Rheumatoid Arthritis

Adalimumab therapy was associated with a significant decrease in sperm count in a 35-year-old man who had taken the biologic for 3 years as treatment for ankylosing spondylitis, according to a case report presented in the March issue of Annals of the Rheumatic Diseases.

Anti-tumor necrosis factor (anti-TNF) agents have been used in rheumatology for more than a decade, and few new side effects have been observed, wrote Dr. Lukas M. Wildi and Dr. Boulos Haraoui of the University of Montreal.

The patient was the father of a healthy 4-year-old, but after 3 years of adalimumab treatment he was tested for infertility. A sperm analysis showed a combination of decreased sperm motility and an unusually low sperm count (0.9 million/mL), which led to a diagnosis of oligoasthenozoospermia (Ann. Rheum. Dis. 2012;71:473-4).

No other cause of the problem was identified, and the patient discontinued adalimumab. After 3 months of no treatment, the patient’s sperm count increased to 6 million/mL, but only 1% of the sperm were normal. However, after 6 months, the sperm count increased to 12 million/mL and the sperm morphology reached the normal range (15%), but sperm motility remained below normal (motile concentration of 3.5 million/mL).

The patient’s symptoms of ankylosing spondylitis recurred, and he opted to resume adalimumab therapy after freezing some sperm, the researchers said.

Previous case series have shown similar reductions in sperm count and quality in men taking infliximab, the researchers said, but no impact on fertility was reported.

Additional studies have shown decreased sperm motility in ankylosing spondylitis patients on conventional treatment compared with those on TNF-alpha blockers, the researchers said. "However, in general, male patients also seem to remain fertile under anti-TNF alpha therapy," they said.

"Imbalances in TNF-alpha level, either too high or too low, seem to influence spermatogenesis and may sometimes lead to infertility," the researchers noted. "The present case demonstrates the reversibility of this adverse event after cessation of therapy and raises an issue not frequently discussed with male patients," they said.

The authors had no financial conflicts to disclose.

Adalimumab therapy was associated with a significant decrease in sperm count in a 35-year-old man who had taken the biologic for 3 years as treatment for ankylosing spondylitis, according to a case report presented in the March issue of Annals of the Rheumatic Diseases.

Anti-tumor necrosis factor (anti-TNF) agents have been used in rheumatology for more than a decade, and few new side effects have been observed, wrote Dr. Lukas M. Wildi and Dr. Boulos Haraoui of the University of Montreal.

The patient was the father of a healthy 4-year-old, but after 3 years of adalimumab treatment he was tested for infertility. A sperm analysis showed a combination of decreased sperm motility and an unusually low sperm count (0.9 million/mL), which led to a diagnosis of oligoasthenozoospermia (Ann. Rheum. Dis. 2012;71:473-4).

No other cause of the problem was identified, and the patient discontinued adalimumab. After 3 months of no treatment, the patient’s sperm count increased to 6 million/mL, but only 1% of the sperm were normal. However, after 6 months, the sperm count increased to 12 million/mL and the sperm morphology reached the normal range (15%), but sperm motility remained below normal (motile concentration of 3.5 million/mL).

The patient’s symptoms of ankylosing spondylitis recurred, and he opted to resume adalimumab therapy after freezing some sperm, the researchers said.

Previous case series have shown similar reductions in sperm count and quality in men taking infliximab, the researchers said, but no impact on fertility was reported.

Additional studies have shown decreased sperm motility in ankylosing spondylitis patients on conventional treatment compared with those on TNF-alpha blockers, the researchers said. "However, in general, male patients also seem to remain fertile under anti-TNF alpha therapy," they said.

"Imbalances in TNF-alpha level, either too high or too low, seem to influence spermatogenesis and may sometimes lead to infertility," the researchers noted. "The present case demonstrates the reversibility of this adverse event after cessation of therapy and raises an issue not frequently discussed with male patients," they said.

The authors had no financial conflicts to disclose.

Adalimumab therapy was associated with a significant decrease in sperm count in a 35-year-old man who had taken the biologic for 3 years as treatment for ankylosing spondylitis, according to a case report presented in the March issue of Annals of the Rheumatic Diseases.

Anti-tumor necrosis factor (anti-TNF) agents have been used in rheumatology for more than a decade, and few new side effects have been observed, wrote Dr. Lukas M. Wildi and Dr. Boulos Haraoui of the University of Montreal.

The patient was the father of a healthy 4-year-old, but after 3 years of adalimumab treatment he was tested for infertility. A sperm analysis showed a combination of decreased sperm motility and an unusually low sperm count (0.9 million/mL), which led to a diagnosis of oligoasthenozoospermia (Ann. Rheum. Dis. 2012;71:473-4).

No other cause of the problem was identified, and the patient discontinued adalimumab. After 3 months of no treatment, the patient’s sperm count increased to 6 million/mL, but only 1% of the sperm were normal. However, after 6 months, the sperm count increased to 12 million/mL and the sperm morphology reached the normal range (15%), but sperm motility remained below normal (motile concentration of 3.5 million/mL).

The patient’s symptoms of ankylosing spondylitis recurred, and he opted to resume adalimumab therapy after freezing some sperm, the researchers said.

Previous case series have shown similar reductions in sperm count and quality in men taking infliximab, the researchers said, but no impact on fertility was reported.

Additional studies have shown decreased sperm motility in ankylosing spondylitis patients on conventional treatment compared with those on TNF-alpha blockers, the researchers said. "However, in general, male patients also seem to remain fertile under anti-TNF alpha therapy," they said.

"Imbalances in TNF-alpha level, either too high or too low, seem to influence spermatogenesis and may sometimes lead to infertility," the researchers noted. "The present case demonstrates the reversibility of this adverse event after cessation of therapy and raises an issue not frequently discussed with male patients," they said.

The authors had no financial conflicts to disclose.

WAIKOLOA, HAWAII – Joint pain arising in a patient with psoriasis is by no means necessarily due to psoriatic arthritis.

Psoriasis patients can get osteoarthritis or rheumatoid arthritis, just like individuals without the skin disease. The distribution pattern of affected joints provides a useful guide as to which arthropathy is involved.

Bruce Jancin/Elsevier Global Medical News

"When a patient who’s got psoriasis comes to me and says, ‘I have a tremendous amount of joint pain,’ the first place I look is the heel. Heel involvement doesn’t happen very often in rheumatoid arthritis. If the heel hurts, it’s probable that the patient has dactylitis and some form of psoriatic arthritis," according to Dr. Daniel E. Furst, the Carl M. Pearson professor of rheumatology at the University of California, Los Angeles.

Another useful clue: Psoriatic arthritis often affects the distal phalangeal joints of the fingers and toes, with accompanying characteristic psoriatic nail changes, but it spares the metacarpophalangeal (MCP) joints. In contrast, MCP involvement is a typical feature of rheumatoid arthritis, he explained at the Hawaii Dermatology Seminar sponsored by Skin Disease Education Foundation (SDEF).

"If only we understood why one joint tends to be affected and not another, we would sure know a whole lot more about psoriatic arthritis, and rheumatoid arthritis for that matter," Dr. Furst observed.

Involvement of the distal interphalangeal (DIP) joints is a common feature in osteoarthritis as well as psoriatic arthritis. However, psoriatic arthritis, unlike osteoarthritis, is an inflammatory arthritis. The affected fingers and toes in a patient with psoriatic arthritis often develop a painful, red, warm, sausage-like swelling of the soft tissue on the entire digit.

"If there’s erythema and squishiness when you push on a painful joint, that’s synovitis, not osteoarthritis," the rheumatologist noted.

Also, osteoarthritis has a strong tendency to involve the carpometacarpal joint of the thumb, a site spared in psoriatic arthritis, he continued.

Psoriatic arthritis often first shows up as a monoarticular, asymmetric arthritis of a larger joint, such as the knee, ankle, or wrist. Rheumatoid arthritis tends to come on much stronger.

"In rheumatoid arthritis, it’s frequently all at once. The patient will say, ‘In a week I went from nothing to pain everywhere.’ Not so in psoriatic arthritis," according to Dr. Furst.

Spondyloarthropathy is common in psoriatic arthritis. It often takes the form of a spondylitis characterized by asymmetric thickening and calcification of the longitudinal ligaments of the spine, resulting in asymmetric syndesmophytes on imaging. The result is a painful and/or stiff low back.

Psoriatic arthritis is widely thought of as a rheumatoid factor–negative disease, but that’s not strictly true. Roughly 15% of psoriatic arthritis patients are rheumatoid factor–positive.

Differentiating psoriatic arthritis from other types of arthritis that occur in psoriasis patients is important from a treatment standpoint. Psoriatic arthritis causes much more bony destruction than recognized until fairly recently, twice as much as rheumatoid arthritis by some measures. The nonbiologic disease-modifying antirheumatic drugs are only marginally effective for joint disease in psoriatic arthritis patients, with the exception of leflunomide (Arava), which has fair benefit for the peripheral arthritis but less for the skin disease.

At present, the tumor necrosis factor (TNF) inhibitors are the most effective agents available for peripheral and axial joint disease in psoriatic arthritis. But the response can be less impressive than in patients with psoriasis-only or rheumatoid arthritis. New therapies on the horizon include agents targeting the inflammatory cytokines interleukins-6, -12, and -15, as well as orally administered small molecules that inhibit Janus kinase, spleen tyrosine kinase, TNF-alpha converting enzyme, or mitogen-activated protein kinase.

"There’s a lot of stuff coming down the pike, including new drugs which have mechanisms of action very different from those most extant in psoriasis. Some of it is going to work. But so far we really don’t know which of it will," Dr. Furst said.

He reported that he serves as a consultant to or recipient of research grants from more than a dozen pharmaceutical companies and the National Institutes of Health.

SDEF and this news organization are owned by Elsevier.

WAIKOLOA, HAWAII – Joint pain arising in a patient with psoriasis is by no means necessarily due to psoriatic arthritis.

Psoriasis patients can get osteoarthritis or rheumatoid arthritis, just like individuals without the skin disease. The distribution pattern of affected joints provides a useful guide as to which arthropathy is involved.

Bruce Jancin/Elsevier Global Medical News

"When a patient who’s got psoriasis comes to me and says, ‘I have a tremendous amount of joint pain,’ the first place I look is the heel. Heel involvement doesn’t happen very often in rheumatoid arthritis. If the heel hurts, it’s probable that the patient has dactylitis and some form of psoriatic arthritis," according to Dr. Daniel E. Furst, the Carl M. Pearson professor of rheumatology at the University of California, Los Angeles.

Another useful clue: Psoriatic arthritis often affects the distal phalangeal joints of the fingers and toes, with accompanying characteristic psoriatic nail changes, but it spares the metacarpophalangeal (MCP) joints. In contrast, MCP involvement is a typical feature of rheumatoid arthritis, he explained at the Hawaii Dermatology Seminar sponsored by Skin Disease Education Foundation (SDEF).

"If only we understood why one joint tends to be affected and not another, we would sure know a whole lot more about psoriatic arthritis, and rheumatoid arthritis for that matter," Dr. Furst observed.

Involvement of the distal interphalangeal (DIP) joints is a common feature in osteoarthritis as well as psoriatic arthritis. However, psoriatic arthritis, unlike osteoarthritis, is an inflammatory arthritis. The affected fingers and toes in a patient with psoriatic arthritis often develop a painful, red, warm, sausage-like swelling of the soft tissue on the entire digit.

"If there’s erythema and squishiness when you push on a painful joint, that’s synovitis, not osteoarthritis," the rheumatologist noted.

Also, osteoarthritis has a strong tendency to involve the carpometacarpal joint of the thumb, a site spared in psoriatic arthritis, he continued.

Psoriatic arthritis often first shows up as a monoarticular, asymmetric arthritis of a larger joint, such as the knee, ankle, or wrist. Rheumatoid arthritis tends to come on much stronger.

"In rheumatoid arthritis, it’s frequently all at once. The patient will say, ‘In a week I went from nothing to pain everywhere.’ Not so in psoriatic arthritis," according to Dr. Furst.

Spondyloarthropathy is common in psoriatic arthritis. It often takes the form of a spondylitis characterized by asymmetric thickening and calcification of the longitudinal ligaments of the spine, resulting in asymmetric syndesmophytes on imaging. The result is a painful and/or stiff low back.

Psoriatic arthritis is widely thought of as a rheumatoid factor–negative disease, but that’s not strictly true. Roughly 15% of psoriatic arthritis patients are rheumatoid factor–positive.

Differentiating psoriatic arthritis from other types of arthritis that occur in psoriasis patients is important from a treatment standpoint. Psoriatic arthritis causes much more bony destruction than recognized until fairly recently, twice as much as rheumatoid arthritis by some measures. The nonbiologic disease-modifying antirheumatic drugs are only marginally effective for joint disease in psoriatic arthritis patients, with the exception of leflunomide (Arava), which has fair benefit for the peripheral arthritis but less for the skin disease.

At present, the tumor necrosis factor (TNF) inhibitors are the most effective agents available for peripheral and axial joint disease in psoriatic arthritis. But the response can be less impressive than in patients with psoriasis-only or rheumatoid arthritis. New therapies on the horizon include agents targeting the inflammatory cytokines interleukins-6, -12, and -15, as well as orally administered small molecules that inhibit Janus kinase, spleen tyrosine kinase, TNF-alpha converting enzyme, or mitogen-activated protein kinase.

"There’s a lot of stuff coming down the pike, including new drugs which have mechanisms of action very different from those most extant in psoriasis. Some of it is going to work. But so far we really don’t know which of it will," Dr. Furst said.

He reported that he serves as a consultant to or recipient of research grants from more than a dozen pharmaceutical companies and the National Institutes of Health.

SDEF and this news organization are owned by Elsevier.

WAIKOLOA, HAWAII – Joint pain arising in a patient with psoriasis is by no means necessarily due to psoriatic arthritis.

Psoriasis patients can get osteoarthritis or rheumatoid arthritis, just like individuals without the skin disease. The distribution pattern of affected joints provides a useful guide as to which arthropathy is involved.

Bruce Jancin/Elsevier Global Medical News

"When a patient who’s got psoriasis comes to me and says, ‘I have a tremendous amount of joint pain,’ the first place I look is the heel. Heel involvement doesn’t happen very often in rheumatoid arthritis. If the heel hurts, it’s probable that the patient has dactylitis and some form of psoriatic arthritis," according to Dr. Daniel E. Furst, the Carl M. Pearson professor of rheumatology at the University of California, Los Angeles.

Another useful clue: Psoriatic arthritis often affects the distal phalangeal joints of the fingers and toes, with accompanying characteristic psoriatic nail changes, but it spares the metacarpophalangeal (MCP) joints. In contrast, MCP involvement is a typical feature of rheumatoid arthritis, he explained at the Hawaii Dermatology Seminar sponsored by Skin Disease Education Foundation (SDEF).

"If only we understood why one joint tends to be affected and not another, we would sure know a whole lot more about psoriatic arthritis, and rheumatoid arthritis for that matter," Dr. Furst observed.

Involvement of the distal interphalangeal (DIP) joints is a common feature in osteoarthritis as well as psoriatic arthritis. However, psoriatic arthritis, unlike osteoarthritis, is an inflammatory arthritis. The affected fingers and toes in a patient with psoriatic arthritis often develop a painful, red, warm, sausage-like swelling of the soft tissue on the entire digit.

"If there’s erythema and squishiness when you push on a painful joint, that’s synovitis, not osteoarthritis," the rheumatologist noted.

Also, osteoarthritis has a strong tendency to involve the carpometacarpal joint of the thumb, a site spared in psoriatic arthritis, he continued.

Psoriatic arthritis often first shows up as a monoarticular, asymmetric arthritis of a larger joint, such as the knee, ankle, or wrist. Rheumatoid arthritis tends to come on much stronger.

"In rheumatoid arthritis, it’s frequently all at once. The patient will say, ‘In a week I went from nothing to pain everywhere.’ Not so in psoriatic arthritis," according to Dr. Furst.

Spondyloarthropathy is common in psoriatic arthritis. It often takes the form of a spondylitis characterized by asymmetric thickening and calcification of the longitudinal ligaments of the spine, resulting in asymmetric syndesmophytes on imaging. The result is a painful and/or stiff low back.

Psoriatic arthritis is widely thought of as a rheumatoid factor–negative disease, but that’s not strictly true. Roughly 15% of psoriatic arthritis patients are rheumatoid factor–positive.

Differentiating psoriatic arthritis from other types of arthritis that occur in psoriasis patients is important from a treatment standpoint. Psoriatic arthritis causes much more bony destruction than recognized until fairly recently, twice as much as rheumatoid arthritis by some measures. The nonbiologic disease-modifying antirheumatic drugs are only marginally effective for joint disease in psoriatic arthritis patients, with the exception of leflunomide (Arava), which has fair benefit for the peripheral arthritis but less for the skin disease.

At present, the tumor necrosis factor (TNF) inhibitors are the most effective agents available for peripheral and axial joint disease in psoriatic arthritis. But the response can be less impressive than in patients with psoriasis-only or rheumatoid arthritis. New therapies on the horizon include agents targeting the inflammatory cytokines interleukins-6, -12, and -15, as well as orally administered small molecules that inhibit Janus kinase, spleen tyrosine kinase, TNF-alpha converting enzyme, or mitogen-activated protein kinase.

"There’s a lot of stuff coming down the pike, including new drugs which have mechanisms of action very different from those most extant in psoriasis. Some of it is going to work. But so far we really don’t know which of it will," Dr. Furst said.

He reported that he serves as a consultant to or recipient of research grants from more than a dozen pharmaceutical companies and the National Institutes of Health.

SDEF and this news organization are owned by Elsevier.

An immediate access clinic significantly reduced the wait times for patients seeking rheumatology assessments, based on data from 660 patients seen between February and December 2009. The findings were published in the March issue of Annals of the Rheumatic Diseases.

