Rheumatoid Arthritis

DESTIN, FLA. – Methadone can be an effective treatment for chronic pain, but there are a number of concerns that must be considered when prescribing this opioid, according to Dr. Perry G. Fine.

Among the benefits of the effective mu-opioid analgesic with N-methyl-

Prescribing this drug requires methadone-specific knowledge and vigilance on the part of the prescriber, as well as a highly responsible patient and/or caregiver who will monitor use and side effects, particularly during titration, according to Dr. Fine, professor of anesthesiology at the Pain Research Center, University of Utah, Salt Lake City.

Potential problems with methadone include drug-drug interactions and cardiac toxicity. Sudden death, even at therapeutic levels, can occur.

Drug-drug interactions can include adverse reactions in patients on monoamine-increasing drugs. Also, serum levels are increased by CYP3A4 and CYP2B6 inhibitors (such as certain antiretrovirals, clarithromycin, itraconazole, erythromycin, fluconazole, grapefruit juice, and more), and this has been associated with multiple overdose deaths, prompting a black-box warning advisory in 2006, Dr. Fine said.

Potential cardiac toxicity is the newest concern; treatment has been shown in some patients to prolong the corrected QT (QTc) interval, and while prescribing guidelines do not yet reflect this, a baseline electrocardiogram is advisable, Dr. Fine said.

According to current guidelines from the American Pain Society–American Academy of Pain Medicine, a reasonable starting dose in most opioid-naive patients is 2.5 mg every 8 hours. Dose increases can begin after a minimum of 10 days. Older patients, or those with renal or hepatic comorbidities, require less frequent dosing, and more cautious dose titration. Methadone treatment is not advisable for breakthrough pain because of its long half-life and variable pharmacokinetics (J. Pain 2009;10:113-20).

Titration, according to Dr. Fine, should include dose increases of 1–2.5 mg every 8 hours in frail, older patients or patients with a history of sleep apnea, and 2.5–5 mg every 8 hours in robust younger patients. Increases should be made every 5–7 days if needed.

Advise patients or caregivers that:

▸ Adequate pain relief from methadone may not occur for several days or weeks.

▸ Methadone should be taken exactly as directed.

▸ Short-acting rescue medications can be used until sufficient baseline analgesia is achieved.

▸ Any signs of increased sedations, mental clouding, snoring, or periodic apnea should be called in (supply an emergency phone number).

▸ No alcohol, benzodiazepines, or other CNS depressants should be used – especially at night – unless specifically prescribed or approved by the physician who prescribed the methadone.

Also, follow up every day during dose titration by a telephone call, through home nursing, or by an office visit, and perform an in-person evaluation weekly until dose stabilization and then monthly thereafter if there are no major ongoing changes in health status, Dr. Fine said.

In-person evaluations should be performed every 3 months once the patient is fully stable, he added.

Dr. Fine has served as an advisory board member for Ameritox, Covidien, King Pharmaceuticals (now Pfizer), Meda Pharmaceuticals, and Purdue Pharma. He is a consultant for Cephalon and Johnson & Johnson.

Older patients or those with renal or hepatic problems need less frequent dosing and more cautious titration.

Source DR. FINE

DESTIN, FLA. – Methadone can be an effective treatment for chronic pain, but there are a number of concerns that must be considered when prescribing this opioid, according to Dr. Perry G. Fine.

Among the benefits of the effective mu-opioid analgesic with N-methyl-

Prescribing this drug requires methadone-specific knowledge and vigilance on the part of the prescriber, as well as a highly responsible patient and/or caregiver who will monitor use and side effects, particularly during titration, according to Dr. Fine, professor of anesthesiology at the Pain Research Center, University of Utah, Salt Lake City.

Potential problems with methadone include drug-drug interactions and cardiac toxicity. Sudden death, even at therapeutic levels, can occur.

Drug-drug interactions can include adverse reactions in patients on monoamine-increasing drugs. Also, serum levels are increased by CYP3A4 and CYP2B6 inhibitors (such as certain antiretrovirals, clarithromycin, itraconazole, erythromycin, fluconazole, grapefruit juice, and more), and this has been associated with multiple overdose deaths, prompting a black-box warning advisory in 2006, Dr. Fine said.

Potential cardiac toxicity is the newest concern; treatment has been shown in some patients to prolong the corrected QT (QTc) interval, and while prescribing guidelines do not yet reflect this, a baseline electrocardiogram is advisable, Dr. Fine said.

According to current guidelines from the American Pain Society–American Academy of Pain Medicine, a reasonable starting dose in most opioid-naive patients is 2.5 mg every 8 hours. Dose increases can begin after a minimum of 10 days. Older patients, or those with renal or hepatic comorbidities, require less frequent dosing, and more cautious dose titration. Methadone treatment is not advisable for breakthrough pain because of its long half-life and variable pharmacokinetics (J. Pain 2009;10:113-20).

Titration, according to Dr. Fine, should include dose increases of 1–2.5 mg every 8 hours in frail, older patients or patients with a history of sleep apnea, and 2.5–5 mg every 8 hours in robust younger patients. Increases should be made every 5–7 days if needed.

Advise patients or caregivers that:

▸ Adequate pain relief from methadone may not occur for several days or weeks.

▸ Methadone should be taken exactly as directed.

▸ Short-acting rescue medications can be used until sufficient baseline analgesia is achieved.

▸ Any signs of increased sedations, mental clouding, snoring, or periodic apnea should be called in (supply an emergency phone number).

▸ No alcohol, benzodiazepines, or other CNS depressants should be used – especially at night – unless specifically prescribed or approved by the physician who prescribed the methadone.

Also, follow up every day during dose titration by a telephone call, through home nursing, or by an office visit, and perform an in-person evaluation weekly until dose stabilization and then monthly thereafter if there are no major ongoing changes in health status, Dr. Fine said.

In-person evaluations should be performed every 3 months once the patient is fully stable, he added.

Dr. Fine has served as an advisory board member for Ameritox, Covidien, King Pharmaceuticals (now Pfizer), Meda Pharmaceuticals, and Purdue Pharma. He is a consultant for Cephalon and Johnson & Johnson.

Older patients or those with renal or hepatic problems need less frequent dosing and more cautious titration.

Source DR. FINE

DESTIN, FLA. – Methadone can be an effective treatment for chronic pain, but there are a number of concerns that must be considered when prescribing this opioid, according to Dr. Perry G. Fine.

Among the benefits of the effective mu-opioid analgesic with N-methyl-

Prescribing this drug requires methadone-specific knowledge and vigilance on the part of the prescriber, as well as a highly responsible patient and/or caregiver who will monitor use and side effects, particularly during titration, according to Dr. Fine, professor of anesthesiology at the Pain Research Center, University of Utah, Salt Lake City.

Potential problems with methadone include drug-drug interactions and cardiac toxicity. Sudden death, even at therapeutic levels, can occur.

Drug-drug interactions can include adverse reactions in patients on monoamine-increasing drugs. Also, serum levels are increased by CYP3A4 and CYP2B6 inhibitors (such as certain antiretrovirals, clarithromycin, itraconazole, erythromycin, fluconazole, grapefruit juice, and more), and this has been associated with multiple overdose deaths, prompting a black-box warning advisory in 2006, Dr. Fine said.

Potential cardiac toxicity is the newest concern; treatment has been shown in some patients to prolong the corrected QT (QTc) interval, and while prescribing guidelines do not yet reflect this, a baseline electrocardiogram is advisable, Dr. Fine said.

According to current guidelines from the American Pain Society–American Academy of Pain Medicine, a reasonable starting dose in most opioid-naive patients is 2.5 mg every 8 hours. Dose increases can begin after a minimum of 10 days. Older patients, or those with renal or hepatic comorbidities, require less frequent dosing, and more cautious dose titration. Methadone treatment is not advisable for breakthrough pain because of its long half-life and variable pharmacokinetics (J. Pain 2009;10:113-20).

Titration, according to Dr. Fine, should include dose increases of 1–2.5 mg every 8 hours in frail, older patients or patients with a history of sleep apnea, and 2.5–5 mg every 8 hours in robust younger patients. Increases should be made every 5–7 days if needed.

Advise patients or caregivers that:

▸ Adequate pain relief from methadone may not occur for several days or weeks.

▸ Methadone should be taken exactly as directed.

▸ Short-acting rescue medications can be used until sufficient baseline analgesia is achieved.

▸ Any signs of increased sedations, mental clouding, snoring, or periodic apnea should be called in (supply an emergency phone number).

▸ No alcohol, benzodiazepines, or other CNS depressants should be used – especially at night – unless specifically prescribed or approved by the physician who prescribed the methadone.

Also, follow up every day during dose titration by a telephone call, through home nursing, or by an office visit, and perform an in-person evaluation weekly until dose stabilization and then monthly thereafter if there are no major ongoing changes in health status, Dr. Fine said.

In-person evaluations should be performed every 3 months once the patient is fully stable, he added.

Dr. Fine has served as an advisory board member for Ameritox, Covidien, King Pharmaceuticals (now Pfizer), Meda Pharmaceuticals, and Purdue Pharma. He is a consultant for Cephalon and Johnson & Johnson.

Older patients or those with renal or hepatic problems need less frequent dosing and more cautious titration.

Source DR. FINE

DESTIN, FLA. – A finding that the response to etanercept is markedly better than the response to sulfasalazine among patients with ankylosing spondylitis is one of a number of recent developments regarding the treatment of the disease, acacording to Dr. Robert Inman.

Among other developments Dr. Inman discussed were new findings regarding predictors of response to treatment, the effects of switching biologics, the effects of discontinuing biologics, and the use of newer biologics for ankylosing spondylitis (AS).

The etanercept findings are from the recently published 48-week randomized controlled ESTHER trial (Effects of Etanercept Versus Sulfasalazine in Early Axial Spondlyoarthritis on Active Inflammatory Lesions as Detected by Whole-Body Magnetic Resonance Imaging).

The percentage of patients in the etanercept vs. sulfasalazine groups who achieved 20% improvement, 40% improvement, or partial response based on Assessment in SpondyloArthritis International Society (ASAS) criteria were 85% vs. 42% (ASAS20), 70% vs. 31% (ASAS40), and 50% vs. 19% (ASASpR), respectively. The percentage of patients in the etanercept vs. sulfasalazine groups who achieved 50% improvement on the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI50) were 65% vs. 28% (Ann. Rheum. Dis. 2011;70:590-6).

“Etanercept far outperformed sulfasalazine,” said Dr. Inman, professor of medicine at Toronto Western Hospital.

Another study, published online in March in Annals of the Rheumatic Diseases, showed that clinical predictors of response to treatment in AS patients include age, presence or absence of human leukocyte antigen B27 subtype (HLA-B27), Bath Ankylosing Spondylitis Functional Index (BASFI) score, and the presence or absence of enthesitis (Ann. Rheum. Dis. 2011;70:973-81).

“This is just clinical bedside analysis,” he said, noting that the findings suggest that an ideal patient for treatment would be a young patient with no enthesitis who is B27 positive and who has a low BASFI. The response rate in such a patient, based on the data, would be well over 80%, but that's not to say patients without all of these characteristics will not respond.

“We've certainly had patients (outside of this ideal group) who have had a great response,” he said.

As for switching and discontinuing biologics, one study reported at the American College of Rheumatology meeting in 2009 (ACR 2009), which assessed outcomes in patients who switched to a second tumor necrosis factor (TNF) inhibitor after failing the first, showed that switchers achieved a reasonable response. Switchers achieved more than half the response rate (about 30%) of that achieved by nonswitchers (49%), but the percentage of patients achieving ASAS20 on the second anti-TNF (52% of nonswitchers and 44% of switchers) was “actually not bad … so there's certainly grounds for switching,” Dr. Inman said, noting that there are enough data in the literature to support that.

Another study reported at ACR 2010 showed that infliximab had continued efficacy in HLA-B27 patients with very early AS even after discontinuation before 16 weeks. About 40% of patients treated with infliximab did not flare through week 40 following drug withdrawal.

“So there may be a subset of patients who, if you capture control very early on, you might be able to switch,” he said.

Several recent studies also have assessed newer biologics for the treatment of AS – with mixed results.

In a disappointing open-label 24-week study of abatacept reported at EULAR 2010, for example, the ASAS20, ASAS40, ASASpR, and BASDAI50 responses in 15 anti-TNF naive patients were 26.7%, 13.3%, 6.7%, and 6.7%, respectively. The only response seen among 15 patients who failed a prior anti-TNF was on the ASAS20, with 20% of patients responding at this level.

“So abatacept does not have a very encouraging signal in ankylosing spondylitis,” Dr. Inman said.

Rituximab, however, was shown in a study presented at EULAR 2009 to be associated with good responses at week 24 of treatment. ASAS20, ASAS40, and BASDAI50 response rates were 50%, 40%, and 50%, respectively, in anti-TNF treatment naive patients, and 30%, 10%, and 0%, respectively, in those who failed a prior anti-TNF drug.

While these response rates aren't quite as good as those seen with anti-TNFs, they are fairly good, and suggest that rituximab is a reasonable choice, particularly in patients with a relative contraindication to an anti-TNF, he said.

However, in a patient who has failed an anti-TNF drug, it's “very unlikely you're going to hit a home run with rituximab,” he added.

Another agent – the anti-IL17A monoclonal antibody secukinumab (AIN57) – was shown in a proof-of-concept study presented at ACR 2010 to be associated with substantially greater ASAS20 response in 30 patients with active AS, compared with placebo (60% vs. 17%). Responses were seen within 1 week in most of the patients.

However, while the response rate was significantly higher than with placebo, the relative change in BASDAI50 was relatively modest and not of the same magnitude typically seen with anti-TNF drugs, he said.

“So I think the jury is still out on the anti-IL17,” he concluded.

Dr. Inman disclosed that he is a consultant for Abbott Laboratories, Merck, Pfizer, and Sanofi-Aventis.

