2011 Midwest Rheumatology Summit

CHICAGO – Physicians may want to be a bit more aggressive in their use of calcium and vitamin D supplementation in patients at high-risk for osteoporotic fracture than has been recommended by the Institute of Medicine, according to Dr. Kenneth G. Saag.

The IOM guidelines on calcium and vitamin D have introduced controversy to a once sleepy area of bone mineral density management, said Dr. Saag, professor of medicine at the University of Alabama at Birmingham.

"Calcium and vitamin D used to be the least controversial part of any lecture on osteoporosis," said Dr. Saag. But no more. The IOM recommends daily allowances of calcium of 1,200 mg/day for women older than age 51 years in a consensus report issued November 2010. "We’ve been thinking maybe 1,500 mg was a better target for certain older adults," said Dr. Saag. He said that IOM recommendations are population based and do not necessarily apply to patients with osteoporosis or low bone mass. "We believe it may be prudent to be a little bit more aggressive in patients with documented osteoporosis."

The IOM report raised questions about calcium safety. A meta-analysis of all large studies of calcium alone – even though calcium is rarely given alone – found trends toward negative cardiovascular effects in individuals taking excess calcium (BMJ 2010;341:c3691).

However, a more recent study of cardiovascular risk did not show increased risk from excess calcium (J. Bone Miner. Res. 2011;26:35-41).

"The controversy in treatment now is not whether we should initiate therapy in high-risk [fracture] patients, but how long should we treat?"

Vitamin D likewise has its share of controversies, including finding the optimal target level, choosing between D₂ and D₃, and assessing the risk of kidney stones. There is also the open question as to whether or not vitamin D increases fracture rates.

Pulse therapy of 50,000 U once or twice a week is not uncommon for patients who are deficient in vitamin D, said Dr. Saag. "Could that be a problem, in terms of long-term fracture risk?"

After the IOM recommendations were issued, the U.S. Preventive Services Task Force issued its own meta-analysis looking at falls, and suggested that vitamin D might be protective against falls (Ann. Intern. Med. 2010;153:815-25).

"We can’t really get the experts to fully concur on many of these different issues," said Dr. Saag.

Dr. Saag’s conclusion was that overzealous use of calcium and/or vitamin D supplements could be deleterious. He believes that vitamin D₃ is a little better than vitamin D₂. As for target level, the IOM report suggested 20 ng/mL as the target, rather than 32 ng/mL, which has been advocated for the past decade. "This is really a target at a population level," said Dr. Saag. Individual patients may differ.

He said that the World Health Organization’s FRAX fracture risk assessment tool can help make treatment decisions for an osteopenic patient. It’s also helpful for the patient who is at very low risk. However, the tool is only for treatment-naive patients, and can lead to underestimating the fracture risk because it does not account for multiple fractures, steroid dose, and other variables. FRAX can also lead to overestimating fracture risk, depending on the quality of data entered, he said. There are limited data on treating those with high absolute risk but reasonable BMD. For the patient on 7.5 mg/day of steroids, it is necessary to adjust the risk upward (J. Clin. Densitom. 2011;14:212-9).

"The controversy in treatment now is not whether we should initiate therapy in high-risk patients, people who have fractured and have low bone mass, but how long should we treat? Do we want to continue, in particular our bisphosphonates, for an extended period of time?" said Dr. Saag.

A study of long-term extensions to the FIT (Fracture Intervention Trial) and FLEX (Long-Term Extension of FIT), which measured lumbar spine and total hip BMD, found that the group continuing alendronate had a persistent rise in bone mineral density.

"But interestingly, the group that switched to placebo didn’t lose all that much bone," said Dr. Saag. "This is consistent with my practice."

The trials’ results suggested that for many women, discontinuing alendronate for up to 5 years did not appear to increase fracture risk significantly at all sites (JAMA 2006;296:2927-38).

No loss of benefit was observed with continued use of bisphosphonates. There were small losses of bone mineral density and heightened fracture risk with discontinuation, but not at all sites.

"There is a persistent fracture risk after discontinuation, if the BMD remains low," said Dr. Saag. The trials have not yet yielded the optimal duration of therapy, but there were no long-term safety concerns, at least in clinical trials.

Oral bisphosphonates were another story. Potential safety issues with them include osteonecrosis of the jaw (ONJ), atypical fractures, and esophageal cancer. However, Dr. Saag did not think that was "that big a concern."

"We know from the oncology literature that it’s maybe [1%-10% of patients who] get these monthly infusions of the potent IV bisphosphonates" who may go on to develop ONJ, he said. But in the setting of osteoporosis, the rough incidence is more likely to be between 1 per 10,000 and 1 per 100,000, he said.

"Calcium and vitamin D used to be the least controversial part of any lecture on osteoporosis."

Atypical femoral fractures have been associated with bisphosphonates, but Dr. Saag said that the past evidence has been circumstantial. However, a recent observational study from Scandinavia found a significant association between bisphosphonate use and the risk of subtrochanteric and femoral shaft fractures in older women (JAMA 2011;305:783-9).

Moving on to denosumab, Dr. Saag praised the drug as highly potent antiresorptive with a well-defined mechanism of action. However, he cited evidence of serious infectious adverse events in four randomized, controlled trials: DEFEND (J. Clin. Endocrinol. Metab. 2008;93:2149-57), DECIDE (J. Bone Miner. Res. 2009;24:153-61), STAND (ASBMR 2008, poster M395), and FREEDOM (N. Engl. J. Med. 2009;361:756-65).

"There appears to be a signal of cellulitis," he said.

A study of the combination of zoledronate and teriparatide and their effect on lumbar spine BMD yielded an interesting point about sequencing (J. Bone Miner. Res. 2011;26:503-11).

"When you give bisphosphonate in a pulsatile way, in contrast to a continuous exposure with the weekly therapy, it actually seems to have less suppressive effects on osteoblasts. And that may be why we see [that] the combination of the two results in more increase in bone mineral density than [does] either agent alone," said Dr. Saag. "We don’t know whether that equates to fracture risk reduction."

Support for this meeting came from Abbott, Amgen, Centocor, Genentech, Human Genome Science, and UCB. Dr. Saag disclosed research funding from the National Institutes of Health, the Agency for Healthcare Research and Quality, the American College of Rheumatology (ACR), Amgen, Lilly, and Merck. He is a member of the board of trustees of the National Osteoporosis Foundation and is chair of the quality of care committee of the ACR; he serves on advisory boards at Amgen, Lilly, Merck, and Novartis.

CHICAGO – Physicians may want to be a bit more aggressive in their use of calcium and vitamin D supplementation in patients at high-risk for osteoporotic fracture than has been recommended by the Institute of Medicine, according to Dr. Kenneth G. Saag.

The IOM guidelines on calcium and vitamin D have introduced controversy to a once sleepy area of bone mineral density management, said Dr. Saag, professor of medicine at the University of Alabama at Birmingham.

"Calcium and vitamin D used to be the least controversial part of any lecture on osteoporosis," said Dr. Saag. But no more. The IOM recommends daily allowances of calcium of 1,200 mg/day for women older than age 51 years in a consensus report issued November 2010. "We’ve been thinking maybe 1,500 mg was a better target for certain older adults," said Dr. Saag. He said that IOM recommendations are population based and do not necessarily apply to patients with osteoporosis or low bone mass. "We believe it may be prudent to be a little bit more aggressive in patients with documented osteoporosis."

The IOM report raised questions about calcium safety. A meta-analysis of all large studies of calcium alone – even though calcium is rarely given alone – found trends toward negative cardiovascular effects in individuals taking excess calcium (BMJ 2010;341:c3691).