"The delay from symptom onset to the first visit with a rheumatologist or start of therapy ranges from several months up to more than 1 year," said Dr. Miriam Gärtner of the Medical University of Vienna and her colleagues.

One reason for the delay in care is the lack of rheumatologists, the researchers said. To help get patients started on therapy sooner, an immediate access clinic (IAC) was established, in which patients could be seen within 1 day to 2 weeks of their referral, or seen immediately for a brief evaluation without a referral.

Of 1,036 patients who were assessed in the clinic during the study period, 660 patients were reevaluated 6-12 months after visiting the clinic. The patients were divided into those who were referred for further care in the clinic (331 patients) and those referred for further care outside of the clinic (329 patients). The average age of the patients was 50 years, and the average duration of symptoms was 24 years; the average pain rating on the visual analog scale of 0-100 mm was 54 mm (Ann. Rheum. Dis. 2012;71:363-8).

At a 6- to 12-month follow-up visit, 75% of the initial diagnoses that had been made at the clinic proved to be correct, the researchers said. "This indicates high reliability of these initial categorizations by an experienced rheumatologist, which often have to be made within only a few minutes, compared with a later and mostly ‘criteria-based’ classification," they said.

Of the patients who were referred for follow-up in the clinic, 213 returned for additional care and 118 did not return. Overall, 90% of those who returned for additional care received treatment depending on their diagnoses, with 25%-73% receiving disease-modifying antirheumatic drugs, 1%-25% receiving biologics, *5%-56% receiving glucocorticoids, and 2%-17% receiving physiotherapy. Of those who did not return for additional care (but were contacted later by phone), 38% said they received additional therapy at their initial visit. Of these, 42% received NSAIDs, 16% received biologics, 13% received synthetic DMARDs or physiotherapy, and 4% received glucocorticoids.

Of the 329 who were reached for follow-up after 6-12 months, 60% reported that their medical problems were "fully resolved," whereas approximately 40% said they were receiving additional medical care.

Approximately one-third of the patients were referred to the clinic because of suspected RA, but their median symptom duration of 9 months was beyond the ideal window of opportunity for effective early treatment (which should be within the first 3 months), the researchers noted.

Men were diagnosed with spondyloarthropathy more often than women, whereas women were more often diagnosed with osteoarthritis.

Also, "no difference in the frequency of final diagnosis of an inflammatory rheumatic disease between physician and self-referred individuals was apparent," the researchers said.

The study findings were limited by the potential unreliability of telephone interviews. But the results suggest that the IAC model is effective for reducing wait times for seeing a rheumatologist, and that the majority of the diagnoses made in this setting were accurate, the researchers said.

"Despite the short time of interaction between patient and rheumatologist at the time of the visit to the IAC, complaints about insufficient attention were very rare," the researchers added. "Apparently, patients appreciated the fact that they had an immediate opportunity to discuss their problems with a specialist, albeit for a short time, and to receive an initial diagnostic assessment and therapeutic recommendations," they said.

Dr. Gärtner and colleagues had no financial conflicts to disclose.

* Correction, 3/2/2012: An earlier version of this story incorrectly reported the percentages of returning patients who received glucocorticoids.

An immediate access clinic significantly reduced the wait times for patients seeking rheumatology assessments, based on data from 660 patients seen between February and December 2009. The findings were published in the March issue of Annals of the Rheumatic Diseases.

"The delay from symptom onset to the first visit with a rheumatologist or start of therapy ranges from several months up to more than 1 year," said Dr. Miriam Gärtner of the Medical University of Vienna and her colleagues.

One reason for the delay in care is the lack of rheumatologists, the researchers said. To help get patients started on therapy sooner, an immediate access clinic (IAC) was established, in which patients could be seen within 1 day to 2 weeks of their referral, or seen immediately for a brief evaluation without a referral.

Of 1,036 patients who were assessed in the clinic during the study period, 660 patients were reevaluated 6-12 months after visiting the clinic. The patients were divided into those who were referred for further care in the clinic (331 patients) and those referred for further care outside of the clinic (329 patients). The average age of the patients was 50 years, and the average duration of symptoms was 24 years; the average pain rating on the visual analog scale of 0-100 mm was 54 mm (Ann. Rheum. Dis. 2012;71:363-8).

At a 6- to 12-month follow-up visit, 75% of the initial diagnoses that had been made at the clinic proved to be correct, the researchers said. "This indicates high reliability of these initial categorizations by an experienced rheumatologist, which often have to be made within only a few minutes, compared with a later and mostly ‘criteria-based’ classification," they said.

Of the patients who were referred for follow-up in the clinic, 213 returned for additional care and 118 did not return. Overall, 90% of those who returned for additional care received treatment depending on their diagnoses, with 25%-73% receiving disease-modifying antirheumatic drugs, 1%-25% receiving biologics, *5%-56% receiving glucocorticoids, and 2%-17% receiving physiotherapy. Of those who did not return for additional care (but were contacted later by phone), 38% said they received additional therapy at their initial visit. Of these, 42% received NSAIDs, 16% received biologics, 13% received synthetic DMARDs or physiotherapy, and 4% received glucocorticoids.

Of the 329 who were reached for follow-up after 6-12 months, 60% reported that their medical problems were "fully resolved," whereas approximately 40% said they were receiving additional medical care.

Approximately one-third of the patients were referred to the clinic because of suspected RA, but their median symptom duration of 9 months was beyond the ideal window of opportunity for effective early treatment (which should be within the first 3 months), the researchers noted.

Men were diagnosed with spondyloarthropathy more often than women, whereas women were more often diagnosed with osteoarthritis.

Also, "no difference in the frequency of final diagnosis of an inflammatory rheumatic disease between physician and self-referred individuals was apparent," the researchers said.

The study findings were limited by the potential unreliability of telephone interviews. But the results suggest that the IAC model is effective for reducing wait times for seeing a rheumatologist, and that the majority of the diagnoses made in this setting were accurate, the researchers said.

"Despite the short time of interaction between patient and rheumatologist at the time of the visit to the IAC, complaints about insufficient attention were very rare," the researchers added. "Apparently, patients appreciated the fact that they had an immediate opportunity to discuss their problems with a specialist, albeit for a short time, and to receive an initial diagnostic assessment and therapeutic recommendations," they said.

Dr. Gärtner and colleagues had no financial conflicts to disclose.

* Correction, 3/2/2012: An earlier version of this story incorrectly reported the percentages of returning patients who received glucocorticoids.

An immediate access clinic significantly reduced the wait times for patients seeking rheumatology assessments, based on data from 660 patients seen between February and December 2009. The findings were published in the March issue of Annals of the Rheumatic Diseases.

"The delay from symptom onset to the first visit with a rheumatologist or start of therapy ranges from several months up to more than 1 year," said Dr. Miriam Gärtner of the Medical University of Vienna and her colleagues.

One reason for the delay in care is the lack of rheumatologists, the researchers said. To help get patients started on therapy sooner, an immediate access clinic (IAC) was established, in which patients could be seen within 1 day to 2 weeks of their referral, or seen immediately for a brief evaluation without a referral.

Of 1,036 patients who were assessed in the clinic during the study period, 660 patients were reevaluated 6-12 months after visiting the clinic. The patients were divided into those who were referred for further care in the clinic (331 patients) and those referred for further care outside of the clinic (329 patients). The average age of the patients was 50 years, and the average duration of symptoms was 24 years; the average pain rating on the visual analog scale of 0-100 mm was 54 mm (Ann. Rheum. Dis. 2012;71:363-8).

At a 6- to 12-month follow-up visit, 75% of the initial diagnoses that had been made at the clinic proved to be correct, the researchers said. "This indicates high reliability of these initial categorizations by an experienced rheumatologist, which often have to be made within only a few minutes, compared with a later and mostly ‘criteria-based’ classification," they said.

Of the patients who were referred for follow-up in the clinic, 213 returned for additional care and 118 did not return. Overall, 90% of those who returned for additional care received treatment depending on their diagnoses, with 25%-73% receiving disease-modifying antirheumatic drugs, 1%-25% receiving biologics, *5%-56% receiving glucocorticoids, and 2%-17% receiving physiotherapy. Of those who did not return for additional care (but were contacted later by phone), 38% said they received additional therapy at their initial visit. Of these, 42% received NSAIDs, 16% received biologics, 13% received synthetic DMARDs or physiotherapy, and 4% received glucocorticoids.

Of the 329 who were reached for follow-up after 6-12 months, 60% reported that their medical problems were "fully resolved," whereas approximately 40% said they were receiving additional medical care.

Approximately one-third of the patients were referred to the clinic because of suspected RA, but their median symptom duration of 9 months was beyond the ideal window of opportunity for effective early treatment (which should be within the first 3 months), the researchers noted.

Men were diagnosed with spondyloarthropathy more often than women, whereas women were more often diagnosed with osteoarthritis.

Also, "no difference in the frequency of final diagnosis of an inflammatory rheumatic disease between physician and self-referred individuals was apparent," the researchers said.

The study findings were limited by the potential unreliability of telephone interviews. But the results suggest that the IAC model is effective for reducing wait times for seeing a rheumatologist, and that the majority of the diagnoses made in this setting were accurate, the researchers said.

"Despite the short time of interaction between patient and rheumatologist at the time of the visit to the IAC, complaints about insufficient attention were very rare," the researchers added. "Apparently, patients appreciated the fact that they had an immediate opportunity to discuss their problems with a specialist, albeit for a short time, and to receive an initial diagnostic assessment and therapeutic recommendations," they said.

Dr. Gärtner and colleagues had no financial conflicts to disclose.

* Correction, 3/2/2012: An earlier version of this story incorrectly reported the percentages of returning patients who received glucocorticoids.

SNOWMASS, COLO. – The risk of herpes zoster isn’t raised in rheumatoid arthritis patients who are on a tumor necrosis factor inhibitor, compared with those on nonbiologic disease-modifying antirheumatic drugs, according to a preliminary analysis from by far the largest study to examine the question.

Findings from the same study also suggested that TNF–inhibiting therapy may actually protect against zoster in patients with psoriasis, psoriatic arthritis, ankylosing spondylitis, or inflammatory bowel disease.

Data from two previous, large, population-based studies looking at the risk of herpes zoster in RA patients on anti-TNF biologics reveal discordant conclusions. These conflicting findings prompted Dr. Kevin L. Winthrop and his coinvestigators in the SABER (Safety Assessment of Biologic Therapy) collaboration to examine the issue in their very large data set.

SABER is a retrospective cohort study involving four large U.S. automated health databases. The as-yet-unpublished SABER herpes zoster analysis included more than 35,000 patients with diseases for which TNF inhibitors are indicated.

During 22,215 person-years of follow-up, the crude rate of herpes zoster among RA patients who were new first-time users of an anti-TNF agent was 12.1 cases per 1,000 person-years, which wasn’t significantly different from the 12.8 per 1,000 rate during 7,165 person-years of follow-up in the control group, which comprised RA patients who were failing on methotrexate and adding another conventional DMARD, usually hydroxychloroquine (Plaquenil).

There were no significant differences in zoster rates among the various anti-TNF agents, Dr. Winthrop said at the symposium, which was sponsored by the American College of Rheumatology.

Intriguingly, going on an anti-TNF agent actually appeared to protect against herpes zoster in SABER participants with psoriasis, psoriatic arthritis, or ankylosing spondylitis. During 4,106 person-years of follow-up, their crude rate of zoster was 4.4 cases per 1,000 person-years, an adjusted 36% lower risk than that in patients on a nonbiologic DMARD, whose rate was 6.8 cases per 1,000 person-years during 3,950 person-years of follow-up, according to Dr. Winthrop, an infectious diseases specialist at Oregon Health and Science University, Portland.

Moreover, new users of infliximab or adalimumab for inflammatory bowel disease had an adjusted 20% reduction in risk of zoster, compared with those on azathioprine or 6-mercaptopurine, he added.

An earlier retrospective cohort study involving 20,357 RA patients in the Veterans Affairs health care system found that patients on adalimumab had an adjusted 47% lower risk of zoster, and those on etanercept had a 38% reduction in risk, compared with patients on conventional DMARDs. Patients on infliximab had a 30% increased risk; however, this trend didn’t reach statistical significance (Clin. Infect. Dis. 2009;48:1364-71).

In sharp contrast, investigators from the prospective German RABBIT registry involving 5,040 RA patients reported that adalimumab was associated with a 3-fold increased risk of herpes zoster compared to nonbiologic DMARD therapy. Infliximab had an adjusted 2.4-fold increased risk, which wasn’t statistically significant. Etanercept wasn’t associated with increased risk (JAMA 2009;301:737-44).

The explanation for the discordant findings in RABBIT and the VA study is unclear. The studies did use somewhat different methodologies. Regardless, it’s worth noting that the number of subjects included in the new SABER analysis was larger than for both of the earlier studies put together.

"Look how robust this is," Dr. Winthrop observed. "We have good, good power. Our interpretation is there is no increased risk of zoster with anti-TNF drugs."

Nonetheless, this is a preliminary analysis. The SABER investigators plan to look next at what happened to prednisone dosing when the RA patients went on anti-TNF therapy or an additional nonbiologic DMARD, something they can do with this cohort but couldn’t do in an earlier SABER publication. Dr. Winthrop said he suspects that the prednisone dose was more likely to be reduced or eliminated in the TNF-inhibitor users, and that this might account for the finding that anti-TNF therapy didn’t increase zoster risk. A half-dozen studies have shown that prednisone therapy is associated with an increased risk of herpes zoster.

Dr. Winthrop said it’s his impression that patients who develop herpes zoster while on anti-TNF therapy don’t have a higher rate of disseminated disease or worse outcomes than do those who are not. In the SABER analysis, the rate of hospitalization for zoster was similarly very low in the biologic and nonbiologic treatment groups.

In response to audience questions, he said he believes it makes sense to give herpes zoster vaccine to RA patients starting at 50 years of age. RA per se is a risk factor for zoster, as is prednisone therapy. There is no evidence of any safety issues in vaccinating patients who take any of the standard DMARDs or anti-TNF agents, although there are no definitive data on that score. It’s possible that pharmacologic immunosuppression blunts the vaccine’s efficacy, but that hasn’t been studied.

Dr. Winthrop reported having no financial conflicts.

SNOWMASS, COLO. – The risk of herpes zoster isn’t raised in rheumatoid arthritis patients who are on a tumor necrosis factor inhibitor, compared with those on nonbiologic disease-modifying antirheumatic drugs, according to a preliminary analysis from by far the largest study to examine the question.

Findings from the same study also suggested that TNF–inhibiting therapy may actually protect against zoster in patients with psoriasis, psoriatic arthritis, ankylosing spondylitis, or inflammatory bowel disease.

Data from two previous, large, population-based studies looking at the risk of herpes zoster in RA patients on anti-TNF biologics reveal discordant conclusions. These conflicting findings prompted Dr. Kevin L. Winthrop and his coinvestigators in the SABER (Safety Assessment of Biologic Therapy) collaboration to examine the issue in their very large data set.

SABER is a retrospective cohort study involving four large U.S. automated health databases. The as-yet-unpublished SABER herpes zoster analysis included more than 35,000 patients with diseases for which TNF inhibitors are indicated.

During 22,215 person-years of follow-up, the crude rate of herpes zoster among RA patients who were new first-time users of an anti-TNF agent was 12.1 cases per 1,000 person-years, which wasn’t significantly different from the 12.8 per 1,000 rate during 7,165 person-years of follow-up in the control group, which comprised RA patients who were failing on methotrexate and adding another conventional DMARD, usually hydroxychloroquine (Plaquenil).

There were no significant differences in zoster rates among the various anti-TNF agents, Dr. Winthrop said at the symposium, which was sponsored by the American College of Rheumatology.

Intriguingly, going on an anti-TNF agent actually appeared to protect against herpes zoster in SABER participants with psoriasis, psoriatic arthritis, or ankylosing spondylitis. During 4,106 person-years of follow-up, their crude rate of zoster was 4.4 cases per 1,000 person-years, an adjusted 36% lower risk than that in patients on a nonbiologic DMARD, whose rate was 6.8 cases per 1,000 person-years during 3,950 person-years of follow-up, according to Dr. Winthrop, an infectious diseases specialist at Oregon Health and Science University, Portland.

Moreover, new users of infliximab or adalimumab for inflammatory bowel disease had an adjusted 20% reduction in risk of zoster, compared with those on azathioprine or 6-mercaptopurine, he added.

An earlier retrospective cohort study involving 20,357 RA patients in the Veterans Affairs health care system found that patients on adalimumab had an adjusted 47% lower risk of zoster, and those on etanercept had a 38% reduction in risk, compared with patients on conventional DMARDs. Patients on infliximab had a 30% increased risk; however, this trend didn’t reach statistical significance (Clin. Infect. Dis. 2009;48:1364-71).

In sharp contrast, investigators from the prospective German RABBIT registry involving 5,040 RA patients reported that adalimumab was associated with a 3-fold increased risk of herpes zoster compared to nonbiologic DMARD therapy. Infliximab had an adjusted 2.4-fold increased risk, which wasn’t statistically significant. Etanercept wasn’t associated with increased risk (JAMA 2009;301:737-44).

The explanation for the discordant findings in RABBIT and the VA study is unclear. The studies did use somewhat different methodologies. Regardless, it’s worth noting that the number of subjects included in the new SABER analysis was larger than for both of the earlier studies put together.

"Look how robust this is," Dr. Winthrop observed. "We have good, good power. Our interpretation is there is no increased risk of zoster with anti-TNF drugs."