A patient who has failed an anti-TNF is unlikely to respond to rituximab, despite its mechanism of action.

Source DR. INMAN

DESTIN, FLA. – A finding that the response to etanercept is markedly better than the response to sulfasalazine among patients with ankylosing spondylitis is one of a number of recent developments regarding the treatment of the disease, acacording to Dr. Robert Inman.

Among other developments Dr. Inman discussed were new findings regarding predictors of response to treatment, the effects of switching biologics, the effects of discontinuing biologics, and the use of newer biologics for ankylosing spondylitis (AS).

The etanercept findings are from the recently published 48-week randomized controlled ESTHER trial (Effects of Etanercept Versus Sulfasalazine in Early Axial Spondlyoarthritis on Active Inflammatory Lesions as Detected by Whole-Body Magnetic Resonance Imaging).

The percentage of patients in the etanercept vs. sulfasalazine groups who achieved 20% improvement, 40% improvement, or partial response based on Assessment in SpondyloArthritis International Society (ASAS) criteria were 85% vs. 42% (ASAS20), 70% vs. 31% (ASAS40), and 50% vs. 19% (ASASpR), respectively. The percentage of patients in the etanercept vs. sulfasalazine groups who achieved 50% improvement on the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI50) were 65% vs. 28% (Ann. Rheum. Dis. 2011;70:590-6).

“Etanercept far outperformed sulfasalazine,” said Dr. Inman, professor of medicine at Toronto Western Hospital.

Another study, published online in March in Annals of the Rheumatic Diseases, showed that clinical predictors of response to treatment in AS patients include age, presence or absence of human leukocyte antigen B27 subtype (HLA-B27), Bath Ankylosing Spondylitis Functional Index (BASFI) score, and the presence or absence of enthesitis (Ann. Rheum. Dis. 2011;70:973-81).

“This is just clinical bedside analysis,” he said, noting that the findings suggest that an ideal patient for treatment would be a young patient with no enthesitis who is B27 positive and who has a low BASFI. The response rate in such a patient, based on the data, would be well over 80%, but that's not to say patients without all of these characteristics will not respond.

“We've certainly had patients (outside of this ideal group) who have had a great response,” he said.

As for switching and discontinuing biologics, one study reported at the American College of Rheumatology meeting in 2009 (ACR 2009), which assessed outcomes in patients who switched to a second tumor necrosis factor (TNF) inhibitor after failing the first, showed that switchers achieved a reasonable response. Switchers achieved more than half the response rate (about 30%) of that achieved by nonswitchers (49%), but the percentage of patients achieving ASAS20 on the second anti-TNF (52% of nonswitchers and 44% of switchers) was “actually not bad … so there's certainly grounds for switching,” Dr. Inman said, noting that there are enough data in the literature to support that.

Another study reported at ACR 2010 showed that infliximab had continued efficacy in HLA-B27 patients with very early AS even after discontinuation before 16 weeks. About 40% of patients treated with infliximab did not flare through week 40 following drug withdrawal.

“So there may be a subset of patients who, if you capture control very early on, you might be able to switch,” he said.

Several recent studies also have assessed newer biologics for the treatment of AS – with mixed results.

In a disappointing open-label 24-week study of abatacept reported at EULAR 2010, for example, the ASAS20, ASAS40, ASASpR, and BASDAI50 responses in 15 anti-TNF naive patients were 26.7%, 13.3%, 6.7%, and 6.7%, respectively. The only response seen among 15 patients who failed a prior anti-TNF was on the ASAS20, with 20% of patients responding at this level.

“So abatacept does not have a very encouraging signal in ankylosing spondylitis,” Dr. Inman said.

Rituximab, however, was shown in a study presented at EULAR 2009 to be associated with good responses at week 24 of treatment. ASAS20, ASAS40, and BASDAI50 response rates were 50%, 40%, and 50%, respectively, in anti-TNF treatment naive patients, and 30%, 10%, and 0%, respectively, in those who failed a prior anti-TNF drug.

While these response rates aren't quite as good as those seen with anti-TNFs, they are fairly good, and suggest that rituximab is a reasonable choice, particularly in patients with a relative contraindication to an anti-TNF, he said.

However, in a patient who has failed an anti-TNF drug, it's “very unlikely you're going to hit a home run with rituximab,” he added.

Another agent – the anti-IL17A monoclonal antibody secukinumab (AIN57) – was shown in a proof-of-concept study presented at ACR 2010 to be associated with substantially greater ASAS20 response in 30 patients with active AS, compared with placebo (60% vs. 17%). Responses were seen within 1 week in most of the patients.

However, while the response rate was significantly higher than with placebo, the relative change in BASDAI50 was relatively modest and not of the same magnitude typically seen with anti-TNF drugs, he said.

“So I think the jury is still out on the anti-IL17,” he concluded.

Dr. Inman disclosed that he is a consultant for Abbott Laboratories, Merck, Pfizer, and Sanofi-Aventis.

A patient who has failed an anti-TNF is unlikely to respond to rituximab, despite its mechanism of action.

Source DR. INMAN

DESTIN, FLA. – A finding that the response to etanercept is markedly better than the response to sulfasalazine among patients with ankylosing spondylitis is one of a number of recent developments regarding the treatment of the disease, acacording to Dr. Robert Inman.

Among other developments Dr. Inman discussed were new findings regarding predictors of response to treatment, the effects of switching biologics, the effects of discontinuing biologics, and the use of newer biologics for ankylosing spondylitis (AS).

The etanercept findings are from the recently published 48-week randomized controlled ESTHER trial (Effects of Etanercept Versus Sulfasalazine in Early Axial Spondlyoarthritis on Active Inflammatory Lesions as Detected by Whole-Body Magnetic Resonance Imaging).

The percentage of patients in the etanercept vs. sulfasalazine groups who achieved 20% improvement, 40% improvement, or partial response based on Assessment in SpondyloArthritis International Society (ASAS) criteria were 85% vs. 42% (ASAS20), 70% vs. 31% (ASAS40), and 50% vs. 19% (ASASpR), respectively. The percentage of patients in the etanercept vs. sulfasalazine groups who achieved 50% improvement on the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI50) were 65% vs. 28% (Ann. Rheum. Dis. 2011;70:590-6).

“Etanercept far outperformed sulfasalazine,” said Dr. Inman, professor of medicine at Toronto Western Hospital.

Another study, published online in March in Annals of the Rheumatic Diseases, showed that clinical predictors of response to treatment in AS patients include age, presence or absence of human leukocyte antigen B27 subtype (HLA-B27), Bath Ankylosing Spondylitis Functional Index (BASFI) score, and the presence or absence of enthesitis (Ann. Rheum. Dis. 2011;70:973-81).

“This is just clinical bedside analysis,” he said, noting that the findings suggest that an ideal patient for treatment would be a young patient with no enthesitis who is B27 positive and who has a low BASFI. The response rate in such a patient, based on the data, would be well over 80%, but that's not to say patients without all of these characteristics will not respond.

“We've certainly had patients (outside of this ideal group) who have had a great response,” he said.

As for switching and discontinuing biologics, one study reported at the American College of Rheumatology meeting in 2009 (ACR 2009), which assessed outcomes in patients who switched to a second tumor necrosis factor (TNF) inhibitor after failing the first, showed that switchers achieved a reasonable response. Switchers achieved more than half the response rate (about 30%) of that achieved by nonswitchers (49%), but the percentage of patients achieving ASAS20 on the second anti-TNF (52% of nonswitchers and 44% of switchers) was “actually not bad … so there's certainly grounds for switching,” Dr. Inman said, noting that there are enough data in the literature to support that.

Another study reported at ACR 2010 showed that infliximab had continued efficacy in HLA-B27 patients with very early AS even after discontinuation before 16 weeks. About 40% of patients treated with infliximab did not flare through week 40 following drug withdrawal.

“So there may be a subset of patients who, if you capture control very early on, you might be able to switch,” he said.

Several recent studies also have assessed newer biologics for the treatment of AS – with mixed results.

In a disappointing open-label 24-week study of abatacept reported at EULAR 2010, for example, the ASAS20, ASAS40, ASASpR, and BASDAI50 responses in 15 anti-TNF naive patients were 26.7%, 13.3%, 6.7%, and 6.7%, respectively. The only response seen among 15 patients who failed a prior anti-TNF was on the ASAS20, with 20% of patients responding at this level.

“So abatacept does not have a very encouraging signal in ankylosing spondylitis,” Dr. Inman said.

Rituximab, however, was shown in a study presented at EULAR 2009 to be associated with good responses at week 24 of treatment. ASAS20, ASAS40, and BASDAI50 response rates were 50%, 40%, and 50%, respectively, in anti-TNF treatment naive patients, and 30%, 10%, and 0%, respectively, in those who failed a prior anti-TNF drug.

While these response rates aren't quite as good as those seen with anti-TNFs, they are fairly good, and suggest that rituximab is a reasonable choice, particularly in patients with a relative contraindication to an anti-TNF, he said.

However, in a patient who has failed an anti-TNF drug, it's “very unlikely you're going to hit a home run with rituximab,” he added.

Another agent – the anti-IL17A monoclonal antibody secukinumab (AIN57) – was shown in a proof-of-concept study presented at ACR 2010 to be associated with substantially greater ASAS20 response in 30 patients with active AS, compared with placebo (60% vs. 17%). Responses were seen within 1 week in most of the patients.

However, while the response rate was significantly higher than with placebo, the relative change in BASDAI50 was relatively modest and not of the same magnitude typically seen with anti-TNF drugs, he said.

“So I think the jury is still out on the anti-IL17,” he concluded.

Dr. Inman disclosed that he is a consultant for Abbott Laboratories, Merck, Pfizer, and Sanofi-Aventis.

A patient who has failed an anti-TNF is unlikely to respond to rituximab, despite its mechanism of action.

Source DR. INMAN

LONDON – The safety profile of tocilizumab in a prospective open-label study of rheumatoid arthritis patients with inadequate responses to biologics or disease-modifying antirheumatic drugs was comparable across the study’s monotherapy, dose-escalated combination therapy, and high-dose combination therapy treatment arms, Dr. Michael E. Weinblatt reported at the annual European Congress of Rheumatology.

This was the "first report of tocilizumab safety and efficacy in a real-world setting" in patients with disease progression, despite treatment with disease-modifying antirheumatic drugs (DMARDs) or biologic agents. The study found the overall safety of the interleukin-6 monoclonal antibody was consistent with that observed in extension studies of the drug’s pivotal phase III program, said Dr. Weinblatt, who is a professor of medicine at Harvard Medical School and codirector of clinical rheumatology at Brigham and Women’s Hospital in Boston.

Of the 836 patients enrolled in Access to Therapy-Safety Trial of Adalimumab in Rheumatoid Arthritis (ACT-STAR), 183 patients who were on a biologic drug only prior to baseline were assigned to 8mg/kg tocilizumab (Actemra) monotherapy every 4 weeks. Another 363 and 360 patients, respectively, who were on DMARDs only or in combination with biologics prior to baseline were randomized to dose-escalating tocilizumab (starting at 4 mg/kg and increasing up to 8 mg/kg at physicians’ discretion) in combination with one or more DMARD or to 8 mg/kg tocilizumab in combination with one or more DMARD, Dr. Weinblatt reported in a late-breaking abstract session.

As per study protocol, all biologic drugs were discontinued prior to baseline, and patients randomized to the dose-escalating tocilizumab/DMARD condition who did not achieve at least 20% improvement in tender and swollen joint count had their tocilizumab dose increased to 8mg/kg, while others in that group could have their dose increased to 8mg/kg at the investigator’s discretion, Dr. Weinblatt explained. Patients on 8mg/kg tocilizumab plus DMARD could have their dose decreased at any time for safety reasons, he noted. The study’s primary outcome was the number of patients who experienced serious adverse events during the study period.

There was no statistical difference in the rates of serious adverse events across all three arms, Dr. Weinblatt reported. In the tocilizumab monotherapy group, eight patients (5.8%) had serious adverse events, leading to three treatment discontinuations and one dose modification. In the dose-escalation arm, 29 (8%) serious adverse events were reported, leading to seven dose modifications and 11 treatment discontinuations. In the high-dose tocilizumab group, 32 (8.4%) serious adverse events led to 11 dose modifications and four treatment discontinuations, he said. Two deaths not related to treatment occurred in the dose escalation group, he noted.

Serious infections were the most common serious adverse event, occurring in 3.6%, 3.9%, and 2.9% of patients in the dose-escalating, high-dose, and monotherapy groups, respectively, Dr. Weinblatt said. There were no reports of tuberculosis in any of the patients, he said. Three nonfatal gastrointestinal perforations occurred in the dose-escalating combination group, "all in patients with comorbidities," he stressed.

A total of 42 patients had abnormal liver function tests, including 26 with liver tests that were twice the upper limit of normal, 14 with values three times the upper limit of normal, and 2 with values exceeding five times the upper limit of normal. These findings are "similar to the values observed in the phase III extension studies, said Dr. Weinblatt. There were no significant between-group differences in the rates of uncommon lab abnormalities, he said.

With respect to treatment efficacy, DAS28 remission and mean change from baseline, and ACR20/50/70 responses were similar across all of the groups, Dr. Weinblatt said. "The results confirm that what we’ve seen in the research program translates to the real-world setting, with similar safety and efficacy numbers," he said in an interview. They also point to the possibility of the drug being used as a first-line agent as rheumatologists become more comfortable with it, particularly if it receives FDA approval for use as monotherapy in patients who have failed DMARDs, he said.

Dr. Weinblatt disclosed financial relationships with Abbott, Centocor Ortho Biotech, and Pfizer/Wyeth.

LONDON – The safety profile of tocilizumab in a prospective open-label study of rheumatoid arthritis patients with inadequate responses to biologics or disease-modifying antirheumatic drugs was comparable across the study’s monotherapy, dose-escalated combination therapy, and high-dose combination therapy treatment arms, Dr. Michael E. Weinblatt reported at the annual European Congress of Rheumatology.