However, a more recent study of cardiovascular risk did not show increased risk from excess calcium (J. Bone Miner. Res. 2011;26:35-41).

"The controversy in treatment now is not whether we should initiate therapy in high-risk [fracture] patients, but how long should we treat?"

Vitamin D likewise has its share of controversies, including finding the optimal target level, choosing between D₂ and D₃, and assessing the risk of kidney stones. There is also the open question as to whether or not vitamin D increases fracture rates.

Pulse therapy of 50,000 U once or twice a week is not uncommon for patients who are deficient in vitamin D, said Dr. Saag. "Could that be a problem, in terms of long-term fracture risk?"

After the IOM recommendations were issued, the U.S. Preventive Services Task Force issued its own meta-analysis looking at falls, and suggested that vitamin D might be protective against falls (Ann. Intern. Med. 2010;153:815-25).

"We can’t really get the experts to fully concur on many of these different issues," said Dr. Saag.

Dr. Saag’s conclusion was that overzealous use of calcium and/or vitamin D supplements could be deleterious. He believes that vitamin D₃ is a little better than vitamin D₂. As for target level, the IOM report suggested 20 ng/mL as the target, rather than 32 ng/mL, which has been advocated for the past decade. "This is really a target at a population level," said Dr. Saag. Individual patients may differ.

He said that the World Health Organization’s FRAX fracture risk assessment tool can help make treatment decisions for an osteopenic patient. It’s also helpful for the patient who is at very low risk. However, the tool is only for treatment-naive patients, and can lead to underestimating the fracture risk because it does not account for multiple fractures, steroid dose, and other variables. FRAX can also lead to overestimating fracture risk, depending on the quality of data entered, he said. There are limited data on treating those with high absolute risk but reasonable BMD. For the patient on 7.5 mg/day of steroids, it is necessary to adjust the risk upward (J. Clin. Densitom. 2011;14:212-9).

"The controversy in treatment now is not whether we should initiate therapy in high-risk patients, people who have fractured and have low bone mass, but how long should we treat? Do we want to continue, in particular our bisphosphonates, for an extended period of time?" said Dr. Saag.

A study of long-term extensions to the FIT (Fracture Intervention Trial) and FLEX (Long-Term Extension of FIT), which measured lumbar spine and total hip BMD, found that the group continuing alendronate had a persistent rise in bone mineral density.

"But interestingly, the group that switched to placebo didn’t lose all that much bone," said Dr. Saag. "This is consistent with my practice."

The trials’ results suggested that for many women, discontinuing alendronate for up to 5 years did not appear to increase fracture risk significantly at all sites (JAMA 2006;296:2927-38).

No loss of benefit was observed with continued use of bisphosphonates. There were small losses of bone mineral density and heightened fracture risk with discontinuation, but not at all sites.

"There is a persistent fracture risk after discontinuation, if the BMD remains low," said Dr. Saag. The trials have not yet yielded the optimal duration of therapy, but there were no long-term safety concerns, at least in clinical trials.

Oral bisphosphonates were another story. Potential safety issues with them include osteonecrosis of the jaw (ONJ), atypical fractures, and esophageal cancer. However, Dr. Saag did not think that was "that big a concern."

"We know from the oncology literature that it’s maybe [1%-10% of patients who] get these monthly infusions of the potent IV bisphosphonates" who may go on to develop ONJ, he said. But in the setting of osteoporosis, the rough incidence is more likely to be between 1 per 10,000 and 1 per 100,000, he said.

"Calcium and vitamin D used to be the least controversial part of any lecture on osteoporosis."

Atypical femoral fractures have been associated with bisphosphonates, but Dr. Saag said that the past evidence has been circumstantial. However, a recent observational study from Scandinavia found a significant association between bisphosphonate use and the risk of subtrochanteric and femoral shaft fractures in older women (JAMA 2011;305:783-9).

Moving on to denosumab, Dr. Saag praised the drug as highly potent antiresorptive with a well-defined mechanism of action. However, he cited evidence of serious infectious adverse events in four randomized, controlled trials: DEFEND (J. Clin. Endocrinol. Metab. 2008;93:2149-57), DECIDE (J. Bone Miner. Res. 2009;24:153-61), STAND (ASBMR 2008, poster M395), and FREEDOM (N. Engl. J. Med. 2009;361:756-65).

"There appears to be a signal of cellulitis," he said.

A study of the combination of zoledronate and teriparatide and their effect on lumbar spine BMD yielded an interesting point about sequencing (J. Bone Miner. Res. 2011;26:503-11).

"When you give bisphosphonate in a pulsatile way, in contrast to a continuous exposure with the weekly therapy, it actually seems to have less suppressive effects on osteoblasts. And that may be why we see [that] the combination of the two results in more increase in bone mineral density than [does] either agent alone," said Dr. Saag. "We don’t know whether that equates to fracture risk reduction."

Support for this meeting came from Abbott, Amgen, Centocor, Genentech, Human Genome Science, and UCB. Dr. Saag disclosed research funding from the National Institutes of Health, the Agency for Healthcare Research and Quality, the American College of Rheumatology (ACR), Amgen, Lilly, and Merck. He is a member of the board of trustees of the National Osteoporosis Foundation and is chair of the quality of care committee of the ACR; he serves on advisory boards at Amgen, Lilly, Merck, and Novartis.

CHICAGO – Physicians may want to be a bit more aggressive in their use of calcium and vitamin D supplementation in patients at high-risk for osteoporotic fracture than has been recommended by the Institute of Medicine, according to Dr. Kenneth G. Saag.

The IOM guidelines on calcium and vitamin D have introduced controversy to a once sleepy area of bone mineral density management, said Dr. Saag, professor of medicine at the University of Alabama at Birmingham.

"Calcium and vitamin D used to be the least controversial part of any lecture on osteoporosis," said Dr. Saag. But no more. The IOM recommends daily allowances of calcium of 1,200 mg/day for women older than age 51 years in a consensus report issued November 2010. "We’ve been thinking maybe 1,500 mg was a better target for certain older adults," said Dr. Saag. He said that IOM recommendations are population based and do not necessarily apply to patients with osteoporosis or low bone mass. "We believe it may be prudent to be a little bit more aggressive in patients with documented osteoporosis."

The IOM report raised questions about calcium safety. A meta-analysis of all large studies of calcium alone – even though calcium is rarely given alone – found trends toward negative cardiovascular effects in individuals taking excess calcium (BMJ 2010;341:c3691).

However, a more recent study of cardiovascular risk did not show increased risk from excess calcium (J. Bone Miner. Res. 2011;26:35-41).

"The controversy in treatment now is not whether we should initiate therapy in high-risk [fracture] patients, but how long should we treat?"

Vitamin D likewise has its share of controversies, including finding the optimal target level, choosing between D₂ and D₃, and assessing the risk of kidney stones. There is also the open question as to whether or not vitamin D increases fracture rates.

Pulse therapy of 50,000 U once or twice a week is not uncommon for patients who are deficient in vitamin D, said Dr. Saag. "Could that be a problem, in terms of long-term fracture risk?"

After the IOM recommendations were issued, the U.S. Preventive Services Task Force issued its own meta-analysis looking at falls, and suggested that vitamin D might be protective against falls (Ann. Intern. Med. 2010;153:815-25).

"We can’t really get the experts to fully concur on many of these different issues," said Dr. Saag.

Dr. Saag’s conclusion was that overzealous use of calcium and/or vitamin D supplements could be deleterious. He believes that vitamin D₃ is a little better than vitamin D₂. As for target level, the IOM report suggested 20 ng/mL as the target, rather than 32 ng/mL, which has been advocated for the past decade. "This is really a target at a population level," said Dr. Saag. Individual patients may differ.