Nonetheless, this is a preliminary analysis. The SABER investigators plan to look next at what happened to prednisone dosing when the RA patients went on anti-TNF therapy or an additional nonbiologic DMARD, something they can do with this cohort but couldn’t do in an earlier SABER publication. Dr. Winthrop said he suspects that the prednisone dose was more likely to be reduced or eliminated in the TNF-inhibitor users, and that this might account for the finding that anti-TNF therapy didn’t increase zoster risk. A half-dozen studies have shown that prednisone therapy is associated with an increased risk of herpes zoster.

Dr. Winthrop said it’s his impression that patients who develop herpes zoster while on anti-TNF therapy don’t have a higher rate of disseminated disease or worse outcomes than do those who are not. In the SABER analysis, the rate of hospitalization for zoster was similarly very low in the biologic and nonbiologic treatment groups.

In response to audience questions, he said he believes it makes sense to give herpes zoster vaccine to RA patients starting at 50 years of age. RA per se is a risk factor for zoster, as is prednisone therapy. There is no evidence of any safety issues in vaccinating patients who take any of the standard DMARDs or anti-TNF agents, although there are no definitive data on that score. It’s possible that pharmacologic immunosuppression blunts the vaccine’s efficacy, but that hasn’t been studied.

Dr. Winthrop reported having no financial conflicts.

SNOWMASS, COLO. – The risk of herpes zoster isn’t raised in rheumatoid arthritis patients who are on a tumor necrosis factor inhibitor, compared with those on nonbiologic disease-modifying antirheumatic drugs, according to a preliminary analysis from by far the largest study to examine the question.

Findings from the same study also suggested that TNF–inhibiting therapy may actually protect against zoster in patients with psoriasis, psoriatic arthritis, ankylosing spondylitis, or inflammatory bowel disease.

Data from two previous, large, population-based studies looking at the risk of herpes zoster in RA patients on anti-TNF biologics reveal discordant conclusions. These conflicting findings prompted Dr. Kevin L. Winthrop and his coinvestigators in the SABER (Safety Assessment of Biologic Therapy) collaboration to examine the issue in their very large data set.

SABER is a retrospective cohort study involving four large U.S. automated health databases. The as-yet-unpublished SABER herpes zoster analysis included more than 35,000 patients with diseases for which TNF inhibitors are indicated.

During 22,215 person-years of follow-up, the crude rate of herpes zoster among RA patients who were new first-time users of an anti-TNF agent was 12.1 cases per 1,000 person-years, which wasn’t significantly different from the 12.8 per 1,000 rate during 7,165 person-years of follow-up in the control group, which comprised RA patients who were failing on methotrexate and adding another conventional DMARD, usually hydroxychloroquine (Plaquenil).

There were no significant differences in zoster rates among the various anti-TNF agents, Dr. Winthrop said at the symposium, which was sponsored by the American College of Rheumatology.

Intriguingly, going on an anti-TNF agent actually appeared to protect against herpes zoster in SABER participants with psoriasis, psoriatic arthritis, or ankylosing spondylitis. During 4,106 person-years of follow-up, their crude rate of zoster was 4.4 cases per 1,000 person-years, an adjusted 36% lower risk than that in patients on a nonbiologic DMARD, whose rate was 6.8 cases per 1,000 person-years during 3,950 person-years of follow-up, according to Dr. Winthrop, an infectious diseases specialist at Oregon Health and Science University, Portland.

Moreover, new users of infliximab or adalimumab for inflammatory bowel disease had an adjusted 20% reduction in risk of zoster, compared with those on azathioprine or 6-mercaptopurine, he added.

An earlier retrospective cohort study involving 20,357 RA patients in the Veterans Affairs health care system found that patients on adalimumab had an adjusted 47% lower risk of zoster, and those on etanercept had a 38% reduction in risk, compared with patients on conventional DMARDs. Patients on infliximab had a 30% increased risk; however, this trend didn’t reach statistical significance (Clin. Infect. Dis. 2009;48:1364-71).

In sharp contrast, investigators from the prospective German RABBIT registry involving 5,040 RA patients reported that adalimumab was associated with a 3-fold increased risk of herpes zoster compared to nonbiologic DMARD therapy. Infliximab had an adjusted 2.4-fold increased risk, which wasn’t statistically significant. Etanercept wasn’t associated with increased risk (JAMA 2009;301:737-44).

The explanation for the discordant findings in RABBIT and the VA study is unclear. The studies did use somewhat different methodologies. Regardless, it’s worth noting that the number of subjects included in the new SABER analysis was larger than for both of the earlier studies put together.

"Look how robust this is," Dr. Winthrop observed. "We have good, good power. Our interpretation is there is no increased risk of zoster with anti-TNF drugs."

Nonetheless, this is a preliminary analysis. The SABER investigators plan to look next at what happened to prednisone dosing when the RA patients went on anti-TNF therapy or an additional nonbiologic DMARD, something they can do with this cohort but couldn’t do in an earlier SABER publication. Dr. Winthrop said he suspects that the prednisone dose was more likely to be reduced or eliminated in the TNF-inhibitor users, and that this might account for the finding that anti-TNF therapy didn’t increase zoster risk. A half-dozen studies have shown that prednisone therapy is associated with an increased risk of herpes zoster.

Dr. Winthrop said it’s his impression that patients who develop herpes zoster while on anti-TNF therapy don’t have a higher rate of disseminated disease or worse outcomes than do those who are not. In the SABER analysis, the rate of hospitalization for zoster was similarly very low in the biologic and nonbiologic treatment groups.

In response to audience questions, he said he believes it makes sense to give herpes zoster vaccine to RA patients starting at 50 years of age. RA per se is a risk factor for zoster, as is prednisone therapy. There is no evidence of any safety issues in vaccinating patients who take any of the standard DMARDs or anti-TNF agents, although there are no definitive data on that score. It’s possible that pharmacologic immunosuppression blunts the vaccine’s efficacy, but that hasn’t been studied.

Dr. Winthrop reported having no financial conflicts.

SNOWMASS, COLO. – A recent, much-ballyhooed, large, observational U.S. study that revised downward the risk of serious infections posed by tumor necrosis factor–alpha inhibitor therapy may have rendered false comfort to prescribing physicians.

The findings of the U.S. multicenter Safety Assessment of Biologic Therapy study (SABER) were roundly celebrated by many rheumatologists, dermatologists, and gastroenterologists who prescribe biologic agents for autoimmune diseases. But the SABER results are strikingly out of step with those of many large, well-conducted patient registries.

Moreover, at least one SABER organizer is skeptical about the validity of the study’s key conclusion that the serious infection risk in patients who’ve started on anti-TNF therapy isn’t significantly different than the risk in those started on methotrexate or another nonbiologic disease-modifying antirheumatic drug (DMARD). He cautioned against taking that conclusion as a lesson from SABER.

"Actually, my belief is that most of our findings in SABER are explained by the fact that anti-TNF agents are prednisone-sparing drugs," Dr. Kevin L. Winthrop said at the symposium, which was sponsored by the American College of Rheumatology. "My belief is that anti-TNF drugs do increase the risk of serious bacterial infections. The fact that they allow people to decrease their prednisone may result in roughly a canceling out of that risk."

SABER was a retrospective cohort study combining data from four large U.S. automated health databases. Investigators were able to compare outcomes in 16,022 patients with rheumatoid arthritis (RA), psoriasis, psoriatic arthritis, ankylosing spondylitis, or inflammatory bowel disease (IBD) who were placed on an anti-TNF biologic vs. an equal number of matched patients who were started on a conventional DMARD.

The rate of serious infections requiring hospitalization during the first year after starting therapy – while impressively high – didn’t differ significantly between the two groups: roughly 8% per year in the RA patients regardless of whether they were on anti-TNF therapy or a conventional DMARD, 5.4% in those with psoriasis or spondyloarthropathies, and 10% in patients with IBD (JAMA 2011;306:2331-9).

But SABER had a major limitation: Data on prednisone use were collected for the year before the new therapy was introduced, but not after, noted Dr. Winthrop, an infectious disease specialist at Oregon Health and Science University, Portland.

"When you put someone on a biologic, you do a lot of things for that person differently than when you put someone on, say, Plaquenil [hydroxychloroquine]. You screen them for tuberculosis, you may counsel them, you give them vaccines, hopefully you decrease their prednisone, and you may even take off some methotrexate if they have good disease control. All of that probably happens to a much greater extent in the biologic arm than the nonbiologic arm," he explained.

Although infliximab was associated with a 23%-26% higher risk of serious infection compared with adalimumab or etanercept in SABER participants with RA, patients on infliximab were also more likely to concurrently be on methotrexate. "That might have been enough to explain this risk difference," according to Dr. Winthrop.

Unlike the SABER findings, a significantly elevated serious infection risk in association with RA patients receiving anti-TNF agents has been reported from the British Society for Rheumatology registry (Arthritis Rheum. 2006;54:2368-76), from a Japanese prospective registry (J. Rheumatol. 2011;38:1258-64), from the CORONNA (Consortium of Rheumatology Researchers of North American) registry (Ann. Rheum. Dis. 2010;69:380-6), and from the German RABBIT registry (Ann. Rheum. Dis. 2011;70:1914-20).

These studies generally showed a time-dependent decline in infection risk in patients treated with anti-TNF agents. But physicians shouldn’t assume that this apparent drop off in risk over time is a real phenomenon; rather, it is largely due to what epidemiologists call survivor bias. In other words, people who develop serious infections or other problems early on drop out of treatment, so the case mix in the registries changes, he explained.

Dr. Winthrop was particularly impressed with what he termed the "very elegant" 5,044-patient RABBIT study, which was designed to be able to answer the question SABER couldn’t – namely, what happens to prednisone dosing when patients go on a TNF inhibitor? The answer, as was well documented in RABBIT, is that the use of prednisone drastically decreases.

Moreover, the German investigators, using a multivariate analysis, identified a set of independent risk factors for serious infection. These included treatment with a TNF inhibitor, which was associated with a 1.8-fold increased risk, compared with conventional DMARDS; treatment with glucocorticoids at 7.5-14 mg/day during the study period, which had a 2.1-fold risk; and treatment with steroids at 15 mg/day or more, which conferred a 4.7-fold increased risk of infection. Other studies have also demonstrated that glucocorticoids convey a high and dose-dependent risk of serious infection.

A key lesson of both RABBIT and SABER is that much of the increased serious infection risk stems from comorbid conditions. The RABBIT investigators identified three additional risk factors: chronic lung disease, chronic kidney disease, and age older than 60 years. RA patients who had these three additional risk factors and were on at least 15 mg/day of prednisone had a serious infection rate of 45% per year if they were on an anti-TNF agent and 25% per year when on a conventional DMARD. If they had two additional risk factors rather than three, their serious infection risk dropped to less than 20% per year on anti-TNF therapy, and about half that on a conventional DMARD.

In contrast, patients with all three additional risk factors who were on less than 7.5 mg/day of prednisone or none at all had a serious infection rate below 10% per year if they were on a TNF inhibitor, and 5% if on a nonbiologic DMARD, Dr. Winthrop noted.

Similarly, SABER participants with chronic obstructive pulmonary disease at baseline had an absolute two- to threefold greater risk of serious infection on a TNF inhibitor or DMARD, compared with patients without COPD. Baseline diabetes mellitus also magnified the serious infection risk in SABER, although not in RABBIT, he continued.

The RABBIT investigators found that improvement in functional capacity resulting from effective treatment significantly reduced the risk of serious infections. Indeed, functional improvement had a greater impact on infection risk than did improvement in the DAS28 (disease activity score based upon a 28-joint count).

SABER was funded by the Food and Drug Administration, the Agency for Healthcare Research and Quality, and the Department of Health and Human Services.

Dr. Winthrop reported having received consultant fees from Abbott, Amgen, and Pfizer as well as research funding from Pfizer.

SNOWMASS, COLO. – A recent, much-ballyhooed, large, observational U.S. study that revised downward the risk of serious infections posed by tumor necrosis factor–alpha inhibitor therapy may have rendered false comfort to prescribing physicians.

The findings of the U.S. multicenter Safety Assessment of Biologic Therapy study (SABER) were roundly celebrated by many rheumatologists, dermatologists, and gastroenterologists who prescribe biologic agents for autoimmune diseases. But the SABER results are strikingly out of step with those of many large, well-conducted patient registries.

Moreover, at least one SABER organizer is skeptical about the validity of the study’s key conclusion that the serious infection risk in patients who’ve started on anti-TNF therapy isn’t significantly different than the risk in those started on methotrexate or another nonbiologic disease-modifying antirheumatic drug (DMARD). He cautioned against taking that conclusion as a lesson from SABER.

"Actually, my belief is that most of our findings in SABER are explained by the fact that anti-TNF agents are prednisone-sparing drugs," Dr. Kevin L. Winthrop said at the symposium, which was sponsored by the American College of Rheumatology. "My belief is that anti-TNF drugs do increase the risk of serious bacterial infections. The fact that they allow people to decrease their prednisone may result in roughly a canceling out of that risk."

SABER was a retrospective cohort study combining data from four large U.S. automated health databases. Investigators were able to compare outcomes in 16,022 patients with rheumatoid arthritis (RA), psoriasis, psoriatic arthritis, ankylosing spondylitis, or inflammatory bowel disease (IBD) who were placed on an anti-TNF biologic vs. an equal number of matched patients who were started on a conventional DMARD.

The rate of serious infections requiring hospitalization during the first year after starting therapy – while impressively high – didn’t differ significantly between the two groups: roughly 8% per year in the RA patients regardless of whether they were on anti-TNF therapy or a conventional DMARD, 5.4% in those with psoriasis or spondyloarthropathies, and 10% in patients with IBD (JAMA 2011;306:2331-9).

But SABER had a major limitation: Data on prednisone use were collected for the year before the new therapy was introduced, but not after, noted Dr. Winthrop, an infectious disease specialist at Oregon Health and Science University, Portland.

"When you put someone on a biologic, you do a lot of things for that person differently than when you put someone on, say, Plaquenil [hydroxychloroquine]. You screen them for tuberculosis, you may counsel them, you give them vaccines, hopefully you decrease their prednisone, and you may even take off some methotrexate if they have good disease control. All of that probably happens to a much greater extent in the biologic arm than the nonbiologic arm," he explained.

Although infliximab was associated with a 23%-26% higher risk of serious infection compared with adalimumab or etanercept in SABER participants with RA, patients on infliximab were also more likely to concurrently be on methotrexate. "That might have been enough to explain this risk difference," according to Dr. Winthrop.

Unlike the SABER findings, a significantly elevated serious infection risk in association with RA patients receiving anti-TNF agents has been reported from the British Society for Rheumatology registry (Arthritis Rheum. 2006;54:2368-76), from a Japanese prospective registry (J. Rheumatol. 2011;38:1258-64), from the CORONNA (Consortium of Rheumatology Researchers of North American) registry (Ann. Rheum. Dis. 2010;69:380-6), and from the German RABBIT registry (Ann. Rheum. Dis. 2011;70:1914-20).

These studies generally showed a time-dependent decline in infection risk in patients treated with anti-TNF agents. But physicians shouldn’t assume that this apparent drop off in risk over time is a real phenomenon; rather, it is largely due to what epidemiologists call survivor bias. In other words, people who develop serious infections or other problems early on drop out of treatment, so the case mix in the registries changes, he explained.

Dr. Winthrop was particularly impressed with what he termed the "very elegant" 5,044-patient RABBIT study, which was designed to be able to answer the question SABER couldn’t – namely, what happens to prednisone dosing when patients go on a TNF inhibitor? The answer, as was well documented in RABBIT, is that the use of prednisone drastically decreases.

Moreover, the German investigators, using a multivariate analysis, identified a set of independent risk factors for serious infection. These included treatment with a TNF inhibitor, which was associated with a 1.8-fold increased risk, compared with conventional DMARDS; treatment with glucocorticoids at 7.5-14 mg/day during the study period, which had a 2.1-fold risk; and treatment with steroids at 15 mg/day or more, which conferred a 4.7-fold increased risk of infection. Other studies have also demonstrated that glucocorticoids convey a high and dose-dependent risk of serious infection.

A key lesson of both RABBIT and SABER is that much of the increased serious infection risk stems from comorbid conditions. The RABBIT investigators identified three additional risk factors: chronic lung disease, chronic kidney disease, and age older than 60 years. RA patients who had these three additional risk factors and were on at least 15 mg/day of prednisone had a serious infection rate of 45% per year if they were on an anti-TNF agent and 25% per year when on a conventional DMARD. If they had two additional risk factors rather than three, their serious infection risk dropped to less than 20% per year on anti-TNF therapy, and about half that on a conventional DMARD.

In contrast, patients with all three additional risk factors who were on less than 7.5 mg/day of prednisone or none at all had a serious infection rate below 10% per year if they were on a TNF inhibitor, and 5% if on a nonbiologic DMARD, Dr. Winthrop noted.

Similarly, SABER participants with chronic obstructive pulmonary disease at baseline had an absolute two- to threefold greater risk of serious infection on a TNF inhibitor or DMARD, compared with patients without COPD. Baseline diabetes mellitus also magnified the serious infection risk in SABER, although not in RABBIT, he continued.

The RABBIT investigators found that improvement in functional capacity resulting from effective treatment significantly reduced the risk of serious infections. Indeed, functional improvement had a greater impact on infection risk than did improvement in the DAS28 (disease activity score based upon a 28-joint count).

SABER was funded by the Food and Drug Administration, the Agency for Healthcare Research and Quality, and the Department of Health and Human Services.

Dr. Winthrop reported having received consultant fees from Abbott, Amgen, and Pfizer as well as research funding from Pfizer.

SNOWMASS, COLO. – A recent, much-ballyhooed, large, observational U.S. study that revised downward the risk of serious infections posed by tumor necrosis factor–alpha inhibitor therapy may have rendered false comfort to prescribing physicians.

The findings of the U.S. multicenter Safety Assessment of Biologic Therapy study (SABER) were roundly celebrated by many rheumatologists, dermatologists, and gastroenterologists who prescribe biologic agents for autoimmune diseases. But the SABER results are strikingly out of step with those of many large, well-conducted patient registries.

