar to the 0.38 per 100-patient-years seen with ustekinumab.

• Serious infections. The serious infection rate in the ustekinumab analysis was 1.1 events per 100 patient-years of exposure, compared with 1.3 events per 100 patient-years in the latest adalimumab analysis, and 1.6 per 100 patient-years of exposure to etanercept in an open-label extension phase of two phase-III trials totaling 912 patients.

"There's no indication that the serious infection rate with ustekinumab is increased beyond that expected with anti–tumor necrosis factor agents. And the per-year ustekinumab analysis shows no evidence of cumulative immunosuppression that would show up in a rising serious infection rate over time; it's absolutely stable over time," he said.

• Nonmelanoma skin cancer. The cumulative rate was 0.6 cases per 100 patient-years of exposure to ustekinumab, compared with 0.7 per 100 patient-years in the adalimumab analysis. As with serious infections, there was no sign of an increased rate of nonmelanoma skin cancers year by year with ustekinumab.

• Other malignancies. The rate of 0.6 per 100 patient-years of exposure to ustekinumab translated to an observed 41 events through 4 years of follow-up, closely similar to the 39 cases to be expected in a healthy population based on extrapolation from the National Cancer Institute's Surveillance, Epidemiology, and End Results database.

Follow-up of participants in the open-label extension of the ustekinumab clinical trials in psoriasis will continue through 5 years of exposure, with additional safety data accruing from clinical trials in psoriatic arthritis, according to Dr. Reich.

Dr. Reich is a consultant to Janssen, which markets ustekinumab outside the United States.

BRIGHTON, ENGLAND – Sjögren’s syndrome may be one of the lesser known autoimmune conditions treated by rheumatologists, but research is by no means less active in trying to find novel biologic approaches to managing the often debilitating disease.

Indeed, a new study will start patient enrollment within the next few months in the United Kingdom. The multicenter TRACTISS (Trial of Anti-B-Cell Therapy in Patients With Primary Sjögren’s Syndrome) will investigate the efficacy of rituximab versus placebo in the treatment of the autoimmune connective tissue disease. The trial is planned to run for 5 years.

"Everything is falling into place to start," Dr. Simon Bowman, a principal investigator for the trial, said in an interview at the annual meeting of the British Society for Rheumatology.

Dr. Bowman, a consultant rheumatologist and honorary clinical reader at the University of Birmingham (England), added: "We’re waiting for the final ethics approval and delivery of the study drug, but the plan is to start patient recruitment in July." The aim is to recruit up to 110 patients.

According to Arthritis Research UK, which is funding the £1 million study, around half a million people in the United Kingdom have Sjögren’s syndrome.

Sjögren’s syndrome is associated with dry eyes, dry mouth, fatigue, and arthritis, Dr. Bowman explained. It can be a very disabling condition, reducing the overall quality of life of those it affects. "It can also lead to cancer of the lymph glands," he warned.

There is no cure, and current treatments for Sjögren’s target the symptoms of dry eyes and dry mouth but not always with great effect. It is hoped that, by looking at the underlying biology of the condition, which involves inflammatory cell infiltration into the salivary and lacrimal glands, more successful treatments can be developed.

"In the era of biologic therapies we should, theoretically at least, be able to devise a therapeutic approach in the glands and to ameliorate or reverse the systemic immune abnormalities," reasoned Dr. Bowman.

"The current approach is very much focused on B-cells," he added, "principally because drugs like rituximab are already available for use."

That’s not to say that a principally B-cell focused drug such as rituximab isn’t having an effect on T-cell infiltration – a predominant feature found in the salivary glands of patients with Sjögren’s syndrome.

"It’s important to bear in mind that any drug that affects the immune system will have a ripple effect, so that a drug that is normally an anti-B-cell agent will also affect the T-cells," Dr. Bowman said.

The issue is to determine if such biologic agents, regardless of whether they target B- or T-cells, could work in Sjögren’s syndrome. Already approved for use in rheumatoid arthritis and in non-Hodgkin’s lymphoma in the U.K., rituximab is backed by clinical efficacy and safety data and is, therefore, a known entity.

Although rituximab may be the "drug of the moment," Dr. Bowman noted that there were other biologic agents that could be of interest, such as belimumab, a monoclonal antibody that inhibits B-cell activation factor of the tumor necrosis factor (BAFF) or a BLyS (B-lymphocyte simulator) inhibitor.

"The [U.S. Food and Drug Administration] is currently looking at belimumab," Dr. Bowman said, adding that the National Institute for Health and Clinical Effectiveness is also considering if this agent is going to be useful for U.K. patients.

If TRACTISS is successful, then further trials will be needed for the drug’s manufacturer, Roche, to obtain a product license for Sjögren’s syndrome in the U.K. Currently, the only way for patients with Sjögren’s syndrome to receive the drug outside of a clinical trial is on a compassionate-use basis, or if they also have non-Hodgkin’s lymphoma.

TRACTISS is being funded by Arthritis Research UK. Dr. Bowman disclosed acting as consultant for Merck-Serono, Roche, and UCB.

BRIGHTON, ENGLAND – Sjögren’s syndrome may be one of the lesser known autoimmune conditions treated by rheumatologists, but research is by no means less active in trying to find novel biologic approaches to managing the often debilitating disease.

Indeed, a new study will start patient enrollment within the next few months in the United Kingdom. The multicenter TRACTISS (Trial of Anti-B-Cell Therapy in Patients With Primary Sjögren’s Syndrome) will investigate the efficacy of rituximab versus placebo in the treatment of the autoimmune connective tissue disease. The trial is planned to run for 5 years.

"Everything is falling into place to start," Dr. Simon Bowman, a principal investigator for the trial, said in an interview at the annual meeting of the British Society for Rheumatology.

Dr. Bowman, a consultant rheumatologist and honorary clinical reader at the University of Birmingham (England), added: "We’re waiting for the final ethics approval and delivery of the study drug, but the plan is to start patient recruitment in July." The aim is to recruit up to 110 patients.

According to Arthritis Research UK, which is funding the £1 million study, around half a million people in the United Kingdom have Sjögren’s syndrome.

Sjögren’s syndrome is associated with dry eyes, dry mouth, fatigue, and arthritis, Dr. Bowman explained. It can be a very disabling condition, reducing the overall quality of life of those it affects. "It can also lead to cancer of the lymph glands," he warned.

There is no cure, and current treatments for Sjögren’s target the symptoms of dry eyes and dry mouth but not always with great effect. It is hoped that, by looking at the underlying biology of the condition, which involves inflammatory cell infiltration into the salivary and lacrimal glands, more successful treatments can be developed.

"In the era of biologic therapies we should, theoretically at least, be able to devise a therapeutic approach in the glands and to ameliorate or reverse the systemic immune abnormalities," reasoned Dr. Bowman.

"The current approach is very much focused on B-cells," he added, "principally because drugs like rituximab are already available for use."

That’s not to say that a principally B-cell focused drug such as rituximab isn’t having an effect on T-cell infiltration – a predominant feature found in the salivary glands of patients with Sjögren’s syndrome.

"It’s important to bear in mind that any drug that affects the immune system will have a ripple effect, so that a drug that is normally an anti-B-cell agent will also affect the T-cells," Dr. Bowman said.

The issue is to determine if such biologic agents, regardless of whether they target B- or T-cells, could work in Sjögren’s syndrome. Already approved for use in rheumatoid arthritis and in non-Hodgkin’s lymphoma in the U.K., rituximab is backed by clinical efficacy and safety data and is, therefore, a known entity.

Although rituximab may be the "drug of the moment," Dr. Bowman noted that there were other biologic agents that could be of interest, such as belimumab, a monoclonal antibody that inhibits B-cell activation factor of the tumor necrosis factor (BAFF) or a BLyS (B-lymphocyte simulator) inhibitor.

"The [U.S. Food and Drug Administration] is currently looking at belimumab," Dr. Bowman said, adding that the National Institute for Health and Clinical Effectiveness is also considering if this agent is going to be useful for U.K. patients.

If TRACTISS is successful, then further trials will be needed for the drug’s manufacturer, Roche, to obtain a product license for Sjögren’s syndrome in the U.K. Currently, the only way for patients with Sjögren’s syndrome to receive the drug outside of a clinical trial is on a compassionate-use basis, or if they also have non-Hodgkin’s lymphoma.

TRACTISS is being funded by Arthritis Research UK. Dr. Bowman disclosed acting as consultant for Merck-Serono, Roche, and UCB.

BRIGHTON, ENGLAND – Sjögren’s syndrome may be one of the lesser known autoimmune conditions treated by rheumatologists, but research is by no means less active in trying to find novel biologic approaches to managing the often debilitating disease.

Indeed, a new study will start patient enrollment within the next few months in the United Kingdom. The multicenter TRACTISS (Trial of Anti-B-Cell Therapy in Patients With Primary Sjögren’s Syndrome) will investigate the efficacy of rituximab versus placebo in the treatment of the autoimmune connective tissue disease. The trial is planned to run for 5 years.

"Everything is falling into place to start," Dr. Simon Bowman, a principal investigator for the trial, said in an interview at the annual meeting of the British Society for Rheumatology.

Dr. Bowman, a consultant rheumatologist and honorary clinical reader at the University of Birmingham (England), added: "We’re waiting for the final ethics approval and delivery of the study drug, but the plan is to start patient recruitment in July." The aim is to recruit up to 110 patients.

According to Arthritis Research UK, which is funding the £1 million study, around half a million people in the United Kingdom have Sjögren’s syndrome.

Sjögren’s syndrome is associated with dry eyes, dry mouth, fatigue, and arthritis, Dr. Bowman explained. It can be a very disabling condition, reducing the overall quality of life of those it affects. "It can also lead to cancer of the lymph glands," he warned.

There is no cure, and current treatments for Sjögren’s target the symptoms of dry eyes and dry mouth but not always with great effect. It is hoped that, by looking at the underlying biology of the condition, which involves inflammatory cell infiltration into the salivary and lacrimal glands, more successful treatments can be developed.

"In the era of biologic therapies we should, theoretically at least, be able to devise a therapeutic approach in the glands and to ameliorate or reverse the systemic immune abnormalities," reasoned Dr. Bowman.

"The current approach is very much focused on B-cells," he added, "principally because drugs like rituximab are already available for use."

That’s not to say that a principally B-cell focused drug such as rituximab isn’t having an effect on T-cell infiltration – a predominant feature found in the salivary glands of patients with Sjögren’s syndrome.

"It’s important to bear in mind that any drug that affects the immune system will have a ripple effect, so that a drug that is normally an anti-B-cell agent will also affect the T-cells," Dr. Bowman said.

The issue is to determine if such biologic agents, regardless of whether they target B- or T-cells, could work in Sjögren’s syndrome. Already approved for use in rheumatoid arthritis and in non-Hodgkin’s lymphoma in the U.K., rituximab is backed by clinical efficacy and safety data and is, therefore, a known entity.