He said that the World Health Organization’s FRAX fracture risk assessment tool can help make treatment decisions for an osteopenic patient. It’s also helpful for the patient who is at very low risk. However, the tool is only for treatment-naive patients, and can lead to underestimating the fracture risk because it does not account for multiple fractures, steroid dose, and other variables. FRAX can also lead to overestimating fracture risk, depending on the quality of data entered, he said. There are limited data on treating those with high absolute risk but reasonable BMD. For the patient on 7.5 mg/day of steroids, it is necessary to adjust the risk upward (J. Clin. Densitom. 2011;14:212-9).

"The controversy in treatment now is not whether we should initiate therapy in high-risk patients, people who have fractured and have low bone mass, but how long should we treat? Do we want to continue, in particular our bisphosphonates, for an extended period of time?" said Dr. Saag.

A study of long-term extensions to the FIT (Fracture Intervention Trial) and FLEX (Long-Term Extension of FIT), which measured lumbar spine and total hip BMD, found that the group continuing alendronate had a persistent rise in bone mineral density.

"But interestingly, the group that switched to placebo didn’t lose all that much bone," said Dr. Saag. "This is consistent with my practice."

The trials’ results suggested that for many women, discontinuing alendronate for up to 5 years did not appear to increase fracture risk significantly at all sites (JAMA 2006;296:2927-38).

No loss of benefit was observed with continued use of bisphosphonates. There were small losses of bone mineral density and heightened fracture risk with discontinuation, but not at all sites.

"There is a persistent fracture risk after discontinuation, if the BMD remains low," said Dr. Saag. The trials have not yet yielded the optimal duration of therapy, but there were no long-term safety concerns, at least in clinical trials.

Oral bisphosphonates were another story. Potential safety issues with them include osteonecrosis of the jaw (ONJ), atypical fractures, and esophageal cancer. However, Dr. Saag did not think that was "that big a concern."

"We know from the oncology literature that it’s maybe [1%-10% of patients who] get these monthly infusions of the potent IV bisphosphonates" who may go on to develop ONJ, he said. But in the setting of osteoporosis, the rough incidence is more likely to be between 1 per 10,000 and 1 per 100,000, he said.

"Calcium and vitamin D used to be the least controversial part of any lecture on osteoporosis."

Atypical femoral fractures have been associated with bisphosphonates, but Dr. Saag said that the past evidence has been circumstantial. However, a recent observational study from Scandinavia found a significant association between bisphosphonate use and the risk of subtrochanteric and femoral shaft fractures in older women (JAMA 2011;305:783-9).

Moving on to denosumab, Dr. Saag praised the drug as highly potent antiresorptive with a well-defined mechanism of action. However, he cited evidence of serious infectious adverse events in four randomized, controlled trials: DEFEND (J. Clin. Endocrinol. Metab. 2008;93:2149-57), DECIDE (J. Bone Miner. Res. 2009;24:153-61), STAND (ASBMR 2008, poster M395), and FREEDOM (N. Engl. J. Med. 2009;361:756-65).

"There appears to be a signal of cellulitis," he said.

A study of the combination of zoledronate and teriparatide and their effect on lumbar spine BMD yielded an interesting point about sequencing (J. Bone Miner. Res. 2011;26:503-11).

"When you give bisphosphonate in a pulsatile way, in contrast to a continuous exposure with the weekly therapy, it actually seems to have less suppressive effects on osteoblasts. And that may be why we see [that] the combination of the two results in more increase in bone mineral density than [does] either agent alone," said Dr. Saag. "We don’t know whether that equates to fracture risk reduction."

Support for this meeting came from Abbott, Amgen, Centocor, Genentech, Human Genome Science, and UCB. Dr. Saag disclosed research funding from the National Institutes of Health, the Agency for Healthcare Research and Quality, the American College of Rheumatology (ACR), Amgen, Lilly, and Merck. He is a member of the board of trustees of the National Osteoporosis Foundation and is chair of the quality of care committee of the ACR; he serves on advisory boards at Amgen, Lilly, Merck, and Novartis.

CHICAGO – The disease activity score outcome in rheumatoid arthritis should be used with caution as a treatment target when the clinical aim is to prevent radiographic progression. The DAS may show that a patient is in remission when in fact the disease is still active.

The van der Heijde/Sharp score is also flawed in that the total mean change is less meaningful than is the probability of progression of rheumatoid arthritis (RA) and may be misleading, said Dr. Edward Keystone.

"The change in the mean Sharp score point is of some importance, but not nearly as important as the proportion of people who are progressing, or those particularly rapid progressors," said Dr. Keystone, professor of medicine at the University of Toronto. In general, a large change in Sharp score points is needed to reduce physical function, noting that a change in 2 points per year will be significant over a decade, he said.

"If you change by 3 [points] a year, in 10 years you’re going to have disability."

Joint space narrowing may be more predictive than are erosions of radiographic progression. "Most methotrexate-inadequate responders, despite the fact that they’re clinically active, may still have less radiographic progression," Dr. Keystone said at the Midwest Rheumatology Summit.

"So how good is methotrexate, in patients failing methotrexate?" he said. "That’s the question."

Remission is the clinical target in RA, but its measurement is complex. True remission is a state of low-disease activity in patients who are not progressing, said Dr. Keystone. Unfortunately, there is dissociation between clinical and radiographic outcomes, and radiographic progression may occur in patients in clinical remission. Patients with active disease may likewise not progress radiographically.

The composite indices defining remission allow for a significant degree of clinical synovitis, and residual synovitis detected with sensitive imaging might explain the progression in structural damage, even in clinical remission (Arthritis Rheum. 2006;4:3761-73).

Joint space narrowing is more predictive of disability than erosion, as demonstrated by the 5-year HAQ.

As for patients with clinical disease activity who do not progress radiographically, Dr. Keystone said that the concept comes from the ACR 20 nonresponders.

"People who do not make an ACR 20 are still responders," said Dr. Keystone. It’s the difference in patient-derived vs. physician-derived outcomes, he said. In established disease, ACR 20 nonresponders to biologics do not seem to progress radiographically but may still improve.

"Why do most people not achieve an ACR 20? It’s not the swollen and tender joint. It’s usually the patient-derived outcome. ... That’s the problem: The patient says ‘I’m not better.’ Therefore when you look at the ACR 20 data, he’s a nonresponder."

Early disease can present conundrums as well.

In the PREMIER study, methotrexate was clinically identical to monotherapy adalimumab. Nevertheless, a 10-point Sharp score change was observed with methotrexate alone, vs. a 5-point Sharp score change with adalimumab monotherapy (Arthritis Rheum. 2006;54:26-37).

"Clinically, they looked alike, but radiographically, adalimumab monotherapy was much better in reducing the Sharp score." However, he said, the mean change in total Sharp score reflects the Total Sharp Score change only of those patients progressing. "And rheumatologists make decisions on the basis of probability, not mean change in [total Sharp score]," he said. The mean change in total Sharp score means less than the probability of progression, and may lead you astray, he said.

The 52-week results from the JESMR (Efficacy and Safety of Etanercept on Active Rheumatoid Arthritis Despite Methotrexate Therapy in Japan) study found that combination therapy of etanercept plus methotrexate resulted in better clinical and radiographic outcomes than etanercept monotherapy, even in patients with active rheumatoid arthritis and despite methotrexate treatment. (Rheumatology 2011;38:1585-92). This led to the conclusion that methotrexate should be continued at the commencement of etanercept therapy even in patients with rheumatoid arthritis who showed an inappropriate response to methotrexate as demonstrated by changes in radiographic progression.