Moreover, at least one SABER organizer is skeptical about the validity of the study’s key conclusion that the serious infection risk in patients who’ve started on anti-TNF therapy isn’t significantly different than the risk in those started on methotrexate or another nonbiologic disease-modifying antirheumatic drug (DMARD). He cautioned against taking that conclusion as a lesson from SABER.

"Actually, my belief is that most of our findings in SABER are explained by the fact that anti-TNF agents are prednisone-sparing drugs," Dr. Kevin L. Winthrop said at the symposium, which was sponsored by the American College of Rheumatology. "My belief is that anti-TNF drugs do increase the risk of serious bacterial infections. The fact that they allow people to decrease their prednisone may result in roughly a canceling out of that risk."

SABER was a retrospective cohort study combining data from four large U.S. automated health databases. Investigators were able to compare outcomes in 16,022 patients with rheumatoid arthritis (RA), psoriasis, psoriatic arthritis, ankylosing spondylitis, or inflammatory bowel disease (IBD) who were placed on an anti-TNF biologic vs. an equal number of matched patients who were started on a conventional DMARD.

The rate of serious infections requiring hospitalization during the first year after starting therapy – while impressively high – didn’t differ significantly between the two groups: roughly 8% per year in the RA patients regardless of whether they were on anti-TNF therapy or a conventional DMARD, 5.4% in those with psoriasis or spondyloarthropathies, and 10% in patients with IBD (JAMA 2011;306:2331-9).

But SABER had a major limitation: Data on prednisone use were collected for the year before the new therapy was introduced, but not after, noted Dr. Winthrop, an infectious disease specialist at Oregon Health and Science University, Portland.

"When you put someone on a biologic, you do a lot of things for that person differently than when you put someone on, say, Plaquenil [hydroxychloroquine]. You screen them for tuberculosis, you may counsel them, you give them vaccines, hopefully you decrease their prednisone, and you may even take off some methotrexate if they have good disease control. All of that probably happens to a much greater extent in the biologic arm than the nonbiologic arm," he explained.

Although infliximab was associated with a 23%-26% higher risk of serious infection compared with adalimumab or etanercept in SABER participants with RA, patients on infliximab were also more likely to concurrently be on methotrexate. "That might have been enough to explain this risk difference," according to Dr. Winthrop.

Unlike the SABER findings, a significantly elevated serious infection risk in association with RA patients receiving anti-TNF agents has been reported from the British Society for Rheumatology registry (Arthritis Rheum. 2006;54:2368-76), from a Japanese prospective registry (J. Rheumatol. 2011;38:1258-64), from the CORONNA (Consortium of Rheumatology Researchers of North American) registry (Ann. Rheum. Dis. 2010;69:380-6), and from the German RABBIT registry (Ann. Rheum. Dis. 2011;70:1914-20).

These studies generally showed a time-dependent decline in infection risk in patients treated with anti-TNF agents. But physicians shouldn’t assume that this apparent drop off in risk over time is a real phenomenon; rather, it is largely due to what epidemiologists call survivor bias. In other words, people who develop serious infections or other problems early on drop out of treatment, so the case mix in the registries changes, he explained.

Dr. Winthrop was particularly impressed with what he termed the "very elegant" 5,044-patient RABBIT study, which was designed to be able to answer the question SABER couldn’t – namely, what happens to prednisone dosing when patients go on a TNF inhibitor? The answer, as was well documented in RABBIT, is that the use of prednisone drastically decreases.

Moreover, the German investigators, using a multivariate analysis, identified a set of independent risk factors for serious infection. These included treatment with a TNF inhibitor, which was associated with a 1.8-fold increased risk, compared with conventional DMARDS; treatment with glucocorticoids at 7.5-14 mg/day during the study period, which had a 2.1-fold risk; and treatment with steroids at 15 mg/day or more, which conferred a 4.7-fold increased risk of infection. Other studies have also demonstrated that glucocorticoids convey a high and dose-dependent risk of serious infection.

A key lesson of both RABBIT and SABER is that much of the increased serious infection risk stems from comorbid conditions. The RABBIT investigators identified three additional risk factors: chronic lung disease, chronic kidney disease, and age older than 60 years. RA patients who had these three additional risk factors and were on at least 15 mg/day of prednisone had a serious infection rate of 45% per year if they were on an anti-TNF agent and 25% per year when on a conventional DMARD. If they had two additional risk factors rather than three, their serious infection risk dropped to less than 20% per year on anti-TNF therapy, and about half that on a conventional DMARD.

In contrast, patients with all three additional risk factors who were on less than 7.5 mg/day of prednisone or none at all had a serious infection rate below 10% per year if they were on a TNF inhibitor, and 5% if on a nonbiologic DMARD, Dr. Winthrop noted.

Similarly, SABER participants with chronic obstructive pulmonary disease at baseline had an absolute two- to threefold greater risk of serious infection on a TNF inhibitor or DMARD, compared with patients without COPD. Baseline diabetes mellitus also magnified the serious infection risk in SABER, although not in RABBIT, he continued.

The RABBIT investigators found that improvement in functional capacity resulting from effective treatment significantly reduced the risk of serious infections. Indeed, functional improvement had a greater impact on infection risk than did improvement in the DAS28 (disease activity score based upon a 28-joint count).

SABER was funded by the Food and Drug Administration, the Agency for Healthcare Research and Quality, and the Department of Health and Human Services.

Dr. Winthrop reported having received consultant fees from Abbott, Amgen, and Pfizer as well as research funding from Pfizer.

SNOWMASS, COLO. – Rheumatoid arthritis patients on tumor necrosis factor inhibitors are at markedly increased risk for both tuberculosis and nontuberculous mycobacterial lung disease, as highlighted in data not yet published from Kaiser Permanente of Northern California that was discussed by investigator Dr. Kevin L. Winthrop at the symposium.

The crude incidence rate of nontuberculous mycobacterial disease in this 3.1-million-member health plan during the study years of 2000-2008 was 4.1 cases/100,000 person-years. The risk rose with age such that among plan members aged 50 years or older the rate was 11.8 cases/100,000 person-years. Plan members with rheumatoid arthritis (RA) who’d never been on a tumor necrosis factor (TNF) inhibitor had a moderately higher rate of 19.2 cases/100,000 person-years, probably because of their use of prednisone. But among 8,418 RA patients on TNF inhibitor therapy, the incidence of nontuberculous mycobacterial pulmonary disease shot up to 112 cases/100,000 person-years.

The tuberculosis incidence followed a similar pattern: 2.8 cases/100,000 person-years among the general Kaiser membership, 5.2 in those aged 50 years or older, 8.7 in RA patients never exposed to a TNF inhibitor, jumping to 56 cases/100,000 person-years among RA patients on an anti-TNF biologic, according to Dr. Winthrop.

In light of these data, physicians need to be on the lookout for nontuberculous mycobacterial pulmonary disease arising in RA patients using a TNF inhibitor.

"You will have patients with this. It’s best to diagnose them early, if possible, and get them off their biologic and also limit or discontinue prednisone," said Dr. Winthrop, an infectious diseases specialist at Oregon Health and Science University, Portland.

It’s his clinical impression, as well as that of other physicians participating in the Infectious Diseases Society of America’s Emerging Infections Network, that people who develop nontuberculous mycobacterial lung disease while on a TNF inhibitor tend to experience more rapid progression of their lung disease, he said at the meeting.

He and his coinvestigators at Kaiser also examined the pulmonary disease rates associated with individual TNF inhibitors. The nontuberculous mycobacterial lung disease rate in patients on etanercept was 35 cases/100,000 person-years of exposure, significantly less than the 116 cases/100,000 person-years with infliximab or 122 with adalimumab.

Similarly, the tuberculosis rate was lowest with etanercept at 17 cases/100,000 person-years as compared to 83 with infliximab and 61 with adalimumab.

The Kaiser experience confirms a 2010 report from the British Society for Rheumatology biologic registry that provided the first solid epidemiologic data showing that TNF inhibitors carry an increased tuberculosis risk. In the U.K. study, etanercept use was associated with a tuberculosis incidence of 39 cases per 100,000 person-years, significantly lower than the 136 cases per 100,000 person-years with infliximab or 144 with adalimumab. In contrast, the tuberculosis rate among more than 3,200 RA patients on a conventional disease-modifying anti-rheumatic drug was zero. The background tuberculosis incidence in the United Kingdom during that time period was about 12 cases/100,000 person-years (Ann. Rheum. Dis. 2010;69:522-8).

"I’m convinced that the monoclonal antibody TNF inhibitors [infliximab and adalimumab] cause more tuberculosis than [does] etanercept. I’m not convinced I know why," Dr. Winthrop admitted.

Numerous potential mechanisms have been floated to explain this differential effect. The two he finds most plausible are that etanercept is less able to penetrate tuberculosis granulomas than are the monoclonal antibody TNF inhibitors, as shown in a mouse model, and the possibility – as yet unproven – that etanercept might also cause less downregulation of CD8 cells producing the antimicrobial peptides perforin and granulysin, which are directed against Mycobacterium tuberculosis.

Dr. Winthrop said the epidemiology of nontuberculous mycobacterial pulmonary disease is changing. Decades ago, it was viewed as a disease of elderly men. As the incidence has climbed during the past 2 decades, however, the disease has come to be recognized as mainly one of postmenopausal women, typically with no history of underlying lung disease or smoking. The phenotype is one of an elderly woman who is tall, slender, and underweight, often with mitral valve prolapse, scoliosis, or pectus defects.

In a large study conducted at four geographically diverse large health plans, the annual prevalence of nontuberculous mycobacterial lung disease among persons age 60 years or older rose from 19.6 cases/100,000 in 1994-1996 to 26.7 cases/100,000 person-years in 2004-2006, a rate two- to threefold greater than the prevalence of tuberculosis at those sites during 2004-2006 (Am. J. Respir. Crit. Care Med. 2010;182:970-6).

Nontuberculous mycobacteria are ubiquitous in tap water and soil. Unlike tuberculosis, which is spread from person to person by coughing, nontuberculous mycobacterial infections are acquired directly from the environment.

Dr. Winthrop said he is reluctant to recommend resuming biologic therapy after a RA patient has been treated for nontuberculous mycobacterial lung disease or coccidioidomycosis.

Dr. Winthrop reported having received consultant fees from Abbott, Amgen, and Pfizer as well as research funding from Pfizer.

SNOWMASS, COLO. – Rheumatoid arthritis patients on tumor necrosis factor inhibitors are at markedly increased risk for both tuberculosis and nontuberculous mycobacterial lung disease, as highlighted in data not yet published from Kaiser Permanente of Northern California that was discussed by investigator Dr. Kevin L. Winthrop at the symposium.

The crude incidence rate of nontuberculous mycobacterial disease in this 3.1-million-member health plan during the study years of 2000-2008 was 4.1 cases/100,000 person-years. The risk rose with age such that among plan members aged 50 years or older the rate was 11.8 cases/100,000 person-years. Plan members with rheumatoid arthritis (RA) who’d never been on a tumor necrosis factor (TNF) inhibitor had a moderately higher rate of 19.2 cases/100,000 person-years, probably because of their use of prednisone. But among 8,418 RA patients on TNF inhibitor therapy, the incidence of nontuberculous mycobacterial pulmonary disease shot up to 112 cases/100,000 person-years.

The tuberculosis incidence followed a similar pattern: 2.8 cases/100,000 person-years among the general Kaiser membership, 5.2 in those aged 50 years or older, 8.7 in RA patients never exposed to a TNF inhibitor, jumping to 56 cases/100,000 person-years among RA patients on an anti-TNF biologic, according to Dr. Winthrop.

In light of these data, physicians need to be on the lookout for nontuberculous mycobacterial pulmonary disease arising in RA patients using a TNF inhibitor.

"You will have patients with this. It’s best to diagnose them early, if possible, and get them off their biologic and also limit or discontinue prednisone," said Dr. Winthrop, an infectious diseases specialist at Oregon Health and Science University, Portland.

It’s his clinical impression, as well as that of other physicians participating in the Infectious Diseases Society of America’s Emerging Infections Network, that people who develop nontuberculous mycobacterial lung disease while on a TNF inhibitor tend to experience more rapid progression of their lung disease, he said at the meeting.

He and his coinvestigators at Kaiser also examined the pulmonary disease rates associated with individual TNF inhibitors. The nontuberculous mycobacterial lung disease rate in patients on etanercept was 35 cases/100,000 person-years of exposure, significantly less than the 116 cases/100,000 person-years with infliximab or 122 with adalimumab.

Similarly, the tuberculosis rate was lowest with etanercept at 17 cases/100,000 person-years as compared to 83 with infliximab and 61 with adalimumab.

The Kaiser experience confirms a 2010 report from the British Society for Rheumatology biologic registry that provided the first solid epidemiologic data showing that TNF inhibitors carry an increased tuberculosis risk. In the U.K. study, etanercept use was associated with a tuberculosis incidence of 39 cases per 100,000 person-years, significantly lower than the 136 cases per 100,000 person-years with infliximab or 144 with adalimumab. In contrast, the tuberculosis rate among more than 3,200 RA patients on a conventional disease-modifying anti-rheumatic drug was zero. The background tuberculosis incidence in the United Kingdom during that time period was about 12 cases/100,000 person-years (Ann. Rheum. Dis. 2010;69:522-8).

"I’m convinced that the monoclonal antibody TNF inhibitors [infliximab and adalimumab] cause more tuberculosis than [does] etanercept. I’m not convinced I know why," Dr. Winthrop admitted.

Numerous potential mechanisms have been floated to explain this differential effect. The two he finds most plausible are that etanercept is less able to penetrate tuberculosis granulomas than are the monoclonal antibody TNF inhibitors, as shown in a mouse model, and the possibility – as yet unproven – that etanercept might also cause less downregulation of CD8 cells producing the antimicrobial peptides perforin and granulysin, which are directed against Mycobacterium tuberculosis.

Dr. Winthrop said the epidemiology of nontuberculous mycobacterial pulmonary disease is changing. Decades ago, it was viewed as a disease of elderly men. As the incidence has climbed during the past 2 decades, however, the disease has come to be recognized as mainly one of postmenopausal women, typically with no history of underlying lung disease or smoking. The phenotype is one of an elderly woman who is tall, slender, and underweight, often with mitral valve prolapse, scoliosis, or pectus defects.

In a large study conducted at four geographically diverse large health plans, the annual prevalence of nontuberculous mycobacterial lung disease among persons age 60 years or older rose from 19.6 cases/100,000 in 1994-1996 to 26.7 cases/100,000 person-years in 2004-2006, a rate two- to threefold greater than the prevalence of tuberculosis at those sites during 2004-2006 (Am. J. Respir. Crit. Care Med. 2010;182:970-6).

Nontuberculous mycobacteria are ubiquitous in tap water and soil. Unlike tuberculosis, which is spread from person to person by coughing, nontuberculous mycobacterial infections are acquired directly from the environment.

Dr. Winthrop said he is reluctant to recommend resuming biologic therapy after a RA patient has been treated for nontuberculous mycobacterial lung disease or coccidioidomycosis.

Dr. Winthrop reported having received consultant fees from Abbott, Amgen, and Pfizer as well as research funding from Pfizer.

SNOWMASS, COLO. – Rheumatoid arthritis patients on tumor necrosis factor inhibitors are at markedly increased risk for both tuberculosis and nontuberculous mycobacterial lung disease, as highlighted in data not yet published from Kaiser Permanente of Northern California that was discussed by investigator Dr. Kevin L. Winthrop at the symposium.

The crude incidence rate of nontuberculous mycobacterial disease in this 3.1-million-member health plan during the study years of 2000-2008 was 4.1 cases/100,000 person-years. The risk rose with age such that among plan members aged 50 years or older the rate was 11.8 cases/100,000 person-years. Plan members with rheumatoid arthritis (RA) who’d never been on a tumor necrosis factor (TNF) inhibitor had a moderately higher rate of 19.2 cases/100,000 person-years, probably because of their use of prednisone. But among 8,418 RA patients on TNF inhibitor therapy, the incidence of nontuberculous mycobacterial pulmonary disease shot up to 112 cases/100,000 person-years.

The tuberculosis incidence followed a similar pattern: 2.8 cases/100,000 person-years among the general Kaiser membership, 5.2 in those aged 50 years or older, 8.7 in RA patients never exposed to a TNF inhibitor, jumping to 56 cases/100,000 person-years among RA patients on an anti-TNF biologic, according to Dr. Winthrop.

In light of these data, physicians need to be on the lookout for nontuberculous mycobacterial pulmonary disease arising in RA patients using a TNF inhibitor.

"You will have patients with this. It’s best to diagnose them early, if possible, and get them off their biologic and also limit or discontinue prednisone," said Dr. Winthrop, an infectious diseases specialist at Oregon Health and Science University, Portland.

It’s his clinical impression, as well as that of other physicians participating in the Infectious Diseases Society of America’s Emerging Infections Network, that people who develop nontuberculous mycobacterial lung disease while on a TNF inhibitor tend to experience more rapid progression of their lung disease, he said at the meeting.

He and his coinvestigators at Kaiser also examined the pulmonary disease rates associated with individual TNF inhibitors. The nontuberculous mycobacterial lung disease rate in patients on etanercept was 35 cases/100,000 person-years of exposure, significantly less than the 116 cases/100,000 person-years with infliximab or 122 with adalimumab.

Similarly, the tuberculosis rate was lowest with etanercept at 17 cases/100,000 person-years as compared to 83 with infliximab and 61 with adalimumab.