Although rituximab may be the "drug of the moment," Dr. Bowman noted that there were other biologic agents that could be of interest, such as belimumab, a monoclonal antibody that inhibits B-cell activation factor of the tumor necrosis factor (BAFF) or a BLyS (B-lymphocyte simulator) inhibitor.

"The [U.S. Food and Drug Administration] is currently looking at belimumab," Dr. Bowman said, adding that the National Institute for Health and Clinical Effectiveness is also considering if this agent is going to be useful for U.K. patients.

If TRACTISS is successful, then further trials will be needed for the drug’s manufacturer, Roche, to obtain a product license for Sjögren’s syndrome in the U.K. Currently, the only way for patients with Sjögren’s syndrome to receive the drug outside of a clinical trial is on a compassionate-use basis, or if they also have non-Hodgkin’s lymphoma.

TRACTISS is being funded by Arthritis Research UK. Dr. Bowman disclosed acting as consultant for Merck-Serono, Roche, and UCB.

LAS VEGAS – Most patients taking etanercept or adalimumab for psoriasis can interrupt therapy and restart when needed, but not all of them will get as good a response the second time around.

With either biologic agent, response rates are slightly higher in patients on continuous therapy than in patients who stop and restart therapy, separate speakers said at a dermatology seminar sponsored by Skin Disease Education Foundation (SDEF).

But for a patient who plans to travel and doesn’t want to take along a case of syringes for etanercept injections, a physician can advise that the psoriasis probably won’t return for a few months after stopping the drug, and that restarting etanercept probably will produce a fairly good response, said Dr. Francisco A. Kerdel, director of the dermatology inpatient service at University of Miami Hospital.

Phase III trials of both drugs included arms that allowed withdrawal from therapy and the possibility of retreatment. "This is what happens in real life," he said. "Patients lose their insurance, or they don’t take their medicine, or they have some kind of surgery. Surgeons won’t operate unless the patients discontinue the drug."

On any dosage of etanercept, patients who discontinued the drug lost about half of the improvement they had gained on therapy at approximately 3 months after stopping treatment.

"Do patients flare faster than this in real life? Yes, but in the studies at least we have some data to suggest that it takes a while for patients’ psoriasis to come back," Dr. Kerdel said. Patients who restarted treatment and again discontinued etanercept had similar responses.

A separate randomized, open-label study comparing continuous versus interrupted etanercept therapy in more than 2,500 psoriasis patients showed there was a better response rate after 24 weeks in the continuous-treatment group (71%) than with interrupted therapy (60%), he said (J. Am. Acad. Dermatol. 2007;56:598-603).

"While you can stop and restart, it’s probably not a good idea," Dr. Kerdel said. "I don’t think you should treat psoriasis like you do a light switch and turn it on and off."

Several long-term safety studies that have followed hundreds of patients out to 3 years suggest that continuous etanercept remains efficacious and there is no cumulative toxicity.

Three-year data on adalimumab also suggest that response rates stabilize over time and that no new toxicities emerge, but for both biologic drugs these may be factors of patient selection, Dr. Kenneth B. Gordon said in a separate presentation.

"I would argue that with every medication there is some lost effect over time," said Dr. Gordon of the University of Chicago. Response rates are more variable initially but tend to stabilize over time, because the patients who stay on treatment tend to be the ones who are doing well on it. "You develop a high responding population that’s going to be able to maintain that response over time," he said.

This means, though, that you can tell patients that "if you get them through the first year, the likelihood is that the drug is going to keep on working," Dr. Gordon said.

An unpublished subanalysis by other investigators of phase III trial data on adalimumab looked at patients with a 75% improvement in Psoriasis Area and Severity Index (PASI 75) score after 33 weeks of adalimumab therapy. Among 227 patients who stopped and restarted adalimumab, retreatment recaptured the therapeutic effects, but never quite to the levels seen in 233 patients on continuous treatment. At week 108, 73% on retreatment and 75% on continuous treatment had a PASI 75.

"It’s important to tell patients that when you stop medication, you can restart and there’s a real good chance that you will recapture response, but it’s not in 100% of patients," Dr. Gordon said.

A separate subanalysis of the same data suggests that patients whose psoriasis returns most vigorously after stopping adalimumab are the least likely to recapture their previous response to treatment fully after restarting the drug. Among 70 whose PASI scores fell below 60 before restarting adalimumab, 58% had a PASI 75 at week 108. In 55 patients with a PASI score of 60-74 when restarting adalimumab, 81% achieved a PASI 75 at week 108. In 102 patients with a PASI score of 75-100 when restarting the drug, 86% had a PASI 75 at week 108, he said.

SDEF and this news organization are owned by Elsevier. Dr. Kerdel and Dr. Gordon have been speakers or consultants for, or have received grants from, Amgen (which markets etanercept), Abbott (which markets adalimumab), Centocor, and Merck. Dr. Kerdel also has had associations with Eisai, Astellas, Genentech, Stiefel, Novartis, and Wyeth. Dr. Gordon has had associations with Lilly, Pfizer, Celgene, and Medicis.

LAS VEGAS – Most patients taking etanercept or adalimumab for psoriasis can interrupt therapy and restart when needed, but not all of them will get as good a response the second time around.

With either biologic agent, response rates are slightly higher in patients on continuous therapy than in patients who stop and restart therapy, separate speakers said at a dermatology seminar sponsored by Skin Disease Education Foundation (SDEF).

But for a patient who plans to travel and doesn’t want to take along a case of syringes for etanercept injections, a physician can advise that the psoriasis probably won’t return for a few months after stopping the drug, and that restarting etanercept probably will produce a fairly good response, said Dr. Francisco A. Kerdel, director of the dermatology inpatient service at University of Miami Hospital.

Phase III trials of both drugs included arms that allowed withdrawal from therapy and the possibility of retreatment. "This is what happens in real life," he said. "Patients lose their insurance, or they don’t take their medicine, or they have some kind of surgery. Surgeons won’t operate unless the patients discontinue the drug."

On any dosage of etanercept, patients who discontinued the drug lost about half of the improvement they had gained on therapy at approximately 3 months after stopping treatment.

"Do patients flare faster than this in real life? Yes, but in the studies at least we have some data to suggest that it takes a while for patients’ psoriasis to come back," Dr. Kerdel said. Patients who restarted treatment and again discontinued etanercept had similar responses.

A separate randomized, open-label study comparing continuous versus interrupted etanercept therapy in more than 2,500 psoriasis patients showed there was a better response rate after 24 weeks in the continuous-treatment group (71%) than with interrupted therapy (60%), he said (J. Am. Acad. Dermatol. 2007;56:598-603).

"While you can stop and restart, it’s probably not a good idea," Dr. Kerdel said. "I don’t think you should treat psoriasis like you do a light switch and turn it on and off."

Several long-term safety studies that have followed hundreds of patients out to 3 years suggest that continuous etanercept remains efficacious and there is no cumulative toxicity.

Three-year data on adalimumab also suggest that response rates stabilize over time and that no new toxicities emerge, but for both biologic drugs these may be factors of patient selection, Dr. Kenneth B. Gordon said in a separate presentation.

"I would argue that with every medication there is some lost effect over time," said Dr. Gordon of the University of Chicago. Response rates are more variable initially but tend to stabilize over time, because the patients who stay on treatment tend to be the ones who are doing well on it. "You develop a high responding population that’s going to be able to maintain that response over time," he said.

This means, though, that you can tell patients that "if you get them through the first year, the likelihood is that the drug is going to keep on working," Dr. Gordon said.

An unpublished subanalysis by other investigators of phase III trial data on adalimumab looked at patients with a 75% improvement in Psoriasis Area and Severity Index (PASI 75) score after 33 weeks of adalimumab therapy. Among 227 patients who stopped and restarted adalimumab, retreatment recaptured the therapeutic effects, but never quite to the levels seen in 233 patients on continuous treatment. At week 108, 73% on retreatment and 75% on continuous treatment had a PASI 75.

"It’s important to tell patients that when you stop medication, you can restart and there’s a real good chance that you will recapture response, but it’s not in 100% of patients," Dr. Gordon said.

A separate subanalysis of the same data suggests that patients whose psoriasis returns most vigorously after stopping adalimumab are the least likely to recapture their previous response to treatment fully after restarting the drug. Among 70 whose PASI scores fell below 60 before restarting adalimumab, 58% had a PASI 75 at week 108. In 55 patients with a PASI score of 60-74 when restarting adalimumab, 81% achieved a PASI 75 at week 108. In 102 patients with a PASI score of 75-100 when restarting the drug, 86% had a PASI 75 at week 108, he said.

SDEF and this news organization are owned by Elsevier. Dr. Kerdel and Dr. Gordon have been speakers or consultants for, or have received grants from, Amgen (which markets etanercept), Abbott (which markets adalimumab), Centocor, and Merck. Dr. Kerdel also has had associations with Eisai, Astellas, Genentech, Stiefel, Novartis, and Wyeth. Dr. Gordon has had associations with Lilly, Pfizer, Celgene, and Medicis.

LAS VEGAS – Most patients taking etanercept or adalimumab for psoriasis can interrupt therapy and restart when needed, but not all of them will get as good a response the second time around.

With either biologic agent, response rates are slightly higher in patients on continuous therapy than in patients who stop and restart therapy, separate speakers said at a dermatology seminar sponsored by Skin Disease Education Foundation (SDEF).

But for a patient who plans to travel and doesn’t want to take along a case of syringes for etanercept injections, a physician can advise that the psoriasis probably won’t return for a few months after stopping the drug, and that restarting etanercept probably will produce a fairly good response, said Dr. Francisco A. Kerdel, director of the dermatology inpatient service at University of Miami Hospital.

Phase III trials of both drugs included arms that allowed withdrawal from therapy and the possibility of retreatment. "This is what happens in real life," he said. "Patients lose their insurance, or they don’t take their medicine, or they have some kind of surgery. Surgeons won’t operate unless the patients discontinue the drug."

On any dosage of etanercept, patients who discontinued the drug lost about half of the improvement they had gained on therapy at approximately 3 months after stopping treatment.

"Do patients flare faster than this in real life? Yes, but in the studies at least we have some data to suggest that it takes a while for patients’ psoriasis to come back," Dr. Kerdel said. Patients who restarted treatment and again discontinued etanercept had similar responses.

A separate randomized, open-label study comparing continuous versus interrupted etanercept therapy in more than 2,500 psoriasis patients showed there was a better response rate after 24 weeks in the continuous-treatment group (71%) than with interrupted therapy (60%), he said (J. Am. Acad. Dermatol. 2007;56:598-603).

"While you can stop and restart, it’s probably not a good idea," Dr. Kerdel said. "I don’t think you should treat psoriasis like you do a light switch and turn it on and off."