This was the "first report of tocilizumab safety and efficacy in a real-world setting" in patients with disease progression, despite treatment with disease-modifying antirheumatic drugs (DMARDs) or biologic agents. The study found the overall safety of the interleukin-6 monoclonal antibody was consistent with that observed in extension studies of the drug’s pivotal phase III program, said Dr. Weinblatt, who is a professor of medicine at Harvard Medical School and codirector of clinical rheumatology at Brigham and Women’s Hospital in Boston.

Of the 836 patients enrolled in Access to Therapy-Safety Trial of Adalimumab in Rheumatoid Arthritis (ACT-STAR), 183 patients who were on a biologic drug only prior to baseline were assigned to 8mg/kg tocilizumab (Actemra) monotherapy every 4 weeks. Another 363 and 360 patients, respectively, who were on DMARDs only or in combination with biologics prior to baseline were randomized to dose-escalating tocilizumab (starting at 4 mg/kg and increasing up to 8 mg/kg at physicians’ discretion) in combination with one or more DMARD or to 8 mg/kg tocilizumab in combination with one or more DMARD, Dr. Weinblatt reported in a late-breaking abstract session.

As per study protocol, all biologic drugs were discontinued prior to baseline, and patients randomized to the dose-escalating tocilizumab/DMARD condition who did not achieve at least 20% improvement in tender and swollen joint count had their tocilizumab dose increased to 8mg/kg, while others in that group could have their dose increased to 8mg/kg at the investigator’s discretion, Dr. Weinblatt explained. Patients on 8mg/kg tocilizumab plus DMARD could have their dose decreased at any time for safety reasons, he noted. The study’s primary outcome was the number of patients who experienced serious adverse events during the study period.

There was no statistical difference in the rates of serious adverse events across all three arms, Dr. Weinblatt reported. In the tocilizumab monotherapy group, eight patients (5.8%) had serious adverse events, leading to three treatment discontinuations and one dose modification. In the dose-escalation arm, 29 (8%) serious adverse events were reported, leading to seven dose modifications and 11 treatment discontinuations. In the high-dose tocilizumab group, 32 (8.4%) serious adverse events led to 11 dose modifications and four treatment discontinuations, he said. Two deaths not related to treatment occurred in the dose escalation group, he noted.

Serious infections were the most common serious adverse event, occurring in 3.6%, 3.9%, and 2.9% of patients in the dose-escalating, high-dose, and monotherapy groups, respectively, Dr. Weinblatt said. There were no reports of tuberculosis in any of the patients, he said. Three nonfatal gastrointestinal perforations occurred in the dose-escalating combination group, "all in patients with comorbidities," he stressed.

A total of 42 patients had abnormal liver function tests, including 26 with liver tests that were twice the upper limit of normal, 14 with values three times the upper limit of normal, and 2 with values exceeding five times the upper limit of normal. These findings are "similar to the values observed in the phase III extension studies, said Dr. Weinblatt. There were no significant between-group differences in the rates of uncommon lab abnormalities, he said.

With respect to treatment efficacy, DAS28 remission and mean change from baseline, and ACR20/50/70 responses were similar across all of the groups, Dr. Weinblatt said. "The results confirm that what we’ve seen in the research program translates to the real-world setting, with similar safety and efficacy numbers," he said in an interview. They also point to the possibility of the drug being used as a first-line agent as rheumatologists become more comfortable with it, particularly if it receives FDA approval for use as monotherapy in patients who have failed DMARDs, he said.

Dr. Weinblatt disclosed financial relationships with Abbott, Centocor Ortho Biotech, and Pfizer/Wyeth.

LONDON – The safety profile of tocilizumab in a prospective open-label study of rheumatoid arthritis patients with inadequate responses to biologics or disease-modifying antirheumatic drugs was comparable across the study’s monotherapy, dose-escalated combination therapy, and high-dose combination therapy treatment arms, Dr. Michael E. Weinblatt reported at the annual European Congress of Rheumatology.

This was the "first report of tocilizumab safety and efficacy in a real-world setting" in patients with disease progression, despite treatment with disease-modifying antirheumatic drugs (DMARDs) or biologic agents. The study found the overall safety of the interleukin-6 monoclonal antibody was consistent with that observed in extension studies of the drug’s pivotal phase III program, said Dr. Weinblatt, who is a professor of medicine at Harvard Medical School and codirector of clinical rheumatology at Brigham and Women’s Hospital in Boston.

Of the 836 patients enrolled in Access to Therapy-Safety Trial of Adalimumab in Rheumatoid Arthritis (ACT-STAR), 183 patients who were on a biologic drug only prior to baseline were assigned to 8mg/kg tocilizumab (Actemra) monotherapy every 4 weeks. Another 363 and 360 patients, respectively, who were on DMARDs only or in combination with biologics prior to baseline were randomized to dose-escalating tocilizumab (starting at 4 mg/kg and increasing up to 8 mg/kg at physicians’ discretion) in combination with one or more DMARD or to 8 mg/kg tocilizumab in combination with one or more DMARD, Dr. Weinblatt reported in a late-breaking abstract session.

As per study protocol, all biologic drugs were discontinued prior to baseline, and patients randomized to the dose-escalating tocilizumab/DMARD condition who did not achieve at least 20% improvement in tender and swollen joint count had their tocilizumab dose increased to 8mg/kg, while others in that group could have their dose increased to 8mg/kg at the investigator’s discretion, Dr. Weinblatt explained. Patients on 8mg/kg tocilizumab plus DMARD could have their dose decreased at any time for safety reasons, he noted. The study’s primary outcome was the number of patients who experienced serious adverse events during the study period.

There was no statistical difference in the rates of serious adverse events across all three arms, Dr. Weinblatt reported. In the tocilizumab monotherapy group, eight patients (5.8%) had serious adverse events, leading to three treatment discontinuations and one dose modification. In the dose-escalation arm, 29 (8%) serious adverse events were reported, leading to seven dose modifications and 11 treatment discontinuations. In the high-dose tocilizumab group, 32 (8.4%) serious adverse events led to 11 dose modifications and four treatment discontinuations, he said. Two deaths not related to treatment occurred in the dose escalation group, he noted.

Serious infections were the most common serious adverse event, occurring in 3.6%, 3.9%, and 2.9% of patients in the dose-escalating, high-dose, and monotherapy groups, respectively, Dr. Weinblatt said. There were no reports of tuberculosis in any of the patients, he said. Three nonfatal gastrointestinal perforations occurred in the dose-escalating combination group, "all in patients with comorbidities," he stressed.

A total of 42 patients had abnormal liver function tests, including 26 with liver tests that were twice the upper limit of normal, 14 with values three times the upper limit of normal, and 2 with values exceeding five times the upper limit of normal. These findings are "similar to the values observed in the phase III extension studies, said Dr. Weinblatt. There were no significant between-group differences in the rates of uncommon lab abnormalities, he said.

With respect to treatment efficacy, DAS28 remission and mean change from baseline, and ACR20/50/70 responses were similar across all of the groups, Dr. Weinblatt said. "The results confirm that what we’ve seen in the research program translates to the real-world setting, with similar safety and efficacy numbers," he said in an interview. They also point to the possibility of the drug being used as a first-line agent as rheumatologists become more comfortable with it, particularly if it receives FDA approval for use as monotherapy in patients who have failed DMARDs, he said.

Dr. Weinblatt disclosed financial relationships with Abbott, Centocor Ortho Biotech, and Pfizer/Wyeth.

DESTIN, FLA. – Opioid rotation is a common and potentially beneficial practice for helping to relieve chronic pain in patients who require ongoing opioid therapy, but there is very little data to guide best practice.

The recommended approach, therefore, is one that focuses on safety, Dr. Perry Fine said at the Congress of Clinical Rheumatology.

Clinicians should consider opioid rotation when patients on chronic opioid therapy experience intolerable adverse effects, or when benefits are inadequate despite dose increases, according to recently published clinical guidelines (J. Pain 2009;10:113-30).

However, it is important to consider a number of factors before making changes in treatment, including demographic, disease-related, and treatment-related factors, as well as comorbidities, concomitant pharmacotherapy, drug sensitivities, and social situation, said Dr. Fine, professor of anesthesiology at the University of Utah, Salt Lake City.

If a decision is made to convert a patient’s treatment, a two-step, safety-focused approach is needed, he said.

Step 1 involves an "automatic safety factor" calculation. That is, the equianalgesic dose of the new opioid should be calculated via an equianalgesic table such as a mu-agonist dose chart, and, with a few exceptions, an automatic dose reduction of 25%-50% should be made, except if the new drug is methadone or transdermal fentanyl.

A 25% reduction for opioids (other than methadone or fentanyl) is adequate in patients with no risk factors and/or if the switch is to a different route of administration of the same drug. A 50% reduction is needed in those receiving a relatively high dose of the current opioid, those who are elderly or frail, and those of Chinese lineage, as the Chinese population has been shown to be at increased risk of poor metabolism of opioid drugs, Dr. Fine said.

If the switch is to methadone, a 75%-90% dose reduction is needed, and if the switch is to transdermal fentanyl, use the reduction that is built into the conversion charts provided in the prescribing information, he advised.

If an oral transmucosal fentanyl citrate formulation is used, start with the lowest dose, he added.

The second safety-focused conversion step involves patient-specific adjustments. The patient should be assessed for pain severity and other medical or psychosocial characteristics, and appropriate additional adjustments should be made to the initial dose of the new opioid. For severe pain, consider a dose increase. If pain is under control, but the patient is experiencing adverse effects, any adjustments to the dose should be minimal.

In patients with specific vulnerabilities such as advanced age, renal insufficiency, or cognitive impairment, an additional 10%-30% dose reduction should be considered, Dr. Fine said.

He used as an example a case involving a patient with mild renal insufficiency who was undergoing a switch from morphine to hydromorphone. The patient had moderate pain, mild confusion, and was on multiple other medications. According to step 1, an automatic 25% reduction in the equianalgesic hydromorphone dose would be calculated. According to step 2, an additional 25% reduction would be taken because of the patient’s decreased renal clearance, cognitive problems, and potential drug-drug interactions. Dosage would then be titrated based on the patient’s response.

It is important that a strategy for frequent assessment of initial response be in place, Dr. Fine said, noting that this may involve regular phone calls to the patient or scheduled office visits. This will allow for improved safety and appropriate titration, he said.

Dr. Fine offered the following examples of initial dose calculation in three common analgesic conversions:

• To convert controlled-release oxycodone (60 mg oral dose twice daily) to controlled-release morphine:

1. Calculate the total oxycodone 24-hour dose (120 mg).

2. Determine the morphine dose equivalency (20 mg oxycodone = 30 mg morphine).

3. Convert the 24-hour oxycodone dose to the morphine dose (120 mg oxycodone = 180 mg morphine).

4. Reduce the morphine dose by 25% (135 mg morphine).

5. Split the total morphine dose to the twice-daily dose (67.5 mg). Because the controlled-release (extended-release) morphine is not provided in this exact dose, give the closest available dose (60 mg, twice daily).

• To convert controlled-release morphine (30 mg oral dose twice daily) to transdermal fentanyl:

1. Calculate the total morphine 24-hour dose (60 mg).

2. Use the prescribing information to determine the oral equivalent dose of transdermal fentanyl (60 mg oral morphine = 25 mcg/hr transdermal fentanyl patch).

3. Prescribe 25 mcg/hr transdermal fentanyl patch to be changed every 3 days. Supply patient with five patches (a 15-day supply); instruct patient on application, and follow-up by phone or in office within 2-3 days.

• To convert methadone (20 mg oral dose three times daily) to extended-release oxymorphone:

1. Calculate the total methadone 24-hour dose (60 mg daily).

2. Use mu-agonist dose chart to calculate oxymorphone dose equivalency to methadone (5 mg methadone = 10 mg oxymorphone).

3. Convert the 24-hour methadone dose to oxymorphone dose (60 mg methadone = 120 mg oxymorphone).

4. Reduce the dose by 50% and split the 50% total calculated oxymorphone dosage to a twice-daily dose. Prescribe oxymorphone ER (30 mg oral dose every 12 hours).

Dr. Fine has served as an advisory board member for Ameritox, Covidien, King (now Pfizer), Meda, and Purdue-Pharma. He also is a consultant for Cephalon and Johnson & Johnson.

DESTIN, FLA. – Opioid rotation is a common and potentially beneficial practice for helping to relieve chronic pain in patients who require ongoing opioid therapy, but there is very little data to guide best practice.

The recommended approach, therefore, is one that focuses on safety, Dr. Perry Fine said at the Congress of Clinical Rheumatology.

Clinicians should consider opioid rotation when patients on chronic opioid therapy experience intolerable adverse effects, or when benefits are inadequate despite dose increases, according to recently published clinical guidelines (J. Pain 2009;10:113-30).

However, it is important to consider a number of factors before making changes in treatment, including demographic, disease-related, and treatment-related factors, as well as comorbidities, concomitant pharmacotherapy, drug sensitivities, and social situation, said Dr. Fine, professor of anesthesiology at the University of Utah, Salt Lake City.

If a decision is made to convert a patient’s treatment, a two-step, safety-focused approach is needed, he said.

Step 1 involves an "automatic safety factor" calculation. That is, the equianalgesic dose of the new opioid should be calculated via an equianalgesic table such as a mu-agonist dose chart, and, with a few exceptions, an automatic dose reduction of 25%-50% should be made, except if the new drug is methadone or transdermal fentanyl.

A 25% reduction for opioids (other than methadone or fentanyl) is adequate in patients with no risk factors and/or if the switch is to a different route of administration of the same drug. A 50% reduction is needed in those receiving a relatively high dose of the current opioid, those who are elderly or frail, and those of Chinese lineage, as the Chinese population has been shown to be at increased risk of poor metabolism of opioid drugs, Dr. Fine said.

If the switch is to methadone, a 75%-90% dose reduction is needed, and if the switch is to transdermal fentanyl, use the reduction that is built into the conversion charts provided in the prescribing information, he advised.