However, only four patients were rapid progressors, said Dr. Keystone, leading him to conclude that it may not be so bad to stop methotrexate, because the probability of being a rapid progressor is not very high.

In early rheumatoid arthritis, radiographic progression influences disability in a short time, according to results of TEMPO (Trial of Etanercept and Methotrexate with Radiographic Patient Outcomes) (Ann. Rheum. Dis. 2008;67:1267-70).

The PREMIER study found a relationship between structural damage, as reflected in the total Sharp score and disability, as measured by the Health Assessment Questionnaire (HAQ) (J. Rheumatol. 2010;37:2237-46). The trial quantified the meaning of progression of joint damage to physical function in early rheumatoid arthritis as a noticeable change in physical function would occur with an approximate 100-unit change in total Sharp score.

Radiographic progression results in disability early in disease, said Dr. Keystone, but a substantial change in total Sharp score is needed to have a noticeable change in physical function in both early and established disease.

Furthermore, joint space narrowing is more predictive of disability than erosion, as demonstrated by the 5-year HAQ (Rheumatology 2004;43:79-84).

"Joint space narrowing determines unemployment," said Dr. Keystone. It has a greater effect than do erosions on disability.

Finally, he said that timing of response is predictive of long-term outcome. The disease state achieved at 12 weeks is a predictor of long-term outcome. The U.S. is the last country in the world to adopt Treat to Target, as described in the EULAR treatment recommendations (Ann. Rheum. Dis. 2010;69:964-75).

It is not just the target achieved, it\'s the time to reach the target that’s important, said Dr. Keystone.

"People who have a lot of pain, a lot of disability at baseline, they often take longer than people who are in the lower disease state. And it’s patient-derived outcomes that made the difference," said Dr. Keystone. "The sicker you are, the worse you are in terms of what the difference or the cost of delay is."

The Foundation for Osteoporosis Research and Education, a CME accredited provider, acknowledged commercial support for this meeting from Abbott, Amgen, Centocor, Genentech, Human Genome Science, and UCB. Dr. Keystone disclosed financial relationships with Abbott, Amgen, AstraZeneca, Biotest, BMS, Centocor, Genentech, Genzyme, Merck, Novartis, Nycomed, Pfizer, Roche, and UCB.

CHICAGO – The disease activity score outcome in rheumatoid arthritis should be used with caution as a treatment target when the clinical aim is to prevent radiographic progression. The DAS may show that a patient is in remission when in fact the disease is still active.

The van der Heijde/Sharp score is also flawed in that the total mean change is less meaningful than is the probability of progression of rheumatoid arthritis (RA) and may be misleading, said Dr. Edward Keystone.

"The change in the mean Sharp score point is of some importance, but not nearly as important as the proportion of people who are progressing, or those particularly rapid progressors," said Dr. Keystone, professor of medicine at the University of Toronto. In general, a large change in Sharp score points is needed to reduce physical function, noting that a change in 2 points per year will be significant over a decade, he said.

"If you change by 3 [points] a year, in 10 years you’re going to have disability."

Joint space narrowing may be more predictive than are erosions of radiographic progression. "Most methotrexate-inadequate responders, despite the fact that they’re clinically active, may still have less radiographic progression," Dr. Keystone said at the Midwest Rheumatology Summit.

"So how good is methotrexate, in patients failing methotrexate?" he said. "That’s the question."

Remission is the clinical target in RA, but its measurement is complex. True remission is a state of low-disease activity in patients who are not progressing, said Dr. Keystone. Unfortunately, there is dissociation between clinical and radiographic outcomes, and radiographic progression may occur in patients in clinical remission. Patients with active disease may likewise not progress radiographically.

The composite indices defining remission allow for a significant degree of clinical synovitis, and residual synovitis detected with sensitive imaging might explain the progression in structural damage, even in clinical remission (Arthritis Rheum. 2006;4:3761-73).

Joint space narrowing is more predictive of disability than erosion, as demonstrated by the 5-year HAQ.

As for patients with clinical disease activity who do not progress radiographically, Dr. Keystone said that the concept comes from the ACR 20 nonresponders.

"People who do not make an ACR 20 are still responders," said Dr. Keystone. It’s the difference in patient-derived vs. physician-derived outcomes, he said. In established disease, ACR 20 nonresponders to biologics do not seem to progress radiographically but may still improve.

"Why do most people not achieve an ACR 20? It’s not the swollen and tender joint. It’s usually the patient-derived outcome. ... That’s the problem: The patient says ‘I’m not better.’ Therefore when you look at the ACR 20 data, he’s a nonresponder."

Early disease can present conundrums as well.

In the PREMIER study, methotrexate was clinically identical to monotherapy adalimumab. Nevertheless, a 10-point Sharp score change was observed with methotrexate alone, vs. a 5-point Sharp score change with adalimumab monotherapy (Arthritis Rheum. 2006;54:26-37).

"Clinically, they looked alike, but radiographically, adalimumab monotherapy was much better in reducing the Sharp score." However, he said, the mean change in total Sharp score reflects the Total Sharp Score change only of those patients progressing. "And rheumatologists make decisions on the basis of probability, not mean change in [total Sharp score]," he said. The mean change in total Sharp score means less than the probability of progression, and may lead you astray, he said.

The 52-week results from the JESMR (Efficacy and Safety of Etanercept on Active Rheumatoid Arthritis Despite Methotrexate Therapy in Japan) study found that combination therapy of etanercept plus methotrexate resulted in better clinical and radiographic outcomes than etanercept monotherapy, even in patients with active rheumatoid arthritis and despite methotrexate treatment. (Rheumatology 2011;38:1585-92). This led to the conclusion that methotrexate should be continued at the commencement of etanercept therapy even in patients with rheumatoid arthritis who showed an inappropriate response to methotrexate as demonstrated by changes in radiographic progression.

However, only four patients were rapid progressors, said Dr. Keystone, leading him to conclude that it may not be so bad to stop methotrexate, because the probability of being a rapid progressor is not very high.

In early rheumatoid arthritis, radiographic progression influences disability in a short time, according to results of TEMPO (Trial of Etanercept and Methotrexate with Radiographic Patient Outcomes) (Ann. Rheum. Dis. 2008;67:1267-70).

The PREMIER study found a relationship between structural damage, as reflected in the total Sharp score and disability, as measured by the Health Assessment Questionnaire (HAQ) (J. Rheumatol. 2010;37:2237-46). The trial quantified the meaning of progression of joint damage to physical function in early rheumatoid arthritis as a noticeable change in physical function would occur with an approximate 100-unit change in total Sharp score.

Radiographic progression results in disability early in disease, said Dr. Keystone, but a substantial change in total Sharp score is needed to have a noticeable change in physical function in both early and established disease.

Furthermore, joint space narrowing is more predictive of disability than erosion, as demonstrated by the 5-year HAQ (Rheumatology 2004;43:79-84).

"Joint space narrowing determines unemployment," said Dr. Keystone. It has a greater effect than do erosions on disability.

Finally, he said that timing of response is predictive of long-term outcome. The disease state achieved at 12 weeks is a predictor of long-term outcome. The U.S. is the last country in the world to adopt Treat to Target, as described in the EULAR treatment recommendations (Ann. Rheum. Dis. 2010;69:964-75).

It is not just the target achieved, it\'s the time to reach the target that’s important, said Dr. Keystone.