The Kaiser experience confirms a 2010 report from the British Society for Rheumatology biologic registry that provided the first solid epidemiologic data showing that TNF inhibitors carry an increased tuberculosis risk. In the U.K. study, etanercept use was associated with a tuberculosis incidence of 39 cases per 100,000 person-years, significantly lower than the 136 cases per 100,000 person-years with infliximab or 144 with adalimumab. In contrast, the tuberculosis rate among more than 3,200 RA patients on a conventional disease-modifying anti-rheumatic drug was zero. The background tuberculosis incidence in the United Kingdom during that time period was about 12 cases/100,000 person-years (Ann. Rheum. Dis. 2010;69:522-8).

"I’m convinced that the monoclonal antibody TNF inhibitors [infliximab and adalimumab] cause more tuberculosis than [does] etanercept. I’m not convinced I know why," Dr. Winthrop admitted.

Numerous potential mechanisms have been floated to explain this differential effect. The two he finds most plausible are that etanercept is less able to penetrate tuberculosis granulomas than are the monoclonal antibody TNF inhibitors, as shown in a mouse model, and the possibility – as yet unproven – that etanercept might also cause less downregulation of CD8 cells producing the antimicrobial peptides perforin and granulysin, which are directed against Mycobacterium tuberculosis.

Dr. Winthrop said the epidemiology of nontuberculous mycobacterial pulmonary disease is changing. Decades ago, it was viewed as a disease of elderly men. As the incidence has climbed during the past 2 decades, however, the disease has come to be recognized as mainly one of postmenopausal women, typically with no history of underlying lung disease or smoking. The phenotype is one of an elderly woman who is tall, slender, and underweight, often with mitral valve prolapse, scoliosis, or pectus defects.

In a large study conducted at four geographically diverse large health plans, the annual prevalence of nontuberculous mycobacterial lung disease among persons age 60 years or older rose from 19.6 cases/100,000 in 1994-1996 to 26.7 cases/100,000 person-years in 2004-2006, a rate two- to threefold greater than the prevalence of tuberculosis at those sites during 2004-2006 (Am. J. Respir. Crit. Care Med. 2010;182:970-6).

Nontuberculous mycobacteria are ubiquitous in tap water and soil. Unlike tuberculosis, which is spread from person to person by coughing, nontuberculous mycobacterial infections are acquired directly from the environment.

Dr. Winthrop said he is reluctant to recommend resuming biologic therapy after a RA patient has been treated for nontuberculous mycobacterial lung disease or coccidioidomycosis.

Dr. Winthrop reported having received consultant fees from Abbott, Amgen, and Pfizer as well as research funding from Pfizer.

Unguided intra-articular betamethasone injections provide rapid and enduring control of inflammation in both small and large peripheral joints when used as a component of a treat-to-target strategy in patients with early rheumatoid arthritis, according to findings from the randomized, placebo-controlled trial.

The findings are among the first to systematically demonstrate efficacy and feasibility of intra-articular glucocorticoid injections when used in combination with disease-modifying antirheumatic drugs (DMARDs) in the setting of early rheumatoid arthritis (RA), Dr. Merete Lund Hetland of Copenhagen University Hospital and her colleagues wrote in a report published online in the Feb. 1 issue of Annals of Rheumatic Diseases.

The 160 DMARD-naive patients who participated in the CIMESTRA (Ciclosporin, Methotrexate, Steroid in RA) study had early active RA of less than 6 months duration. They were randomized to receive either 7.5 mg-20 mg of methotrexate weekly plus 2.5 mg/kg per day of ciclosporin or methotrexate plus placebo-ciclosporin. Both groups were given intra-articular injections of 7 mg/mL of betamethasone in up to four swollen joints at baseline and at weeks 2, 4, 6, and 8, and then every 4 weeks thereafter for up to 2 years. Since the combination and monotherapy groups had similar clinical and radiographic outcomes, as well as a similar number of injections and cumulative betamethasone dose after 5 years, data from both treatment arms were pooled for the current analysis.

A total of 2,166 injections were given, including 1,373 first injections, 531 second injections, and 262 third injections. The median dose of betamethasone decreased from 28 mg at baseline to 0 mg at the following visits, and the cumulative dose after 2 years was 77 mg, which corresponds to less than 1 mg prednisolone daily. The median cumulative number of injections per patient was 13.

Within 2 weeks of the initial joint injections, the median 28-joint count Disease Activity Score (DAS28) had decreased from 5.5 to 3. By 6 weeks, the DAS28 had decreased to 2.6, the investigators wrote (Ann. Rheum. Dis. 2012 Feb. 1[doi:10.1136/annrheumdis-2011-200632]).

"Thus, the median number of swollen and tender joints had decreased sharply to 0 and 3, respectively, and remained low. By weeks 2, 4, and 6, respectively, 50%, 58.1%, and 61.7% of patients had achieved a good EULAR response, and 39%, 42%, and 47% were in DAS28 remission," they said.

The injections also provided good long-term efficacy. After 1 and 2 years, 62.3% and 55.5%, respectively, of the swollen joints injected at baseline had not relapsed.

An analysis by joint area showed that benefits of joint injection persisted at 2 years was 51.2% for elbows, 60.1% for ankles, 54.8% for wrists, 55.3% for knees, 52.3% for metacarpophalangeal (MCP) joints, 53.6% for metatarsophalangeal (MTP) joints, 49.5% for shoulders, and 73.7% for proximal interphalangeal (PIP) joints. Persistence of join injection benefits was significantly higher for first-time injections.

For example, the 1-year survival was 63.6% for first-time injections, compared with 48.7% and 32.4% for second and third injections, respectively. The 2-year survival for first-time injections was 56.6%, compared with 43.4% and 31.3% for second and third injections, respectively.

Both the magnetic resonance imaging synovitis score of MCP joints and anticyclic citrullinated peptide (anti-CCP) positivity each were significantly associated with persistence of joint injection benefits (hazard ratios, 1.078 per synovitis score unit, and 0.661, respectively). The anti-CCP finding "may reflect the emerging pattern of different pathogenesis and treatment responses in anti-CCP–positive and –negative disease," the investigators noted, adding: "The increased joint injection survival in our anti-CCP–positive patients with RA may indicate that the local immunosuppressive effect of joint injections targets specific processes in these patients. To this end, it is of particular interest that antibodies against citrullinated proteins seem locally to enhance the inflammatory process in experimental murine autoimmune arthritis."

In contract, serum C-reactive protein and immunoglobulin M–rheumatoid factor (IgM-RF) were not associated with persistence of joint injection benefits in this study, they noted.

Patients in CIMESTRA had at least two swollen joints at baseline and had not received glucocorticoid treatment within 4 weeks prior to enrollment. All patients received calcium and vitamin D supplementation, and those with a Z score of less than 0 in the femoral neck or lumbar spine also received 10 mg/day of alendronate.

Treatment was well tolerated. No cases of septic arthritis or aseptic necrosis occurred. One patient had a spontaneous spinal fracture, but other adverse events occurred only rarely and were mild and transient.

The findings indicate that unguided intra-articular injections of betamethasone in patients with early RA result in rapid, effective, and long-lasting inflammatory control in both small and large peripheral joints and that these injections are a well tolerated component in a treatment strategy aimed at remission, the investigators said.

Rheumatologists should consider including such injections in combination with aggressive DMARD treatment as part of a treat to target strategy in patients with early RA, they concluded.

The CIMESTRA study was supported by a grant from the Danish Rheumatism Association. Novartis Healthcare Denmark A/S provided ciclosporin and placebo-ciclosporin and sponsored an independent good clinical practice monitor. Nycomed provided methotrexate, folic acid and calcium/vitamin D. Schering-Plough provided injectable betamethasone. Merck Sharp and Dohme provided alendronate. The authors had no individual disclosures to report.

Unguided intra-articular betamethasone injections provide rapid and enduring control of inflammation in both small and large peripheral joints when used as a component of a treat-to-target strategy in patients with early rheumatoid arthritis, according to findings from the randomized, placebo-controlled trial.

The findings are among the first to systematically demonstrate efficacy and feasibility of intra-articular glucocorticoid injections when used in combination with disease-modifying antirheumatic drugs (DMARDs) in the setting of early rheumatoid arthritis (RA), Dr. Merete Lund Hetland of Copenhagen University Hospital and her colleagues wrote in a report published online in the Feb. 1 issue of Annals of Rheumatic Diseases.

The 160 DMARD-naive patients who participated in the CIMESTRA (Ciclosporin, Methotrexate, Steroid in RA) study had early active RA of less than 6 months duration. They were randomized to receive either 7.5 mg-20 mg of methotrexate weekly plus 2.5 mg/kg per day of ciclosporin or methotrexate plus placebo-ciclosporin. Both groups were given intra-articular injections of 7 mg/mL of betamethasone in up to four swollen joints at baseline and at weeks 2, 4, 6, and 8, and then every 4 weeks thereafter for up to 2 years. Since the combination and monotherapy groups had similar clinical and radiographic outcomes, as well as a similar number of injections and cumulative betamethasone dose after 5 years, data from both treatment arms were pooled for the current analysis.

A total of 2,166 injections were given, including 1,373 first injections, 531 second injections, and 262 third injections. The median dose of betamethasone decreased from 28 mg at baseline to 0 mg at the following visits, and the cumulative dose after 2 years was 77 mg, which corresponds to less than 1 mg prednisolone daily. The median cumulative number of injections per patient was 13.

Within 2 weeks of the initial joint injections, the median 28-joint count Disease Activity Score (DAS28) had decreased from 5.5 to 3. By 6 weeks, the DAS28 had decreased to 2.6, the investigators wrote (Ann. Rheum. Dis. 2012 Feb. 1[doi:10.1136/annrheumdis-2011-200632]).

"Thus, the median number of swollen and tender joints had decreased sharply to 0 and 3, respectively, and remained low. By weeks 2, 4, and 6, respectively, 50%, 58.1%, and 61.7% of patients had achieved a good EULAR response, and 39%, 42%, and 47% were in DAS28 remission," they said.

The injections also provided good long-term efficacy. After 1 and 2 years, 62.3% and 55.5%, respectively, of the swollen joints injected at baseline had not relapsed.

An analysis by joint area showed that benefits of joint injection persisted at 2 years was 51.2% for elbows, 60.1% for ankles, 54.8% for wrists, 55.3% for knees, 52.3% for metacarpophalangeal (MCP) joints, 53.6% for metatarsophalangeal (MTP) joints, 49.5% for shoulders, and 73.7% for proximal interphalangeal (PIP) joints. Persistence of join injection benefits was significantly higher for first-time injections.

For example, the 1-year survival was 63.6% for first-time injections, compared with 48.7% and 32.4% for second and third injections, respectively. The 2-year survival for first-time injections was 56.6%, compared with 43.4% and 31.3% for second and third injections, respectively.

Both the magnetic resonance imaging synovitis score of MCP joints and anticyclic citrullinated peptide (anti-CCP) positivity each were significantly associated with persistence of joint injection benefits (hazard ratios, 1.078 per synovitis score unit, and 0.661, respectively). The anti-CCP finding "may reflect the emerging pattern of different pathogenesis and treatment responses in anti-CCP–positive and –negative disease," the investigators noted, adding: "The increased joint injection survival in our anti-CCP–positive patients with RA may indicate that the local immunosuppressive effect of joint injections targets specific processes in these patients. To this end, it is of particular interest that antibodies against citrullinated proteins seem locally to enhance the inflammatory process in experimental murine autoimmune arthritis."

In contract, serum C-reactive protein and immunoglobulin M–rheumatoid factor (IgM-RF) were not associated with persistence of joint injection benefits in this study, they noted.

Patients in CIMESTRA had at least two swollen joints at baseline and had not received glucocorticoid treatment within 4 weeks prior to enrollment. All patients received calcium and vitamin D supplementation, and those with a Z score of less than 0 in the femoral neck or lumbar spine also received 10 mg/day of alendronate.

Treatment was well tolerated. No cases of septic arthritis or aseptic necrosis occurred. One patient had a spontaneous spinal fracture, but other adverse events occurred only rarely and were mild and transient.

The findings indicate that unguided intra-articular injections of betamethasone in patients with early RA result in rapid, effective, and long-lasting inflammatory control in both small and large peripheral joints and that these injections are a well tolerated component in a treatment strategy aimed at remission, the investigators said.

Rheumatologists should consider including such injections in combination with aggressive DMARD treatment as part of a treat to target strategy in patients with early RA, they concluded.

The CIMESTRA study was supported by a grant from the Danish Rheumatism Association. Novartis Healthcare Denmark A/S provided ciclosporin and placebo-ciclosporin and sponsored an independent good clinical practice monitor. Nycomed provided methotrexate, folic acid and calcium/vitamin D. Schering-Plough provided injectable betamethasone. Merck Sharp and Dohme provided alendronate. The authors had no individual disclosures to report.

Unguided intra-articular betamethasone injections provide rapid and enduring control of inflammation in both small and large peripheral joints when used as a component of a treat-to-target strategy in patients with early rheumatoid arthritis, according to findings from the randomized, placebo-controlled trial.

The findings are among the first to systematically demonstrate efficacy and feasibility of intra-articular glucocorticoid injections when used in combination with disease-modifying antirheumatic drugs (DMARDs) in the setting of early rheumatoid arthritis (RA), Dr. Merete Lund Hetland of Copenhagen University Hospital and her colleagues wrote in a report published online in the Feb. 1 issue of Annals of Rheumatic Diseases.

The 160 DMARD-naive patients who participated in the CIMESTRA (Ciclosporin, Methotrexate, Steroid in RA) study had early active RA of less than 6 months duration. They were randomized to receive either 7.5 mg-20 mg of methotrexate weekly plus 2.5 mg/kg per day of ciclosporin or methotrexate plus placebo-ciclosporin. Both groups were given intra-articular injections of 7 mg/mL of betamethasone in up to four swollen joints at baseline and at weeks 2, 4, 6, and 8, and then every 4 weeks thereafter for up to 2 years. Since the combination and monotherapy groups had similar clinical and radiographic outcomes, as well as a similar number of injections and cumulative betamethasone dose after 5 years, data from both treatment arms were pooled for the current analysis.

A total of 2,166 injections were given, including 1,373 first injections, 531 second injections, and 262 third injections. The median dose of betamethasone decreased from 28 mg at baseline to 0 mg at the following visits, and the cumulative dose after 2 years was 77 mg, which corresponds to less than 1 mg prednisolone daily. The median cumulative number of injections per patient was 13.

Within 2 weeks of the initial joint injections, the median 28-joint count Disease Activity Score (DAS28) had decreased from 5.5 to 3. By 6 weeks, the DAS28 had decreased to 2.6, the investigators wrote (Ann. Rheum. Dis. 2012 Feb. 1[doi:10.1136/annrheumdis-2011-200632]).

"Thus, the median number of swollen and tender joints had decreased sharply to 0 and 3, respectively, and remained low. By weeks 2, 4, and 6, respectively, 50%, 58.1%, and 61.7% of patients had achieved a good EULAR response, and 39%, 42%, and 47% were in DAS28 remission," they said.

The injections also provided good long-term efficacy. After 1 and 2 years, 62.3% and 55.5%, respectively, of the swollen joints injected at baseline had not relapsed.

An analysis by joint area showed that benefits of joint injection persisted at 2 years was 51.2% for elbows, 60.1% for ankles, 54.8% for wrists, 55.3% for knees, 52.3% for metacarpophalangeal (MCP) joints, 53.6% for metatarsophalangeal (MTP) joints, 49.5% for shoulders, and 73.7% for proximal interphalangeal (PIP) joints. Persistence of join injection benefits was significantly higher for first-time injections.

For example, the 1-year survival was 63.6% for first-time injections, compared with 48.7% and 32.4% for second and third injections, respectively. The 2-year survival for first-time injections was 56.6%, compared with 43.4% and 31.3% for second and third injections, respectively.

Both the magnetic resonance imaging synovitis score of MCP joints and anticyclic citrullinated peptide (anti-CCP) positivity each were significantly associated with persistence of joint injection benefits (hazard ratios, 1.078 per synovitis score unit, and 0.661, respectively). The anti-CCP finding "may reflect the emerging pattern of different pathogenesis and treatment responses in anti-CCP–positive and –negative disease," the investigators noted, adding: "The increased joint injection survival in our anti-CCP–positive patients with RA may indicate that the local immunosuppressive effect of joint injections targets specific processes in these patients. To this end, it is of particular interest that antibodies against citrullinated proteins seem locally to enhance the inflammatory process in experimental murine autoimmune arthritis."

In contract, serum C-reactive protein and immunoglobulin M–rheumatoid factor (IgM-RF) were not associated with persistence of joint injection benefits in this study, they noted.

Patients in CIMESTRA had at least two swollen joints at baseline and had not received glucocorticoid treatment within 4 weeks prior to enrollment. All patients received calcium and vitamin D supplementation, and those with a Z score of less than 0 in the femoral neck or lumbar spine also received 10 mg/day of alendronate.

Treatment was well tolerated. No cases of septic arthritis or aseptic necrosis occurred. One patient had a spontaneous spinal fracture, but other adverse events occurred only rarely and were mild and transient.

The findings indicate that unguided intra-articular injections of betamethasone in patients with early RA result in rapid, effective, and long-lasting inflammatory control in both small and large peripheral joints and that these injections are a well tolerated component in a treatment strategy aimed at remission, the investigators said.

Rheumatologists should consider including such injections in combination with aggressive DMARD treatment as part of a treat to target strategy in patients with early RA, they concluded.

The CIMESTRA study was supported by a grant from the Danish Rheumatism Association. Novartis Healthcare Denmark A/S provided ciclosporin and placebo-ciclosporin and sponsored an independent good clinical practice monitor. Nycomed provided methotrexate, folic acid and calcium/vitamin D. Schering-Plough provided injectable betamethasone. Merck Sharp and Dohme provided alendronate. The authors had no individual disclosures to report.

Joint replacement surgery continues to become less common in patients with rheumatoid arthritis, probably reflecting the widespread adoption of disease modifying antirheumatic drugs, judging from findings of a population-based study published in this month’s Journal of Rheumatology.