If an oral transmucosal fentanyl citrate formulation is used, start with the lowest dose, he added.

The second safety-focused conversion step involves patient-specific adjustments. The patient should be assessed for pain severity and other medical or psychosocial characteristics, and appropriate additional adjustments should be made to the initial dose of the new opioid. For severe pain, consider a dose increase. If pain is under control, but the patient is experiencing adverse effects, any adjustments to the dose should be minimal.

In patients with specific vulnerabilities such as advanced age, renal insufficiency, or cognitive impairment, an additional 10%-30% dose reduction should be considered, Dr. Fine said.

He used as an example a case involving a patient with mild renal insufficiency who was undergoing a switch from morphine to hydromorphone. The patient had moderate pain, mild confusion, and was on multiple other medications. According to step 1, an automatic 25% reduction in the equianalgesic hydromorphone dose would be calculated. According to step 2, an additional 25% reduction would be taken because of the patient’s decreased renal clearance, cognitive problems, and potential drug-drug interactions. Dosage would then be titrated based on the patient’s response.

It is important that a strategy for frequent assessment of initial response be in place, Dr. Fine said, noting that this may involve regular phone calls to the patient or scheduled office visits. This will allow for improved safety and appropriate titration, he said.

Dr. Fine offered the following examples of initial dose calculation in three common analgesic conversions:

• To convert controlled-release oxycodone (60 mg oral dose twice daily) to controlled-release morphine:

1. Calculate the total oxycodone 24-hour dose (120 mg).

2. Determine the morphine dose equivalency (20 mg oxycodone = 30 mg morphine).

3. Convert the 24-hour oxycodone dose to the morphine dose (120 mg oxycodone = 180 mg morphine).

4. Reduce the morphine dose by 25% (135 mg morphine).

5. Split the total morphine dose to the twice-daily dose (67.5 mg). Because the controlled-release (extended-release) morphine is not provided in this exact dose, give the closest available dose (60 mg, twice daily).

• To convert controlled-release morphine (30 mg oral dose twice daily) to transdermal fentanyl:

1. Calculate the total morphine 24-hour dose (60 mg).

2. Use the prescribing information to determine the oral equivalent dose of transdermal fentanyl (60 mg oral morphine = 25 mcg/hr transdermal fentanyl patch).

3. Prescribe 25 mcg/hr transdermal fentanyl patch to be changed every 3 days. Supply patient with five patches (a 15-day supply); instruct patient on application, and follow-up by phone or in office within 2-3 days.

• To convert methadone (20 mg oral dose three times daily) to extended-release oxymorphone:

1. Calculate the total methadone 24-hour dose (60 mg daily).

2. Use mu-agonist dose chart to calculate oxymorphone dose equivalency to methadone (5 mg methadone = 10 mg oxymorphone).

3. Convert the 24-hour methadone dose to oxymorphone dose (60 mg methadone = 120 mg oxymorphone).

4. Reduce the dose by 50% and split the 50% total calculated oxymorphone dosage to a twice-daily dose. Prescribe oxymorphone ER (30 mg oral dose every 12 hours).

Dr. Fine has served as an advisory board member for Ameritox, Covidien, King (now Pfizer), Meda, and Purdue-Pharma. He also is a consultant for Cephalon and Johnson & Johnson.

DESTIN, FLA. – Opioid rotation is a common and potentially beneficial practice for helping to relieve chronic pain in patients who require ongoing opioid therapy, but there is very little data to guide best practice.

The recommended approach, therefore, is one that focuses on safety, Dr. Perry Fine said at the Congress of Clinical Rheumatology.

Clinicians should consider opioid rotation when patients on chronic opioid therapy experience intolerable adverse effects, or when benefits are inadequate despite dose increases, according to recently published clinical guidelines (J. Pain 2009;10:113-30).

However, it is important to consider a number of factors before making changes in treatment, including demographic, disease-related, and treatment-related factors, as well as comorbidities, concomitant pharmacotherapy, drug sensitivities, and social situation, said Dr. Fine, professor of anesthesiology at the University of Utah, Salt Lake City.

If a decision is made to convert a patient’s treatment, a two-step, safety-focused approach is needed, he said.

Step 1 involves an "automatic safety factor" calculation. That is, the equianalgesic dose of the new opioid should be calculated via an equianalgesic table such as a mu-agonist dose chart, and, with a few exceptions, an automatic dose reduction of 25%-50% should be made, except if the new drug is methadone or transdermal fentanyl.

A 25% reduction for opioids (other than methadone or fentanyl) is adequate in patients with no risk factors and/or if the switch is to a different route of administration of the same drug. A 50% reduction is needed in those receiving a relatively high dose of the current opioid, those who are elderly or frail, and those of Chinese lineage, as the Chinese population has been shown to be at increased risk of poor metabolism of opioid drugs, Dr. Fine said.

If the switch is to methadone, a 75%-90% dose reduction is needed, and if the switch is to transdermal fentanyl, use the reduction that is built into the conversion charts provided in the prescribing information, he advised.

If an oral transmucosal fentanyl citrate formulation is used, start with the lowest dose, he added.

The second safety-focused conversion step involves patient-specific adjustments. The patient should be assessed for pain severity and other medical or psychosocial characteristics, and appropriate additional adjustments should be made to the initial dose of the new opioid. For severe pain, consider a dose increase. If pain is under control, but the patient is experiencing adverse effects, any adjustments to the dose should be minimal.

In patients with specific vulnerabilities such as advanced age, renal insufficiency, or cognitive impairment, an additional 10%-30% dose reduction should be considered, Dr. Fine said.

He used as an example a case involving a patient with mild renal insufficiency who was undergoing a switch from morphine to hydromorphone. The patient had moderate pain, mild confusion, and was on multiple other medications. According to step 1, an automatic 25% reduction in the equianalgesic hydromorphone dose would be calculated. According to step 2, an additional 25% reduction would be taken because of the patient’s decreased renal clearance, cognitive problems, and potential drug-drug interactions. Dosage would then be titrated based on the patient’s response.

It is important that a strategy for frequent assessment of initial response be in place, Dr. Fine said, noting that this may involve regular phone calls to the patient or scheduled office visits. This will allow for improved safety and appropriate titration, he said.

Dr. Fine offered the following examples of initial dose calculation in three common analgesic conversions:

• To convert controlled-release oxycodone (60 mg oral dose twice daily) to controlled-release morphine:

1. Calculate the total oxycodone 24-hour dose (120 mg).

2. Determine the morphine dose equivalency (20 mg oxycodone = 30 mg morphine).

3. Convert the 24-hour oxycodone dose to the morphine dose (120 mg oxycodone = 180 mg morphine).

4. Reduce the morphine dose by 25% (135 mg morphine).

5. Split the total morphine dose to the twice-daily dose (67.5 mg). Because the controlled-release (extended-release) morphine is not provided in this exact dose, give the closest available dose (60 mg, twice daily).

• To convert controlled-release morphine (30 mg oral dose twice daily) to transdermal fentanyl:

1. Calculate the total morphine 24-hour dose (60 mg).

2. Use the prescribing information to determine the oral equivalent dose of transdermal fentanyl (60 mg oral morphine = 25 mcg/hr transdermal fentanyl patch).

3. Prescribe 25 mcg/hr transdermal fentanyl patch to be changed every 3 days. Supply patient with five patches (a 15-day supply); instruct patient on application, and follow-up by phone or in office within 2-3 days.

• To convert methadone (20 mg oral dose three times daily) to extended-release oxymorphone:

1. Calculate the total methadone 24-hour dose (60 mg daily).

2. Use mu-agonist dose chart to calculate oxymorphone dose equivalency to methadone (5 mg methadone = 10 mg oxymorphone).

3. Convert the 24-hour methadone dose to oxymorphone dose (60 mg methadone = 120 mg oxymorphone).

4. Reduce the dose by 50% and split the 50% total calculated oxymorphone dosage to a twice-daily dose. Prescribe oxymorphone ER (30 mg oral dose every 12 hours).

Dr. Fine has served as an advisory board member for Ameritox, Covidien, King (now Pfizer), Meda, and Purdue-Pharma. He also is a consultant for Cephalon and Johnson & Johnson.

DESTIN, FLA. – A finding that the response to etanercept is markedly better than the response to sulfasalazine among patients with ankylosing spondylitis is one of a number of recent developments regarding the treatment of the disease, Dr. Robert Inman said at the Congress of Clinical Rheumatology.

Among other developments Dr. Inman discussed were new findings regarding predictors of response to treatment, the effects of switching biologics, the effects of discontinuing biologics, and the use of newer biologics for ankylosing spondylitis (AS).

The etanercept findings are from the recently published 48-week randomized controlled ESTHER trial (Effects of etanercept versus sulfasalazine in early axial spondlyoarthritis on active inflammatory lesions as detected by whole-body MRI).

The percentage of patients in the etanercept vs. sulfasalazine groups who achieved 20% improvement, 40% improvement, or partial response based on Assessment in SpondyloArthritis International Society (ASAS) criteria were 85% vs. 42% (ASAS20), 70% vs. 31% (ASAS40), and 50% vs. 19% (ASASpR), respectively. The percentage of patients in the etanercept vs. sulfasalazine groups who achieved 50% improvement on the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI50) were 65% vs. 28% (Ann. Rheum. Dis. 2011;70:590-6).

"Etanercept far outperformed sulfasalazine," said Dr. Inman, professor of medicine at Toronto Western Hospital.

Another study, published online in March in Annals of the Rheumatic Diseases, showed that clinical predictors of response to treatment in AS patients include age, presence or absence of human leukocyte antigen B27 subtype (HLA-B27), Bath Ankylosing Spondylitis Functional Index (BASFI) score, and the presence or absence of enthesitis (Ann. Rheum. Dis. 2011;70:973-81).

"This is just clinical bedside analysis," he said, noting that the findings suggest that an ideal patient for treatment would be a young patient with no enthesitis who is B27 positive and who has a low BASFI. The response rate in such a patient, based on the data, would be well over 80%, but that’s not to say patients without all of these characteristics will not respond.

"We’ve certainly had patients (outside of this ideal group) who have had a great response," he said.

As for switching and discontinuing biologics, one study reported at the American College of Rheumatology meeting in 2009 (ACR 2009), which assessed outcomes in patients who switched to a second tumor necrosis factor (TNF) inhibitor after failing the first, showed that switchers achieved a reasonable response. Switchers achieved more than half the response rate (about 30%) of that achieved by nonswitchers (49%), but the percentage of patients achieving ASAS20 on the second anti-TNF (52% of nonswitchers and 44% of switchers) was "actually not bad ... so there’s certainly grounds for switching," Dr. Inman said, noting that there are enough data in the literature to support that.

Another study reported at ACR 2010 showed that infliximab had continued efficacy in HLA-B27 patients with very early AS even after discontinuation before 16 weeks. About 40% of patients treated with infliximab did not flare through week 40 following drug withdrawal.

"So there may be a subset of patients who, if you capture control very early on, you might be able to switch," he said.

Several recent studies also have assessed newer biologics for the treatment of AS – with mixed results.

In a disappointing open-label 24-week study of abatacept reported at EULAR 2010, for example, the ASAS20, ASAS40, ASASpR, and BASDAI50 responses in 15 anti-TNF naive patients were 26.7%, 13.3%, 6.7% and 6.7%, respectively. The only response seen among 15 patients who failed a prior anti-TNF was on the ASAS20, with 20% of patients responding at this level.

"So abatacept does not have a very encouraging signal in ankylosing spondylitis," Dr. Inman said.

Rituximab, however, was shown in a study presented at EULAR 2009 to be associated with good responses at week 24 of treatment. ASAS20, ASAS40 and BASDAI50 response rates were 50%, 40%, and 50%, respectively in anti-TNF treatment naive patients, and 30%, 10%, and 0%, respectively, in those who failed a prior anti-TNF drug.

While these response rates aren’t quite as good as those seen with anti-TNFs, they are fairly good, and suggest that rituximab is a reasonable choice, particularly in patients with a relative contraindication to an anti-TNF, he said.

However, in a patient who has failed an anti-TNF drug, it’s "very unlikely you’re going to hit a home run with rituximab," he added.

Another agent – the anti-IL17A monoclonal antibody secukinumab (AIN57) – was shown in a proof-of-concept study presented at ACR 2010 to be associated with substantially greater ASAS20 response in 30 patients with active AS, compared with placebo (60% vs. 17%). Responses were seen within 1 week in most of the patients.

However, while the response rate was significantly higher than with placebo, the relative change in BASDAI50 was relatively modest and not of the same magnitude typically seen with anti-TNF drugs, he said.

"So I think the jury is still out on the anti-IL17," he concluded.

Dr. Inman disclosed that he is a consultant for Abbott Laboratories, Merck , Pfizer, and Sanofi-Aventis.

DESTIN, FLA. – A finding that the response to etanercept is markedly better than the response to sulfasalazine among patients with ankylosing spondylitis is one of a number of recent developments regarding the treatment of the disease, Dr. Robert Inman said at the Congress of Clinical Rheumatology.

Among other developments Dr. Inman discussed were new findings regarding predictors of response to treatment, the effects of switching biologics, the effects of discontinuing biologics, and the use of newer biologics for ankylosing spondylitis (AS).

The etanercept findings are from the recently published 48-week randomized controlled ESTHER trial (Effects of etanercept versus sulfasalazine in early axial spondlyoarthritis on active inflammatory lesions as detected by whole-body MRI).

The percentage of patients in the etanercept vs. sulfasalazine groups who achieved 20% improvement, 40% improvement, or partial response based on Assessment in SpondyloArthritis International Society (ASAS) criteria were 85% vs. 42% (ASAS20), 70% vs. 31% (ASAS40), and 50% vs. 19% (ASASpR), respectively. The percentage of patients in the etanercept vs. sulfasalazine groups who achieved 50% improvement on the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI50) were 65% vs. 28% (Ann. Rheum. Dis. 2011;70:590-6).