Several long-term safety studies that have followed hundreds of patients out to 3 years suggest that continuous etanercept remains efficacious and there is no cumulative toxicity.

Three-year data on adalimumab also suggest that response rates stabilize over time and that no new toxicities emerge, but for both biologic drugs these may be factors of patient selection, Dr. Kenneth B. Gordon said in a separate presentation.

"I would argue that with every medication there is some lost effect over time," said Dr. Gordon of the University of Chicago. Response rates are more variable initially but tend to stabilize over time, because the patients who stay on treatment tend to be the ones who are doing well on it. "You develop a high responding population that’s going to be able to maintain that response over time," he said.

This means, though, that you can tell patients that "if you get them through the first year, the likelihood is that the drug is going to keep on working," Dr. Gordon said.

An unpublished subanalysis by other investigators of phase III trial data on adalimumab looked at patients with a 75% improvement in Psoriasis Area and Severity Index (PASI 75) score after 33 weeks of adalimumab therapy. Among 227 patients who stopped and restarted adalimumab, retreatment recaptured the therapeutic effects, but never quite to the levels seen in 233 patients on continuous treatment. At week 108, 73% on retreatment and 75% on continuous treatment had a PASI 75.

"It’s important to tell patients that when you stop medication, you can restart and there’s a real good chance that you will recapture response, but it’s not in 100% of patients," Dr. Gordon said.

A separate subanalysis of the same data suggests that patients whose psoriasis returns most vigorously after stopping adalimumab are the least likely to recapture their previous response to treatment fully after restarting the drug. Among 70 whose PASI scores fell below 60 before restarting adalimumab, 58% had a PASI 75 at week 108. In 55 patients with a PASI score of 60-74 when restarting adalimumab, 81% achieved a PASI 75 at week 108. In 102 patients with a PASI score of 75-100 when restarting the drug, 86% had a PASI 75 at week 108, he said.

SDEF and this news organization are owned by Elsevier. Dr. Kerdel and Dr. Gordon have been speakers or consultants for, or have received grants from, Amgen (which markets etanercept), Abbott (which markets adalimumab), Centocor, and Merck. Dr. Kerdel also has had associations with Eisai, Astellas, Genentech, Stiefel, Novartis, and Wyeth. Dr. Gordon has had associations with Lilly, Pfizer, Celgene, and Medicis.

Pregnant women taking tumor necrosis factor inhibitors at conception experienced a higher rate of spontaneous abortion than did patients who did not.

The data, culled from the British Society for Rheumatology Biologics Registry, is from the "largest detailed prospective collection of pregnancy outcomes in women with arthritis-related diseases exposed to anti-TNF therapy" to date, according to the authors.

Despite its relatively large size, however, the study was unable to control for the looming possibility that disease severity itself plays a role in adverse pregnancy outcomes, as the authors readily admitted.

Nevertheless, "no firm conclusions can be drawn about the safety of anti-TNF therapy during pregnancy and, without further evidence, guidelines which suggest these drugs should be avoided at the time of conception must remain," recommended the authors.

The study was led by Dr. Suzanne M. M. Verstappen of the University of Manchester’s Arthritis Research UK Epidemiology Unit and was published online in Annals of the Rheumatic Diseases.

Dr. Verstappen and her colleagues looked at women in the registry who received adalimumab, etanercept, or infliximab either at conception or at any time prior to conception. A subset was also exposed to methotrexate and/or leflunomide at time of conception in addition to the anti-TNFs, two drugs with a "known risk of adverse pregnancy outcomes," according to the authors.

A fourth cohort with active rheumatoid arthritis had no history of anti-TNF use, but rather received nonbiological disease-modifying antirheumatic drugs (DMARDs), excluding methotrexate and leflunomide (Ann. Rheum. Dis. 2011 [doi:10.1136/ard.2010.140822]).

Among cohort Ia, which included 20 women (21 pregnancies) who took anti-TNFs plus either methotrexate and/or leflunomide at conception, there were 10 live births, 4 terminations, and 7 (33%) spontaneous abortions (miscarriages occurring prior to 20 weeks or to viability outside the womb).

Among cohort Ib, which included 44 women who took anti-TNFs at conception, but not methotrexate or leflunomide, there were 50 pregnancies. They included 32 live births among this cohort, 4 terminations, 12 spontaneous abortions (24%) and 2 intrauterine deaths (occurring post-20 weeks).

There was also one neonatal death registered.

The women who had taken anti-TNFs in the past, but not at the time of conception (cohort II), did have seemingly better outcomes: the 59 pregnancies (54 women) resulted in live births in 46 cases (including one of two twins), terminations in 2, and spontaneous abortions in 10 (17%). There were two intrauterine deaths, including the twin death.

Finally, among the 10 pregnancies in 10 women who had no history of anti-TNF use (cohort III), there were zero terminations and one spontaneous abortion (10%).

In all cohorts, the majority of patients had RA, and the majority took etanercept.

The baseline disease activity score-28 (DAS28) was significantly higher in the anti-TNF cohorts, vs. cohort III: 6.5, 6.1, and 6.0 in cohorts Ia, Ib, and II, respectively, vs. 5.1 in cohort III.

Dr. H. Michael Belmont, medical director of New York University’s Hospital for Joint Diseases, as well as the director of the lupus clinic at Bellevue Hospital, New York, commented that, until more data are available, "The default choice would be to avoid these drugs during pregnancy. Certainly starting their use in a women contemplating conception should be delayed based on the data on hand."

Dr. Belmont, who was not affiliated with this study, joined the authors in pointing to a 2009 study by Carter et al., which found an increased observed: expected incidence of VACTERL defects (vertebral abnormalities, anal atresia, and/or cardiac, trachea, esophageal, renal, and limb abnormalities) in children born to women taking anti-TNFs (J. Rheumatol. 2009;36:635-41).

However, "The total observed number [of children born with VACTERL abnormalities] was small, 19 newborns, and the actual rate could not be calculated, as the authors relied on the [Food & Drug Administration] base of adverse events but did not know the [actual] number of exposed pregnancies, having to rely instead on historical controls to determine the expected ratio," he conceded.

On the other hand, Dr. Arthur Kavanaugh, a rheumatologist and director of the at the University of California San Diego’s Center for Innovative Therapy pointed to flaws in the current study’s analysis.

"The other explanation [for the finding of increased spontaneous abortion among anti-TNF users] is that it’s the disease more than the drug, so that people who have worse RA are going to have pregnancy outcomes that are not necessarily as good, and you just don’t know that from this because there’s only 10 people in the DMARD-only arm," he said in an interview.

"That’s just incredibly small. If you have one different outcome in that group, it would make a humongous difference in how you look at the data."

He added: "You can’t ignore the disease, and it’s the disease itself that’s going to affect the outcome as well."

Dr. Kavanaugh, like Dr. Belmont, was not affiliated with the study.

The study investigators disclosed that the British Society for Rheumatology receives restricted income from Abbott Laboratories, Biovitrum, Shering-Plough, Wyeth Pharmaceuticals, and Roche. They added that they had no personal competing interests in relation to this study.

Dr. Kavanaugh disclosed that he has done research for the makers of TNF inhibitors, including Abbot Laboratories, Amgen, Centocor, and UCB. Dr. Belmont did not make any disclosures relevant to this study.

The British Society for Rheumatology receives funding from several pharmaceutical companies, including the makers of anti-TNFs.

Pregnant women taking tumor necrosis factor inhibitors at conception experienced a higher rate of spontaneous abortion than did patients who did not.

The data, culled from the British Society for Rheumatology Biologics Registry, is from the "largest detailed prospective collection of pregnancy outcomes in women with arthritis-related diseases exposed to anti-TNF therapy" to date, according to the authors.

Despite its relatively large size, however, the study was unable to control for the looming possibility that disease severity itself plays a role in adverse pregnancy outcomes, as the authors readily admitted.

Nevertheless, "no firm conclusions can be drawn about the safety of anti-TNF therapy during pregnancy and, without further evidence, guidelines which suggest these drugs should be avoided at the time of conception must remain," recommended the authors.

The study was led by Dr. Suzanne M. M. Verstappen of the University of Manchester’s Arthritis Research UK Epidemiology Unit and was published online in Annals of the Rheumatic Diseases.

Dr. Verstappen and her colleagues looked at women in the registry who received adalimumab, etanercept, or infliximab either at conception or at any time prior to conception. A subset was also exposed to methotrexate and/or leflunomide at time of conception in addition to the anti-TNFs, two drugs with a "known risk of adverse pregnancy outcomes," according to the authors.

A fourth cohort with active rheumatoid arthritis had no history of anti-TNF use, but rather received nonbiological disease-modifying antirheumatic drugs (DMARDs), excluding methotrexate and leflunomide (Ann. Rheum. Dis. 2011 [doi:10.1136/ard.2010.140822]).

Among cohort Ia, which included 20 women (21 pregnancies) who took anti-TNFs plus either methotrexate and/or leflunomide at conception, there were 10 live births, 4 terminations, and 7 (33%) spontaneous abortions (miscarriages occurring prior to 20 weeks or to viability outside the womb).

Among cohort Ib, which included 44 women who took anti-TNFs at conception, but not methotrexate or leflunomide, there were 50 pregnancies. They included 32 live births among this cohort, 4 terminations, 12 spontaneous abortions (24%) and 2 intrauterine deaths (occurring post-20 weeks).

There was also one neonatal death registered.

The women who had taken anti-TNFs in the past, but not at the time of conception (cohort II), did have seemingly better outcomes: the 59 pregnancies (54 women) resulted in live births in 46 cases (including one of two twins), terminations in 2, and spontaneous abortions in 10 (17%). There were two intrauterine deaths, including the twin death.

Finally, among the 10 pregnancies in 10 women who had no history of anti-TNF use (cohort III), there were zero terminations and one spontaneous abortion (10%).

In all cohorts, the majority of patients had RA, and the majority took etanercept.

The baseline disease activity score-28 (DAS28) was significantly higher in the anti-TNF cohorts, vs. cohort III: 6.5, 6.1, and 6.0 in cohorts Ia, Ib, and II, respectively, vs. 5.1 in cohort III.

Dr. H. Michael Belmont, medical director of New York University’s Hospital for Joint Diseases, as well as the director of the lupus clinic at Bellevue Hospital, New York, commented that, until more data are available, "The default choice would be to avoid these drugs during pregnancy. Certainly starting their use in a women contemplating conception should be delayed based on the data on hand."

Dr. Belmont, who was not affiliated with this study, joined the authors in pointing to a 2009 study by Carter et al., which found an increased observed: expected incidence of VACTERL defects (vertebral abnormalities, anal atresia, and/or cardiac, trachea, esophageal, renal, and limb abnormalities) in children born to women taking anti-TNFs (J. Rheumatol. 2009;36:635-41).