"People who have a lot of pain, a lot of disability at baseline, they often take longer than people who are in the lower disease state. And it’s patient-derived outcomes that made the difference," said Dr. Keystone. "The sicker you are, the worse you are in terms of what the difference or the cost of delay is."

The Foundation for Osteoporosis Research and Education, a CME accredited provider, acknowledged commercial support for this meeting from Abbott, Amgen, Centocor, Genentech, Human Genome Science, and UCB. Dr. Keystone disclosed financial relationships with Abbott, Amgen, AstraZeneca, Biotest, BMS, Centocor, Genentech, Genzyme, Merck, Novartis, Nycomed, Pfizer, Roche, and UCB.

CHICAGO – The disease activity score outcome in rheumatoid arthritis should be used with caution as a treatment target when the clinical aim is to prevent radiographic progression. The DAS may show that a patient is in remission when in fact the disease is still active.

The van der Heijde/Sharp score is also flawed in that the total mean change is less meaningful than is the probability of progression of rheumatoid arthritis (RA) and may be misleading, said Dr. Edward Keystone.

"The change in the mean Sharp score point is of some importance, but not nearly as important as the proportion of people who are progressing, or those particularly rapid progressors," said Dr. Keystone, professor of medicine at the University of Toronto. In general, a large change in Sharp score points is needed to reduce physical function, noting that a change in 2 points per year will be significant over a decade, he said.

"If you change by 3 [points] a year, in 10 years you’re going to have disability."

Joint space narrowing may be more predictive than are erosions of radiographic progression. "Most methotrexate-inadequate responders, despite the fact that they’re clinically active, may still have less radiographic progression," Dr. Keystone said at the Midwest Rheumatology Summit.

"So how good is methotrexate, in patients failing methotrexate?" he said. "That’s the question."

Remission is the clinical target in RA, but its measurement is complex. True remission is a state of low-disease activity in patients who are not progressing, said Dr. Keystone. Unfortunately, there is dissociation between clinical and radiographic outcomes, and radiographic progression may occur in patients in clinical remission. Patients with active disease may likewise not progress radiographically.

The composite indices defining remission allow for a significant degree of clinical synovitis, and residual synovitis detected with sensitive imaging might explain the progression in structural damage, even in clinical remission (Arthritis Rheum. 2006;4:3761-73).

Joint space narrowing is more predictive of disability than erosion, as demonstrated by the 5-year HAQ.

As for patients with clinical disease activity who do not progress radiographically, Dr. Keystone said that the concept comes from the ACR 20 nonresponders.

"People who do not make an ACR 20 are still responders," said Dr. Keystone. It’s the difference in patient-derived vs. physician-derived outcomes, he said. In established disease, ACR 20 nonresponders to biologics do not seem to progress radiographically but may still improve.

"Why do most people not achieve an ACR 20? It’s not the swollen and tender joint. It’s usually the patient-derived outcome. ... That’s the problem: The patient says ‘I’m not better.’ Therefore when you look at the ACR 20 data, he’s a nonresponder."

Early disease can present conundrums as well.

In the PREMIER study, methotrexate was clinically identical to monotherapy adalimumab. Nevertheless, a 10-point Sharp score change was observed with methotrexate alone, vs. a 5-point Sharp score change with adalimumab monotherapy (Arthritis Rheum. 2006;54:26-37).

"Clinically, they looked alike, but radiographically, adalimumab monotherapy was much better in reducing the Sharp score." However, he said, the mean change in total Sharp score reflects the Total Sharp Score change only of those patients progressing. "And rheumatologists make decisions on the basis of probability, not mean change in [total Sharp score]," he said. The mean change in total Sharp score means less than the probability of progression, and may lead you astray, he said.

The 52-week results from the JESMR (Efficacy and Safety of Etanercept on Active Rheumatoid Arthritis Despite Methotrexate Therapy in Japan) study found that combination therapy of etanercept plus methotrexate resulted in better clinical and radiographic outcomes than etanercept monotherapy, even in patients with active rheumatoid arthritis and despite methotrexate treatment. (Rheumatology 2011;38:1585-92). This led to the conclusion that methotrexate should be continued at the commencement of etanercept therapy even in patients with rheumatoid arthritis who showed an inappropriate response to methotrexate as demonstrated by changes in radiographic progression.

However, only four patients were rapid progressors, said Dr. Keystone, leading him to conclude that it may not be so bad to stop methotrexate, because the probability of being a rapid progressor is not very high.

In early rheumatoid arthritis, radiographic progression influences disability in a short time, according to results of TEMPO (Trial of Etanercept and Methotrexate with Radiographic Patient Outcomes) (Ann. Rheum. Dis. 2008;67:1267-70).

The PREMIER study found a relationship between structural damage, as reflected in the total Sharp score and disability, as measured by the Health Assessment Questionnaire (HAQ) (J. Rheumatol. 2010;37:2237-46). The trial quantified the meaning of progression of joint damage to physical function in early rheumatoid arthritis as a noticeable change in physical function would occur with an approximate 100-unit change in total Sharp score.

Radiographic progression results in disability early in disease, said Dr. Keystone, but a substantial change in total Sharp score is needed to have a noticeable change in physical function in both early and established disease.

Furthermore, joint space narrowing is more predictive of disability than erosion, as demonstrated by the 5-year HAQ (Rheumatology 2004;43:79-84).

"Joint space narrowing determines unemployment," said Dr. Keystone. It has a greater effect than do erosions on disability.

Finally, he said that timing of response is predictive of long-term outcome. The disease state achieved at 12 weeks is a predictor of long-term outcome. The U.S. is the last country in the world to adopt Treat to Target, as described in the EULAR treatment recommendations (Ann. Rheum. Dis. 2010;69:964-75).

It is not just the target achieved, it\'s the time to reach the target that’s important, said Dr. Keystone.

"People who have a lot of pain, a lot of disability at baseline, they often take longer than people who are in the lower disease state. And it’s patient-derived outcomes that made the difference," said Dr. Keystone. "The sicker you are, the worse you are in terms of what the difference or the cost of delay is."

The Foundation for Osteoporosis Research and Education, a CME accredited provider, acknowledged commercial support for this meeting from Abbott, Amgen, Centocor, Genentech, Human Genome Science, and UCB. Dr. Keystone disclosed financial relationships with Abbott, Amgen, AstraZeneca, Biotest, BMS, Centocor, Genentech, Genzyme, Merck, Novartis, Nycomed, Pfizer, Roche, and UCB.

CHICAGO – Understanding of the thrombosis risks associated with antiphospholipid syndrome has increased dramatically over the past 12 months, judging from the recent literature on the subject.

Dr. Joan T. Merrill told attendees at a seminar at the Midwest Rheumatology Summit that the annual incidence rate of thrombosis in patients with antiphospholipid antibodies was 1.86% in a prospective multicenter study of 258 patients reported this year (Ann. Rheum. Dis. 2011;70:1083-6).

"Almost 2% per year, and that kind of gets you to 20% at 10 years," said Dr. Merrill. "That’s pretty high, and that’s pretty scary." Hypertension predicts thrombosis, as does the lupus anticoagulant test and lack of thromboprophylaxis during high-risk periods such as post surgery or long airplane flights.

Autoantibodies directed against complement-like structures lead to inflammatory events, including cell-mediated events that lead to a prothrombotic state. "And then, just as you see in atherosclerosis ... when the winds are propitious, what you get is a thrombotic event," said Dr. Merrill, medical director of the Lupus Foundation of America and director of the clinical pharmacology research program at the Oklahoma Medical Research Foundation.