"Etanercept far outperformed sulfasalazine," said Dr. Inman, professor of medicine at Toronto Western Hospital.

Another study, published online in March in Annals of the Rheumatic Diseases, showed that clinical predictors of response to treatment in AS patients include age, presence or absence of human leukocyte antigen B27 subtype (HLA-B27), Bath Ankylosing Spondylitis Functional Index (BASFI) score, and the presence or absence of enthesitis (Ann. Rheum. Dis. 2011;70:973-81).

"This is just clinical bedside analysis," he said, noting that the findings suggest that an ideal patient for treatment would be a young patient with no enthesitis who is B27 positive and who has a low BASFI. The response rate in such a patient, based on the data, would be well over 80%, but that’s not to say patients without all of these characteristics will not respond.

"We’ve certainly had patients (outside of this ideal group) who have had a great response," he said.

As for switching and discontinuing biologics, one study reported at the American College of Rheumatology meeting in 2009 (ACR 2009), which assessed outcomes in patients who switched to a second tumor necrosis factor (TNF) inhibitor after failing the first, showed that switchers achieved a reasonable response. Switchers achieved more than half the response rate (about 30%) of that achieved by nonswitchers (49%), but the percentage of patients achieving ASAS20 on the second anti-TNF (52% of nonswitchers and 44% of switchers) was "actually not bad ... so there’s certainly grounds for switching," Dr. Inman said, noting that there are enough data in the literature to support that.

Another study reported at ACR 2010 showed that infliximab had continued efficacy in HLA-B27 patients with very early AS even after discontinuation before 16 weeks. About 40% of patients treated with infliximab did not flare through week 40 following drug withdrawal.

"So there may be a subset of patients who, if you capture control very early on, you might be able to switch," he said.

Several recent studies also have assessed newer biologics for the treatment of AS – with mixed results.

In a disappointing open-label 24-week study of abatacept reported at EULAR 2010, for example, the ASAS20, ASAS40, ASASpR, and BASDAI50 responses in 15 anti-TNF naive patients were 26.7%, 13.3%, 6.7% and 6.7%, respectively. The only response seen among 15 patients who failed a prior anti-TNF was on the ASAS20, with 20% of patients responding at this level.

"So abatacept does not have a very encouraging signal in ankylosing spondylitis," Dr. Inman said.

Rituximab, however, was shown in a study presented at EULAR 2009 to be associated with good responses at week 24 of treatment. ASAS20, ASAS40 and BASDAI50 response rates were 50%, 40%, and 50%, respectively in anti-TNF treatment naive patients, and 30%, 10%, and 0%, respectively, in those who failed a prior anti-TNF drug.

While these response rates aren’t quite as good as those seen with anti-TNFs, they are fairly good, and suggest that rituximab is a reasonable choice, particularly in patients with a relative contraindication to an anti-TNF, he said.

However, in a patient who has failed an anti-TNF drug, it’s "very unlikely you’re going to hit a home run with rituximab," he added.

Another agent – the anti-IL17A monoclonal antibody secukinumab (AIN57) – was shown in a proof-of-concept study presented at ACR 2010 to be associated with substantially greater ASAS20 response in 30 patients with active AS, compared with placebo (60% vs. 17%). Responses were seen within 1 week in most of the patients.

However, while the response rate was significantly higher than with placebo, the relative change in BASDAI50 was relatively modest and not of the same magnitude typically seen with anti-TNF drugs, he said.

"So I think the jury is still out on the anti-IL17," he concluded.

Dr. Inman disclosed that he is a consultant for Abbott Laboratories, Merck , Pfizer, and Sanofi-Aventis.

DESTIN, FLA. – A finding that the response to etanercept is markedly better than the response to sulfasalazine among patients with ankylosing spondylitis is one of a number of recent developments regarding the treatment of the disease, Dr. Robert Inman said at the Congress of Clinical Rheumatology.

Among other developments Dr. Inman discussed were new findings regarding predictors of response to treatment, the effects of switching biologics, the effects of discontinuing biologics, and the use of newer biologics for ankylosing spondylitis (AS).

The etanercept findings are from the recently published 48-week randomized controlled ESTHER trial (Effects of etanercept versus sulfasalazine in early axial spondlyoarthritis on active inflammatory lesions as detected by whole-body MRI).

The percentage of patients in the etanercept vs. sulfasalazine groups who achieved 20% improvement, 40% improvement, or partial response based on Assessment in SpondyloArthritis International Society (ASAS) criteria were 85% vs. 42% (ASAS20), 70% vs. 31% (ASAS40), and 50% vs. 19% (ASASpR), respectively. The percentage of patients in the etanercept vs. sulfasalazine groups who achieved 50% improvement on the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI50) were 65% vs. 28% (Ann. Rheum. Dis. 2011;70:590-6).

"Etanercept far outperformed sulfasalazine," said Dr. Inman, professor of medicine at Toronto Western Hospital.

Another study, published online in March in Annals of the Rheumatic Diseases, showed that clinical predictors of response to treatment in AS patients include age, presence or absence of human leukocyte antigen B27 subtype (HLA-B27), Bath Ankylosing Spondylitis Functional Index (BASFI) score, and the presence or absence of enthesitis (Ann. Rheum. Dis. 2011;70:973-81).

"This is just clinical bedside analysis," he said, noting that the findings suggest that an ideal patient for treatment would be a young patient with no enthesitis who is B27 positive and who has a low BASFI. The response rate in such a patient, based on the data, would be well over 80%, but that’s not to say patients without all of these characteristics will not respond.

"We’ve certainly had patients (outside of this ideal group) who have had a great response," he said.

As for switching and discontinuing biologics, one study reported at the American College of Rheumatology meeting in 2009 (ACR 2009), which assessed outcomes in patients who switched to a second tumor necrosis factor (TNF) inhibitor after failing the first, showed that switchers achieved a reasonable response. Switchers achieved more than half the response rate (about 30%) of that achieved by nonswitchers (49%), but the percentage of patients achieving ASAS20 on the second anti-TNF (52% of nonswitchers and 44% of switchers) was "actually not bad ... so there’s certainly grounds for switching," Dr. Inman said, noting that there are enough data in the literature to support that.

Another study reported at ACR 2010 showed that infliximab had continued efficacy in HLA-B27 patients with very early AS even after discontinuation before 16 weeks. About 40% of patients treated with infliximab did not flare through week 40 following drug withdrawal.

"So there may be a subset of patients who, if you capture control very early on, you might be able to switch," he said.

Several recent studies also have assessed newer biologics for the treatment of AS – with mixed results.

In a disappointing open-label 24-week study of abatacept reported at EULAR 2010, for example, the ASAS20, ASAS40, ASASpR, and BASDAI50 responses in 15 anti-TNF naive patients were 26.7%, 13.3%, 6.7% and 6.7%, respectively. The only response seen among 15 patients who failed a prior anti-TNF was on the ASAS20, with 20% of patients responding at this level.

"So abatacept does not have a very encouraging signal in ankylosing spondylitis," Dr. Inman said.

Rituximab, however, was shown in a study presented at EULAR 2009 to be associated with good responses at week 24 of treatment. ASAS20, ASAS40 and BASDAI50 response rates were 50%, 40%, and 50%, respectively in anti-TNF treatment naive patients, and 30%, 10%, and 0%, respectively, in those who failed a prior anti-TNF drug.

While these response rates aren’t quite as good as those seen with anti-TNFs, they are fairly good, and suggest that rituximab is a reasonable choice, particularly in patients with a relative contraindication to an anti-TNF, he said.

However, in a patient who has failed an anti-TNF drug, it’s "very unlikely you’re going to hit a home run with rituximab," he added.

Another agent – the anti-IL17A monoclonal antibody secukinumab (AIN57) – was shown in a proof-of-concept study presented at ACR 2010 to be associated with substantially greater ASAS20 response in 30 patients with active AS, compared with placebo (60% vs. 17%). Responses were seen within 1 week in most of the patients.

However, while the response rate was significantly higher than with placebo, the relative change in BASDAI50 was relatively modest and not of the same magnitude typically seen with anti-TNF drugs, he said.

"So I think the jury is still out on the anti-IL17," he concluded.

Dr. Inman disclosed that he is a consultant for Abbott Laboratories, Merck , Pfizer, and Sanofi-Aventis.

Workers with rheumatic diseases need to inform their employers of their condition, in the hope that the employers will respond by modifying the job enough to make it safer. That is the goal of an ongoing campaign to educate employers and employees about rheumatoid arthritis that is being sponsored by the U.K. National Rheumatoid Arthritis Society.

More than 56% of patients with RA stopped working within a year of receiving their diagnosis, according to the 2010 National Rheumatoid Arthritis Survey that will be discussed today by Clare Jacklin, external affairs manager of the National Rheumatoid Arthritis Society (NRAS). Ms. Jacklin said in an interview that the society is working to address this most startling finding. Although the 2010 survey focused on Scotland, a similar study in 2007 showed the same issues spanning the entire United Kingdom.

To achieve this goal, NRAS led a series of 10 workshops throughout the United Kingdom in 2010 to educate employers and employees about RA.

"With the right information at the right time, people are given the confidence to disclose their condition to their employers and many lost jobs can be avoided," Ms. Jacklin said in an interview. The most common areas of employment for respondents with a full or part-time job were professionals (nearly 35%), office workers (approximately 30%), and health workers (about 25%).

Since starting the campaign in 2007, the society has experienced an influx of calls to their help center for information and support in work-related issues, Ms. Jacklin said. She added that the majority of calls come from recently diagnosed patients who are unsure how to talk to their manager or colleagues about their disease. Others who call the society’s help center don’t know their rights and think they are experiencing discrimination. In addition to employer awareness, NRAS is seeking U.K. government support so that even small businesses can accommodate their employees with a chronic condition to continue working, Ms. Jacklin said.

Of the 45 respondents in the 2010 survey who reported that they were not working because of their disease, 56% (25 respondents) said they stopped working 1 year after diagnosis, and 80% (36 respondents) after 6 years. However, within the same group that reported they’d stopped working, 51% (23 respondents) said they would return to work if they could find a job that would accommodate their disease. Those who reported still working said that their work is often affected by their pain (64.4%) or fatigue (81.1%). An additional 58.8% said that they are often unable to carry out their duties because of physical limitations, and 55.6% have had to take time off work. NRAS included responses from 198 participants in their survey results.

NRAS would like to see the government reward employers who support people with disabilities in order to highlight the benefit of such accommodations to everyone: the individual, the company, the economy, and society, Ms. Jacklin said. NRAS recommendations for improvement in the workplace include expedited access to a rheumatology team for managing flares and drug side effects, increased government education and support, increased flexibility and support from the employer, and patient awareness of their own rights.

Ms. Jacklin reported no financial conflicts of interest.

Workers with rheumatic diseases need to inform their employers of their condition, in the hope that the employers will respond by modifying the job enough to make it safer. That is the goal of an ongoing campaign to educate employers and employees about rheumatoid arthritis that is being sponsored by the U.K. National Rheumatoid Arthritis Society.

More than 56% of patients with RA stopped working within a year of receiving their diagnosis, according to the 2010 National Rheumatoid Arthritis Survey that will be discussed today by Clare Jacklin, external affairs manager of the National Rheumatoid Arthritis Society (NRAS). Ms. Jacklin said in an interview that the society is working to address this most startling finding. Although the 2010 survey focused on Scotland, a similar study in 2007 showed the same issues spanning the entire United Kingdom.

To achieve this goal, NRAS led a series of 10 workshops throughout the United Kingdom in 2010 to educate employers and employees about RA.

"With the right information at the right time, people are given the confidence to disclose their condition to their employers and many lost jobs can be avoided," Ms. Jacklin said in an interview. The most common areas of employment for respondents with a full or part-time job were professionals (nearly 35%), office workers (approximately 30%), and health workers (about 25%).

Since starting the campaign in 2007, the society has experienced an influx of calls to their help center for information and support in work-related issues, Ms. Jacklin said. She added that the majority of calls come from recently diagnosed patients who are unsure how to talk to their manager or colleagues about their disease. Others who call the society’s help center don’t know their rights and think they are experiencing discrimination. In addition to employer awareness, NRAS is seeking U.K. government support so that even small businesses can accommodate their employees with a chronic condition to continue working, Ms. Jacklin said.

Of the 45 respondents in the 2010 survey who reported that they were not working because of their disease, 56% (25 respondents) said they stopped working 1 year after diagnosis, and 80% (36 respondents) after 6 years. However, within the same group that reported they’d stopped working, 51% (23 respondents) said they would return to work if they could find a job that would accommodate their disease. Those who reported still working said that their work is often affected by their pain (64.4%) or fatigue (81.1%). An additional 58.8% said that they are often unable to carry out their duties because of physical limitations, and 55.6% have had to take time off work. NRAS included responses from 198 participants in their survey results.

NRAS would like to see the government reward employers who support people with disabilities in order to highlight the benefit of such accommodations to everyone: the individual, the company, the economy, and society, Ms. Jacklin said. NRAS recommendations for improvement in the workplace include expedited access to a rheumatology team for managing flares and drug side effects, increased government education and support, increased flexibility and support from the employer, and patient awareness of their own rights.

Ms. Jacklin reported no financial conflicts of interest.

Workers with rheumatic diseases need to inform their employers of their condition, in the hope that the employers will respond by modifying the job enough to make it safer. That is the goal of an ongoing campaign to educate employers and employees about rheumatoid arthritis that is being sponsored by the U.K. National Rheumatoid Arthritis Society.

More than 56% of patients with RA stopped working within a year of receiving their diagnosis, according to the 2010 National Rheumatoid Arthritis Survey that will be discussed today by Clare Jacklin, external affairs manager of the National Rheumatoid Arthritis Society (NRAS). Ms. Jacklin said in an interview that the society is working to address this most startling finding. Although the 2010 survey focused on Scotland, a similar study in 2007 showed the same issues spanning the entire United Kingdom.