However, "The total observed number [of children born with VACTERL abnormalities] was small, 19 newborns, and the actual rate could not be calculated, as the authors relied on the [Food & Drug Administration] base of adverse events but did not know the [actual] number of exposed pregnancies, having to rely instead on historical controls to determine the expected ratio," he conceded.

On the other hand, Dr. Arthur Kavanaugh, a rheumatologist and director of the at the University of California San Diego’s Center for Innovative Therapy pointed to flaws in the current study’s analysis.

"The other explanation [for the finding of increased spontaneous abortion among anti-TNF users] is that it’s the disease more than the drug, so that people who have worse RA are going to have pregnancy outcomes that are not necessarily as good, and you just don’t know that from this because there’s only 10 people in the DMARD-only arm," he said in an interview.

"That’s just incredibly small. If you have one different outcome in that group, it would make a humongous difference in how you look at the data."

He added: "You can’t ignore the disease, and it’s the disease itself that’s going to affect the outcome as well."

Dr. Kavanaugh, like Dr. Belmont, was not affiliated with the study.

The study investigators disclosed that the British Society for Rheumatology receives restricted income from Abbott Laboratories, Biovitrum, Shering-Plough, Wyeth Pharmaceuticals, and Roche. They added that they had no personal competing interests in relation to this study.

Dr. Kavanaugh disclosed that he has done research for the makers of TNF inhibitors, including Abbot Laboratories, Amgen, Centocor, and UCB. Dr. Belmont did not make any disclosures relevant to this study.

The British Society for Rheumatology receives funding from several pharmaceutical companies, including the makers of anti-TNFs.

Pregnant women taking tumor necrosis factor inhibitors at conception experienced a higher rate of spontaneous abortion than did patients who did not.

The data, culled from the British Society for Rheumatology Biologics Registry, is from the "largest detailed prospective collection of pregnancy outcomes in women with arthritis-related diseases exposed to anti-TNF therapy" to date, according to the authors.

Despite its relatively large size, however, the study was unable to control for the looming possibility that disease severity itself plays a role in adverse pregnancy outcomes, as the authors readily admitted.

Nevertheless, "no firm conclusions can be drawn about the safety of anti-TNF therapy during pregnancy and, without further evidence, guidelines which suggest these drugs should be avoided at the time of conception must remain," recommended the authors.

The study was led by Dr. Suzanne M. M. Verstappen of the University of Manchester’s Arthritis Research UK Epidemiology Unit and was published online in Annals of the Rheumatic Diseases.

Dr. Verstappen and her colleagues looked at women in the registry who received adalimumab, etanercept, or infliximab either at conception or at any time prior to conception. A subset was also exposed to methotrexate and/or leflunomide at time of conception in addition to the anti-TNFs, two drugs with a "known risk of adverse pregnancy outcomes," according to the authors.

A fourth cohort with active rheumatoid arthritis had no history of anti-TNF use, but rather received nonbiological disease-modifying antirheumatic drugs (DMARDs), excluding methotrexate and leflunomide (Ann. Rheum. Dis. 2011 [doi:10.1136/ard.2010.140822]).

Among cohort Ia, which included 20 women (21 pregnancies) who took anti-TNFs plus either methotrexate and/or leflunomide at conception, there were 10 live births, 4 terminations, and 7 (33%) spontaneous abortions (miscarriages occurring prior to 20 weeks or to viability outside the womb).

Among cohort Ib, which included 44 women who took anti-TNFs at conception, but not methotrexate or leflunomide, there were 50 pregnancies. They included 32 live births among this cohort, 4 terminations, 12 spontaneous abortions (24%) and 2 intrauterine deaths (occurring post-20 weeks).

There was also one neonatal death registered.

The women who had taken anti-TNFs in the past, but not at the time of conception (cohort II), did have seemingly better outcomes: the 59 pregnancies (54 women) resulted in live births in 46 cases (including one of two twins), terminations in 2, and spontaneous abortions in 10 (17%). There were two intrauterine deaths, including the twin death.

Finally, among the 10 pregnancies in 10 women who had no history of anti-TNF use (cohort III), there were zero terminations and one spontaneous abortion (10%).

In all cohorts, the majority of patients had RA, and the majority took etanercept.

The baseline disease activity score-28 (DAS28) was significantly higher in the anti-TNF cohorts, vs. cohort III: 6.5, 6.1, and 6.0 in cohorts Ia, Ib, and II, respectively, vs. 5.1 in cohort III.

Dr. H. Michael Belmont, medical director of New York University’s Hospital for Joint Diseases, as well as the director of the lupus clinic at Bellevue Hospital, New York, commented that, until more data are available, "The default choice would be to avoid these drugs during pregnancy. Certainly starting their use in a women contemplating conception should be delayed based on the data on hand."

Dr. Belmont, who was not affiliated with this study, joined the authors in pointing to a 2009 study by Carter et al., which found an increased observed: expected incidence of VACTERL defects (vertebral abnormalities, anal atresia, and/or cardiac, trachea, esophageal, renal, and limb abnormalities) in children born to women taking anti-TNFs (J. Rheumatol. 2009;36:635-41).

However, "The total observed number [of children born with VACTERL abnormalities] was small, 19 newborns, and the actual rate could not be calculated, as the authors relied on the [Food & Drug Administration] base of adverse events but did not know the [actual] number of exposed pregnancies, having to rely instead on historical controls to determine the expected ratio," he conceded.

On the other hand, Dr. Arthur Kavanaugh, a rheumatologist and director of the at the University of California San Diego’s Center for Innovative Therapy pointed to flaws in the current study’s analysis.

"The other explanation [for the finding of increased spontaneous abortion among anti-TNF users] is that it’s the disease more than the drug, so that people who have worse RA are going to have pregnancy outcomes that are not necessarily as good, and you just don’t know that from this because there’s only 10 people in the DMARD-only arm," he said in an interview.

"That’s just incredibly small. If you have one different outcome in that group, it would make a humongous difference in how you look at the data."

He added: "You can’t ignore the disease, and it’s the disease itself that’s going to affect the outcome as well."

Dr. Kavanaugh, like Dr. Belmont, was not affiliated with the study.

The study investigators disclosed that the British Society for Rheumatology receives restricted income from Abbott Laboratories, Biovitrum, Shering-Plough, Wyeth Pharmaceuticals, and Roche. They added that they had no personal competing interests in relation to this study.

Dr. Kavanaugh disclosed that he has done research for the makers of TNF inhibitors, including Abbot Laboratories, Amgen, Centocor, and UCB. Dr. Belmont did not make any disclosures relevant to this study.

The British Society for Rheumatology receives funding from several pharmaceutical companies, including the makers of anti-TNFs.

Cases of a rare, aggressive, and usually fatal lymphoma continue to be reported in people being treated with tumor necrosis factor blockers, azathioprine, and/or mercaptopurine, the Food and Drug Administration announced in an April 14 statement.

The reports of the lymphoma, hepatosplenic T-cell lymphoma (HSTCL), have primarily involved adolescents and young adults being treated with these agents for Crohn’s disease or ulcerative colitis. One patient, however, was being treated for psoriasis, and two others for rheumatoid arthritis.

Most patients were on a combination of treatments that are known to suppress the immune system, but there have been cases in patients taking azathioprine or mercaptopurine alone, the statement said.

"The risks and benefits of using TNF blockers, azathioprine, and/or mercaptopurine should be carefully weighed when prescribing these drugs to children and young adults, especially for the treatment of Crohn’s disease and ulcerative colitis," according to the FDA.

The statement recommends that health care professionals monitor patients on these treatments for malignancies and educate patients and their caregivers about the signs and symptoms of HSTCL, which can include splenomegaly, hepatomegaly, abdominal pain, persistent fever, night sweats, and weight loss.

The statement also notes that people with rheumatoid arthritis, Crohn’s, ankylosing spondylitis, psoriatic arthritis, and plaque psoriasis "may be more likely to develop lymphoma," compared with the general U.S. population, making it difficult to estimate the increased risk of malignancies associated with TNF blockers, azathioprine and/or mercaptopurine.

As of Dec. 31, 2010, the FDA’s Adverse Event Reporting System (AERS), the medical literature, and the Cancer Survivors Network had received the following unduplicated reports of HSTCL:

20 cases in patients taking infliximab (Remicade), including 18 patients also taking mercaptopurine or azathioprine.

• 1 case in a patient taking etanercept (Enbrel).

• 2 cases in patients taking adalimumab (Humira).

• 5 cases in patients taking a combination of infliximab and adalimumab (including 4 patients also taking mercaptopurine or azathioprine).

• 12 cases in patients taking azathioprine.

• 3 cases in patients taking mercaptopurine.

No cases have been reported in the TNF blockers certolizumab pegol (Cimzia) and golimumab (Simponi).

Reports of serious adverse events associated with these and other drugs should be reported online to the FDA’s MedWatch program or by phone to 800-332-1088.

Cases of a rare, aggressive, and usually fatal lymphoma continue to be reported in people being treated with tumor necrosis factor blockers, azathioprine, and/or mercaptopurine, the Food and Drug Administration announced in an April 14 statement.

The reports of the lymphoma, hepatosplenic T-cell lymphoma (HSTCL), have primarily involved adolescents and young adults being treated with these agents for Crohn’s disease or ulcerative colitis. One patient, however, was being treated for psoriasis, and two others for rheumatoid arthritis.

Most patients were on a combination of treatments that are known to suppress the immune system, but there have been cases in patients taking azathioprine or mercaptopurine alone, the statement said.

"The risks and benefits of using TNF blockers, azathioprine, and/or mercaptopurine should be carefully weighed when prescribing these drugs to children and young adults, especially for the treatment of Crohn’s disease and ulcerative colitis," according to the FDA.

The statement recommends that health care professionals monitor patients on these treatments for malignancies and educate patients and their caregivers about the signs and symptoms of HSTCL, which can include splenomegaly, hepatomegaly, abdominal pain, persistent fever, night sweats, and weight loss.

The statement also notes that people with rheumatoid arthritis, Crohn’s, ankylosing spondylitis, psoriatic arthritis, and plaque psoriasis "may be more likely to develop lymphoma," compared with the general U.S. population, making it difficult to estimate the increased risk of malignancies associated with TNF blockers, azathioprine and/or mercaptopurine.

As of Dec. 31, 2010, the FDA’s Adverse Event Reporting System (AERS), the medical literature, and the Cancer Survivors Network had received the following unduplicated reports of HSTCL:

20 cases in patients taking infliximab (Remicade), including 18 patients also taking mercaptopurine or azathioprine.

• 1 case in a patient taking etanercept (Enbrel).

• 2 cases in patients taking adalimumab (Humira).

• 5 cases in patients taking a combination of infliximab and adalimumab (including 4 patients also taking mercaptopurine or azathioprine).