Risk factors for thrombosis are higher in people who have multiple antiphospholipid antibody types (Arthritis Res. Ther. 2011;13:R118). This can be a reason to order multiple tests if insurance providers challenge those tests, said Dr. Merrill. Higher-titer autoantibodies also increase the risk of thrombosis (Acta Obstet. Gynecol. Scand. 2011 July 5 [doi: 10.1111/j.1600-0412. 2011.01236.x]), and antibodies with higher avidity will increase the risk of thrombosis (Lupus 2011;20:1166-71).

The syndrome complicates pregnancy as well.

The odds of women with preeclampsia having anticardiolipin antibodies, versus pregnancy without preeclampsia, were statistically significant (odds ratio, 2.86; 95% confidence interval, 1.37-5.98) in a recent study (Obstet. Gynecol. 2010;116:1433-43), and the odds with severe preeclampsia were much higher (OR, 11.15; CI, 2.66-46.75).

Dr. Merrill advised keeping this increased risk in mind, "since we have lupus patients and we are probably more likely [to order the anticardiolipin screen] than the average obstetrician."

Patients with lupus or antiphospholipid syndrome also often have migraines, and a 2011 study found that patients with a history of migraines have increased thrombotic risk (J. Thromb. Haemost. 2011;9:1350-4). Dr. Merrill advised being aware that what appears to be a migraine in a patient with the antiphospholipid antibody might actually be a thrombotic event, especially if the patient is a young woman.

Significant barriers still exist to evidence-based recommendations, according to information presented last year at the 13th International Congress on Antiphospholipid Antibodies. The barriers include poor standardization of tests.

"Around the country, at different labs, you’re going to get different results. In my place in Oklahoma, I may not even be thinking the same people have lupus that you do," said Dr. Merrill.

Other barriers are a poor understanding of pathogenic risk, heterogeneous patients, and studies that are retrospective and not population based.

A case was made at the end of last year for thrombin inhibition in antiphospholipid syndrome (Acta Clin. Croat. 2010;49:469-77). This could be good news for patients, since current univalent thrombin inhibitors are oral agents, which spare the patient the pain of injecting low-molecular-weight heparin. However, low-molecular-weight heparin may be safe long term for patients with the antiphospholipid syndrome (Ann. Rheum. Dis. 2011;70:1652-4).

"There’s been discussion for many years about the role of statins in the antiphospholipid syndrome," said Dr. Merrill. In a laboratory setting, fluvastatin inhibited markers of a prothrombotic state (Ann. Rheum. Dis. 2011;70:675-82). "It doesn’t provide you with the clinical evidence we like to see, but it’s what we have so far," she said.

The Midwest Rheumatology Summit acknowledged educational grants from Abbott, Amgen, Centocor, Genentech, Human Genome Science, and UCB. Dr. Merrill acknowledged consulting for Human Genome Sciences, Lilly, EMD Serono, GlaxoSmithKline, and Pfizer; receiving grants from Pfizer and Genentech/Roche; and receiving speaker honoraria from Human Genome Sciences/GlaxoSmithKline and Lilly.

CHICAGO – Understanding of the thrombosis risks associated with antiphospholipid syndrome has increased dramatically over the past 12 months, judging from the recent literature on the subject.

Dr. Joan T. Merrill told attendees at a seminar at the Midwest Rheumatology Summit that the annual incidence rate of thrombosis in patients with antiphospholipid antibodies was 1.86% in a prospective multicenter study of 258 patients reported this year (Ann. Rheum. Dis. 2011;70:1083-6).

"Almost 2% per year, and that kind of gets you to 20% at 10 years," said Dr. Merrill. "That’s pretty high, and that’s pretty scary." Hypertension predicts thrombosis, as does the lupus anticoagulant test and lack of thromboprophylaxis during high-risk periods such as post surgery or long airplane flights.

Autoantibodies directed against complement-like structures lead to inflammatory events, including cell-mediated events that lead to a prothrombotic state. "And then, just as you see in atherosclerosis ... when the winds are propitious, what you get is a thrombotic event," said Dr. Merrill, medical director of the Lupus Foundation of America and director of the clinical pharmacology research program at the Oklahoma Medical Research Foundation.

Risk factors for thrombosis are higher in people who have multiple antiphospholipid antibody types (Arthritis Res. Ther. 2011;13:R118). This can be a reason to order multiple tests if insurance providers challenge those tests, said Dr. Merrill. Higher-titer autoantibodies also increase the risk of thrombosis (Acta Obstet. Gynecol. Scand. 2011 July 5 [doi: 10.1111/j.1600-0412. 2011.01236.x]), and antibodies with higher avidity will increase the risk of thrombosis (Lupus 2011;20:1166-71).

The syndrome complicates pregnancy as well.

The odds of women with preeclampsia having anticardiolipin antibodies, versus pregnancy without preeclampsia, were statistically significant (odds ratio, 2.86; 95% confidence interval, 1.37-5.98) in a recent study (Obstet. Gynecol. 2010;116:1433-43), and the odds with severe preeclampsia were much higher (OR, 11.15; CI, 2.66-46.75).

Dr. Merrill advised keeping this increased risk in mind, "since we have lupus patients and we are probably more likely [to order the anticardiolipin screen] than the average obstetrician."

Patients with lupus or antiphospholipid syndrome also often have migraines, and a 2011 study found that patients with a history of migraines have increased thrombotic risk (J. Thromb. Haemost. 2011;9:1350-4). Dr. Merrill advised being aware that what appears to be a migraine in a patient with the antiphospholipid antibody might actually be a thrombotic event, especially if the patient is a young woman.

Significant barriers still exist to evidence-based recommendations, according to information presented last year at the 13th International Congress on Antiphospholipid Antibodies. The barriers include poor standardization of tests.

"Around the country, at different labs, you’re going to get different results. In my place in Oklahoma, I may not even be thinking the same people have lupus that you do," said Dr. Merrill.

Other barriers are a poor understanding of pathogenic risk, heterogeneous patients, and studies that are retrospective and not population based.

A case was made at the end of last year for thrombin inhibition in antiphospholipid syndrome (Acta Clin. Croat. 2010;49:469-77). This could be good news for patients, since current univalent thrombin inhibitors are oral agents, which spare the patient the pain of injecting low-molecular-weight heparin. However, low-molecular-weight heparin may be safe long term for patients with the antiphospholipid syndrome (Ann. Rheum. Dis. 2011;70:1652-4).

"There’s been discussion for many years about the role of statins in the antiphospholipid syndrome," said Dr. Merrill. In a laboratory setting, fluvastatin inhibited markers of a prothrombotic state (Ann. Rheum. Dis. 2011;70:675-82). "It doesn’t provide you with the clinical evidence we like to see, but it’s what we have so far," she said.

The Midwest Rheumatology Summit acknowledged educational grants from Abbott, Amgen, Centocor, Genentech, Human Genome Science, and UCB. Dr. Merrill acknowledged consulting for Human Genome Sciences, Lilly, EMD Serono, GlaxoSmithKline, and Pfizer; receiving grants from Pfizer and Genentech/Roche; and receiving speaker honoraria from Human Genome Sciences/GlaxoSmithKline and Lilly.

CHICAGO – Understanding of the thrombosis risks associated with antiphospholipid syndrome has increased dramatically over the past 12 months, judging from the recent literature on the subject.

Dr. Joan T. Merrill told attendees at a seminar at the Midwest Rheumatology Summit that the annual incidence rate of thrombosis in patients with antiphospholipid antibodies was 1.86% in a prospective multicenter study of 258 patients reported this year (Ann. Rheum. Dis. 2011;70:1083-6).