Previous studies have found a trend for declining rates of joint surgery in patients with RA since 1985. In this study, "we examined whether the prior sex differences and use trends in reduced surgical intervention for RA persist in patients diagnosed after 1995, and evaluated the effect of RA surgery on survival in these patients," wrote Dr. Courtney A. Shourt and her associates from the Mayo Clinic in Rochester, Minn. (J. Rheumatol. 2012 Jan. 15 [doi:10.3899/jrheum.111056]).

"The possible contribution of RA-related joint surgery to excess mortality in patients with RA is largely unexplored," they pointed out.

A retrospective medical record review was performed using data from the Rochester Epidemiology Project (www.rochesterproject.org). The researchers reviewed records from a population-based cohort of 813 adult residents of Olmsted County, Minn., who had incident RA between Jan. 1, 1980, and Dec. 31, 2007. All cases were followed longitudinally until Dec. 31, 2008; death; or migration out of the county.

All joint surgeries were marginally associated with mortality (hazard ratio, 1.3; 95% confidence interval, 0.96-1.8; P = .09), but joint reconstructive procedures (JRPs) showed a significant association with mortality, adjusted for known RA mortality risk factors, compared with findings in patients not requiring JRP (HR, 2.8; 95% CI, 1.9-4.1; P less than .001). "The need for joint replacement surgery is still a marker of bad disease," commented Dr. Eric L. Matteson, professor of medicine and chair of rheumatology at the Mayo Clinic, in an interview.

The proportion of patients undergoing RA-related surgeries dropped between the two time periods of 1980-94 and 1995-2007. Of the 813 Olmsted County residents in the analysis, 189 underwent at least one surgical procedure involving joints, during a mean follow up of 9.6 years. The cumulative incidence of any joint surgery at 10 years after RA incidence for the 1980-94 cohort was 27.3%, compared with 19.5% for the 1995-2007 cohort (P = 0.08), which was not statistically significant.

More aggressive use of effective DMARDs with a reduction in the progression of radiographic joint damage was suggested as a possible reason for the decline in surgical procedures. "These findings reveal that modern medical management strategy has had markedly beneficial effects on the disease course," with less damage to the target small- and medium-size joints such as the hands, wrists, and feet than in past decades, noted Dr. Matteson, one of the report’s authors.

The greatest reduction in surgeries was seen in soft tissue procedures (synovectomy, tendon repair, tendon transfer, meniscus repair, ligament release, and/or cartilage repair). These decreased from 12% in 1980-94 to 6% in 1995-2007 at 10 years after RA incidence (P = .012).

No differences were found in the cumulative incidence of total hip arthroplasty (P = .77) or total knee arthroplasty (P = .18) between the time periods, reported the authors. Addressing the continued need for surgery on weight-bearing joints, particularly total knee and total hip arthroplasties, Dr. Matteson added, "in this respect patients are beginning to be more like people from the general population who have hip and knee replacements for osteoarthritis."

Study coinvestigator Cynthia Crowson of the Mayo Clinic’s biostatistics division noted in an interview that "persons with RA are requiring fewer surgeries, which may indicate [that] current management strategies are leading to less disability among patients who have developed RA since 1995" compared with previous times.

The study was supported by a grant from the National Institutes of Health, and was made possible by the Rochester Epidemiology Project. The authors reported having no financial disclosures.

Joint replacement surgery continues to become less common in patients with rheumatoid arthritis, probably reflecting the widespread adoption of disease modifying antirheumatic drugs, judging from findings of a population-based study published in this month’s Journal of Rheumatology.

Previous studies have found a trend for declining rates of joint surgery in patients with RA since 1985. In this study, "we examined whether the prior sex differences and use trends in reduced surgical intervention for RA persist in patients diagnosed after 1995, and evaluated the effect of RA surgery on survival in these patients," wrote Dr. Courtney A. Shourt and her associates from the Mayo Clinic in Rochester, Minn. (J. Rheumatol. 2012 Jan. 15 [doi:10.3899/jrheum.111056]).

"The possible contribution of RA-related joint surgery to excess mortality in patients with RA is largely unexplored," they pointed out.

A retrospective medical record review was performed using data from the Rochester Epidemiology Project (www.rochesterproject.org). The researchers reviewed records from a population-based cohort of 813 adult residents of Olmsted County, Minn., who had incident RA between Jan. 1, 1980, and Dec. 31, 2007. All cases were followed longitudinally until Dec. 31, 2008; death; or migration out of the county.

All joint surgeries were marginally associated with mortality (hazard ratio, 1.3; 95% confidence interval, 0.96-1.8; P = .09), but joint reconstructive procedures (JRPs) showed a significant association with mortality, adjusted for known RA mortality risk factors, compared with findings in patients not requiring JRP (HR, 2.8; 95% CI, 1.9-4.1; P less than .001). "The need for joint replacement surgery is still a marker of bad disease," commented Dr. Eric L. Matteson, professor of medicine and chair of rheumatology at the Mayo Clinic, in an interview.

The proportion of patients undergoing RA-related surgeries dropped between the two time periods of 1980-94 and 1995-2007. Of the 813 Olmsted County residents in the analysis, 189 underwent at least one surgical procedure involving joints, during a mean follow up of 9.6 years. The cumulative incidence of any joint surgery at 10 years after RA incidence for the 1980-94 cohort was 27.3%, compared with 19.5% for the 1995-2007 cohort (P = 0.08), which was not statistically significant.

More aggressive use of effective DMARDs with a reduction in the progression of radiographic joint damage was suggested as a possible reason for the decline in surgical procedures. "These findings reveal that modern medical management strategy has had markedly beneficial effects on the disease course," with less damage to the target small- and medium-size joints such as the hands, wrists, and feet than in past decades, noted Dr. Matteson, one of the report’s authors.

The greatest reduction in surgeries was seen in soft tissue procedures (synovectomy, tendon repair, tendon transfer, meniscus repair, ligament release, and/or cartilage repair). These decreased from 12% in 1980-94 to 6% in 1995-2007 at 10 years after RA incidence (P = .012).

No differences were found in the cumulative incidence of total hip arthroplasty (P = .77) or total knee arthroplasty (P = .18) between the time periods, reported the authors. Addressing the continued need for surgery on weight-bearing joints, particularly total knee and total hip arthroplasties, Dr. Matteson added, "in this respect patients are beginning to be more like people from the general population who have hip and knee replacements for osteoarthritis."

Study coinvestigator Cynthia Crowson of the Mayo Clinic’s biostatistics division noted in an interview that "persons with RA are requiring fewer surgeries, which may indicate [that] current management strategies are leading to less disability among patients who have developed RA since 1995" compared with previous times.

The study was supported by a grant from the National Institutes of Health, and was made possible by the Rochester Epidemiology Project. The authors reported having no financial disclosures.

Joint replacement surgery continues to become less common in patients with rheumatoid arthritis, probably reflecting the widespread adoption of disease modifying antirheumatic drugs, judging from findings of a population-based study published in this month’s Journal of Rheumatology.

Previous studies have found a trend for declining rates of joint surgery in patients with RA since 1985. In this study, "we examined whether the prior sex differences and use trends in reduced surgical intervention for RA persist in patients diagnosed after 1995, and evaluated the effect of RA surgery on survival in these patients," wrote Dr. Courtney A. Shourt and her associates from the Mayo Clinic in Rochester, Minn. (J. Rheumatol. 2012 Jan. 15 [doi:10.3899/jrheum.111056]).

"The possible contribution of RA-related joint surgery to excess mortality in patients with RA is largely unexplored," they pointed out.

A retrospective medical record review was performed using data from the Rochester Epidemiology Project (www.rochesterproject.org). The researchers reviewed records from a population-based cohort of 813 adult residents of Olmsted County, Minn., who had incident RA between Jan. 1, 1980, and Dec. 31, 2007. All cases were followed longitudinally until Dec. 31, 2008; death; or migration out of the county.

All joint surgeries were marginally associated with mortality (hazard ratio, 1.3; 95% confidence interval, 0.96-1.8; P = .09), but joint reconstructive procedures (JRPs) showed a significant association with mortality, adjusted for known RA mortality risk factors, compared with findings in patients not requiring JRP (HR, 2.8; 95% CI, 1.9-4.1; P less than .001). "The need for joint replacement surgery is still a marker of bad disease," commented Dr. Eric L. Matteson, professor of medicine and chair of rheumatology at the Mayo Clinic, in an interview.

The proportion of patients undergoing RA-related surgeries dropped between the two time periods of 1980-94 and 1995-2007. Of the 813 Olmsted County residents in the analysis, 189 underwent at least one surgical procedure involving joints, during a mean follow up of 9.6 years. The cumulative incidence of any joint surgery at 10 years after RA incidence for the 1980-94 cohort was 27.3%, compared with 19.5% for the 1995-2007 cohort (P = 0.08), which was not statistically significant.

More aggressive use of effective DMARDs with a reduction in the progression of radiographic joint damage was suggested as a possible reason for the decline in surgical procedures. "These findings reveal that modern medical management strategy has had markedly beneficial effects on the disease course," with less damage to the target small- and medium-size joints such as the hands, wrists, and feet than in past decades, noted Dr. Matteson, one of the report’s authors.

The greatest reduction in surgeries was seen in soft tissue procedures (synovectomy, tendon repair, tendon transfer, meniscus repair, ligament release, and/or cartilage repair). These decreased from 12% in 1980-94 to 6% in 1995-2007 at 10 years after RA incidence (P = .012).

No differences were found in the cumulative incidence of total hip arthroplasty (P = .77) or total knee arthroplasty (P = .18) between the time periods, reported the authors. Addressing the continued need for surgery on weight-bearing joints, particularly total knee and total hip arthroplasties, Dr. Matteson added, "in this respect patients are beginning to be more like people from the general population who have hip and knee replacements for osteoarthritis."

Study coinvestigator Cynthia Crowson of the Mayo Clinic’s biostatistics division noted in an interview that "persons with RA are requiring fewer surgeries, which may indicate [that] current management strategies are leading to less disability among patients who have developed RA since 1995" compared with previous times.

The study was supported by a grant from the National Institutes of Health, and was made possible by the Rochester Epidemiology Project. The authors reported having no financial disclosures.

Oral glucocorticoid therapy increases the risk of serious infection in elderly patients with rheumatoid arthritis, even when the drugs were stopped as long as 2.5 years earlier, according to findings from a recently published study.

The researchers used a novel, weighted cumulative dose model to assess serious infection risk associated with glucocorticoid exposure, providing greater accuracy over conventional models.

Conducted in Quebec, the case-control analysis assessed the infection risk in 16,207 patients who were at least 65 years of age and who had rheumatoid arthritis (RA). The findings showed that taking a 5 mg/day dose of prednisolone for 12 months increases risk of serious infection by 55%, compared to non-users. Furthermore, this risk was found to increase cumulatively to 100% (odds ratio, 2.00; 95% confidence interval, 1.69 to 2.26) in patients who took prednisolone for 3 years (Ann. Rheum. Dis. 2012 Jan. 12 [doi:10.1136/annrheumdis-2011-200702]).

"This is important as many physicians consider a 5 mg [daily prednisolone equivalent dosage] a ‘physiological dose’ that may not have important harms," according to Dr. William G. Dixon, Medical Research Council Clinician Scientist at the University of Manchester (England).

The investigators noted that 1,927 patients developed a first serious infection after an average 3.8 years of follow up. Patients who are currently or recently taking glucocorticoid therapy had the greatest risk of serious infection. The analysis showed that a current user on 5 mg/day prednisolone had an increased risk over non-users of 11% (OR, 1.11), 30% (OR, 1.30), and 55% (OR, 1.46) after 1 month, 3 months, and 12 months of use respectively.

"The risk associated with 5 mg prednisolone taken for the last 3 years was similar to that associated with 30 mg taken for the last month," noted Dr. Dixon and his associates.

The impact of discontinuation of glucocorticoid therapy was also investigated. Discontinuing a 2-year course of a 10-mg daily dose of prednisolone for 6 months was found to halve risk compared to continued use (OR, 1.87; CI, 1.32 to 2.63).

Dr. Dixon used a weighted, cumulative-dose model to assess the risk of serious infection associated with glucocorticoid exposure. This enabled doses to be given a weighting determined by how recently the patient took that dose. The authors note that this model "provides a far superior fit than all conventional models."

Dr. Jeffrey Curtis commented in an interview that the weighted cumulative dose model represents an advance. "The advance here is that there may be preferable ways to model steroid dose that allow for different estimations of risk, and presumably more accurate estimations. In the model used here, the researchers take into account the patients’ history of steroid therapy."

However, the study did not resolve the issue of confounding by indication, in which the effects of more active and severe disease can be difficult to disentangle from the effects of drugs, noted Dr. Curtis, who is director of the Arthritis Clinical Intervention Program Division of Clinical Immunology and Rheumatology at the University of Alabama at Birmingham.

"I think the risks with steroid therapy may produce different estimations of risk depending on the data source used, and the pattern of use in any particular disease. Analysis needs to be done by disease."

Addressing the issue of whether serious infection risk in patients with autoimmune diseases was associated with glucocorticoids, biologics, or non-biologic treatments, Dr. Curtis referred to a recently published paper he coauthored (JAMA 2011;306:2331-9). "We found a significantly increased risk of serious infection for steroid therapy but no greater risk overall for tumor necrosis factor (TNF)–alpha antagonists compared to patients receiving non-biologic treatments in a range of autoimmune diseases."

The study was funded by the Canadian Institutes of Health Research and the Canadian Foundation for Innovation. The lead author received support from a Medical Research Council Clinician Scientist Fellowship. The authors did not report having any other financial disclosures. Dr. Curtis is a consultant to various pharmaceutical companies that manufacture biologic therapies but he has no disclosures of relevance to glucocorticoids.

Oral glucocorticoid therapy increases the risk of serious infection in elderly patients with rheumatoid arthritis, even when the drugs were stopped as long as 2.5 years earlier, according to findings from a recently published study.

The researchers used a novel, weighted cumulative dose model to assess serious infection risk associated with glucocorticoid exposure, providing greater accuracy over conventional models.

Conducted in Quebec, the case-control analysis assessed the infection risk in 16,207 patients who were at least 65 years of age and who had rheumatoid arthritis (RA). The findings showed that taking a 5 mg/day dose of prednisolone for 12 months increases risk of serious infection by 55%, compared to non-users. Furthermore, this risk was found to increase cumulatively to 100% (odds ratio, 2.00; 95% confidence interval, 1.69 to 2.26) in patients who took prednisolone for 3 years (Ann. Rheum. Dis. 2012 Jan. 12 [doi:10.1136/annrheumdis-2011-200702]).

"This is important as many physicians consider a 5 mg [daily prednisolone equivalent dosage] a ‘physiological dose’ that may not have important harms," according to Dr. William G. Dixon, Medical Research Council Clinician Scientist at the University of Manchester (England).

The investigators noted that 1,927 patients developed a first serious infection after an average 3.8 years of follow up. Patients who are currently or recently taking glucocorticoid therapy had the greatest risk of serious infection. The analysis showed that a current user on 5 mg/day prednisolone had an increased risk over non-users of 11% (OR, 1.11), 30% (OR, 1.30), and 55% (OR, 1.46) after 1 month, 3 months, and 12 months of use respectively.

"The risk associated with 5 mg prednisolone taken for the last 3 years was similar to that associated with 30 mg taken for the last month," noted Dr. Dixon and his associates.

The impact of discontinuation of glucocorticoid therapy was also investigated. Discontinuing a 2-year course of a 10-mg daily dose of prednisolone for 6 months was found to halve risk compared to continued use (OR, 1.87; CI, 1.32 to 2.63).

Dr. Dixon used a weighted, cumulative-dose model to assess the risk of serious infection associated with glucocorticoid exposure. This enabled doses to be given a weighting determined by how recently the patient took that dose. The authors note that this model "provides a far superior fit than all conventional models."

Dr. Jeffrey Curtis commented in an interview that the weighted cumulative dose model represents an advance. "The advance here is that there may be preferable ways to model steroid dose that allow for different estimations of risk, and presumably more accurate estimations. In the model used here, the researchers take into account the patients’ history of steroid therapy."

However, the study did not resolve the issue of confounding by indication, in which the effects of more active and severe disease can be difficult to disentangle from the effects of drugs, noted Dr. Curtis, who is director of the Arthritis Clinical Intervention Program Division of Clinical Immunology and Rheumatology at the University of Alabama at Birmingham.

"I think the risks with steroid therapy may produce different estimations of risk depending on the data source used, and the pattern of use in any particular disease. Analysis needs to be done by disease."

Addressing the issue of whether serious infection risk in patients with autoimmune diseases was associated with glucocorticoids, biologics, or non-biologic treatments, Dr. Curtis referred to a recently published paper he coauthored (JAMA 2011;306:2331-9). "We found a significantly increased risk of serious infection for steroid therapy but no greater risk overall for tumor necrosis factor (TNF)–alpha antagonists compared to patients receiving non-biologic treatments in a range of autoimmune diseases."

The study was funded by the Canadian Institutes of Health Research and the Canadian Foundation for Innovation. The lead author received support from a Medical Research Council Clinician Scientist Fellowship. The authors did not report having any other financial disclosures. Dr. Curtis is a consultant to various pharmaceutical companies that manufacture biologic therapies but he has no disclosures of relevance to glucocorticoids.

Oral glucocorticoid therapy increases the risk of serious infection in elderly patients with rheumatoid arthritis, even when the drugs were stopped as long as 2.5 years earlier, according to findings from a recently published study.

The researchers used a novel, weighted cumulative dose model to assess serious infection risk associated with glucocorticoid exposure, providing greater accuracy over conventional models.