• 12 cases in patients taking azathioprine.

• 3 cases in patients taking mercaptopurine.

No cases have been reported in the TNF blockers certolizumab pegol (Cimzia) and golimumab (Simponi).

Reports of serious adverse events associated with these and other drugs should be reported online to the FDA’s MedWatch program or by phone to 800-332-1088.

Cases of a rare, aggressive, and usually fatal lymphoma continue to be reported in people being treated with tumor necrosis factor blockers, azathioprine, and/or mercaptopurine, the Food and Drug Administration announced in an April 14 statement.

The reports of the lymphoma, hepatosplenic T-cell lymphoma (HSTCL), have primarily involved adolescents and young adults being treated with these agents for Crohn’s disease or ulcerative colitis. One patient, however, was being treated for psoriasis, and two others for rheumatoid arthritis.

Most patients were on a combination of treatments that are known to suppress the immune system, but there have been cases in patients taking azathioprine or mercaptopurine alone, the statement said.

"The risks and benefits of using TNF blockers, azathioprine, and/or mercaptopurine should be carefully weighed when prescribing these drugs to children and young adults, especially for the treatment of Crohn’s disease and ulcerative colitis," according to the FDA.

The statement recommends that health care professionals monitor patients on these treatments for malignancies and educate patients and their caregivers about the signs and symptoms of HSTCL, which can include splenomegaly, hepatomegaly, abdominal pain, persistent fever, night sweats, and weight loss.

The statement also notes that people with rheumatoid arthritis, Crohn’s, ankylosing spondylitis, psoriatic arthritis, and plaque psoriasis "may be more likely to develop lymphoma," compared with the general U.S. population, making it difficult to estimate the increased risk of malignancies associated with TNF blockers, azathioprine and/or mercaptopurine.

As of Dec. 31, 2010, the FDA’s Adverse Event Reporting System (AERS), the medical literature, and the Cancer Survivors Network had received the following unduplicated reports of HSTCL:

20 cases in patients taking infliximab (Remicade), including 18 patients also taking mercaptopurine or azathioprine.

• 1 case in a patient taking etanercept (Enbrel).

• 2 cases in patients taking adalimumab (Humira).

• 5 cases in patients taking a combination of infliximab and adalimumab (including 4 patients also taking mercaptopurine or azathioprine).

• 12 cases in patients taking azathioprine.

• 3 cases in patients taking mercaptopurine.

No cases have been reported in the TNF blockers certolizumab pegol (Cimzia) and golimumab (Simponi).

Reports of serious adverse events associated with these and other drugs should be reported online to the FDA’s MedWatch program or by phone to 800-332-1088.

WAILEA, HAWAII – Moderate to severe psoriasis is an independent risk factor for a variety of adverse pregnancy outcomes, according to Dr. Jennifer C. Cather.

Yet much remains unknown about the impact of psoriasis and its treatment in pregnancy. For this reason, every psoriasis patient who becomes pregnant while on a biologic agent should be strongly encouraged to enter one of the pregnancy registries, Dr. Cather said at the Hawaii Dermatology Seminar sponsored by Skin Disease Education Foundation (SDEF).

She recommended the Organization of Teratology Information Specialists (OTIS), because the group helps inform concerned patients. OTIS operates pregnancy registries for women taking etanercept (Enbrel) or adalimumab (Humira). In addition, pharmaceutical companies that market biologics maintain pregnancy registries for their agents.

The Food and Drug Administration rates methotrexate and acitretin as pregnancy category X drugs and cyclosporine as a category C drug. The anti–tumor necrosis factor agents are category B – meaning animal studies have shown no fetal risk – as are alefacept (Amevive) and ustekinumab (Stelara).

"That doesn’t mean I think you should give a category B agent to people who are pregnant or are planning pregnancy, because I think that the best drug in pregnancy is probably no drug, or light treatment if you can get away with that," said Dr. Cather, who is in private practice in Dallas.

Still, there is sometimes no satisfactory alternative to using a biologic agent in pregnancy. Two of the toughest challenges Dr. Cather said she encounters in her clinical practice arise in such situations. One involves the psoriasis patient who calls and says that her ob.gyn. told her to come off the biologic therapy immediately.

The other challenge is the patient whose psoriasis worsens during pregnancy to the extent that she needs to start on a biologic agent or switch to another one. This is not an uncommon situation, Dr. Cather noted, citing a University of California, Irvine, study which found that while psoriasis improved during pregnancy in 55% of pregnant patients, it worsened in 23%. Postpartum, psoriasis worsened in 65% (Arch. Dermatol. 2005;141:601-6).

A recent retrospective matched cohort study of pregnancy outcomes in psoriasis patients involved 68 deliveries in 35 women with moderate to severe psoriasis and 237 deliveries in 236 controls in Israel.

The incidence of pregnancy-induced hypertensive diseases was 7.4% in the psoriasis patients, significantly greater than the 2.1% rate in controls. Premature rupture of membranes occurred in 16% of psoriasis patients, compared with 5.5% of controls. The 24% incidence of large-for-gestational-age newborns among the psoriasis patients’ babies was twice that of controls. Macrosomia occurred in 13% of the babies of women with psoriasis, compared with 4.2% of matched controls.

In this multivariate analysis, moderate to severe psoriasis was also an independent risk factor for previous spontaneous and induced abortions (J. Eur. Acad. Dermatol. Venereol. 2010 Nov. 25 doi: 10.1111/j.1468-3083.2010.03917.x]).

Dr. Cather’s biologics of choice for psoriasis and psoriatic arthritis, whether during pregnancy or not, are TNF-antagonists. She has been monitoring her own psoriasis patients who have been on biologic agents during pregnancy and has not noted any increase in adverse outcomes. While she finds this somewhat reassuring, the definitive answers will come from the large pregnancy registries.

Nursing mothers on methotrexate, acitretin, or cyclosporine should not breast-feed. The risk of using anti–tumor necrosis factor agents during breast-feeding is "probably negligible," she said.

Psoriasis patients have a below-average rate of childbearing. Theories abound as to why. Possibilities include an increased infertility rate, voluntary childlessness due to concern about genetic transmission of psoriasis to the next generation, and the interference with sexual activity that has been documented in patients with active disease.

"I do have people who say they never want to have children because of their disease. That’s a very sad conversation," Dr. Cather said.

Intriguingly, there is some recent evidence to suggest anti-TNF therapy may improve the results of in vitro fertilization in women with infertility and recurrent spontaneous abortion. The therapeutic rationale is that TNF-alpha has been shown to have antireproductive effects.

In a nonrandomized study involving 75 women without psoriasis under age 38 with Th1/Th2 cytokine elevation undergoing IVF for infertility, investigators found that implantation, clinical pregnancy, and live birth rates were significantly higher in those on adalimumab and IVIG than in patients on neither (Am. J. Repro. Immunol. 2009;61:113-20). This is a controversial study among assisted reproduction specialists, Dr. Cather noted.

She disclosed that she serves as a consultant to Amgen (manufacturer of Enbrel), Abbott (manufacturer of Humira), and Centocor (manufacturer of Stelara) and has received research grants from Amgen, Celgene, and Pfizer.

SDEF and this news organization are owned by Elsevier.

WAILEA, HAWAII – Moderate to severe psoriasis is an independent risk factor for a variety of adverse pregnancy outcomes, according to Dr. Jennifer C. Cather.

Yet much remains unknown about the impact of psoriasis and its treatment in pregnancy. For this reason, every psoriasis patient who becomes pregnant while on a biologic agent should be strongly encouraged to enter one of the pregnancy registries, Dr. Cather said at the Hawaii Dermatology Seminar sponsored by Skin Disease Education Foundation (SDEF).

She recommended the Organization of Teratology Information Specialists (OTIS), because the group helps inform concerned patients. OTIS operates pregnancy registries for women taking etanercept (Enbrel) or adalimumab (Humira). In addition, pharmaceutical companies that market biologics maintain pregnancy registries for their agents.

The Food and Drug Administration rates methotrexate and acitretin as pregnancy category X drugs and cyclosporine as a category C drug. The anti–tumor necrosis factor agents are category B – meaning animal studies have shown no fetal risk – as are alefacept (Amevive) and ustekinumab (Stelara).

"That doesn’t mean I think you should give a category B agent to people who are pregnant or are planning pregnancy, because I think that the best drug in pregnancy is probably no drug, or light treatment if you can get away with that," said Dr. Cather, who is in private practice in Dallas.

Still, there is sometimes no satisfactory alternative to using a biologic agent in pregnancy. Two of the toughest challenges Dr. Cather said she encounters in her clinical practice arise in such situations. One involves the psoriasis patient who calls and says that her ob.gyn. told her to come off the biologic therapy immediately.

The other challenge is the patient whose psoriasis worsens during pregnancy to the extent that she needs to start on a biologic agent or switch to another one. This is not an uncommon situation, Dr. Cather noted, citing a University of California, Irvine, study which found that while psoriasis improved during pregnancy in 55% of pregnant patients, it worsened in 23%. Postpartum, psoriasis worsened in 65% (Arch. Dermatol. 2005;141:601-6).

A recent retrospective matched cohort study of pregnancy outcomes in psoriasis patients involved 68 deliveries in 35 women with moderate to severe psoriasis and 237 deliveries in 236 controls in Israel.

The incidence of pregnancy-induced hypertensive diseases was 7.4% in the psoriasis patients, significantly greater than the 2.1% rate in controls. Premature rupture of membranes occurred in 16% of psoriasis patients, compared with 5.5% of controls. The 24% incidence of large-for-gestational-age newborns among the psoriasis patients’ babies was twice that of controls. Macrosomia occurred in 13% of the babies of women with psoriasis, compared with 4.2% of matched controls.

In this multivariate analysis, moderate to severe psoriasis was also an independent risk factor for previous spontaneous and induced abortions (J. Eur. Acad. Dermatol. Venereol. 2010 Nov. 25 doi: 10.1111/j.1468-3083.2010.03917.x]).

Dr. Cather’s biologics of choice for psoriasis and psoriatic arthritis, whether during pregnancy or not, are TNF-antagonists. She has been monitoring her own psoriasis patients who have been on biologic agents during pregnancy and has not noted any increase in adverse outcomes. While she finds this somewhat reassuring, the definitive answers will come from the large pregnancy registries.

Nursing mothers on methotrexate, acitretin, or cyclosporine should not breast-feed. The risk of using anti–tumor necrosis factor agents during breast-feeding is "probably negligible," she said.

Psoriasis patients have a below-average rate of childbearing. Theories abound as to why. Possibilities include an increased infertility rate, voluntary childlessness due to concern about genetic transmission of psoriasis to the next generation, and the interference with sexual activity that has been documented in patients with active disease.