To achieve this goal, NRAS led a series of 10 workshops throughout the United Kingdom in 2010 to educate employers and employees about RA.

"With the right information at the right time, people are given the confidence to disclose their condition to their employers and many lost jobs can be avoided," Ms. Jacklin said in an interview. The most common areas of employment for respondents with a full or part-time job were professionals (nearly 35%), office workers (approximately 30%), and health workers (about 25%).

Since starting the campaign in 2007, the society has experienced an influx of calls to their help center for information and support in work-related issues, Ms. Jacklin said. She added that the majority of calls come from recently diagnosed patients who are unsure how to talk to their manager or colleagues about their disease. Others who call the society’s help center don’t know their rights and think they are experiencing discrimination. In addition to employer awareness, NRAS is seeking U.K. government support so that even small businesses can accommodate their employees with a chronic condition to continue working, Ms. Jacklin said.

Of the 45 respondents in the 2010 survey who reported that they were not working because of their disease, 56% (25 respondents) said they stopped working 1 year after diagnosis, and 80% (36 respondents) after 6 years. However, within the same group that reported they’d stopped working, 51% (23 respondents) said they would return to work if they could find a job that would accommodate their disease. Those who reported still working said that their work is often affected by their pain (64.4%) or fatigue (81.1%). An additional 58.8% said that they are often unable to carry out their duties because of physical limitations, and 55.6% have had to take time off work. NRAS included responses from 198 participants in their survey results.

NRAS would like to see the government reward employers who support people with disabilities in order to highlight the benefit of such accommodations to everyone: the individual, the company, the economy, and society, Ms. Jacklin said. NRAS recommendations for improvement in the workplace include expedited access to a rheumatology team for managing flares and drug side effects, increased government education and support, increased flexibility and support from the employer, and patient awareness of their own rights.

Ms. Jacklin reported no financial conflicts of interest.

LONDON – An induction and maintenance treatment model works well for many patients with rheumatoid arthritis who start on potent, combined therapy very early in the course of their disease, based on 78-week follow-up of more than 200 patients in a randomized, controlled study.

The results showed that most patients who, within a few months of their onset of RA, began a regimen that combined the tumor necrosis factor (TNF) inhibitor adalimumab with methotrexate and who then reached a low level of disease activity after 22-26 weeks on the combined regimen could then switch to methotrexate monotherapy and remain at a low disease-activity state for the following year, Dr. Paul Emery and his associates reported in a poster at the annual European Congress of Rheumatology. Nearly half of the patients who began on the adalimumab plus methotrexate regimen reached a low disease activity state after 26 weeks.

The finding has important implications for the necessary duration of treatment with a TNF inhibitor, a member of the expensive class of biologic RA drugs.

"The key finding is that if you start patients on a biologic drug first, they do not take the biologic for life. You can probably stop [the biologic] in the majority of patients. The key is to treat patients when their disease is still completely reversible, hit them as hard as you can safely, and then hope to withdraw the biologic and [still] have a profound effect" on their disease that would not be possible if the biologic treatment was withheld until later, Dr. Emery said in an interview.

"It is an oncologic approach of induction and maintenance. The usual paradigm has been to use the cheap drugs" (disease-modifying antirheumatic drugs like methotrexate) first, and then, for the patients who failed to respond, to treat with a TNF inhibitor. But that approach delays treatment with the biologic until later in the course of RA. And at that point, withdrawal of the TNF inhibitor is harder because patients would then be left on just the drug (methotrexate) to which they had already failed to respond, he said.

Further analysis of the data collected in this study also holds the promise of finding demographic or clinical features to identify the patients who would best respond to initial combined therapy with a TNF inhibitor and methotrexate, followed by withdrawal of the biologic drug.

"We could use biomarkers to personalize [treatment], to target this approach to patients" who will likely succeed with induction and maintenance, said Dr. Emery, professor of rheumatology and head of the academic unit of musculoskeletal medicine at the University of Leeds (England). He plans to "define the subpopulation of very early RA patients who are capable of achieving and sustaining optimal therapeutic outcomes with early initiation of adalimumab and methotrexate, followed by biologic-free treatment.

Additional related issues that require further study include identifying what is the maximum level of disease activity that patients can have at the end of TNF-inhibitor treatment and still remain in a state of low disease activity. Another issue is whether patients who have disease recurrence when they are switched from combined treatment to methotrexate monotherapy can then restart the TNF inhibitor and still have a good response the second time.

The new analysis used data that were collected in the OPTIMA (Optimal Protocol for Treatment Initiation with Methotrexate and Adalimumab Combination Therapy in Patients with Early RA) trial, conducted at 175 sites in 20 countries worldwide, including more than 50 U.S. centers. Between December 2006 and September 2010, the investigators randomized 1,032 patients with recently diagnosed RA to treatment with either adalimumab plus methotrexate or placebo plus methotrexate. Researchers administered 40 mg adalimumab once every other week, and they titrated methotrexate to a maximum dosage of 20 mg/week.

The analysis reported by Dr. Emery and his associates focused on patients who initially received the combined active treatment. Within that treatment group, they selected the 44% of patients who, at week 22-26, achieved a state of low disease activity, defined as a DAS28 (disease activity score based on a 28-joint count) less than 3.2. They randomized 102 of these patients to continue on methotrexate monotherapy and 105 patients to remain on combined therapy with methotrexate and adalimumab. These patients averaged 50 years of age, nearly three-quarters were women, 90% were white, and, at the time they entered the study, they had been diagnosed with RA for an average of 4 months.

The study’s primary end point was a DAS28-CRP (based on C-reactive protein) score of less than 3.2, and radiographic changes on the modified total Sharp score of 0.5 or less at week 78 of the study, after spending 1 year on the randomized, maintenance therapies. The percentage of patients who met this criterion was 55% in those who were treated with methotrexate monotherapy for 1 year and 70% among those who were kept on the dual regimen, a statistically significant difference.

But other, less stringent measures of disease activity showed fairly good maintenance with methotrexate monotherapy. For example, the percentage of patients at 78 weeks with low disease activity based on a DAS28-CRP score of less than 3.2 was 81% in the methotrexate monotherapy group and 91% among the patients on both active drugs. Of the patients on methotrexate alone, 84% had an SDAI (Simplified Disease Activity Index) of 11 or less at 78 weeks, as did 92% of those on methotrexate plus adalimumab. There was no radiographic progression in 81% of the patients in the monotherapy arm at 78 weeks and in 89% of the patients on both drugs. An ACR 50 (American College of Rheumatology scale showing a 50% improvement) response was recorded at 78 weeks in 80% of patients on methotrexate only and in 89% of patients on methotrexate plus adalimumab.

"On the whole, patients on methotrexate [monotherapy] did extremely well and maintained their responses," Dr. Emery said. These are "the first global, randomized, controlled data on discontinuation of a TNF inhibitor after successful achievement of stable, low disease activity. The data suggest that for a large proportion of very early RA patients, a 26-week course of adalimumab and methotrexate, followed by 52 weeks of methotrexate monotherapy, may be a viable option to allow for the achievement of good outcomes."

The study is funded by Abbott, the company that markets adalimumab (Humira). Dr. Emery said that he has received research support from and has been a consultant to Abbott, Bristol-Myers Squibb, Merck, Pfizer, and Roche.

LONDON – An induction and maintenance treatment model works well for many patients with rheumatoid arthritis who start on potent, combined therapy very early in the course of their disease, based on 78-week follow-up of more than 200 patients in a randomized, controlled study.

The results showed that most patients who, within a few months of their onset of RA, began a regimen that combined the tumor necrosis factor (TNF) inhibitor adalimumab with methotrexate and who then reached a low level of disease activity after 22-26 weeks on the combined regimen could then switch to methotrexate monotherapy and remain at a low disease-activity state for the following year, Dr. Paul Emery and his associates reported in a poster at the annual European Congress of Rheumatology. Nearly half of the patients who began on the adalimumab plus methotrexate regimen reached a low disease activity state after 26 weeks.

The finding has important implications for the necessary duration of treatment with a TNF inhibitor, a member of the expensive class of biologic RA drugs.

"The key finding is that if you start patients on a biologic drug first, they do not take the biologic for life. You can probably stop [the biologic] in the majority of patients. The key is to treat patients when their disease is still completely reversible, hit them as hard as you can safely, and then hope to withdraw the biologic and [still] have a profound effect" on their disease that would not be possible if the biologic treatment was withheld until later, Dr. Emery said in an interview.

"It is an oncologic approach of induction and maintenance. The usual paradigm has been to use the cheap drugs" (disease-modifying antirheumatic drugs like methotrexate) first, and then, for the patients who failed to respond, to treat with a TNF inhibitor. But that approach delays treatment with the biologic until later in the course of RA. And at that point, withdrawal of the TNF inhibitor is harder because patients would then be left on just the drug (methotrexate) to which they had already failed to respond, he said.

Further analysis of the data collected in this study also holds the promise of finding demographic or clinical features to identify the patients who would best respond to initial combined therapy with a TNF inhibitor and methotrexate, followed by withdrawal of the biologic drug.

"We could use biomarkers to personalize [treatment], to target this approach to patients" who will likely succeed with induction and maintenance, said Dr. Emery, professor of rheumatology and head of the academic unit of musculoskeletal medicine at the University of Leeds (England). He plans to "define the subpopulation of very early RA patients who are capable of achieving and sustaining optimal therapeutic outcomes with early initiation of adalimumab and methotrexate, followed by biologic-free treatment.

Additional related issues that require further study include identifying what is the maximum level of disease activity that patients can have at the end of TNF-inhibitor treatment and still remain in a state of low disease activity. Another issue is whether patients who have disease recurrence when they are switched from combined treatment to methotrexate monotherapy can then restart the TNF inhibitor and still have a good response the second time.

The new analysis used data that were collected in the OPTIMA (Optimal Protocol for Treatment Initiation with Methotrexate and Adalimumab Combination Therapy in Patients with Early RA) trial, conducted at 175 sites in 20 countries worldwide, including more than 50 U.S. centers. Between December 2006 and September 2010, the investigators randomized 1,032 patients with recently diagnosed RA to treatment with either adalimumab plus methotrexate or placebo plus methotrexate. Researchers administered 40 mg adalimumab once every other week, and they titrated methotrexate to a maximum dosage of 20 mg/week.

The analysis reported by Dr. Emery and his associates focused on patients who initially received the combined active treatment. Within that treatment group, they selected the 44% of patients who, at week 22-26, achieved a state of low disease activity, defined as a DAS28 (disease activity score based on a 28-joint count) less than 3.2. They randomized 102 of these patients to continue on methotrexate monotherapy and 105 patients to remain on combined therapy with methotrexate and adalimumab. These patients averaged 50 years of age, nearly three-quarters were women, 90% were white, and, at the time they entered the study, they had been diagnosed with RA for an average of 4 months.

The study’s primary end point was a DAS28-CRP (based on C-reactive protein) score of less than 3.2, and radiographic changes on the modified total Sharp score of 0.5 or less at week 78 of the study, after spending 1 year on the randomized, maintenance therapies. The percentage of patients who met this criterion was 55% in those who were treated with methotrexate monotherapy for 1 year and 70% among those who were kept on the dual regimen, a statistically significant difference.

But other, less stringent measures of disease activity showed fairly good maintenance with methotrexate monotherapy. For example, the percentage of patients at 78 weeks with low disease activity based on a DAS28-CRP score of less than 3.2 was 81% in the methotrexate monotherapy group and 91% among the patients on both active drugs. Of the patients on methotrexate alone, 84% had an SDAI (Simplified Disease Activity Index) of 11 or less at 78 weeks, as did 92% of those on methotrexate plus adalimumab. There was no radiographic progression in 81% of the patients in the monotherapy arm at 78 weeks and in 89% of the patients on both drugs. An ACR 50 (American College of Rheumatology scale showing a 50% improvement) response was recorded at 78 weeks in 80% of patients on methotrexate only and in 89% of patients on methotrexate plus adalimumab.

"On the whole, patients on methotrexate [monotherapy] did extremely well and maintained their responses," Dr. Emery said. These are "the first global, randomized, controlled data on discontinuation of a TNF inhibitor after successful achievement of stable, low disease activity. The data suggest that for a large proportion of very early RA patients, a 26-week course of adalimumab and methotrexate, followed by 52 weeks of methotrexate monotherapy, may be a viable option to allow for the achievement of good outcomes."

The study is funded by Abbott, the company that markets adalimumab (Humira). Dr. Emery said that he has received research support from and has been a consultant to Abbott, Bristol-Myers Squibb, Merck, Pfizer, and Roche.

LONDON – An induction and maintenance treatment model works well for many patients with rheumatoid arthritis who start on potent, combined therapy very early in the course of their disease, based on 78-week follow-up of more than 200 patients in a randomized, controlled study.

The results showed that most patients who, within a few months of their onset of RA, began a regimen that combined the tumor necrosis factor (TNF) inhibitor adalimumab with methotrexate and who then reached a low level of disease activity after 22-26 weeks on the combined regimen could then switch to methotrexate monotherapy and remain at a low disease-activity state for the following year, Dr. Paul Emery and his associates reported in a poster at the annual European Congress of Rheumatology. Nearly half of the patients who began on the adalimumab plus methotrexate regimen reached a low disease activity state after 26 weeks.

The finding has important implications for the necessary duration of treatment with a TNF inhibitor, a member of the expensive class of biologic RA drugs.

"The key finding is that if you start patients on a biologic drug first, they do not take the biologic for life. You can probably stop [the biologic] in the majority of patients. The key is to treat patients when their disease is still completely reversible, hit them as hard as you can safely, and then hope to withdraw the biologic and [still] have a profound effect" on their disease that would not be possible if the biologic treatment was withheld until later, Dr. Emery said in an interview.