Conducted in Quebec, the case-control analysis assessed the infection risk in 16,207 patients who were at least 65 years of age and who had rheumatoid arthritis (RA). The findings showed that taking a 5 mg/day dose of prednisolone for 12 months increases risk of serious infection by 55%, compared to non-users. Furthermore, this risk was found to increase cumulatively to 100% (odds ratio, 2.00; 95% confidence interval, 1.69 to 2.26) in patients who took prednisolone for 3 years (Ann. Rheum. Dis. 2012 Jan. 12 [doi:10.1136/annrheumdis-2011-200702]).

"This is important as many physicians consider a 5 mg [daily prednisolone equivalent dosage] a ‘physiological dose’ that may not have important harms," according to Dr. William G. Dixon, Medical Research Council Clinician Scientist at the University of Manchester (England).

The investigators noted that 1,927 patients developed a first serious infection after an average 3.8 years of follow up. Patients who are currently or recently taking glucocorticoid therapy had the greatest risk of serious infection. The analysis showed that a current user on 5 mg/day prednisolone had an increased risk over non-users of 11% (OR, 1.11), 30% (OR, 1.30), and 55% (OR, 1.46) after 1 month, 3 months, and 12 months of use respectively.

"The risk associated with 5 mg prednisolone taken for the last 3 years was similar to that associated with 30 mg taken for the last month," noted Dr. Dixon and his associates.

The impact of discontinuation of glucocorticoid therapy was also investigated. Discontinuing a 2-year course of a 10-mg daily dose of prednisolone for 6 months was found to halve risk compared to continued use (OR, 1.87; CI, 1.32 to 2.63).

Dr. Dixon used a weighted, cumulative-dose model to assess the risk of serious infection associated with glucocorticoid exposure. This enabled doses to be given a weighting determined by how recently the patient took that dose. The authors note that this model "provides a far superior fit than all conventional models."

Dr. Jeffrey Curtis commented in an interview that the weighted cumulative dose model represents an advance. "The advance here is that there may be preferable ways to model steroid dose that allow for different estimations of risk, and presumably more accurate estimations. In the model used here, the researchers take into account the patients’ history of steroid therapy."

However, the study did not resolve the issue of confounding by indication, in which the effects of more active and severe disease can be difficult to disentangle from the effects of drugs, noted Dr. Curtis, who is director of the Arthritis Clinical Intervention Program Division of Clinical Immunology and Rheumatology at the University of Alabama at Birmingham.

"I think the risks with steroid therapy may produce different estimations of risk depending on the data source used, and the pattern of use in any particular disease. Analysis needs to be done by disease."

Addressing the issue of whether serious infection risk in patients with autoimmune diseases was associated with glucocorticoids, biologics, or non-biologic treatments, Dr. Curtis referred to a recently published paper he coauthored (JAMA 2011;306:2331-9). "We found a significantly increased risk of serious infection for steroid therapy but no greater risk overall for tumor necrosis factor (TNF)–alpha antagonists compared to patients receiving non-biologic treatments in a range of autoimmune diseases."

The study was funded by the Canadian Institutes of Health Research and the Canadian Foundation for Innovation. The lead author received support from a Medical Research Council Clinician Scientist Fellowship. The authors did not report having any other financial disclosures. Dr. Curtis is a consultant to various pharmaceutical companies that manufacture biologic therapies but he has no disclosures of relevance to glucocorticoids.

Remission has become an accepted goal in the management of rheumatoid arthritis, but its definition remains in flux.

About a year ago, a panel assembled jointly by the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR) published two provisional definitions of remission in rheumatoid arthritis (RA) for clinical trials: a Simplified Disease Activity Index (SDAI) score of 3.3 or less; or no more than 1 tender and 1 swollen on a 28-joint examination, a C reactive protein (CRP) level of 1 mg/dL or less, and a patient global assessment score of 1 or less on a 0-10 scale (Arthritis Rheum. 2011;63:573-86; Ann. Rheum. Dis. 2011;70:404-13).

The ACR/EULAR panel explicitly said that their definitions of remission were intended for use only in clinical trials for the time being, and the group did not yet endorse their use in routine clinical practice, in part because the definitions had not yet been tested in that setting, and in part because in clinical practice data on acute phase reactants, such as CRP, "are frequently not immediately available."

Dr. David T. Felson, professor of medicine and epidemiology at Boston University as well as first author on the ACR/EULAR remission paper, noted in an interview that "We studied data from clinical trials to develop these remission criteria, and trial patients are not generalizable to those in practice, nor are their assessments as comprehensive."

But even with the new definitions not formally designed for routine practice, their designation by a combined ACR and EULAR panel appears to have helped solidify remission as the benchmark goal for management of most RA patients, capping a decade-long trend. It’s already well accepted that remission is achievable in "at least half" of patients with new-onset RA, noted Dr. James R. O’Dell and Dr. Ted R. Mikuls in an editorial that accompanied the publication of the provisional definition (Arthritis Rheum. 2011;63:587-9). The remission rate in patients with long-standing RA is much lower, more on the order of perhaps 10%, Dr. O’Dell said in an interview.

Noted Dr. Daniel E. Furst: "When I started working on rheumatoid arthritis, we used the word remission with the hope that some day it would be possible. Because of advances in treatment, over the last 10 years it has become possible, and consequently it is totally appropriate that we aim for remission."

The provisional definitions that the panel set for clinical trials serve as "a reasonable set of criteria" for routine practice, said Dr. Furst, who is Carl M. Pearson professor in rheumatology at the University of California, Los Angeles and a member of the ACR/EULAR panel.

"I do this all the time. It requires physicians to routinely quantify patient responses, which is not common right now, but it will become more common. The need for a lab test [measurement of CRP] as part of the definition makes it a little more difficult to use because it usually takes some time to get the blood-test result. What I do is a CDAI [Clinical Disease Activity Index, the sum of tender and swollen joint counts, and physician and patient global assessments] at the same time that I’m obtaining the other results that take time. That’s more practical to do in everyday practice," he said in an interview.

"Right now, my associates and I generally use a DAS28, but we’re rethinking that," in part prompted by the new remission definitions, said Dr. O’Dell, who is Larson professor of medicine and chief of rheumatology at the University of Nebraska in Omaha. "DAS28 is an imperfect measure. I can have a patient with a very low [ESR] of 2 [mm/hr] and their DAS28 will look pretty good until they have three or four swollen joints. But the flip side is I can have a patient who is doing terrific, with no swollen joints, and their [ESR] is 25. Since the ARC/EULAR definition, we have thought about whether we should do more CDAI or SDAI. [ESR] and CRP give information in a different way than what we get from joints, but they often aren’t available in real time.

"The ACR Quality Measures Committee will issue a white paper in late spring on the disease activity measures that it thinks are feasible and that clinicians can use, including the CADI, SDAI, DAS28, RAPID3 [Routine Assessment of Patient Index Data 3], and PAS [Patient Activity Score]. It’s far more important that physicians measure a patient’s disease activity with some scale than which scale you use," he said in an interview. "If you don’t want to do 28-joint counts, then do a RAPID3. The ACR/EULAR panel set its remission criteria for trials, but for routine practice there should be more flexibility" for physicians to use the scale that best fits their approach to practice, Dr. O’Dell said. "The RAPID3 is much easier to do and is available in real time, and is very good. It’s not quite as good as some others, but if that’s what you use, you’ll do fine."

Assessing the ACR/EULAR Criteria’s Performance

In addition to not having been derived from patients in routine practice, the ACR/EULAR definitions of remission may also show variability from physician to physician, and unstable reproducibility within individual patients.

Last November, researchers from the Arthritis and Rheumatology Clinics of Kansas in Wichita and their collaborators published an analysis that applied the ACR/EULAR provisional remission definition to patients in two cohorts: 1,341 patients from the Department of Veteran’s Affairs, and 1,153 patients in a cohort assembled at the Arthritis and Rheumatology Clinics of Kansas. The two ACR/EULAR criteria identified about 5%-10% of patients as being in remission at any one time, depending on the cohort and specific definition applied, they reported (Arthritis Rheum. 2011;63:3204-15).

However, the probability of a specific patient being in remission at two or more visits ranged from 2%-5%. The analysis also showed "substantial evidence to indicate that inter-rater reliability is poor with respect to the examination of tender and swollen joints." The authors estimated that the probability of remission using the ACR/EULAR definitions in these two cohorts could vary by twofold depending solely on the physician examiner and independent of disease activity.

The researchers concluded that "problems with reliability and agreement limit the usefulness of these criteria in the individual patient." But several rheumatologists interviewed noted that variability among physicians in scoring swollen and tender joint counts is expected. The finding simply underscores that the best way to serially monitor joint status in a patient is for the same physician to do it every time. They also commented that the low rates of remission seen in this study highlight just how challenging it is to maintain RA patients at a very low level of disease activity.

"These criteria were developed for clinical trials, and I agree that they’re reasonable for trials," said Dr. Frederick Wolfe, the senior author on this study and a member of the ACR/EULAR definition panel. "Until now, there were lots of different ideas of what was remission, which limited its use. We wanted to make a standard for remission [in trials], and did a pretty good job. But in the clinic, physicians know more than they can get from questionnaires," he said in an interview.

For example, Dr. Wolfe cited a study he and his associates ran in which patients were asked what influenced their global self rating. "We found that some patients who all physicians would agree were in remission gave themselves poor scores because they had pain in other regions, mostly back pain, or because of fatigue, or other things" not related to RA. "In clinical practice, we’d ask patients to ignore that, or to explain their high global self-assessment score, so in the clinic you can decide whether patients are in remission," said Dr. Wolfe, director of the National Databank for Rheumatic Diseases in Wichita, Kan.

For measuring RA activity in routine practice, Dr. Wolfe said that he favors the CDAI "as an overall measure of disease activity." He also endorsed patient-centered measures of pain, such as the Health Assessment Questionnaire (HAQ), global self-assessment, RAPID3, and the PAS.

A more positive assessment of the ACR/EULAR definitions in clinical practice came from a recent study that applied them to a cohort of 535 RA patients at Brigham and Women’s Hospital in Boston followed for 2 years by serial joint radiographs. The authors examined the ability of the definitions to predict good radiographic and functional outcomes over time in these clinical-practice patients. They found that 30 patients (6%) of the 535 met the four-part ACR/EULAR definition of remission at baseline, while 26 (5%) met the CDAI definition, 37 (7%) met a SDAI definition of remission, and 106 (20%) met a DAS28-CRP definition. The best of these measures for predicting freedom from radiographic joint progression during 2 years of follow-up was the CDAI, with a positive likelihood ratio of 2.8, followed closely by the four-part ACR/EULAR definition, with a positive likelihood ratio of 2.7. The ratio for SDAI was 2.1, and for DAS28-CRP 1.5 (Ann. Rheum. Dis. 2011 Oct. 12 [doi:10.1136/ard.2011.154625]).

"Our findings strengthen the applicability of the ACR/EULAR criteria in clinical practice," the researchers concluded, and also noted that "the findings might have been different in a patient population of early RA patients." The cohort they examined had been diagnosed with RA for a median of 11 years, with 75% diagnosed for 4 years or longer.

The authors also said "a significant proportion of patients who do not fulfill the remission criteria still experience a good outcome of their disease, especially for radiographic joint damage. ... A byproduct of more stringent remission criteria as a treatment target will be more patients in low disease activity with good disease outcome, potentially risking overtreatment."

Several other assessments of the remission criteria in other data sets are on the way, Dr. O’Dell said. "I’ve heard of them, and people are talking about them," and these reports will likely appear in the literature over the next year. Advance word is that the remission criteria "stood up very well," Dr. O’Dell added.

Is Remission the Right Goal?

The last comment from the Brigham and Women’s group raises the important question of whether remission is the best target for most RA patients or is low disease activity enough.

"About 10%-20% of patients in trials reach remission according to the new definitions. Newly diagnosed patients tend to have disease that is more responsive to treatment, so that the proportion achieving remission is likely to be higher, but probably not reaching 40%," said Dr. Felson. "In trials, regimens will target" the new ARC/EULAR definition, "but I’m less sure about this as a target for patients [in routine practice]. It may be difficult for many patients to reach this threshold, even with optimal current treatment."

For the time being, in patients with an established RA diagnosis using MRI or ultrasound to pick up inflammation that is not clinically apparent "is not practical," said Dr. O’Dell. One area where joint imaging may be especially helpful is in patients who are doing well on treatment and can be considered for tapering down treatment. Studies are now looking at whether ultrasound or MRI can identify patients who are good candidates for dose reductions, Dr. O’Dell said.

"Remission, whether you define it with the new definition or an older one, is necessary for the long-term health of patients," said Dr. Furst. "The goal is preventing x-ray damage, and allowing patients to have optimal long-term function and quality of life. That’s what remission criteria are all about: They give physicians a measuring stick for telling how well a patient is doing" with respect to these long-term treatment goals. "There is always a balance between achieving these goals and making sure the patient is not harmed" by aggressive treatment. The ACR/EULAR criteria "emphasize the need to quantify patient response, and in that sense they are slowly changing practice," Dr. Furst said.

"There is no doubt that there is increasing movement toward treating to a target, but most rheumatologists don’t believe that remission is the right goal for every patient." said Dr. O’Dell. "We’d love to have remission, but sometimes it’s more problematic than it’s worth. What we don’t know is the long-term difference between a patient who is barely in remission compared with one who is close but not in remission. How far should we push it? If the patient is not having trouble with treatment, then we should definitely push it. If a patient is on 20 mg/week of methotrexate and is nearly there, then trying 25 mg of methotrexate/week is clearly the right thing to do in most patients. But if the patient is not at remission but also is not always tolerating 20 mg/week, if they don’t feel good the day after their dose, what’s the right answer? We don’t know; it’s clinical judgment."

Dr. Felson, Dr. O’Dell and Dr. Wolfe said they had no disclosures. Dr. Furst said that he has financial relationships with Abbott, Actelion, Amgen, Biogen Idec, Bristol-Myers Squibb, Centocor, Genentech, Gilead, GlaxoSmithKline, Merck, Nitec, Novartis, Roche, UCB, Wyeth, and Xoma.

Remission has become an accepted goal in the management of rheumatoid arthritis, but its definition remains in flux.

About a year ago, a panel assembled jointly by the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR) published two provisional definitions of remission in rheumatoid arthritis (RA) for clinical trials: a Simplified Disease Activity Index (SDAI) score of 3.3 or less; or no more than 1 tender and 1 swollen on a 28-joint examination, a C reactive protein (CRP) level of 1 mg/dL or less, and a patient global assessment score of 1 or less on a 0-10 scale (Arthritis Rheum. 2011;63:573-86; Ann. Rheum. Dis. 2011;70:404-13).

The ACR/EULAR panel explicitly said that their definitions of remission were intended for use only in clinical trials for the time being, and the group did not yet endorse their use in routine clinical practice, in part because the definitions had not yet been tested in that setting, and in part because in clinical practice data on acute phase reactants, such as CRP, "are frequently not immediately available."

Dr. David T. Felson, professor of medicine and epidemiology at Boston University as well as first author on the ACR/EULAR remission paper, noted in an interview that "We studied data from clinical trials to develop these remission criteria, and trial patients are not generalizable to those in practice, nor are their assessments as comprehensive."

But even with the new definitions not formally designed for routine practice, their designation by a combined ACR and EULAR panel appears to have helped solidify remission as the benchmark goal for management of most RA patients, capping a decade-long trend. It’s already well accepted that remission is achievable in "at least half" of patients with new-onset RA, noted Dr. James R. O’Dell and Dr. Ted R. Mikuls in an editorial that accompanied the publication of the provisional definition (Arthritis Rheum. 2011;63:587-9). The remission rate in patients with long-standing RA is much lower, more on the order of perhaps 10%, Dr. O’Dell said in an interview.

Noted Dr. Daniel E. Furst: "When I started working on rheumatoid arthritis, we used the word remission with the hope that some day it would be possible. Because of advances in treatment, over the last 10 years it has become possible, and consequently it is totally appropriate that we aim for remission."

The provisional definitions that the panel set for clinical trials serve as "a reasonable set of criteria" for routine practice, said Dr. Furst, who is Carl M. Pearson professor in rheumatology at the University of California, Los Angeles and a member of the ACR/EULAR panel.

"I do this all the time. It requires physicians to routinely quantify patient responses, which is not common right now, but it will become more common. The need for a lab test [measurement of CRP] as part of the definition makes it a little more difficult to use because it usually takes some time to get the blood-test result. What I do is a CDAI [Clinical Disease Activity Index, the sum of tender and swollen joint counts, and physician and patient global assessments] at the same time that I’m obtaining the other results that take time. That’s more practical to do in everyday practice," he said in an interview.

"Right now, my associates and I generally use a DAS28, but we’re rethinking that," in part prompted by the new remission definitions, said Dr. O’Dell, who is Larson professor of medicine and chief of rheumatology at the University of Nebraska in Omaha. "DAS28 is an imperfect measure. I can have a patient with a very low [ESR] of 2 [mm/hr] and their DAS28 will look pretty good until they have three or four swollen joints. But the flip side is I can have a patient who is doing terrific, with no swollen joints, and their [ESR] is 25. Since the ARC/EULAR definition, we have thought about whether we should do more CDAI or SDAI. [ESR] and CRP give information in a different way than what we get from joints, but they often aren’t available in real time.

"The ACR Quality Measures Committee will issue a white paper in late spring on the disease activity measures that it thinks are feasible and that clinicians can use, including the CADI, SDAI, DAS28, RAPID3 [Routine Assessment of Patient Index Data 3], and PAS [Patient Activity Score]. It’s far more important that physicians measure a patient’s disease activity with some scale than which scale you use," he said in an interview. "If you don’t want to do 28-joint counts, then do a RAPID3. The ACR/EULAR panel set its remission criteria for trials, but for routine practice there should be more flexibility" for physicians to use the scale that best fits their approach to practice, Dr. O’Dell said. "The RAPID3 is much easier to do and is available in real time, and is very good. It’s not quite as good as some others, but if that’s what you use, you’ll do fine."