"I do have people who say they never want to have children because of their disease. That’s a very sad conversation," Dr. Cather said.

Intriguingly, there is some recent evidence to suggest anti-TNF therapy may improve the results of in vitro fertilization in women with infertility and recurrent spontaneous abortion. The therapeutic rationale is that TNF-alpha has been shown to have antireproductive effects.

In a nonrandomized study involving 75 women without psoriasis under age 38 with Th1/Th2 cytokine elevation undergoing IVF for infertility, investigators found that implantation, clinical pregnancy, and live birth rates were significantly higher in those on adalimumab and IVIG than in patients on neither (Am. J. Repro. Immunol. 2009;61:113-20). This is a controversial study among assisted reproduction specialists, Dr. Cather noted.

She disclosed that she serves as a consultant to Amgen (manufacturer of Enbrel), Abbott (manufacturer of Humira), and Centocor (manufacturer of Stelara) and has received research grants from Amgen, Celgene, and Pfizer.

SDEF and this news organization are owned by Elsevier.

WAILEA, HAWAII – Moderate to severe psoriasis is an independent risk factor for a variety of adverse pregnancy outcomes, according to Dr. Jennifer C. Cather.

Yet much remains unknown about the impact of psoriasis and its treatment in pregnancy. For this reason, every psoriasis patient who becomes pregnant while on a biologic agent should be strongly encouraged to enter one of the pregnancy registries, Dr. Cather said at the Hawaii Dermatology Seminar sponsored by Skin Disease Education Foundation (SDEF).

She recommended the Organization of Teratology Information Specialists (OTIS), because the group helps inform concerned patients. OTIS operates pregnancy registries for women taking etanercept (Enbrel) or adalimumab (Humira). In addition, pharmaceutical companies that market biologics maintain pregnancy registries for their agents.

The Food and Drug Administration rates methotrexate and acitretin as pregnancy category X drugs and cyclosporine as a category C drug. The anti–tumor necrosis factor agents are category B – meaning animal studies have shown no fetal risk – as are alefacept (Amevive) and ustekinumab (Stelara).

"That doesn’t mean I think you should give a category B agent to people who are pregnant or are planning pregnancy, because I think that the best drug in pregnancy is probably no drug, or light treatment if you can get away with that," said Dr. Cather, who is in private practice in Dallas.

Still, there is sometimes no satisfactory alternative to using a biologic agent in pregnancy. Two of the toughest challenges Dr. Cather said she encounters in her clinical practice arise in such situations. One involves the psoriasis patient who calls and says that her ob.gyn. told her to come off the biologic therapy immediately.

The other challenge is the patient whose psoriasis worsens during pregnancy to the extent that she needs to start on a biologic agent or switch to another one. This is not an uncommon situation, Dr. Cather noted, citing a University of California, Irvine, study which found that while psoriasis improved during pregnancy in 55% of pregnant patients, it worsened in 23%. Postpartum, psoriasis worsened in 65% (Arch. Dermatol. 2005;141:601-6).

A recent retrospective matched cohort study of pregnancy outcomes in psoriasis patients involved 68 deliveries in 35 women with moderate to severe psoriasis and 237 deliveries in 236 controls in Israel.

The incidence of pregnancy-induced hypertensive diseases was 7.4% in the psoriasis patients, significantly greater than the 2.1% rate in controls. Premature rupture of membranes occurred in 16% of psoriasis patients, compared with 5.5% of controls. The 24% incidence of large-for-gestational-age newborns among the psoriasis patients’ babies was twice that of controls. Macrosomia occurred in 13% of the babies of women with psoriasis, compared with 4.2% of matched controls.

In this multivariate analysis, moderate to severe psoriasis was also an independent risk factor for previous spontaneous and induced abortions (J. Eur. Acad. Dermatol. Venereol. 2010 Nov. 25 doi: 10.1111/j.1468-3083.2010.03917.x]).

Dr. Cather’s biologics of choice for psoriasis and psoriatic arthritis, whether during pregnancy or not, are TNF-antagonists. She has been monitoring her own psoriasis patients who have been on biologic agents during pregnancy and has not noted any increase in adverse outcomes. While she finds this somewhat reassuring, the definitive answers will come from the large pregnancy registries.

Nursing mothers on methotrexate, acitretin, or cyclosporine should not breast-feed. The risk of using anti–tumor necrosis factor agents during breast-feeding is "probably negligible," she said.

Psoriasis patients have a below-average rate of childbearing. Theories abound as to why. Possibilities include an increased infertility rate, voluntary childlessness due to concern about genetic transmission of psoriasis to the next generation, and the interference with sexual activity that has been documented in patients with active disease.

"I do have people who say they never want to have children because of their disease. That’s a very sad conversation," Dr. Cather said.

Intriguingly, there is some recent evidence to suggest anti-TNF therapy may improve the results of in vitro fertilization in women with infertility and recurrent spontaneous abortion. The therapeutic rationale is that TNF-alpha has been shown to have antireproductive effects.

In a nonrandomized study involving 75 women without psoriasis under age 38 with Th1/Th2 cytokine elevation undergoing IVF for infertility, investigators found that implantation, clinical pregnancy, and live birth rates were significantly higher in those on adalimumab and IVIG than in patients on neither (Am. J. Repro. Immunol. 2009;61:113-20). This is a controversial study among assisted reproduction specialists, Dr. Cather noted.

She disclosed that she serves as a consultant to Amgen (manufacturer of Enbrel), Abbott (manufacturer of Humira), and Centocor (manufacturer of Stelara) and has received research grants from Amgen, Celgene, and Pfizer.

SDEF and this news organization are owned by Elsevier.

NEW YORK – The 18%-20% of systemic lupus erythematosus patients who test positive for platelet C4d face a much greater likelihood of having a future cardiovascular event, stroke, or death than those who are not platelet C4d positive, according to Dr. Susan M. Manzi, who presented the results at a rheumatology meeting sponsored by New York University.

"The only factor that predicted mortality greater than being positive for P-C4d [platelet C4d] was having cancer," said Dr. Manzi, chair of the department of medicine and codirector of the Lupus Center of Excellence at West Penn Allegheny Health System, Pittsburgh.

In the study of 356 patients with systemic lupus erythematosus (SLE), which was carried out between July 2001 and August 2009, 70 tested positive for P-C4d (20%) and 286 tested negative. This confirms a previous study that found that P-C4d was present in 18% of SLE patients and that P-C4d was highly specific for SLE (Arthritis Rheum. 2006;54:670-4). "P-C4d carries a 95% specificity for SLE," said Dr. Manzi, who is also vice chair and professor of medicine at Temple University, Philadelphia.

Patients who were P-C4d positive had twice as many cardiovascular events (36 vs. 18, P = .001). The odds ratio of having a cardiovascular event was 2.09 for positive P-C4d (P = .02), which was much higher than for smoking (OR 1.36), SLE disease duration (0.99), or the presence of renal disease (1.42). The odds ratio for aPL antibodies was 2.30 (P = 0.004).

The results for stroke were even more striking. Thirteen patients with P-C4d had stroke, compared with three in those who tested negative for P-C4d (P = .002). There was nearly a fivefold increased risk of stroke in this group (OR 4.96, CI 1.75-14.06, P = .003). Almost three times as many patients had a pulmonary embolism in the P-C4d group, compared with controls (11 vs. 4, P = .007).

Fourteen SLE patients (4%) died during the follow-up. Of those, more P-C4d-positive patients died compared with those who tested negative for P-C4d (11% vs. 2%, P = .002). Causes of death included infection (4), cardiac arrest (2), congestive heart failure (1), cancer (2), hemorrhage (1), and unspecified (4). The risk of all-cause mortality was increased almost eightfold in those who were P-C4d positive (OR 7.92, CI 2.13-29.48, P = .002). Only cancer (OR 19.74) surpassed being P-C4d as a risk for all-cause mortality in multivariate regression analysis.

"Usually when we measure complement in the circulation, we measure the parent protein C4 in the plasma. When complement is activated, it breaks down into fragments and we see that one fragment, C4d, can covalently bind to cell surfaces. So, as we study how these fragments of complement activation bind to cells, we are exploring their potential use as disease biomarkers and prognostic indicators," Dr. Manzi said.

Dr. Manzi serves on the advisory boards of Bristol-Myers Squibb, Human Genome Sciences, and Cephalon. She receives funding for research from Amgen USA, Aspreva Pharmaceuticals, Bristol-Myers Squibb, Cephalon, Genentech, Human Genome Sciences, and Immunomedics.

NEW YORK – The 18%-20% of systemic lupus erythematosus patients who test positive for platelet C4d face a much greater likelihood of having a future cardiovascular event, stroke, or death than those who are not platelet C4d positive, according to Dr. Susan M. Manzi, who presented the results at a rheumatology meeting sponsored by New York University.

"The only factor that predicted mortality greater than being positive for P-C4d [platelet C4d] was having cancer," said Dr. Manzi, chair of the department of medicine and codirector of the Lupus Center of Excellence at West Penn Allegheny Health System, Pittsburgh.

In the study of 356 patients with systemic lupus erythematosus (SLE), which was carried out between July 2001 and August 2009, 70 tested positive for P-C4d (20%) and 286 tested negative. This confirms a previous study that found that P-C4d was present in 18% of SLE patients and that P-C4d was highly specific for SLE (Arthritis Rheum. 2006;54:670-4). "P-C4d carries a 95% specificity for SLE," said Dr. Manzi, who is also vice chair and professor of medicine at Temple University, Philadelphia.

Patients who were P-C4d positive had twice as many cardiovascular events (36 vs. 18, P = .001). The odds ratio of having a cardiovascular event was 2.09 for positive P-C4d (P = .02), which was much higher than for smoking (OR 1.36), SLE disease duration (0.99), or the presence of renal disease (1.42). The odds ratio for aPL antibodies was 2.30 (P = 0.004).

The results for stroke were even more striking. Thirteen patients with P-C4d had stroke, compared with three in those who tested negative for P-C4d (P = .002). There was nearly a fivefold increased risk of stroke in this group (OR 4.96, CI 1.75-14.06, P = .003). Almost three times as many patients had a pulmonary embolism in the P-C4d group, compared with controls (11 vs. 4, P = .007).

Fourteen SLE patients (4%) died during the follow-up. Of those, more P-C4d-positive patients died compared with those who tested negative for P-C4d (11% vs. 2%, P = .002). Causes of death included infection (4), cardiac arrest (2), congestive heart failure (1), cancer (2), hemorrhage (1), and unspecified (4). The risk of all-cause mortality was increased almost eightfold in those who were P-C4d positive (OR 7.92, CI 2.13-29.48, P = .002). Only cancer (OR 19.74) surpassed being P-C4d as a risk for all-cause mortality in multivariate regression analysis.