"It is an oncologic approach of induction and maintenance. The usual paradigm has been to use the cheap drugs" (disease-modifying antirheumatic drugs like methotrexate) first, and then, for the patients who failed to respond, to treat with a TNF inhibitor. But that approach delays treatment with the biologic until later in the course of RA. And at that point, withdrawal of the TNF inhibitor is harder because patients would then be left on just the drug (methotrexate) to which they had already failed to respond, he said.

Further analysis of the data collected in this study also holds the promise of finding demographic or clinical features to identify the patients who would best respond to initial combined therapy with a TNF inhibitor and methotrexate, followed by withdrawal of the biologic drug.

"We could use biomarkers to personalize [treatment], to target this approach to patients" who will likely succeed with induction and maintenance, said Dr. Emery, professor of rheumatology and head of the academic unit of musculoskeletal medicine at the University of Leeds (England). He plans to "define the subpopulation of very early RA patients who are capable of achieving and sustaining optimal therapeutic outcomes with early initiation of adalimumab and methotrexate, followed by biologic-free treatment.

Additional related issues that require further study include identifying what is the maximum level of disease activity that patients can have at the end of TNF-inhibitor treatment and still remain in a state of low disease activity. Another issue is whether patients who have disease recurrence when they are switched from combined treatment to methotrexate monotherapy can then restart the TNF inhibitor and still have a good response the second time.

The new analysis used data that were collected in the OPTIMA (Optimal Protocol for Treatment Initiation with Methotrexate and Adalimumab Combination Therapy in Patients with Early RA) trial, conducted at 175 sites in 20 countries worldwide, including more than 50 U.S. centers. Between December 2006 and September 2010, the investigators randomized 1,032 patients with recently diagnosed RA to treatment with either adalimumab plus methotrexate or placebo plus methotrexate. Researchers administered 40 mg adalimumab once every other week, and they titrated methotrexate to a maximum dosage of 20 mg/week.

The analysis reported by Dr. Emery and his associates focused on patients who initially received the combined active treatment. Within that treatment group, they selected the 44% of patients who, at week 22-26, achieved a state of low disease activity, defined as a DAS28 (disease activity score based on a 28-joint count) less than 3.2. They randomized 102 of these patients to continue on methotrexate monotherapy and 105 patients to remain on combined therapy with methotrexate and adalimumab. These patients averaged 50 years of age, nearly three-quarters were women, 90% were white, and, at the time they entered the study, they had been diagnosed with RA for an average of 4 months.

The study’s primary end point was a DAS28-CRP (based on C-reactive protein) score of less than 3.2, and radiographic changes on the modified total Sharp score of 0.5 or less at week 78 of the study, after spending 1 year on the randomized, maintenance therapies. The percentage of patients who met this criterion was 55% in those who were treated with methotrexate monotherapy for 1 year and 70% among those who were kept on the dual regimen, a statistically significant difference.

But other, less stringent measures of disease activity showed fairly good maintenance with methotrexate monotherapy. For example, the percentage of patients at 78 weeks with low disease activity based on a DAS28-CRP score of less than 3.2 was 81% in the methotrexate monotherapy group and 91% among the patients on both active drugs. Of the patients on methotrexate alone, 84% had an SDAI (Simplified Disease Activity Index) of 11 or less at 78 weeks, as did 92% of those on methotrexate plus adalimumab. There was no radiographic progression in 81% of the patients in the monotherapy arm at 78 weeks and in 89% of the patients on both drugs. An ACR 50 (American College of Rheumatology scale showing a 50% improvement) response was recorded at 78 weeks in 80% of patients on methotrexate only and in 89% of patients on methotrexate plus adalimumab.

"On the whole, patients on methotrexate [monotherapy] did extremely well and maintained their responses," Dr. Emery said. These are "the first global, randomized, controlled data on discontinuation of a TNF inhibitor after successful achievement of stable, low disease activity. The data suggest that for a large proportion of very early RA patients, a 26-week course of adalimumab and methotrexate, followed by 52 weeks of methotrexate monotherapy, may be a viable option to allow for the achievement of good outcomes."

The study is funded by Abbott, the company that markets adalimumab (Humira). Dr. Emery said that he has received research support from and has been a consultant to Abbott, Bristol-Myers Squibb, Merck, Pfizer, and Roche.

Unguided intra-articular injection of betamethasone in small and large peripheral joints in patients with early rheumatoid arthritis results in rapid, effective, and long-lasting inflammatory control when used in combination with systemic medication, according to findings from a 2-year "treat to target" study.

Dr. Merete Lund Hetland, an associate professor at the University of Copenhagen and consultant in rheumatology, said in an interview that "unguided intra-articular injections should be used much more in routine care of early RA, not only in the large joints, but also in smaller joints such as proximal interphalangeal and metacarpophalangeal joints.

"The study was a ‘treat-to-target’ study, aiming at complete inflammatory control [that is, no swollen joints] using conventional DMARDs [disease-modifying antirheumatic drugs] together with intra-articular injections with betamethasone," she added.

The results are part of the CIMESTRA (Cyclosporine, Methotrexate, Steroid in RA) trial, which showed that "continuous methotrexate and intra-articular corticosteroid treatment resulted in excellent clinical response and disease control at 2 years, and the radiographic erosive progression was minimal" (Ann. Rheum. Dis. 2008;67:815-22; Arthritis Rheum. 2006;54:1401-9

The study investigated the short- and long-term efficacy of unguided intra-articular injections with betamethasone. Investigators determined the effect of repeated injections on pathology visible on MRI, anti–cyclic citrullinated peptide (anti-CCP) antibodies, and IgM-rheumatoid factor status.

For the study, 160 patients with early RA (duration less than 6 months) received intra-articular betamethasone in a maximum of four swollen joints at each visit. They received the injections at 2-week intervals for 8 weeks, then every 4 weeks in combination with step-up DMARDs during 2 years.

In all, 1,373 unique joints, including wrists, knees, shoulders, ankles, elbows, metacarpophalangeal (MCP) joints, and proximal interphalangeal (PIP) joints, were injected; 531 joints were injected a second time, and 262 a third time.

The patients were treated with methotrexate as monotherapy or in combination with cyclosporine.

Short-term efficacy was assessed by EULAR good-response criteria. Long-term efficacy was assessed by Kaplan-Meier plots of joint-injection survival.

After the first year, 62.3% of the joints that were injected at baseline had not relapsed. After 2 years, 55.5% of the injected joints had not relapsed. All joint areas had good 2-year joint injection survival, which was highest for the PIP joints (73.7%). The 2-year joint response was higher for first injections (56.6%) than for second (43.4%) and third injections (31.3%).

The average total dosage of betamethasone injected after 2 years was 11 mL.

Adverse events were mild and transient, with injections being well tolerated.

A high MRI synovitis score for MCP joints and anti-CCP negativity were associated with poorer joint-injection survival, whereas C-reactive protein and IgM-RF were not, according to the study.

Limitations of the study included the fact that "patients also were treated with DMARDs. Thus, after 6-8 weeks, the effect of DMARD treatment intermingled with the effect of steroids. However, this also reflects real-life practice," said Dr. Hetland.

A new study is underway in which they will investigate "the efficacy of joint injections in patients with early RA receiving TNF [tumor necrosis factor] inhibitor treatment," she added.

"We expect to present 1-year data at the ACR [in Chicago in 2011]."

The study was funded by the Danish Arthritis Foundation. Novartis, Pfizer, and MSD Pharmaceuticals provided study drugs and an independent Good Clinical Practice monitor. Dr. Hetland has received grants and/or honoraria from the Danish Arthritis Association, Abbott, Pfizer, Bristol-Myers Squibb, MSD, UCB, and Roche.

Unguided intra-articular injection of betamethasone in small and large peripheral joints in patients with early rheumatoid arthritis results in rapid, effective, and long-lasting inflammatory control when used in combination with systemic medication, according to findings from a 2-year "treat to target" study.

Dr. Merete Lund Hetland, an associate professor at the University of Copenhagen and consultant in rheumatology, said in an interview that "unguided intra-articular injections should be used much more in routine care of early RA, not only in the large joints, but also in smaller joints such as proximal interphalangeal and metacarpophalangeal joints.

"The study was a ‘treat-to-target’ study, aiming at complete inflammatory control [that is, no swollen joints] using conventional DMARDs [disease-modifying antirheumatic drugs] together with intra-articular injections with betamethasone," she added.

The results are part of the CIMESTRA (Cyclosporine, Methotrexate, Steroid in RA) trial, which showed that "continuous methotrexate and intra-articular corticosteroid treatment resulted in excellent clinical response and disease control at 2 years, and the radiographic erosive progression was minimal" (Ann. Rheum. Dis. 2008;67:815-22; Arthritis Rheum. 2006;54:1401-9

The study investigated the short- and long-term efficacy of unguided intra-articular injections with betamethasone. Investigators determined the effect of repeated injections on pathology visible on MRI, anti–cyclic citrullinated peptide (anti-CCP) antibodies, and IgM-rheumatoid factor status.

For the study, 160 patients with early RA (duration less than 6 months) received intra-articular betamethasone in a maximum of four swollen joints at each visit. They received the injections at 2-week intervals for 8 weeks, then every 4 weeks in combination with step-up DMARDs during 2 years.

In all, 1,373 unique joints, including wrists, knees, shoulders, ankles, elbows, metacarpophalangeal (MCP) joints, and proximal interphalangeal (PIP) joints, were injected; 531 joints were injected a second time, and 262 a third time.

The patients were treated with methotrexate as monotherapy or in combination with cyclosporine.

Short-term efficacy was assessed by EULAR good-response criteria. Long-term efficacy was assessed by Kaplan-Meier plots of joint-injection survival.

After the first year, 62.3% of the joints that were injected at baseline had not relapsed. After 2 years, 55.5% of the injected joints had not relapsed. All joint areas had good 2-year joint injection survival, which was highest for the PIP joints (73.7%). The 2-year joint response was higher for first injections (56.6%) than for second (43.4%) and third injections (31.3%).

The average total dosage of betamethasone injected after 2 years was 11 mL.

Adverse events were mild and transient, with injections being well tolerated.

A high MRI synovitis score for MCP joints and anti-CCP negativity were associated with poorer joint-injection survival, whereas C-reactive protein and IgM-RF were not, according to the study.

Limitations of the study included the fact that "patients also were treated with DMARDs. Thus, after 6-8 weeks, the effect of DMARD treatment intermingled with the effect of steroids. However, this also reflects real-life practice," said Dr. Hetland.

A new study is underway in which they will investigate "the efficacy of joint injections in patients with early RA receiving TNF [tumor necrosis factor] inhibitor treatment," she added.

"We expect to present 1-year data at the ACR [in Chicago in 2011]."

The study was funded by the Danish Arthritis Foundation. Novartis, Pfizer, and MSD Pharmaceuticals provided study drugs and an independent Good Clinical Practice monitor. Dr. Hetland has received grants and/or honoraria from the Danish Arthritis Association, Abbott, Pfizer, Bristol-Myers Squibb, MSD, UCB, and Roche.

Unguided intra-articular injection of betamethasone in small and large peripheral joints in patients with early rheumatoid arthritis results in rapid, effective, and long-lasting inflammatory control when used in combination with systemic medication, according to findings from a 2-year "treat to target" study.

Dr. Merete Lund Hetland, an associate professor at the University of Copenhagen and consultant in rheumatology, said in an interview that "unguided intra-articular injections should be used much more in routine care of early RA, not only in the large joints, but also in smaller joints such as proximal interphalangeal and metacarpophalangeal joints.

"The study was a ‘treat-to-target’ study, aiming at complete inflammatory control [that is, no swollen joints] using conventional DMARDs [disease-modifying antirheumatic drugs] together with intra-articular injections with betamethasone," she added.

The results are part of the CIMESTRA (Cyclosporine, Methotrexate, Steroid in RA) trial, which showed that "continuous methotrexate and intra-articular corticosteroid treatment resulted in excellent clinical response and disease control at 2 years, and the radiographic erosive progression was minimal" (Ann. Rheum. Dis. 2008;67:815-22; Arthritis Rheum. 2006;54:1401-9

The study investigated the short- and long-term efficacy of unguided intra-articular injections with betamethasone. Investigators determined the effect of repeated injections on pathology visible on MRI, anti–cyclic citrullinated peptide (anti-CCP) antibodies, and IgM-rheumatoid factor status.

For the study, 160 patients with early RA (duration less than 6 months) received intra-articular betamethasone in a maximum of four swollen joints at each visit. They received the injections at 2-week intervals for 8 weeks, then every 4 weeks in combination with step-up DMARDs during 2 years.

In all, 1,373 unique joints, including wrists, knees, shoulders, ankles, elbows, metacarpophalangeal (MCP) joints, and proximal interphalangeal (PIP) joints, were injected; 531 joints were injected a second time, and 262 a third time.

The patients were treated with methotrexate as monotherapy or in combination with cyclosporine.

Short-term efficacy was assessed by EULAR good-response criteria. Long-term efficacy was assessed by Kaplan-Meier plots of joint-injection survival.

After the first year, 62.3% of the joints that were injected at baseline had not relapsed. After 2 years, 55.5% of the injected joints had not relapsed. All joint areas had good 2-year joint injection survival, which was highest for the PIP joints (73.7%). The 2-year joint response was higher for first injections (56.6%) than for second (43.4%) and third injections (31.3%).

The average total dosage of betamethasone injected after 2 years was 11 mL.

Adverse events were mild and transient, with injections being well tolerated.

A high MRI synovitis score for MCP joints and anti-CCP negativity were associated with poorer joint-injection survival, whereas C-reactive protein and IgM-RF were not, according to the study.

Limitations of the study included the fact that "patients also were treated with DMARDs. Thus, after 6-8 weeks, the effect of DMARD treatment intermingled with the effect of steroids. However, this also reflects real-life practice," said Dr. Hetland.

A new study is underway in which they will investigate "the efficacy of joint injections in patients with early RA receiving TNF [tumor necrosis factor] inhibitor treatment," she added.