"Almost 2% per year, and that kind of gets you to 20% at 10 years," said Dr. Merrill. "That’s pretty high, and that’s pretty scary." Hypertension predicts thrombosis, as does the lupus anticoagulant test and lack of thromboprophylaxis during high-risk periods such as post surgery or long airplane flights.

Autoantibodies directed against complement-like structures lead to inflammatory events, including cell-mediated events that lead to a prothrombotic state. "And then, just as you see in atherosclerosis ... when the winds are propitious, what you get is a thrombotic event," said Dr. Merrill, medical director of the Lupus Foundation of America and director of the clinical pharmacology research program at the Oklahoma Medical Research Foundation.

Risk factors for thrombosis are higher in people who have multiple antiphospholipid antibody types (Arthritis Res. Ther. 2011;13:R118). This can be a reason to order multiple tests if insurance providers challenge those tests, said Dr. Merrill. Higher-titer autoantibodies also increase the risk of thrombosis (Acta Obstet. Gynecol. Scand. 2011 July 5 [doi: 10.1111/j.1600-0412. 2011.01236.x]), and antibodies with higher avidity will increase the risk of thrombosis (Lupus 2011;20:1166-71).

The syndrome complicates pregnancy as well.

The odds of women with preeclampsia having anticardiolipin antibodies, versus pregnancy without preeclampsia, were statistically significant (odds ratio, 2.86; 95% confidence interval, 1.37-5.98) in a recent study (Obstet. Gynecol. 2010;116:1433-43), and the odds with severe preeclampsia were much higher (OR, 11.15; CI, 2.66-46.75).

Dr. Merrill advised keeping this increased risk in mind, "since we have lupus patients and we are probably more likely [to order the anticardiolipin screen] than the average obstetrician."

Patients with lupus or antiphospholipid syndrome also often have migraines, and a 2011 study found that patients with a history of migraines have increased thrombotic risk (J. Thromb. Haemost. 2011;9:1350-4). Dr. Merrill advised being aware that what appears to be a migraine in a patient with the antiphospholipid antibody might actually be a thrombotic event, especially if the patient is a young woman.

Significant barriers still exist to evidence-based recommendations, according to information presented last year at the 13th International Congress on Antiphospholipid Antibodies. The barriers include poor standardization of tests.

"Around the country, at different labs, you’re going to get different results. In my place in Oklahoma, I may not even be thinking the same people have lupus that you do," said Dr. Merrill.

Other barriers are a poor understanding of pathogenic risk, heterogeneous patients, and studies that are retrospective and not population based.

A case was made at the end of last year for thrombin inhibition in antiphospholipid syndrome (Acta Clin. Croat. 2010;49:469-77). This could be good news for patients, since current univalent thrombin inhibitors are oral agents, which spare the patient the pain of injecting low-molecular-weight heparin. However, low-molecular-weight heparin may be safe long term for patients with the antiphospholipid syndrome (Ann. Rheum. Dis. 2011;70:1652-4).

"There’s been discussion for many years about the role of statins in the antiphospholipid syndrome," said Dr. Merrill. In a laboratory setting, fluvastatin inhibited markers of a prothrombotic state (Ann. Rheum. Dis. 2011;70:675-82). "It doesn’t provide you with the clinical evidence we like to see, but it’s what we have so far," she said.

The Midwest Rheumatology Summit acknowledged educational grants from Abbott, Amgen, Centocor, Genentech, Human Genome Science, and UCB. Dr. Merrill acknowledged consulting for Human Genome Sciences, Lilly, EMD Serono, GlaxoSmithKline, and Pfizer; receiving grants from Pfizer and Genentech/Roche; and receiving speaker honoraria from Human Genome Sciences/GlaxoSmithKline and Lilly.

CHICAGO – Data from two new trials, one in press and the other ongoing, suggest that two established tumor necrosis factor inhibitors may be the safest drugs for treatment of rheumatoid arthritis in a patient with active hepatitis C virus infection.

The recent pilot study (Journal of Hepatology, in press) of 50 patients with coexisting rheumatoid arthritis (RA) and hepatitis C virus (HCV) infection clearly demonstrated that adding etanercept to traditional antiviral therapy was associated with clearing HCV and normalizing liver enzymes, Dr. Leonard H. Calabrese said at the Midwest Rheumatology Summit.

"This was kind of an opening salvo to us, saying, this is our drug. We should be looking at this ... to see if it’s an option to use to treat autoinflammatory disease and, in particular, rheumatoid arthritis," said Dr. Calabrese.

The ongoing Partner Trial is designed to answer the question of whether a tumor necrosis factor (TNF) inhibitor enhances antiviral responses to traditional therapy, specifically the efficacy of infliximab as an adjunct to peginterferon alfa-2b and ribavirin in the treatment of HCV genotype 1.

"One thing that is not a good idea is to use hepatotoxic drugs (like) methotrexate," said Dr. Calabrese.

Treatment is not the only challenge in caring for the patient with overlapping RA and HCV; just making the HCV diagnosis can be difficult.

"The most undiagnosed infection in our country is hepatitis C. There are probably about 3 million people walking around who are infected, who don't know it," said Dr. Calabrese, professor of medicine at the Cleveland Clinic’s Lerner College of Medicine at Case Western Reserve University. Most patients with undiagnosed hepatitis C have chronic infection, which is relatively asymptomatic, he said. "That’s why screening programs are essential."

He described a 49-year-old woman with a history of polyarthritis who presented for evaluation after a 7-month history of migratory arthritis involving feet, hands, wrists, and knees. The patient had a "fairly normal" hemogram and normal alanine transaminase (ALT) and was positive for the anti–cyclic citrullinated peptide (CCP) antibody.

"The most undiagnosed infection in our country is hepatitis C."

"So she clearly has rheumatoid arthritis ... and is an excellent candidate for methotrexate," he said. Lab results showed the woman to be positive for the HCV antibody, and negative for hepatitis B surface antigen and hepatitis B core antibody.

"So the question is, does this patient have active hepatitis C infection?" said Dr. Calabrese. And if so, how would that influence treatment decisions?

Nearly half of patients with chronic HCV have ALTs within the normal range, so the test has no negative predictive value. "The gold standard of diagnosis in HCV is the presence of fibrosis on liver biopsy," said Dr. Calabrese. "The reality is that if you have people with persistently normal ALT levels, upon biopsy, 75% have some evidence of damage, and about a third of them have advanced fibrosis."

This patient was found to have a normal ALT-38 u/mL, to have 1.2 million copies/mL of HCV-RNA, and to have genotype 1. Her liver appeared normal on ultrasound.

This patient has normal ALT but clearly has HCV, he said. "Normal liver enzymes do nothing at this juncture to tell us that this patient does not have a significant problem." While a biopsy is invasive, it has a very acceptable rate of complications, he said.

The alternative to biopsy is the transient elastography test, widely used in Europe. It is noninvasive and accurate, but not yet approved in the United States.

And the 49-year-old woman? "Patients such as this I would treat with a TNF-inhibitor monotherapy, and if that patient needs treatment, or my hepatologist says ‘I want to start this patient on therapy for hepatitis C next month’? Let’s do it – and keep them right on their TNF-inhibitor. We have enough data now to know that it’s probably a safe thing," he said.

Dr. Calabrese disclosed consultant and/or speaking income from Abbott, Amgen, Bristol-Myers Squibb, Centocor, Genentech, Pfizer, and Roche. The Midwest Rheumatology Summit acknowledged educational grants from Abbott, Amgen, Centocor, Genentech, Human Genome Science, and UCB.

CHICAGO – Data from two new trials, one in press and the other ongoing, suggest that two established tumor necrosis factor inhibitors may be the safest drugs for treatment of rheumatoid arthritis in a patient with active hepatitis C virus infection.