"Usually when we measure complement in the circulation, we measure the parent protein C4 in the plasma. When complement is activated, it breaks down into fragments and we see that one fragment, C4d, can covalently bind to cell surfaces. So, as we study how these fragments of complement activation bind to cells, we are exploring their potential use as disease biomarkers and prognostic indicators," Dr. Manzi said.

Dr. Manzi serves on the advisory boards of Bristol-Myers Squibb, Human Genome Sciences, and Cephalon. She receives funding for research from Amgen USA, Aspreva Pharmaceuticals, Bristol-Myers Squibb, Cephalon, Genentech, Human Genome Sciences, and Immunomedics.

NEW YORK – The 18%-20% of systemic lupus erythematosus patients who test positive for platelet C4d face a much greater likelihood of having a future cardiovascular event, stroke, or death than those who are not platelet C4d positive, according to Dr. Susan M. Manzi, who presented the results at a rheumatology meeting sponsored by New York University.

"The only factor that predicted mortality greater than being positive for P-C4d [platelet C4d] was having cancer," said Dr. Manzi, chair of the department of medicine and codirector of the Lupus Center of Excellence at West Penn Allegheny Health System, Pittsburgh.

In the study of 356 patients with systemic lupus erythematosus (SLE), which was carried out between July 2001 and August 2009, 70 tested positive for P-C4d (20%) and 286 tested negative. This confirms a previous study that found that P-C4d was present in 18% of SLE patients and that P-C4d was highly specific for SLE (Arthritis Rheum. 2006;54:670-4). "P-C4d carries a 95% specificity for SLE," said Dr. Manzi, who is also vice chair and professor of medicine at Temple University, Philadelphia.

Patients who were P-C4d positive had twice as many cardiovascular events (36 vs. 18, P = .001). The odds ratio of having a cardiovascular event was 2.09 for positive P-C4d (P = .02), which was much higher than for smoking (OR 1.36), SLE disease duration (0.99), or the presence of renal disease (1.42). The odds ratio for aPL antibodies was 2.30 (P = 0.004).

The results for stroke were even more striking. Thirteen patients with P-C4d had stroke, compared with three in those who tested negative for P-C4d (P = .002). There was nearly a fivefold increased risk of stroke in this group (OR 4.96, CI 1.75-14.06, P = .003). Almost three times as many patients had a pulmonary embolism in the P-C4d group, compared with controls (11 vs. 4, P = .007).

Fourteen SLE patients (4%) died during the follow-up. Of those, more P-C4d-positive patients died compared with those who tested negative for P-C4d (11% vs. 2%, P = .002). Causes of death included infection (4), cardiac arrest (2), congestive heart failure (1), cancer (2), hemorrhage (1), and unspecified (4). The risk of all-cause mortality was increased almost eightfold in those who were P-C4d positive (OR 7.92, CI 2.13-29.48, P = .002). Only cancer (OR 19.74) surpassed being P-C4d as a risk for all-cause mortality in multivariate regression analysis.

"Usually when we measure complement in the circulation, we measure the parent protein C4 in the plasma. When complement is activated, it breaks down into fragments and we see that one fragment, C4d, can covalently bind to cell surfaces. So, as we study how these fragments of complement activation bind to cells, we are exploring their potential use as disease biomarkers and prognostic indicators," Dr. Manzi said.

Dr. Manzi serves on the advisory boards of Bristol-Myers Squibb, Human Genome Sciences, and Cephalon. She receives funding for research from Amgen USA, Aspreva Pharmaceuticals, Bristol-Myers Squibb, Cephalon, Genentech, Human Genome Sciences, and Immunomedics.

NEW YORK – Because juvenile dermatomyositis is a rare disease and its symptoms often differ from those seen in adult dermatomyositis, physicians may not recognize it and diagnosis can be delayed, Dr. Brian Feldman said.

He described a recent practice survey that found variability in juvenile dermatomyositis (JDM) treatment and, in the absence of randomized controlled trials, urged clinicians to consult newly created consensus protocols developed by rheumatologists and to gather data that may help to optimize treatment and minimize side effects in the future for those with JDM.

Photo courtesy http://en.wikipedia.org/wiki/File:Dermatomyositis4.jpg

Dr. Feldman described a 15-year-old patient who had progressively deteriorated over a 3-year period despite being seen by pediatricians and dermatologists. His initial symptoms included fatigue and elevated muscle enzymes, including aspartate transaminase (AST), alanine transaminase (ALT), lactate dehydrogenase (LDH), and creatine phosphokinase (CPK).

Within a year, the patient developed a purple skin rash on his hands, elbows, and knees. He later developed Raynaud's syndrome and muscle weakness with decreased range of motion that interfered with participation in sports and other activities of daily living.

Upon examination, he was quite thin with a scaly rash over his knuckles (Gottron's papules), healing skin ulcerations on his hands (from severe Raynaud's), periungual erythema, and lipodystrophy and erythema of his forearms. Magnetic resonance imaging showed acute inflammation of his shoulder girdle, said Dr. Feldman, chief of pediatric rheumatology at the Hospital for Sick Children in Toronto.

Dr. Feldman said that one of the best diagnostic clues for JDM comes from microscopic examination of nail folds. In this case, the patient had tortuous, bushy nail folds, dilated or missing capillaries (capillary density of 3 per mm of nailfold length while normal ranges from 7-11 per mm), and cuticular overgrowth indicative of JDM.

The different presentation seen with children compared with adults may hinder a correct diagnosis. For instance, calcinosis is seen much more frequently in children than adults. Children are less likely to have some of the systemic symptoms, such as fever, poor weight gain, and pulmonary effects, and they almost never have cardiac problems. Unlike adults with dermatomyositis or polymyositis who appear to have a fourfold increased risk of malignancy, very few cases of malignancy have been associated with JDM. Children are more likely to experience dysphonia/dysphagia but are as likely to have arthritic symptoms (around 58% of each group). Myositis specific antibodies do not seem to play as important a diagnostic role for children as adults.

Children who develop JDM appear to have a better prognosis than adults. Although adults with myositis have appreciable mortality (about 10%) and progressive disability, which may be related to treatment of a long-term condition such as avascular necrosis or osteoporosis with compression fracture, findings from Dr. Feldman's group show that outcomes were often excellent in children. "We have not had a single death from JDM in 30 years," he said.

About two-thirds of children with JDM have a polycyclic, chronic, unremitting disease course, but about one-third follow a monocyclic course and have disease symptoms that last for 2-3 years and then go away, with, or potentially even without, treatment.

In a very small proportion of these patients, symptoms may return many years later. "The message here is that when the disease goes away, it almost certainly is gone forever," Dr. Feldman noted.

It is possible to predict which patients will follow a chronic course and which patients will have early remission. In his experience, the risk of persistent disease falls by half if Gottron's rash disappears within 3 months of diagnosis (Arthritis Rheum. 2008;58:3585-92).

The results of a recent practice survey by the Childhood Arthritis and Rheumatology Research Alliance (CARRA) of almost 200 pediatric rheumatologists in North America found both similarities and differences in treatment approaches to JDM (J. Rheumatol. 2010;37:1953-61).

Corticosteroids and methotrexate (MTX) are mainstays of care, but the route and pattern of corticosteroid administration varied: 82% of respondents initially pulsed with high-dose intravenous methylprednisolone (IVMP) while 18% prescribed oral prednisone. MTX was used concurrently with steroids 84% of the time. Sixteen percent reported also using IV immunoglobulin, with or without MTX, for more severe disease, refractory disease, and prominent cutaneous disease. Hydroxychloroquine was given for milder cases, especially for rash, while cyclophosphamide was prescribed for ulcerative disease or for patients with pulmonary symptoms.

While these findings reflect the current prescribing practices, there are almost no randomized controlled trials of medications for JDM, Dr. Feldman pointed out.

This reflects in part the rare nature of the disease, its complexity, the difficulty of conducting studies in children, and the high cost of randomized controlled trials. There have been studies using advanced analytic techniques to provide strong comparative data in lieu of an randomized controlled trial. One such study by Dr. Feldman and associates (Arthritis Rheum. 2008;59:989-95) showed that more aggressive corticosteroid therapy does not give better 3-year outcomes.

A recent randomized controlled trial presented at the annual meeting of the American College of Rheumatology looked at dermatomyositis in 76 adults and 48 children and found that 80% had a response to rituximab within a year of treatment. Interpretation of the study may have been limited by the design, which allowed patients to receive add-on medications during the trial.

In light of the CARRA study's findings of heterogeneity in the treatment of JDM and the absence of randomized controlled trials, a group of 12 pediatric rheumatologists met to study treatments in JDM using a new approach: by developing consensus treatment protocols (Arthritis Care Res. 2010;62:219-25).

"This is similar to what has been done in pediatric oncology," said Dr. Feldman, who was one of the participants. "We are hoping physicians throughout the world will take these protocols off the shelf, and by using standardized doses, follow-up, and measurements, we will be able to accumulate enough evidence over time to know which is the best therapy."

In brief, the group recommended three protocols for the treatment of patients with moderately severe JDM: pulse IVMP plus MTX; IVMP, MTX, plus IVIG; or oral prednisone plus MTX. The third protocol is the one followed most often at the Hospital for Sick Children. The treatment protocols are not intended as treatment recommendations, although it is hoped that a physician will choose to follow the standardized protocol that most closely reflects his or her preferred practice. It is presented as a "first step to allow comparison of different approaches to the treatment of JDM," he said.

Dr. Feldman has done contracted research with Bayer Healthcare Pharmaceuticals. He referenced unlabeled/unapproved uses of drugs or products in his presentation.

NEW YORK – Because juvenile dermatomyositis is a rare disease and its symptoms often differ from those seen in adult dermatomyositis, physicians may not recognize it and diagnosis can be delayed, Dr. Brian Feldman said.

He described a recent practice survey that found variability in juvenile dermatomyositis (JDM) treatment and, in the absence of randomized controlled trials, urged clinicians to consult newly created consensus protocols developed by rheumatologists and to gather data that may help to optimize treatment and minimize side effects in the future for those with JDM.

Photo courtesy http://en.wikipedia.org/wiki/File:Dermatomyositis4.jpg

Dr. Feldman described a 15-year-old patient who had progressively deteriorated over a 3-year period despite being seen by pediatricians and dermatologists. His initial symptoms included fatigue and elevated muscle enzymes, including aspartate transaminase (AST), alanine transaminase (ALT), lactate dehydrogenase (LDH), and creatine phosphokinase (CPK).

Within a year, the patient developed a purple skin rash on his hands, elbows, and knees. He later developed Raynaud's syndrome and muscle weakness with decreased range of motion that interfered with participation in sports and other activities of daily living.