Assessing the ACR/EULAR Criteria’s Performance

In addition to not having been derived from patients in routine practice, the ACR/EULAR definitions of remission may also show variability from physician to physician, and unstable reproducibility within individual patients.

Last November, researchers from the Arthritis and Rheumatology Clinics of Kansas in Wichita and their collaborators published an analysis that applied the ACR/EULAR provisional remission definition to patients in two cohorts: 1,341 patients from the Department of Veteran’s Affairs, and 1,153 patients in a cohort assembled at the Arthritis and Rheumatology Clinics of Kansas. The two ACR/EULAR criteria identified about 5%-10% of patients as being in remission at any one time, depending on the cohort and specific definition applied, they reported (Arthritis Rheum. 2011;63:3204-15).

However, the probability of a specific patient being in remission at two or more visits ranged from 2%-5%. The analysis also showed "substantial evidence to indicate that inter-rater reliability is poor with respect to the examination of tender and swollen joints." The authors estimated that the probability of remission using the ACR/EULAR definitions in these two cohorts could vary by twofold depending solely on the physician examiner and independent of disease activity.

The researchers concluded that "problems with reliability and agreement limit the usefulness of these criteria in the individual patient." But several rheumatologists interviewed noted that variability among physicians in scoring swollen and tender joint counts is expected. The finding simply underscores that the best way to serially monitor joint status in a patient is for the same physician to do it every time. They also commented that the low rates of remission seen in this study highlight just how challenging it is to maintain RA patients at a very low level of disease activity.

"These criteria were developed for clinical trials, and I agree that they’re reasonable for trials," said Dr. Frederick Wolfe, the senior author on this study and a member of the ACR/EULAR definition panel. "Until now, there were lots of different ideas of what was remission, which limited its use. We wanted to make a standard for remission [in trials], and did a pretty good job. But in the clinic, physicians know more than they can get from questionnaires," he said in an interview.

For example, Dr. Wolfe cited a study he and his associates ran in which patients were asked what influenced their global self rating. "We found that some patients who all physicians would agree were in remission gave themselves poor scores because they had pain in other regions, mostly back pain, or because of fatigue, or other things" not related to RA. "In clinical practice, we’d ask patients to ignore that, or to explain their high global self-assessment score, so in the clinic you can decide whether patients are in remission," said Dr. Wolfe, director of the National Databank for Rheumatic Diseases in Wichita, Kan.

For measuring RA activity in routine practice, Dr. Wolfe said that he favors the CDAI "as an overall measure of disease activity." He also endorsed patient-centered measures of pain, such as the Health Assessment Questionnaire (HAQ), global self-assessment, RAPID3, and the PAS.

A more positive assessment of the ACR/EULAR definitions in clinical practice came from a recent study that applied them to a cohort of 535 RA patients at Brigham and Women’s Hospital in Boston followed for 2 years by serial joint radiographs. The authors examined the ability of the definitions to predict good radiographic and functional outcomes over time in these clinical-practice patients. They found that 30 patients (6%) of the 535 met the four-part ACR/EULAR definition of remission at baseline, while 26 (5%) met the CDAI definition, 37 (7%) met a SDAI definition of remission, and 106 (20%) met a DAS28-CRP definition. The best of these measures for predicting freedom from radiographic joint progression during 2 years of follow-up was the CDAI, with a positive likelihood ratio of 2.8, followed closely by the four-part ACR/EULAR definition, with a positive likelihood ratio of 2.7. The ratio for SDAI was 2.1, and for DAS28-CRP 1.5 (Ann. Rheum. Dis. 2011 Oct. 12 [doi:10.1136/ard.2011.154625]).

"Our findings strengthen the applicability of the ACR/EULAR criteria in clinical practice," the researchers concluded, and also noted that "the findings might have been different in a patient population of early RA patients." The cohort they examined had been diagnosed with RA for a median of 11 years, with 75% diagnosed for 4 years or longer.

The authors also said "a significant proportion of patients who do not fulfill the remission criteria still experience a good outcome of their disease, especially for radiographic joint damage. ... A byproduct of more stringent remission criteria as a treatment target will be more patients in low disease activity with good disease outcome, potentially risking overtreatment."

Several other assessments of the remission criteria in other data sets are on the way, Dr. O’Dell said. "I’ve heard of them, and people are talking about them," and these reports will likely appear in the literature over the next year. Advance word is that the remission criteria "stood up very well," Dr. O’Dell added.

Is Remission the Right Goal?

The last comment from the Brigham and Women’s group raises the important question of whether remission is the best target for most RA patients or is low disease activity enough.

"About 10%-20% of patients in trials reach remission according to the new definitions. Newly diagnosed patients tend to have disease that is more responsive to treatment, so that the proportion achieving remission is likely to be higher, but probably not reaching 40%," said Dr. Felson. "In trials, regimens will target" the new ARC/EULAR definition, "but I’m less sure about this as a target for patients [in routine practice]. It may be difficult for many patients to reach this threshold, even with optimal current treatment."

For the time being, in patients with an established RA diagnosis using MRI or ultrasound to pick up inflammation that is not clinically apparent "is not practical," said Dr. O’Dell. One area where joint imaging may be especially helpful is in patients who are doing well on treatment and can be considered for tapering down treatment. Studies are now looking at whether ultrasound or MRI can identify patients who are good candidates for dose reductions, Dr. O’Dell said.

"Remission, whether you define it with the new definition or an older one, is necessary for the long-term health of patients," said Dr. Furst. "The goal is preventing x-ray damage, and allowing patients to have optimal long-term function and quality of life. That’s what remission criteria are all about: They give physicians a measuring stick for telling how well a patient is doing" with respect to these long-term treatment goals. "There is always a balance between achieving these goals and making sure the patient is not harmed" by aggressive treatment. The ACR/EULAR criteria "emphasize the need to quantify patient response, and in that sense they are slowly changing practice," Dr. Furst said.

"There is no doubt that there is increasing movement toward treating to a target, but most rheumatologists don’t believe that remission is the right goal for every patient." said Dr. O’Dell. "We’d love to have remission, but sometimes it’s more problematic than it’s worth. What we don’t know is the long-term difference between a patient who is barely in remission compared with one who is close but not in remission. How far should we push it? If the patient is not having trouble with treatment, then we should definitely push it. If a patient is on 20 mg/week of methotrexate and is nearly there, then trying 25 mg of methotrexate/week is clearly the right thing to do in most patients. But if the patient is not at remission but also is not always tolerating 20 mg/week, if they don’t feel good the day after their dose, what’s the right answer? We don’t know; it’s clinical judgment."

Dr. Felson, Dr. O’Dell and Dr. Wolfe said they had no disclosures. Dr. Furst said that he has financial relationships with Abbott, Actelion, Amgen, Biogen Idec, Bristol-Myers Squibb, Centocor, Genentech, Gilead, GlaxoSmithKline, Merck, Nitec, Novartis, Roche, UCB, Wyeth, and Xoma.

Remission has become an accepted goal in the management of rheumatoid arthritis, but its definition remains in flux.

About a year ago, a panel assembled jointly by the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR) published two provisional definitions of remission in rheumatoid arthritis (RA) for clinical trials: a Simplified Disease Activity Index (SDAI) score of 3.3 or less; or no more than 1 tender and 1 swollen on a 28-joint examination, a C reactive protein (CRP) level of 1 mg/dL or less, and a patient global assessment score of 1 or less on a 0-10 scale (Arthritis Rheum. 2011;63:573-86; Ann. Rheum. Dis. 2011;70:404-13).

The ACR/EULAR panel explicitly said that their definitions of remission were intended for use only in clinical trials for the time being, and the group did not yet endorse their use in routine clinical practice, in part because the definitions had not yet been tested in that setting, and in part because in clinical practice data on acute phase reactants, such as CRP, "are frequently not immediately available."

Dr. David T. Felson, professor of medicine and epidemiology at Boston University as well as first author on the ACR/EULAR remission paper, noted in an interview that "We studied data from clinical trials to develop these remission criteria, and trial patients are not generalizable to those in practice, nor are their assessments as comprehensive."

But even with the new definitions not formally designed for routine practice, their designation by a combined ACR and EULAR panel appears to have helped solidify remission as the benchmark goal for management of most RA patients, capping a decade-long trend. It’s already well accepted that remission is achievable in "at least half" of patients with new-onset RA, noted Dr. James R. O’Dell and Dr. Ted R. Mikuls in an editorial that accompanied the publication of the provisional definition (Arthritis Rheum. 2011;63:587-9). The remission rate in patients with long-standing RA is much lower, more on the order of perhaps 10%, Dr. O’Dell said in an interview.

Noted Dr. Daniel E. Furst: "When I started working on rheumatoid arthritis, we used the word remission with the hope that some day it would be possible. Because of advances in treatment, over the last 10 years it has become possible, and consequently it is totally appropriate that we aim for remission."

The provisional definitions that the panel set for clinical trials serve as "a reasonable set of criteria" for routine practice, said Dr. Furst, who is Carl M. Pearson professor in rheumatology at the University of California, Los Angeles and a member of the ACR/EULAR panel.

"I do this all the time. It requires physicians to routinely quantify patient responses, which is not common right now, but it will become more common. The need for a lab test [measurement of CRP] as part of the definition makes it a little more difficult to use because it usually takes some time to get the blood-test result. What I do is a CDAI [Clinical Disease Activity Index, the sum of tender and swollen joint counts, and physician and patient global assessments] at the same time that I’m obtaining the other results that take time. That’s more practical to do in everyday practice," he said in an interview.

"Right now, my associates and I generally use a DAS28, but we’re rethinking that," in part prompted by the new remission definitions, said Dr. O’Dell, who is Larson professor of medicine and chief of rheumatology at the University of Nebraska in Omaha. "DAS28 is an imperfect measure. I can have a patient with a very low [ESR] of 2 [mm/hr] and their DAS28 will look pretty good until they have three or four swollen joints. But the flip side is I can have a patient who is doing terrific, with no swollen joints, and their [ESR] is 25. Since the ARC/EULAR definition, we have thought about whether we should do more CDAI or SDAI. [ESR] and CRP give information in a different way than what we get from joints, but they often aren’t available in real time.

"The ACR Quality Measures Committee will issue a white paper in late spring on the disease activity measures that it thinks are feasible and that clinicians can use, including the CADI, SDAI, DAS28, RAPID3 [Routine Assessment of Patient Index Data 3], and PAS [Patient Activity Score]. It’s far more important that physicians measure a patient’s disease activity with some scale than which scale you use," he said in an interview. "If you don’t want to do 28-joint counts, then do a RAPID3. The ACR/EULAR panel set its remission criteria for trials, but for routine practice there should be more flexibility" for physicians to use the scale that best fits their approach to practice, Dr. O’Dell said. "The RAPID3 is much easier to do and is available in real time, and is very good. It’s not quite as good as some others, but if that’s what you use, you’ll do fine."

Assessing the ACR/EULAR Criteria’s Performance

In addition to not having been derived from patients in routine practice, the ACR/EULAR definitions of remission may also show variability from physician to physician, and unstable reproducibility within individual patients.

Last November, researchers from the Arthritis and Rheumatology Clinics of Kansas in Wichita and their collaborators published an analysis that applied the ACR/EULAR provisional remission definition to patients in two cohorts: 1,341 patients from the Department of Veteran’s Affairs, and 1,153 patients in a cohort assembled at the Arthritis and Rheumatology Clinics of Kansas. The two ACR/EULAR criteria identified about 5%-10% of patients as being in remission at any one time, depending on the cohort and specific definition applied, they reported (Arthritis Rheum. 2011;63:3204-15).

However, the probability of a specific patient being in remission at two or more visits ranged from 2%-5%. The analysis also showed "substantial evidence to indicate that inter-rater reliability is poor with respect to the examination of tender and swollen joints." The authors estimated that the probability of remission using the ACR/EULAR definitions in these two cohorts could vary by twofold depending solely on the physician examiner and independent of disease activity.

The researchers concluded that "problems with reliability and agreement limit the usefulness of these criteria in the individual patient." But several rheumatologists interviewed noted that variability among physicians in scoring swollen and tender joint counts is expected. The finding simply underscores that the best way to serially monitor joint status in a patient is for the same physician to do it every time. They also commented that the low rates of remission seen in this study highlight just how challenging it is to maintain RA patients at a very low level of disease activity.

"These criteria were developed for clinical trials, and I agree that they’re reasonable for trials," said Dr. Frederick Wolfe, the senior author on this study and a member of the ACR/EULAR definition panel. "Until now, there were lots of different ideas of what was remission, which limited its use. We wanted to make a standard for remission [in trials], and did a pretty good job. But in the clinic, physicians know more than they can get from questionnaires," he said in an interview.

For example, Dr. Wolfe cited a study he and his associates ran in which patients were asked what influenced their global self rating. "We found that some patients who all physicians would agree were in remission gave themselves poor scores because they had pain in other regions, mostly back pain, or because of fatigue, or other things" not related to RA. "In clinical practice, we’d ask patients to ignore that, or to explain their high global self-assessment score, so in the clinic you can decide whether patients are in remission," said Dr. Wolfe, director of the National Databank for Rheumatic Diseases in Wichita, Kan.

For measuring RA activity in routine practice, Dr. Wolfe said that he favors the CDAI "as an overall measure of disease activity." He also endorsed patient-centered measures of pain, such as the Health Assessment Questionnaire (HAQ), global self-assessment, RAPID3, and the PAS.

A more positive assessment of the ACR/EULAR definitions in clinical practice came from a recent study that applied them to a cohort of 535 RA patients at Brigham and Women’s Hospital in Boston followed for 2 years by serial joint radiographs. The authors examined the ability of the definitions to predict good radiographic and functional outcomes over time in these clinical-practice patients. They found that 30 patients (6%) of the 535 met the four-part ACR/EULAR definition of remission at baseline, while 26 (5%) met the CDAI definition, 37 (7%) met a SDAI definition of remission, and 106 (20%) met a DAS28-CRP definition. The best of these measures for predicting freedom from radiographic joint progression during 2 years of follow-up was the CDAI, with a positive likelihood ratio of 2.8, followed closely by the four-part ACR/EULAR definition, with a positive likelihood ratio of 2.7. The ratio for SDAI was 2.1, and for DAS28-CRP 1.5 (Ann. Rheum. Dis. 2011 Oct. 12 [doi:10.1136/ard.2011.154625]).

"Our findings strengthen the applicability of the ACR/EULAR criteria in clinical practice," the researchers concluded, and also noted that "the findings might have been different in a patient population of early RA patients." The cohort they examined had been diagnosed with RA for a median of 11 years, with 75% diagnosed for 4 years or longer.

The authors also said "a significant proportion of patients who do not fulfill the remission criteria still experience a good outcome of their disease, especially for radiographic joint damage. ... A byproduct of more stringent remission criteria as a treatment target will be more patients in low disease activity with good disease outcome, potentially risking overtreatment."

Several other assessments of the remission criteria in other data sets are on the way, Dr. O’Dell said. "I’ve heard of them, and people are talking about them," and these reports will likely appear in the literature over the next year. Advance word is that the remission criteria "stood up very well," Dr. O’Dell added.

Is Remission the Right Goal?

The last comment from the Brigham and Women’s group raises the important question of whether remission is the best target for most RA patients or is low disease activity enough.

"About 10%-20% of patients in trials reach remission according to the new definitions. Newly diagnosed patients tend to have disease that is more responsive to treatment, so that the proportion achieving remission is likely to be higher, but probably not reaching 40%," said Dr. Felson. "In trials, regimens will target" the new ARC/EULAR definition, "but I’m less sure about this as a target for patients [in routine practice]. It may be difficult for many patients to reach this threshold, even with optimal current treatment."

For the time being, in patients with an established RA diagnosis using MRI or ultrasound to pick up inflammation that is not clinically apparent "is not practical," said Dr. O’Dell. One area where joint imaging may be especially helpful is in patients who are doing well on treatment and can be considered for tapering down treatment. Studies are now looking at whether ultrasound or MRI can identify patients who are good candidates for dose reductions, Dr. O’Dell said.

"Remission, whether you define it with the new definition or an older one, is necessary for the long-term health of patients," said Dr. Furst. "The goal is preventing x-ray damage, and allowing patients to have optimal long-term function and quality of life. That’s what remission criteria are all about: They give physicians a measuring stick for telling how well a patient is doing" with respect to these long-term treatment goals. "There is always a balance between achieving these goals and making sure the patient is not harmed" by aggressive treatment. The ACR/EULAR criteria "emphasize the need to quantify patient response, and in that sense they are slowly changing practice," Dr. Furst said.

"There is no doubt that there is increasing movement toward treating to a target, but most rheumatologists don’t believe that remission is the right goal for every patient." said Dr. O’Dell. "We’d love to have remission, but sometimes it’s more problematic than it’s worth. What we don’t know is the long-term difference between a patient who is barely in remission compared with one who is close but not in remission. How far should we push it? If the patient is not having trouble with treatment, then we should definitely push it. If a patient is on 20 mg/week of methotrexate and is nearly there, then trying 25 mg of methotrexate/week is clearly the right thing to do in most patients. But if the patient is not at remission but also is not always tolerating 20 mg/week, if they don’t feel good the day after their dose, what’s the right answer? We don’t know; it’s clinical judgment."

Dr. Felson, Dr. O’Dell and Dr. Wolfe said they had no disclosures. Dr. Furst said that he has financial relationships with Abbott, Actelion, Amgen, Biogen Idec, Bristol-Myers Squibb, Centocor, Genentech, Gilead, GlaxoSmithKline, Merck, Nitec, Novartis, Roche, UCB, Wyeth, and Xoma.