The recent pilot study (Journal of Hepatology, in press) of 50 patients with coexisting rheumatoid arthritis (RA) and hepatitis C virus (HCV) infection clearly demonstrated that adding etanercept to traditional antiviral therapy was associated with clearing HCV and normalizing liver enzymes, Dr. Leonard H. Calabrese said at the Midwest Rheumatology Summit.

"This was kind of an opening salvo to us, saying, this is our drug. We should be looking at this ... to see if it’s an option to use to treat autoinflammatory disease and, in particular, rheumatoid arthritis," said Dr. Calabrese.

The ongoing Partner Trial is designed to answer the question of whether a tumor necrosis factor (TNF) inhibitor enhances antiviral responses to traditional therapy, specifically the efficacy of infliximab as an adjunct to peginterferon alfa-2b and ribavirin in the treatment of HCV genotype 1.

"One thing that is not a good idea is to use hepatotoxic drugs (like) methotrexate," said Dr. Calabrese.

Treatment is not the only challenge in caring for the patient with overlapping RA and HCV; just making the HCV diagnosis can be difficult.

"The most undiagnosed infection in our country is hepatitis C. There are probably about 3 million people walking around who are infected, who don't know it," said Dr. Calabrese, professor of medicine at the Cleveland Clinic’s Lerner College of Medicine at Case Western Reserve University. Most patients with undiagnosed hepatitis C have chronic infection, which is relatively asymptomatic, he said. "That’s why screening programs are essential."

He described a 49-year-old woman with a history of polyarthritis who presented for evaluation after a 7-month history of migratory arthritis involving feet, hands, wrists, and knees. The patient had a "fairly normal" hemogram and normal alanine transaminase (ALT) and was positive for the anti–cyclic citrullinated peptide (CCP) antibody.

"The most undiagnosed infection in our country is hepatitis C."

"So she clearly has rheumatoid arthritis ... and is an excellent candidate for methotrexate," he said. Lab results showed the woman to be positive for the HCV antibody, and negative for hepatitis B surface antigen and hepatitis B core antibody.

"So the question is, does this patient have active hepatitis C infection?" said Dr. Calabrese. And if so, how would that influence treatment decisions?

Nearly half of patients with chronic HCV have ALTs within the normal range, so the test has no negative predictive value. "The gold standard of diagnosis in HCV is the presence of fibrosis on liver biopsy," said Dr. Calabrese. "The reality is that if you have people with persistently normal ALT levels, upon biopsy, 75% have some evidence of damage, and about a third of them have advanced fibrosis."

This patient was found to have a normal ALT-38 u/mL, to have 1.2 million copies/mL of HCV-RNA, and to have genotype 1. Her liver appeared normal on ultrasound.

This patient has normal ALT but clearly has HCV, he said. "Normal liver enzymes do nothing at this juncture to tell us that this patient does not have a significant problem." While a biopsy is invasive, it has a very acceptable rate of complications, he said.

The alternative to biopsy is the transient elastography test, widely used in Europe. It is noninvasive and accurate, but not yet approved in the United States.

And the 49-year-old woman? "Patients such as this I would treat with a TNF-inhibitor monotherapy, and if that patient needs treatment, or my hepatologist says ‘I want to start this patient on therapy for hepatitis C next month’? Let’s do it – and keep them right on their TNF-inhibitor. We have enough data now to know that it’s probably a safe thing," he said.

Dr. Calabrese disclosed consultant and/or speaking income from Abbott, Amgen, Bristol-Myers Squibb, Centocor, Genentech, Pfizer, and Roche. The Midwest Rheumatology Summit acknowledged educational grants from Abbott, Amgen, Centocor, Genentech, Human Genome Science, and UCB.

CHICAGO – Data from two new trials, one in press and the other ongoing, suggest that two established tumor necrosis factor inhibitors may be the safest drugs for treatment of rheumatoid arthritis in a patient with active hepatitis C virus infection.

The recent pilot study (Journal of Hepatology, in press) of 50 patients with coexisting rheumatoid arthritis (RA) and hepatitis C virus (HCV) infection clearly demonstrated that adding etanercept to traditional antiviral therapy was associated with clearing HCV and normalizing liver enzymes, Dr. Leonard H. Calabrese said at the Midwest Rheumatology Summit.

"This was kind of an opening salvo to us, saying, this is our drug. We should be looking at this ... to see if it’s an option to use to treat autoinflammatory disease and, in particular, rheumatoid arthritis," said Dr. Calabrese.

The ongoing Partner Trial is designed to answer the question of whether a tumor necrosis factor (TNF) inhibitor enhances antiviral responses to traditional therapy, specifically the efficacy of infliximab as an adjunct to peginterferon alfa-2b and ribavirin in the treatment of HCV genotype 1.

"One thing that is not a good idea is to use hepatotoxic drugs (like) methotrexate," said Dr. Calabrese.

Treatment is not the only challenge in caring for the patient with overlapping RA and HCV; just making the HCV diagnosis can be difficult.

"The most undiagnosed infection in our country is hepatitis C. There are probably about 3 million people walking around who are infected, who don't know it," said Dr. Calabrese, professor of medicine at the Cleveland Clinic’s Lerner College of Medicine at Case Western Reserve University. Most patients with undiagnosed hepatitis C have chronic infection, which is relatively asymptomatic, he said. "That’s why screening programs are essential."

He described a 49-year-old woman with a history of polyarthritis who presented for evaluation after a 7-month history of migratory arthritis involving feet, hands, wrists, and knees. The patient had a "fairly normal" hemogram and normal alanine transaminase (ALT) and was positive for the anti–cyclic citrullinated peptide (CCP) antibody.

"The most undiagnosed infection in our country is hepatitis C."

"So she clearly has rheumatoid arthritis ... and is an excellent candidate for methotrexate," he said. Lab results showed the woman to be positive for the HCV antibody, and negative for hepatitis B surface antigen and hepatitis B core antibody.

"So the question is, does this patient have active hepatitis C infection?" said Dr. Calabrese. And if so, how would that influence treatment decisions?

Nearly half of patients with chronic HCV have ALTs within the normal range, so the test has no negative predictive value. "The gold standard of diagnosis in HCV is the presence of fibrosis on liver biopsy," said Dr. Calabrese. "The reality is that if you have people with persistently normal ALT levels, upon biopsy, 75% have some evidence of damage, and about a third of them have advanced fibrosis."

This patient was found to have a normal ALT-38 u/mL, to have 1.2 million copies/mL of HCV-RNA, and to have genotype 1. Her liver appeared normal on ultrasound.

This patient has normal ALT but clearly has HCV, he said. "Normal liver enzymes do nothing at this juncture to tell us that this patient does not have a significant problem." While a biopsy is invasive, it has a very acceptable rate of complications, he said.

The alternative to biopsy is the transient elastography test, widely used in Europe. It is noninvasive and accurate, but not yet approved in the United States.

And the 49-year-old woman? "Patients such as this I would treat with a TNF-inhibitor monotherapy, and if that patient needs treatment, or my hepatologist says ‘I want to start this patient on therapy for hepatitis C next month’? Let’s do it – and keep them right on their TNF-inhibitor. We have enough data now to know that it’s probably a safe thing," he said.

Dr. Calabrese disclosed consultant and/or speaking income from Abbott, Amgen, Bristol-Myers Squibb, Centocor, Genentech, Pfizer, and Roche. The Midwest Rheumatology Summit acknowledged educational grants from Abbott, Amgen, Centocor, Genentech, Human Genome Science, and UCB.