Upon examination, he was quite thin with a scaly rash over his knuckles (Gottron's papules), healing skin ulcerations on his hands (from severe Raynaud's), periungual erythema, and lipodystrophy and erythema of his forearms. Magnetic resonance imaging showed acute inflammation of his shoulder girdle, said Dr. Feldman, chief of pediatric rheumatology at the Hospital for Sick Children in Toronto.

Dr. Feldman said that one of the best diagnostic clues for JDM comes from microscopic examination of nail folds. In this case, the patient had tortuous, bushy nail folds, dilated or missing capillaries (capillary density of 3 per mm of nailfold length while normal ranges from 7-11 per mm), and cuticular overgrowth indicative of JDM.

The different presentation seen with children compared with adults may hinder a correct diagnosis. For instance, calcinosis is seen much more frequently in children than adults. Children are less likely to have some of the systemic symptoms, such as fever, poor weight gain, and pulmonary effects, and they almost never have cardiac problems. Unlike adults with dermatomyositis or polymyositis who appear to have a fourfold increased risk of malignancy, very few cases of malignancy have been associated with JDM. Children are more likely to experience dysphonia/dysphagia but are as likely to have arthritic symptoms (around 58% of each group). Myositis specific antibodies do not seem to play as important a diagnostic role for children as adults.

Children who develop JDM appear to have a better prognosis than adults. Although adults with myositis have appreciable mortality (about 10%) and progressive disability, which may be related to treatment of a long-term condition such as avascular necrosis or osteoporosis with compression fracture, findings from Dr. Feldman's group show that outcomes were often excellent in children. "We have not had a single death from JDM in 30 years," he said.

About two-thirds of children with JDM have a polycyclic, chronic, unremitting disease course, but about one-third follow a monocyclic course and have disease symptoms that last for 2-3 years and then go away, with, or potentially even without, treatment.

In a very small proportion of these patients, symptoms may return many years later. "The message here is that when the disease goes away, it almost certainly is gone forever," Dr. Feldman noted.

It is possible to predict which patients will follow a chronic course and which patients will have early remission. In his experience, the risk of persistent disease falls by half if Gottron's rash disappears within 3 months of diagnosis (Arthritis Rheum. 2008;58:3585-92).

The results of a recent practice survey by the Childhood Arthritis and Rheumatology Research Alliance (CARRA) of almost 200 pediatric rheumatologists in North America found both similarities and differences in treatment approaches to JDM (J. Rheumatol. 2010;37:1953-61).

Corticosteroids and methotrexate (MTX) are mainstays of care, but the route and pattern of corticosteroid administration varied: 82% of respondents initially pulsed with high-dose intravenous methylprednisolone (IVMP) while 18% prescribed oral prednisone. MTX was used concurrently with steroids 84% of the time. Sixteen percent reported also using IV immunoglobulin, with or without MTX, for more severe disease, refractory disease, and prominent cutaneous disease. Hydroxychloroquine was given for milder cases, especially for rash, while cyclophosphamide was prescribed for ulcerative disease or for patients with pulmonary symptoms.

While these findings reflect the current prescribing practices, there are almost no randomized controlled trials of medications for JDM, Dr. Feldman pointed out.

This reflects in part the rare nature of the disease, its complexity, the difficulty of conducting studies in children, and the high cost of randomized controlled trials. There have been studies using advanced analytic techniques to provide strong comparative data in lieu of an randomized controlled trial. One such study by Dr. Feldman and associates (Arthritis Rheum. 2008;59:989-95) showed that more aggressive corticosteroid therapy does not give better 3-year outcomes.

A recent randomized controlled trial presented at the annual meeting of the American College of Rheumatology looked at dermatomyositis in 76 adults and 48 children and found that 80% had a response to rituximab within a year of treatment. Interpretation of the study may have been limited by the design, which allowed patients to receive add-on medications during the trial.

In light of the CARRA study's findings of heterogeneity in the treatment of JDM and the absence of randomized controlled trials, a group of 12 pediatric rheumatologists met to study treatments in JDM using a new approach: by developing consensus treatment protocols (Arthritis Care Res. 2010;62:219-25).

"This is similar to what has been done in pediatric oncology," said Dr. Feldman, who was one of the participants. "We are hoping physicians throughout the world will take these protocols off the shelf, and by using standardized doses, follow-up, and measurements, we will be able to accumulate enough evidence over time to know which is the best therapy."

In brief, the group recommended three protocols for the treatment of patients with moderately severe JDM: pulse IVMP plus MTX; IVMP, MTX, plus IVIG; or oral prednisone plus MTX. The third protocol is the one followed most often at the Hospital for Sick Children. The treatment protocols are not intended as treatment recommendations, although it is hoped that a physician will choose to follow the standardized protocol that most closely reflects his or her preferred practice. It is presented as a "first step to allow comparison of different approaches to the treatment of JDM," he said.

Dr. Feldman has done contracted research with Bayer Healthcare Pharmaceuticals. He referenced unlabeled/unapproved uses of drugs or products in his presentation.

NEW YORK – Because juvenile dermatomyositis is a rare disease and its symptoms often differ from those seen in adult dermatomyositis, physicians may not recognize it and diagnosis can be delayed, Dr. Brian Feldman said.

He described a recent practice survey that found variability in juvenile dermatomyositis (JDM) treatment and, in the absence of randomized controlled trials, urged clinicians to consult newly created consensus protocols developed by rheumatologists and to gather data that may help to optimize treatment and minimize side effects in the future for those with JDM.

Photo courtesy http://en.wikipedia.org/wiki/File:Dermatomyositis4.jpg

Dr. Feldman described a 15-year-old patient who had progressively deteriorated over a 3-year period despite being seen by pediatricians and dermatologists. His initial symptoms included fatigue and elevated muscle enzymes, including aspartate transaminase (AST), alanine transaminase (ALT), lactate dehydrogenase (LDH), and creatine phosphokinase (CPK).

Within a year, the patient developed a purple skin rash on his hands, elbows, and knees. He later developed Raynaud's syndrome and muscle weakness with decreased range of motion that interfered with participation in sports and other activities of daily living.

Upon examination, he was quite thin with a scaly rash over his knuckles (Gottron's papules), healing skin ulcerations on his hands (from severe Raynaud's), periungual erythema, and lipodystrophy and erythema of his forearms. Magnetic resonance imaging showed acute inflammation of his shoulder girdle, said Dr. Feldman, chief of pediatric rheumatology at the Hospital for Sick Children in Toronto.

Dr. Feldman said that one of the best diagnostic clues for JDM comes from microscopic examination of nail folds. In this case, the patient had tortuous, bushy nail folds, dilated or missing capillaries (capillary density of 3 per mm of nailfold length while normal ranges from 7-11 per mm), and cuticular overgrowth indicative of JDM.

The different presentation seen with children compared with adults may hinder a correct diagnosis. For instance, calcinosis is seen much more frequently in children than adults. Children are less likely to have some of the systemic symptoms, such as fever, poor weight gain, and pulmonary effects, and they almost never have cardiac problems. Unlike adults with dermatomyositis or polymyositis who appear to have a fourfold increased risk of malignancy, very few cases of malignancy have been associated with JDM. Children are more likely to experience dysphonia/dysphagia but are as likely to have arthritic symptoms (around 58% of each group). Myositis specific antibodies do not seem to play as important a diagnostic role for children as adults.

Children who develop JDM appear to have a better prognosis than adults. Although adults with myositis have appreciable mortality (about 10%) and progressive disability, which may be related to treatment of a long-term condition such as avascular necrosis or osteoporosis with compression fracture, findings from Dr. Feldman's group show that outcomes were often excellent in children. "We have not had a single death from JDM in 30 years," he said.

About two-thirds of children with JDM have a polycyclic, chronic, unremitting disease course, but about one-third follow a monocyclic course and have disease symptoms that last for 2-3 years and then go away, with, or potentially even without, treatment.

In a very small proportion of these patients, symptoms may return many years later. "The message here is that when the disease goes away, it almost certainly is gone forever," Dr. Feldman noted.

It is possible to predict which patients will follow a chronic course and which patients will have early remission. In his experience, the risk of persistent disease falls by half if Gottron's rash disappears within 3 months of diagnosis (Arthritis Rheum. 2008;58:3585-92).

The results of a recent practice survey by the Childhood Arthritis and Rheumatology Research Alliance (CARRA) of almost 200 pediatric rheumatologists in North America found both similarities and differences in treatment approaches to JDM (J. Rheumatol. 2010;37:1953-61).

Corticosteroids and methotrexate (MTX) are mainstays of care, but the route and pattern of corticosteroid administration varied: 82% of respondents initially pulsed with high-dose intravenous methylprednisolone (IVMP) while 18% prescribed oral prednisone. MTX was used concurrently with steroids 84% of the time. Sixteen percent reported also using IV immunoglobulin, with or without MTX, for more severe disease, refractory disease, and prominent cutaneous disease. Hydroxychloroquine was given for milder cases, especially for rash, while cyclophosphamide was prescribed for ulcerative disease or for patients with pulmonary symptoms.

While these findings reflect the current prescribing practices, there are almost no randomized controlled trials of medications for JDM, Dr. Feldman pointed out.

This reflects in part the rare nature of the disease, its complexity, the difficulty of conducting studies in children, and the high cost of randomized controlled trials. There have been studies using advanced analytic techniques to provide strong comparative data in lieu of an randomized controlled trial. One such study by Dr. Feldman and associates (Arthritis Rheum. 2008;59:989-95) showed that more aggressive corticosteroid therapy does not give better 3-year outcomes.

A recent randomized controlled trial presented at the annual meeting of the American College of Rheumatology looked at dermatomyositis in 76 adults and 48 children and found that 80% had a response to rituximab within a year of treatment. Interpretation of the study may have been limited by the design, which allowed patients to receive add-on medications during the trial.

In light of the CARRA study's findings of heterogeneity in the treatment of JDM and the absence of randomized controlled trials, a group of 12 pediatric rheumatologists met to study treatments in JDM using a new approach: by developing consensus treatment protocols (Arthritis Care Res. 2010;62:219-25).

"This is similar to what has been done in pediatric oncology," said Dr. Feldman, who was one of the participants. "We are hoping physicians throughout the world will take these protocols off the shelf, and by using standardized doses, follow-up, and measurements, we will be able to accumulate enough evidence over time to know which is the best therapy."

In brief, the group recommended three protocols for the treatment of patients with moderately severe JDM: pulse IVMP plus MTX; IVMP, MTX, plus IVIG; or oral prednisone plus MTX. The third protocol is the one followed most often at the Hospital for Sick Children. The treatment protocols are not intended as treatment recommendations, although it is hoped that a physician will choose to follow the standardized protocol that most closely reflects his or her preferred practice. It is presented as a "first step to allow comparison of different approaches to the treatment of JDM," he said.

Dr. Feldman has done contracted research with Bayer Healthcare Pharmaceuticals. He referenced unlabeled/unapproved uses of drugs or products in his presentation.