"We expect to present 1-year data at the ACR [in Chicago in 2011]."

The study was funded by the Danish Arthritis Foundation. Novartis, Pfizer, and MSD Pharmaceuticals provided study drugs and an independent Good Clinical Practice monitor. Dr. Hetland has received grants and/or honoraria from the Danish Arthritis Association, Abbott, Pfizer, Bristol-Myers Squibb, MSD, UCB, and Roche.

LONDON – Statin therapy can reverse one of the most important side effects observed in clinical trials of the experimental oral biologic tofacitinib in rheumatoid arthritis, a study has shown.

Concomitant treatment with atorvastatin significantly lessened dyslipidemia observed in a cohort of rheumatoid arthritis patients taking tofacitinib in a phase II trial.

Of 111 rheumatoid arthritis patients enrolled in the study, tofacitinib-treated patients who took atorvastatin (Lipitor) following an open-label lead-in period had a 35% reduction in mean low-density lipoprotein cholesterol (LDL-C) compared with a 5.8% increase observed in tofacitinib-treated patients randomized to concomitant placebo. Those who took atorvastatin had improvements in other lipid measures as well, reported Dr. Iain McInnes of the University of Glasgow (Scotland).

Treatment with tofacitinib, an oral Janus kinase (JAK) inhibitor being investigated as a targeted immunomodulator, has been associated with increases in serum lipids, including LDL and HDL cholesterol and triglycerides in phase II and III rheumatoid arthritis trials, said Dr. McInnes. The same effect is seen with other JAK inhibitors. Certain proinflammatory cytokines have been shown to have an effect on serum lipid levels. Considering the synergy between inflammation and lipid metabolism, "it should be no surprise at all that an agent that modifies inflammation can also cause metabolic changes," he said at the annual European Congress of Rheumatology.

To evaluate whether use of a lipid-lowering drug could safely and effectively modulate lipid increases associated with tofacitinib treatment, Dr. McInnes and his colleagues evaluated the lipid levels of study patients who completed 6 weeks of 10-mg tofacitinib twice daily and were subsequently randomized to an additional 6 weeks of treatment with concomitant atorvastatin or placebo.

From baseline to week 6 of tofacitinib therapy, the average increases for the predominantly female study group (mean age, 52 years) were 185-230 mg/dL for total cholesterol; 109-126 mg/dL for LDL-C; 51-67 mg/dL for high-density lipoprotein cholesterol (HDL-C); 136-165 mg/dL for apolipoprotein A-1; 87-97 mg/dL for apolipoprotein B; and 100-109 mg/dL for triglycerides, Dr. McInnes reported. By week 12, total cholesterol, LDL-C, apolipoprotein B, and triglycerides were significantly decreased in the atorvastatin patients relative to placebo, "to levels below those observed at baseline," he said, while the HDL-C levels increased similarly in both the placebo and atorvastatin groups from week 6 to week 12.

With respect to clinical responses, at week 6, a minimum 20% improvement in American College of Rheumatology criteria (ACR20) was seen in 76% of the study population. "By week 12, 82.6% of the atorvastatin group exhibited an ACR20 response, compared with 65.2% of the placebo group, and 67.4% of the atorvastatin group vs. 45.7% exhibited a minimum 50% improvement in ACR criteria [ACR50)," said Dr. McInnes, who noted that, although the differences in clinical response between the atorvastatin and placebo groups were not statistically significant, the trend toward additional improvements are notable and warrant further study.

In safety analyses, the investigators observed a safety profile similar to that reported in other tofacitinib trials in rheumatoid arthritis, said Dr. McInnes. Specifically, treatment-related adverse events were experienced by 23.4% of the patients during the first 6 weeks of the study, and by 10% of the atorvastatin group and 17% of the placebo group from week 6 to week 12, said Dr. McInnes. Serious adverse events, including pneumonia, occurred in 1.8% of the patients during the open-label phase of the study, he said, noting that none of the atorvastatin patients and 2.1% of the placebo patients experienced serious adverse events between weeks 6 and 12.

"The findings of this study are important in that they demonstrate that any changes in lipids are reversible by addition of a statin," Dr. McInnes said in an interview. "It’s too early to determine how statins and tofacitinib will be used in standard of care. More data are required at this stage."

Dr. Joel Kremer agreed. The chief of medicine at Albany Medical College in New York, Dr. Kremer was the lead investigator of a phase III trial that he reported at the meeting. Data from the phase III trial demonstrated the efficacy of tofacitinib in rheumatoid arthritis patients who failed to respond to treatment with other disease-modifying antirheumatic drugs.

In an interview, Dr. Kremer noted that it’s uncertain whether concurrent lipid-lowering therapy will be considered routine standard of care with tofacitinib in rheumatoid arthritis patients, "but it probably will become quite common, as it is becoming common with Actemra [tocilizumab]."

Dr. McInnes and Dr. Kremer disclosed receiving grant and research support from and serving as consultants for Pfizer.

LONDON – Statin therapy can reverse one of the most important side effects observed in clinical trials of the experimental oral biologic tofacitinib in rheumatoid arthritis, a study has shown.

Concomitant treatment with atorvastatin significantly lessened dyslipidemia observed in a cohort of rheumatoid arthritis patients taking tofacitinib in a phase II trial.

Of 111 rheumatoid arthritis patients enrolled in the study, tofacitinib-treated patients who took atorvastatin (Lipitor) following an open-label lead-in period had a 35% reduction in mean low-density lipoprotein cholesterol (LDL-C) compared with a 5.8% increase observed in tofacitinib-treated patients randomized to concomitant placebo. Those who took atorvastatin had improvements in other lipid measures as well, reported Dr. Iain McInnes of the University of Glasgow (Scotland).

Treatment with tofacitinib, an oral Janus kinase (JAK) inhibitor being investigated as a targeted immunomodulator, has been associated with increases in serum lipids, including LDL and HDL cholesterol and triglycerides in phase II and III rheumatoid arthritis trials, said Dr. McInnes. The same effect is seen with other JAK inhibitors. Certain proinflammatory cytokines have been shown to have an effect on serum lipid levels. Considering the synergy between inflammation and lipid metabolism, "it should be no surprise at all that an agent that modifies inflammation can also cause metabolic changes," he said at the annual European Congress of Rheumatology.

To evaluate whether use of a lipid-lowering drug could safely and effectively modulate lipid increases associated with tofacitinib treatment, Dr. McInnes and his colleagues evaluated the lipid levels of study patients who completed 6 weeks of 10-mg tofacitinib twice daily and were subsequently randomized to an additional 6 weeks of treatment with concomitant atorvastatin or placebo.

From baseline to week 6 of tofacitinib therapy, the average increases for the predominantly female study group (mean age, 52 years) were 185-230 mg/dL for total cholesterol; 109-126 mg/dL for LDL-C; 51-67 mg/dL for high-density lipoprotein cholesterol (HDL-C); 136-165 mg/dL for apolipoprotein A-1; 87-97 mg/dL for apolipoprotein B; and 100-109 mg/dL for triglycerides, Dr. McInnes reported. By week 12, total cholesterol, LDL-C, apolipoprotein B, and triglycerides were significantly decreased in the atorvastatin patients relative to placebo, "to levels below those observed at baseline," he said, while the HDL-C levels increased similarly in both the placebo and atorvastatin groups from week 6 to week 12.

With respect to clinical responses, at week 6, a minimum 20% improvement in American College of Rheumatology criteria (ACR20) was seen in 76% of the study population. "By week 12, 82.6% of the atorvastatin group exhibited an ACR20 response, compared with 65.2% of the placebo group, and 67.4% of the atorvastatin group vs. 45.7% exhibited a minimum 50% improvement in ACR criteria [ACR50)," said Dr. McInnes, who noted that, although the differences in clinical response between the atorvastatin and placebo groups were not statistically significant, the trend toward additional improvements are notable and warrant further study.

In safety analyses, the investigators observed a safety profile similar to that reported in other tofacitinib trials in rheumatoid arthritis, said Dr. McInnes. Specifically, treatment-related adverse events were experienced by 23.4% of the patients during the first 6 weeks of the study, and by 10% of the atorvastatin group and 17% of the placebo group from week 6 to week 12, said Dr. McInnes. Serious adverse events, including pneumonia, occurred in 1.8% of the patients during the open-label phase of the study, he said, noting that none of the atorvastatin patients and 2.1% of the placebo patients experienced serious adverse events between weeks 6 and 12.

"The findings of this study are important in that they demonstrate that any changes in lipids are reversible by addition of a statin," Dr. McInnes said in an interview. "It’s too early to determine how statins and tofacitinib will be used in standard of care. More data are required at this stage."

Dr. Joel Kremer agreed. The chief of medicine at Albany Medical College in New York, Dr. Kremer was the lead investigator of a phase III trial that he reported at the meeting. Data from the phase III trial demonstrated the efficacy of tofacitinib in rheumatoid arthritis patients who failed to respond to treatment with other disease-modifying antirheumatic drugs.

In an interview, Dr. Kremer noted that it’s uncertain whether concurrent lipid-lowering therapy will be considered routine standard of care with tofacitinib in rheumatoid arthritis patients, "but it probably will become quite common, as it is becoming common with Actemra [tocilizumab]."

Dr. McInnes and Dr. Kremer disclosed receiving grant and research support from and serving as consultants for Pfizer.

LONDON – Statin therapy can reverse one of the most important side effects observed in clinical trials of the experimental oral biologic tofacitinib in rheumatoid arthritis, a study has shown.

Concomitant treatment with atorvastatin significantly lessened dyslipidemia observed in a cohort of rheumatoid arthritis patients taking tofacitinib in a phase II trial.

Of 111 rheumatoid arthritis patients enrolled in the study, tofacitinib-treated patients who took atorvastatin (Lipitor) following an open-label lead-in period had a 35% reduction in mean low-density lipoprotein cholesterol (LDL-C) compared with a 5.8% increase observed in tofacitinib-treated patients randomized to concomitant placebo. Those who took atorvastatin had improvements in other lipid measures as well, reported Dr. Iain McInnes of the University of Glasgow (Scotland).

Treatment with tofacitinib, an oral Janus kinase (JAK) inhibitor being investigated as a targeted immunomodulator, has been associated with increases in serum lipids, including LDL and HDL cholesterol and triglycerides in phase II and III rheumatoid arthritis trials, said Dr. McInnes. The same effect is seen with other JAK inhibitors. Certain proinflammatory cytokines have been shown to have an effect on serum lipid levels. Considering the synergy between inflammation and lipid metabolism, "it should be no surprise at all that an agent that modifies inflammation can also cause metabolic changes," he said at the annual European Congress of Rheumatology.

To evaluate whether use of a lipid-lowering drug could safely and effectively modulate lipid increases associated with tofacitinib treatment, Dr. McInnes and his colleagues evaluated the lipid levels of study patients who completed 6 weeks of 10-mg tofacitinib twice daily and were subsequently randomized to an additional 6 weeks of treatment with concomitant atorvastatin or placebo.

From baseline to week 6 of tofacitinib therapy, the average increases for the predominantly female study group (mean age, 52 years) were 185-230 mg/dL for total cholesterol; 109-126 mg/dL for LDL-C; 51-67 mg/dL for high-density lipoprotein cholesterol (HDL-C); 136-165 mg/dL for apolipoprotein A-1; 87-97 mg/dL for apolipoprotein B; and 100-109 mg/dL for triglycerides, Dr. McInnes reported. By week 12, total cholesterol, LDL-C, apolipoprotein B, and triglycerides were significantly decreased in the atorvastatin patients relative to placebo, "to levels below those observed at baseline," he said, while the HDL-C levels increased similarly in both the placebo and atorvastatin groups from week 6 to week 12.

With respect to clinical responses, at week 6, a minimum 20% improvement in American College of Rheumatology criteria (ACR20) was seen in 76% of the study population. "By week 12, 82.6% of the atorvastatin group exhibited an ACR20 response, compared with 65.2% of the placebo group, and 67.4% of the atorvastatin group vs. 45.7% exhibited a minimum 50% improvement in ACR criteria [ACR50)," said Dr. McInnes, who noted that, although the differences in clinical response between the atorvastatin and placebo groups were not statistically significant, the trend toward additional improvements are notable and warrant further study.

In safety analyses, the investigators observed a safety profile similar to that reported in other tofacitinib trials in rheumatoid arthritis, said Dr. McInnes. Specifically, treatment-related adverse events were experienced by 23.4% of the patients during the first 6 weeks of the study, and by 10% of the atorvastatin group and 17% of the placebo group from week 6 to week 12, said Dr. McInnes. Serious adverse events, including pneumonia, occurred in 1.8% of the patients during the open-label phase of the study, he said, noting that none of the atorvastatin patients and 2.1% of the placebo patients experienced serious adverse events between weeks 6 and 12.

"The findings of this study are important in that they demonstrate that any changes in lipids are reversible by addition of a statin," Dr. McInnes said in an interview. "It’s too early to determine how statins and tofacitinib will be used in standard of care. More data are required at this stage."

Dr. Joel Kremer agreed. The chief of medicine at Albany Medical College in New York, Dr. Kremer was the lead investigator of a phase III trial that he reported at the meeting. Data from the phase III trial demonstrated the efficacy of tofacitinib in rheumatoid arthritis patients who failed to respond to treatment with other disease-modifying antirheumatic drugs.

In an interview, Dr. Kremer noted that it’s uncertain whether concurrent lipid-lowering therapy will be considered routine standard of care with tofacitinib in rheumatoid arthritis patients, "but it probably will become quite common, as it is becoming common with Actemra [tocilizumab]."

Dr. McInnes and Dr. Kremer disclosed receiving grant and research support from and serving as consultants for Pfizer.

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 (Rheumatology News, May 2011, p. 1).

"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 rheumatologist 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 (Rheumatology News, May 2011, p. 1).

"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 rheumatologist 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 (Rheumatology News, May 2011, p. 1).

"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 rheumatologist 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.